Documente Academic
Documente Profesional
Documente Cultură
Adaptat dupa
www.HIVMedicine.com
De Hoffmann-Kamps et al.,
1
Autori care au contribuit:
3
Editors of the original text:
5
© Toate drepturile rezervate
Tot materialul din aceasta carte este protejat de copiere. Nici o
parte a acestei carti nu poate fi reprodusa si/sau distribuita fara
pemisiunea scrisa a autorului.
6
Prefata
7
Autori care au contribuit
9
Cuprins
Capitolul 1 : Patogeneza infectiei cu HIV-1 14
Introducere
Structura HIV-1
Ciclul de replicare HIV
HIV si sistemul imunitar
Bibliografie
12
Capitolul 5 : Sindromul de lipodistrofie 233
Antecedente
Manifestari clinice
HAART, sindromul de lipodistrofie si riscul cardiovascular
Patogeneza
Diagnostic
Tratament
Bibliografie
13
Introducere
Capitolul 1:
Patogeneza infectiei cu HIV-1
Andrea Rubbert si Mario Ostowski
Introducere
De la descrierea initiala a virusului imunodeficientei umane de tip 1 (HIV-1) in
1983(1,2) si HIV-2 in 1986(3), aceste doua virusuri au fost identificate de
aproape 20 de ani drept cauza principala a sindromului imunodeficientei
umane dobandite(SIDA). Datorita faptului ca HIV-1 reprezinta principala
cauza a SIDA in lume azi, discutia noastra va fi in primul rand limitata la
infectia cu HIV-1.
In toata lumea, numarul persoanelor infectate cu HIV-1 depaseste 40
milioane, majoritatea carora traiesc in tarile in curs de dezvoltare din
Asia,Africa sub- sahariana si America de Sud.
Introducerea inhibitorilor de proteaze si a inhibitorilor non-nucleozidici de
revers transcriptaze(NNRTI) in tratamentul antiretroviral in 1995, a
reprezentat debutul ‘erei’ terapiei antiretrovirale intens active (HAART), si a
dus la imbunatatirea dramatica a nivelului mortalitatii si morbiditatii infectiei
HIV, dupa cum a fost demonstrat de incidenta mai scazuta a infectiilor
oportuniste, a tumorilor, si o scadere a numarului de decese. In ciuda tuturor
avantajelor terapeutice dobandite in decursul ultimei decade, inclusiv
dezvoltarea terapiei antiretrovirale intens active(HAART), din momentul in
care o persoana a fost infectata, eradicarea completa a virusului ramane o
imposibilitate. Pe langa acestea, s-au ivit noi probleme legate de toxicitatea
de scurta si lunga durata a tratamentului si de aparitia de mutatii rezistente,
atat in cazul virusurilor aflate in circulatie cat si in cazul celor transmise. In
majoritatea tarilor din Asia de SE si Africa, incidenta si prevalenta infectiei cu
HIV-1 continua sa creasca si sa le depaseasca pe cele ale Europei si
Americii de Nord. In orice caz, datorita costului ridicat al tratamentului
medicamentos, si lipsei infrastructurii din domeniul sanatatii, in aceste tari in
curs de dezvoltare, utilizarea pe scara larga a HAART nu este in prezent
posibila. Evolutia pandemiei HIV-1, din aceasta cauza, depinde in principal de
masura in care tarile in curs de dezvoltare, cu o prevalenta crescuta de HIV-
1, pot sa beneficieze de progresele medicale din Europa si America de Nord,
si daca un vaccin profilactic care sa-si faca efectul poate fi disponibil in viitorul
apropiat.
Intelegera imunopatogeniei infectiei cu HIV-1 reprezinta o prima cerinta
pentru imbunatatirea strategiilor terapeutice, dezvoltarea terapiei imune si a
14
vaccinurilor profilactice. Ca si in cazul altor infectii cauzate de virusuri,
evolutia infectiei cu HIV-1 depinde atat de gazda, cat si de factorii virali.
Evolutia infectiei cu HIV-1 la persoanele infectate cu HIV poate varia foarte
mult, chiar daca infectia primara are aceeasi sursa(4). La unele persoane, cu
o infectie HIV care nu a progresat pe termen lung(nu se produce scaderea
numarului de CD4, sau infectia cronica exista de cel putin 7 ani fara sa apara
SIDA), a fost identificat un virion incomplet(5). Din aceasta cauza, infectia cu
un astfel de virion, sau cu un virion care prezinta o capacitate scazuta de
replicare, poate prelungi evolutia clinica a infectiei cu HIV-1. La majoritate
persoanelor, infectia HIV-1 este caracterizata de un virus apt de a se replica,
precum si de un turn-over crescut al virionilor produsi zilnic.
Factorii care tin de gazda pot de asemeni sa influenteze daca o persoana
infectata cu HIV-1 va dezvolta sau nu in timp scurt imunodeficienta sau daca
aceasta persoana apartine categoriei de persoane la care infectia nu
progreseaza pe termen lung, care reprezinta aproximativ 5% din totalul
pacientilor infectati.
Identificarea si caracterizarea factorilor care tin de gazda si care contribuie la
evolutia infectiei HIV, inclusiv mecanismele de aparare imunologice si factorii
genetici, vor fi esentiale pentru intelegerea imunopatogeniei infectiei HIV, si
pentru dezvoltarea terapiei imunologice si a strategiilor profilactice.
Structura HIV-1
HIV-1 este un retrovirus si apartine familiei lentivirusurilor. Infectia cu
lentivirusuri se caracterizeaza in mod normal printr-o evolutie cronica a bolii,
o latenta clinica de lunga durata, replicare virala intensa si de implicarea
SNC. Infectia cu Visna la oi, cu virusul imunodeficientei simiene(SIV) la
maimute, sau cu virusul imunodeficientei feline(FIV) la pisici, sunt exemple
tipice de infectii cu lentivirusuri.
Utilizand microscopia electronica, HIV-1 si HIV-2 seamana izbitor de mult
unul cu altul. Ceea ce deosebeste 1 de 2 este greutatea moleculara a
proteinelor lor, precum si existenta diferentelor la nivelul genelor accesorii.
HIV-2 este din punct de vedere genetic, mult mai apropiat de SIV descoperit
la sootey mangabeys (SIVsm) decat HIV-1, si este posibil sa fi fost introdus in
cadrul populatiei umane de catre maimute. Atat HIV-1 cat si HIV-2 se replica
la nivelul celulelor T CD4+ si sunt considerate patogene la persoanele
infectate, desi deficienta imuna poate fi mai putin severa decat in cazul
persoanelor infectate cu HIV-2.
15
constituite fiecare din trimerii unei glicoproteine externe gp120 si proteina
transmembranara gp41. Legatura intre gp120 si gp41 este destul de slaba, si
de aceea gp120 poate fi eliberat in mod spontan in mediul local.
Glicoproteina gp120 mai poate fi evidentiata in ser(6), precum si in tesutul
limfatic al pacientilor infectati cu HIV(7). In timpul procesului de inmugurire,
virusul poate sa incorporeze din membrana celulei gazda in structura
invelisului sau lipoproteic, diferite proteine care apartin gazdei, cum ar fi HLA
de clasa I si II, sau proteine de adeziune, cum ar fi ICAM-1 care ar putea
facilita adeziunea la alte celule tinta. Proteina matrice p17 este ancorata in
interiorul membranei virale lipoproteice.
Antigenul p24 contine 2 copii ale ARN-ului HIV-1. ARN-ul HIV-1 face parte
dintr-un complex acid nucleic-proteine care e compus din nucleoproteina p7
si revers transcriptaza p66(RT). Particula virala contine intreg echipamentul
enzimatic necesar pentru replicare: o revers transcriptaza(RT), o integraza p
32 si o proteaza p11(vezi 8)(Fig 1).
Fig 1: Structura unei particule virion HIV. Pentru explicatii detaliate, vezi text.
16
Organizarea genomului viral
Majoritatea retrovirusurilor apte de replicare depind de 3 gene: gag, pol, si
env; gag inseamna ‘antigen de grup’, pol reprezinta polimerazele, si env
provine de la ‘invelis’(envelope)(vezi 9)(Fig 2). Schema structurala clasica a
genomului retroviral este: 5’LTR-gag-pol-env-LTR 3’(regiuni repetitive
lungi=’long terminal repeat’) reprezinta cele 2 capete ale genomului viral care
sunt legate de ADN-ul celular al celulei gazda dupa integrare, si care nu
codifica nici o proteina virala. Genele gag si env codifica nucleocapsida si
glicoproteinele membranei virale; genele pol codifica revers transcriptaza si
alte enzime. Pe langa acestea, HIV-1 mai contine un ARN de 9kB, 6 gene
(vif,vpu,vpr,tat,rev,si nef) care contribuie la realizarea complexitatii sale
genetice. Nef, vif, vpr, si vpu au fost clasificate drept gene accesorii in trecut,
deoarece nu erau absolute necesare in conditiile replicarii in vitro. In orice
caz, reglarea si functionarea acestor gene accesorii a fost studiata si descrisa
mai detaliat in ultimii ani. Genele accesorii, nef, tat, si rev sunt produse in
perioada de inceput a ciclului de replicare virala.
19
Receptorii pentru chemokine drept coreceptori pentru
patrunderea HIV
20
sangele periferic si liniile celulare, si folosesc CXCR4 pentru a patrunde la
nivelul celulelor tinta CD4+. Izolarile M-tropic pot sa infecteze celulele T
CD4+, monocitele si macrofagele, si depind de utilizarea lui CCR5 si CD4
pentru patrunderea virusului. Interactiunea gp120 si a receptorilor celulari
poate fi acum mai bine inteleasa. Gp120 in primul rand, se leaga de anumiti
epitopi ai CD4. Legarea de CD4 induce modificari conformationale la nivelul
lui gp120, care promoveaza o interactiune mai eficienta a inelului V3 al gp120
cu respectivul co-receptor. Fuziunea membranei este dependenta de legatura
intre co-receptor si gp120. gp41, ca si portiune transmembranara a invelisului
glicoproteic gp160, este esentiala pentru fuziunea membranelor virale si a
celulei gazda. Ca si in cazul hemaglutininei gripei, s-a presupus ca dupa
unirea lui gp120 de CD4, o modificare conformationala este de asemeni
indusa la nivelul lui gp41, care permite lui gp41 sa-si insereze capatul NH2-
terminal hidrofobic in membrana celulei tinta. Gp41 a fost comparata cu o
‘cursa pentru soareci’(mouse trap), si o analiza cristalografica a structurii
ectodomanic a lui gp41 pare sa confirme aceasta ipoteza(29). Identificarea
secventei de aminoacizi esentiali in acest proces a fost folosita pentru
sintetizarea peptidelor care se pot atasa lui gp41 in cadrul domeniilor care
sunt de importanta maxima pentru inducerea modificarilor conformationale si
care pot inhiba fuziunea membranelor.
22
Expresia co-receptorilor pe limfocitele CD4+ depinde de nivelul lor de
activitate.
CXCR4 este in principal exprimat pe celulele T naive, in timp ce CCR5 este
prezent pe celulele T efectoare/cu memorie activate. In timpul primelor faze
ale infectiei HIV-1, sunt detectate in primul rand izolari HIV-1 M-trope.
Interesant este ca izolarile HIV-1 M –trope sunt transmise preferential,
indiferent daca „donorul” intretine sau nu izolarile T-trope. In prezent, este
inca neclar daca aceasta preferinta pentru „in vivo” a izolarilor HIV-1 M-trope
este determinata de transportul selectiv al izolarilor M-trope de catre celulele
dendritice localizate submucos sau daca citokinele locale/ chemokinele
specifice climatului, favorizeaza replicarea virusurilor M-trope. Recente studii
ale lui Cheng Meyer si a colaboratorilor sai au sugerat ca virusurile HIV-1 M-
trope sunt mult mai capabile sa se „ascunda” de sistemul imunitar prin
replicarea in macrofage, fata de virusurile T-trope, astfel oferindu-le un
avantaj pentru supravietuire in pacientul infectat.
Blocajul CCR5 din aceasta cauza pare sa reprezinte o tinta promitatoare
pentru interventia terapeutica. In vitro, anticorpii monoclonali pentru
CCR5(2D7 si altii), sunt capabili sa blocheze patrunderea virusurilor izolari
HIV care utilizeaza CCR5 in celulele T CD4+ si macrofage. Moleculele
inhibitorii mici ale CCR5 au fost create, si sunt testate din punct de vedere
clinic in prezent. Studiile in vitro, precum si experimentele care folosesc
soareci SCID, sugereaza ca blocajul virusurilor izolari utilizatoare de
CCR5poate modifica tropismul in sensul unei folosiri mai accentuate a
CXCR4.
Moleculele inhibitoare mici cum ar fi T22, ALX40-4C sau AMD3100 sunt
caabile de a inhiba CXCR4(59,60) si sunt supuse deja testarilor preclinice si
clinice. Desi uzul terapeutic al blocantilor receptorilor pentru chemokine pare
sa fie promitator, multe intrebari raman inca fara raspuns. Analogii
chemokinici cum ar fi AOP-Rantes nu numai ca produc inhibitie, dar prezinta
de asemenea activitate agonista si se poate sa nu se lege numai de CCR5.
Folosind soareci anesteziati, s-a demonstrat ca absenta lui CXCR4 sau SDF-
1 este asociata cu defecte severe in hematopoeza si dezvoltarea
cerebelului(61). In prezent, ramane neclar daca blocarea lui CXCR4 post-
natal sau la persoanele adulte poate afecta de asemenea organele.
23
Fig 4: Ciclul de viata al HIV in interiorul unei celule T CD4+.
24
ADN-ului proviral cu degradarea ARN t este completa. Revers transcriptia
consta in obtinerea unui ADN dublu catenar cu zone LTR la fiecare capat.
HIV-1 patrunde in celulele T pasive, si revers transcriptia poate consta in
acumularea de ADN proviral al HIV, neintegrant. In orice caz, activarea
celulara este necesara pentru integrarea ADN-ului proviral HIV in genomul
celulei gazda dupa transportul complexului de pre-integrare in nucleu(38).
Activarea celulara poate sa survina in vitro dupa stimularea cu antigene sau
mitogene, in vivo, activarea sistemului imun poate fi observata dupa contactul
cu antigenul sau vaccinare, sau in cursul unei infectii oportuniste. In plus, s-a
evidentiat faptul ca gp120 al HIV-1 in sine poate activa celula infectanta
pentru a realiza integrarea. In afara monocitelor, macrofagelor si microgliilor,
celulele T CD4+ pasive infectate mai tarziu, care contin ADN proviral ne-
integrat, reprezinta rezervoare celulare cu viata lunga pentru HIV(39). Din
moment ce infectia naturala cu HIV-1 este caracterizata de cicluri continue de
replicare virala in celulele T CD4+ activate, latenta virala in aceste celule T
CD4+ inactive reprezinta un fenomen accidental si nu e probabil important in
patogeneza acestei boli. Acest mic rezervor de provirus latent in celulele T
CD4+ pasive castiga importanta la persoanele care sunt in tratament HAART,
din moment ce antiviralele nu sunt capabile sa afecteze provirusurile care nu
se replica si din aceasta cauza, virusul va persista in acele celule si va fi apt
pentru replicare si inducerea aparitiei de noi faze ale infectiei, daca
tratamentul este intrerupt. Din aceasta cauza, existenta acestui rezervor
latent a impiedicat HAART in incercarea de a eradica complet virusul in cazul
pacientilor infectati.
Factorii de transcriptie celulara, cum ar fi NF-KB, pot de asemeni sa se
ataseze regiunilor LTR. Dupa stimularea cu mitogene sau citokine, NF-KB
este transferat la nivelul nucleului, unde se uneste de regiunea LTR a HIV,
astfel initiind transcriptia genelor HIV. Transcriptia apare de obicei in sinteza
initiala a proteinelor reglatoare a HIV-1, cum ar fi tat sau rev. Tat se uneste
de TAR(elementul de raspuns la transactivare) la capatul ARN-ului HIV in
nucleu si stimuleaza transcriptia si formarea de trancriptii mai lungi de ARN.
Rev activeaza expresia genelor structurale si enzimatice si inhiba sinteza de
proteine reglatoare, astfel promovand formarea de particule virale mature.
Proteinele codificate de pol si gag formeaza nucleul particulelor HIV mature;
produsele genelor codificate de env formeaza „spinii” gp120 ai invelisului
viral. „Spinii” gp120 ai invelisului, sunt sintetizati ca molecule precursoare de
dimensiuni mari ale gp160 si sunt clivate de proteaza HIV-1 in gp120 si gp41.
Proteinele gag sunt de asemenea derivate dintr-o molecula precursoare 53kD
de dimensiuni mari, din care proteaza HIV cliveaza proteinele gag p24, p17,
p9 si p7. Clivarea moleculelor precursoare de catre proteaza HIV-1 este
necesara pentru generarea de particule virale infectioase, si prin aceasta,
proteaza virala reprezinta o alta tinta interesanta pentru blocarea
terapeutica(40). Formarea de noi particule virale este un proces pas cu pas :
un nou virus este format de catre ARN-ul HIV-1, proteina gag si diferite
enzime pol, si se deplaseaza catre suprafata celulei. Moleculele precursoare
25
mari sunt clivate de proteaza HIV-1, care determina inmugurirea particulelor
virale infectioase prin membrana celulei gazda. In timpul procesului de
inmugurire, membranele lipidice ale virusurilor pot sa incorporeze diferite
proteine ale celulelor gazda si sa se imbogateasca cu anumite fosfolipide si
colesterol. Spre deosebire de celulele T, unde inmugurirea apare la suprafata
celulei si virionii sunt eliberati in spatiul extracelular, procesul de inmugurire la
nivelul monocitelor si macrofagelor determina acumularea virionilor in
vacuolele celulare.
Replicarea retrovirusurilor este supusa erorilor si este caracterizata de o rata
crescuta a mutatiilor spontane. In medie, revers transcriptia duce la 1-10 erori
per genom si per ciclu de replicare. Mutatiile pot duce la formarea unor specii
virale incompetente de replicare, dar pot sa apara si mutatii care determina
aparitia rezistentei la medicamente, care, tinand cont ca exista o presiune a
selectiei sub influenta anumitor medicamente antiretrovirale si inhibarea
replicarii virale, poate fi in continua crestere.
In plus, procesul de replicare virala este dinamic si se modifica repede la
persoanele infectate la o rata medie de 109 noi particule virale ce sunt
produse si apoi distruse pe zi. De aceea, la fiecare individ, datorita replicarii
virale extensive si ritmului mutatiilor, exista o acumulare de variante de
virusuri asemanatoare in cadrul populatiei de virusuri la care se face referire
prin „quasispecii” virale. Presiunea selectiei in special pe mutatiile pre-
existente, poate sa nu fie numai exercitata de anumite medicamente, dar de
asemenea de catre componente ale sistemului imun, cum ar fi anticorpii de
neutralizare sau celulele T citotoxice(CTL).
26
gradul de maturare. DC imature, au capacitatea de a prelua si procesa
antigenele straine, dar nu au capacitatea deosebita de stimulare a celulelor T.
In orice caz, DC mature prezinta o capacitate imunostimulatoare dominanta.
DC in tesuturi si celulele Langerhans, care sunt DC specializate din piele si
zonele de mucoasa, reprezinta un fenotip mult mai imatur si pot sa treaca de
antigene. Din momentul in care aceste DC au trecut de antigene, migreaza in
tesuturile limfoide unde dezvolta un fenotip matur.
Stimularea limfocitelor T CD8+ si formarea de celule T citotoxice antigen-
specifice(CTL) depind de prezenta unei peptide impreuna cu antigenele MHC
de clasa I-a. DC pot sa devina infectate cu virusuri, de exemplu virusul gripei.
Proteinele virale sunt produse apoi in interiorul citoplasmei celulare,
asemanator cu proteinele celulare, apoi degradate in peptide virale si
transferate din citosol in reticulul endoplasmatic, unde sunt legate de
antigenele MHC de clasa I-a. Aceste complexe, peptide-MHC de clasa I
migreaza la suprafata DC. Numarul complexelor antigen specifice MHC de
clasa I este de obicei limitat, si ar trebui sa fie recunoscute in final de clone
ale celulelor T rare, pana la o proportie de 1:100.000 sau mai putin.
Receptorul celulelor T(TCR) poate prezenta o afinitate destul de scazuta de
unire(1mM sau mai putin). Densitatea crescuta a moleculelor co-stimulatoare
pe suprafata DC, in orice caz, favorizeaza formarea complexului TCR-MHC:
interactiunea peptidica permite aparitia unei semnalari eficiente in celulele T
si are ca efect proliferarea(expansiunea clonala) a celulelor T. Celulele
infectate de virus sau celulele tumorale, de cele mai multe ori nu prezinta
molecule co-stimulatoare, si asfel, pot sa nu fie capabile sa induca o
expansiune clonala a celulelor efectoare. Acest lucru subliniaza cat de
impotant este sa avem un sistem de celule prezentatoare de antigen, inalt
specializate, de exemplu DC.
27
Numai cateva DC si mici cantitati de Ag sunt suficiente pentru a induce un
raspuns Ag-specific al celulelor T, astfel demonstrand potentialul
imunostimulator al DC. Prezenta moleculelor de adeziune si a lectinelor, cum
ar fi DC-SIGN, favorizeaza agregarea CD si a celulelor T si promoveaza
implicarea receptorilor celulelor T(TCR). DC-SIGN este o lectina tip C care s-
a demonstrat de asemenea ca uneste lentivirusurile cum ar fi SIV si HIV-1 si -
2 prin interactiunea dintre gp120 cu carbohidratii. In vivo, studii
imunohistochimice exprima prezenta DC-SIGN in DC submucoase si
intradermale, sugerand o implicare a DC-SIGN in transmiterea verticala si
prin intermediul mucoaselor a HIV. Expresia DC-SIGN s-a demonstrat ca
stimuleaza transmiterea HIV la celulele T si permit utilizarea co-receptorilor
daca prezenta lor este limitata. Asfel, DC-SIGN poate reprezenta un
mecanism in cadrul caruia HIV-1 este preluat de DC in tesutul mucos. Este
mai apoi transportat de DC la tesuturile limfoide, unde HIV-1 poate infecta
toate celulele T CD4+ restante.
Replicarea virala in cadrul tesutului limfatic este deja extinsa in primele faze
ale bolii(42,43). In timpul fazei initiale a infectiei HIV-1, se produce o crestere
a nivelului viral in plasma, urmata de o scadere relativa a viremiei. In acest
timp, este generat un raspuns puternic din partea celulelor T citotoxice
specifice HIV-1, care coincide cu supresia initiala a nivelului viremiei din
plasma la majoritatea pacientilor. Virionii sunt prinsi de reteaua de celule
dendritice foliculare din cadrul tesutului limfoid. Macrofagele, si celulele T
CD4+ pasive si activate, sunt principalele tinte ale infectiei. In cursul infectiei
cu HIV-1, tesutul limfoid reprezinta principalul loc de replicare HIV-1.
Frecventa celulelor care contin ADN proviral este de 5-10 ori mai mare in
tesutul limfoid fata de celulele mononucleare periferice aflate in circulatie in
sange, si diferenta in replicarea virala in tesutul limfoid o depaseste pe cea
din sangele periferic de aproximativ 10-100 de ori. Astfel, virusul se
acumuleaza in principal in nodulii limfatici.
Dupa patrunderea HIV-1 in celulele T CD4+ pasive si dupa terminarea
revers-transcriptiei, genomul viral e reprezentat de ADN-ul proviral neintegrat
HIV. Activarea celulelor T CD4+ e necesara pentru integrarea ADN-ului HIV
in genomul celulei gazda si, prin urmare, este o prima cerinta pentru sinteza
de noi virioni. Legat de acest aspect, microclimatul tesutului limfoid reprezinta
mediul optim pentru replicare virala. Contactul strans dintre celulele T CD4+
si celulele prezentatoare de Ag, prezenta virionilor infectanti pe suprafata
FDC, si o productie crescuta de citokine pro-inflamatorii de tipul IL-1, IL-6 sau
TNF alfa, favorizeaza inductia replicarii virale in celulele infectate si
augmenteaza replicarea virala in celulele care produc deja virusul. Ar trebui
retinut ca atat IL-1 si TNF alfa induc NF-kb care se unesc cu LTR a HIV-1
pentru a promova transcriptia provirala. Importanta unei activari induse de Ag
28
a celulelor T CD4+ este subliniata de mai multe studii in vivo & in vitro, care
demonstreaza o crestere a nivelului de replicare a HIV-1 in asociere cu
vaccinarea anti-tetanos si influenza(gripa) sau o infectie cu Mycobacterium
tuberculosis(44). Desi beneficiile clinice ale vaccinarii impotriva agentilor
patogeni comuni( de exemplu gripa & tetanos) in cazul pacientilor infectati cu
HIV depasesc potentialul risc al unei cresteri temporare a incarcaturii virale,
acest studiu indica faptul ca in orice situatie in care sistemul imun e activat,
poate sa apara de asemenea replicare virala sporita.
Pacientii aflati in curs de tratament cu HAART demonstreaza o scadere
dramatica a numarului de celule T CD4+ infectate din tesutul limfatic(45). In
orice caz, la toti pacientii examinati pana acum, se constata persistenta unui
fond comun de celule T infectate pasiv, in ciuda inhibarii cu succes a viremiei
plasmatice(39). Aceste celule infectate tarziu sunt cele care pot determina
mai tarziu aparitia de noi cicluri de replicare virala, daca medicatia antivirala
este oprita.
In cursul evolutiei naturale a infectiei HIV-1, numarul celulelor T CD4+ scade
lent in timp ce viremia plasmatica creste la majoritatea pacientilor. Daca se
efectueaza o analiza secventiala a tesutului limfoid, evolutia bolii este
reflectata de distrugerea arhitecturii tesutului limfoid. Variate studii
imunohistologice indica faptul ca paracortexul nodulilor limfatici reprezinta
locul principal unde este initiata replicarea HIV(42,43). Infectia in celulele T
CD4+ inconjuratoare, precum si initierea activarii celulelor T de catre DC,
contribuie la raspandirea HIV-1 in cadrul mediului limfatic.
29
Un studiu initial efectuat de Kaslow in 1996, a demonstrat ca HLA B14, B27,
B51, B57 si C8 sunt asociate cu o evolutie lenta a bolii; invers, prezenta HLA
A23, B37 si B49 a fost asociata cu dezvoltarea rapida a imunodeficientei(47).
Toti pacientii cu HLA B35 au prezentat simptome SIDA dupa 8 ani de la
infectare.
Studii mai recente au sugerat ca gruparile discordante cu o
„nepotrivire”(mismatch) la moleculele HLA de clasa I au un efect protector in
legatura cu transmiterea heterosexuala(48).
Studii efectuate in vitro la pacientii HLA B57 pozitivi, demonstreaza ca acesti
pacienti prezinta HLA B57 cu restrictie CTL legata de peptidele HIV-1. In
orice caz, e posibil ca identificarea celulelor HLA protectoare sau a peptidelor
restrictionate HLA la pacientii infectati cu HIV-1, cu o evolutie a bolii benigna,
nu indica neaparat ca aceleasi alele sau peptide sunt esentiale pentru
„design”-ul unui vaccin protector. Kaul si colab. Au putut demonstra ca
celulele T CD8+ provenite de la femeile africane expuse infectiei, dar
neinfectate, recunosc diferiti epitopi, fata de celulele T CD8+ provenite de la
femeile africane infectate cu HIV-1(49). Acesta sugereaza ca epitopii
sistemului imun se comporta diferit fata de cei cu actiune de aparare
impotriva infectiei.
Antigenele HLA de clasa a II-a sunt esentiale pentru dezvoltarea unui
raspuns din partea celulelor T CD4+ specific HIV-1. Rosenberg(1997) a fost
primul care a demonstrat ca pacientii infectati cu HIV-1, cu o evolutie a bolii
non-progresiva pe termen lung aveau celule T CD4+ specifice HIV-1, care
puteau prolifera impotriva Ag HIV-1(50). Identificarea alelelor HLA de clasa a
II-a protectoare sau nefavorabile este mai putin bine elaborata, fata de
cunostintele legate de alelele HLA de clasa I protectoare. Grupuri de copii
infectati cu HIV pe cale verticala si adulti infectati HIV demonstreaza un efect
protector al HLA DR13(51).
30
Raspunsuri ale CTL specifice HIV au fost detectate la persoanele expuse la
HIV-1, dar neinfectate. Au fost identificate CTL nef-specifice la partenerii
heterosexuali HIV-1 negativi ai pacientilor infectati cu HIV, si CTL env-
specifice in cadrul personalului dinh domeniul sanitar seronegativ dupa
expunerea la materiale infectate cu HIV-1(intepaturi de ac)(54).
Prezenta raspunsului din partea CTL nu este corelat numai cu scaderea
viremiei plasmatice in timpul fazelor initiale ale infectiei HIV. Pacientii care au
urmat cu intrerupere un tratament structurat, in special cand HAART a fost
inceput din fazele initiale ale infectiei, au demonstrat aparitia de CTL HIV-
specifice in timpul intreruperilor.
Oricum, este in continuare neclar la majoritatea pacientilor care prezinta un
raspuns temporar din partea CTL, de ce acest raspuns al CTL se diminueaza
mai tarziu. Aparitia mutantilor virali „de scapare”, ar putea explica de ce
epitopii care au fost in prealabil recunoscuti, nu mai sunt imunodominanti.
Proteina nef poate sa regleze Ag HLA de clasa I si prin urmare sa
contracareze recunoasterea celulelor infectate de CTL. In plus, majoritatea
persoanelor infectate prezinta raspunsuri ale CTL ce pot fi detectate. Este
neclar de ce nu sunt capabile sa controleze virusul. Interesant este ca, CTL
provenite de la pacientii infectati cu HIV prezinta o lipsa de perforin si un
fenotip imatur, desi posibilitatea de a secreta chemokine si citokine nu este
afectata. Este posibil ca CTL la majoritatea pacientilor infectati cu HIV-1, desi
pot fi detectate, sa fie incomplete si de aceea incapabile sa elimine complet
virusul. Celulele T CD8+ pot fi infectate cu HIV, desi acest lucru n-a fost
demonstrat pentru celulele T CD8+ HIV-specifice. Ramane neclar daca
celulele T CD8+ pot sa exprime temporar CD4, si care co-receptori de
chemokine mediaza infectarea acestor celule T CD8+.
In plus fata de activitatea citotoxica directionata impotriva celulelor infectate
HIV, celulele T CD8+ provenite de la pacientii infectati cu HIV-1 prezinta o
activitate inhibitorie remarcabila a HIV-1, care inhiba replicarea HIV-1 in
culturile celulare autologe si alogenice(55). In ciuda numeroaselor eforturi,
identitatea acestei activitati inhibitorii(„CAF”) nu a fost clarificata pana in
prezent, desi chemokinele, cum ar fi MIP-1alfa, MIP-1beta, RANTES(24), IL-
16(56), chemokinele MDC(57) si defensinele, pot fi considerate
raspunzatoare pentru cel putin o parte din inhibare.
31
este considerat a fi un raspuns al sistemului imun cu rol protector. Studii
efectuate pe persoane expuse HIV, dar neinfectate au aratat ca dupa
stimularea in vitro cu Ag env HIV-1(gp120/gp160) si peptide, celulele T ale
acestor persoane sintetizeaza IL-2, in contrast fata de persoanele ne-
expuse(58). Studii similare au fost efectuate in cazul personalului din
domeniul medical dupa inteparea cu ace, si la nou-nascutii proveniti din
mame infectate cu HIV. Desi aceste observatii pot sa indice faptul ca un
raspuns imun de tip TH1 are potential protector, trebuie considerat faptul ca
raspunsuri imune similare au putut de asemenea sa fi fost generate dupa
contactul cu particule virale non-infectante, si de aceea, nu inseamna
neaparat ca este un mijloc de protectie impotriva unui virus capabil de
replicare.
Asocierea dintre raspunsul imun umoral specific HIV-1 si evolutia bolii este
mai putin descrisa. O progresie lenta a imunodeficientei a fost observata la
pacientii cu titru de Ac anti-p24 crescut(63), cu persistenta Ac de neutralizare
impotriva virusului primar si autolog(64), si lipsa Ac impotriva anumitor epitopi
gp120(62).
Persoanele infectate cu HIV a caror boala nu evolueaza pe termen lung, au
tendinta de a prezenta o activitate larga de neutralizare a izolarilor primare si
se caracterizeaza prin persistenta Ac neutralizanti ai virusurilor autologe. In
prezent, este neclar daca prezenta Ac neutralizanti in LTNP reprezinta o
etapa a mecanismului de protectie, sau daca doar reflecta integritatea unui
sistem imun relativ intact. Persoanele care prezinta un risc crescut de
infectare HIV, dar care sunt considerate „expuse ne-infectate”, prin definitie,
sunt reprezentate de indivizi care nu raspund infectiei HIV-1 prin prezenta de
Ac detectabili. Aceasta definitie sugereaza faptul ca un raspuns imun umoral
sistemic poate sa nu fie un mecanism protector esential. S-a demonstrat ca
aceste persoane pot prezenta un raspuns local al Ig A impotriva proteinelor
HIV-1 care nu sunt detectate prin metode uzuale de testare cu Ac(65,66). De
aceea, Ig A locale mai degraba decat Ig G sistemice, pot fi asociate cu
protectie fata de infectia HIV-1. Exista de asemenea anumite dovezi ca unii
Ac anti HIV-1 pot sa mareasca rata de infectare a celulelor T CD4+.
Studii mai mult sau mai putin recente au aratat ca Ac neutralizanti exista la
persoane infectate cu HIV-1; in orice caz, ei par sa ramana in urma in timp.
Aceasta inseamna ca persoanele vor dezvolta Ac neutralizanti ai propriilor
virusuri in timp, oricum, pana in momentul in care acesti Ac se dezvolta, noile
virusuri aflate in circulatie in plasma vor deveni rezistente la neutralizare, desi
cele mai vechi sunt in prezent sensibile la Ac curenti din serul pacientilor.
Astfel, raspunsul Ac pare sa loveasca o tinta in miscare, permitand astfel
virusurilor sa scape mereu. Dobandirea altor cunostinte legate de intelegerea
mecanismului de „scapare” umorala, vor conduce cel mai probabil la
potentiale tratamente noi.
32
Cunostintele aprofundate si intelegerea mecanismelor patofiziologice din
timpul infectiei cu HIV-1 nu au contribuit numai la dezvoltarea strategiilor
terapiei antiretrovirale, dar au dat nastere la noi aplicatii terapeutice, cum ar fi
terapia cu citokine, IL-2 si vaccinarea terapeutica. Oricum, cea mai
importanta provocare si, astfel, cerinta de o mai buna intelegere a
imunopatogenezei infectiei HIV-1, ramane dezvoltarea unui vaccin protector,
care este de urgenta necesar pentru a pune capat epidemiilor, in special in
tarile subsahariene si SE Asiei.
Bibliografie
33
11. Aiken C, Konner J, Landau NR, Lenburg ME, Trono D. Nef induces CD4
endocytosis: Requirement for a critical dileucine motif in the
membraneproximal
CD4 cytoplasmic do-main. Cell 1994, 76: 853-64.
http://amedeo.com/lit.php?id=8124721
12. Collins KL, Chen BK, Walker BD, Baltimore D. HIV-1 nef protein protects
infected primary cells against killing by cytotoxic T lymphocytes. Nature
1998, 391: 397-401. http://amedeo.com/lit.php?id=9450757
13. Peter F. HIV nef: The mother of all evil? Immunity, 1998, 9: 433-7.
14. Miller RH, Sarver N. HIV accessory proteins as therapeutic targets. Nat
Med 1997, 3: 389-94.
15. Bour S, Schubert U, Strebel K. The HIV type 1 vpu protein specifically
binds to the cytoplasmic domain of CD4: Implications for the mechanism
of degradation. J Virol 1995, 69: 1510-20.
http://amedeo.com/lit.php?id=7853484
16. Cullen BR. HIV-1 auxiliary proteins: making connections in a dying cell.
Cell 1998, 93: 685-92.
17. Schooley RT, Merigan TC, Gaut P, et al. Recombinant soluble CD4
therapy
in patients with AIDS and ARC. Ann Intern Med 1990, 112: 247-53.
http://amedeo.com/lit.php?id=2297203
18. Bour S, Geleziunas R, Wainberg MA. The HIV type 1 (HIV-1) CD4
receptor
and its central role in promotion of HIV-1 infection. Microbiol Rev
1995, 59: 63-93. http://amedeo.com/lit.php?id=7708013
19. Banda NK, Bernier J, Kurahara DK, et al. Cross-linking CD4 by HIV
gp120 primes T cells for activation induced apoptosis. J Exp Med 1992,
176: 1099-106. http://amedeo.com/lit.php?id=1402655
20. Dalgleish AG, Beverley PC, Clapham PR, et al. The CD4 (T4) antigen is
an essential component of the receptor for the AIDS retrovirus. Nature
1984, 312: 763-7. http://amedeo.com/lit.php?id=6096719
21. Klatzmann D, Champagne E, Chamaret S, et al. T-lymphocyte T4
molecule
behaves as the receptor for human retrovirus LAV. Nature 1984,
312: 767-8. http://amedeo.com/lit.php?id=6083454
22. Edwards TG, Hoffman TL, Baribaud F, et al. Relationships between CD4
independence, neutralization sensitivity and exposure of a CD4-induced
epitope in an HIV-1 envelope protein. J Virol 2001, 75:5230-9.
http://amedeo.com/lit.php?id=11333905
23. Levy JA, Mackewicz CE, Barker E. Controlling HIV pathogenesis: the role
of thenoncytotoxic anti-HIV response of CD8+ T cells. Immunol Today
1996,17: 217-24. http://amedeo.com/lit.php?id=8991383
24. Cocchi F, DeVico AL, Garzino-Demo A, Arya S, Gallo RC, Lusso P.
Identification
of RANTES, MIP-1a, and MIP-1ß as the major HIV-suppressive
34
factors produced by CD8+ T cells. Science 1995, 270: 1811-5.
http://amedeo.com/lit.php?id=8525373
25. Deng H, Liu R, Ellmeier W, et al. Identification of a major co-receptor for
primary isolates of HIV-1. Nature 1996, 381: 661-6.
http://amedeo.com/lit.php?id=8649511
26. Doranz BJ, Rucker J, Yi Y, et al. A dual-tropic primary HIV-1 isolate that
uses fusin and the ß-chemo-kine receptors CKR-5, CKR-3, and CKR-2b
as fusion cofactors. Cell 1996, 85: 1149-58.
http://amedeo.com/lit.php?id=8674120
27. Dragic T, Litwin V, Allaway GP, et al. HIV-1 entry into CD4+ cells is
mediated
by the chemokine receptor CC-CKR-5. Nature 1996, 381: 667-73.
http://amedeo.com/lit.php?id=8649512
28. Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor:
functional
cDNA cloning of a seven-transmembrane, G protein-coupled receptor.
Science 1996, 272: 872-7. http://amedeo.com/lit.php?id=8629022
29. Chan DC, Fass D, Berger JM, Kim PS. Core structure of gp41 from the
HIV envelope glycoprotein. Cell 1997, 89: 263-73.
http://amedeo.com/lit.php?id=9108481
30. Kilby JM, Hopkins S, Venetta TM, et al. Potent suppression of HIV-1
replication in humans by T-20, a peptide inhibitor of gp41-mediated virus
entry. Nat Med 1998, 4: 1302-7. http://amedeo.com/lit.php?id=9809555
31. Deng HK, Unutmaz D, Kewalramani VN, Littman DR. Expression cloning
of new receptors used by simian and human immunodeficiency viruses.
Nature 1997, 388: 296-300. http://amedeo.com/lit.php?id=9230441
32. Liao F, Alkhatib G, Peden KWC, Sharma G, Berger EA, Farber JM.
STRL-33, a novel chemokine receptor-like protein, functions as a fusion
cofactor for both macrophage-tropic and T cell line-tropic HIV-1. J Exp
Med 1997, 185: 2015-23. http://amedeo.com/lit.php?id=9166430
33. Liu R, Paxton WA, Choe S, et al. Homozygous defect in HIV-1 coreceptor
accounts for resistance of some multiply-exposed individuals to HIV-1
infection. Cell 1996, 86: 367-77. http://amedeo.com/lit.php?id=8756719
34. Biti R, Ffrench RF, Young J, Bennetts B, Stewart G, Liang T. HIV-1
infection
in an individual homozygous for the CCR5 deletion allele. Nature
Med 1997, 3: 252-3.
35. Dean M, Carrington M, Winkler C, et al. Genetic restrictions of HIV-1
infection and progression to AIDS by a deletion allele of the CKR5 structural
gene. Science 1996, 273: 1856-62.
http://amedeo.com/lit.php?id=8791590
36. Anzala AO, Ball TB, Rostron T, O'Brien SJ, Plummer FA, Rowland-Jones
SL. CCR2-64I allele and genotype association with delayed AIDS progression
in African women. Lancet 1998, 351: 1632-3.
35
37. Winkler C, Modi W, Smith MW, et al. Genetic restriction of AIDS
pathogenesis
by an SDF-1 chemokine gene variant. Science 1998, 279: 389-
93. http://amedeo.com/lit.php?id=9430590
38. Zack JA, Arrigo SJ, Weitsman SR, Go AS, Haislip A, Chen ISY. HIV-1
entry into quiescent primary lymphocytes: Molecular analysis reveals a
labile, latent viral structure. Cell 1990, 61: 213-22.
http://amedeo.com/lit.php?id=2331748
39. Chun TW, Carruth L, Finzi D, et al. Quantification of latent tissue
reservoirs
and total body viral load in HIV-1 infection. Nature 1997,387:183-8.
http://amedeo.com/lit.php?id=9144289
40. Kohl NE, Emini EA, Schleif WA, et al. Active HIV protease is required for
viral infectivity. Proc Natl Acad Sci USA, 1988, 85: 4686-90.
http://amedeo.com/lit.php?id=3290901
41. Geijtenbeek TB, Torensma R, van Vliet SJ, et al. Identification of
DCSIGN,
a novel dendritic cell-specific ICAM-3 receptor that supports primary
immuen responses. Cell 2000, 100: 575-85.
http://amedeo.com/lit.php?id=10721994
42. Embretson J, Zupancic M, Ribas JL, et al. Massive covert infection of
helper T lymphocytes and macrophages by HIV during the incubation pe
riod of AIDS. Nature 1993, 362: 359-62.
http://amedeo.com/lit.php?id=8096068
43. Pantaleo G, Graziosi C, Demarest JF, et al. HIV infection is active and
progressive in lymphoid tissue during the clinically latent stage of disease.
Nature 1993, 362: 355-8. http://amedeo.com/lit.php?id=8455722
44. O’Brien WA, Grovit-Ferbas K, Namazi A, et al. HIV-type 1 replication can
be increased in peripheral blood of seropositive patients after influenza
vaccination. Blood 1995, 86: 1082-9.
http://amedeo.com/lit.php?id=7620162
45. Tenner-Racz K, Stellbrink HJ, van Lunzen J, et al. The unenlarged lymph
nodes of HIV-1-infected, asymptomatic patients with high CD4 T cell
counts are sites for virus replication and CD4 T cell proliferation. The impact
of HAART. J Exp Med 1998, 187: 949-59.
http://amedeo.com/lit.php?id=9500797
46. Carrington M, Nelson GW, Martin MP, et al. HLA and HIV-1: heterozygote
advantage and B*35-Cw*04 disadvantage. Science 1999: 12, 28:
1748-52. http://amedeo.com/lit.php?id=10073943
47. Kaslow RA, Carrington M, Apple R, et al. Influence of combinations of
human major histocompatibility complex genes on the course of HIV-1
infection. Nat Med 1996: 2: 405-11.
http://amedeo.com/lit.php?id=8597949
48. Lockett SF, Robertson JR, Brettle RP, et al. Mismatched human
leukocyte
36
antigen alleles protect against heterosexual HIV transmission. J Acq
Imm Defic Syndr 2001: 27: 277-80.
http://amedeo.com/lit.php?id=11464148
49. Kaul R, Rowland-Jones SL, Kimani J, et al. New insights into HIV-1
specific
cytotoxic T-lymphocyte responses in exposed, persistently seronegative
Kenyan sex workers. Immunol Lett 2001, 79: 3-13.
http://amedeo.com/lit.php?id=11595284
50. Rosenberg ES, Billingsley JM, Caliendo AM, et al. Vigorous HIV-1-
specific CD4+ T cell responses associa-ted with control of viremia. Science
1997, 278: 1447-50. http://amedeo.com/lit.php?id=9367954
51. Keet IP, Tang J, Klein MR, et al. Consistent associations of HLA class I
and II and transporter gene products with progression of HIV type 1 infection
in homosexual men. J Infect Dis 1999, 180: 299-309.
http://amedeo.com/lit.php?id=10395843
52. Goulder PJ, Phillips RE, Colbert RA, et al. Late escape from an
immundominant
cytotoxic T-lymphocyte response associated with progression
to AIDS. Nat Med 1997, 3: 212-7. http://amedeo.com/lit.php?id=9018241
53. Ogg GS, Jin X, Bonhoeffer S, et al. Quantitation of HIV-1-specific
cytotoxic
T lymphocytes and plasma load of viral RNA. Science 1998, 279:
2103-6. http://amedeo.com/lit.php?id=9516110
54. Pinto LA, Sullivan J, Berzofsky JA, et al. Env-specific cytotoxic T
lymphocyte
responses in HIV seronegative health care workers occupationally
exposed to HIV contaminated body fluids. J Clin Invest 1995, 96: 867-76.
http://amedeo.com/lit.php?id=7635981
55. Walker CM, Moody DJ, Stites DP, Levy JA. CD8+ lymphocytes can
control
HIV infection in vitro by suppressing viral replication. Science 1986,
234: 1563-6. http://amedeo.com/lit.php?id=2431484
56. Baier M, Werner A, Bannert N, Metzner K, Kurth R. HIV suppression by
interleukin-16. Nature 1995, 378: 563.
57. Pal R, Garzino-Demo A, Markham PD, et al. Inhibition of HIV-1 infection
by the ß-chemokine MDC. Science 1997, 278: 695-8.
http://amedeo.com/lit.php?id=9381181
58. Clerici M, Giorgi JV, Chou CC, et al. Cell-mediated immune response to
HIV (HIV) type-1 in seronegative homosexual men with a recent sexual
exposure to HIV-1. J Infect Dis 1992, 165: 1012-9.
http://amedeo.com/lit.php?id=1533867
59. Murakami T, Nakajima T, Koyanagi Y, et al. A small molecule CXCR4
inhibitor that blocks T cell line-tropic HIV-1 infection. J Exp Med 1997,
186: 1389-93. http://amedeo.com/lit.php?id=9334379
60. Schols D, Struyf S, Van Damme J, et al. Inhibition of T-tropic HIV strains
37
by selective antagonization of the chemokine receptor CXCR4. J Exp
Med 1997, 186: 1383-8. http://amedeo.com/lit.php?id=9334378
61. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR. Function of
the chemokine receptor CXCR4 in haematopoiesis and in cerebellar
development.
Nature 1998, 393: 595-9.
http://amedeo.com/lit.php?id=9634238
62. Wong MT, Warren RQ, Anderson SA, et al. Longitudinal analysis of the
humoral immune response to HIV type 1 gp160 epitopes in rapidly
progressing
and nonprogressing HIV-1 infected subjects. J Infect Dis 1993,
168: 1523-7. http://amedeo.com/lit.php?id=7504036
63. Hogervorst E, Jurriaans S, de Wolf F, et al. Predictors for non-and slow
progression in HIV type 1 infection: low viral RNA copy numbers in serum
and maintenance of high HIV-1 p24-specific but not V3-specific antibody
levels. J Infect Dis 1995, 171: 811-21.
http://amedeo.com/lit.php?id=7706807
64. Montefiori DC, Pantaleo G, Fink LM, et al. Neutralizing and
infectionenhancing
antibody responses to HIV type 1 in long-term nonprogressors.
J Infect Dis 1996, 173: 60-7. http://amedeo.com/lit.php?id=8537683
65. Mazzoli S, Trabattoni D, Lo Caputo S, et al. HIV-specific mucosal and
cellular immunity in HIV-seronegative partners of HIV-seropositive individuals.
Nat Med 1997, 3:1250-7. http://amedeo.com/lit.php?id=9359700
66. Saha K, Zhang J, Gupta A et al. Isolation of primary HIV-1 that target
CD8+ T lymphocytes using CD8 as a receptor. Nat Med 2001, 7: 65-72.
http://amedeo.com/lit.php?id=11135618
38
Capitolul 2: Infectia acuta cu HIV-1
Marcus Altfeld si Bruce D. Walker
Introducere
Infectia acuta cu HIV-1 se prezinta in 40-90% din cazuri ca o boala tranzitorie
simptomatica, asociata cu un nivel ridicat de replicare virala a HIV-1, precum
si un raspuns imun expansiv specific virusului. Datorita faptului ca se
raporteaza 14.000 noi cazuri/zi in lume, reprezinta un diagnostic diferential
important in cazuri de febra de etiologie necunoscuta, urticarie de aspect
maculopapular si limfadenopatie.
Diagnosticul infectiei acute nu este pus corect in majoritatea cazurilor,
datorita faptului ca se presupune ca alte afectiuni virale(gripa) sunt
responsabile de aparitia simptomelor, si nu se pot detecta Ac specifici HIV-1
in fazele initiale ale infectiei. De aceea, diagnosticarea necesita un nivel inalt
de experienta clinica, bazata pe simptomele clinice si pe existenta in
antecedente a expunerii, in plus fata de efectuarea de teste de laborator
specifice(detectarea ARN-ului HIV-1 sau Ag p24 si a Ac HIV-1 negativi) care
sa confirme diagnosticul.
Un diagnostic precis precoce al infectiei cu HIV-1 acute este foarte important,
pentru ca pacientii pot beneficia de tratament inca din fazele initiale ale
infectiei(vezi mai jos), si infectarea partenerilor sexuali poate fi astfel
prevenita.
Semne si simptome
Dupa o perioada de incubatie de cateva zile pana la cateva saptamani,
majoritatea cazurilor se prezinta cu o afectiune acuta asemanatoare gripei.
Simptomele cele mai frecvente(vezi tabelul 1) sunt febra, urticaria de aspect
maculopapulos, ulceratii orale, limfadenopatie, artralgii, faringite, stare de rau,
scadere in greutate, meningita aseptica si mialgii. Intr-un studiu recent
publicat de Hecht, febra (80%) si starea de rau (68%) au prezentat
sensibilitatea cea mai mare in stabilirea diagnosticului clinic de infectie acuta
cu HIV-1, in timp ce pierderea in greutate (86%) si ulceratiile orale (85%), au
prezentat cea mai mare specificitate. In acest studiu, simptomele febra si
urticarie, in special in combinatie, urmate de aparitia ulceratiilor orale si
faringita au inregistrat cea mai inalta valoare predictiva pozitiva pentru
diagnosticarea infectiei acute cu HIV-1. Intr-un alt studiu efectuat de Daar,
febra, urticaria, mialgia, artralgia si transpiratiile nocturne reprezinta cele mai
bune indicii ale infectiei acute cu HIV-1.
39
Simptom Frecventa Sansele de aparitie (95% Cl)
Febra 80% 5,2(2,3-11,7)
Urticarie 51% 4,8(2,4-9,8)
Ulceratii orale 37% 3,1(1,5-6,6)
Artralgii 54% 2,6(1,3-5,1)
Faringita 44% 2,6(1,3-5,1)
Pierderea apetitului 54% 2,5(1,2-4,8)
Scadere in greutate >2,5kg 32% 2,8(1,3-6,0)
Stare de rau 68% 2,2(1,1-4,5)
Mialgii 49% 2,1(1,1-4,2)
Febra si urticarie 46% 8,3(3,6-19,3)
From: Hecht FM et al. use of laboratory tests and clinical symptoms for
identification of primary HIV infection. AIDS 2002, 16: 1119-1129
Faza simptomatica a infectiei acute cu HIV-1 are o durata cuprinsa intre 7-10
zile, si rareori mai mare de 14 zile. Severitatea si durata persistentei
simptomelor are implicatii in stabilirea prognosticului, astfel simptomele
severe si prelungite sunt asociate cu o evolutie mai rapida a bolii. Natura
nespecifica a simptomelor reprezinta o mare provocare pentru clinician si
subliniaza importanta existentei in antecedente a expunerii.
Diagnosticul
40
confirmat ulterior cu un test de Ac HIV-1 pozitiv(seroconversie) in
saptamanile care urmeaza.
In timpul infectiei acute cu HIV-1, se inregistreaza frecvent o scadere marcata
a numarului de celule CD4+, care mai tarziu creste iar, dar de obicei nu se
normalizeaza pana la valoarea initiala. Mai mult, numarul de celule CD8+
creste initial, care poate determina un raport CD4+/CD8+ mai mic de 1.
Mononucleoza infectioasa (MNI) reprezinta cel mai important diagnostic
diferential. Hepatita, gripa, toxoplasmoza, sifilisul si efectele secundare ale
medicamentelor pot fi de asemenea luate in considerare.
Pe scurt, cal mai important pas in diagnosticarea infectiei acute cu HIV-1 este
includerea acesteia in diagnosticul diferential. Suspiciunea clinica a unei
infectii acute cu HIV-1 necesita numai efectuarea unui test de Ac HIV-1 si
posibil, repetarea testelor de determinare a incarcaturii virale HIV-1, dupa
cum s-a aratat in algoritmul din fig 1(adaptat dupa Hecht, SIDA 2002).
Tratament
Scopul terapiei antiretrovirale in infectia acuta cu HIV-1 este acela de a
reduce numarul de celule infectate, de a pastra raspunsul imun specific HIV-1
si daca este posibil, coborarea nivelului prag viral pe termen lung. Diferite
studii efectuate recent au aratat ca tratamentul infectiei acute cu HIV-1
41
permite supresia virala pe termen lung, duce la conservarea si chiar
cresterea raspunsului din partea celulelor T helper specifice HIV-1 si permite
conservarea unei populatii virale extrem de omogene.
Primele studii efectuate pe pacientii care erau tratati in cursul infectiei acute
cu HIV-1 si care ulterior au urmat un tratament structurat cu intreruperi, au
aratat ca raspunsul imun HIV-1 specific putea fi sporit la acesti pacienti.
Majoritatea pacientilor erau ulterior capabili sa urmeze un tratament
discontinuu, si s-a inregistrat cel putin controlul temporar al replicarii virale, cu
ramanerea „set point-ului” viral sub 5.000 copii/ml pe o perioada mai lunga de
3 ani la unii pacienti. In orice caz, la anumite persoane, incarcatura virala a
atins valori mai mari in timpul perioadelor mai lungi ce au urmat, necesitand
initierea tratamentului.
Beneficiile clinice pe termen lung ale initierii timpuri a tratamentului nu au fost
inca dovedite. De asemenea, nu se cunoaste cat de lunga poate fi perioada
cuprinsa intre infectia acuta si initierea terapiei, fara a pierde beneficiile
imunologice, virologice si clinice. Din perspectiva acestor intrebari fara
raspuns, pacientii cu infectii acute cu HIV-1 ar trebui tratati in cadrul unor
programe clinice controlate. Daca acest lucru nu e posibil, optiunea unui
tratament standard de prima linie(standard first-line treatment) ar trebui luata
in considerare si discutata. De obicei, tratamentul continua cel putin 1 an,
urmat de intreruperi structurate ale tratamentului, efectuate in cadrul studiilor
controlate. Este important in timpul sedintelor de consiliere sa se indice clar
lipsa datelor legate de beneficiile clinice si sa se ia in considerare riscurile
terapiei antiretrovirale si ale intreruperilor tratamentului, inclusiv toxicitatea
medicamentelor, dezvoltarea rezistentei, sindromul acut retroviral in timpul
rebound-ului viral si transmiterea HIV-1 si suprainfectarea in timpul
intreruperii tratamentului.
Bibliografie
43
Capitolul 3: Terapia HIV 2003
1. Perspective
Christian Hoffmann
44
Aceasta nu a reprezentat ultima descoperire. Pana in acel moment, primele
studii cu inhibitori de proteaze(Pi), o noua clasa de medicamente, au fost in
curs de desfasurare de mai multe luni.Pi au fost realizate in laboratoare
utilizand cunostintele legate de structura moleculara a HIV si proteazei –
valoarea lor clinica a fost initial necunoscuta. Datele preliminare si multiple
zvonuri erau deja puse in circulatie. In toamna 1995, o competitie acerba s-a
dezvoltat intre 3 companii: Abbott, Roche si MSD. Studiile pentru obtinerea
aprobarii pentru cele 3 Pi, Ritonavir, Saquinavir si Indinavir au fost realizate
cu mult efort, cu scopul de a introduce primele PI pe piata. Monitorizarea
acestor studii ale companiilor diferite a durat saptamani. Noaptea tarziu,
dosare cu rapoarte legate de cazuri trebuiau perfectionate si sutelor de
intrebari le trebuiau raspunsuri. Toate aceste eforturi au dus la obtinerea
aprobarii, intre 1995 si martie 1996, pentru toate cele 3 Pi, mai intai
Saquinavir, urmat de Ritonavir si Indinavir.
Multi clinicieni(inclusiv autorul), nu erau la curent in acel moment cu ce s-a
intamplat pe parcursul acestor luni. SIDA a ramas omniprezenta. Pacientii
continuau sa moara, din moment ce numai un numar relativ scazut participau
la testarile PI si foarte putini erau tratati corespunzator conform standardelor
curente.
Indoielile au continuat sa existe. S-au pus prea multe sperante in anii anteriori
in legatura cu presupusele tratamente miraculoase. Prin ianuarie 1996, alte
subiecte erau mult mai importante: medicina paliativa, tratamentul sidromului
CMV,MAC si SIDA, managementul durerii, terapia ambulatorie prin perfuzie,
chiar si eutanasierea.in februarie 1996. In timpul celei de-a 3a conferinte
avand ca tema Retrovirusurile si Infectiile oportuniste(CROI) din Washington,
multi si-au recapatat speranta cand Bill Cameron a prezentat primele date ale
studiului ABT-247. Auditoriul era amutit. Astfel s-a aflat ca simpla adaugare a
solutiilor orale de Ritonavir scade frecventa mortalitatii si SIDA de la 38% la
22%(Cameron et al 1998). Acestea erau rezultate senzationale in comparatie
cu toate celelalte publicate pana atunci!
Dar pentru multi, terapia combinata care a fost folosita pe scara larga din
1996, a venit prea tarziu. Unii pacienti intr-un stadiu avansat de SIDA au
reusit sa-si mai revina in timpul acestor luni, dar chiar si in 1996, multi au
murit. Desi rata SIDA in marile centre a fost redusa la jumatate intre 1992 si
1996(Brodt et al 1997), in centrele mai mici cam al 5-lea pacient a murit in
acel an.
In orice caz, potentialul noilor medicamente devenea lent evident, si
Conferinta Globala SIDA din Vancouver, cateva luni mai tarziu, in iunie 1996,
parca era o „sarbatoare” a PI. Chiar si canalele de stiri raportau in amanunt
despre „cocktailurile SIDA”. Expresia nestiintifica „terapie antiretrovirala
intens activa”(HAART) a inceput sa fie folosita pe scara larga. Clinicienii erau
pe punctul de a fi „infectati” de acest entuziasm.
Pana in acel moment, David Ho, „Omul Anului” din revista Time in 1996, a
adus lumina in ceea ce priveste cinetica HIV pana acum inteleasa gresit, prin
lucrarea lui(Ho et al 1995, Perelson et al 1996). Un an mai devreme, Ho a
45
imtrodus deja sloganul „loveste cu putere si devreme”(hit hard and early), si
aproape toti clinicienii il credeau pe cuvant.
Lucrurile pareau ca merg bine. Prin iunie 1996, primul inhibitor de revers
transcriptaza non-nucleozidic, Nevirapin, a primit aprobarea, si o a III-a clasa
de medicamente introdusa. Nelfinavir, alt PI, si-a facut aparitia. Majoritatea
pacientilor pareau sa tolereze bine aceste medicamente. 30 de
pastile/comprimate pe zi? Nici o problema, daca ajuta. Si inca cum ajutau!
Numarul cazurilor de SIDA a fost drastic redus. In decursul a numai 4 ani,
intre 1994-1998, incidenta SIDA in Europa a scazut de la 30,7 la 2,5 la 100
pacienti ani – la mai putin de 1/10. Reducerea incidentei anumitor OI de
temut, in special CMV si MAC, a fost chiar mai dramatica. Oftalmologii din
domeniul HIV au trebuit sa-si gaseasca noi domenii de activitate. Testarile
extinse ale OI planuite cu doar cateva luni inainte, au inceput sa se clatine
datorita lipsei pacientilor. Unitati spitalicesti, care primisera donatii
substantiale, au trebuit sa fie inchise sau sa se reorienteze spre un alt
domeniu. Primii pacienti au inceput sa paraseasca spitalele, si s-au intors la
serviciu; serviciile de asistenta medicala ambulatorie au fost inchise.
Saloanele ocupate de pacientii cu SIDA au fost ocupate de alti pacienti.
46
antiretrovirale ale anilor ce au urmat: lipodistrofie. Si astfel, vechea zicala
medicala s-a dovedit adevarata si in cazul HAART: toate medicamentele
eficiente au efecte secundare. Cauza principala a lipodistrofiei a ramas
complet neelucidata. Apoi, la inceputul anului 1999, o noua ipoteza s-a ivit din
Olanda: „toxicitate mitocondriala”. A devenit un termen omniprezent in
medicina HIV de azi.
47
In ciuda scepticismului, este important sa nu uitam ce poate face HAART.
HAART poate sa realizeze de multe ori miracole! Criptosporidioza si
sarcomul Kaposi au disparut pur si simplu; PML poate fi chiar vindecat
complet; profilaxia secundara pentru CMV poate fi oprita, si, mai presus de
toate, pacientii se simt mult mai bine, desi unii consilieri pe problema SIDA nu
vor totusi sa admita acest lucru.
Acest lucru inseamna de asemenea ca multi clinicieni tineri din tarile vestice
care au intrat in domeniul medicinei HIV la sfarsitul anilor 90, de cele mai
multe ori nu mai stiu ce inseamna SIDA , de fapt SIDA pentru ei este un
accident, ale carui urmari pot fi depasite. Ei nu au trecut prin „epoca de
piatra” a SIDA.
Clinicienii HIV sunt bine sfatuiti, poate mai bine decat alti clinicieni, sa nu uite
„epoca de piatra”, si in acelasi timp sa fie deschisi unor abordari mai noi.
Bibliografie
48
factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy.
Lancet 1999, 354:1112-5. http://amedeo.com/lit.php?id=10509516
3. Brodt HR, Kamps BS, Gute P, et al. Changing incidence of AIDS-defining
illnesses in the era of antiretroviral combination therapy. AIDS 1997,
11:1731-8. http://amedeo.com/lit.php?id=9386808
4. Cameron DW, Heath-Chiozzi M, Danner S, et al. Randomised
placebocontrolled
trial of ritonavir in advanced HIV-1 disease. Lancet 1998,
351:543-9. http://amedeo.com/lit.php?id=9492772
5. Concorde: MRC/ANRS randomised double-blind controlled trial of
immediate
and deferred zidovudine in symptom-free HIV infection. Lancet
1994, 343:871-81. http://amedeo.com/lit.php?id=7908356
6. Consensus Statement on Antiretroviral Treatment for AIDS in Poor
Countries by Individual Members of the Faculty of Harvard University.
2001. http://hiv.net/link.php?id=182
7. Delta: a randomised double-blind controlled trial comparing combinations
of zidovudine plus didanosine or zalcitabine with zidovudine alone in
HIVinfected
individuals. Lancet 1996, 348: 283-91.
http://amedeo.com/lit.php?id=8709686
8. Gulick RM, Mellors JW, Havlir D, et al. 3-year suppression of HIV viremia
with indinavir, zidovudine, and lamivudine. Ann Intern Med 2000, 133:35-
9. http://amedeo.com/lit.php?id=10877738
9. Hamilton JD, Hartigan PM, Simberkoff MS, et al. A controlled trial of early
versus late treatment with zidovudine in symptomatic HIV infection. N
Engl J Med 1992, 326:437-43. http://amedeo.com/lit.php?id=1346337
10. Hammer SM, Katzenstein DA, Hughes MD et al. A trial comparing
nucleoside
monotherapy with combination therapy in HIV-infected adults
with CD4 cell counts from 200 to 500 per cubic millimeter. N Engl J Med
1996, 335:1081-90. http://amedeo.com/lit.php?id=8813038
11. Harrington M, Carpenter CC. Hit HIV-1 hard, but only when necessary.
Lancet 2000, 355:2147-52. http://amedeo.com/lit.php?id=10902643
12. Ho DD. Time to hit HIV, early and hard. N Engl J Med 1995, 333:450-1.
13. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M.
Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.
Nature 1995, 373:123-6. http://amedeo.com/lit.php?id=7816094
14. Kirk O, Mocroft A, Katzenstein TL, et al. Changes in use of antiretroviral
therapy in regions of Europe over time. AIDS 1998, 12: 2031-9.
http://amedeo.com/lit.php?id=9814872
15. Mocroft A, Katlama C, Johnson AM, et al. AIDS across Europe, 1994-98:
the EuroSIDA study. Lancet 2000, 356:291-6.
http://amedeo.com/lit.php?id=11071184.
16. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1
49
dynamics in vivo: virion clearance rate, infected cell life-span, and viral
generation time. Science 1996, 271:1582-6.
http://amedeo.com/lit.php?id=8599114
17. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic
HIV infection. A controlled trial in persons with fewer than 500 CD4-
positive cells per cubic millimeter. N Engl J Med 1990, 322:941-9.
http://amedeo.com/lit.php?id=1969115
50
2. Trecerea in revista a medicamentelor antiretrovirale
Christian Hoffmann
Ingelheim
Inhibitori de proteaze(PI)
51
Kaletra LPV Lopinavir/ Ritonavir Abbott
Mecanism de actiune
Analogii de nucleozide („nukes”) se mai numesc si inhibitori nucleozidici de
revers transcriptaza. Tinta lor este enzima RT a HIV. Actionand ca substrat
alternativ sau „blocuri false”, ei intra in competitie cu nucleozidele fiziologice,
de care se deosebesc printr-o modificare in molecula de zahar(riboza).
Incorporarea analogilor de nucleozide opreste sinteza ADN-ului, din moment
ce puntile fosfodiesterice nu mai pot fi realizate pentru stabilizarea catenei
duble.
52
incrucisata intre analogii de nucleozide(vezi de asemenea capitolul legat de
Rezistenta).
53
pare sa fie bun pe termen lung, in special in ceea ce priveste toxicitatea
mitocondriala(Carr et al 2002).
d4T – Stavudina (Zerit) a fost cel de-al doilea analog de timidina care a fost
introdus dupa AZT. La inceputul tratamentului toleranta e mai buna decat
pentru AZT, generand mai putine efecte secundare gastro-intestinale si
mielotoxicitate limitata. Este la fel de eficient si a fost timp de mai multi ani cel
54
mai frecvent prescris agent antiretroviral. Recent, legat mai mult de
toxicitatea pe termen lung decat de eficienta, s-a dezvaluit faptul ca d4T pare
a fi asociat cu un numar mai mare de probleme fata de alti analogi
nucleozidici. Creste riscul de acidoza lactica si hiperlactacidemie, in special in
combinatie cu ddI sau 3TC(Gerard et al 2000, Miller et al 2000, Mokrzycki et
al 2000, John et al 2001). Au existat preocupari in legatura cu rapoartele
recente legate de slabiciunea neuromusculara progresiva: 22 din 25 pacienti
(7 cazuri fatale), care prezentau simptome similare celor din sindromul
Guillain-Barre si hiperlactacidemie au primit d4T, 11 din acestia d4T + ddI
(Marcus et al 2002. Lipodistrofia este probabil mai frecventa la d4T. Intr-un
grup german, riscul de lipoatrofie s-a dublat dupa un an de tratament(Mauss
et al 2002); intr-un grup elvetian s-a triplat dupa 2 ani(Bernasconi et al 2002).
Alte informatii, cu o exceptie(Bogner et al 2001), merg in aceeasi
directie(Chene et al 2002).
Chiar mai importanta decat datele oferite de studiile de grup este publicarea
primelor studii care demonstreaza efectele pozitive asupra lipoatrofiei
realizate de intreruperea tratamentului cu d4T(si inlocuirea cu alte „nukes”):
intr-un studiu realizat la intamplare in Australia, in care la 111 pacienti cu
lipoatrofie care urmau tratament stabil HAART, li s-a inlocuit d4T sau AZT cu
Abacavir sau nu, cele mai bune rezultate s-au observat in grupul d4T(Carr et
al 2002). Efectul observat la 24 de saptamani era moderat. Tesutul gras
subcutanat crecut care a fost detectat prin scanare dexa, nu era vizibil clinic.
Astfel, poate dura ani, dupa cum a concluzionat autorul, pana ce lipoatrofia
sa se imbunatateasca vizibil dupa intreruperea d4T. Un efect pozitiv, desi din
nou slab, a fost descris in doua studii in care s-a inlocuit d4T(John et al 2002,
McGomsey et al 2002). Astfel, avand in vedere mecanismul de rezistenta,
pacientilor care iau d4T cu lipoatrofie severa, ar trebui sa li se inlocuiasca cu
abacavir. Nu exista, insa, asigurari in ceea ce priveste rezolutia lipoatrofiei, si,
mai presus de toate, este necesara foarte multa rabdare.
55
Tenofovir (Viread) actioneaza ca un bloc fals, similar analogilor de
nucleozide, avand drept tinta enzima revers transcriptaza. In orice caz, in
plus fata de pentoza si de baza nucleica, este monofosforilat, si de aceea
este considerat un analog de nucleotide. O descriere mai precisa a
substantei este data de tenofovir DF (disoproxil fumarate), care este un
fosfonat din care componentul fosfonat este indepartat de o esteraza serica si
care este activat intracelular in doi pasi de fosforilare (Robbins et al 1998).
56
monoterapie, AZT + 3TC erau superioare fata de AZT + ddC(Bartlett et al
1996).
Desi ACTG 384, ultimul studiu important legat de acest subiect mai trebuie
completat, balanta pare sa se incline in favoarea AZT + 3TC. Rezultatele
preliminare, prezentate recent in cadrul Conferintei Globale pe tema SIDA din
Barcelona(Robbins et al 2002, Shaferet al 2002), erau problematice: AZT +
3TC este din punct de vedere virologic superioara d4T + ddI, desi numai in
combinatie cu efavirenz; o combinare cu nelfinavir nu a demonstrat nici un alt
beneficiu. Trebuie sa se dea o explicatie plauzibila.
Alegerea uneia din cele 3 combinatii AZT + 3TC, AZT + ddI, sau d4T + 3TC
este necesara aproape intotdeauna. Din prisma studiilor recente legate de
acidoza lactica si lipoatrofie, alegerea combinatiei d4T + ddI trebuie facuta cu
grija si monitorizata.
Alte combinatii, cum ar fi AZT + ABC, d4T + ABC, ABC + 3TC sau ddI + 3TC
par de asemenea acceptabile, dar nu beneficiaza de atatea date clinice. ddI +
3TC pot sa dea rezultate mai putin bune fata de AZT + 3TC sau d4T + 3TC,
dupa cum s-a sugerat prin studiul ACTG 306(Kuritzkes et al 1999).
Combinatii cum ar fi AZT + d4T, ddC + 3TC, d4T + ddC, si ddI + ddC ar trebui
evitate. S-a demonstrat de asemenea ca schimbarea continua a tratamentului
57
de baza cu nuke cu scopul de a preveni dezvoltarea rezistentei nu are efecte
pozitive si probabil creaza confuzii in randul pacientilor(Molina et al 1999).
58
efavirenz(Nunez et al 2002). In orice caz, mai multe studii efectuate pe
grupuri de pacienti au indicat superioritatea efavirenz-ului. Intr-un studiu
italian, esecul tratamentului cu nevirapina era de 2.08 ori mai posibil decat
pentru efavirenz(Cozzi-Lepri et al 2002), si in studiile SIDA din Europa(Euro-
SIDA study) acest factor era de 1.75(Phillips et al 2001). Astfel de analize ar
trebui interpretate cu grija, din moment ce au fost studiate grupuri de pacienti
extrem de heterogene, cu antecedente variate de tratament. Acest lucru a
fost recent subliniat de rezultatele indelung asteptate cu nerabdare ale
Studiului 2NN(„The double non-nucleoside study”). 2NN este primul test
realizat la scara larga care a comparat regimurile din HAART cu nevirapina si
efavirenz. Testul a aratat ca nevirapina si efavirenz erau comparabile in ceea
ce priveste eficienta virologica si imunologica dupa 48 de saptamani de
terapie. Oricum, nevirapina si efavirenz au reactii adverse diferite care trebuie
luate in considerare in cazul alegerii acestora(vezi mai jos).
59
functionale hepatice este de preferat. Urticaria apare in 15-20 % din cazuri si
conduce la intreruperi la 7% din pacienti(Miller et al 1997). In cazurile de
urticarie izolate sau cresterea izolata a transaminazelor( de 5 ori limita
maxima normala), tratamentul poate fi continuat. Insa, tratamentul ar trebui
intrerupt in caz de urticarie asociata cu transaminaze usor crescute(>2 ori
normal). Pacientii cu hepatite cronice sunt supusi unui risc mai
mare(Sulkowski et al 2000). De asemenea, se pare ca exista o corelare cu
nivelul plasmatic(Gonzalez et al 2002). Este important sa retinem ca
toxicitatea hepatica poate sa apara chiar si dupa cateva luni(Sulkowski et al
2002).
Efavirenz poate cauza efecte secundare slabe la nivelul SNC si din aceasta
cauza ar trebui administrat seara. Aceste tulburari includ de obicei vertij
dimineata si somnolenta; pot de asemenea sa apara cosmaruri. Efectele
secundare sunt probabil corelate cu un nivel crecut din plasma(Marzolini et al
2001). Intr-unul din studii, dupa 4 saptamani de tratament cu efavirenz, 66%
din pacienti se plangeau de vertij, 48% de visuri ciudate, 37% de somnolenta
si 35% de insomnii. Desi aceste simptome pareau a se rezolva prin
continuarea tratamentului( frecventa acestor plangeri la 24 saptamani era de
numai 13, 18, 13 si respectiv 7%), pacientii trebuiau preveniti asupra
posibilelor efecte secundare(Fumaz et al 2002). Pana azi, nu se cunosc prea
multe despre efectele asupra capacitatii de a conduce. Recomandam ca
efavirenz sa nu fie prescris pacientilor in timpul perioadelor de examinare,
pilotilor sau celor care lucreaza/opereaza macarale. Pacientii cu tulburari de
concentrare/atentie ar trebui sa evite activitati de tipul condusului sau
operarea masinilor grele(vezi prospect). Efavirenz este contraindicat in
sarcina. Lipidele nu sunt la fel de favorabil afectate ca si cu
nevirapina(Hoffmann et al 2000), dar fenomenul de hepatotoxicitate este mai
putin frecvent.
60
Delavirdina(Rescriptor) : Datorita poverii constituite de aceasta pastila si
necesitatii de a fi administrata de 3 ori/zi, delavirdina este prescrisa foarte rar,
desi se presupune a fi la fel de eficienta ca si nevirapina si efavirenz(Wood et
al 1999, Conway 2000).
Inhibitori de proteaze(PI)
Mecanism de actiune si eficienta
Proteaza HIV imparte poliproteina virala gag-pol in subunitatile sale
functionale. Inhibarea proteazei, care previne unirea proteolitica si maturarea,
duce la eliberarea particulelor virale care sunt incapabile de a infecta noi
celule. Avand la indemana cunostintele legate de structura moleculara a
proteazei codificate de virus, primii inhibitori de proteaze au fost creati la
inceputul anilor 90: aceste substante au fost modificate de o asemenea
maniera incat se potrivesc exact in regiunea activa enzimatica a proteazei
HIV(analiza detaliata : Deeks 1997, Somadossi 1999, Eron 2001).
61
al 2001). In mod similar, studiul CHEESE nu a gasit nici o diferenta intre
saquinavir-SGC si indinavir(Cohen et al 1999).
62
preconizeaza ca Ageneraza va fi scoasa de pe piata de indata ce
medicamentul care o va succede va fi disponibil. Acest lucru va duce la o
competitie serioasa in ceea ce priveste Lopinavirul in cadrul terapiei de
recuperare.
Cel mai frecvent intalnit efect secundar al nelfinavirului este diareea, care
poate fi destul de severa. Puterea antiretrovirala a nelfinavirului este mai
redusa decat cea a PI stimulate(Walmsley et al 2002). In studiul Agouron 511
care a dus la obtinerea aprobarii, 61% din pacienti (cu tratament de baza
AZT+3TC), au prezentat un nivel sanguin sub 50 copii/ml la 48
saptamani(Saag et al 2001). Substanta are un profil bun in ceea ce priveste
rezistenta. Mutatia primara D30N in cadrul nelfinavirului reduce forma
virala(Martinez et al 1999) si nu influenteaza eficacitatea altor PI. Din pacate
insa, alte mutatii, care dimpotriva, pot sa pericliteze succesul tratamentelor
anterioare pot sa apara destul de frecvent. O noua formula care sa permita
reducerea la 2*2capsule zilnic este in curs de dezvoltare, care poate sa
modifice tendinta de scadere a vanzarilor nelfinavirului datorita stransei
competitii.
65
Cand se realizeaza stimularea saquinavirului, este de preferat sa se ia in
considerare utilizarea Invirazei® in loc de Fortovaza®. Intr-un studiu recent
publicat(Kurowski et al 2002), nivelul boosted de saquinavir era chiar mai
mare pentru Inviraza®, care este de asemenea mai bine tolerata in ceea ce
priveste tulburarile gastro-intestinale decat Fortovaza®. Interesant este ca,
inviraza este de aproximativ 2 ori mai scumpa decat Fortovaza® – o
problema pe care producatorul Hoffmann – La Roche ca trebui sa o abordeze
in viitorul apropiat, daca, dupa cum este de asteptat, va genera presiuni din
partea celor aflati in sprijinul pacientilor.
2x 2x6
Saquinavir/ritona 400/400 Eficienta buna, dar problematica
vir datorita ratei crescute de efecte
secundare
2x 2x3
Indinavir/ritonavir 800/100 Rata crescuta de nefrolitiaza(?)
2x 2x5
Indinavir/ritonavir 400/400 Date farmacocinetice bune
2x 2x3
Lopinavir/ritonavi 400/100 Numai combinatii fixe intr-o capsula
r
Nelfinavir/ritonavi Nu e recomandata
r
3x 3x6
Saquinavir/nelfin 600/750 Numai combinatii booster bine
avir documentate fara ritonavir, dar prea
multe pastile de 3 ori pe zi
2x 2x5
Amprenavir/riton 600/100 Aprobat de FDA
avir
66
Combinatia indinavir/ritonavir a fost cercetata de asemenea in amanunt.
Exista date ce atesta o farmacocinetica buna pentru doza 800/100(Van
Heeswijk et al 1999). Intr-un studiu pilot mai restrans in ceea ce priveste
aceasta combinatie, insa, rezultatele atesta nefrolitiaza la 19/57
pacienti(Voigt et al 2001). Doza 400/400 se presupune ca genereaza efecte
secundare mai slabe. Combinatia indinavir/ritonavir pare a fi asociata cu un
risc crescut de efecte secundare. In studii de tipul BEST, sau NICE, trecerea
de la indinavir la indinavir/ritonavir s-a demonstrat a avea o rata usor mai
crescuta de aparitie a efectelor secundare si renuntare(Gatell et al 2000,
Harley et al 2001, Shulman et al 2002).
1. Bartlett JA, Benoit SL, Johnson VA, et al. Lamivudine plus zidovudine
compared with zalcitabine plus zidovudine in patients with HIV infection.
A randomized, double-blind, placebo-controlled trial. Ann Intern Med
1996, 125: 161-72. http://amedeo.com/lit.php?id=8686973
2. Bernasconi E, Boubaker K, Junghans C, et al. Abnormalities of body fat
distribution in HIV-infected persons treated with antiretroviral drugs: J Acquir
Immune Defic Syndr 2002, 31:50-5.
67
http://amedeo.com/lit.php?id=12352150
3. Bogner JR, Vielhauer V, Beckmann RA, et al. Stavudine versus zidovudine
and the development of lipodystrophy. J Acquir Immune Defic
Syndr 2001, 27: 237-44. http://amedeo.com/lit.php?id=11464142
4. Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity
induced
by nucleoside-analogue reverse-transcriptase inhibitors is a key
factor in the pathogenesis of ART-related lipodystrophy. Lancet 1999,
354:1112-5. http://amedeo.com/lit.php?id=10509516
5. Burger DM, Aarnoutse RE, Hugen PW. Pros and cons of therapeutic drug
monitoring of antiretroviral agents. Curr Opin Inf Dis 2002, 15: 17-22.
6. Cameron DW, Heath-Chiozzi M, Danner S, et al. Randomised
placebocontrolled
trial of ritonavir in advanced HIV-1 disease. Lancet 1998,
351:543-9. http://amedeo.com/lit.php?id=9492772
7. Cameron DW, Japour AJ, Xu Y, et al. Ritonavir and saquinavir combination
therapy for the treatment of HIV infection. AIDS 1999, 13: 213-24.
http://amedeo.com/lit.php?id=10202827
8. Carr A, Chuah J, Hudson J, et al. A randomised, open-label comparison
of three HAART regimens including two nucleoside analogues and indinavir
for previously untreated HIV-1 infection: the OzCombo1 study. AIDS
2000, 14: 1171-80. http://amedeo.com/lit.php?id=10894281
9. Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside
analogs in patients with HIV lipoatrophy: a randomized trial. JAMA 2002,
288:207-15. http://amedeo.com/lit.php?id=12095385
10. Chene G, Angelini E, Cotte L, et al. Role of long-term nucleosideanalogue
therapy in lipodystrophy and metabolic disorders in HIVinfected
patients. Clin Infect Dis 2002, 34: 649-57.
http://amedeo.com/lit.php?id=11810598
11. Cohen Stuart JW, Schuurman R, Burger DM, et al. Randomized trial
comparing saquinavir soft gelatin capsules versus indinavir as part of triple
therapy (CHEESE study). AIDS 1999, 13: F53-8.
http://amedeo.com/lit.php?id=10357371
12. Condra JH, Petropoulos CJ, Ziermann R, et al. Drug resistance and
predicted
virologic responses to HIV type 1 protease inhibitor therapy. J Infect
Dis 2000, 182: 758-65. http://amedeo.com/lit.php?id=10950769
13. Condra JH, Schleif WA, Blahy OM, et al. In vivo emergence of HIV-1
variants resistant to multiple protease inhibitors. Nature 1995, 374:569-
71. http://amedeo.com/lit.php?id=7700387
14. Conway B. Initial therapy with protease inhibitor-sparing regimens:
evaluation of nevirapine and delavirdine. Clin Infect Dis. 2000, Suppl
2:S130-4. http://amedeo.com/lit.php?id=10860897
15. Cozzi-Lepri A, Phillips AN, d'Arminio Monforte A, et al. Virologic and
immunologic
68
response to regimens containing nevirapine or efavirenz in
combination with 2 nucleoside analogues in the Italian Cohort Naive
Antiretrovirals (I.Co.N.A.) study. J Infect Dis 2002, 185: 1062-9.
http://amedeo.com/lit.php?id=11930316
16. Deeks SG, Grant RM, Beatty GW, et al. Activity of a ritonavir plus
saquinavir-
containing regimen in patients with virologic evidence of indinavir or
ritonavir failure. AIDS 1998, 12: F97-102.
http://amedeo.com/lit.php?id=9677159
17. Deeks SG, Smith M, Holodniy M, Kahn JO. HIV-1 protease inhibitors. A
review for clinicians. JAMA 1997, 277: 145-53.
http://amedeo.com/lit.php?id=8990341
18. Dragstedt UB, Gerstoft J, Youle M. The interim analysis of a phase IV
randomised, open-label, multicentre trial to evaluate the safety and efficacy
of lopinavir/ritonavir (400mg/100mg bid) versus saquinavir/ritonavir
(1000mg/100mg bid) in adult HIV-1 infected patients. Abstract 14.5, 6th
International Congress on Drug Therapy in HIV Infection 2002, Glasgow,
Scotland
19. Duval X, Lamotte C, Race E, et al. Amprenavir inhibitory quotient and
virological response in HIV-infected patients on an amprenavir-containing
salvage regimen without or with ritonavir. Antimicrob Agents Chemother
2002, 46:570-4. http://amedeo.com/lit.php?id=11796381
20. Eron JJ JR, Murphy RL, Peterson D, et al. A comparison of stavudine,
didanosine and indinavir with zidovudine, lamivudine and indinavir for the
initial treatment of HIV-1 infected individuals: selection of thymidine analog
regimen therapy (START II). AIDS 2000, 14: 1601-10.
http://amedeo.com/lit.php?id=10983647
21. Eron JJ JR. HIV-1 protease inhibitors. Clin Infect Dis 2000, 30 Suppl 2:
S160-70. http://amedeo.com/lit.php?id=10860901
22. Eshleman SH, Jackson JB. Nevirapine resistance after single dose
prophylaxis.
AIDS Rev 2002, 4:59-63.
http://amedeo.com/lit.php?id=12152519
23. Fätkenheuer G, Theisen A, Rockstroh J, et al. Virological treatment failure
of protease inhibitor therapy in an unselected cohort of HIV-infected
patients. AIDS 1997, 11:F113-6. http://amedeo.com/lit.php?id=9386799
24. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. Pharmacokinetic
interactions between protease inhibitors and statins in HIV seronegative
volunteers: ACTG Study A5047. AIDS 2002, 16:569-
77.http://amedeo.com/lit.php?id=11873000
25. Fisac C, Fumero E, Crespo M, et al. Metabolic and body composition
changes in patients switching from a PI-containing regimen to abacavir,
efavirenz or nevirapine. 12 month results of a randomized study (Lipnefa).
Abstract ThPE7354, XIV International AIDS Conference 2002,
Barcelona, Spain.
69
26. Foudraine NA, de Jong JJ, Weverling J, et al. An open randomized
controlled
trial of zidovudine plus lamivudine versus stavudine plus lamivudine.
AIDS 1998, 12: 1513-9. http://amedeo.com/lit.php?id=9727573
27. French M, Amin J, Roth N, et al. Randomized, open-label, comparative
trial to evaluate the efficacy and safety of three antiretroviral drug
combinations
including two nucleoside analogues and nevirapine for previously
untreated HIV-1 Infection: the OzCombo 2 study. HIV Clin Trials 2002,
3:177-85. http://amedeo.com/lit.php?id=12032876
28. Friedl AC, Ledergerber B, Flepp M, et al. Response to first protease
inhibitor-
and efavirenz-containing antiretroviral combination therapy. The
Swiss HIV Cohort Study. AIDS 2001, 15: 1793-800.
http://amedeo.com/lit.php?id=11579241
29. Fumaz CR, Tuldra A, Ferrer MJ, et al. Quality of life, emotional status,
and adherence of HIV-1-infected patients treated with efavirenz versus
PI-containing regimens. J Acquir Immune Defic Syndr 2002, 29:244-53.
http://amedeo.com/lit.php?id=11873073
30. Galli M, Ridolfo AL, Adorni F, et al. Body habitus changes and metabolic
alterations in protease inhibitor-naive HIV-1-infected patients treated with
two nucleoside reverse transcriptase inhibitors. J Acquir Immune Defic
Syndr 2002, 29: 21-31. http://amedeo.com/lit.php?id=11782586
31. Gatell JM, Lange J, Arnaiz JA, et al. A randomized study comparing
continued
indinavir (800 mg tid) vs switching to indinavir/ritonavir (800/100
mg bid) in HIV patients having achieved viral load suppression with indinavir
plus 2 nucleoside analogues The BID Efficacy and Safety Trial
(BEST). Abstract WeOrB484, XIII International AIDS Conference 2000,
Durban, South Africa.
32. Gerard Y, Maulin L, Yazdanpanah Y, et al. Symptomatic
hyperlactataemia:
an emerging complication of ART. AIDS 2000, 14:2723-30.
http://amedeo.com/lit.php?id=11125891
33. Gerstoft J, Dragstedt UB, Cahn P. Final analysis of a randomised trial to
evaluate safety and efficacy of indinavir/ritonavir versus saquinavir/
ritonavir in adult HIV-1 infection: the MaxCmin1 trial. Abstract 2853,
ICAAC 2002, San Diego, USA.
34. Gisolf EH, van Heeswijk RP, Hoetelmans RW, Danner SA. Decreased
exposure to saquinavir in HIV-1-infected patients after long-term antiretroviral
therapy including ritonavir and saquinavir. AIDS 2000, 14: 801-5.
http://amedeo.com/lit.php?id=10839587
35. Gonzalez de Requena D, Nunez M, Jimenez-Nacher I, Soriano V. Liver
toxicity caused by nevirapine. AIDS 2002, 16:290-1.
http://amedeo.com/lit.php?id=11807315
70
36. Graham NM. Metabolic disorders among HIV-infected patients treated
with protease inhibitors: a review. J Acquir Immune Defic Syndr 2000, 25
Suppl 1: S4-11. http://amedeo.com/lit.php?id=11126425
37. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir,
zidovudine,
and lamivudine in adults with HIV infection and prior antiretroviral
therapy. N Engl J Med 1997, 337: 734-9.
http://amedeo.com/lit.php?id=9287228
38. Hammer SM, Katzenstein DA, Hughes MD et al. A trial comparing
nucleoside
monotherapy with combination therapy in HIV-infected adults
with CD4 cell counts from 200 to 500/ul. N Engl J Med 1996, 335:1081-
90. http://amedeo.com/lit.php?id=8813038
39. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two
nucleoside analogues plus indinavir in persons with HIV infection and
CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials
Group 320 Study Team. N Engl J Med 1997, 337:725-33.
http://amedeo.com/lit.php?id=9287227
40. Harley W, DeJeus E, Pistole M, et al. A 24-week randomized, controlled,
open-label evaluation of adherence and convenience of continuing indinavir
versus switching to ritonavir/indinavir 400/400 mg bid. Abstract 334,
8th CROI 2001, Chicago, USA.
http://www.retroconference.org/2001/abstracts/abstracts/abstracts/334.ht
m
41. Havlir DV, Gilbert PB, Bennett K, et al. Effects of treatment intensification
with hydroxyurea in HIV-infected patients with virologic suppression.
AIDS 2001, 15: 1379-88. http://amedeo.com/lit.php?id=11504959
42. Havlir DV, Tierney C, Friedland GH, et al. In vivo antagonism with
zidovudine
plus stavudine combination therapy. J Infect Dis 2000, 182:
321-5. http://amedeo.com/lit.php?id=10882616
43. Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in
HLA-B region and hypersensitivity reactions to abacavir. Lancet 2002,
359:1121-2. http://amedeo.com/lit.php?id=11943262
44. HIV Trialists' Collaborative Group. Zidovudine, didanosine, and
zalcitabine
in the treatment of HIV infection: meta-analyses of the randomised
evidence. Lancet 1999, 353: 2014-25.
http://amedeo.com/lit.php?id=10376616
45. Hoffmann C, Jaegel-Guedes E, Wolf E, et al. PI to Efavirenz switch effect
on lipids in HIV-positive patients. Abstract WePeB4185, XIII International
AIDS Conference 2000, Durban, South Africa.
46. John M, James I, McKinnon E, et al. A randomised, controlled, open-label
study of revision of antiretroviral regimens containing stavudine and/or a
protease inhibitor to Zidovudine/Lamivudine/Abacavir to prevent or reverse
71
lipoatrophy: 48-week data. Abstract 700, 9th CROI 2002, Seattle.
http://63.126.3.84/2002/Abstract/13277.htm
47. John M, Moore CB, James IR, et al. Chronic hyperlactatemia in
HIVinfected
patients taking ART. AIDS 2001, 15: 717-23.
http://amedeo.com/lit.php?id=11371686
48. Kahn JO, Lagakos SW, Richman DD, et al. A controlled trial comparing
continued zidovudine with didanosine in HIV infection. N Engl J Med
1992, 327:581-7. http://amedeo.com/lit.php?id=1353607
49. Katzenstein TL, Kirk O, Pedersen C, et al. The danish protease inhibitor
study: a randomized study comparing the virological efficacy of 3 protease
inhibitor-containing regimens for the treatment of HIV type 1 infection.
J Infect Dis 2000, 182: 744-50.
http://amedeo.com/lit.php?id=10950767
50. Kearney BP, Damle B, Plummer A, et al. Pharmacokinetic evaluation of
tenofovir DF and enteric-coated didanosine. Abstract 9026, XIV International
AIDS Conference 2002, Barcelona, Spain.
51. Kempf DJ, Marsh KC, Kumar G, et al. Pharmacokinetic enhancement of
inhibitors of the HIV protease by coadministration with ritonavir. Antimi
crob Agents Chemother 1997, 41:654-60.
http://amedeo.com/lit.php?id=9056009
52. Kirk O, Mocroft A, Pradier C, et al. Clinical outcome among HIV-infected
patients starting saquinavir hard gel compared to ritonavir or indinavir.
AIDS 2001, 15: 999-1008. http://amedeo.com/lit.php?id=11399982
53. Kuritzkes DR, Marschner I, Johnson VA, et al. Lamivudine in combination
with zidovudine, stavudine, or didanosine in patients with HIV-1 infection.
A randomized, double-blind, placebo-controlled trial. AIDS 1999, 13: 685-
94. http://amedeo.com/lit.php?id=10397563
54. Kurowski M, Kaeser B, Sawyer A, et al. Low-dose ritonavir moderately
enhances nelfinavir exposure. Clin Pharmacol Ther 2002, 72:123-32.
http://amedeo.com/lit.php?id=12189359
55. Kurowski M, Kaeser B, Sawyer A, Popescu M, Mrozikiewicz A. Low-dose
ritonavir moderately enhances nelfinavir exposure. Clin Pharmacol Ther
2002, 72:123-32. http://amedeo.com/lit.php?id=12189359
56. Kurowski M, Sternfeld T, Hill A, Moecklinghoff C. comparative
pharmacokinetics
and short-term safety of twice daily (bid) fortovase/ritonavir and
invirase/ritonavir. Abstract 432, 9th CROI 2002, Seattle, USA.
http://63.126.3.84/2002/Abstract/13486.htm
57. Lafeuillade A, Poggi C, Djediouane A,. A pilot study of a combination of
three reverse transcriptase inhibitors in HIV-1 infection. Antivir Ther 1997,
2: 219-27. http://amedeo.com/lit.php?id=11327441
58. Lallemand F, Salhi Y, Linard F, Giami A, Rozenbaum W. Sexual
dysfunction
in 156 ambulatory HIV-infected men receiving HAART combinations
72
with and without protease inhibitors. J Acquir Immune Defic Syndr 2002,
30: 187-90. http://amedeo.com/lit.php?id=12045681
59. Mallal S, Nolan D, Witt C, et al. Association between presence of HLAB*
5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1
reversetranscriptase
inhibitor abacavir. Lancet 2002, 359:727-32.
http://amedeo.com/lit.php?id=11888582
60. Marcus K, Truffa M, Boxwell D, Toerner J. Recently identified adverse
events secondary to NRTI therapy in HIV-infected individuals: cases from
the FDA’s adverse event reporting system. Abstract LB14, 9th CROI
2002, Seattle, USA
http://www.retroconference.org//2002/Abstract/14036.htm
61. Martin C, Sonnerborg A, Svensson JO, Stahle L. Indinavir-based
treatment
of HIV-1 infected patients: efficacy in the central nervous system.
AIDS 1999, 13: 1227-32. http://amedeo.com/lit.php?id=10416527
62. Martinez-Picado X, Savara A, Sutton L, D’Aquila R. Replicative fitness of
protease inhibitor-resistant mutants of HIV-1. J Virol 1999, 73: 3744-
3752.
63. Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T.
Efavirenz
plasma levels can predict treatment failure and central nervous
system side effects in HIV-1-infected patients. AIDS 2001, 15: 71-5.
http://amedeo.com/lit.php?id=11192870
64. Mauss S, Corzillius M, Wolf E, et al. Risk factors for the HIV-associated
lipodystrophy syndrome in a closed cohort of patients after 3 years of
antiretroviral treatment. HIV Med 2002, 3:49-55.
http://amedeo.com/lit.php?id=12059951
65. McComsey G, Lonergan T, Fisher R, et al. Improvements in lipoatrophy
are observed after 24 weeks when stavudine is replaced by either abacavir
or zidovudine. Abstract 701, 9th CROI 2002, Seattle.
http://63.126.3.84/2002/Abstract/12662.htm
66. McMahon D, Lederman M, Haas DW, et al. Antiretroviral activity and
safety of abacavir in combination with selected HIV-1 protease inhibitors
in therapy-naive HIV-1-infected adults. Antivir Ther 2001, 6:105-14.
http://amedeo.com/lit.php?id=11491415
67. Miller KD, Cameron M, Wood LV, et al. Lactic acidosis and hepatic
steatosis
associated with use of stavudine: report of four cases. Ann Intern
Med 2000, 133:192-6. http://amedeo.com/lit.php?id=10906833
68. Miller V, Stark T, Loeliger AE, Lange JM. The impact of the M184V
substitution
in HIV-1 reverse transcriptase on treatment response. HIV Med
2002, 3:135-45. http://amedeo.com/lit.php?id=12010361
69. Miller V, Staszewski S, Boucher CAB, Phair JP. Clinical experience with
73
non-nucleoside reverse transcriptase inhibitors. AIDS 1997, 11 (suppl A):
S157-164.
70. Mitsuyasu RT, Skolnik PR, Cohen SR, et al. Activity of the soft gelatin
formulation of saquinavir in combination therapy in antiretroviral-naive
patients. NV15355 Study Team. AIDS 1998,12:F103-9.
http://amedeo.com/lit.php?id=9708399
71. Mokrzycki MH, Harris C, May H, Laut J, Palmisano J. Lactic acidosis
associated with stavudine administration: a report of five cases. Clin Infect
Dis 2000; 30: 198-200. http://amedeo.com/lit.php?id=10619755
72. Molina JM, Chene G, Ferchal F, et al. The ALBI trial: a randomized
controlled
trial comparing stavudine plus didanosine with zidovudine plus
lamivudine and a regimen alternating both combinations in previously
untreated patients infected with HIV. J Infect Dis 1999, 180: 351-8.
http://amedeo.com/lit.php?id=10395849
73. Moyle G, Pozniak A, Opravil M, et al. The SPICE study: 48-week activity
of combinations of saquinavir soft gelatin and nelfinavir with and without
nucleoside analogues. J Acquir Immune Defic Syndr 2000, 23: 128-37.
http://amedeo.com/lit.php?id=10737427
74. Moyle GJ, Gazzard BG. Finding a role for zalcitabine in the HAART era.
Antivir Ther 1998, 3: 125-37. http://amedeo.com/lit.php?id=10682130
75. Noble S, Goa KL. Amprenavir: a review of its clinical potential in patients
with HIV infection. Drugs 2000, 60:1383-410.
http://amedeo.com/lit.php?id=11152018
76. Nunez M, Soriano V, Martin-Carbonero L, et al. SENC trial: a randomized,
open-label study in HIV-infected naive individuals. HIV Clin Trials
2002; 3:186-94.
77. Phillips AN, Pradier C, Lazzarin A, et al. Viral load outcome of
nonnucleoside
reverse transcriptase inhibitor regimens for 2203 mainly
antiretroviral-experienced patients. AIDS 2001;15:2385-95.
http://amedeo.com/lit.php?id=11740189
78. Picard V, Angelini E, Maillard A, et al. Comparison of genotypic and
phenotypic
resistance patterns of HIV type 1 isolates from patients treated
with stavudine and didanosine or zidovudine and lamivudine. J Infect Dis
2001, 184:781-4. http://amedeo.com/lit.php?id=11517441
79. Piscitelli SC, Gallicano KD. Interactions among drugs for HIV and
opportunistic
infections. N Engl J Med 2001, 344:984-96.
80. Raboud JM, Rae S, Vella S, et al. Meta-analysis of two randomized
controlled
trials comparing combined zidovudine and didanosine therapy with
combined zidovudine, didanosine, and nevirapine therapy in patients with
HIV. INCAS study team. J Acquir Immune Defic Syndr 1999, 22: 260-6.
74
http://amedeo.com/lit.php?id=10770346
81. Robbins BL, Srinivas RV, Kim C, et al. Anti-HIV activity and cellular
metabolism
of a potential prodrug of the acyclic nucleoside phosphonate 9-
R-(2-phosphonomethoxypropyl)adenine (PMPA),
Bis(isopropyloxymethylcarbonyl)PMPA. Antimicrob Agents Chemother
1998, 42:612-7. http://amedeo.com/lit.php?id= 9517941
82. Robbins G, Shafer R, Smeaton L, et al. Antiretroviral strategies in naive
HIV+ subjects: comparisons of sequential 3-drug regimens (ACTG 384).
Abstract LbOr20A, XIV International AIDS Conference 2002, Barcelona,
Spain.
83. Roge BT, Katzenstein TL, Gerstoft J. Comparison of P-triglyceride levels
among patients with HIV on randomized treatment with ritonavir, indinavir
or ritonavir/saquinavir. Scand J Infect Dis 2001, 33:306-11.
http://amedeo.com/lit.php?id=11345223
84. Saag MS, Tebas P, Sension M, et al. Randomized, double-blind
comparison
of two nelfinavir doses plus nucleosides in HIV-infected patients
(Agouron study 511). AIDS 2001, 15:1971-8.
http://amedeo.com/lit.php?id=11600825
85. Schooley RT, Ruane P, Myers RA, et al. Tenofovir DF in
antiretroviralexperienced
patients: results from a 48-week, randomized, double-blind
study. AIDS 2002, 16:1257-63. http://amedeo.com/lit.php?id=12045491
86. Schrooten W, Colebunders R, Youle M, et al. Sexual dysfunction
associated
with protease inhibitor containing HAART. AIDS 2001, 15: 1019-23.
http://amedeo.com/lit.php?id=11399984
87. Sension MG, Bellos NC, Johnson J, et al. Lamivudine 300 mg QD versus
continued lamivudine 150 mg BID with stavudine and a protease inhibitor
in suppressed patients. HIV Clin Trials 2002, 3:361-70.
http://amedeo.com/lit.php?id=12407485
88. Shafer R, Robbins G, Smeaton L, et al. Antiretroviral strategies in naive
HIV+ subjects: comparison of 4-drug versus sequential 3-drug regimens
(ACTG 384). Abstract LbOr20B, XIV International AIDS Conference
2002, Barcelona, Spain.
89. Sham HL, Kempf DJ, Molla A, et al. ABT-378, a highly potent inhibitor of
the HIV protease. Antimicrob Agents Chemother 1998, 42:3218-24.
http://amedeo.com/lit.php?id=9835517
90. Shulman N, Zolopa A, Havlir D, et al. virtual inhibitory quotient predicts
response to ritonavir boosting of indinavir-based therapy in HIV-infected
patients with ongoing viremia. Antimicrob Agents Chemother 2002,
46:3907-3916. http://amedeo.com/lit.php?id=12435695
91. Smith D, Hales G, Roth N, et al. A randomized trial of nelfinavir, ritonavir,
or delavirdine in combination with saquinavir-SGC and stavudine in
75
treatment-experienced HIV-1-infected patients. HIV Clin Trials 2001,
2:97-107. http://amedeo.com/lit.php?id=11590517
92. Sommadossi JP. HIV protease inhibitors: pharmacologic and metabolic
distinctions. AIDS 1999, 13 Suppl 1: S29-40.
http://amedeo.com/lit.php?id=10546783
93. Squires KE, Gulick R, Tebas P, et al. A comparison of stavudine plus
lamivudine versus zidovudine plus lamivudine in combination with indinavir
in antiretroviral naive individuals with HIV infection: selection of thymidine
analog regimen therapy (START I). AIDS 2000, 14: 1591-600.
http://amedeo.com/lit.php?id=10983646
94. Staszewski S, Gallant J, Pozniak AL, et al. Efficacy and saefty of tenofovir
disoproxil fumarate versus stavudine when used in combination with
lamivudine and efavirenz in HIV-1 infected patients naive to antiretroviral
therapy: 48-week interim results. Abstract LB17, XIV International AIDS
Conference 2002, Barcelona, Spain.
95. Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus
zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus
zidovudine
and lamivudine in the treatment of HIV-1 infection in adults.
Study 006 Team. N Engl J Med 1999, 341:1865-73.
http://amedeo.com/lit.php?id=10601505
96. Stellbrink HJ, Hawkins DA, Clumeck N, et al. Randomised, multicentre
phase III study of saquinavir plus zidovudine plus zalcitabine in previously
untreated or minimally pretreated hiv-infected patients. Clin Drug Invest
2000, 20:295-307.
97. Stellbrink HJ, van Lunzen J, Westby M, et al. Effects of interleukin-2 plus
highly active antiretroviral therapy on HIV-1 replication and proviral DNA
(COSMIC trial). AIDS 2002, 16:1479-87.
http://amedeo.com/lit.php?id=12131185
98. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity
associated with antiretroviral therapy in adults infected with HIV and the
role of hepatitis C or B virus infection. JAMA 2000, 283: 74-80.
http://amedeo.com/lit.php?id=10632283
99. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD.
Hepatotoxicity
associated with nevirapine or efavirenz-containing antiretroviral
therapy: role of hepatitis C and B infections. Hepatology 2002, 35:182-9.
http://amedeo.com/lit.php?id=11786975
100. Suo Z, Johnson KA. Selective inhibition of HIV-1 reverse transcriptase
by
an antiviral inhibitor, (R)-9-(2-Phosphonylmethoxypropyl)adenine. J Biol
Chem 1998, 273:27250-8. http://amedeo.com/lit.php?id=9765248
101. Torre D, Tambini R, Speranza F. Nevirapine or efavirenz combined with
two nucleoside reverse transcriptase inhibitors compared to HAART: a
meta-analysis of randomized clinical trials. HIV Clin Trials 2001, 2: 113-
76
21. http://amedeo.com/lit.php?id=11590519
102. Van der Valk M, Kastelein JJ, Murphy RL, et al. Nevirapine-containing
antiretroviral therapy in HIV-1 infected patients results in an antiatherogenic
lipid profile. AIDS 2001, 15: 2407-14.
http://amedeo.com/lit.php?id=11740191
103. Van Heeswijk RP, Veldkamp AI, Hoetelmans RM, et al. The steady-state
plasma pharmacokinetics of indinavir alone and in combination with a low
dose of ritonavir in twice daily dosing regimens in HIV-1-infected individuals.
AIDS 1999, 13: F95-9. http://amedeo.com/lit.php?id=10513637
104. Veldkamp AI, Weverling GJ, Lange JM, et al. High exposure to
nevirapine
in plasma is associated with an improved virological response in
HIV-1-infected individuals. AIDS 2001; 15: 1089-95.
http://amedeo.com/lit.php?id=11416710
105. Voigt E, Wickesberg A, Wasmuth JC, et al. First-line ritonavir/indinavir
100/800 mg twice daily plus nucleoside reverse transcriptase inhibitors in
a German multicentre study: 48-week results. HIV Med 2002, 3:277-282.
http://amedeo.com/lit.php?id=12444946
106. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus
nelfinavir
for the initial treatment of HIV infection. N Engl J Med 2002, 346:2039-
46. http://amedeo.com/lit.php?id=12087139
107. Wensing AM, Reedijk M, Richter C, Boucher CA, Borleffs JC. Replacing
ritonavir by nelfinavir or nelfinavir/saquinavir as part of HAART leads to
an improvement of triglyceride levels. AIDS 2001, 15:2191-3.
108. Wood R, Hawkins DA, Moyle G, et al. Second placebo-controlled study
in
naive individuals confirms the role of delavirdine in highly active antiretroviral,
protease-sparing treatment. Abstract 624. 6th CROI 1999, Chicago,
USA. http://www.retroconference.org/99/abstracts/624.htm
77
ART 2003/2004: Orizontul si mai departe
Aceasta trecere in revista pune accent pe medicamentele care sunt deja intr-
un stadiu avansat de dezvoltare. Datorita numarului mare de substante care
sunt testate in prezent, nu se pretinde a fi completa. Unele produse sunt pe
cale sa obtina aprobarea si au fost disponibile in cadrul unor programe cu
acces larg. Cel putin 4 se presupune a fi aprobate in urmatorul an/in urmatorii
doi ani: d4T XR, emtricitabina, fos-amprenavir, atazanavir. Noul inhibitor T20
a fost aprobat in SUA in martie 2003.
Noi „nukes”
Stavudina (Zerit) va fi in curand disponibila ca d4T XR(extended release)
intr-o formula capsulata o data/zilnic(75mg si 100mg). Formula este stabila,
nu are tendinta de a se acumula, si pare sa cauzeze un nivel mai scazut de
polineuropatie, posibil datorita nivelelor minime.
78
DAPD (Amdoxovir) este un analog de guanine dezvoltat de Triangle. DAPD
este transformat in vivo in DXG cu putere crescuta. Este in prezent testat in
studiile Phase I/II (Corbett et al 2001). DAPD este eficient impotriva virusurilor
rezistente la zidovudina/ lamivudina, inclusiv virusurile cu o insertie la nivelul
codonului 69, care confera multi-rezistenta impotriva tuturor analogilor de
nucleozide. Sensibilitatea pare sa fie redusa in prezenta mutatiilor cum ar
K65R si L74V(Chong et al 2002, Mewshaw et al 2002). In culturile celulare,
medicamentul are efecte sinergice cu inhibitorul de fuziune T-20, lucru care
ar putea fi folositor in viitor(Trembley et al 2002). La fel de imbucuratoare este
si eficienta sa buna impotriva virusului hepatitei B. Rapoarte privind anomalii
ale cristalinului sunt mai putin satisfacatoare. Desi asocierea cu DAPD inca
nu este sigura, FDA a cerut imediat companiei sa studieze aceasta problema
inainte de continuarea studiilor.
Lobucavir – de la BMS
Noi NNRTI
Spre deosebire de celelalte clase de medicamente, industria are urmatorul
motto: Daca nu putem realiza un nou medicament care sa fie cel putin
eficient impotriva virusurilor rezistente la efavirenz si nevirapina, am putea la
79
fel de bine sa stopam cercetarile. Medicamentele „me-too”(asemanatoare
celor deja existente) nu sunt necesare. Intre timp, diferite medicamente au
fost deja abandonate; drumul catre obtinerea aprobarii este deosebit de lung
si greu pentru NNRTI, desi sunt relativ ieftine de dezvoltat. Multe din
medicamentele prezentate mai jos nu vor atinge din aceasta cauza
dezvoltarea pe piata.
TMC 125 este un nou NNRTI de generatia a II-a. Este eficient atat impotriva
virusurilor rebele cat si a virusurilor cu aproape toate mutatiile NNRTI
clasice(cum ar fi K103N, Y181C). Intr-un studiu Phase IIB, in care 16 pacienti
aflati in tratament stabil cu ART, majoritatea cu mai multe mutatii NNRTI au
fost tratati cu 900mg TMC 125 BID timp de 7 zile, incarcatura virala a scazut
cu o medie de 0.9 log, si in unele cazuri a crescut pana la 1.7log(Gazzard et
al 2002, Sankatsing et al 2002). Chiar si dupa acest termen limita, incarcatura
virala a continuat sa descreasca. TMC 125 era bine tolerat. Timpul de
injumatatire este lung si medicamentul este metabolizat in ficat. Desi primele
date farmacocinetice au indicat interactiuni defavorabile cu PI(in special cu
indinavir si saquinavir), TMC 125 pare sa evolueze intr-un medicament
puternic si promitator, cu o bariera genetica crescuta.
80
Capravirina (AG1549, initial S-1153) este un NNRTI destul de avansat, care
a fost dezvoltat initial de Shionogi Pharmaceuticals(Fujivara et al 1998) si
ulterior vandut lui Agouron. Capravirina este eficienta in vivo chiar si impotriva
virusurilor ce prezinta mutatia K103N(Wolfe et al 2001) si a fost un candidat
in care s-au pus multe sperante in lupta impotriva virusurilor rezistente la
NNRTI. Dupa ce studiile efectuate pe caini au demonstrat o frecventa
neobisnuit de mare de vasculita dupa doze crescute, Agouron a oprit
desfasurarea studiilor clinice Phase II/III. Evaluari ale sigurantei au aratat ca
medicamentul capravirina nu cauzeaza asemenea efecte secundare la
oameni(Hawley et al 2002), si intre timp, dezvoltarea sa continua. Doza va fi
probabil fixata la 2*700mg/zi.
Atevirdina – de la Upjohn
HBY-097 – de la Hoechst-Bayer
81
cand fos-amprenavir este stimulat cu ritonavir. Acesta este un lucru pozitiv,
fata de 8 pastile care se luau de 2 ori pe zi, care reprezinta doza standard de
amprenavir, neacceptabila de altfel.
82
Cresterea nivelului de bilirubina pare a fi o problema frecventa. Mecanismul
seamana cu cel din sindromul Gilbert(si nivele crescute de indinavir); exista
nivele crescute de bilirubina indirecta datorita conjugarii reduse din ficat. Desi
pana azi nu au fost descrise tulburari hepatice grave, functia hepatica ar
trebui monitorizata.
83
HIV Clin Trials 2001, 2:307-16.
http://amedeo.com/lit.php?id=11590533
2. Bethell RC, Allard B, De Muys JM, et al. BCH-13520, a new
heterosubstituted
nucleoside analogue, is an effective inhibitor of drug-resistant
HIV-1. Abstract 386, 9th CROI 2002, Seattle, USA.
http://63.126.3.84/2002/Abstract/13340.htm
3. Blum MR, Moxham CP, Kargl DJ, et al. A pharmacokinetic interaction
evaluation of MKC-442 and nelfinavir in healthy male and female volunteers.
Abstract 12380, 12th International AIDS Conference 1998, Geneva,
Switzerland.
4. Cahn P, Percival L, Phanuphak P, et al. Phase II 24-week data from
study AI424-008: Comparative results of BMS-232632, stavudine, lamivudine
as HAART for treatment-naive HIV-infected patients. Abstract 5,
1st IAS Conference on HIV Pathogenesis and Treatment 2001, Buenos
Aires, Argentina.
5. Chong Y, Borroto-Esoda K, Furman PA, Schinazi RF, Chu CK. Molecular
mechanism of DAPD/DXG against zidovudine- and lamivudine-drug resistant
mutants: a molecular modelling approach. Antivir Chem Chemother
2002, 13:115-28. http://amedeo.com/lit.php?id=12238529
6. Colonno RJ, Friborg J, Rose RE, Lam E, Parkin N. Identification of amino
acid substitutions correlated with reduced atazanavir susceptibility in patients
treated with atazanavir-containing regimens. Antiviral Ther 2002,
7:S4. Abstract 4.
7. Corbett AH, Rublein JC. DAPD. Curr Opin Investig Drugs 2001, 2:348-53.
http://amedeo.com/lit.php?id=11575703
8. Delehanty J, Wakeford C, Hulett L, et al. A phase I/II randomized,
controlled
study of FTC versus 3TC in HIV-infected patients. Abstract 16, 6th
CROI 1999, Chicago, USA.
9. Fujiwara T, Sato A, el-Farrash M, et al. S-1153 inhibits replication of
known drug-resistant strains of HIV-1. Antimicrob Agents Chemother
1998, 42:1340-5. Original-Artikel
http://aac.asm.org/cgi/content/full/42/6/1340?view=full&pmid=9624472
10. Gazzard B, Pozniak A, Arasteh K, et al.TMC125, A next-generation
NNRTI, demonstrates high potency after 7 days therapy in
treatmentexperienced
HIV-1-infected individuals with phenotypic NNRTI resistance.
Abstract 4, 9th CROI 2002, Seattle, USA.
http://63.126.3.84/2002/Abstract/14022.htm
11. Hawley P, Diniz-Piraino S, Paxton W. et al. Absence of risk of vasculitis
in a hiv population taking capravirine-results of an active monitoring plan.
Abstract TuPeB4549. XIV International AIDS Conference 2002, Barcelona,
Spain
12. Jeffrey S, Corbett J, Bacheler L. In vitro NNRTI resistance of recombinant
84
HIV carrying mutations observed in efavirenz treatment failures. Abstract
110, 6th CROI Chicago 1999, USA.
13. Johnson D, Sanne I, Baraldi E, et al. A phase II, open-label study to
evaluate the antiviral activity, safety, and tolerability of emivirine (EMV,
MKC-442) and stavudine + didanosine. Abstract 502, 39th ICAAC 1999,
San Francisco, USA.
14. Kim EY, Vrang L, Oberg B, Merigan TC. Anti-HIV type 1 activity of 3'-
fluoro-3'-deoxythymidine for several different multidrug-resistant mutants.
AIDS Res Hum Retroviruses 2001, 17:401-7.
http://amedeo.com/lit.php?id=11282008
15. Larder BA, Hertogs K, Bloor S, et al. Tipranavir inhibits broadly protease
inhibitor-resistant HIV-1 clinical samples. AIDS 2000, 14:1943-8.
http://amedeo.com/lit.php?id=10997398
16. McCallister S, Sabo J, Galitz L, Mayers D. An open-label steady state
investigation of the pharmacokinetics of tipranavir and ritonavir and their
effects on cytochrome P-450 (3A4) activity in normal healthy volunteers
(BI 1182.5). Abstract 434, 9th CROI 2002, Seattle, USA.
http://63.126.3.84/2002/Abstract/13434.htm
17. McCreedy B, Borroto-Esoda K, Harris J, et al. Genotypic and phenotypic
analysis of HIV-1 from patients receiving therapy containing two NRTIs in
combination with the NNRTI, emivirine (MKC-442). Abstract 1173, 39th
ICAAC 1999, San Francisco, USA.
18. Mewshaw JP, Myrick FT, Wakefield DA, et al. Dioxolane guanosine, the
active form of the prodrug diaminopurine dioxolane, is a potent inhibitor of
drug-resistant HIV-1 isolates from patients for whom standard nucleoside
therapy fails. J Acquir Immune Defic Syndr 2002, 29:11-20.
http://amedeo.com/lit.php?id=11782585
19. Molina J, Perusat S, Ferchal F, et al. Once-daily combination therapy with
emtricitabine, didanosine and efavirenz in treatment-naive HIV-infected
adults: 64-week follow-up of the ANRS 091 trial. Abstract 321, 8th CROI
2001, Chicago, USA.
20. Piliero P, Cahn C, Pantaleo G, et al. Atazanavir: A Once-Daily Protease
Inhibitor with a Superior Lipid Profile: Results of Clinical Trials Beyond
Week 48. Abstract 706, 9th CROI 2002, Seattle, USA.
http://63.126.3.84/2002/Abstract/13827.htm
21. Pollard R, Ive P, Farthing C, et al. Stavudine XR vs stavudine IR as part
of potent antiretroviral combination therapy: 24-week safety and antiviral
efficacy. Abstract 411, 9th CROI 2002, Seattle, USA.
http://63.126.3.84/2002/Abstract/13559.htm
22. Preston S, Piliero P, O'Mara E, et al. Evaluation of steady-state
interaction
between atazanavir and efavirenz. Abstract 443, 9th CROI 2002, Seattle,
USA. http://63.126.3.84/2002/Abstract/13543.htm
23. Robinson BS, Riccardi KA, Gong YF, et al. BMS-232632, a highly potent
HIV protease inhibitor that can be used in combination with other available
85
antiretroviral agents. Antimicrob Agents Chemother 2000, 44:2093-
2099. Original-Artikel:
http://aac.asm.org/cgi/content/full/44/8/2093?view=full&pmid=10898681
24. Rodriguez-French A, Nadler J, and the Neat Study Team. The NEAT
Study: GW433908 efficacy and safety in anti-retroviral therapy naive
subjects, preliminary 24-week results. Abstract H-166, 42th ICAAC 2002,
San Diego, USA.
25. Ruiz N, Nusrat R, Lauenroth-Mai E, et al. Study DPC 083-203, a phase II
comparison of 100 and 200 mg once-daily DPC 083 and 2 NRTIs in patients
failing a NNRTI-containing regimen. Abstract 6, 9th CROI 2002,
Seattle, USA. http://63.126.3.84/2002/Abstract/13700.htm
26. Saag M, Cahn P, Raffi F, et al. A randomized, double-blind, multicenter
comparison of emtricitabine QD to stavudine BID. Abstract LB1, 42nd
ICAAC 2002, San Diego, USA.
27. Sankatsing S, Weverling G, van't Klooster G, et al. TMC125 monotherapy
for 1 week results in a similar initial rate of decline of HIV-1 RNA as therapy
with a 5-drug regimen. Abstract 5, 9th CROI 2002, Seattle, USA.
http://63.126.3.84/2002/Abstract/13427.htm
28. Schinazi RF, Mellors J, Bazmi H, et al. DPC 817: a cytidine nucleoside
analog with activity against zidovudine- and lamivudine-resistant viral
variants. Antimicrob Agents Chemother 2002, 46:1394-401.
http://amedeo.com/lit.php?id=11959574
29. Schwartz R, Kazanjian P, Slater L. Resistance to tipranavir is uncommon
in a randomized trial of tipranavir/ritonavir in multiple PI-failure patients
(BI 1182.2). Abstract 562, 9th CROI 2002, Seattle, USA.
http://63.126.3.84/2002/Abstract/13757.htm
30. Sierra-Madero J. Antiviral activity, safety and phamacokinetics of
mozenavir
(DMP 450), a novel cyclic urea protease inhibitor, in combination
with d4t and 3tc in treatment-naïve hiv-1 infected patients (study DMP-
102). Abstract 2, 1st IAS Conference on HIV Pathogenesis and Treatment
2001, Buenos Aires, Argentina.
31. Squires K, Gatell J, Piliero P, et al. AI424-007: 48-week safety and
efficacy
results from a phase II study of a once-daily HIV-1 protease inhibitor,
BMS-232632. Abstract 15, 8th CROI 2001, Chicago, USA.
32. Squires KE, Thiry A, Giordano M, for the AI424-034 International Study
Team. Atazanavir QD and efavirenz QD with fixed-dose ZDV+3TC:
Comparison of antiviral efficacy and safety through wk 24 (AI424-034).
Abstract H-1076, 42nd ICAAC 2002, San Diego, USA.
33. Szczech GM, Furman P, Painter GR, et al. Safety assessment, in vitro
and in vivo, and pharmacokinetics of emivirine, a potent and selective
nonnucleoside reverse transcriptase inhibitor of HIV type 1. Antimicrob
Agents Chemother 2000, 44:123-30.
http://amedeo.com/lit.php?id=10602732
86
34. Thomas S, Cass L, Prince W, Segal M. Brain and CSF entry of the novel
non-nucleoside reverse transcriptase inhibitor, GW420867X. Neuroreport
2000, 11:3811-5. http://amedeo.com/lit.php?id=11117496
35. Tremblay C, Poulain D, Hicks JL, et al. T-20 and DAPD have synergistic
in vitro anti-HIV interactions. Abstract 393, 9th CROI 2002, Seattle, USA.
http://63.126.3.84/2002/Abstract/13137.htm
36. Wire MB, Ballow C, Preston S, et al. An assessment of plasma
amprenavir
pharmacokinetics following administration of two GW433908 and ritonavir
regimens in combination with efavirenz in healthy adult subjects
(APV10010). Abstract 443, 9th CROI 2002, Seattle, USA.
http://63.126.3.84/2002/Abstract/13503.htm
37. Wolfe P, Hawley P, Boccia G, et al. Safety and efficacy of capravirine
versus placebo in HIV-infected patients failing a NNRTI-containing regimen:
results of a phase II, double blind, placebo controlled trial. Abstract
323, 8th CROI 2001, Chicago, USA.
http://www.retroconference.org//2001/abstracts/abstracts/abstracts/323.ht
m
87
Inhibitori ai intrarii
Exista 3 pasi esentiali pentru patrunderea HIV in celulele T CD4+:
- legarea HIV de receptorul CD4(„atasare” – tinta inhibitorilor de atasare)
- legarea de co-receptori (tinta antagonistilor de co-receptori), si in ultimul
rand,
- fuzionarea virusului si a celulei (tinta a inhibitorilor de fuziune).
Inhibitori de atasare
BMS-806 este un inhibitor de atasare „timpuriu”, care, independent de co-
receptori, se leaga de gp120 a HIV specific si reversibil, si previne astfel
atasarea HIV la limfocitele T CD4+(Lin et al 2002). Are biodisponibilitate
orala cu legare de proteine plasmatice scazute si probabil poate fi
administrat sub forma de tableta. Studii efectuate pe animale au
demonstrat o buna tolerabilitate. Exista sperante ca ar avea un efect aditiv,
poate chiar sinergic cu alti inhibitori de intrare. Entuziasmul legat de acest
medicament a fost usor temperat deoarece s-a demonstrat ca izolari HIV
diferite au prezentat diferente in ceea ce priveste sensibilitatea la BMS
806, indicand potentiala dezvoltare rapida a rezistentei.
Antagonisti de co-receptori
SCH-C este un antagonist de receptor CCR-5 cu biodisponibilitate orala si
o activitate puternica in vitro impotriva a numeroase izolari HIV(Strizki et al
2001). La voluntari sanatosi, efectele secundare cum ar fi aritmia (intervale
QT – mai lungi) apareau in principal la doze mai mari. Aceasta problema
pare sa nu apara la doze reduse, si FDA a dat unda verde pentru
dezvoltarea ulterioara. Un studiu pilot efectuat pe 12 pacienti, care au
primit SCH-C timp de 10 zile (doza a fost semnificativ redusa la
88
2*25mg/zilnic) a aratat ca toti cei 10 pacienti au inregistrat o scadere a
incarcaturii virale cu mai mult de 0,5log si 4 pacienti cu mai mult de
1,0log(Reynes et al 2002). Acest efect a persistat chiar cateva zile dupa
terminarea terapiei. Insa, mutantii virali „de scapare” au fost descrisi deja
pentru SCH-C, care au rezistenta incrucisata fata de alti antagonisti de
receptor CCR5(Rilley et al 2002, Xu et al 2002). SCH-D se presupune a fi
mult mai puternic si mai bine tolerat fata de SCH-C, si din acesta cauza
pare a avea sanse mai bune pentru o dezvoltare ulterioara(Chen et al
2002). Insa, primele rapoarte au descris dezvoltarea rezistentei, probabil
datorita schimbarilor in gena env a HIV.
Inhibitori de fuziune
T-20 (Enfuvirtide, Fuzeon®) : Nu trece nici o zi fara ca T-20 sa fie mentionat
in media, si fiecare pacient se intreaba pe sine precum si pe medicul sau, de
ce el/ea nu primeste inca acest „nou medicament”. T-20 este prototipul
inhibitorilor de fuziune. Este o peptida relativ mare, formata din 36 amino-
acizi, si prin urmare trebuie administrata subcutanat (injectabil) ca si insulina.
Se leaga de o structura intermediara a proteinei-gp41, care apare in timpul
patrunderii HIV in celula tinta, in timpul fuziunii.
In unul din studiile initiale cu T-20, pacientilor HIV li s-au administrat doze
diferite intravenos ca monoterapie. A existat un efect legat de doza, si cu o
doza mai mare de 2*100mg pe zi, incarcatura virala medie a fost redusa cu
aproape 2log(Kilby et al 1998). Datorita faptului ca infuzia de 2 ori zilnic nu
89
este practica, primul studiu al administrarii subcutanate a fost initiat la scurt
timp dupa. 78 pacienti care au avut o experienta bogata de tratament, au
primit T-20 in plus fata de HAART – fie prin intermediul unei pompe de
insulina(insulin pomp) sau de 2 ori zilnic subcutanat(Kilby et al 2002). Din nou
s-au inregistrat efecte pozitive legate de doza in ceea ce priveste incarcatura
virala, la ambele grupuri. Insa, supresia maxima era mai redusa fata de
infuzii, si scaderea maxima a fost de 1,6log. Mai important este faptul ca,
efectul a fost de scurta durata; dupa 28 zile, in majoritatea cazurilor,
incarcatura virala a revenit la nivelul de baza/initial. Principalele efecte
secundare din acest studiu erau reactiile (in mare parte usoare) de la locul
injectarii.
Datele preliminare si de alfel nesperat de bune din primul studiu Phase III au
dus la atragerea atentiei din partea mediei pentru T-20 in vara anului 2002
(Henry et al 2002, Clotet et al 2002). TORO1(„T-20 versus regimuri
optimizate”, anterior, studiul T20-301), a recrutat 491 pacientidin America de
Nord si Brazilia. Pacienti alesi la intamplare in raport de 2:1 sa primeasca
2*90mg T-20 subcutanat sau nu, sau un regim HAART optimizat(Henry et al
2002). Aproape toti pacientii au fost pre-tratati serios si au dezvoltat virusuri
multirezistente la locul de intrare. Din nou, rezultatele erau uimitoare:
adaugarea T-20 a redus in mod evident incarcatura virala fata de terapia
optimizata. La 24 saptamani, reducerea incarcaturii virale era de 1.70log in
grupul T-20, fata de 0.76log in grupul de control – o diferenta surprinzatoare
de 0.93log. in TORO-2 (T20-302), acelasi tipar a fost testat la 504 pacienti in
Europa si Australia (Clotet et al 2002). Diferenta la 24 saptamani era 1.43
versus 0.65log – o diferenta de 0.78log.
90
Pe scurt, evaluarea si perspectivele T20: Pacientii cu o incarcatura virala bine
controlata sau care inca au ca optiune HAART „clasica”, probabil nu vor avea
nevoie imediat de T-20. Pentru terapia de recuperare, insa, medicamentul
pare a fi destul de folositor. Trebuie sa fie stresant faptul ca nici in acest
context nu pot fi realizate minuni, efectul antiviral dupa un an fiind de doar
1log. Desi nu exista inca date provenite din studii cu rezultate clinice, pacientii
care in prezent nu au alte optiuni de tratament pot beneficia clinic de acest
medicament.
T-20 a fost aprobat in SUA in martie 2003. Se presupune ca medicamentul
nu va fi imediat disponibil pentru toti pacientii, deoarece exista probleme
logistice importante care trebuiesc inca rezolvate in procesul de fabricatie.
Conform Roche, acesta este unul dintre cele mai complicate medicamente
care au fost fabricate vreodata de acesta firma: este necesara parcurgerea a
106 pasi pentru sintetizarea sa. Acest lucru se traduce prin costuri/cheltuieli
de productie ridicate; astfel, este de asteptat ca si costul unui regim HAART
ce include T-20 sa fie dublu fata de unul fara.
T-20 nu este atat de senzational precum a fost descris in ultimile 12 luni. Din
punct de vedere medical, reprezinta o reusita majora ca acest mecanism de
actiune pentru inhibarea replicarii virale functioneaza intr-adevar. O
combinatie a diferiti inhibitori de intrare, care se spera ca vor actiona sinergic,
atat unul cu celalalt, cat si cu HAART, este foarte probabil sa inhibe
replicarea HIV mai eficient decat HAART clasic.
Inhibitori de integraze
Integraza este una din cele 3 enzime cheie codificate de gena pol a HIV.
Acesta enzima este implicata in integrarea ADN-ului viral in genomul
91
gazda(Nair 2002). Inhibitorii de integraze difera fata de inhibitorii de intrare
prin faptul ca ei nu previn patrunderea virusului in celule. Desi celulele umane
probabil nu au integraze, dezvoltarea unor medicamente noi si eficiente in
cadrul acestei clase se dovedeste a fi dificila, si progresul este lent(Debyser
et al 2002). In ultimii ani au aparut destule medicamente, numai pentru ca sa
dispara la fel de usor.
95
Imunoterapia si importanta ei in practica
In ultimii ani, in plus fata de ART “conventional”, strategiile de tratament
imunologic au fost studiate in amanunt(vezi: Mitsuyasu 2002, Sereti et Lane
2001). Un numar tot mai mare de studii care fac referire la interleukina-2 sau
hidroxiuree, sunt publicate. Tuturor acestor terapii le lipsesc dovezile
beneficiilor/ avantajelor clinice. La unele studii importante se face referire mai
jos.
Interleukina-2
Interleukina 2(IL-2, aldesleukin, Proleukin®) este o citokina care e produsa de
celulele T activate si duce la proliferarea si producerea de citokine de catre
celulele T, B si NK(vezi: Paredes et al 2002). A fost implicata in domeniul
oncologiei de ani intregi: IL-2 era deja folosita la inceputul anilor 90, fie
intravenos sau ca perfuzie continua la pacientii infectati cu HIV(Wood et al
1993). Acum se administreaza de obicei subcutanat.
Cel mai impotant efect al IL-2 in medicina HIV este cresterea numarului
celulelor T CD4+ si CD8+, care in anumite cazuri poate fi destul de
impresionanta(Kovacs et al 1996). Mai multe studii realizate la intamplare au
demonstrat cresteri semnificative al celulelor T CD4+. Dupa administrarea de
IL2, initial creste numarul de celule cu memorie CD45RO+, urmate de
celulele T CD45RA+ tinere. Durata de viata a celulelor T CD4+ si CD8+
poate fi de asemenea mai mare. IL2 este administrata de obicei in doze de
2*4.5milioane subcutanat timp de 5 zile, in cicluri, la intervale de 6-8
saptamani(Davey et al 2000, Losso et al 2000, Abrams et al 2002, Lelezari et
al 2000, Hengge et al 1998). Tratamentul zilnic cu doze reduse a fost de
asemenea studiat(vezi Smith 2001). Dupa 24 pana la 48 saptamani,
cresterea numarului de celule CD4+ era cu 100-250 celule mai mare in
grupul IL2 decat in celalalt. Incarcatura virala de obicei ramanea neafectata
de IL2.
In toate studiile mai mari, combinarea IL2 cu HAART s-a demonstrat pana
acum a fi relativ sigura. Totusi, medicamentul are efecte secundare
96
considerabile; febra, frisoanele si uneori simptomele severe asemanatoare
celor din gripa cu mialgii sunt de obicei cele care limiteaza doza. Efectele
secundare sunt rezultatul eliberarii de citokine indusa de IL2 si se rezolva
invariabil la 2-3 zile dupa ultima doza. Paracetamolul, odihna si administrarea
solutiilor bogate in electroliti ar putea fi de ajutor. Efectele secundare, care
sunt mai severe decat in cazul interferonului, nu pot fi suprimate in intregime.
Unii cercetatori pun in discutie rationamentul tratamentului cu IL2, sustinand
ca ar putea fi doar o incercare a produselor cosmetice de laborator( celulele T
ok, pacient bolnav). In plus, au fost exprimate indoieli cu privire la calitatea
raspunsului imun. Sunt celulele T CD4+ generate de IL2 de aceeasi calitate
ca si limfocitele T CD4+ „normale”, si – mai important – cresterile chiar previn
SIDA? Au pacientii intr-adevar avantaje clinice de pe urma acestor
tratamente cu IL2? Se cunosc de asemenea putine lucruri despre utilizarea
pe termen lung a IL2 – cel mai indelungat studiu realizat pana azi a durat 3
ani(Gougeon et al 2001).
Toate ca toate, IL2 trebuie inca privita cu scepticism pe baza datelor curente.
In opinia noastra, putini pacienti se pot califica pentru terapia cu IL2. Acestia
sunt pacienti lipsiti de raspuns imunologic, pacienti a caror numar de CD4+
ramane mai mic de 100/µl in ciuda supresiei virale bune de-a lungul unor
perioade mai mari de timp.
97
Hidroxiureea (Litalir®)
Hidroxiureea este un agent chemoterapeutic mai vechi, cu toxicitate relativ
redusa, care mai este folosita azi in hematologie ( in principal in leucemia
mielogena cronica). Inhiba sinteza ADN prin intermediul reductazei de
ribonucleotide, si duce la reducerea intracelulara de trifosfat-deoxinucleotide.
A fost demonstrat in anul 1994 un efect sinergic asupra replicarii HIV in
combinatie cu didanozina.
98
In octombrie 1999, BMS a primit o avertizare din partea FDA pentru ca a
promovat cu prea mult entuziasm hidroxiureea pentru terapia
HIV(http://hiv.net/link.php?id=164). Suntem de parere ca hidroxiureea nu ar
trebui folosita in afara studiilor clinice.
Interferonul
Efectul antiretroviral al interferonului este cunoscut de mai multi ani(Milvan
1996). Efectul a 3 milioane U.I. zilnic s.c. este de circa 0,5-1 log (Haas et al
2000). Doze mai mari pot sa determine un efect mai pronuntat(Hatzakis et al
2001). Efectul antiviral al interferonului nu a fost cercetat in amanunt initial,
datorita caii de administrare sc si efectelor sale secundare. Recent, au existat
indicatii ca medicamentul poate fi folositor pentru terapia de recuperare.
Interferonul pegilat( pegilare= proces prin care o substanta denumita
polietilen glicol PEG este atasat unei proteine pentru a extinde activitatea
proteinei; cand este folosit in cazul medicamentelor recomandate pe reteta,
substantele active raman in organism o perioada mai lunga de timp pana
cand sunt dezintegrate si eliminate) permite acum administrarea
saptamanala, si eficacitatea imbunatatita cu medicamentul pegilat este
anticipata in analogie cu studiile legate de infectia cu hepatita C. Schering-
Plough este implicat in prezent in incercarea de a obtine aprobarea pentru
acest produs. Insa, au existat si piedici, ca si in cazul IL-2, si a fost abandonat
un studiu multinational important al pacientilor cu experienta in tratament, in
octombrie 2002, datorita recrutarii insuficiente.
Alte imunoterapii
Prototipul vaccinului terapeutic a inregistrat dezastre cu ani in urma.
Remune®, un vaccin terapeutic format dintr-un virus al carui invelis era
distrus (gp 120), care a fost dezvoltat de o echipa condusa de Jonas Salk,
desi intr-adevar imunogenic, nu pare sa furnizeze vreun beneficiu
clinic(prelungirea vietii si intarzierea progresiei bolii). Un studiu extins a fost
intrerupt prematur in mai 1999, deoarece nu a fost demonstrat la participarea
la studiu nici un avantaj. Mai mult de 2500 pacienti au luat parte in medie timp
de 89 saptamani in acest studiu multinational, care a fost realizat pentru a
evalua adaugarea Remune la HAART. In plus fata de lipsa avantajelor
clinice, nu au putut fi demonstrate nici macar avantaje in ceea ce priveste
numarul de celule CD4+ sau incarcatura virala(Kahn et al 2000). Acest
produs este probabil acum invechit, desi au existat rapoarte indoielnice in
principal din Thailanda, care sustineau existenta anumitor efecte.
Bibliografie
1. Abrams DI, Bebchuk JD, Denning ET, et al. Randomized, open-label
study of the impact of two doses of subcutaneous recombinant interleukin-
2 on viral burden in patients with HIV-1 infection and CD4+ cell
counts of >or=300/mm3: CPCRA 059. J Acquir Immune Defic Syndr
2002, 29: 221-31. http://amedeo.com/lit.php?id=11873071
2. Aladdin H, Ullum H, Katzenstein T, et al. Immunological and virological
changes in antiretroviral naive HIV infected patients randomized to GCSF
or placebo simultaneously with initiation of HAART. Scand J Immunol
2000, 51:520-5. http://amedeo.com/lit.php?id=10792845
3. Angel JB, High K, Rhame F, et al. Phase III study of
granulocytemacrophage
colony-stimulating factor in advanced HIV disease: effect on
infections, CD4 cell counts and HIV suppression. Leukine/HIV Study
Group. AIDS 2000, 14:387-95. http://amedeo.com/lit.php?id=10770541
4. Angel JB, Jacobson MA, Skolnik PR, A multicenter, randomized,
doubleblind,
placebo-controlled trial of recombinant human interleukin-10 in HIVinfected
subjects. AIDS 2000, 14:2503-8.
http://amedeo.com/lit.php?id=11101061
5. Bredt BM, Higuera-Alhino D, Shade SB, et al. Short-term effects of
cannabinoids
on immune phenotype and function in HIV-1-infected patients.
J Clin Pharmacol 2002, 42:82S-89S.
http://amedeo.com/lit.php?id=12412840
6. Brites C, Gilbert MJ, Pedral-Sampaio D, et al. A randomized,
placebocontrolled
trial of granulocyte-macrophage colony-stimulating factor and
nucleoside analogue therapy in AIDS. J Infect Dis 2000, 182: 1531-5.
http://amedeo.com/lit.php?id=11023477
7. Calabrese LH, Lederman MM, Spritzler J, et al. Placebo-controlled trial of
Cyclosporin-A in HIV-1 disease: Implications for solid organ transplantation.
J Acquir Immune Defic Syndr 2002, 29:359-362.
http://amedeo.com/lit.php?id=11917239
8. Chun TW, Engel D, Mizell SB, et al. Effect of interleukin-2 on the pool of
latently infected, resting CD4+ T cells in HIV-1-infected patients receiving
HAART. Nat Med 1999, 5:651-5. http://amedeo.com/lit.php?id=10371503
9. Davey RT JR, Murphy RL, Graziano FM, et al. Immunologic and virologic
effects of subcutaneous interleukin 2 in combination with ART: A randomized
controlled trial. JAMA 2000, 284: 183-9.
http://amedeo.com/lit.php?id=10889591
101
10. Davidson M, Min YI, Holbrook JT, et al. Use of filgrastim as adjuvant
therapy in patients with AIDS-related cytomegalovirus retinitis. AIDS
2002, 16: 757-65. http://amedeo.com/lit.php?id=11964532
11. Dybul M, Hidalgo B, Chun TW, et al. Pilot study of the effects of
intermittent
interleukin-2 on HIV-specific immune responses in patients treated
during recently acquired HIV infection. J Infect Dis 2002; 185: 61-8.
http://amedeo.com/lit.php?id=11756982
12. Emery S, Abrams DI, Cooper DA, et al. The evaluation of subcutaneous
proleukin (interleukin-2) in a randomized international trial: rationale, design,
and methods of ESPRIT. Control Clin Trials 2002; 23:198-220.
http://amedeo.com/lit.php?id=11943448
13. Gougeon ML, Rouzioux C, Liberman I, et al. Immunological and
virological
effects of long term IL-2 therapy in HIV-1-infected patients. AIDS
2001, 15:1729-31. Abstract: http://amedeo.com/lit.php?id=11546950
14. Haas DW, Lavelle J, Nadler JP, et al. A randomized trial of interferon
alpha therapy for HIV type 1 infection. AIDS Res Hum Retrovir 2000,
16:183-90. http://amedeo.com/lit.php?id=10710206
15. Hatzakis A, Gargalianos P, Kiosses V, et al. Low-dose IFN-alpha
monotherapy
in treatment-naive individuals with HIV-1 infection: evidence of
potent suppression of viral replication. J Interferon Cytokine Res 2001,
21:861-9. http://amedeo.com/lit.php?id= 11710999
16. Havlir DV, Gilbert PB, Bennett K, et al. Effects of treatment intensification
with hydroxyurea in HIV-infected patients with virologic suppression.
AIDS 2001; 15: 1379-88. http://amedeo.com/lit.php?id=11504959
17. Hellinger JA, Iwane MK, Smith JJ, et al. A randomized study of the safety
and antiretroviral activity of hydroxyurea combined with didanosine in
persons infected with HIV type 1. J Infect Dis 2000, 181: 540-7.
http://amedeo.com/lit.php?id=10669337
18. Hengge UR, Goos M, Esser S, et al. Randomized, controlled phase II trial
of subcutaneous interleukin-2 in combination with HAART in HIV patients.
AIDS 1998; 12: F225-34. http://amedeo.com/lit.php?id=9863864
19. Jacobson MA, Spritzler J, Landay A, et al. A Phase I, placebo-controlled
trial of multi-dose recombinant human interleukin-12 in patients with HIV
infection. AIDS 2002, 16:1147-54.
http://amedeo.com/lit.php?id=12004273
20. Kahn JO, Cherng DW, Mayer K, Murray H, Lagakos S. Evaluation of HIV-
1 immunogen, an immunologic modifier, administered to patients infected
with HIV having 300 to 549 x 10(6)/L CD4 cell counts: A randomized
controlled trial. JAMA 2000, 284:2193-202.
http://amedeo.com/lit.php?id=11056590
21. Kovacs JA, Vogel S, Albert JM, et al. Controlled trial of interleukin-2
infusions
102
in patients infected with the HIV. N Engl J Med. 1996, 335:1350-6.
http://amedeo.com/lit.php?id=8857018
22. Kuritzkes DR, Parenti D, Ward DJ, et al. Filgrastim prevents severe
neutropenia
and reduces infective morbidity in patients with advanced HIV
infection: results of a randomized, multicenter, controlled trial. AIDS 1998,
12:65-74. http://amedeo.com/lit.php?id=9456256
23. Lafeuillade A, Hittinger G, Chadapaud S, et al. The HYDILE trial: efficacy
and tolerance of a quadruple combination of reverse transcriptase inhibitors
versus the same regimen plus hydroxyurea or hydroxyurea and interleukin-
2 in HIV-infected patients failing PI-based combinations. HIV
Clin Trials 2002, 3:263-71. http:// amedeo.com/lit.php?id=12187499
24. Lalezari JP, Beal JA, Ruane PJ, et al. Low-dose daily subcutaneous
interleukin-
2 in combination with HAART in HIV+ patients: a randomized
controlled trial. HIV Clin Trials 2000, 1:1-15.
http://amedeo.com/lit.php?id=11590500
25. Lisziewicz J, Rosenberg E, Lieberman J, et al. Control of HIV despite the
discontinuation of antiretroviral therapy. N Engl J Med 1999, 340:1683-4.
26. Lori F, Jessen H, Lieberman J, et al. Treatment of HIV infection with
hydroxyurea,
didanosine, and a protease inhibitor before seroconversion is
associated with normalized immune parameters and limited viral reservoir.
J Infect Dis 1999, 180: 1827-32.
http://amedeo.com/lit.php?id=10558937
27. Lori F, Malykh A, Cara A, et al. Hydroxyurea as an inhibitor of HIV-type 1
replication. Science 1994, 266:801-5. http://
amedeo.com/lit.php?id=7973634
28. Losso MH, Belloso WH, Emery S, et al. A randomized, controlled, phase
II trial comparing escalating doses of subcutaneous interleukin-2 plus
antiretrovirals versus antiretrovirals alone in HIV-infected patients with
CD4+ cell counts /=350/mm3. J Infect Dis 2000, 181:1614-21.
http://amedeo.com/lit.php?id=10823761
29. Margolis DM, Kewn S, Coull JJ, et al. The addition of mycophenolate
mofetil to antiretroviral therapy including abacavir is associated with depletion
of intracellular deoxyguanosine triphosphate and a decrease in
plasma HIV-1 RNA. J Acquir Immune Defic Syndr 2002, 31:45-9.
http://amedeo.com/lit.php?id=12352149
30. Mildvan D, Bassiakos Y, Zucker ML, et al. Synergy, activity and
tolerability
of zidovudine and interferon-alpha in patients with symptomatic HIV-1
infection: ACTG 068. Antivir Ther 1996; 1: 77-88.
http://amedeo.com/lit.php?id=11321183
31. Mitsuyasu R. Immune therapy: non-HAART management of HIV-infected
patients. J Infect Dis 2002, 185 (Suppl 2): S115-22.
103
http://amedeo.com/lit.php?id=12001032
32. Moore RD, Keruly JC, Chaisson RE. Incidence of pancreatitis in
HIVinfected
patients receiving nucleoside reverse transcriptase inhibitor
drugs. AIDS 2001, 15:617-20.
33. Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence of neuropathy
in HIV-infected patients on monotherapy versus those on combination
therapy with didanosine, stavudine and hydroxyurea. AIDS 2000, 14:
273-8. http://amedeo.com/lit.php?id=10716503
34. Paredes R, Lopez Benaldo de Quiros JC, Fernandez-Cruz E, Clotet B,
Lane HC. The potential role of interleukin-2 in patients with HIV infection.
AIDS Rev 2002; 4:36-40.
35. Press N, Kimel G, Harris M, et al. Case series assessing the safety of
mycophenolate as part of multidrug rescue treatment regimens. HIV Clin
Trials 2002, 3:17-20. http://amedeo.com/lit.php?id=11819181
36. Rizzardi GP, Harari A, Capiluppi B, et al. Treatment of primary HIV-1
infection with cyclosporin A coupled with HAART. J Clin Invest 2002,
109:681-688. http://amedeo.com/lit.php?id=11877476
37. Rodriguez CG, Vila J, Capurro AF,. Combination therapy with
hydroxyurea
versus without hydroxyurea as first line treatment options for antiretroviral-
naive patients. HIV Clin Trials 2000, 1:1-8.
http://amedeo.com/lit.php?id=11590492
38. Rutschmann OT, Opravil M, Iten A, et al. A placebo-controlled trial of
didanosine plus stavudine, with and without hydroxyurea, for HIV infection.
The Swiss HIV Cohort Study. AIDS 1998, 12: F71-7.
http://amedeo.com/lit.php?id=9631134
39. Rutschmann OT, Opravil M, Iten A, et al. Didanosine plus stavudine with
or without hydroxyurea in HIV-1-infected patients: 1 year follow-up. Antivir
Ther 1998, 3 (Suppl 4): 65-7. http://amedeo.com/lit.php?id=10723515
40. Sereti I, Lane HC. Immunopathogenesis of HIV: implications for
immunebased
therapies. Clin Infect Dis 2001, 32: 1738-55.
http://amedeo.com/lit.php?id=11360217
41. Skowron G, Stein D, Drusano G, et al. The safety and efficacy of
granulocyte-
macrophage colony-stimulating factor (Sargramostim) added to
indinavir- or ritonavir-based antiretroviral therapy: a randomized doubleblind,
placebo-controlled trial. J Infect Dis 1999, 180:1064-71.
http://amedeo.com/lit.php?id=10479132
42. Smith KA. Low-dose daily interleukin-2 immunotherapy: accelerating
immune restoration and expanding HIV-specific T-cell immunity without
toxicity. AIDS 2001, 15 Suppl 2: S28-35..
http://amedeo.com/lit.php?id=11424974
43. Stellbrink HJ, Hufert FT, Tenner-Racz K, et al. Kinetics of productive and
104
latent HIV infection in lymphatic tissue and peripheral blood during triple-
drug combination therapy with or without additional interleukin-2. Antivir
Ther 1998, 3: 209-14. http://amedeo.com/lit.php?id=10682140
44. Stellbrink HJ, van Lunzen J, Westby M, et al. Effects of interleukin-2 plus
highly active antiretroviral therapy on HIV-1 replication and proviral DNA
(COSMIC trial). AIDS 2002, 16:1479-87. http://
amedeo.com/lit.php?id=12131185
45. Wood R, Montoya JG, Kundu SK, Schwartz DH, Merigan TC. Safety and
efficacy of polyethylene glycol-modified interleukin-2 and zidovudine in
HIV type 1 infection: a phase I/II study. J Infect Dis 1993, 167:519-25.
http://amedeo.com/lit.php?id=8095058
46. Zala C, Salomon H, Ochoa C, et al. Higher rate of toxicity with no
increased
efficacy when hydroxyurea is added to a regimen of stavudine
plus didanosine and nevirapine in primary HIV infection. J Acquir Immune
Defic Syndr 2002, 29: 368-73. http://amedeo.com/lit.php?id=11917241
105
3. Obiective si Principii de terapie
Christian Hoffmann
106
Succesul tratamentului virologic este de obicei reprezentat de o scadere a
incarcaturii virale la valori sub nivelul de detectare de 50 copii/ml. Se bazeaza
pe faptul ca, cu cat este mai rapida si completa scaderea incarcaturii virale,
cu atat efectul terapeutic este mai indelungat(Kempf et al 1998, Powderly et
al 1999, Raboud et al 1998). In testul INCAS, riscul relativ de esec al
tratamentuli ( definit aici ca o crestere de >5000 copii/ml), la pacientii care au
atins o incarcatura virala <20 copii/ml era de 20 ori mai scazuta fata de cei
care nu au atins niciodata un nivel mai mic de 400 copii/ml (Raboud et al
1998). In cazul HAART, incarcatura virala descreste in 2 faze (vezi de
asemenea capitolul legat de „Monitorizare”). Exista o descrestere initiala
foarte rapida in primele saptamani, urmata de o faza mai lenta, in care
viremia plasmatica scade lent. O scadere sub nivelul de detectare ar trebui
atinsa in 3-4 luni; in cazurile in care incarcatura virala de baza este foarte
mare, poate dura 4 sau 5 luni. O incarcatura virala peste nivelul de detectare
dupa 6 luni de tratament este in general interpretata ca esec. Acelasi lucru e
valabil daca se confirma fenomenul de „rebound” a incarcaturii virale la o a II-
a determinare, dupa un scurt interval de timp. In asemenea cazuri, ar trebui
luate in considerare imbunatatiri in ceea ce priveste terapia(complianta,
modificari in cadrul regimului).
Blips sunt cresteri tranzitorii ale incarcaturii virale. Ele apar la 20-40% din
pacienti, si s-a demonstrat a fi asociate cu un nivel mai crescut de replicare
virala. Blips adeseori ingrijoreaza atat pacientul cat si medicul. Daca este sa
facem o referire stricta, daca cineva defineste succesul virologic ca fiind <50
copii/ml, blips semnifica esecul tratamentului. Insa, tot mai multe date indica
faptul ca blips par sa nu aiba consecinte pe termen mediu, si nu indica
neaparat esecul imunologic sau nici macar clinic (Havlir et al 2001, Moore et
al 2002, Sklar et al 2002). Acest lucru este valabil atat pentru pacientii aflati in
terapie "first-line" cat si pentru pacientii cu experienta bogata legata de
tratament. Insa, urmarirea mai indelungata este inca necesara pentru a
exclude posibilitatea ca pacientii cu blips ocazionale sa fie mai expusi riscului
108
de dezvoltare a rezistentei. In cel putin o analiza recenta, riscul de esec a
tratamentului dupa 18 luni era aproximativ dublu (Greub et al 2002). Conform
datelor care sunt disponibile in prezent, blips nu ar trebui sa necesite o
schimbare imediata a terapiei. Ele pot si ar trebui, in orice caz, sa creasca
sansele de dialog cu pacientul in ceea ce priveste complianta. Ar trebui
remarcat ca incarcatura virala ar putea de asemenea sa creasca temporar
dupa imunizare (Kolber et al 2002).
Raspuns discordant
_____________________________________________________________
* Raspunsul imunologic: cresteri ale numarului de celule T CD4+ >100/µl
dupa 30 luni (Piketty et al 2001) sau >50/µl dupa 6 luni (Grabar et al 2000).
Raspunsul virologic: continuu cel putin 1 log sub valoarea de baza sau
<500copii/ml (Piketty et al 2001), sau <1000 copii/ml (Grabar et al 2000).
Succesul clinic este aproape intotdeauna evaluat via rezultate clinice (boli
specifice SIDA, moarte), desi imbunatatirea HAART la un pacient cu
simptome constitutionale considerabile ar trebui de asemenea interpretata
drept succes clinic. Cu privire la riscul de progresie a bolii, raspunsul
imunologic este cel putin la fel de important ca si cel virologic(Tabelul 3.2).
Esecul clinic este de obicei definit prin dezvoltarea unei boli asociate SIDA
sau evolutie letala. Insa, imbolnavirea nu este intotdeauna capabila sa indice
esecul clinic al tratamentului. Un exemplu bun este reprezentat de sindromul
de reconstituire imuna, in care o infectie pre-existenta, subclinica, devine
aparenta pe parcursul primelor saptamani dupa initierea terapiei
antiretrovirale. Pe de alta parte, daca un pacient prezinta efecte secundare
grave sau chiar moare ca urmare a acestora, acest lucru ar trebui de
asemenea interpretat ca esec al tratamentului.
Tabelul 3.3: Caz clinic (femeie, 41 ani) prezinta progrese in tratament datorita
HAART*
112
Iun 97 Oprirea HAART datorita polineuropatiei
Iulie AZT+3TC+IDV 17(4%) 141.000
97
Mar 147(22%) <50
98
Mar AZT+3TC+IDV+NVP 558(24%) 100
99
Mar 942(31%) <50
00
Mar 1132(33%) <50
02
SILCAAT, un studiu extins realizat in mai multe centre, care a “inrolat” in jur
de 2.000 pacienti cu mai putin de 300 celule T CD4+/µl a fost definitivat in
octombrie 2002, datorita faptului ca numarul rezultatelor clinice atins era prea
scazut pentru a permite detectarea adecvata a oricarei diferente.
*MAC, PCP, CMV. Mortalitate/ morbiditate fiecare pentru 100py (pacienti an)
Bibliografie
1. Cameron DW, Heath-Chiozzi M, Danner S, et al. Randomised
placebocontrolled
trial of ritonavir in advanced HIV-1 disease. The Advanced HIV
Disease Ritonavir Study Group. Lancet 1998, 351:543-9.
http://amedeo.com/lit.php?id=9492772
2. Cozzi Lepri A, Phillips AN, d'Arminio Monforte A, et al. When to start
HAART in chronically HIV-infected patients: evidence from the ICONA
study. AIDS 2001, 15:983-90. http://amedeo.com/lit.php?id=11399980
3. Deeks SG, Barbour JD, Grant RM, Martin JN. Duration and predictors of
CD4 T-cell gains in patients who continue combination therapy despite
detectable plasma viremia. AIDS 2002, 16: 201-7.
http://amedeo.com/lit.php?id=11807304
4. Deeks SG. Determinants of virological response to antiretroviral therapy:
implications for long-term strategies. Clin Infect Dis 2000, 30 Suppl 2:
S177-84. http://amedeo.com/lit.php?id=10860903
5. Freedberg KA, Losina E, Weinstein MC, et al. The cost effectiveness of
combination antiretroviral therapy for HIV disease. N Engl J Med 2001,
344:824-31. http://amedeo.com/lit.php?id=11248160
6. Goetz MB, Boscardin WJ, Wiley D, Alkasspooles S. Decreased recovery
of CD4 lymphocytes in older HIV-infected patients beginning HAART.
AIDS 2001, 15:1576-9. http://amedeo.com/lit.php?id=11504992
114
7. Grabar S, Le Moing V, Goujard C, et al. Clinical outcome of patients with
HIV-1 infection according to immunologic and virologic response after 6
months of HAART. Ann Intern Med 2000, 133: 401-10.
http://amedeo.com/lit.php?id=10975957
8. Greub G, Cozzi-Lepri A, Ledergerber B, et al. Intermittent and sustained
low-level HIV viral rebound in patients receiving potent antiretroviral therapy.
AIDS 2002, 16:1967-9.
9. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two
nucleoside analogues plus indinavir in persons with HIV infection and
CD4 cell counts of 200 per cubic millimeter or less. ACTG 320 Study
Team. N Engl J Med 1997, 337:725-33.
http://amedeo.com/lit.php?id=9287227
10. Havlir DV, Bassett R, Levitan D, et al. Prevalence and predictive value of
intermittent viremia with combination HIV therapy. JAMA 2001, 286:171-
9. http://amedeo.com/lit.php?id=11448280
11. Hosseinipur M, Cohen MS, Vernazza PL, Kashuba AD. Can antiretroviral
therapy be used to prevent sexual transmission of HIV type 1? Clin Infect
Dis 2002, 34: 1391-5. http://amedeo.com/lit.php?id=11981736
12. Kaufmann D, Pantaleo G, Sudre P, Telenti A. CD4-cell count in HIV-1-
infected individuals remaining viraemic with HAART. Swiss HIV Cohort
Study. Lancet 1998, 351:723-4.
13. Kaufmann G, Perrin L, Pantaleo G. CD4 T-lymphocyte recovery in
individuals
with advanced HIV-1 infection receiving potent antiretroviral therapy
for 4 years: The Swiss HIV Cohort Study. Abstract LB4, 9th CROI
2002, Seattle, USA.
http://www.retroconference.org//2002/Abstract/14064.htm
14. Kempf DJ, Rode RA, Xu Y, et al. The duration of viral suppression during
protease inhibitor therapy for HIV-1 infection is predicted by plasma HIV-
1 RNA at the nadir. AIDS 1998, 12: F9-14.
http://amedeo.com/lit.php?id=9543434
15. Kolber MA, Gabr AH, De La Rosa A, et al. Genotypic analysis of plasma
HIV-1 RNA after influenza vaccination of patients with previously
undetectable
viral loads. AIDS 2002, 16: 537-42.
http://amedeo.com/lit.php?id=11872996
16. Kotler DP, Shimada T, Snow G, et al. Effect of combination antiretroviral
therapy upon rectal mucosal HIV RNA burden and mononuclear cell
apoptosis. AIDS 1998, 12:597-604.
http://amedeo.com/lit.php?id=9583599
17. Le Moing V, Chene G, Carrieri MP, et al. Predictors of virological rebound
in HIV-1-infected patients initiating a protease inhibitor-containing regimen.
AIDS 2002, 16:21-9. http://amedeo.com/lit.php?id=11741159
18. Le Moing V, Thiebaut R, Chene G, et al. Predictors of long-term increase
in CD4(+) cell counts in HIV-infected patients receiving a protease inhibitor-
115
containing antiretroviral regimen. J Infect Dis 2002, 185: 471-80.
http://amedeo.com/lit.php?id=11865399
Ledergerber B, Egger M, Erard V, et al. AIDS-related opportunistic illnesses
occurring after initiation of potent antiretroviral therapy: the Swiss
HIV Cohort Study. JAMA 1999, 282: 2220-6.
http://amedeo.com/lit.php?id=1060597
19. Ledergerber B, Egger M, Opravil M. et al. Clinical progression and
virological
failure on HAART in HIV-1 patients: a prospective cohort study.
Lancet 1999, 353: 863 –868.
20. Lederman MM, McKinnis R, Kelleher D, et al. Cellular restoration in HIV
infected persons treated with abacavir and a protease inhibitor: age inversely
predicts naive CD4 cell count increase. AIDS 2000, 14: 2635-42.
http://amedeo.com/lit.php?id=11125881
21. Liuzzi G, Chirianni A, Bagnarelli P, et al. A combination of nucleoside
analogues and a protease inhibitor reduces HIV-1 RNA levels in semen:
implications for sexual transmission of HIV infection. Antivir Ther 1999,
4:95-9. http://amedeo.com/lit.php?id=10682154
22. Marimoutou C, Chene G, Mercie P, et al. Prognostic factors of combined
viral load and CD4+ cell count responses under triple antiretroviral therapy,
Aquitaine cohort, 1996-1998. J Acquir Immune Defic Syndr 2001,
27:161-7. http://amedeo.com/lit.php?id=11404538
23. Mezzaroma I, Carlesimo M, Pinter E, et al. Clinical and immunologic
response without decrease in virus load in patients with AIDS after 24
months of HAART. Clin Infect Dis 1999, 29:1423-30.
http://amedeo.com/lit.php?id=10585790
24. Mocroft A, Katlama C, Johnson AM, et al. AIDS across Europe, 1994-98:
the EuroSIDA study. Lancet 2000, 356:291-6.
http://amedeo.com/lit.php?id=11071184
25. Mocroft A, Brettle R, Kirk O, et al. Changes in the cause of death among
HIV positive subjects across Europe: results from the EuroSIDA study.
AIDS 2002, 16:1663-71. http://amedeo.com/lit.php?id= 12172088
26. Moore AL, Youle M, Lipman M, et al. Raised viral load in patients with
viral suppression on HAART: transient increase or treatment failure?
AIDS 2002, 16:615-8. http://amedeo.com/lit.php?id=11873005
27. Palella FJ JR, Delaney KM, Moorman AC, et al. Declining morbidity and
mortality among patients with advanced HIV infection. N Engl J Med
1998, 338:853-60. http://amedeo.com/lit.php?id=9516219
28. Phillips AN, Miller V, Sabin C, et al. Durability of HIV-1 viral suppression
over 3.3 years with multi-drug antiretroviral therapy in previously drugnaive
individuals. AIDS 2001, 15: 2379-84.
http://amedeo.com/lit.php?id=11740188
29. Phillips AN, Staszewski S, Weber R, et al. HIV viral load response to ART
according to the baseline CD4 cell count and viral load. JAMA 2001,
286:2560-7. http://amedeo.com/lit.php?id=11722270
116
30. Piketty C, Castiel P, Belec L, et al. Discrepant responses to triple
combination
antiretroviral therapy in advanced HIV disease. AIDS 1998,
12:745-50. http://amedeo.com/lit.php?id=9619806
31. Piketty C, Weiss L, Thomas F, et al. Long-term clinical outcome of
HIVinfected
patients with discordant immunologic and virologic responses to
a protease inhibitor-containing regimen. J Infect Dis 2001, 183:1328-35.
http://amedeo.com/lit.php?id=11294663
32. Powderly WG, Saag MS, Chapman S, et al. Predictors of optimal
virological
response to potent ART. AIDS 1999, 13:1873-80.
http://amedeo.com/lit.php?id=10513645
33. Raboud JM, Montaner JS, Conway B, et al. Suppression of plasma viral
load below 20 copies/ml is required to achieve a long-term response to
therapy. AIDS 1998, 12: 1619-24. http://amedeo.com/lit.php?id=9764780
34. Raboud JM, Rae S, Vella S, et al. Meta-analysis of two randomized
controlled
trials comparing combined zidovudine and didanosine therapy with
combined zidovudine, didanosine, and nevirapine therapy in patients with
HIV. J Acquir Immune Defic Syndr 1999, 22:260-6.
http://amedeo.com/lit.php?id=10770346
35. Raffi F, Chene G, Lassalle R, et al. Progression to AIDS or death as
endpoints
in HIV clinical trials. HIV Clin Trials 2001, 2:330-5.
http://amedeo.com/lit.php?id=11590536
36. Renaud M, Katlama C, Mallet A, et al. Determinants of paradoxical CD4
cell reconstitution after protease inhibitor-containing antiretroviral regimen.
AIDS 1999, 13:669-76. http://amedeo.com/lit.php?id=10397561
37. Salzberger B, Rockstroh J, Wieland U, et al. Clinical efficacy of protease
inhibitor based antiretroviral combination therapy--a prospective cohort
study. Eur J Med Res 1999, 4:449-55.
http://amedeo.com/lit.php?id=10585299
38. Sendi PP, Bucher HC, Harr T, et al. Cost effectiveness of HAART in
HIVinfected
patients. Swiss HIV Cohort Study. AIDS 1999, 13:1115-22.
http://amedeo.com/lit.php?id=10397543
39. Sklar PA, Ward DJ, Baker RK, et al. Prevalence and clinical correlates of
HIV viremia ('blips') in patients with previous suppression below the limits
of quantification. AIDS 2002, 16:2035-41.
http://amedeo.com/lit.php?id=12370502
40. Stellbrink HJ, Hawkins DA, Clumeck N, et al. Randomised, multicentre
phase III study of saquinavir plus zidovudine plus zalcitabine in previously
untreated or minimally pretreated HIV-infected patients. Clin Drug Invest
2000, 20:295-307.
117
41. Teixeira L, Valdez H, McCune JM, et al. Poor CD4 T cell restoration after
suppression of HIV-1 replication may reflect lower thymic function. AIDS
2001, 15:1749-56. http://amedeo.com/lit.php?id=11579235
42. Thiebaut R, Morlat P, Jacqmin-Gadda H, et al. Clinical progression of
HIV-1 infection according to the viral response during the first year of
antiretroviral treatment. Groupe d'Epidemiologie du SIDA en Aquitaine
(GECSA). AIDS 2000, 14:971-8. http://amedeo.com/lit.php?id=10853978
43. Valdez H, Connick E, Smith KY, et al. Limited immune restoration after 3
years' suppression of HIV-1 replication in patients with moderately advanced
disease. AIDS 2002, 16:1859-66.
http://amedeo.com/lit.php?id=12351945
44. Viard JP, Mocroft A, Chiesi A, et al. Influence of age on CD4 cell recovery
in HIV-infected patients receiving highly active antiretroviral therapy: evi
dence from the EuroSIDA study. J Infect Dis 2001, 183: 1290-4.
http://amedeo.com/lit.php?id=11262215
118
Eradicarea – Este posibila?
In acest moment, eradicarea HIV in sensul unei vindecari nu este realista.
Desi chiar din 1997, multi inca mai visau la eradicare, cercetatori de renume
inclina acum inspre pesimism. Problema tine de prezenta celulelor T CD4+
infectate latent, care reprezinta probabil un rezervor pe viata. Timpul de
injumatatire al acestui rezervor este 44 luni, si conform estimarilor recente,
eradicarea ar putea dura 60-73 ani (Finzi et al 1999). Chiar dupa ani de
supresie virala suficienta pana la sub 20-50 copii/ml, transcriptia virala
celulara inca se mai realizeaza (Dornadulla et al 1999, Furtado et al 1999,
Zhang et al 1999, Sharkey et al 2000). Acest lucru este valabil in particular
pentru celulele sangvine, dar se aplica de asemenea in cazul nodulilor
limfatici si spermei (Lafeuillade et al 2001, Nunnari et al 2002). Metode
diferite au fost folosite pentru a incerca sa distruga aceste rezervoare latente
(IL-2, hidroxiureea, OKT), dar toate au dat gres (Kulkowsky et al 2002,
Pomerantz et al 2002). La ultima Conferinta Globala SIDA, Bob Siliciano a
prezentat o imagine sumbra a situatiei (Siliciano 2002: eradicarea nu e
posibila in conditiile medicamentelor existente in prezent. Rezervoarele nu
pot fi eliminate. Celulele infectate latent difera fata de celulele neinfectate
printr-un singur detaliu, care este greu de detectat folosind metodele curente
si nu poate fi tintit specific. Distrugerea acestor rezervoare sau doar completa
eliminare a celulelor cu memorie este fie lipsita de success, prea toxica sau
mult prea periculoasa. Sa speram ca viitoare capitole vor putea fi dedicate
acestui subiect.
Reducerea costurilor
Terapiile antiretrovirale sunt scumpe. Medicamentele care se administreaza
singure au costuri cuprinse intre 250-1.000$ pe luna, in functie de
medicament si de tara in care e prescris. Chiar si in cazul claselor de
medicamente, exista diferente uimitoare. In unele tari, Crixivan este relativ
ieftin, la aproximativ ½ din pretul Agenerazei. Un regim combinat cu trizivir si
Kaletra ajunge pana la cel putin 2.000$ pe luna. Este important prin urmare
sa cunoastem costurile si problemele legate de pret ale unor companii
farmaceutice. De exemplu, de ce Inviraza stimulata costa de aproape doua
ori mai mult decat Fortovaza stimulata in Germania?
119
In ciuda acestor costuri ridicate, efectul pozitiv al HAART ramane
neindoielnic. Aproximari pe care se poate pune baza au apreciat cheltuielile
ca fiind cuprinse intre 13.000$ si 23.000$ per QUALY aditional ( an de viata
cu calitate ajustata; Fredberg et al 2001) – relativ ieftin in comparatie cu multe
alte terapii HAART poate evita tratamentele scumpe ale infectiilor oportuniste,
costuri de internare sau asistenta a pacientului. Intr-un studiu german, intre
1997-2001, cheltuielile totale anuale per pacient au scazut de la 35.865 euro
la 24.482 euro (Stoll et al 2002). Multi pacienti sunt capabili sa-si reia
activitatea (serviciul), care duce la o reducere economica totala a costurilor
(Sendi et al 1999).
Din moment ce HAART este scump, cand tratamentul este modificat, fie
pentru a reduce cat de cat povara medicamentatiei sau datorita ingrijorarii
legate de toxicitatea pe termen lung, este justificata cererea adresata
pacientului de a utiliza intai stocurile existente. Pacientii cu asigurare privata,
apreciaza acest lucru, dar chiar si pacientii care au o asigurare de sanatate
de stat ar trebui constientizati asupra costurilor medicamentelor – nu pentru a
cauza sentimente de vinovatie, sau pentru a transfera lipsurile sistemului
sanitar pacientului, ci mai degraba sa creeze un grad de constientizare a
valorii acestui tratament. Initial, numai o cutie de tablete ar trebui prescrisa,
chiar daca, de exemplu, o cutie de Retrovir prescrisa in doza standard – la 15
ani dupa aprobare! – este de ajuns numai pentru 20 zile. Numai prin aceasta
modalitate de abordare, putem sa impiedicam aparitia intolerantei la un
pacient care ramane cu mai multe medicamente. Ar trebui evitata prescrierea
medicamentelor pe mai mult de 3 luni.
Preventie
Cu cat mai redusa e incarcatura virala, cu atat gradul de infectiozitate al
pacientului e mai mic. Un studiu de prospectare a 415 cupluri HIV-
discordante din Uganda au aratat ca din 90 de noi infectii pe o perioada de
pana la 30 luni, nici una nu a aparut de la un partener infectat cu o
incarcatura virala sub 1.500 copii/ml. riscul de infectare a crescut cu fiecare
log de incarcatura virala cu un factor de 2,45 (Quinn et al 2000). Intr-un studiu
din Tailanda a 493 pacienti, acest factor era 1,81 – si aici nu a fost inregistrat
nici un caz de infectie sub 1094 copii/ml (Tovanabutra 2002). In aceste limite,
HAART poate astfel sa serveasca drept o masura de prevenire (Hosseinipur
et al 2002).
120
pare a fi adevarat pentru mucoasa vaginala si anorectala, riscul individual
ramane dificil de aproximat (Lampinen et al 2000, Cu-Uvin et al 2000). Mai
mult, nivelul incarcaturii virale din sange si alte fluide corporale nu sunt
corelate intotdeauna unele cu celelalte ( vezi de asemenea capitolul legat de
“Monitorizare”).
122
Daca complianta ramane scazuta
In ciuda tuturor eforturilor noastre, unii pacienti nu vor putea sa-si
imbunatateasca complianta. Medicii si alti furnizori de servicii de sanatate,
sunt sfatuiti sa nu ia acest fapt personal, sau sa se simta jigniti daca un
pacient nu doreste sa participe la progresele medicinei. Desi este dificil sa
acceptam perspectiva/ opiniile celorlalti legate de viata, toleranta si
acceptarea ar trebui sa ramana fundamentale pentru interactiunile
personalului medical cu pacientii lor. Unii medici, in special cei care trateaza
populatii selective de pacienti in cadrul universitar, uneori uita de realitatea
reprezentata de practica medicala de rutina. Sustinerea cu tarie a principiilor
medicinei moderne de obicei nu ajuta in acest caz, si presiunea exercitata
asupra pacientilor realizeaza chiar mai putin.
Duesbergians
Un caz special este reprezentat de pacientii care refuza terapia
antiretrovirala in totalitate din principiu. Acesti pacienti sunt deseori tratati
de medici care se autointituleaza “duesbergians” (dupa Peter Duesberg,
un virolog din SUA, care nu recunoaste legatura dintre HIV si SIDA). Este
stresant sa stai deoparte si sa privesti cum acesti pacienti se indreapta cu
rapiditate spre prapastie. Consilierea ar trebui sa se faca detaliat, si sa fie
insotita de documentatie scrisa cand este posibil. Iata un exemplu din
practica curenta in 2001:
Din fericire, asemenea cazuri sunt mai putin frecvente astazi. Scepticismul
initial cu privire la HAART a scazut semnificativ in lumina succeselor
coplesitoare din ultimii ani. Si, exista (slava Domnului) acum mai putina
publicitate legata de Peter Duesberg, cel putin in ceea ce priveste
respectul fata de activitatea HIV. Acest sector se micsoreaza.
127
4. Cand sa initiem HAART
Christian Hoffmann
Oricum, cel mai bun moment pentru initierea terapiei este supus unor
dezbateri controversate. Riscul SIDA trebuie evaluat comparativ cu
toxicitatea pe termen lung si rezistenta. Dupa „loveste cu putere si devreme”
din 1996, care recomanda terapia din primele stadii ale infectiei, multi medici
au devenit intre timp mai ezitanti. Procuparile legate de toxicitatea pe termen
lung si de realizarea eradicarii ce nu poate fi realizata in viitorul apropiat, au
dus la criterii rigide (U.S: Yeni et al 2002, British guidelines: HIVA 2001,
http://www.bhiva.org/guidelines .pdf).
128
daca este disponibila
Infectie HIV Numarul CD4 >350 Amanarea tratamentului
asimptomatica stabilita celule/ µl si orice
incarcatura virala
Numarul CD4 200-350 Incepeti tratamentul in
cel/ µl acestelimite, tinand cont
de rata de declin a CD4,
simptome, dorintele
pacientului si
incarcatura virala
Numarul CD4 <200 cel/ Trateaza
µl si orice incarcatura
virala
Afectiuni Trateaza
grave/recurente
asociate HIV sau SIDA
130
urgenta)
Oct 97 Pacientul refuza 402(33) 29.500
HAART
(recomdat de
urgenta)
Oct 98 Pacientul refuza 440(30) 13.000
HAART
(recomdat de
urgenta)
Oct 99 Pacientul refuza 393(29) 13.500
HAART
(recomdat de
urgenta)
Oct 00 Pacientul refuza 520(30) 12.500
HAART
(recomandat)
Iun 02 Medicul nu 521(29) 7.440
doreste sa
inceapa HAART
NA= nedisponibile
131
Este raspunsul virologic mai putin durabil in cazul unui numar
redus de celule CD4+ si a unei incarcaturi virale crescute?
La prima vedere, multe grupuri de studiu au demonstrat ca raspunsul
virologic este mai scazut daca numarul de CD4+ la inceputul tratamentului
era redus si incarcatura virala era crescuta (Casado et al 1998, Mocroft et al
1998 si 2000, Miller et al 1999, Wit et al 1999, Deeks et al 1999, Chaisson et
al 2000, Grabar et al 2000, Le Moing et al 2000, Yamashita et al 2001,
Skowron et al 2001). Ar putea parea simplu: cu cat incarcatura virala e mai
mare, si numarul de celule CD4+ e mai mic, cu atat HAART are un succes
virologic mai redus. Cei care sustineau initierea de timpuriu a HAART citeaza
frecvent aceste date. Ei trec cu vederea 3 puncte importante:
In primul rand, acest lucru nu e valabil in cazul celor 2 grupuri mari in care au
fost observati/studiati numai pacienti care abia incepeau tratamentul (Cozzi
Lepri et al 2001, Phillips et al 2001). Acestea ne confirma observatiile noastre
ca, chiar si un pacient care abia a inceput tratamentul cu o incarcatura virala
ridicata si un numar redus de CD4+ are sanse de realizare a unei supresii a
incarcaturii virale suficiente si pe termen lung. In aceste conditii, valorile de
laborator initiale sunt mai putin importante – daca pacientul se conformeaza!
Chiar si in grupul francez APROCO, in care au existat diferente mai mari intre
pacientii care abia incepeau tratamentul si cei deja experimentati (Le Moing
et al 2002), pacientii care incepeau tratamentul cu o incarcatura virala ridicata
prezentau in cel mai bun caz o tendinta negativa nesemnificativa. Acea
incarcatura virala si numarul de CD4+ aveau valori predictive in toate studiile
de grup in cadrul carora majoritatea pacientilor (pana la 91%) inclusi era de
obicei pre-tratati cu NRTI, indica un lucru: la pacientii cu terapie prelungita
(terapie mono sau duala), succesul virologic al HAART ar putea fi compromis.
Terapia anterioara cu analogi nucleozidici a reprezentat un factor de risc
pentru esecul tratamentului virologic in multe grupuri (Casado et al 1998,
Deeks et al 1999, Chaisson et al 2000, Grabar et al 2000, Le MOing et al
2002). Din moment ce acum, din fericire, mai sunt foarte putini pacienti care
urmeaza monoterapie sau terapie duala, care trebuie sa treaca la HAART,
este justificat sa ne concentram exclusiv asupra pacientilor care incep
tratamentul.
In al doilea rand, riscul relativ de esec virologic era deseori crescut numai la
pacientii cu imunosupresie substantiala (<50-100 celule CD4+/µl) sau
incarcatura virala foarte mare (>100.000 copii/ml). La nivele mai mari de 200
celule CD4+/µl sau o incarcatura virala sub 100.000copii/ml, in mod normal
nu ar trebui observate diferente (vezi mai jos).
In al treilea rand, nu stiu daca vreunul din aceste studii au luat in considerare
complianta. Un pacient care incepe HAART in conditii de urgenta cu 30 celule
CD4+/µl (si care se presupune ca a mers la medic cu putin timp inainte sau
chiar dupa manifestarea clinica a SIDA) poate avea o idee diferita legata de
132
boala si sanatate si poate sa fie mai putin binevoitor decat cineva care cauta
un sfat, cu un numar bun de CD4+ si care incepe HAART dupa o reflectie
amanuntita. Aderenta reprezenta un indicator important in unul din putinele
studii in care a fost inclus (Le Moing et al 2002).
133
2001, Sterling et al 2001, Egger et al 2002). In special pacientii cu un numar
foarte redus de celule CD4+ (<50/ µl) continua sa fie expusi unui risc crescut
de SIDA (Hogg et al 2000). In alte grupuri, riscul continua sa fie crescut chiar
si sub un numar de CD4+ de 200 celule/ µl(Phillips et al 2001, Sterling et al
2001). Un grup italian a aratat ca riscul crescut de evolutie clinica era asociat
cu un numar de CD4+ care nu crestea si care ramanea sub 50 celule CD4+/
µl (Cozzi Lepri et al 2001).
Cel mai extins studiu pana acum legat de acest subiect a fost publicat in 2002
de ART Cohort Collaboration. Aici, cateva grupuri au fost alese , si aproape
13.000 pacienti care urmau HAART au fost analizati. Datele pareau clare
(Egger et al 2002). Nivele de baza CD4+ erau corelate in principal cu
probabilitatea de SIDA sau moarte. Comparat cu pacientii care au inceput
HAART avand sub 50 celule CD4+/ µl, riscurile erau semnificativ mai reduse
la pacientii cu nivele crescute de celule T helper (vezi tabelul de mai jos).
Tabelul 4.3: Riscul evolutiei in ART Cohort Collaboration (Egger et al 2002)
Insa, chiar si in aceste conditii, riscul SIDA dupa initierea HAART este doar
usor crescut. Intr-o analiza a pacientilor care abia au inceput tratamentul din
aceste 3 grupuri de studiu europene – grupul elvetian, grupul Frankfurt Clinic
si EuroSIDA – la pacientii cu mai putin de 200 celule CD4+/ µl la inceputul
tratamentului, au fost inregistrate 8,3 noi diagnosticari SIDA la 100 pacienti
134
ani; daca celulele CD4+ >350/ µl, incidenta era 1,8/100 pacienti ani. Ratele
mortalitatii erau de 2,9 versus 0,7/100 pacienti ani.
Sub 200 celule CD4+/ µl, riscul de infectii severe creste cu timpul, si initierea
rapida a HAART devine o urgenta. Dar, chiar si in astfel de cazuri, este vorba
mai mult de saptamani decat de zile. In prezent incepem profilaxia PCP la
pacientii care se prezinta pentru prima oara cu <200 celule CD4+/ µl. Primele
2-3 saptamani sunt folosite pentru procedurile de diagnostic (fundoscopie,
radiografii toracice, ultrasunete), si pentru a realiza consiliere cu caracter
informativ. Se ia de asemenea in considerare daca pacientul ar putea fi un
candidat pentru incadrarea intr-un studiu clinic si incercam sa obtinem o
impresie legata de statutul psihosocial al persoanelor (vezi capitolul 5).
HAART este inceput numai daca aceste probleme au fost rezolvate.
136
deveni disponibile combinatii cu o tolerabilitate mai buna pe termen lung.
Evaluarea indicatiilor de tratament trebuie din aceasta cauza re-examinata in
mod continuu in lumina noilor schimbari.
137
Indicatii practice pentru initierea terapiei la pacientii
asimptomatici
Sub 200 celule CD4+/µl, tratamentul ar trebui inceput cat mai devreme.
Insa, chiar si aici, ar trebui asigurat timpul necesar pentru a cunoaste
pacientul, de a furniza consiliere corespunzatoare si mai intai de a
incepe cu profilaxia sau procedurile de diagnostic (fundoscopie!) – nu
este vorba de obicei de inceperea tratamentului in decursul numai a
cateva zile!
Peste 200 celule CD4+/µl, mai este timp – istoricul individual al
pacientului trebuie luat in considerare.
O scadere de mai mult de 80-100 CD4+/µl pe an este prea mult! Nu
amanati prea mult!
Exista o variabilitate considerabila a valorilor de laborator. Din aceasta
cauza, o singura determinare a numarului CD4+ (mai ales cand
valoarea este intre 200-350/µl, ar trebui intotdeauna repetata inainte de
a incepe tratamentul.
Peste 350 celule CD4+/µl: Asteptati. Monitorizati cel putin la fiecare 3
luni.
Cu cat incarcatura virala este mai mare, cu atat mai frecvente ar trebui
sa fie determinarile CD4+: la o incarcatura virala > 50.000 copii/ml
controalele ar trebui realizate cel putin o data la fiecare 2 luni.
Initierea tratamentului ar putea fi justificata la nivele peste 350 celule
CD4+/µl – daca incarcatura virala este foarte crescuta, nivelul CD4+
scade rapid sau pacientul o cere (dupa o consiliere atenta).
Verificati inainte de termen daca un pacient ar putea fi potrivit pentru
incadrarea intr-un studiu clinic.
• “Cu cat numarul de CD4+ este mai scazut, cu atat mai mult pacientul
va fi supus riscurilor mai tarziu”.
(Contra: Aceasta afirmatie se aplica in principal pacientilor cu
imunosupresie substantiala la care problema initierii terapiei nu este
dezbatuta. Cu cat incepe mai devreme, cu atat vor apare mai multe
reactii toxice pe termen lung!).
• “Un numar mai scazut CD4+ implica de multe ori faptul ca este
posibil un success imunologic – virologic moderat – intr-un anumit
moment, distrugerea sistemului imun este ireversibila!”.
138
(Contra: Acest lucru este adevarat in principal pentru pacientii cu
imunosupresie substantiala. In orice caz, raspunsul virologic nu pare sa
fie redus la pacientii care abia au inceput tratamentul).
• “Cu cat se asteapta mai mult, cu atat virusul devine mai potrivit via
generatia de quasispecii si variantele de “scapare” imuna, si cu atat
mai dificil este de tratat”.
(Contra: Ipoteza de laborator interesanta. Dar, unde sunt datele clinice
relevante?)
• “HIV ar trebui tratata cat mai devreme posibil, ca orice alte boala
infectioasa”.
(Contra: HIV nu este asemenea oricarei alte boli infectioase. HIV nu
poate fi vindecata ca orice alta infectie bacteriana. Virusurile Herpes,
pentru care nu exista tratament, sunt tratate de asemenea dupa cum e
nevoie).
139
(Contra: Ar putea fi adevarat pentru anumiti pacienti, dar nu pentru toti.
Exista indicii ca raspunsul calitativ ramane afectat).
• “Nu e niciodata prea tarziu pentru a incepe terapia la valori ale CD4+
cuprinse intre 200-350”.
(Contra: Cine poate fi sigur? Unele boli asociate cu SIDA pot sa apara
destul de rar chiar si in acest caz; nu exista nici o certitudine ca PML
sau limfomul nu vor aparea, si in caz ca apar, sfaturile bune sunt greu
de gasit).
Bibliografie:
1. BHIVA Writing Committee, BHIVA Executive Committee. British HIV
Association
(BHIVA) guidelines for the treatment of HIV-infected adults with
antiretroviral therapy. HIV Med 2001, 2:276-313.
2. Casado JL, Perez-Elias MJ, Antela A, et al. Predictors of long-term
respones
to protease inhibitor therapy in a cohort of HIV-infected patients.
AIDS. 1998, 12:F131-F135. http://amedeo.com/lit.php?id=9708403
3. Chaisson RE, Keruly JC, Moore RD. Association of initial CD4 cell count
and viral load with response to HAART. JAMA 2000, 284:3128–29.
Originalarbeit:
http://jama.ama-assn.org/issues/v284n24/ffull/jlt1227-
6.html#rc1r5
4. Cozzi Lepri A, Phillips AN, d'Arminio Monforte A, et al. When to start
HAART in chronically HIV-infected patients: evidence from the ICONA
study. AIDS 2001, 15:983-90. http://amedeo.com/lit.php?id=11399980
5. Deeks SG, Hecht FM, Swanson M, et al. HIV RNA and CD4 cell count
response to protease inhibitor therapy in an urban AIDS clinic: response
to both initial and salvage therapy. AIDS 1999, 13:F35-43.
http://amedeo.com/lit.php?id=10397555
6. Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients
starting HAART: a collaborative analysis of prospective studies. Lancet
2002, 360:119-29. http://amedeo.com/lit.php?id=12126821
7. Gorochov G, Neumann AU, Kereveur A, Parizot C, Li T, Katlama C et al.
Perturbation of CD4+ and CD8+ T-cell repertoires during progression to
AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nat
Med 1998, 4: 215-21. http://amedeo.com/lit.php?id=9461196
8. Grabar S, Pradier C, Le Corfec E, et al. Factors associated with clinical
and virological failure in patients receiving a triple therapy including a
protease inhibitor. AIDS 2000, 14:141-9.
http://amedeo.com/lit.php?id=10708284
9. Hoffmann C, Chow KU, Wolf E, et al. HIV-associated Hodgkin’s Disease
in the era of HAART – is there an improvement in survival? Abstract 504,
140
DGHO München 2002.
10. Hogg RS, Yip B, Chan KJ, et al. Rates of disease progression by baseline
CD4 cell count and viral load after initiating triple-drug therapy. JAMA
2001, 286:2568-77. Originalarbeit: http://jama.amaassn.
org/issues/v286n20/ffull/joc10361.html
11. Kaplan JE, Hanson DL, Jones JL, Dworkin MS. Viral load as an
independent
risk factor for opportunistic infections in HIV-infected adults and
adolescents. AIDS 2001, 15:1831-6.
http://amedeo.com/lit.php?id=11579245
12. Kaufmann G, Perrin L, Pantaleo G. CD4 T-lymphocyte recovery in
individuals
with advanced HIV-1 infection receiving potent antiretroviral therapy
for 4 years: The Swiss HIV Cohort Study. Abstract LB4, 9th CROI
2002, Seattle, USA.
http://www.retroconference.org//2002/Abstract/14064.htm
13. Lange CG, Valdez H, Medvik K, Asaad R, Lederman MM. CD4+
Tlymphocyte
nadir and the effect of highly active antiretroviral therapy on
phenotypic and functional immune restoration in HIV-1 infection. Clin
Immunol
2002, 102:154-61. http://amedeo.com/lit.php?id=11846457
14. Le Moing V, Chene G, Carrieri MP, et al. Predictors of virological rebound
in HIV-1-infected patients initiating a protease inhibitor-containing regimen.
AIDS 2002, 16:21-9. http://amedeo.com/lit.php?id=11741159
15. Ledergerber B, Egger M, Opravil M, et al. Clinical progression and
virological
failure on highly active antiretroviral therapy in HIV-1 patients: a
prospective cohort study. Swiss HIV Cohort Study. Lancet 1999,
353:863-8. http://amedeo.com/lit.php?id=10093977
16. Lederman MM. Immune restoration and CD4+ T-cell function with
antiretroviral
therapies. AIDS 2001, Suppl 2:S11-5.
http://amedeo.com/lit.php?id=11424971
17. Lyles RH, Munoz A, Yamashita TE, et al. Natural history of HIV type 1
viremia after seroconversion and proximal to AIDS in a large cohort of
homosexual men. J Infect Dis 2000, 181:872-880.
http://amedeo.com/lit.php?id=10720507.
18. Mellors JW, Munoz AM, Giorgi JV, et al. Plasma viral load and CD4+
lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med.
1997, 126:946-954. http://amedeo.com/lit.php?id=9182471.
19. Miller V, Staszewski S, Sabin C, et al. CD4 lymphocyte count as a
predictor
of the duration of HAART-induced suppression of HIV load. J Infect
Dis 1999, 180:530-3. http://amedeo.com/lit.php?id=10395876
141
20. Mocroft A, Devereux H, Kinloch-de-Loes S, et al. Immunological,
virological
and clinical response to highly active antiretroviral therapy treatment
regimens in a complete clinic population. AIDS 2000, 14:1545-1552.
21. Mocroft A, Gill MJ, Davidson W, Phillips AN. Predictors of a viral response
and subsequent virological treatment failure in patients with HIV
starting a protease inhibitor. AIDS 1998, 12:2161-2167.
22. Opravil M, Ledergerber B, Furrer H, et al. Clinical efficacy of early
initiation
of HAART in patients with asymptomatic HIV infection and CD4 cell
count > 350 x 10(6)/l. AIDS 2002, 16:1371-81.
http://amedeo.com/lit.php?id=12131214
23. Pezzotti P, Pappagallo M, Phillips AN, et al. Response to HAART
according
to duration of HIV infection. J Acquir Immune Defic Syndr 2001,
26:473-9. http://amedeo.com/lit.php?id=11391168
24. Phillips AN, Staszewski S, Weber R, et al. HIV viral load response to ART
according to the baseline CD4 cell count and viral load. JAMA 2001,
286:2560-7. http://amedeo.com/lit.php?id=11722270
25. Piketty C, Castiel P, Belec L, et al. Discrepant responses to triple
combination
antiretroviral therapy in advanced HIV disease. AIDS 1998,
12:745-50. http://amedeo.com/lit.php?id=9619806
26. Powderly WG, Saag MS, Chapman S, Yu G, Quart B, Clendeninn NJ.
Predictors of optimal virological response to potent antiretroviral therapy.
AIDS 1999,13:1873-1880.
27. Powderly WG. Long-term exposure to lifelong therapies. J Acquir Immune
Defic Syndr 2002, 29 Suppl 1: S28-40.
http://amedeo.com/lit.php?id=11832699
28. Renaud M, Katlama C, Mallet A, et al. Determinants of paradoxical CD4
cell reconstitution after protease inhibitor-containing antiretroviral regimen.
AIDS 1999, 13:669-76. http://amedeo.com/lit.php?id=10397561
29. Skowron G, Street JC, Obee EM. Baseline CD4+ cell count, not viral
load, correlates with virologic suppression induced by potent antiretroviral
therapy. J Acquir Immune Defic Syndr 2001, 28: 313-9.
http://amedeo.com/lit.php?id=11707666
30. Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus
zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus
zidovudine
and lamivudine in the treatment of HIV-1 infection in adults. N
Engl J Med 1999, 341:1865-1873.
31. Sterling TR, Chaisson RE, Moore RD. HIV-1 RNA, CD4 T-lymphocytes,
and clinical response to HAART. AIDS 2001, 15:2251-7.
http://amedeo.com/lit.php?id=11698698
32. Tortajada C, Garcia F, Plana M, Gallart T, Maleno MJ, Miro JM et al.
142
Comparison of T-cell subsets' reconstitution after 12 months of highly active
antiretroviral therapy initiated during early versus advanced states of
HIV disease. J Acquir Immune Defic Syndr 2000, 25: 296-305.
http://amedeo.com/lit.php?id=11114829
33. Wit FW, van Leeuwen R, Weverling GJ. et al. Outcome and predictors of
failure of HAART: One-year follow-up of a cohort of HIV type 1-infected
persons. J Inf Dis 1999, 179: 790–798.
http://amedeo.com/lit.php?id=10068573
34. Yamashita TE, Phair JP, Munoz A, et al. Immunologic and virologic
response
to HAART in the Multicenter AIDS Cohort Study. AIDS 2001,
15:735-46. http://amedeo.com/lit.php?id=11371688
35. Yeni PG, Hammer SM, Carpenter CC, et al. Antiretroviral treatment for
adult HIV infection in 2002: updated recommendations of the International
AIDS Society-USA Panel. JAMA 2002, 288: 222-35.
http://amedeo.com/lit.php?id=12095387.
143
5. Cum sa incepi tratamentul cu HAART
Christian Hoffmann
Pentru multi pacienti, numarul de tablete sau necesitatea unui anumit consum
alimentar sunt factori decisivi. Gama de regimuri initiale aprobate si
recomandate variaza de la 2 la 16 tablete pe zi. Multi gasesc inacceptabil
faptul ca trebuie sa ia pastilele la anumite ore in decursul zilei, sau pe
stomacul gol, sau cu alimente cu continut crescut de lipide. Pacientii din ziua
de azi au cerinte mai mari decat acum 3 sau 4 ani. Chiar si dimensiunile
tabletelor pot reprezenta o problema pentru unii pacienti. Asemenea subiecte
trebuie abordate inainte de a initia terapia.
Afectiuni asociate
Fiecare pacient trebuie sa fie chestionat in amanunt si examinat in ceea ce
priveste posibilele afectiuni asociate inainte de a incepe tratamentul. In
particular, hepatita cronica trebuie sa fie luata in considerare in alegerea unui
regim. Riscul de hepatotoxicitate grava la nevirapina sau ritonavir este foarte
mare la acesti pacienti (Den Brinker et al 2000, Martinez et al 2001, Saves et
al 1999, Sulkowski et al 2000+2002). Alte afectiuni trebuie de asemeni
retinute (vezi tabelul de mai jos).
145
Tabelul 5.1: Afectiuni asociate care necesita atentie la administrarea anumitor
medicamente. Aceste recomandari nu reprezinta contraindicatii absolute.
Afectiune Atentie la
Hepatita C activa Nevirapina, PI stimulate
Hepatita B activa Nevirapina, PI stimulate
(in contrast: lamivudina si tenofovirul par a fi
benefice)
Anemie Zidovudina, posibil de asemenea lamivudina
Polineuropatie Stavudina, zalcitabina, didanozina
Afectiuni renale Indinavir, posibil de asemenea tenofovir
Diabet mellitus PI (in special daca un NIDDM prezinta risc de
a deveni IDDM!)
HTA Indinavir
Infarct miacardic PI (potential benefice: nevirapina)
Psihoze, alte afectiuni SNC Efavirenz
Diaree cronica Nelfinavir, alte PI
Abuz activ de substante, Probabil nici un NNRTI, nici ritonavir
substitutie
146
Medicamentele sau alcoolul pot de asemenea sa interactioneze cu HAART.
Pentru cei aflati in cadrul programelor de inlocuire, cerinta de metadona
poate fi semnificativ mai crescuta de anumite medicamente antiretrovirale
cum ar fi nevirapina sau efavirenz. Pe scurt, acest lucru este de asemeni
valabil in cazul ritonavirului si nelfinavirului. Alte combinatii pot duce la alte
efecte chiar si mai periculoase. Au fost inregistrate cateva decese dupa
administrarea simultana de ritonavir si amfetamina sau ecstasy, sau cu acidul
gama hidroxibutiric, narcotic comun (GHB, Samsonit® sau „ecstasy lichid”;
Hales et al 2000, Harrington et al 1999). Ritonavir in special poate inhiba
metabolizarea a diferite medicamente cum ar fi amfetamina, ketamine sau
LSD (excelenta analiza in Antoniou et Tseng 2002). Atat medicii cat si
pacientii sunt sfatuiti sa poarte o conversatie libera despre medicamente
inainte de inceperea terapiei. Marijuana si THC par a avea un potential redus
de interactiune (Kosel et al 2002).
147
384 (vezi mai jos), efavirenz a fost mai eficient decat nelfinavir. In studiul
spaniol aleator, open-label COMBINE, a existat o tendinta in favoarea
nevirapinei fata de nelfinavir, dar diferenta nu era semnificativa (Podzamczer
et al 2002).
148
Trei analogi nucleozidici
AZT+3TC+abacavir (Trizivir®, vezi mai jos) – este combinatia tripla NRTI cea
mai investigata, si este acum disponibila sub forma unei singure tablete. Cel
putin 2 studii au demonstrat ca la pacientii cu o incarcatura virala mare
(>100.000/ml), eficienta era inferioara combinatiilor PI (Staszewski et al 2001,
Vibhagool et al 2001). Din aceasta cauza, tripla combinatie pare mai putin
puternica. Date legate de combinatii triple cu nukes au fost de asemenea
publicate. Studiul Atlantic a furnizat date in plus despre d4T+ddI+3TC, si
exista rezultate si pentru AZT+ddI+3TC, de ex. (Lafeuillade et al 1997). Au
avut experiente bune cu d4T+ddI+abacavir (Hoffmann et al 2000). In studiul
CLASS aleator, combinarea d4T+3TC+abacavir s-a dovedit de asemenea
destul de eficienta (Bartlett et al 2002). In plus fata de un potential mai scazut
pentru interactiuni medicamentoase, un regim triplu nuke prezinta de
asemenea avantajul unei poveri reduse a medicatiei si permite pastrarea
NNRTI si PI pentru regimurile ulterioare.
Studiile care comparau aceste 3 strategii initiale diferite au fost destul de rare.
E de inteles, companiile farmaceutice prezinta un interes limitat de a risca
stabilirea inferioritatii unuia din produsele lor. Asemenea studii sunt de obicei
realizate independent, dar de obicei se desfasoara mai lent si uneori nu sunt
la fel de bine monitorizate.
Studiul Atlantic: 298 pacienti au fost alesi la intamplare pentru studiul open-
label, si au primit d4T+ddI+3TC versus d4T+ddI+nevirapina versus
d4T+ddI+Indinavr (Squires et al 2000). Dupa 48 saptamani, 49%, 49% si
respective 40% din pacienti au atins o incarcatura virala <50 copii/ml in
analiza ITT. In analiza celor care efectuau tratamentul (nu sunt incluse
renuntarile), insa, a fost observata o diferenta semnificativa in favoarea
indinavirului fata de 3TC, o tendinta a nevirapinei fata de 3TC si nici o
diferenta intre nevirapina si indinavir. Pentru incarcaturi virale mari (upper
quartile) , analiza ITT a dezvaluit o incarcatura virala sub nivelul de detectare
la 48%, 28% si, respectiv 26% din pacienti. Aceste diferente nu erau
semnificative. Design-ul studiului nu a permis detectarea unor diferente
semnificative.
150
Regimuri initiale recomandate
Combinatii posibile pentru terapia initiala sunt prezentate in tabelul 5.3.
De notat este ca, multe alte combinari sunt posibile. Acestea pot fi
acceptabile in cazuri individuale sau in studii de investigare, dar nu pot
fi date recomandari generale pentru utilizarea lor.
151
Terapii initiale de succes
AZT+3TC plus nevirapina sau efavirenz
AZT+3TC+ABC
Aceasta este combinatia cea mai usoara in ceea ce priveste povara
medicatiei. Doua tablete de Trizivir® zilnic sunt greu de invins! Se
potriveste nu numai pacientilor cu probleme de complianta, dar si celor
cu o lista lunga de medicamente administrate simultan si un potential
crescut pentru interactiuni medicamentoase (tuberculoza si terapia
MAC, warfarina). Combinatia este de obicei bine tolerata, desi este
necesara consiliere intensiva asupra sindromului de hipersensibilitate.
De data recenta, a fost descris un caz de sindrom Stevens-Johnson
(Bossi et al 2002). Respectand doza de zidovudina, acelasi lucru se
aplica pentru Trizivir® ca si pentru Combivir® – ar putea fi prea mare
pentru anumiti pacienti.
153
studiul Australian OzCombo2, d4T+ddI in combinatie cu nevirapina era la fel
de eficient ca si d4T+3TC sau AZT+3TC (French et al 2002).
Combinatii viitoare
Combinatiile viitoare, trebuie sa fie mai eficiente, simple si mai bine tolerate.
In orice caz, nu putem intotdeauna astepta noi medicamente sa apara! Prin
urmare, exista trei modalitati de abordare care sunt in prezent investigate in
ceea ce priveste medicamentele disponibile: combinatii care necesita dozare
numai o data-zilnic; combinatii fara analogi nucleozidici; si combinatii care sa
foloseasca mai mult de 3 medicamente active. Aceste abordari se presupune
ca vor conduce la modificari importante in terapia antiretrovirala in urmatori 2
ani.
Zona „nuke-free”
Testarile EASIER realizate in mai multe centre tinteste a stabili daca analogii
nucleozidici sunt chiar necesari: pacientii primesc indinavir/ritonavir si
efavirenz, si primesc aleator d4T sau nu. Primele rezultate la 74 pacienti
demonstreaza rezultate comparabile la markeri surogat; d4T nu a prezentat
nici un efect in plus (Stek et al 2002). In studiul BIKS, pacientii (unii cu
experienta de tratament) primeau o combinatie lipsita de nuke – lopinavir/r si
efavirenz (Allavena et al 2002); date preliminare indica de asemenea ca o
astfel de abordare s-ar putea dovedi de succes.
In orice caz, din moment ce terapiile fara nuke nu pot fi recomandate inca, cel
putin nu pentru terapiile initiale, dar par a deveni importante in viitor (Joly et al
2002).
O data zilnic
In prezent, numai patru medicamente sunt aprobate pentru dozarea o data pe
zi: didanozina, efavirenz, lamivudina si tenofovir. Alti candidati dintre analogii
nucleozidici includ stavudina, care va fi lansata in curand sub forma de
capsule cu eliberare treptata(extended release), si abacavir.
156
posibili. In studiul M99-056, pacientii care nu aveau experienta in tratament
erau alesi la intamplare, avand un tratament de baza cu d4T+3TC, sa
primeasca lopinavir/r fie o data-zilnic (1x 6 tablete) sau obisnuita doza de 2x
zilnic (2x 3 tablete). La 48 saptamani, nu a putut fi demonstrata nici o
diferenta fie in succesul tratamentului sau in ceea ce priveste efectele
secundare (Eron et al 2002). Toate aceste combinatii stimulate au insa in
comun o povara a medicatiei crescuta – intre 6 si 9 tablete sau capsule. Cu
asemenea regimuri de tratament este de aceea improbabil sa se obtina o
mare relevanta, in special cu PI administrate o data-zilnic de tipul atazanavir
care va deveni disponibil in curand.
De aceea, de-a lungul urmatoarelor 12-24 luni vor deveni disponibile noi
optiuni pentru regimurile cu administrare o data-zilnic. Primele studii efectuate
la pacienti fara experienta de tratament prezinta rezultate promitatoare (vezi
tabelul de mai jos).
n combinatia Procentaj
<50 copii/ml
Molina 2000 40 ddI+EFV+emtricitabina 93% dupa 24
saptamani
Mole 2001 10 ddI+3TC+IDV 1200/RTV 400 80% dupa 12
saptamani
Maggiolo 2001 75 ddI+3TC+EFV 77% dupa 48
saptamani
Skowron 2002 11 ddI+3TC+EFV+AFV 91% dupa 48
saptamani
Rosenbach 25 ABC+3TC+APV 1200/RTV In asteptare
2002 300
Insa, unii clinicieni speculeaza ideea daca o abordare mai intesiva ar putea fi
folositoare la unii pacienti. Dezvoltarea rapida a rezistentei, care este mai
frecventa la pacientii cu o incarcatura virala crescuta, este o problema din ce
in ce mai mare. Anumiti medici au inceput deja terapia initiala cu 4 sau 5
medicamente, pentru ca apoi sa simplifice regimul printr-o combinatie tripla
din moment ce incarcatura virala a scazut sub nivelul de detectare dupa
cateva luni.
158
devin relativ tolerabile cand pacientul si medicul stiu ca regimul de tratament
va fi redus semnificativ dupa cateva saptamani. O combinatie buna, in
experienta noastra, este AZT+3TC+ABC plus un PI stimulat, cum ar fi
lopinavir/r.
159
intreaga. Saquinavir-SGC nu ar trebui luat in considerare din moment ce
povara medicatiei este prea mare; nu se poate astepta de la nici un pacient
azi sa ia 3x6 capsule zilnic. Amprenavir (pentru care exista date relativ bune:
Goodgame et al 2000), delavirdina si tenofovir ar trebui de asemenea excluse
din regimurile initiale, pentru ca nu au fost aprobate in acest scop.
160
In studiul French Trilege, 279 pacienti aflati in tratament HAART, erau
distribuiti aleator in 3 grupuri de studiu de diferite intensitati (Pialoux et al
1998, Flander et al 2002). La 18 luni, 83 pacienti aveau o incarcatura virala >
500 copii/ml – 10 cu AZT+3TC+IDV, 46 cu AZT+3TC si 27 cu AZT+IDV. Insa,
pacientii care urmau o terapie duala temporara nu au dezvoltat se pare vreo
rezistenta majora (Deschamps et al 2000). Dupa alte 18 luni dupa alegerea
aleatorie, nu au putut fi prezentate diferente. Un numar de pacienti aflati in
grupurile de terapie duala au trecut inapoi la regimul original.
Cel de-al treilea studiu, care a spulberat in final toate sperantele terapiei de
intretinere, a fost ACTG 343, care a recrutat 316 pacienti cu o incarcatura
virala <200 copii/ml de mai mult de 2 ani. Pacientii fie au continuat sa
primeasca AZT+3TC+IDV sau au trecut la un regim simplificat cu AZT+3TC
sau indinavir. Rata de esec a tratamentului (incarcatura virala >200 copii/ml)
era de 23% in ambele grupuri de intretinere versus numai 4% la pacientii care
au continuat terapia (Havlir et al 1998).
Cazul nu este inca inchis, insa, pentru combinatiile duble cu PI. Succesul
terapiei de salvare (salvage) (vezi capitolul corespunzator) a aratat ca un
asemenea tratament ar putea sa fie eficient pana la urma. In studiul
Prometheus, pacientii care nu au mai luat PI si d4T (fie in parte, fie complet)
au primit aleator un regim pe baza de saquinavir/ritonavir plus/minus d4T.
Dupa 48 saptamani, 88% versus 91% din pacienti din analiza celor aflati in
timpul tratamentului aveau o incarcatura virala de <400 copii/ml. Insa, la
pacientii cu o incarcatura virala crescuta, strategia dubla PI s-a dovedit a fi
precara (Gisolf et al 2000).
161
fost demonstrate intre pacienti care au primit 3 medicamente imediat si cei
care au inceput cu numai 2 medicamente (Gulick et al 1998). Studiul CNA
3003 (Ait-Khaled 2002) furnizeaza un alt exemplu: 173 pacienti fara
experienta de tratament au fost alesi la intamplare intr-un studiu double-blind
pentru a primi o combinatie de AZT+3TC+ABC versus AZT+3TC. In
saptamana 16, pacientii din grupul cu terapie duala puteau trece open-label
la AZT+3TC+ABC sau sa adauge alte medicamente antiretrovirale daca
incarcatura virala era >400 copii/ml. In saptamana 16, incarcatura virala era
sub 400copii/ml in 10% in grupul cu terapie tripla versus 62% in grupul cu
terapie duala. Mai important, in grupul cu terapie duala, 37 (versus 3) pacienti
au dezvoltat mutatia M184V. desi abacavir a ramas eficient in majoritatea
cazurilor in care a fost adaugat si TAMs au reprezentat exceptia, acest
exemplu arata cat de rapid poate sa apara rezistenta. Astfel, initierea terapiei
triple treptat, dupa cum e practicata uneori datorita ingrijorarii legate de prea
multe efecte secundare, este gresita si periculoasa.
Bibliografie:
1. Ait-Khaled M, Rakik A, Griffin P, et al. Mutations in HIV-1 reverse
transcriptase
during therapy with abacavir, lamivudine and zidovudine in HIV-
1-infected adults with no prior antiretroviral therapy. Antivir Ther 2002,
7:43-51. http://amedeo.com/lit.php?id=12008787
2. Allavena C, Lafeuillade A, Bentana M, et al. Lopinavir/ritonavir-efavirenz:
preliminary assessment of a potent nucleoside-sparing dual antiretroviral
regimen. Abstract 5798, XIV International AIDS Conference 2002, Barcelona,
Spain.
3. Antoniou T, Tseng AL. Interactions between recreational drugs and
antiretroviral agents. Ann Pharmacother 2002, 36:1598-613.
http://amedeo.com/lit.php?id=12243611
4. AVANTI 2. Randomized, double-blind trial to evaluate the efficacy and
safety of zidovudine plus lamivudine versus zidovudine plus lamivudine
plus indinavir in HIV-infected antiretroviral-naive patients. AIDS 2000,
14:367-74. http://amedeo.com/lit.php?id=10770538
5. Bartlett JA, DeMasi R, Quinn J, Moxham C, Rousseau F. Overview of the
effectiveness of triple combination therapy in antiretroviral-naive HIV-1
infected adults. AIDS 2001, 15: 1369-77.
http://amedeo.com/lit.php?id=11504958
6. Bartlett JA, Johnson J, Herrera G, et al. Abacavir/lamivudine in
combination
with efavirenz, amprenavir/ritonavir or stavudine: ESS40001
(CLASS) preliminary 48 week results. Abstract TuOrB1189, XIV International
AIDS Conference 2002, Barcelona, Spain.
7. Bartlett JA, Johnson J, Herrera G, Sosa N, Rodriguez AE, Shaefer MS.
Abacavir/lamivudine in combination with efavirenz, amprenavir/ritonavir
162
or stavudine: ESS40001 (CLASS) preliminary 48 week results. Abstract
TuOrB1189, XIV International AIDS Conference 2002, Barcelona, Spain.
8. Bossi P, Roujeau JC, Bricaire F, Caumes E. Stevens-Johnson syndrome
associated with abacavir therapy. Clin Infect Dis 2002,35:902.
9. Cardiello PG, van Heeswijk RP, Hassink EA, et al. Simplifying protease
inhibitor therapy with once-daily dosing of saquinavir soft-gelatin capsules/
ritonavir (1600/100 mg): HIVNAT study. J AIDS 2002, 29:464-70.
http://amedeo.com/lit.php?id=11981362
10. Carosi G, Castelli F, Suter F, et al. Antiviral potency of HAART regimens
and clinical success are not strictly coupled in real life conditions: evidence
from the MASTER-1 study. HIV Clin Trials 2001, 2:399-407.
http://amedeo.com/lit.php?id=11673814
11. Carr A, Chuah J, Hudson J, et al. A randomised, open-label comparison
of three HAART regimens including two nucleoside analogues and indinavir
for previously untreated HIV-1 infection: the OzCombo1 study. AIDS
2000, 14:1171-80. http://amedeo.com/lit.php?id=10894281
12. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations
between dose regimens and medication compliance. Clin Ther 2001,
23:1296-310. http://amedeo.com/lit.php?id=11558866
13. Cohen C, Shen Y, Rode R, et al. Effect of Nucleoside (NRTI)
intensification
on prevalence of morphologic abnormalities (moas) at year 5 of ritonavir
plus saquinavir therapy in an HIV-infected cohort. Abstract 683, 9th
CROI 2002, Seattle, USA.
14. Conway B, Prasad J, Reynolds R, et al. Nevirapine and protease
inhibitor-
based regimens in a directly observed therapy program for intravenous
drug users. Abstract 545, 9th CROI Seattle, USA.
http://63.126.3.84/2002/Abstract/13231.htm
15. D'Aquila RT, Hughes MD, Johnson VA, et al. Nevirapine, zidovudine, and
didanosine compared with zidovudine and didanosine in patients with
HIV-1 infection. A randomized, double-blind, placebo-controlled trial. Ann
Intern Med 1996, 124:1019-30.. http://amedeo.com/lit.php?id=8633815
16. Den Brinker M, Wit FW, Wertheim-van Dillen PM, et al. Hepatitis B and C
virus co-infection and the risk for hepatotoxicity of HAART in HIV-1 infection.
AIDS 2000, 14: 2895-902. http://amedeo.com/lit.php?id=11153671
17. Descamps D, Flandre P, Calvez V, et al. Mechanisms of virologic failure
in previously untreated HIV-infected patients from a trial of
inductionmaintenance
therapy. Trilege. JAMA 2000, 283: 205-11.
http://amedeo.com/lit.php?id=10634336
18. Eron JJ JR, Murphy RL, Peterson D, et al. A comparison of stavudine,
didanosine and indinavir with zidovudine, lamivudine and indinavir for the
initial treatment of HIV-1 infected individuals: selection of thymidine analog
regimen therapy (START II). AIDS 2000, 14: 1601-10.
163
http://amedeo.com/lit.php?id=10983647
19. Eron JJ, Bernstein B, King M. Once-daily vs twice-daily kaletra (lopinavir/
ritonavir) in antiretroviral-naïve HIV+ patients: 48-week follow-up. Abstract
409, 9th CROI 2002, Seattle, USA.
20. Eron JJ, Yetzer ES, Ruane PJ, et al. Efficacy, safety, and adherence with
a twice-daily combination lamivudine/zidovudine tablet formulation, plus a
protease inhibitor, in HIV infection. AIDS 2000, 14: 671-81.
http://amedeo.com/lit.php?id=10807190
21. Felipe G, Hernando K, Antonia SM, et al. An open randomized study
comparing D4T + DDI and nevirapine (qD) vs. D4T+DDI and nevirapine
BID in antiretroviral-naive, chronic HIV-1-infected patients in very early
stages: Spanish scan study. Final Results. Abstract 1156, XIII International
AIDS Conference 2000, Durban, South Africa.
22. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. Pharmacokinetic
interactions between protease inhibitors and statins in HIV seronegative
volunteers: ACTG Study A5047. AIDS 2002, 16:569-77.
http://amedeo.com/lit.php?id=11873000
23. Fischl M, Ribaudo H, Collier C, et al. A randomized trial comparing 2 4-
drug antiretroviral regimens with a 3-drug regimen in advanced hiv disease.
Astract 41, 9th CROI 2002, Seattle, USA.
http://63.126.3.84/2002/Abstract/12847.htm
24. Flander P, Raffi F, Descamps D, et al. Final analysis of the Trilege
induction-
maintenance trial: results at 18 months. AIDS 2002, 16:561-8.
http://amedeo.com/lit.php?id=11872999
25. Frank I. Once-daily HAART: toward a new treatment paradigm. J Acquir
Immune Defic Syndr 2002, Suppl 1:10-5.
http://63.126.3.84/2002/Abstract/13596.htm
26. French M, Amin J, Roth N, et al. Randomized, open-label, comparative
trial to evaluate the efficacy and safety of three antiretroviral drug
combinations
including two nucleoside analogues and nevirapine for previously
untreated HIV-1 Infection: the OzCombo 2 study. HIV Clin Trials 2002,
3:177-85. http://amedeo.com/lit.php?id=12032876
27. Friedl AC, Ledergerber B, Flepp M, et al. Response to first protease
inhibitor-
and efavirenz-containing antiretroviral combination therapy. The
Swiss HIV Cohort Study. AIDS 2001, 15: 1793-800.
http://amedeo.com/lit.php?id=11579241
28. Garcia F, Knobel H, Sambeat MA, et al. Comparison of twice-daily
stavudine
plus once- or twice-daily didanosine and nevirapine in early
stages of HIV infection: the scan study. AIDS 2000, 14:2485-94.
http://amedeo.com/lit.php?id=11101059
29. Gartland M. AVANTI 3: a randomized, double-blind trial to compare the
164
efficacy and safety of lamivudine plus zidovudine versus lamivudine plus
zidovudine plus nelfinavir in HIV-1-infected antiretroviral-naive patients.
Antivir Ther 2001, 6:127-34. http://amedeo.com/lit.php?id=11491417
30. Gisolf EH, Jurriaans S, Pelgrom J, et al. The effect of treatment
intensification
in HIV-infection: a study comparing treatment with ritonavir/
saquinavir and ritonavir/saquinavir/stavudine. Prometheus Study
Group. AIDS 2000, 14:405-13. http://amedeo.com/lit.php?id=10770543
31. Goodgame JC, Pottage JC Jr, Jablonowski H, et al. Amprenavir in
combination
with lamivudine and zidovudine versus lamivudine and zidovudine
alone in HIV-1-infected antiretroviral-naive adults. Amprenavir
PROAB3001 International Study Team. Antivir Ther 2000, 5: 215-25.
http://amedeo.com/lit.php?id=11075942
32. Gulick RM, Mellors JW, Havlir D, et al. Simultaneous vs sequential
initiation
of therapy with indinavir, zidovudine, and lamivudine for HIV-1 infection:
100-week follow-up. JAMA 1998, 280:35-41.
33. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir,
zidovudine,
and lamivudine in adults with HIV infection and prior antiretroviral
therapy. N Engl J Med 1997, 337: 734-9.
http://amedeo.com/lit.php?id=9287228
34. Haas DW, Arathoon E, Thompson MA, et al. Comparative studies of
twotimes-
daily versus three-times-daily indinavir in combination with zidovudine
and lamivudine. AIDS 2000, 14: 1973-8.
http://amedeo.com/lit.php?id=10997402
35. Haberl A, Gute P, Carlebach A, et al. Once-daily therapy (NVP/DDI/3TC)
for the IVDU HIV-1 infected population of the Frankfurt HIV cohort. Abstract
22398, 12th World AIDS Conference 1998, Geneva, Switzerland.
36. Hales G, Roth N, Smith D. Possible fatal interaction between protease
inhibitors and methamphetamine. Antivir Ther 2000, 5:19.
37. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two
nucleoside analogues plus indinavir in persons with HIV infection and
CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials
Group 320 Study Team. N Engl J Med 1997, 337: 725-33.
http://amedeo.com/lit.php?id=9287227
38. Harrington RD, Woodward JA, Hooton TM, Horn JR. Life-threatening
interactions between HIV-1 protease inhibitors and the illicit drugs MDMA
and gamma-hydroxybutyrate. Arch Intern Med 1999, 159:2221-4.
39. Harris M. Evaluation of the pharmacokinetics of the concurrent
administration
of two NNRTIs, nevirapine/delavirdine and nevirapine/efavirenz,
in patients receiving multi-drug rescue therapy. Abstract 14, 3rd International
165
Workshop on Salvage Therapy for HIV Infection 2000, Chicago,
USA.
40. Havlir DV, Marschner IC, Hirsch MS, et al. Maintenance antiretroviral
therapies in HIV infected patients with undetectable plasma HIV RNA after
triple-drug therapy. ACTG 343 Team. N Engl J Med 1998, 339:1261-
8. http://amedeo.com/lit.php?id=9791141
41. Havlir DV, Tierney C, Friedland GH, et al. In vivo antagonism with
zidovudine
plus stavudine combination therapy. J Infect Dis 2000, 182:321-
5. http://amedeo.com/lit.php?id=10882616
42. Henry K, Erice A, Tierney C, et al. A randomized, controlled, double-blind
study comparing the survival benefit of four different reverse transcriptase
inhibitor therapies (three-drug, two-drug, and alternating drug) for the
treatment of advanced AIDS. ACTG 193A Study Team. J AIDS Hum
Retrovirol
1998,19:339-49. http://amedeo.com/lit.php?id=9833742
43. Herman JS, Ives NJ, Nelson M, et al. Incidence and risk factors for the
development of indinavir-associated renal complications. J Antimicrob
Chemother 2001, 48:355-360.
44. Hoffmann C, Jaegel-Guedes E, Wolf E, et al. PI-sparing in ART-naive
HIV+ patients: Efficacy and Tolerability of D4T/DDI plus Efavirenz (EFV)
vs D4T/DDI plus Abacavir (ABC). Abstract WePeB4181, XIII International
AIDS Conference 2000, Durban, South Africa
45. Hugen PW, Burger DM, ter Hofstede HJ, et al. Dose-finding study of a
once-daily indinavir/ritonavir regimen. J Acquir Immune Defic Syndr 2000,
25: 236-45. http://amedeo.com/lit.php?id=11115954
46. Joly V, Descamps D, Yeni P. NNRTI plus PI combinations in the
perspective
of nucleoside-sparing or nucleoside-failing antiretroviral regimens.
AIDS Rev 2002, 4:128-39. http://amedeo.com/lit.php?id=12416447
47. Jordan R, Gold L, Cummins C, Hyde C. Systematic review and
metaanalysis
of evidence for increasing numbers of drugs in antiretroviral
combination therapy. BMJ 2002, 324:757.
http://amedeo.com/lit.php?id=11923157
48. Jordan W, Jefferson R, Yemofio F, et al. Nevirapine (NVP) + efavirenz
(EFV) + didanosine (DDI): a very simple, safe, and effective once-daily
171
6. Cand sa schimbam HAART
Christian Hoffmann
a) Care sunt motivele pentru care incarcatura virala este crescuta sau
inca crescuta?
O incarcatura virala >50 copii/ml nu inseamna neaparat ca au aparut mutatii
de rezistenta. Poate sa indice de asemenea nivele plasmatice insuficiente
(monitorizare daca este posibil!). Complianta este de asemenea importanta.
172
Posibilele dificultati ale regimului ar trebui abordate deschis: Este vorba de
numarul de pastile? Cauzeaza probleme restrictiile legate de consumul
alimentar? Ar fi mai bun un tratament o data pe zi? Mai exista si alte motive,
cum ar fi depresia? Riscul de dezvoltare a rezistentei datorita non-compliantei
ar trebui revizuit. Daca incarcatura virala nu scade sub nivelul de detectare
sau daca isi revine(rebound) ca urmare a terapiei initiale la un pacient
compliant (monitorizati blips la intervale scurte!), tratamentul ar trebui
modificat cat mai curand posibil.
174
sursa n Treceti la cand virologic Efectl trecerii
Barreiro 135 NVP 24 Schimbare Lipide nemodificate, LD
2000 Avantajoasa imbunatatit
Martinez 93 EFV Tendinta contra Lipide partial
2001 schimbarii imbunatatite, LD
imbunatatit, LA inrautatit
Becker 346 EFV 48 Schimbare Lipide nemodificate, LD
2001 Avantajoasa imbunatatit
Carr 81
ABC+NVP 24 n.s. Lipide imbunatatite, LD
2001 + imbunatatite, LA
ADF+HU inrautatite
Clumeck 211 ABC 24 Schimbare Lipide imbunatatite
2001 Avantajoasa
Ruiz 106 NVP 48 n.s. Lipide imbunatatite, LD
2001 nemodificat
Negredo 77 NVP 48 n.s. Lipide imbunatatite
2002 sau EFV numai la NVP, LD
nemodificat
Opravil 163 ABC 84 Tendinta contra Lipide imbunatatite
2002 schimbarii
Fisac 92 NVP sau 48 NVP/EFV Lipide imbunatatite in
2002 EFV sau similar, special in grupul NVP,
ABC Tendinta contra LD nemodificat.
abacavir
*in toate studiile alegerea la intamplare era contra continuarii PI. Toate aveau
un design open-label. La momentul schimbarii, toti pacientii se aflau in
tratament cu PI de cateva luni cu incarcaturi virale sub nivelul de detectare. In
toate studiile calitatea vietii (daca era testata) era imbunatatita in grupul care
a realizat schimbarea.
LD=lipodistrofie, LA=lipoatrofie, n.s.=nesemnificativ (not significant).
175
7.Cum sa modifici HAART
Christian Hoffmann
Modalitatea de a schimba o terapie care are succes dar este intolerabila din
punct de vedere al efectelor secundare este de obicei simpla. Medicamentul
suspectat ar trebui inlocuit cu un alt medicament din aceeasi clasa.
Dificultatile apar daca se alterneaza medicamente care sunt contraindicate
datorita toxicitatii potentiale sau daca se suspecteaza mutatii rezistente la
aceste medicamente. In unele cazuri, incidenta efectelor secundare poate fi
folosita drept oportunitate de a modifica terapia sau de a reduce povara
medicatiei.
176
nevirapina si stavudina. Urmatorul tabel prezinta posibilitati de tratament in
prezenta mutatiilor de rezistenta individuale.
La pacientii care au fost tratati exclusiv cu NRTI, (in particular dupa tratament
prelungit), aceasta strategie este in general lipsita de succes. Mutatii de
rezistenta excesive de obicei exista, astfel incat este necesara o modificare
completa a HAART. Cel putin 2 studii aleatorii (si partial blind) au aratat ca
cele mai multe avantaje se obtin prin trecerea la un NNRTI plus un PI plus cel
putin un nou analog nucleozidic. Acest lucru a fost demonstrat atat pentru
nelfinavir plus efavirenz si indinavir plus efavirenz (Albrecht et al 2001, Haas
et al 2001). La pacientii tratati anterior cu NRTI sau NNRTI, un PI trebuie
folosit. Se intra in domeniul terapiei de salvare cand da gres un regim bazat
pe PI (vezi capitolul urmator: „Terapia de salvare”).
Bibliografie:
1. Albrecht MA, Bosch RJ, Hammer SM, et al. Nelfinavir, efavirenz, or both
after the failure of nucleoside treatment of HIV infection. N Engl J Med
2001, 345:398-407. http://amedeo.com/lit.php?id=11496850
2. Barreiro P, Soriano V, Blanco F, et al. Risks and benefits of replacing
protease inhibitors by nevirapine in HIV-infected subjects under long-term
successful triple combination therapy. AIDS 2000, 14: 807-12.
http://amedeo.com/lit.php?id=10839588
3. Becker S, Rachlis A, Gill J, et al. Successful Substitution of Protease
Inhibitors with Efavirenz in patients with undetectable viral loads - A
prospective,
randomized, multicenter, open-label study (DMP 049). Abstract
20, 8th CROI 2001, Chicago.
http://www.retroconference.org/2001/abstracts/abstracts/abstracts/20.htm
4. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet
2000, 356: 1423-30
5. Carr A, Hudson J, Chuah J, et al. HIV protease inhibitor substitution in
patients with lipodystrophy: a randomized, controlled, open-label, multicentre
study. AIDS 2001, 15: 1811-22.
http://amedeo.com/lit.php?id=11579243
6. Clumeck N, Goebel F, Rozenbaum W, et al. Simplification with
abacavirbased
triple nucleoside therapy versus continued protease inhibitorbased
HAART in HIV-1-infected patients with undetectable plasma HIV-1
RNA. AIDS 2001, 15: 1517-26. http://amedeo.com/lit.php?id=11504984
7. Fätkenheuer G, Römer K, Cramer P, Franzen C, Salzberger B. High rate
of changes of first antiretroviral combination regimen in an unselected
cohort of HIV-1 infected patients. Abstract 50, 8th ECCAT 2001, Athens,
Greece.
8. Fisac C, Fumero E, Crespo M, et al. Metaboic and body composition
changes in patients switching from a PI-containing regimen to Abacavir,
Efavirenz or Nevirapine. 12 month results of a randomized study (Lipnefa).
Abstract ThPE7354, XIV International AIDS Conference 2002,
Barcelona, Spain.
9. Haas DW, Fessel WJ, Delapenha RA, et al. Therapy with efavirenz plus
indinavir in patients with extensive prior nucleoside reverse-transcriptase
178
inhibitor experience: a randomized, double-blind, placebo-controlled trial.
J Infect Dis 2001,183:392-400. http://amedeo.com/lit.php?id=11133370
10. Katlama C, Clotet B, Plettenberg A, et al. Intensification of stable
background
therapy with abacavir in antiretroviral therapy experienced patients:
48-week data from a randomized, double-blind trial. HIV Med
2001, 2:27-34. http://amedeo.com/lit.php?id=11737373
11. Martinez E, Romeu J, Garcia-Viejo A, et al. An open randomized study
on the replacement of HIV-1 protease inhibitors by efavirenz in chronically
suppressed HIV-1-infected patients with lipodystrophy. Abstract 668,
8th CROI 2001, Chicago, USA.
http://www.retroconference.org//2001/abstracts/abstracts/abstracts/668.ht
m
12. Mocroft A, Phillips AN, Miller V, et al. The use of and response to
secondline
protease inhibitor regimens: results from the EuroSIDA study. AIDS
2001, 15:201-9. http://amedeo.com/lit.php?id=11216928
13. Mocroft A, Youle M, Moore A, et al. Reasons for modification and
discontinuation
of antiretrovirals: results from a single treatment centre. AIDS
2001, 15:185-94. http://amedeo.com/lit.php?id=11216926
14. Murphy RL, Smith WJ. Switch studies: a review. HIV Med 2002, 3:146-
55. Review. http://amedeo.com/lit.php?id=12010362
15. Negredo E, Cruz L, Paredes R, et al. Virological, immunological, and
clinical impact of switching from protease inhibitors to nevirapine or to
efavirenz in patients with HIV infection and long-lasting viral suppression.
Clin Infect Dis. 2002, 34:504-10. http://amedeo.com/lit.php?id=11797178
16. Opravil M, Hirschel B, Lazzarin A, et al. A randomized trial of simplified
maintenance therapy with abacavir, lamivudine, and zidovudine in HIV
infection. J Infect Dis 2002, 185: 1251-60.
http://amedeo.com/lit.php?id=12001042
17. Ruiz L, Negredo E, Domingo P, et al. Antiretroviral treatment
simplification
with nevirapine in protease inhibitor-experienced patients with HIVassociated
lipodystrophy: 1-year prospective follow-up of a multicenter,
randomized, controlled study. J Acquir Immune Defic Syndr 2001, 27:
229-36. http://amedeo.com/lit.php?id=11464141
18. Schooley RT, Ruane P, Myers RA, Tenofovir DF in
antiretroviralexperienced
patients: results from a 48-week, randomized, double-blind
study. AIDS 2002, 16:1257-63. http://amedeo.com/lit.php?id=12045491
19. Soriano V. Sequencing antiretroviral drugs. AIDS 2001, 15: 547-551.
20. Van Heeswijk RP, Veldkamp AI, Mulder JW, et al. Once-daily dosing of
saquinavir and low-dose ritonavir in HIV-1-infected individuals: a
pharmacokinetic
179
pilot study. AIDS 2000, 14: F103-10.
http://amedeo.com/lit.php?id=10894270
180
8. Terapia de salvare (Salvage therapy)
Christian Hoffmann
Context
Termenul “terapie de salvare” nu este definit clar. Este folosit in prezent
pentru a se face referire la diferite situatii atat in medicina HIV cat si in
oncologie creand confuzie. Unii clinicieni aduc in discutie terapia de salvare
numai daca toate clasele de medicamente au dat gres, in timp ce altii
folosesc termenul de la terapia de linie secunda incolo. Pana acum nu s-a
ajuns la un consens asupra definitiei. Noi o definim ca metoda de abordare
terapeutica cand cel putin un regim ce continea PI a dat gres.
Cu cat mai mult timp are virusul pentru a dezvolta rezistenta, cu atat mai de
necontrolat devine!
In plus, variate studii au aratat ca de obicei numai 30 la 50% din pacientii la
care au esuat regimurile PI sunt capabili sa prezinte o incarcatura virala sub
nivelul de detectare la o combinatie stimulata cum ar fi ritonavir/saquinavir
(Deeks et al 1998, Fätkenheur et al 1999, Hall et al 1999, Paredes et al
1999). Raspunsul la ritonavir/saquinavir ar putea fi usor imbunatatit daca
regimul initial continea nelfinavir (Tebas et al 1999); acest lucru se datoreaza
in principal mutatiei specifice D30N pentru nelfinavir.
181
Cele cateva studii salvage disponibile sunt prezentate in urmatorul tabel.
Studiul ACTG 398 recent publicat este pana in prezent cel mai mare studiu
salvage aleator (Hammer et al 2002). A folosit 481 pacienti cu o incarcatura
virala > 1.000copii/ml si pre-tratament extensiv, si au primit fie un al doilea PI
(in functie de tratamentul anterior) sau nu. Observatiile anterioare au fost
confirmate. Numai 31% din pacienti au atins o incarcatura virala <200
copii/ml dupa 24 saptamani. In grupul care primea 2 PI, rata era semnificativ
mai crescuta (35% versus 23%). Per ansamblu, raspunsul la regimul de
salvare era – pana la introducerea lopinavir/r – destul de modest (vezi:
Battegay et al 1999).
183
Pe de alta parte, un mic studiu de observatie a aratat raspunsuri mai bune la
combinarea lopinavir/r + saquinavir decat la lopinavir/r + amprenavir (Zala et
al 2002). Intr-un studiu german a unor pacienti cu vasta experienta de
tratament ( in medie 9 tratamente diferite!) carora le-a fost schimbat
tratamentul din diferite motive (rezistenta, toxicitate) cu o combinatie a
lopinavir/r +saquinavir, 19/33 pacienti au atins o incarcatura virala < 50
copii/ml dupa 24 saptamani (Staszewski et al 2002). Unii pacienti au intrerupt
terapia inainte de a incepe regimul de salvare.
Mega-, Giga-HAART
Conform sloganului „cu cat mai mlt, cu atat mai bine”, mai multe studii au
aratat ca diferite combinatii de tratament intensificate, descrise de asemenea
ca „Mega-HAART” sau „Giga-HAART” – ar putea intr-adevar sa fie eficiente.
Succesul acestor studii in principal necontrolate, pot fi dezbatute. Folosind
regimuri cu 5 sau 6 medicamente, s-a obtinut o supresie suficienta a
incarcaturii virale la un procent variabil de pacienti (22-52%; Grossman et al
1999, Miller et al 2000, Montaner et al 2001, Piketty et al 2002, Youle et al
2002).
Potrivit unor critici, toate studiile „salvage” pot fi considerate drept modalitati
de administrare pe termen scurt a cocktailurilor otravitoare. Insa, multe
dileme trebuie inca rezolvate. Regimurile Mega-HAART de obicei nu sunt
individualizate. In plus, succesul lor este in functie de 3 variabile: rezistenta,
nivele plasmatice si aderenta. Ultima este probabil sa fie intotdeauna dificila
cu asemenea terapii. Numai pacientii bine informati si extrem de complianti ar
trebui din aceasta cauza luati in considerare pentru regimurile Mega-HAART.
In plus, orice interactiuni medicamentoase sunt greu de prevazut in acest
context, si nivelele plasmatice ar trebui masurate de cate ori este posibil.
Majoritatea PI, insa, pot fi combinate unele cu altele, destul de bine fara a
cauza interactiuni sau toxicitati semnificative (Van Heeswijk et al 2001, Eron
et al 2001).
184
In ciuda tuturor discutiilor privind Mega sau Giga – HAART, pentru unii
pacienti principalul scop al tratamentului de a obtine o incarcatura virala sub
nivelul de detectare ar trebui abandonat. Uneori ar putea fi mai intelept sa
reducem obstacolele si sa asteptam noi optiuni cum ar fi tipranavir sau
inhibitorii de intrare. Acesti pacienti ar trebui monitorizati in centre mai mari
unde noi optiuni vor fi disponibile, si unde clinicienii au experienta cu
regimurile intensificate. Irosirea unui singur nou medicament ar trebui
evitata;daca e posibil ar trebui folosite 2 sau mai multe medicamente
eficiente!
Hipersusceptibilitatea NNRTI
Formele virale sunt considerate hipersusceptibile la anumite medicamente
daca IC50 (50% concentratie inhibitorie) pentru medicament este mai scazuta
decat cea a tipului „wild” in testele de rezistenta fenotipica. Acest fenomen
pentru care corespondentul biochimic este inca subiect de dezbatere, apare
in general foarte rar cu analogii nucleozidici, dar destul de frecvent cu NNRTI,
si in majoritatea cazurilor pentru virusuri care au dezvoltat mutatii rezistente
la analogi nucleozidici.
185
Sfaturi practice pentru terapia de salvare
1. prima intrebare: Ce tratament anterior a urmat pacientul si pentru ce
perioada – daca acest aspect este neclar, ar trebui realizat un test de
rezistenta (nici un test de rezistenta in cursul perioadei de intrerupere a
tratamentului!).
2. dupa adresarea primului punct, folositi cat mai multe medicamente noi
(active) posibil, dar fiti atenti asupra potentialelor efecte secundare!
3. nu asteptati prea mult pentru modificare, oferind virusului posibilitatea de a
dezvolta alte mutatii de rezistenta-cu cat mai mare este incarcatura virala la
momentul modificarii, cu atat mai putine sunt sansele de succes.
4. folositi lopinavir/r! Luati de asemenea in considerare dubla stimulare
(double boosting), preferabil cu saquinavir.
5. a mai luat pacientul NNRTI? Daca nu, este momentul prielnic! Daca da, si
daca exista rezistenta la NNRTI: incetati administrarea NNRTI!
6. numarul de celule CD4+ si antecedentele permit intreruperi ale
tratamentului inaintea unui regim de salvare?
7. nu cereti prea mult de la pacient! Nu orice pacient este potrivit pentru
Mega- sau Giga-HAART.
8. incurajati pacientul! Inhibitorii de intrare, tipranavir sau TMC125 devin deja
disponibile, si nu exista asa ceva ca „ne-tratabil”. Ar putea fi de multe ori
posibil sa „se hiberneze” (asteptare a noi medicamente).
9. nu exploatati imediat un singur nou medicament – daca starea pacientului
si numarul de celule CD4+ permit, asteptati cel putin un al doilea nou
medicament.
Bibliografie
1. Albrecht MA, Bosch RJ, Hammer SM, et al. Nelfinavir, efavirenz, or both
after the failure of nucleoside treatment of HIV infection. N Engl J Med
2001, 345:398-407. http://amedeo.com/lit.php?id=11496850
2. Back D, Khoo S, Gibbons S. The role of therapeutic drug level monitoring
in clinical practice. Abstract S20, 9th CROI 2002, Seattle, USA.
3. Battgay M, Harr T, Sponagel L. Salvage treatment against HIV. Ann Med
1999, 31: 253-260. http://amedeo.com/lit.php?id=10480756
4. Benson CA, Deeks SG, Brun SC, et al. Safety and antiviral activity at 48
weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside
reversetranscriptase
inhibitors in HIV type 1-infected protease inhibitorexperienced
patients. J Infect Dis 2002, 185:599-607.
http://amedeo.com/lit.php?id=11865416
5. Boffito M, Arnaudo I, Raiteri R, et al. Clinical use of lopinavir/ritonavir in a
salvage therapy setting: pharmacokinetics and pharmacodynamics. AIDS
2002, 16:2081-3. http://amedeo.com/lit.php?id=12370509
6. Chavanet P, Piroth L, Grappin M, et al. Randomized salvage therapy with
186
saquinavir-ritonavir versus saquinavir-nelfinavir for highly protease inhibitor-
experienced HIV-infected patients. HIV Clin Trials 2001, 2:408-12.
http://amedeo.com/lit.php?id=11673815
7. Deeks SG, Grant RM, Beatty GW, et al. Activity of a ritonavir plus
saquinavir-
containing regimen in patients with virologic evidence of indinavir or
ritonavir failure. AIDS 1998, 12: F97-102.
http://amedeo.com/lit.php?id=9677159
8. Deeks SG, Hecht FM, Swanson M, et al. HIV RNA and CD4 cell count
response to protease inhibitor therapy in an urban AIDS clinic: response
to both initial and salvage therapy. AIDS 1999, 13: F35-43.
http://amedeo.com/lit.php?id=10397555
9. Eron JJ, Haubrich R, Lang W, et al. A phase II trial of dual protease
inhibitor
therapy: amprenavir in combination with indinavir, nelfinavir, or
saquinavir. J Acquir Immune Defic Syndr 2001, 26: 458-61.
http://amedeo.com/lit.php?id=11391165
10. Fätkenheuer G, Hoetelmans RM, Hunn N, et al. Salvage therapy with
regimens containing ritonavir and saquinavir in extensively pretreated
HIV-infected patients. AIDS 1999, 13: 1485-9.
http://amedeo.com/lit.php?id=10465071
11. Grossman H, Frechette G, Reyes F. Mega-HAART: complex protective
regimens for HAART failure. Antiviral Therapy 1999, 4 (Supplement 1):
Abstract 23, 2nd International Workshop on Salvage Therapy for HIV
Infection
1999, Toronto, Canada.
12. Hall CS, Raines CP, Barnett SH, Moore RD, Gallant JE. Efficacy of
salvage
therapy containing ritonavir and saquinavir after failure of single
protease inhibitor-containing regimens. AIDS 1999, 13: 1207-12.
http://amedeo.com/lit.php?id=10416524
13. Hammer SM, Vaida F, Bennett KK, et al. Dual vs single protease inhibitor
therapy following antiretroviral treatment failure: a randomized trial. JAMA
2002, 288: 169-80. http://amedeo.com/lit.php?id=12095381
14. Haubrich RH, Kemper CA, Hellmann NS, et al. The clinical relevance of
non-nucleoside reverse transcriptase inhibitor hypersusceptibility: a
prospective
cohort analysis. AIDS 2002, 16:F33-40.
http://amedeo.com/lit.php?id=12370520
15. Jensen-Fangel S, Thomsen HF, Larsen L, Black FT, Obel N. The effect
of nevirapine in combination with nelfinavir in heavily pretreated HIV-1-
infected patients: a prospective, open-label, controlled, randomized
study. J Acquir Immune Defic Syndr 2001, 27:124-9.
http://amedeo.com/lit.php?id=11404533
187
16. Katlama C, Dominguez S, Duvivier C, et al. Benefits of treatment
interruption
in patients with multiple therapy failures, CD4 cells <200 /mm3
and HIV RNA >50 000 cp/ml (GIGHAART ANRS 097). Abstract 5887,
XIV International AIDS Conference 2002, Barcelona, Spain.
17. Katzenstein D, Bosch RJ, Wang N for the ACTG 364 Study Team.
Baseline
phenotypic susceptibility and virologic failure over 144 weeks among
nucleoside RT inhibitor experienced subjects in ACTG 364. Abstract 591,
9th CROI 2002, Seattle, USA.
18. Kempf DJ, Isaacson JD, King MS, et al. Identification of genotypic
changes in HIV protease that correlate with reduced susceptibility to the
protease inhibitor lopinavir among viral isolates from protease
inhibitorexperienced
patients. J Virol 2001, 75:7462-9.
http://amedeo.com/lit.php?id=11462018
19. Masquelier B, Breilh D, Neau D, et al. HIV-1 genotypic and
pharmacokinetic
determinants of the virological response to lopinavir-ritonavircontaining
therapy in protease inhibitor-experienced patients. Antimicrob
Agents Chemother 2002, 46:2926-32.
http://amedeo.com/lit.php?id=12183249
20. Mellors J, Bennett FVK, Hellmann NS for the ACTG 398 Study Team.
Efavirenz hypersusceptibility improves virologic response to multidrug
salvage regimens in ACTG 398. Abstract 45, 9th CROI 2002, Seattle,
USA. http://www.retroconference.org/2002/Abstract/12985.htm
21. Miller V, Cozzi-Lepri A, Hertogs K, et al. HIV drug susceptibility and
treatment response to mega-HAART regimen in patients from the Frankfurt
HIV cohort. Antivir Ther 2000, 5:49-55.
http://amedeo.com/lit.php?id=10846593
22. Mocroft A, Phillips AN, Miller V, et al. The use of and response to
secondline
protease inhibitor regimens: results from the EuroSIDA study. AIDS
2001, 15:201-9. http://amedeo.com/lit.php?id=11216928
23. Molla A, Mo H, Vasavanonda S, Han L, et al. In vitro antiviral interaction
of lopinavir with other protease inhibitors. Antimicrob Agents Chemother
2002, 46:2249-53. http://amedeo.com/lit.php?id=12069982
24. Montaner JS, Harrigan PR, Jahnke N, et al. Multiple drug rescue therapy
for HIV-infected individuals with prior virologic failure to multiple regimens.
AIDS 2001, 15:61-9. http://amedeo.com/lit.php?id=11192869
25. Paredes R, Puig T, Arno A, et al. High-dose saquinavir plus ritonavir:
long-term efficacy in HIV-positive protease inhibitor-experienced patients
and predictors of virologic response. J Acquir Immune Defic Syndr 1999,
22:132-8. http://amedeo.com/lit.php?id=10843526
26. Piketty C, Race E, Castiel P, et al. Phenotypic resistance to protease
188
inhibitors in patients who fail on HAART predicts the outcome at 48
weeks of a five-drug combination including ritonavir, saquinavir and efavirenz.
AIDS 2002, 14: 626-8.
27. Raguin G, Chene G, Morand-Joubert L, et al. Salvage therapy with
lopinavir/
ritonavir, amprenavir +/- an additional boost with ritonavir in HIV infected
patients with multiple treatment failure: Final 26-week results of
Puzzle 1 - ANRS104 study. Abstract H-1078, 42th ICAAC 2002, San Diego,
USA.
28. Sadler BM, Gillotin C, Lou Y, et al. Pharmacokinetic study of HIV protease
inhibitors used in combination with amprenavir. Antimicrob Agents
Chemother 2001, 45:3663-8.
29. Staszewski S, Dauer B, Stephan C, et al. Switch to a simple boosted
double protease inhibitor regimen of lopinavir/r and saquinavir without reverse
transcriptase inhibitors after multiple therapy failures. Abstract
4427, XIV International AIDS Conference 2002, Barcelona, Spain.
30. Stephan C, Lutz T, Kurowski M, et al. Lopinavir/Ritonavir versus Ritonavir
100 mg boosted Saquinavir plasma levels. Abstract 4561, XIV International
AIDS Conference 2002, Barcelona, Spain.
31. Tebas P, Patick AK, Kane EM, et al. Virologic responses to a ritonavir--
saquinavir-containing regimen in patients who had previously failed nelfinavir.
AIDS 1999, 13: F23-8. http://amedeo.com/lit.php?id=10202820
32. van Heeswijk RP, Veldkamp A, Mulder JW, et al. Combination of protease
inhibitors for the treatment of HIV-1-infected patients: a review of
pharmacokinetics and clinical experience. Antivir Ther 2001, 6:201-29.
http://amedeo.com/lit.php?id=11782591&dopt=11878403
33. Whitcomb JM, Deeks S, Huang W. Reduced susceptibility to NRTI is
associated with NNRTI hypersensitivity in virus from HIV-1-infected patients.
Abstract 234, 7th CROI 2000, San Francisco, USA.
http://www.retroconference.org/2000/abstracts/234.htm
34. Whitcomb JM, Huang W, Limoli K, et al. Hypersusceptibility to
nonnucleoside
reverse transcriptase inhibitors in HIV-1: clinical, phenotypic
and genotypic correlates. AIDS 2002, 16:F41-7.
http://amedeo.com/lit.php?id=12370521
35. Youle M, Tyrer M, Fisher M, et al. Brief report: two-year outcome of a
multidrug regimen in patients who did not respond to a protease inhibitor
regimen. J Acquir Immune Defic Syndr. 2002, 29:58-61.
http://amedeo.com/lit.php?id=11782591&dopt=Abstract
36. Zala C, Patterson P, Coll P, et al. Virological response and safety at 48
weeks of double boosted protease inhibitors with lopinavir/r plus either
saquinavir or amprenavir in heavily pretreated HIV infected patients. Abstract
4492, XIV International AIDS Conference 2002, Barcelona, Spain.
189
9. Cand sa oprim HAART
O recenzie curenta a intreruperilor de tratament
Christian Hoffmann
Cu greu se gaseste vreun alt subiect care sa fi generat discutii mai aprinse in
ultimii 4 ani decat intreruperea tratamentului. Insa, in dezbaterile asupra
riscurilor sau avantajelor posibile, multe aspecte sunt deseori confuze, fara a
se face diferentierea intre
• Intreruperi de tratament structurate(structured treatment interruption)
(STI)
• Tratament intermitent structurat (structured intermittent treatment)
• Perioade in care medicamentele nu sunt administrate (‚Drug holidays”)
• Administrarea neregulata a medicamentului, si
• Intreruperi permanente ale terapiei.
Motivele si scopurile intreruperilor de tratament pot varia foarte mult. Cand
este vorba de rationamente sau riscuri, ar trebui sa fie clar de ce se intrerupe
tratamentul:
• Din dorinta pacientului
• Pentru a imbunatati complianta si psihicul pacientului (dispare „sentinta
pe viata”)
• Pentru a reduce toxicitatea pe termen lung
• Din motive imunologice
• Ca strategie de salvare
190
ani (Davey et al 1999, Chun et al 2000). Incarcatura virala de obicei revine
la o valoare deasupra nivelului de detectare in decursul a 10-20 zile
(Davey et al 1999, Harrigan et al 1999, Garcia et al 1999). Durata de timp
pana la dublarea incarcaturii virale plasmatice este de circa 1,6-2,0 zile.
Incarcatura virala in diferite segmente, cum ar fi SNC se modifica in
plasma(Garcia et al 1999, Neumann et al 1999, Smith et al 2001) si acest
lucru se aplica probabil si pentru sperma si lichidul vaginal; pacientii
trebuie prin urmare informati despre riscul crescut de transmitere a HIV.
Ocazional, o revenire initiala a incarcaturii virale este observata (De Jong
et al 1997, Birk et al 2001). Numai dupa cateva saptamani, incarcatura
virala se stabileste la nivelul sau initial, anterior tratamentului (Hatano et al
2000). Virusul care revine in mod evident nu provine din rezervoarele
latente; trebuie sa existe si alte populatii, din care aceste noi virusuri sa
provina in decursul unei perioade de timp atat de scurte (Chun et al 2000,
Ho 2000, Imamichi et al 2001).
191
Insa, in cazul unei singure intreruperi a tratamentului, probabilitatea
dezvoltarii rezistentei la pacientii individuali poate sa nu fie in particular
crescuta, dupa cum Studiul francez COMET a aratat in 1999. La 10
pacienti, nici o rezistenta nu s-a dezvoltat in timpul intreruperilor de
tratament si dupa re-initierea terapiei, incarcatura virala era suprimata din
nou fara probleme (Neumann et al 1999). Dar, nu exista in prezent nici o
certitudine precum ca astfel de intreruperi pot sa nu duca la dezvoltarea
culturilor rezistente, care doar necesita mai mult timp pana cand sunt
capabile sa domine tipul wild (wild-type).
Tabelul de mai jos descrie exemplul unui pacient care se simtea bine din
punct de vedere clinic si care a cerut o intrerupere a tratamentului pentru
cateva saptamani. Stoparea si inceperea repetata a HAART probabil a
condus in ultimul rand la rezistenta in acest caz.
192
Fenomenele autoimune in contextul intreruperilor de tratament dupa cum a
fost observat la acesti pacienti nu au fost descrise anterior. Cresterea
acuta a incarcaturii virale care poate aparea, poate sa se prezinte
ocazional ca sindrom retroviral. Simptomele sunt similare infectiei acute
HIV, cu limfadenopatie, febra, astenie si stare de discomfort fizic (Colven
et al 2000, Kilby et al 2000, Zeller et al 2001).
193
STI – din motive imunologice
Nici un alt pacient nu a devenit la fel de faimos precum un barbat cu
infectie acuta tratat intr-o clinica particulara din Berlin acum cativa ani, si
care, cu o incarcatura virala de aproximativ 80.000 copii/ml, a inceput
HAART cuprins din didanozina, indinavir si hidroxiuree. Virusul a devenit
rapid nedetectabil. Dupa cateva dificultati – si 2 intreruperi scurte ale
tratamentului – HAART a fost in final intrerupt dupa 176 zile. Uimitor este
ca, chiar fara medicamente, viremia plasmatica in cazul acestui pacient a
ramas sub nivelul de detectare pentru mai mult de 4 ani.
195
Insa, daca aceste efecte sunt de durata si aduc beneficii pe termen lung
ramane neclar. In plus, la pacientii avansati din punct de vedere
imunologic, riscul intreruperii tratamentului trebuie luat in considerare. La
pacientii cu o trecere la tipul „wild”, incarcatura virala creste mai
semnificativ si celulele T helper scad la un nivel mai redus (Deeks et al
2001). Acest lucru confirma alte studii (Hawley – Foss et al 2001) si
propria noastra experienta, aceea ca chiar si pacientii cu rezistenta multi-
medicamentoasa beneficiaza clinic din continuarea tratamentului, desi
incarcatura virala ar putea sa nu fie inhibata suficient (vezi capitolul legat
de „Recuperare/Salvare”).
Intreruperea permanenta
Pot pacientii care, conform normelor actuale, au inceput HAART prea
devreme in timpul euforiei post-Vancouver sa opreasca tratamentul din
nou, pentru moment? Un studiu de observatie a 101 pacienti a aratat ca
acest lucru ar putea fi posibil la multi pacienti. 67% din pacientii acestui
studiu de la Universitatea John Hopkins au intrerupt HAART pe o perioada
medie de 74 saptamani. Cu cat nivelul de celule T CD4+ era mai crescut
la initierea terapiei, cu atat era posibila o intrerupere mai indelungata a
HAART (Parish et al 2002). Urmatorul tabel prezinta un astfel de exemplu.
(Nota: incarcatura virala a fost masurata prin mai multe metode pentru a
exclude erorile. Valorile relative ale CD4+ erau intre 13-15% pentru
intreaga perioada).
197
Oricum, nu exista in prezent informatii cu privire la avantajele sau
dezavantajele intreruperii tratamentului la astfel de pacienti. Decizia de
continuare sau intrerupere a tratamentului poate fi luata numai in functie
de caz.
198
Sfaturi practice pentru intreruperea tratamentului
Bibliografie:
1. Birk M, Svedhem V, Sonnerborg A. Kinetics of HIV-1 RNA and resistance-
associated mutations after cessation of antiretroviral combination
therapy. AIDS 2001, 15: 1359-68.
http://amedeo.com/lit.php?id=11504957
2. Bonhoeffer S, Rembiszewski M, Ortiz GM, Nixon DF. Risks and benefits
of structured antiretroviral drug therapy interruptions in HIV-1 infection.
AIDS 2000, 14:2313-22. http://amedeo.com/lit.php?id=11089619
199
3. Chun TW, Davey RT Jr, Engel D, Lane HC, Fauci AS. Re-emergence of
HIV after stopping therapy. Nature 1999, 401:874-5.
4. Chun TW, Davey RT Jr, Ostrowski M, et al. Relationship between
preexisting
viral reservoirs and the re-emergence of plasma viremia after
discontinuation of HAART. Nat Med 2000, 6:757-761.
http://amedeo.com/lit.php?id=10888923
5. Colven R, Harrington RD, Spach DH, Cohen CJ, Hooton TM. Retroviral
rebound syndrome after cessation of suppressive ART in three patients
with chronic HIV infection. Ann Intern Med 2000, 133: 430-4.
http://amedeo.com/lit.php?id=10975960
6. Cote HC, Brumme ZL, Craib KJ, et al. Changes in mitochondrial DNA as
a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med
2002, 346:811-20. http://amedeo.com/lit.php?id=11893792
7. Davey RT Jr, Bhat N, Yoder C, et al. HIV-1 and T cell dynamics after
interruption of HAART in patients with a history of sustained viral
suppression.
Proc Natl Acad Sci U S A 1999, 96:15109-14.
http://amedeo.com/lit.php?id=10611346
8. De Jong MD, de Boer RJ, de Wolf F, et al. Transient overshoot of HIV-1
viraemia after early discontinuation of antiretroviral treatment: role of target
cell availability. AIDS 1997, 11:F79-84
http://amedeo.com/lit.php?id=9302437
9. Deeks SG, Wrin T, Liegler T, et al. Virologic and immunologic
consequences
of discontinuing combination antiretroviral-drug therapy in HIVinfected
patients with detectable viremia. N Engl J Med 2001, 344: 472-
80. http://amedeo.com/lit.php?id=11172188
10. Delaugerre C, Valantin MA, Mouroux M, et al. Re-occurrence of HIV-1
drug mutations after treatment re-initiation following interruption in patients
with multiple treatment failure. AIDS 2001, 15: 2189-91.
http://amedeo.com/lit.php?id=11684940
11. Devereux HL, Youle M, Johnson MA, Loveday C. Rapid decline in
detectability
of HIV-1 drug resistance mutations after stopping therapy.
AIDS 1999, 13: F123-7. http://amedeo.com/lit.php?id=10630517
12. Dorman KS, Kaplan AH, Lange K, Sinsheimer JS. Mutation takes no
vacation: can structured treatment interruptions increase the risk of
drugresistant
HIV-1? J Acquir Immune Defic Syndr 2000, 25: 398-402.
http://amedeo.com/lit.php?id=11141239
13. Dybul M, Chun TW, Yoder C, et al. Short-cycle structured intermittent
treatment of chronic HIV infection with highly active antiretroviral therapy:
effects on virologic, immunologic, and toxicity parameters. Proc Natl Acad
Sci U S A. 2001, 98: 15161-6. Original-Artikel:
200
http://www.pnas.org/cgi/content/full/98/26/15161
14. Garcia F, Plana M, Ortiz GM, et al. The virological and immunological
consequences of structured treatment interruptions in chronic HIV-1 infection.
AIDS 2001, 15: F29-40. http://amedeo.com/lit.php?id=11416735
15. Garcia F, Plana M, Vidal C, et al. Dynamics of viral load rebound and
immunological changes after stopping effective antiretroviral therapy.
AIDS 1999, 13: F79-86 http://amedeo.com/lit.php?id=10449278
16. Harrigan PR, Whaley M, Montaner JS. Rate of HIV-1 RNA rebound upon
stopping antiretroviral therapy. AIDS 1999; 13: F59-62.
http://amedeo.com/lit.php?id=10371167
17. Haslett PA, Nixon DF, Shen Z, et al. Strong HIV-specific CD4+ T cell
responses in a cohort of chronically infected patients are associated with
interruptions in anti-HIV chemotherapy. J Infect Dis 2000, 181: 1264-72.
http://amedeo.com/lit.php?id=10751137
18. Hatano H, Miller KD, Yoder CP, et al. Metabolic and anthropometric
consequences
of interruption of HAART. AIDS 2000, 14: 1935-42.
http://amedeo.com/lit.php?id=10997397
19. Hatano H, Vogel S, Yoder C, et al. Pre-HAART HIV burden approximates
post-HAART viral levels following interruption of therapy in patients with
sustained viral suppression. AIDS 2000, 14: 1357-63.
http://amedeo.com/lit.php?id=10930150
20. Hawley-Foss N, Mbisa G, Lum JJ, et al. Effect of cessation of HAART
during a discordant response: implications for scheduled therapeutic
interruptions.
Clin Infect Dis 2001, 33: 344-8.
http://amedeo.com/lit.php?id=11438900
21. Hirschel B, Fagaard C, Oxenius A, et al. SSITT: a prospective trial of
treatment interruption in HIV infection. Abstract 528, 9th CROI 2002, Seattle,
USA
22. Ho DD, Zhang L. HIV-1 rebound after anti-retroviral therapy. Nat Med
2000, 6:736-737. http://amedeo.com/lit.php?id=11919491
23. Imamichi H, Crandall KA, Natarajan V, et al. HIV type 1 quasi species
that rebound after discontinuation of HAART are similar to the viral quasi
species present before initiation of therapy. J Infect Dis 2001, 183: 36-50.
http://amedeo.com/lit.php?id=11106537
24. Izopet J, Massip P, Souryis C, et al. Shift in HIV resistance genotype after
treatment interruption and short-term antiviral effect following a new salvage
regimen. AIDS 2000, 14: 2247-55.
25. Jaeger H, Wolf E, Hoffmann C, et al. CD4 disadvantage and improved
blood lipids in a large controlled 18-month trial of treatment interruptions
(TIs). Abstract WePeB5880, XIV International AIDS conference 2002,
Barcelona, Spain.
26. Katlama C, Dominguez S, Duvivier C, et al. Benefits of treatment
interruption
201
in patients with multiple therapy failures, CD4 cells <200 /mm3
and HIV RNA >50 000 cp/ml (GIGHAART ANRS 097). Abstract 5887,
XIV International AIDS Conference 2002, Barcelona, Spain.
27. Kilby JM, Goepfert PA, Miller AP, et al. Recurrence of the acute HIV
syndrome
after interruption of ART in a patient with chronic HIV infection: A
case report. Ann Intern Med 2000, 133: 435-8.
http://amedeo.com/lit.php?id=10975961
28. Lisziewicz J, Rosenberg E; Lieberman J, et al. Control of HIV despite the
discontinuation of antiretroviral therapy. N Engl J Med 1999, 340:1683-4.
29. Lori F, Lewis MG, Xu J, et al. Control of SIV rebound through structured
treatment interruptions during early infection. Science 2000, 290:1591-3.
30. Lori F, Lisziewicz J. Structured treatment interruptions for the
management
of HIV infection. JAMA 2001, 286: 2981-7.
http://amedeo.com/lit.php?id=11743839
203
10. Monitorizarea
Christian Hoffmann
Incarcatura virala
Incarcatura virala reprezinta numarul de copii virale din sange. Pe langa
numarul de celule CD4+, incarcatura virala a devenit cel mai important
marker surogat pentru infectia HIV (Hughes et al 1997, Mellors et al 1997,
Lyles et al 2000, Ghani et al 2001), furnizand informatii de pret asupra
indicatiilor pentru terapia antiretrovirala si asupra valorii critice care determina
succesul terapiei. Alti markeri surogat folositi frecvent in trecut, cum ar fi p24,
neopterin sau microglobulina-ß2, sunt acum invechite. Analizele incarcaturii
virale masoara cantitatea de ARN-HIV (material genetic viral), care este
corelat direct cu nuamarul de virusuri. Unitatile sunt copiile virale/ml (sau
echivalenti genomici). O modificare de unul sau mai multi log este atribuita
modificarii incarcaturii virale de una sau mai multe puteri ale lui 10.
Evaluare/ Apreciere
Cu cat mai mare este incarcatura virala, cu atat mai mare este riscul unei
scaderi a celulelor CD4+, care are ca urmare progresia bolii sau aparitia
afectiunilor asociate SIDA (Mellors et al 1997, Lyles et al 2000). O incarcatura
virala > 100.000copii/ml (5,0log) este in general considerata crescuta, o
valoare <10.000copii/ml – scazuta. Aceste valori nu au valoare absoluta si
servesc ca puncte de referinta.
204
Efectele viremiei plasmatice asupra statusului imun pot varia foarte mult de la
un individ la altul. Exista unii pacienti, a caror numar de celule CD4+ ramane
stabil pentru perioade relativ lungi in ciuda incarcaturii virale crescute, in timp
ce altii inregistreaza o scadere rapida in ciuda nivelelor relativ scazute ale
incarcaturii virale. Incarcatura virala este probabil, in general, mai scazuta la
femei decat la barbati. Intr-o meta-analiza, diferenta era 41% sau 0,23log
(95% interval limita 0,16 – 0,31 log) (Napravnik et al 2002). Motivul este
neclar. Este inca in discutie daca acest fenomen are impact asupra indicatiilor
de tratament.
Metode
3 metode sau analize sunt folosite in prezent pentru a masura incarcatura
virala: Reverse Transcription Poymerase Chain Reaction (RT-PCR),
branched chain ADN (b-ADN) (lant ramificat ADN); si Nucleic Acid Sequence-
Based Amplification (NASBA). Ele difera atat in ceea ce priveste nivelele de
detectare si in gama in care masuratorile pot fi considerae de incredere sau
reproductibile (vezi tabelul de mai jos). In toate metodele, cantitatea redusa
de ARN viral trebuie intai amplificata pentru a permite masuratorile. In cazul
PCR si NASBA, ARN-ul viral este transformat in cateva etape enzimatice si
apoi amplificat pana la valori ce pot fi masurate. ADN-B nu necesita aceasta
etapa enzimatica; amplificarea semnalului survine prin legarea fragmentelor
de ADN ramificat la ARN viral.
Desi variabilitatea in cadrul studiilor este destul de buna pentru toate cele 3
metode si ne putem astepta la valori reproductibile, variatiile metodologice
trebuie luate in considerare la interpretarea rezultatelor. Diferente de mai
putin de 0,3-0,5log nu sunt considerate semnificative.
O scadere de la 4,3 la 3,9log, de exemplu (ce corespunde unei descresteri de
la aprox. 20.000 la 8.000 copii virale/ml), nu semnifica neaparat o scadere a
incarcaturii virale. Acelasi lucru este valabil pentru cresteri ale incarcaturii
virale. Pot fi irelevante modificari de pana la trei ori. Pacienti care, dupa
simpla ascultare a unor cifre, isi fac frecvent griji fara a fi necesar sau devin
optimisti din false motive ar trebui atentionati asupra acestui aspect.
Factori ce intervin
Cu cat incarcatura virala este mai mare la initierea terapiei, cu atat dureaza
mai mult sa scada sub nivelul de detectare. Intr-un studiu, limita era intre 15
zile cu o incarcatura virala de baza de 1.000 fata de 113 zile cu o valoare de
baza de 1 milion copii virale/ml (Rizzardi et al 2000). Urmatoarea schema
prezinta descresterea bifazica tipica a incarcaturii virale dupa nivele crescute
initial (in acest caz aproape 4 milioane copii/ml).
Dupa initierea terapiei, incarcatura virala ar trebui sa fie sub 5.000 copii/ml
dupa o luna. Valori mai crescute prezic esecul in a atinge valori sub detectare
(Maggiolo et al 2000).
208
Celulele CD4+
Celulele CD4+ sunt limfocite T ce exprima pe suprafata lor receptorul
CD4. La aceasta subpopulatie de limfocite se mai face referire prin
celulele T helper. In afara incarcaturii virale, masurarea nivelului celulelor
CD4+ este cel mai important parametru sau marker surogat in medicina
HIV. Permite o estimare pe care se poate pune baza a riscului individual
de SIDA. Fiecare pacient HIV ar fi trebuit sa-si determine celulele CD4+ in
ultimele 6 luni! Sunt in general acceptate 2 valori de referinta: peste 400-
500 celule CD4+/µl, afectiunile severe asociate SIDA sunt foarte rare; sub
200 celule CD4+/µl, riscul de morbiditate legata de SIDA creste
semnificativ cu cresterea duratei de imunosupresie.
209
Figura 2. Exemplu de pacient pentru variatiile celulelor CD4+/µl intr-o
perioada de 4 ani. Incarcatura virala era in mod continuu sub 50 copii/ml,
HAART a ramas neschimbat.
Factori influentatori
210
Cinetica celulelor CD4+ in HAART
Similar cu incarcatura virala, o crestere bifazica a celulelor CD4+ survine dupa initierea HAART
(Renaud et al 1999, Le Moing et al 2002), cu o crestere rapida in decursul
primelor 3, 4 luni, si o crestere mult mai lenta dupa aceea. Intr-un studiu a
aproape 1.000 pacienti, numarul celulelor CD4+ a crescut cu 21/µl pe luna
in timpul primelor 3 luni. In urmatoarele 21 luni, aceasta rata era de numai
5,5 celule CD4+/µl pe luna (Le Moing et al 2002). Cresterea rapida initiala
a celulelor CD4+ se datoreaza probabil redistributiei, care este urmata de
noua productie de celule T tinere (Pakker et al 1998). Apoptoza diminuata
poate de asmenea sa joace un rol (Roger et al 2002).
211
valorile relative (procentajul) si raportul CD4+/CD8+ cu rezultatele
precedente!
Nu tulburati pacientul cu scaderi aparente – daca supresia virala
este suficienta, scaderea nu este de obicei legata de HIV! Numai
rezultate extrem de implauzibile ar trebui repetate.
Daca incarcatura virala este sub nivelul de detectare, masuratorile
de 3 ori pe luna ale celulelor CD4+ sunt suficiente.
Numarul de CD4+ si incarcatura virala ar trebui discutate de catre
medic.
212
CD4+, cu atat mai putin frecvent sunt necesare fundoscopiile. Examinari
ginecologice regulate cu frotiuri PAP sunt de asemenea recomandate (vezi
de asemenea indrumarile europene: http://hiv.net/link.php?id=185). Oricum,
asemenea criterii/indrumari sunt interpretate foarte diferit.
213
Anumite probleme asociate cu TDM ii limiteaza gama larga de utilizare.
Determinarea analogilor nucleozidici, de exemplu, este lipsita de sens din
moment ce sunt transformati in metaboliti activi numai intracelular.
Determinarea NNRTI sau PI poate astfel determina nivelele unei singure
componente a unei combinatii (care da gres). Alte probleme includ nu numai
formele virale cu nivele diferite de rezistenta, diferite concentratii inhibitorii,
legare variabila a proteinelor, si variabilitate in functie de timp a nivelelor
plasmatice, dar de asemenea probleme metodologice cu analizele, ca si cu
lipsa unor limite definite clar. Multe incertitudini raman astfel in determinarea
nivelelor terapeutice ale medicamentelor. Pana cand vor fi disponibile date
provenite din studii aleatorii, care sa dovedeasca valoarea clinica a TDM, atat
masurarea cat si interpretarea rezultatelor ar trebui lasate in seama unor
centre specializate.
Bibliografie:
1. Acosta EP, Kakuda TN, Brundage RC, Anderson PL, Fletcher CV.
Pharmacodynamics
of HIV type 1 protease inhibitors. Clin Infect Dis 2000,
Suppl 2:S151-9. http://amedeo.com/lit.php?id=10860900
2. Back D, Gatti G, Fletcher C, et al. Therapeutic drug monitoring in HIV
infection: current status and future directions. AIDS 2002, Suppl 1:S5-37.
Review. http://amedeo.com/lit.php?id=12035820
3. Burger DM, Aarnoutse RE, Hugen PW. Pros and cons of therapeutic drug
monitoring of antiretroviral agents. Curr Opin Infect Dis 2002, 15:17-22.
http://amedeo.com/lit.php?id= 11964901
4. Coste J, Montes B, Reynes J, et al. Comparative evaluation of three
assays
for the quantitation of HIV type 1 RNA in plasma. J Med Virol 1996,
50:293-302. http://amedeo.com/lit.php?id=8950685
5. Demeter LM, Hughes MD, Coombs RW, et al. Predictors of virologic and
clinical outcomes in HIV-1-infected patients receiving concurrent treatment
with indinavir, zidovudine, and lamivudine. ACTG Protocol 320. Ann
Intern Med 2001, 135: 954-64. http://amedeo.com/lit.php?id=11730396
6. Dieleman JP, Gyssens IC, van der Ende ME, de Marie S, Burger DM.
Urological complaints in relation to indinavir plasma concentrations in
214
HIV-infected patients. AIDS 1999, 13:473-8.
http://amedeo.com/lit.php?id=10197375
7. Durant J, Clevenbergh P, Garraffo R, et al. Importance of protease inhibitor
plasma levels in HIV-infected patients treated with genotypicguided
therapy: pharmacological data from the Viradapt Study. AIDS
2000, 14:1333-9. http://amedeo.com/lit.php?id=10930147
8. Farber CM, Barath AA, Dieye T. The effects of immunization in HIV type
1 infection. N Engl J Med 1996, 335:817; discussion 818-9.
9. Gatti G, Di Biagio A, Casazza R, et al. The relationship between ritonavir
plasma levels and side-effects: implications for therapeutic drug monitoring.
AIDS 1999, 13:2083-9. http://amedeo.com/lit.php?id= 10546861
10. Ghani AC, de Wolf F, Ferguson NM, et al. Surrogate markers for disease
progression in treated HIV infection. J Acquir Immune Defic Syndr 2001;
28: 226-31.. Abstract: http://amedeo.com/lit.php?id=11694828
11. Goletti D, Weissman D, Jackson RW, et al. Effect of Mycobacterium
tuberculosis
on HIV replication. Role of immune activation. J Immunol
1996, 157:1271-8. http://amedeo.com/lit.php?id=8757635
12. Gonzalez de Requena D, Nunez M, Jimenez-Nacher I, Soriano V. Liver
toxicity caused by nevirapine. AIDS 2002, 16:290-1.
http://amedeo.com/lit.php?id=11807315
13. Gorochov G, Neumann AU, Kereveur A, et al. Perturbation of CD4+ and
CD8+ T-cell repertoires during progression to AIDS and regulation of the
CD4+ repertoire during antiviral therapy. Nat Med 1998, 4: 215-21.
http://amedeo.com/lit.php?id=9461196
14. Ho DD, Neumann AU, Perelson AS, et al. Rapid turnover of plasma
virions
and CD4 lymphocytes in HIV-1 infection. Nature 1995, 373:123-6.
http://amedeo.com/lit.php?id=7816094
15. Hoover DR. Would confirmatory retesting of CD4+ cells to verify AIDS
status be too expensive? J Acquir Immune Defic Syndr 1993, 6:537-9.
16. Hughes MD, Johnson VA, Hirsch MS, et al. Monitoring plasma HIV-1
RNA levels in addition to CD4+ lymphocyte count improves assessment
of antiretroviral therapeutic response. ACTG 241 Protocol Virology
Substudy Team. Ann Intern Med 1997; 126: 929-38.. Abstract:
http://amedeo.com/lit.php?id=9182469
17. Kaufmann GR, Bloch M, Zaunders JJ, Smith D, Cooper DA. Long-term
immunological response in HIV-1-infected subjects receiving potent
antiretroviral therapy. AIDS 2000, 14: 959-69.
http://amedeo.com/lit.php?id=10853977
18. Kitchen CM, Kitchen SG, Dubin JA, Gottlieb MS. Initial virological and
immunologic response to HAART predicts long-term clinical outcome.
Clin Infect Dis 2001; 33: 466-72. http://amedeo.com/lit.php?id=11462181
19. Kolber MA, Gabr AH, De La Rosa A, et al. Genotypic analysis of plasma
215
HIV-1 RNA after influenza vaccination of patients with previously
undetectable
viral loads. AIDS 2002, 16: 537-42.
http://amedeo.com/lit.php?id=11872996
20. Kolte L, Dreves AM, Ersboll AK, et al. Association between larger thymic
size and higher thymic output in HIV-infected patients receiving HAART.
J Infect Dis 2002, 185:1578-85. http://amedeo.com/lit.php?id=12023763
21. Lange CG, Valdez H, Medvik K, Asaad R, Lederman MM. CD4+
Tlymphocyte
nadir and the effect of HAART on phenotypic and functional
immune restoration in HIV-1 infection. Clin Immunol 2002, 102:154-61.
http://amedeo.com/lit.php?id=11846457
22. Le Moing V, Thiebaut R, Chene G, et al. Predictors of long-term increase
in CD4(+) cell counts in HIV-infected patients receiving a protease inhibitor-
containing antiretroviral regimen. J Infect Dis 2002, 185: 471-80.
http://amedeo.com/lit.php?id=11865399
23. Lederman MM. Immune restoration and CD4+ T-cell function with
antiretroviral
therapies. AIDS 2001, Suppl 2:S11-5.
http://amedeo.com/lit.php?id=11424971
24. Lepri AC, Miller V, Phillips AN, et al. The virological response to HAART
over the first 24 weeks of therapy according to the pre-therapy viral load
and the weeks 4-8 viral load. AIDS 2001, 15: 47-54.
http://amedeo.com/lit.php?id=11192867
25. Lyles RH, Munoz A, Yamashita TE, et al. Natural history of HIV type 1
viremia after seroconversion and proximal to AIDS in a large cohort of
homosexual men. J Infect Dis 2000, 181:872-880.
http://amedeo.com/lit.php?id=10720507
26. Maggiolo F, Migliorino M, Pirali A. Duration of viral suppression in patients
on stable therapy for HIV-1 infection is predicted by plasma HIV
RNA level after 1 month of treatment. J Acquir Immune Defic Syndr 2000,
25:36-43. http://amedeo.com/lit.php?id=11064502
27. Malone JL, Simms TE, Gray GC, et al. Sources of variability in repeated
T-helper lymphocyte counts from HIV type 1-infected patients: total
lymphocyte
count fluctuations and diurnal cycle are important. J Acquir Immune
Defic Syndr 1990, 3:144-51. http://amedeo.com/lit.php?id=1967309
28. Marzolini C, Telenti A, Decosterd LA, et al. Efavirenz plasma levels can
predict treatment failure and central nervous system side effects in HIV-1-
infected patients. AIDS 2001, 15: 71-5.
http://amedeo.com/lit.php?id=11192870
29. Mellors JW, Munoz AM, Giorgi JV, et al. Plasma viral load and CD4+
lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med
1997, 126:946-954. http://amedeo.com/lit.php?id=9182471.
30. Napravnik S, Poole C, Thomas JC, Eron JJ Jr. Gender difference in HIV
216
RNA levels: a meta-analysis of published studies. J Acquir Immune Defic
Syndr 2002, 31:11-9. http://amedeo.com/lit.php?id=12352145
31. Notermans DW, Pakker NG, Hamann D, et al. Immune reconstitution
after 2 years of successful potent ART in previously untreated HIV type 1-
infected adults. J Infect Dis 1999, 180: 1050-6.
http://amedeo.com/lit.php?id=10479130
32. O'Brien WA, Grovit-Ferbas K, Namazi A, et al. HIV-type 1 replication can
be increased in peripheral blood of seropositive patients after influenza
vaccination. Blood 1995, 86:1082-9.
http://amedeo.com/lit.php?id=7620162
33. Pakker NG, Notermans DW, de Boer RJ, et al. Biphasic kinetics of
peripheral
blood T cells after triple combination therapy in HIV-1 infection: a
composite of redistribution and proliferation. Nat Med 1998, 4: 208-14.
http://amedeo.com/lit.php?id=9461195
34. Parekh B, Phillips S, Granade TC, et al. Impact of HIV type 1 subtype
variation on viral RNA quantitation. AIDS Res Hum Retroviruses 1999,
15:133-42. http://amedeo.com/lit.php?id=10029245
35. Perelson AS, Essunger P, Cao Y, et al. Decay characteristics of HIV-1-
infected compartments during combination therapy. Nature 1997,
387:188-91. http://amedeo.com/lit.php?id=9144290
36. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1
dynamics in vivo: virion clearance rate, infected cell life-span, and viral
generation time. Science 1996, 271:1582-6.
http://amedeo.com/lit.php?id=8599114
37. Polis MA, Sidorov IA, Yoder C, et al. Correlation between reduction in
plasma HIV-1 RNA concentration 1 week after start of antiretroviral
treatment and longer-term efficacy. Lancet 2001, 358: 1760-5
http://amedeo.com/lit.php?id=11734232
38. Renaud M, Katlama C, Mallet A, et al. Determinants of paradoxical CD4
cell reconstitution after protease inhibitor-containing antiretroviral regimen.
AIDS 1999, 13:669-76. http://amedeo.com/lit.php?id=10397561
39. Rizzardi GP, DeBoer RJ, Hoover S, et al. Predicting the duration of
antiretroviral treatment needed to suppress plasma HIV-1 RNA. J Clin Invest
2000, 105:777-782. http://amedeo.com/lit.php?id=10727446
40. Roger PM, Breittmayer JP, Durant J, et al. Early CD4(+) T cell recovery in
HIV-infected patients receiving effective therapy is related to a
downregulation
of apoptosis and not to proliferation. J Infect Dis 2002, 185:
463-70. http://amedeo.com/lit.php?id=11865398
41. Telenti A. New developments in laboratory monitoring of HIV-1 infection.
Clin Microbiol Infect 2002, 8:137-43.
http://amedeo.com/lit.php?id=12010168
42. Thiebaut R, Morlat P, Jacqmin-Gadda H, et al. Clinical progression of
HIV-1 infection according to the viral response during the first year of
217
antiretroviral treatment. AIDS 2000, 14: 971-8.
http://amedeo.com/lit.php?id=10853978
43. Veldkamp AI, Weverling GJ, Lange JM, et al. High exposure to nevirapine
in plasma is associated with an improved virological response in
HIV-1-infected individuals. AIDS 2001; 15: 1089-95.
http://amedeo.com/lit.php?id=11416710
44. Viard JP, Mocroft A, Chiesi A, et al. Influence of age on CD4 cell recovery
in HIV-infected patients receiving HAART: evidence from the EuroSIDA
study. J Infect Dis 2001, 183: 1290-4.
http://amedeo.com/lit.php?id=11262215
45. Walter EA, Gilliam B, Delmar JA, et al. Clinical implications of identifying
non-B subtypes of HIV type 1 infection. Clin Infect Dis 2000, 31:798-802.
46. Wu H, Kuritzkes DR, McClernon DR, et al. Characterization of viral
dynamics
in HIV type 1-infected patients treated with combination antiretroviral
therapy: relationships to host factors, cellular restoration, and virologic
end points. J Infect Dis 1999, 179: 799-807.
http://amedeo.com/lit.php?id=10068574
218
Capitolul 4:
Managementul efectelor secundare
Christiane Schieferstein
Tulburari SNC
Pana la 40% din pacienti, tratamentul cu efavirenz duce la efecte
secundare la nivelul SNC, cum ar fi ameteli/vertij, insomnie, si cosmaruri;
chiar si modificari de dispozitie, depresii si depersonalizari pot aparea.
Aceste efecte secundare sunt observate in principal in timpul primelor zile
si saptamani de tratament. Intreruperea terapiei devine necesara doar la
3% din pacienti. Exista o legatura intre nivelele plasmatice crescute de
efavirenz si aparitia simptomelor la nivelul SNC (Marzolini et al 2001).
Lorazepamul poate diminua aceste efecte secundare, si haloperidolul pote
fi administrat pentru atacurile de panica si cosmaruri. Pacientii ar trebui
informati despre natura acestor simptome, si ca se asteapta de obicei
rezolvarea acestora dupa o perioada scurta de timp. Aceste efecte
secundare se observa rareori la alti NNRTI (Highleyman 2000).
Polineuropatia periferica
Polineuropatia periferica este in majoritatea cazurilor cauzata de analogii
nucleozidici zalcitabina, didanozina, si stavudina. De obicei se manifesta
printr-o distributie simetrica distala si paralizie sensorimotorie. Pacientii se
plang de parestezii si dureri la nivelul mainilor si picioarelor, care de multe ori
debuteaza treptat dupa cateva luni de terapie. Infectia HIV propriu-zisa poate
duce la polineuropatie periferica, dar forma indusa medicamentos devine
aparenta mult mai devreme si se poate dezvolta in decursul unei perioade
scurte de timp. Pacientii ar trebui informati ca ar trebui sa-si consulte medicul
curant cat mai devreme posibil daca tulburarile tipice apar/se dezvolta.
221
si nu sunt intotdeauna complet reversibile. Tratamentul este dificil, si nu
exista terapie specifica.
Probleme renale
Problemele renale apar in special in tratamentul cu indinavir, si sunt cauzate
de cristalele de indinavir, care pot fi descoperite in urina la pana la 20% din
pacienti. Aproximativ 10% din pacienti dezvolta nefrolitiaza, care nu e vizibila
pe radiografii, insotita de colici renale. Insuficienta renala este rara (Olyaei et
al 2000, Kopp 2002). Simptomele de colica acuta includ dureri de spate si
dureri costale, precum si dureri abdominale, care pot iradia in regiunea
inghinala sau genitala( a testiculelor). Poate aparea de asemenea hematurie.
Evaluarile ar trebui sa includa un examen fizic, teste de urina si teste ale
functiei renale si ultrasunete. Pentru terapia acuta, analgezia i.v. (de exemplu
metamizole 1 pana la 2,5g) sau diclofenac (de exemplu 100 – 150 mg) poate
fi administrata in combinatie cu medicamente spasmolitice (de exemplu
butilscopolamina, 20 mg i.v.). acestea usureaza de obicei simptomele destul
de rapid, si pot fi repetate dupa cateva minute daca simptomele continua.
Daca aceasta abordare este lipsita de succes, poate fi administrata petidina
50-100 mg i.v. sau i.m. Lichidele ar trebui administrate cu moderatie in timpul
colicilor.
Hepatotoxicitatea
Testele de functionalitate hepatica crescute pot fi cauzate de medicamente,
hepatita virala sau abuz de alcool. Ele apar la 2-18% din pacientii cu HAART,
independent de clasele de medicamente folosite (Bartlett et al 2001).
222
Hepatotoxicitatea severa si insuficienta hepatica au fost observate in timpul
tratamentului cu nevirapina, si pacientii care luau PI, indinavir si ritonavir cu
afectiuni hepatice pre-existente, ar trebui sa primeasca aceste medicamente
numai sub monitorizare stricta (Sulkowski et al 2000/2002).
Anemia, leucopenia
5 pana la 10% din pacientii care iau zidovudina, dezvolta anemie (Carr et al
2001). Neutropenia apare mai putin frecvent. Cei mai afectati sunt pacientii
cu infectie HIV avansata si mielosupresie pre-existenta, la chimoterapie sau
co-medicatie cu alte medicamente mielotoxice. Monitorizarea lunara a
sangelui este importanta, pentru ca anemia se poate dezvolta chiar si dupa
ani de tratament. In caz de anemie severa, ar trebui intrerupta administrarea
zidovudinei; rareori, ar putea fi necesara o transfuzie sangvina. Tratamentul
cu eritropoietina sau G-CSF este o optiune, dar ar trebui evitata ca optiune pe
223
termen lung daca e posibil, datorita costurilor crescute asociate. Anemia este
observata mai putin frecvent la stavudina, lamivudina si abacavir; leucopenia
poate aparea la indinavir, abacavir sau tenofovir. Pentru mai multe informatii
legate de trombocitopenie, vezi capitolul intitulat “Trombocitopenia asociata
HIV”.
Alergiile
Alergiile apar de aproximativ 100 de ori mai frecvent la persoanele infectate
HIV decat la populatia generala (Roujeau et al 1994). Alergiile la
medicamentele antiretrovirale apar la toate NNRTI, la fel ca si in cazul
analogului nucleozidic, abacavir (vezi mai jos) si PI, amprenavir. Nevirapina si
delavirdina pot cauza o usoara urticarie la 15 pana la 20% din pacienti, dintre
care 7% vor intrerupe tratamentul. Urticaria este observata mai putin frecvent
la efavirenz, pentru care numai 2% din pacienti intrerup administrarea
medicamentelor (Carr et al 2001). Abacavir determina o reactie de
hipersensibilitate la aproximativ 2-4% din pacienti, care ar putea fi letale (vezi
Hewitt 2002). O predispozitie genetica pentru reactia de hipersensibilitate
(HSR) la abacavir a fost adusa in discutie. 2 studii au gasit o corelatie intre
tipul HLA (in particular HLA-B 57) si aparitia HSR (Hetherington et al 2002,
Mallal et al 2002).
Alergii la NNRTI
Alergia la NNRTI este o reactie reversibila, sistemica si in mod tipic se
prezinta sub forma unei eruptii eritematoase, maculopapulare, pruriginoase si
confluente, distribuite in principal la nivelul trunchiului si membrelor. Febra
poate precede eruptia. Alte simptome includ (partial severe) mialgie,
oboseala si ulceratiile mucoase. Alergia debuteaza de obicei in a 2-a sau a 3-
a saptamana de tratament. Daca simptomele apar dupa 8 saptamani de la
initierea terapiei, alte medicamente ar trebui suspectate. Reactii severe de
tipul sindromului Stevens-Johnson, necroliza epidermala toxica (sindromul
Lyell’s) sau hepatita anicterica sunt rare.
Hipersensibilitatea la abacavir
224
Eruptia asociata cu reactia de hipersensibilitate la abacavir este de multe ori
discreta, in contrast cu reactiile pielii la nevirapina si efavirenz; la 30% din
pacienti pot sa nu apara deloc (Hewitt 2002). 80% din pacienti au febra. In
plus fata de o stare de rau/discomfort fizic general (care se inrautateste de la
o zi la alta!), alte simptome frecvente includ efectele secundare gastro-
intestinale cum ar fi greturile, varsaturile, diareea si durerile abdominale.
Simptomele respiratorii cum ar fi dispneea, tusea si durerile de gat sunt rare.
Modificari ale analizelor sangelui, cresterea transaminazelor hepatice,
fosfataza alcalina, creatinina si LDH pot insoti HSR. De obicei nu apare
eozinofilie. A fost descris un caz de sindrom Stevens-Johnson (Bossi et al
2002). HSR apare dupa o perioada medie de 8 zile, si in decursul primelor 6
saptamani in 93% din cazuri.
Daca abacavir este intrerupt la timp, HSR este complet reversibil in cateva
zile. Daca HSR nu este diagnosticata, poate fi fatala. Dupa intreruperea
abacavirului, un tratament in plus de suport include hidratarea intravenoasa si
posibil steroizi.
Acidoza lactica
In comparatie cu hiperlactacidemia asimptomatica, care apare la aproximativ
15% din pacientii tratati cu NRTI (Carr et al 2001, Gerard et al 2000), acidoza
lactica este o complicatie rara, dar care pune in pericol viata pacientului.
Apare cel mai frecvent la tratamentul cu stavudina si didanozina. Factorii de
risc sunt obezitatea, sexul feminin si sarcina. NRTI se presupune a cauza
toxicitate mitocondriala prin inhibarea polimerazei ADN mitocondriale.
Incidenta este de aproximativ 3,9/1000 NRTI pacienti ani (John et al 2001).
225
Simptomele clinice, cum ar fi oboseala, greturile si varsaturile, durerile
abdominale, pierderile in greutate si dispneea sunt foarte nespecifice si se
pot dezvolta acut sau mai treptat. Rezultatele analizelor sangelui arata
niveluri ridicate de acid lactic cu sau fara acidoza metabolica ( sangele ar
trebui recoltat intr-un tub racit oxalat fluorurat cu transportare pe gheata si
masurarea nivelului de acid lactic la 4 ore). CPK, LDH, lipaza, amilaza, γGT
si anion gap ar putea fi crescute; bicarbonatul seric ar putea fi scazut.
Steatoza hepatica poate fi deseori observata la examinarea cu ultrasunete
sau CT.
Pancreatita
In plus fata de acidoza lactica, pancreatita este o alta potentiala complicatie
fatala, probabil cauzata de toxicitatea mitocondriala. Nu se deosebeste de
pancreatita de orice alta etiologie, nici clinic, nici prin teste de laborator. Este
226
cauzata in principal de didanozina, si ocazional de stavudina, lamivudina si
zalcitabina. Combinarea de stavudina plus didanozina plus hidroxiuree poarta
un risc crescut de pancreatita. Consumul de alcool si tratamentul cu
pentamidina reprezinta de asemenea factori de risc.
Necroza avasculara
Necroza avasculara apare in aproximativ 0,4% din pacientii HIV, si de aceea
este semnificativ mai frecventa decat in populatia generala (Cheonis 2002). O
asociere cu PI a fost emisa, pana acum fara dovada unei corelatii directe.
Factorii de risc pentru necroza avasculara sunt abuzul de alcool,
hiperlipidemia, tratamentul cu steroizi, hipercoagulabilitatea,
hemoglobinopatia, accidentarile, abuzul de nicotina si pancreatita cronica.
Cea mai obisnuita localizare a necrozei este capul femural si cea mai putin
frecventa, capul humerusului. Initial, pacientii se plang de dureri la exercitare
de presiune pe articulatia afectata, cu simptome care se inrautatesc cu
fiecare zi si saptamana. Fazele initiale ar putea fi asimptomatice, dar sunt
urmate de dureri osoase severe si mobilitate redusa. Necroza capului femural
produce dureri in regiunea soldului sau regiunea inghinala, care pot iradia la
genunchi.
227
Alti factori de risc trebuie identificati si eliminati. Daca este posibil, ar trebui
intrerupta administrarea de steroizi si tratamentul cu PI ar trebui modificat.
Fizioterapia este recomandata. Medicamentele AINS (de exemplu ibuprofen)
reprezinta tratamentul de electie pentru analgezie.
Osteopenia/Osteoporoza
Persoanele infectate HIV au o densitate osoasa mai redusa decat persoanele
neinfectate. Densitatea osoasa este determinata prin masurarea absorbtiei
radiatiei X (de ex. DEXA scan) sau undelor de ultrasunete. Rezultatele sunt
date sub forma numarului de deviatii standard ( scorul T (the T-score)), fata
de valoarea medie la persoanele tinere si sanatoase. Valori intre -1 si -2,5
deviatii standard (SD) sunt cunoscute sub numele de osteopenie, valori peste
-2,5 SD ca osteoporoza. In plus fata de infectia HIV, alti factori cum ar fi
malnutritia, tesuturile grase diminuate, tratamentul cu steroizi, imobilizarea si
tratamentul cu PI si NRTI par a juca un rol in patogeneza acestei afectiuni.
Osteopenia si osteoporoza sunt de multe ori asimptomatice. Osteoporoza
apare in principal la nivelul vertebrelor, bratelor si soldurilor.
Lipodistrofia, Dislipidemia
Efectele secundare pe termen lung ale HAART includ tulburari metabolice
cum ar fi lipodistrofia, hiperlipidemia si rezistenta la insulina. Exista multiple
tulburari pentru care etiologia nu este stabilita cu certitudine. Multe afectiuni
nu pot fi atribuite unor anumite medicamente sau clase de medicamente.
Pentru detalii vezi capitolul intitulat: “Sindromul de lipodistrofie”.
Bibliografie
1. Bartl R. Osteoporose bei AIDS-Patienten: Rationale Diagnostik und
Therapie. In: Hoffmann C, Jäger H (Hrsg.): AIDS. Die Auseinandersetzung
geht weiter. Landsberg/ Lech: Verlag Moderne Industrie, 2002.
2. Bartlett JG, Gallant JE. 2001 - 2002 Medical Management of HIV Infection.
Published by John Hopkins University, Division of Infectious Diseases.
2001. http://hiv.net/link.php?id=16
3. Bossi P, Roujeau JC, Bricaire F, et al. Stevens-Johnson syndrome
associated
with abacavir therapy. Clin Infect Dis 2002, 35:902
4. Boubaker K, Sudre P, Bally F, et al. Changes in renal function associated
with indinavir. AIDS 1998, 12:F249-54.
http://amedeo.com/lit.php?id=9875572
5. Brinkman K, Vrouenraets S, Kauffmann R, et al. Treatment of nucleoside
reverse transcriptase inhibitor-induced lactic acidosis. AIDS 2000,
14:2801-2.
6. Brinkman K. Management of hyperlactatemia: no need for routine lactate
measurements. AIDS 2001, 15:795-7.
7. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet
2001, 356:1423-1430. http://amedeo.com/lit.php?id=11052597
8. Carr A, Morey A, Mallon P, et al. Fatal portal hypertension, liver failure,
and mitochondrial dysfunction after HIV-1 nucleoside analogue-induced
229
hepatitis and lactic acidaemia. Lancet 2001, 357:1412-4.
http://amedeo.com/lit.php?id=11356442
9. Carr A, Samaras K Thorisdottir A, et al. Diagnosis, prediction, and natural
course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia,
and diabetes mellitus: a cohort study. Lancet 1999, 353:2093-9.
http://amedeo.com/lit.php?id=10382692
10. Cheonis N. Osteonecrosis and HIV Disease. BETA. 2002 Winter; 15:22-
9. http://www.sfaf.org/treatment/beta/b49/b49osteonecrosis.html
11. Cheonis N. Osteoporosis and HIV Disease. BETA. 2001 Summer-
Fall;14:26-34. http://hiv.net/link.php?id=17
12. Coopman SA, Johnson RA, Platt R, Stern RS. Cutaneous disease and
drug reactions in HIV infection. N Engl J Med. 1993, 328:1670-4.
http://amedeo.com/lit.php?id=8487826
13. Gerard Y, Maulin L, Yazdanpanah Y, et al. Symptomatic
hyperlactataemia:
an emerging complication of antiretroviral therapy. AIDS 2000,
14:2723-30. http://amedeo.com/lit.php?id=11125891
14. Hardy H, Esch LD, Morse GD. Glucose disorders associated with HIV
and its drug therapy. Ann Pharmacother 2001, 35:343-51.
http://amedeo.com/lit.php?id=11516363
15. Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in
HLA-B region and hypersensitivity reactions to abacavir. Lancet 2002,
359:1121-2. http://amedeo.com/lit.php?id=11943262
16. Hewitt RG. Abacavir hypersensitivity reaction. Clin Infect Dis 2002,
34:1137-42. http://amedeo.com/lit.php?id=11915004
17. Highleyman L. Adverse effects associated with antiretroviral therapy.
BETA, Spring, 2000. http://hiv.net/link.php?id=18
18. Highleyman L. Managing nausea, vomiting, and diarrhea. BETA. 2002
Spring;15(2):29-39. http://hiv.net/link.php?id=15
19. John M, Moore CB, James IR, et al. Chronic hyperlactatemia in
HIVinfected
patients taking ART. AIDS 2001, 15:795-7.
http://amedeo.com/lit.php?id=11371686
20. Knobel H, Miro JM, Domingo P, et al. Failure of a short-term prednisone
regimen to prevent nevirapine-associated rash: a double-blind
placebocontrolled
trial. J Acquir Immune Defic Syndr 2001, 28:14-18.
http://amedeo.com/lit.php?id=11579272
21. Kopp JB. Renal Dysfunction in HIV-1-infected Patients. Curr Infect Dis
Rep 2002, 4:449-460. http://amedeo.com/lit.php?id=12228033
22. Lichterfeld M, Spengler U, Rockstroh J. Hepatotoxizität der
antiretroviralen
Therapie. Arzneimitteltherapie. 2001, 19:250 - 258.
23. Mallal S, Nolan D, Witt C, Masel G, et al. Association between presence
of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1
230
reverse-transcriptase inhibitor abacavir. Lancet 2002, 359:727-32.
http://amedeo.com/lit.php?id=11888582
24. Marzolini C, Telenti A, Decosterd LA, et al. Efavirenz plasma levels can
predict treatment failure and central nervous system side effects in HIV-1-
infected patients. AIDS 2001, 15:71-5.
http://amedeo.com/lit.php?id=11192870
25. McArthur JC, Yiannoutsos C, Simpson DM, et al. A phase II trial of nerve
growth factor for sensory neuropathy associated with HIV infection.
ACTG Team 291. Neurology 2000, 54:1080-8.
http://amedeo.com/lit.php?id=10720278
26. Modest GA, Fuller J. Abacavir and diabetes. N Engl J Med 2001,
344:142-4.
27. Olyaei AJ, deMattos AM, Bennett WM. Renal toxicity of protease
inhibitors.
Curr Opin Nephrol Hypertens 2000, 9:473-6.
http://amedeo.com/lit.php?id=10990364
28. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N
Engl J Med 1994, 331:1272-85.
29. Schwarze S. Die "dunkle Seite der HAART" - Nebenwirkungen und wie
man sie in den Griff bekommt. In: Hoffman C, Jäger H (Hrsg.): AIDS. Die
Auseinandersetzung geht weiter. Landsberg/ Lech: Verlag Moderne Industrie
mi, 2002.
30. Sherman DS, Fish DN. management of protease inhibitor - associated
Diarrhea. Clin Infect Dis 2000, 30:908-14.
http://amedeo.com/lit.php?id=10854364
31. Sulkowski MS, Thomas DL, Chaisson RE, et al. Hepatotoxicity associated
with antiretroviral therapy in adults infected with HIV and the role of
Hepatitis C or B Infection. JAMA 2000, 283: 74 - 80.
http://amedeo.com/lit.php?id=10632283
32. Sulkowski MS, Thomas DL, Mehta SH, et al. Hepatotoxicity associated
nevirapine or efavirenz-containing antiretroviral therapy: role of Hepatitis
C and B Infection. Hepatology 2002, 35:182-189.
http://amedeo.com/lit.php?id=11786975
33. Tebas P, Powderly WG, Claxton S, et al. Accelerated bone mineral loss
in HIV-infected patients receiving potent antiretroviral therapy. AIDS
2000, 14:F63-7. http://amedeo.com/lit.php?id=10770534
231
Capitolul 5:
Sindromul de lipodistrofie
Context
Manifestari clinice
Lipodistrofia a fost descrisa initial drept o afectiune caracterizata prin
pierderea regionala sau generalizata de grasime subcutanata. Formele
neasociate-HIV, cum ar fi lipodistrofia congenitala sau lipodistrofia partial
familiala, sunt de frecventa foarte redusa. In general, aceste forme sunt
asociate cu anormalitati metabolice complexe si sunt dificil de tratat.
Termenul de “sindrom de lipodistrofie” in HIV a fost introdus pentru o
afectiune medicala complexa ce include redistribuirea aparent anormala a
grasimii si tulburarile metabolice observate la pacientii HIV care primesc
terapie cu inhibitori de proteaze (Carr et al 1998). De atunci, alte afectiuni,
cum ar fi osteopenia si hiperlactemia, au fost rezumate in diagnosticul de
sindrom de lipodistrofie. Dar, chiar dupa ani de la prima descriere, inca nu
exista nici un consens asupra unei definitii pentru sindromul de lipodistrofie la
pacientii HIV. Astfel, diagnosticul de lipodistrofie se bazeaza de multe ori mai
232
mult pe o interpretare mai individuala decat pe o clasificare evaluata. In
ultimul rand, modificarile in distributia grasimii trebuie considerate ca fiind mai
degraba procese dinamice cu diverse trasaturi si o intensitate neregulata de-
a lungul timpului.
Lipodistrofia asociata HIV include modificari atat clinice cat si metabolice. Cel
mai remarcabil semn clinic este pierderea grasimii subcutanate (lipoatrofie) la
nivelul fetei (periorbital, temporal), si la nivelul extremitatilor. Cea din urma
ocazional duce la aparitia de vene proeminente asemanatoare varicelor.
Pierderea grasimii periferice poate fi insotita de o acumulare a grasimii
viscerale care poate cauza simptome usoare gastro-intestinale. Obezitatea
viscerala, ca unica trasatura a redistribuirii anormale a grasimii, pare sa apara
la un numar minoritar de pacienti. In contrast cu descrierile precedente,
pernutele dorso-cervicale de grasime la pacientii HIV par a fi mai mari fata de
cele observate la populatia de control, dar nu au o frecventa mai ridicata
(Zolopa et al 2003). Pacientii HIV de sex feminin uneori se plang de mariri
dureroase ale sanilor care au fost atribuite sindromului de lipodistrofie.
Ramane neclar daca ginecomastia la pacientii de sex masculin este o
componenta a sindromului. In prezent, se strang dovezi precum
componentele clinice majore – lipoatrofia, adipozitatea centrala si combinarea
amandorura – rezulta din procese de dezvoltare patogenice diferite.
233
liberi crescuti (FFA= free fatty acids) si HDL scazut (high density lipoprotein).
Deseori aceste anormalitati metabolice apar sau se deterioreaza inainte de
manifestarea redistribuirii grasimii. Frecventa rezistentei la insulina si
intolerantei la glucoza a fost raportata in literatura de 20 pana la 50% in
functie de design-ul studiului si metodele de determinare/masurare. Pacientii
lipodistrofici prezinta cele mai mari rate de tulburari metabolice. Diabetul
evident este mai putin frecvent cu o rata de aparitie intre 1 si 6%.
Hiperlipidemiile reprezinta un efect secundar frecvent observat al terapiei antiretrovirale, in special
in combinatii ce includ inhibitori de proteaze. Dat fiind faptul ca multi pacienti
HIV se prezinta cu nivele HDL deja scazute, acestea nu mai sunt reduse in
plus de medicamentele antiretrovirale. Hipertrigliceridemiile reprezinta
anormalitati lipidice esentiale, fie singure sau in combinatie cu
hipercolesterinemia. Nivelele lipidice de obicei ating un platou si raman
stabile dupa cateva saptamani dupa initierea sau modificarea terapiei HIV.
Toti inhibitorii de proteaze duc potential la hiperlipidemie, desi in masuri
diferite. De exemplu, Ageneraza (Amprenavir ®) pare a fi mai putin frecvent
asociata cu dislipidemia. In contrast, ritonavir (Norvir ®) duce de multe ori la
hiper-trigliceridemie legata de nivelul de medicamente. Cresteri de 200% a
nivelului de trigliceride si de 30-40% a nivelului colesterolului au fost descrise
dupa terapia pe termen scurt cu ritonavir. Observatii similare au fost facute la
persoanele sanatoase.
234
HAART, Sindromul de lipodistrofie si Riscul
cardiovascular
Redistribuirea grasimii si tulburarile in metabolismul glucozei si grasimilor
seamana cu o situatie clinica care este cunoscuta ca “sindromul metabolic” la
pacientii HIV-negativi. Aceasta afectiune include simptome de tipul
adipozitatii centrale, rezistenta la insulina si hiper-insulinemie, hiper-lipidemie
( LDL crescute, Lp (a) hiper-trigliceridemie si HDL scazute) si hiper-
coagulopatie. Dat fiind riscul cardiovascular bine stabilit ce rezulta din acest
sindrom metabolic, exista tot mai multe ingrijorari in ceea ce priveste un
potential risc crescut de infarct miocardic legat de terapie la pacientii HIV.
Aceste temeri sunt sustinute de rapoarte de hipertensiune arteriala in
HAART, o rata crescuta de fumatori printre pacientii HIV si nivele crescute de
activator tisular de plasminogen ( tissue plasminogen activator tPA) si
inhibitor-1 de activator de plasminogen (plasminogen activator inhibitor-1 PAI-
1) la pacientii cu lipodistrofie. Desi multe din studiile in principal retrospective
care se ocupau cu acest subiect sunt neconcludente, date recente dintr-un
studiu extins, international ( D:A:D study) furnizeaza dovezi pentru un risc
relativ crescut de infarct miocardic la 27% in timpul primilor 7 ani de HAART
(Friis-Møller et al 2003). Este oricum, de notat faptul ca varsta, sexul
masculin, fumatul si afectiuni pre-existente ale arterei coronare erau inca
asociate cu un risc mai crescut de dezvoltare a episoadelor cardiovasculare
decat HAART in acest studiu.
Patogeneza
Pentru o mai buna intelegere a patogenezei anormalitatilor metabolice
complexe, este util sa separam aspectele individuale ale sindromului de
lipodistrofie: adipocite/ redistribuirea grasimii, metabolism lipidic si
metabolismul carbohidratilor. Se face acest lucru pentru ca este foarte posibil
ca sindromul de lipodistrofie sa nu fie un sindrom stereotipic ci mai degraba
un amalgam de trasaturi clinice diferite, probabil de cauze multifactoriale.
Studii publicate in ultimii ani ofera dovezi pentru 2 presupuneri fundamentale:
prima, lipoatrofia si lipoacumularea rezulta din motive divergente sau numai
partial suprapuse patogenetice. A doua, NRTI, NNRTI, PI si chiar
medicamentele din fiecare clasa contribuie la sindromul de lipodistrofie si
caracteristicile sale individuale prin mecanisme diferite, probabil suprapuse si
in mod sigur sinergice.
NRTI si lipodistrofia
Tiparele redistribuirii grasimii la pacientii care primesc exclusiv NRTI sunt
deosebite de cele observate la pacienti in timpul terapiei PI. Pierderea de
grasime periferica este simptomul major observat la NRTI, desi cateva studii
clinice descriu o crestere a grasimii intra-abdominale minima la acesti
pacienti, care este evident mai redusa decat pentru PI. Dat fiind acest lucru,
in mod obisnuit, numai o crestere usoara a trigliceridelor a fost observata,
terapia NRTI exclusiva parand a avea un impact minor asupra metabolismului
lipidic. FFA crescuti postprandial la pacientii cu lipodistrofie, impreuna cu
experimentele in vitro, au dus la formularea ipotezei ca NRTI pot afecta
proteinele de legare a acizilor grasi (FABP – fatty acid binding proteins) care
sunt responsabile pentru incorporarea de grasime celulara si transportul
intracelular al grasimii. In contrast, adaugarea de stavudina (Zerit®) la un
regim PI dual nu a determinat o crestere suplimentara a nivelului de
colesterol total sau trigliceride.
Este bine stiut ca terapia NRTI pe termen lung poate cauza toxicitate
mitocondriala. Manifestarea clinica a acestor efecte secundare se prezinta
236
sub forma unor simptome de genul steatoza hepatica, hiperlactatemie severa
si polineuropatie. Ca explicatie pentru aceste simptome, a fost propusa
“ipoteza pol-g”, care mai tarziu a fost extinsa pentru a dezvalui lipoatrofia
observata la NRTI (Brinkman et al 1999). Pentru a mentine un nivel
bioenergetic corespunzator pentru functionarea celulara precisa, toate
celulele active metabolic depind de sinteza persistenta de ADN mitocondrial
(mt) mediat de polimeraza g. Mitocondriile necesita aport constant de
nucleozide pentru acest proces. Polimeraza g ADN mitocondrial retine atat
activitatea polimerazei ADN cat si activitatea polimerazei ADN ARN-
dependenta. Cea din urma este probabil responsabila pentru activitatea
revers transcriptazei HIV si astfel susceptibilitatea sa pentru interactiunile cu
NRTI.
237
S-a sugerat ideea bazata pe experimentele in vitro ca PI de tipul saquinavir
(Invirase ®/ Fortovase ®), indinavir (Crixivan ®), si ritonavir (Norvir ®) sunt
capabile sa inhibe degradarea proteazomala a apolipoproteinei B ducand la
acumularea intracelulara a acestei lipoproteine si eliberare excesiva ca
raspuns la FFA (Liang et al 2001). Utilizand izotopi stabili in vivo, alti autori au
demonstrat o crestere dramatica a turnover-ului FFA insotita de lipoliza
crescuta si clearance scazut al VLDL bogate in trigliceride si chilomicroni
(Shekar et al 2002).
Diagnostic
Atat lipsa unei definitii oficiale si nesiguranta legata de patogeneza si
posibilele consecinte pe termen lung, duc la o discutie continua despre
criteriile/indrumarile potrivite pentru evaluarea si managementul sindromului
de lipodistrofie HIV si anormalitatilor sale metabolice. In afara studiilor clinice,
diagnosticul se bazeaza in principal pe aparitia semnelor aparent clinice si
raportarea lor de catre pacienti. Acest lucru pare suficient pentru evaluarea
clinica de rutina in special cand modificarea aspectului fizic se dezvolta destul
de rapid si sever. Totusi, pentru investigatii clinice, in special epidemiologice
si de interventie, sunt necesare determinari mai demne de incredere. Dar, in
acest moment, nici o tehnica nu a demonstrat o sensibilitate, specificitate sau
valoare predictiva suficienta pentru a diagnostica definitiv sindromul de
lipodistrofie-HIV prin comparatie cu rezultatele obtinute in cadrul populatiei
“normale”. O definitie propusa de Carr et al (1999)a fost frecvent utilizata
pana acum (Tabelul 1). Un studiu recent desfasurat in mai multe centre
pentru dezvoltarea unui obiectiv si a unei definitii cu aplicabilitate larga
propune un model ce include varsta, sexul, durata infectiei HIV, stadiul HIV,
raportul talie/sold, “anion gap” (diferenta dintre suma cationilor si anionilor din
plasma sau ser), HDL colesterol seric, transportul de grasime
trunchi/periferie, procentul de grasime la nivelul picioarelor si raportul de
grasime intra-abdominala/extra-abdominala. Utilizand acesti parametri,
diagnosticul lipodistrofiei avea o sensibilitate de 79% si o specificitate de
80%. Desi acest model este in principal pentru cercetare si contine date
detaliate privind compozitia corpului, modele si sisteme de notare alternative,
incorporarea numai a datelor clinice si metabolice, a dat de asemenea
rezultate rezonabile (pentru mai multe informatii vezi
http://www.med.unsw.edu.au/nchecr).
240
(de exemplu depuneri de grasime dorso-cervicale extinse, DD=diagnostic
diferential pentru procese non-benigne si infectii). DEXA este potrivita pentru
examinarea grasimii apendiculare, care este formata aproape in intregime din
SAT si a fost folosita cu succes in studii epidemiologice. Totusi, SAT si VAT
nu pot fi deosebite de DEXA, fapt care limiteaza evaluarea modificarilor in
grasimea trunchiului. Aplicatiile sonografiei pentru a masura anumite
compartimente adipoase, inclusiv cele de la nivelul fetei, necesita
investigatori cu experienta si au fost minim aplicate in infectia HIV pana
acum. Analiza impedantei bioelectrice estimeaza compozitia intregului corp si
nu poate fi recomandata pentru masurarea distributiei de grasime anormala.
Terapia
Pana acum, cele mai multe incercari de a imbunatati sau chiar de a inversa
distributia anormala a grasimii prin modificarea tratamentului antiretroviral, au
avut un succes modest. In particular, pierderea grasimii periferice pare a fi
rezistenta la majoritatea interventiilor terapeutice. Componentele metabolice
ale sindromului ar putea fi mai usor de imbunatatit (Tabelul 2).
Recomadari
242
Varsta ( barbati ≥ 45 ani, femei ≥ 55 ani sau menopauza prematura fara
inlocuire hormanala, antecedente familiale pozitive de CHD prematura (la
rudele de gradul I < 55 ani si rude de sex feminin de gradul I < 65 ani),
fumatul, hipertensiunea ( tensiune ≥ 140/90 mm Hg sau administrarea de
medicamente antihipertensive), HDL < 40 mg/dl (1,0 mmol/l). Daca HDL
colesterol este peste > 60 mg/dl (1,6 mmol/l), scadeti un factor de risc din
total (dupa Dubé et al 2000 si Schambelan et al 2002)
Masuri specifice
Date fiind indicatiile extensive precum PI sunt vinovatele care contribuie
substantial la efectele secundare metabolice, numeroase incercari au fost
facute pentru a inlocui componenta PI a unui regim cu nevirapina, efavirenz
sau abacavir. Intr-adevar, aceste “switch-studies” (studii de inlocuire) au
demonstrat imbunatatiri substantiale, desi nu normalizarea lipidelor serice
si/sau rezistentei la insulina la multi pacienti. Totusi, modificarile lipodistrofice
au esuat in a se imbunatati din punct de vedere clinic desi tehnicile de
imagistica au dezvaluit cateva recuperari minore. In conditii de includere si de
studiu foarte stricte, majoritatea pacientilor au mentinut supresia virala
completa dupa modificarea HAART, dar nu toate aceste studii au inclus
grupuri de control cu terapie antiretrovirala nemodificata. Cele mai
avantajoase modificari ale parametrilor metabolici au fost observate dupa
inlocuirea PI cu nevirapina sau abacavir. Aceasta optiune insa nu este
intotdeauna potrivita si avantajul clinic al supresiei virale eficiente si functiei
imune imbunatatite trebuie considerate in lumina antecedentelor de
medicamente administrate, incarcaturii virale curente si mutatiilor de
rezistenta. Cand optiunile sunt limitate, medicamentele antiretrovirale care
243
pot duce la cresteri ale lipidelor nu ar trebui refuzate de teama exacerbarii
suplimentare a tulburarilor lipidice.
Bibliografie
Bastard JP, Caron M, Vidal H, Jan V, Auclair M, Vigouroux C et al.
Association
between altered expression of adipogenic factor SREBP1 in lipoatrophic
adipose
tissue from HIV-1-infected patients and abnormal adipocyte differentiation
and insulin resistance. Lancet 2002; 359(9311):1026-1031.
Behrens G, Dejam A, Schmidt H, Balks HJ, Brabant G, Korner T, Stoll M,
Schmidt RE. Impaired glucose tolerance, beta cell function and lipid
metabolism
in HIV patients under treatment with protease inhibitors. AIDS 1999; 13:F63-
70.
Behrens GM, Stoll M, Schmidt RE. Lipodystrophy syndrome in HIV infection:
what is it, what causes it and how can it be managed? Drug Saf 2000; 23:57-
76.
Behrens GMN, Boerner A-R, Weber K, v d Hoff J, Ockenga J, Brabant G,
Schmidt RE. Impaird glucose phosphorylation and transport in skeletal
muscle
causes insulin resistance in HIV-1 infected patients with lipodystrophy. J Clin
Invest 2002; 110:1319-1327.
Brinkman K, Smeitink JA, Romijn JA,Reiss, P. Mitochondrial toxicity induced
by
nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the
pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet
1999;354:1112-1115.
245
Caron M, Auclair M, Vigouroux C, Glorian M, Forest C, Capeau J. The HIV
protease inhibitor indinavir impairs sterol regulatory element- binding protein-
1
intranuclear localization, inhibits preadipocyte differentiation, and induces
insulin
resistance. Diabetes 2001; 50(6):1378-1388.
Carr A, Emery S, Law M, Puls R, Lundgren JD, Powderly WG. An objective
case definition of lipodystrophy in HIV-infected adults: a case-control study.
Lancet 2003;361:726-35
Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, Cooper DA. A
syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance
in
patients receiving HIV protease inhibitors. AIDS 1998; 12:F51-8.
Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA.
Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-
associated
lipodystrophy, hyperlipidaemia,and diabetes mellitus: a cohort study. Lancet
1999; 353:2093-9.
Currier J, Kendall M, Henry K, Torriani F, Storey S, Shikuma C, Mickelberg K,
Alston B, Basar M, Zackin R, Hodis H. Carotid intima-media thickness in
HIVinfected
and uninfected adults: ACTG 5078. Abtracts of the 10th Conference on
Retroviruses and Opportunistic Infections, Boston, 2003, Feb 10-14, abstract
131.
Dube MP, Sprecher D, Henry WK, Aberg JA, Torriani FJ, Hodis HN,
Schouten
J, Levin J, Myers G, Zackin R, Nevin T, Currier JS. Preliminary guidelines for
the evaluation and management of dyslipidemia in adults infected with human
immunodeficiency virus and receiving antiretroviral therapy:
recommendations
of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group.
Clin Infect Dis 2000; 31:1216-24.
Friis-Møller N, Weber R, D’Arminio Monforte A, El-Sadr W, Reiss P, DabisF,
Morfeld L, De Witt S, Pradier C, Calvo G, Law M, Kirk O, Sabin C, Lundgren
JD.
Exposure to HAART is associated with an increased risk of myocardial
infarction:
the D:A:D study. Abtracts of the 10th Conference on Retroviruses and
Opportunistic Infections, Boston, 2003, Feb 10-14, abstract 130.
Gan SK, Samaras K, Thompson CH, Kraegen EW, Carr A, Cooper DA,
Chisholm DJ. Altered myocellular and abdominal fat partitioning predict
disturbance
in insulin action in HIV protease inhibitor-related lipodystrophy.Diabetes
2002;51:3163-9.
246
John M, Nolan D, Mallal S. Antiretroviral therapy and the lipodystrophy
syndrome.
Antivir Ther 2001;6:9-20.
Lafaurie M, Dolivo M, Boulu D, Finel H, Porcher R, Madelaine I, Molina JM.
Treatment of facial lipoatrophy with injections of polylactic acid in HIV-infected
patients. Abtracts of the 10th Conference on Retroviruses and Opportunistic
Infections, Boston, 2003, Feb 10-14, abstract 720
Liang J-S, Distler O, Cooper DA, Jamil H, Deckelbaum RJ, Ginsberg HN,
Struley SL. HIV protease inhibitors protect apolipoprotein B from degradation
by
the proteasome: A potential mechanism for protease inhibitor-induced
hyperlpidemia.
Nat Med 2001; 7:1327-1331
Mallal SA, John M, Moore CB, James IR, McKinnon EJ. Contribution of
nucleoside
analogue reverse transcriptase inhibitors to subcutaneous fat wasting in
patients with HIV infection. AIDS 2000; 14:1309-16.
Meininger G, Hadigan C, Laposata M, Brown J, Rabe J, Louca J et al.
Elevated
concentrations of free fatty acids are associated with increased insulin
response
to standard glucose challenge in human immunodeficiency virus-infected
subjects
with fat redistribution. Metabolism 2002; 51(2):260-266.
Murata H, Hruz PW, Mueckler M. Indinavir inhibits the glucose transporter
isoform
Glut4 at physiologic concentrations. AIDS 2002; 16(6):859-863.
Nolan D, John M, Mallal S. Antiretoviral therapy and the lipodystrophy
syndrome,
part 2: concepts in aetiopathogenesis. Antivir Ther 2001; 6:145-60.
Noor MA, Lo JC , Mulligan K, Schwarz JM, Halvorsen RA, Schambelan M et
al.
Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS 2001;
15(7):F11-F18.
Noor MA, Seneviratne T, Aweeka FT, Lo JC, Schwarz JM, Mulligan K et al.
Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a
randomized,
placebo-controlled study. AIDS 2002; 16(5):F1-F8.
Purnell JQ, Zambon A, Knopp RH, Pizzuti DJ, Achari R, Leonard JM et al.
Effect
of ritonavir on lipids and post-heparin lipase activities in normal subjects.
AIDS 2000; 14(1):51-57.
Saint-Marc T, Partisani M, Poizot-Martin I, Rouviere O, Bruno F, Avellaneda
R,
247
Lang JM, Gastaut JA, Touraine JL. Fat distribution evaluated by computed
tomography
and metabolic abnormalities in patients undergoing antiretroviral
therapy: preliminary results of the LIPOCO study. AIDS. 2000; 14:37-49.
Schambelan M, Benson CA, Carr A, Currier JS, Dube MP, Gerber JG,
Grinspoon
SK, Grunfeld C, Kotler DP, Mulligan K, Powderly WG, Saag MS.
Management
of metabolic complications associated with antiretroviral therapy for
HIV-1 infection: recommendations of an International AIDS-Society-USA
panel.
J Acquir Immune Defic Syndr 2002; 31:257-275.
Sekhar RV, Jahoor F, White AC, Pownall HJ, Visnegarwala F, Rodriguez-
Barradas MC, Sharma M, Reeds PJ, Balasubramanyam A. Metabolic basis of
HIV-lipodystrophy syndrome. Am J Physiol Endocrinol Metab.
2002;283:E332-
7.
Valantin MA, Aubron-Olivier C, Ghosn J, Laglenne E, Pauchard M, Schoen H,
Katz P, Costagliola D, Katlama C. Polylactic acid implants (New-Fillâ) in the
correction of facial lipoatrophy in HIV—infected patients (VEGA study):
results
at 72 weeks. Abtracts of the 10th Conference on Retroviruses and
Opportunistic
Infections, Boston, 2003, Feb 10-14, abstract 719
van der Valk M, Bisschop PH, Romijn JA, Ackermans MT, Lange JM, Endert
E
et al. Lipodystrophy in HIV-1-positive patients is associated with insulin
resistance
in multiple metabolic pathways. AIDS 2001; 15(16):2093-2100.
Walli R, Herfort O, Michl GM, Demant T, Jager H, Dieterle C et al. Treatment
with protease inhibitors associated with peripheral insulin resistance and
impaired
oral glucose tolerance in HIV-1-infected patients . AIDS 1998;
12(15):F167-F173.
Zolopa A, Benson C, Bacchetti P, Tien PC, Grunfeld C. Buffalo hump in men
with HIV infection: larger, but not more common. Abtracts of the 10th
Conference
on Retroviruses and Opportunistic Infections, Boston, 2003, Feb 10-14,
abstract 734.
248
Analize pentru testarea rezistentei
Determinarea fenotipului
Testele de rezistenta fenotipica implica cuantificarea directa a sensibilitatii
medicamentelor.
249
Replicarea virala este determinata in culturile celulare sub presiune selectiva
a concentratiilor crescande ale medicamentelor antiretrovirale si este
comparata cu tipul “wild”.
Determinarea genotipului
Analizele genotipice se bazeaza pe analiza mutatiilor asociate cu rezistenta.
Acestea sunt determinate de secventierea directa a genomului HIV amplificat
sau de tehnicile de hibridizare specifice cu tipul “wild” sau oligonucleotide
mutante. Testele de genotip detecteaza numai mutanti virali formati din cel
putin 20 pana la 30% din populatia totala si reprezinta o masuratoare
indirecta a rezistentei la medicamente. Mutatii care sunt asociate cu
sensibilitate redusa au fost descrise in amanunt pentru majoritatea
medicamentelor HIV, dar numarul crescut de modele de rezistenta diferite,
care poate cuprinde si mutatii compensatorii, fac ca determinarea gradului de
rezistenta la anumite medicamente sa fie dificila.
Unele din cele mai importante baze de date pentru profilurile de rezistenta si
sistemele interpretationale sunt disponibile la urmatoarele adrese web:
Stanford-Database: http://hiv.net/link.php?id=24
250
Los Alamos-Database: http://hiv.net/link.php?id=25
geno2pheno (Arevir): http://hiv.net/link.php?id=26.
Context
In cadrul secventei de nucleotide a genomului HIV, un grup de 3 nucleotide,
denumite codon, defineste un anumit aminoacid in secventa de proteine.
Mutatii de rezistenta sunt descrise folosind un numar, care arata pozitia
codonului relevant, si 2 litere. Litera care precede numarul corespunde
amino-acidului specificat de catre codonul din aceasta pozitie pentru virusul
de tip “wild”. Litera de dupa numar descrie aminoacidul care este produs din
codonul modificat.
Mecanisme de rezistenta
NRTI: Analogii nucleozidici si nucleotidici (NRTI) sunt pro-medicamente si
devin eficiente numai dupa ce sunt transformate in trifosfati. Analogii
nucleotidici necesita numai 2 in loc de 3 etape de fosforilare. NRTI fosforilate
intra in competitie cu dNTP aparut in mod natural(desoxynucleotide
triphosphates). Incorporarea unui NRTI fosforilat in ADN-ul proviral blocheaza
alungirea suplimentara a ADN-ului proviral si duce la intreruperea lantului.
Studiile clinice
Relevanta clinica a testarii rezistentei inaintea modificarii terapiei, a fost
demonstrata in mai multe studii prospective, controlate, atat pentru testarile
rezistentei genotipice (Durant et al 1999, Baxter et al 1999, Tural et al 2001),
cat si fenotipice (Cohen et al 2000). Pacientii ai caror medici curanti au fost
informati asupra existentei mutatiilor inainte ca terapia sa fie modificata de
obicei prezentau descresteri mai semnificative ale incarcaturii virale decat
pacientii la care tratamentul a fost modificat fara cunoasterea profilului de
rezistenta.
NRTI
Pentru anumite NRTI, cum ar fi lamivudina, si pentru NNRTI, se poate
dezvolta un grad inalt de rezistenta cu o singura mutatie (Havlir et al 1996,
Schuurman et al 1995). Din acest motiv, asemenea medicamente ar trebui
folosite numai in regimurile extrem de eficiente. Insa, intr-o analiza
retrospectiva a 5 studii extinse, rezultatul tratamentului nu s-a dovedt a fi
inferior in prezenta mutatiei M184V lamivudin-specifice. Motivul ar putea fi ca
mutatia M184V duce la replicare virala redusa si forma virala redusa (Sharma
252
et al 1999). In monoterapia cu lamivudina, dupa 52 saptamani, incarcatura
virala a ramas 0,5 log sub nivelele initiale in ciuda dezvoltarii precoce a
mutatiei M184V (Eron et al 1995).
NNRTI
O singura mutatie poate conferi un grad inalt de rezistenta la unul sau mai
multe NNRTI. Mutatia K103N relativ frecventa duce la o crestere de 20-30 ori
a rezistentei la toate NNRTI disponibile (Petropolus et al 2000). Utilizarea in
254
continuare a NNRTI in prezenta acestei mutatii din aceasta cauza nu este
recomandata.
PI
Spectrul mutatiilor la PI a fost descris pe larg. Desi exista un nivel crescut de
rezistenta incrucisata intre saquinavir, nelfinavir, indinavir si ritonavir, mutatiile
primare sunt relativ specifice pentru fiecare medicamente. Daca tratamentul
este modificat devreme cu o alta combinatie PI, adica inainte de acumularea
catorva mutatii, regimul ulterior ar putea fi inca de succes.
255
G48V apare in principal pentru saquinavir si duce la o crestere de 10-ori a
rezistentei la saquinavir – in combinatie cu L90M, duce la rezistenta crescuta,
de peste 100-ori, la saquinavir (Jakobson et al 1995).
Nu au fost descrise mutatii specifice pentru lopinavir pana acum. Insa, mutatii
in pozitiile 10, 20, 24, 46, 53, 54, 63, 71, 82, 84, 90 sunt asociate cu o
sensibilitate redusa ca si in cazul tuturor celorlalte PI (Kempf et al 2001). In
particular, mutatiile K20M/R si F53L in combinatie cu alte cateva mutatii au
dus la o reducere semnificativa a sensibilitatii.
256
Noi medicamente
Urmatorul capitol descrie profilurile de rezistenta al catorva noi medicamente
antiretrovirale.
TMC 125, un NNRTI de generatia a doua, care este eficient atat impotriva
virusurilor de tip “wild” cat si virusurilor cu mutatii la NNRTI de tipul L100I,
K103N, Y181C, Y188L si/sau G190A/S (gazzard et al 2002).
257
La pacientii cu experienta in PI, acumularea altor mutatii la PI, in particular
I84V, duce simultan la o reducere suplimentara a sensibilitatii la alte PI.
Rezumat
Studii controlate au aratat ca testarea rezistentei imbunatateste tratamentul
antiretroviral la pacientii HIV. Desi criteriile tratamentului HIV recomanda in
general testarea rezistentei, si primele studii farmaco-economice
demonstreaza ca aceste teste pot fi chiar eficiente in ceea ce priveste costul
(Weinstein et al 2001), testele de rezistenta inca nu sunt acoperite de
asigurarea de sanatate publica in multe tari.
258
Tabele de rezistenta
260
P236L
261
Bibliografie:
1. Balotta C, Berlusconi A, Pan A, et al. Virologic and immunologic outcome
in recent seroconverters bearing resistance-related mutations treated
with NRTI or NRTI plus PI regimens. Abstract 370, 7th ECCATH 1999,
Lisbon, Portugal.
2. Baxter JD, Mayers DL, Wentworth DN, Neaton JD, Merigan TC. A pilot
study of the Short-term effects of antiretroviral management based on
plasma genotypic antiretroviral resistance testing (GART) in patients failing
antiretroviral therapy. Avstract LB8, 6th CROI 1999, Chicago, USA.
3. Chaix C, Grenier-Sennelier C, Durant J, et al. Economic Evaluation of
drug resistance genotyping for the adaptation of treatment in HIV-infected
patients in the VIRADAPT study. Abstract 105, 3rd International Workshop
on HIV Drug Resistance and Treatment Strategies 1999, San Diego,
CA, USA.
4. Cohen C, Kessler H, Hunt S, et al. Phenotypic resistance testing
significantly
improves response to therapy: final analysis of a randomized trial
(VIRA 3001). Antiviral The. 2000, 5: (supl 3): 67. Abstract 84.
5. Colonno R et al. BMS-232632 sensitivity of a panel of HIV-1 clinical
isolates
resistant to one or more approved protease inhibitors. Antiviral
Therapy 2000, 5: Abstract 8.
6. Colonno RJ, Friborg J, Rose RE, Lam E, Parkin N. Identification of amino
acid substitutions correlated with reduced atazanavir susceptibility in patients
treated with atazanavir-containing regimens. Antiviral Ther 2002,
7:S4. Abstract 4.
7. Craig C, Goddard C, Whittaker L et al. HIV-1 genotype and phenotype
during dual therapy (NV15436 sub-study). Abstract 103, 7th ECCATH
1999, Lisbon, Portugal.
8. De Mendoza C, Gallego O, Soriano V. Mechanisms of Resistance to
Antiviral Drugs – Clinical Implications. AIDS Rev 2002, 4: 64-82.
http://amedeo.com/lit.php?id=12152520
9. Dezube BJ, Jacobs MS, Leoung G, et al. A second generation
nonnucleoside
reverse transcriptase inhibitor, AG1549, in patients with HIV-
1: a phase I study. Abstract 200, 7th ECCAT 1999, Lisbon, Portugal.
10. Drake JW. Rates of spontaneous mutation among RNA viruses. Proc
Natl Acad Sci U S A. 1993, 90:4171-4175.
http://amedeo.com/lit.php?id=8387212
11. Drug Resistance Mutations Group of the International AIDS Society-USA
2001. Special Contribution. Drug Resistance Update. Dec. 2001: Volume
9: Issue 6.
12. Durant J, Clevenbergh P, Halfon et al. Drug-resistance genotyping in
HIV-1 therapy: the VIRADAPT randomised controlled trial. Lancet 1999,
262
353:2195-99. http://amedeo.com/lit.php?id=10392984
13. Eron JJ, Benoit SL, Jemsek J, et al. Treatment with lamivudine,
zidovudine,
or both in HIV-positive patients with 200 to 500 CD4+ cells per
cubic millimeter. N Engl J Med 1995, 333:1662-1669.
http://amedeo.com/lit.php?id=7477218
14. Fiske WD, Brennan JM, Harrison RR, et al. Pharmacokinetics of a
Second-
Generation NNRTI, DPC 083, after Multiple Oral Doses in Healthy
Volunteers. Abstract 99, 7th CROI 2000, San Francisco, USA..
15. Gazzard B, Pozniak A, Arasteh K, et al. TMC125, a next-generation
NNRTI, demonstrates high potency after 7 days therapy in
treatmentexperienced
HIV-1-infected individuals with phenotypic NNRTI resistance.
Abstract 4, 9th CROI 2002, Chicago, USA.
16. Gong YF, Robinson BS, Rose RE, et al. In vitro resistance profile of the
HIV type 1 protease inhibitor BMS-232632. Antimicrobial Agents and
Chemotherapy 2000, 44:2319-2316.
http://amedeo.com/lit.php?id=10952574
17. Harrigan PR, Stone C, Griffin P, et al. Resistance profile of the HIV type 1
reverse transcriptase inhibitor abacavir (1592U89) after monotherapy and
combination therapy. J Infect Dis 2000, 181:912-920.
http://amedeo.com/lit.php?id=10720512
18. Havlir DV, Gamst A, Eastman S, Richman DD. Nevirapine-resistant HIV:
kinetics of replication and estimated prevalence in untreated patients. J
Virol 1996, 70:7894-7899. http://amedeo.com/lit.php?id=8892912
19. Jacobsen H, Yasargil K, Winslow DL, et al. Characterization of HIV type 1
mutants with decreased sensitivity to proteinase inhibitor Ro 31-8959.
Virology
1995, 206:527-534. http://amedeo.com/lit.php?id=7831807
20. Kempf D, Xu Y, Brun S, et al. Baseline genotype and phenotype do not
predict response to ABT-378/Ritonavir in PI-experienced patients at 24
and 48 weeks. Abstract 731, 7th CROI 2000, San Francisco, USA.
21. Kempf DJ, Isaacson JD, King MS, et al. Identification of genotypic
changes in HIV protease that correlate with reduced susceptibility to the
protease inhibitor lopinavir among viral isolates from protease
inhibitorexperienced
patients. J Virol 2001, 75:7462-9.
http://amedeo.com/lit.php?id=11462018
22. Lacey SF, Larder BA. Novel mutation (V75T) in HIV type 1 reverse
transcriptase
confers resistance to 2',3'-didehydro-2',3'- dideoxythymidine in
cell culture. Antimicrob.Agents Chemother 1994, 38:1428-1432.
http://amedeo.com/lit.php?id=7522429
23. Lanier ER, Kubota M, Yau L, et al. Diverse effects of NRTI-associated
263
mutations on resistance to abacavir, stavudine and zidovudine in the
ZORRO trial. Abstract 1761, 41st ICAAC 2001, Chicago, USA.
http://hiv.net/link.php?id=27
24. Lange J, Hill A, Ait-Khaled M, et al. Does the M184V mutation affect the
efficacy of HAART. Abstract 384, 7th ECCATH 1999, Lisbon, Portugal.
25. Larder B, de Vroey V, Dehertogh P, et al. Predicting HIV-1 phenotypic
resistance from genotype using a large phenotype-genotype relational
database. Abstract 106, 7th ECCATH 1999, Lisbon, Portugal.
26. Larder BA, Kemp SD. Multiple mutations in HIV-1 reverse transcriptase
confer high-level resistance to zidovudine (AZT). Science 1989,
246:1155-1158. http://amedeo.com/lit.php?id=2479983
27. Larder BA, Bloor S. Analysis of clinical isolates and site-directed mutants
reveals the genetic determinants of didanosine resistance. Antivir Ther
2001, 6:38.
28. Larder B, Hertogs K, Bloor S, et al. Tipranavir inhibits broadly protease
inhibitor-resistant HIV-1 clinical samples. AIDS 2000: 14: 1943-8.
http://amedeo.com/lit.php?id=10997398
29. Loveday C, Devereux H, Huckett L, Johnson M. High prevalence of
multiple
drug resistance mutations in a UK HIV/AIDS patient population.
AIDS 1999, 13: 627-628. http://amedeo.com/lit.php?id=10203393
30. Martinez-Picado J, Savara AV, Sutton L, et al. Replicative fitness of
protease
inhibitor-resistant mutants of HIV type 1. J Virol 1999, 73:3744-
3752. http://amedeo.com/lit.php?id=10196268
31. Masquelier B, Race E, Tamalet C, et al. Genotypic and phenotypic
resistance
patterns of HIV type 1 variants with insertions or deletions in the
reverse transcriptase (RT): multicenter study of patients treated with RT
inhibitors. Antimicrob Agents Chemother 2001, 45:1836-42.
http://amedeo.com/lit.php?id=11353634
32. Meyer PR, Matsuura SE, Schinazi RF, So AG, Scott WA. Differential
removal of thymidine nucleotide analogues from blocked DNA chains by
HIV reverse transcriptase in the presence of physiological concentrations
of 2'-deoxynucleoside triphosphates. Antimicrob Agents Chemother
2000, 44:3465-72. http://amedeo.com/lit.php?id=11083661
33. Miller V, Hertogs K, Bloor, et al. Prevalence of phenotypic and genotypic
resistance in recently infected, antiretroviral inexperienced patients: The
German HIV-research initiative cohort. Abstract 381, 7th ECCATH 1999,
Lisbon, Portugal.
34. Miller MD, Margot NA, Hertogs K, Larder B, Miller V. Antiviral activity of
tenofovir (PMPA) against nucleoside-resistant clinical HIV samples.
Nucleosides
Nucleotides Nucleic Acids 2001, 20:1025-8.
http://amedeo.com/lit.php?id=11562951
264
35. Naeger LK, Margot NA, Miller MD. Increased drug susceptibility of HIV-1
reverse transcriptase mutants containing M184V and zidovudineassociated
mutations: analysis of enzyme processivity, chain-terminator
removal and viral replication. Antivir Ther 2001, 6:115-26.
http://amedeo.com/lit.php?id=11491416
36. Nijhuis M, Schuurman R, de Jong D, et al. Increased fitness of drug
resistant
HIV-1 protease as a result of acquisition of compensatory mutations
during suboptimal therapy. AIDS 1999, 13:2349-59.
http://amedeo.com/lit.php?id=10597776
37. Perelson AS, Neumann AU, Markowitz M, et al. HIV-1 dynamics in vivo:
virion clearance rate, infected cell life-span, and viral generation time.
Science 1996, 271:1582-1586. http://amedeo.com/lit.php?id=8599114
38. Petropoulos CJ, Parkin NT, Limoli KL, et al. A novel phenotypic drug
susceptibility assay for HIV type 1. Antimicrob Agents Chemother 2000,
44:920-8. http://amedeo.com/lit.php?id=10722492
39. Potts KE, Fujivara T, Sato A, et al. Antiviral activity and resistance profile
of AG1549, a novel hiv-1 non-nucleoside reverse transcriptase inhibitor.
Abstract 12, 6th CROI 1999, Chicago, USA.
40. Schmidt B, Walter H, Marcus U, et al. Cross-Resistance to Amprenavir in
PI-Treated Patients. Abstract 276, 7th CROI 2000, San Francisco, USA..
41. Schuurman R, Nijhuis M, van Leeuwen R, et al. Rapid changes in HIV
type 1 RNA load and appearance of drug-resistant virus populations in
persons treated with lamivudine (3TC). J Infect Dism 1995, 171:1411-
1419. http://amedeo.com/lit.php?id=7539472
42. Shulman NS, Winters MA, Shafer RW, et al. Subtle changes in
susceptibility
to stavudine predict virologic response to stavudine monotherapy
after zidovudine treatment. Antiviral Ther 2001, 6(Suppl 1):124. Abstract
124.
43. Schwartz R, Kazanjian P, Slater L. resistance to tipranavir is uncommon
in a randomized trial of tipranavir/ritonavir (tpv/rtv) in multiple PI-failure
patients. Abstract 562, 9th CROI 2002, Chicago IL, USA.
44. Sharma PL, Crumpacker CS. Decreased processivity of HIV type 1
reverse
transcriptase (RT) containing didanosine-selected mutation
Leu74Val: a comparative analysis of RT variants Leu74Val and lamivudine-
selected Met184Val. J Virol 1999, 73:8448-56.
http://amedeo.com/lit.php?id=10482597
45. Shafer RW, Iversen AK, Winters MA, et al. The AIDS Clinical Trials
Group 143 Virology Team. Drug resistance and heterogeneous long-term
virologic responses of HIV type 1-infected subjects to zidovudine and
didanosine
combination therapy. J Infect Dis 1995, 172:70-78.
http://amedeo.com/lit.php?id=7541064
265
46. Shafer R. Stanford HIV RT and Protease Sequence Database 1998-
2002a. http://hiv.net/link.php?id=28
47. Shafer R. Stanford HIV RT and Protease Sequence Database 1998-
2002b. http://hiv.net/link.php?id=29
48. Shafer R. Stanford HIV RT and Protease Sequence Database 1998-
2002c. http://hiv.net/link.php?id=30
49. Snowden W, Shortino D, Klein A, et al. Development of amprenavir
resistance
in NRTI-experienced patients: alternative mechanisms and correlation
with baseline resistance to concomitant NRTIs [abstract 108].
Antivir Ther 2000; 5(Supplement 3):84.
50. Tural C, Ruiz L, Holtzer C, et al. Utility of HIV genotyping and clinical
expert advice - The Havana trial. Abstract 434, 8th CROI 2001, Chicago,
USA..
51. Tisdale M, Alnadaf T, Cousens D. Combination of mutations in HIV type 1
reverse transcriptase required for resistance to the carbocyclic nucleoside
1592U89. Antimicrob Agents Chemother 1997, 41:1094-1098.
http://amedeo.com/lit.php?id=9145875
52. Vandamme AM, Van Laethen and de Clercq E. Managing resistance to
anti-HIV drugs. Drugs 1999, 57:337/361.
53. Weinstein MC, Goldie SJ, Losina E, et al. Cost-Effectiveness of
resistance
testing in HIV. Ann Intern Med 2001, 134:440-450.
http://amedeo.com/lit.php?id=11255519
54. Whitcomb J, Deeks S, Huang W, et al. Reduced susceptibility to NRTI is
associated with NNRTI hypersensitivity in virus from HIV-1-infected patients.
Abstract 234, 7th CROI 2000 San Francisco, CA, USA.
55. Winters MA, Shafer RW, Jellinger RA, et al. HIV type 1 reverse
transcriptase
genotype and drug susceptibility changes in infected individuals
receiving dideoxyinosine monotherapy for 1 to 2 years. Antimicrob.
Agents Chemother 1997, 41:757-762.
http://amedeo.com/lit.php?id=9087484
266
Abacavir (ABC)
Capitolul 7: Profiluri ale medicamentelor
Bernd Sebastian Kamps
Christian Hoffmann
Abacavir (ABC)
Reactia de hipersensibilitate, desi rara, complica folosirea abacavir-ului.
Abacavir ar trebui prescris de clinicienii HIV!
Mod de prezentare: Ziagen ®: tablete 300 mg; 20 mg/ml solutii orale, 240
ml
Trizivir ®: Tablete continand 300 mg abacavir si 150 mg lamivudina si 300 mg
zidovudina
Producator: GlaxoSmithKline
Doza orala: 300 mg bid. Abacavir poate fi administrat cu sau fara mancare.
Interactiuni: 0,7 g/kg etanol (de exemplu 0,5 l vin) creste AUC al abacavir cu
41% si creste timpul de injumatatire cu 26%.
Surse Internet:
USA: http://hiv.net/link.php?id=53
Amprenavir (APV)
Bibliografie:
268
5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1
reversetranscriptase
inhibitor abacavir. Lancet 2002, 359: 727-32.
http://amedeo.com/lit.php?id=11888582
8. Opravil M, Hirschel B, Lazzarin A, et al. A randomized trial of simplified
maintenance therapy with abacavir, lamivudine, and zidovudine in HIV
infection. J Infect Dis 2002, 185: 1251-60.
http://amedeo.com/lit.php?id=12001042
9. Sankatsing SU, Prins JM. Agranulocytosis and fever seven weeks after
starting abacavir. AIDS 2001, 15: 2464-5.
10. Toerner JG, Cvetkovich T. Kawasaki-like syndrome: abacavir
hypersensitivity?
Clin Infect Dis 2002; 34: 131-3.
11. Wasmuth JC, Herhaus C, Römer K, et al. Efficacy and safety of abacavir
plus efavirenz as a salvage regimen in HIV-infected individuals after 48
weeks. AIDS 2002, 16: 1077-8.
12. Wit FW, Wood R, Horban A, et al. Prednisolone does not prevent
hypersensitivity
reactions in antiretroviral drug regimens containing abacavir
with or without nevirapine. AIDS 2001, 15: 2423-2429.
http://amedeo.com/lit.php?id=11740193
Amprenavir (APV)
Forme de prezentare:
Amprenavir (APV)
50 mg capsule
150 mg capsule
15 mg/ml solutie orala, 240 ml
Producator: GlaxoSmithKline
269
Indicatii: Infectia HIV cu tratament anterior cu PI
Doza orala: 8 capsule amprenavir bid de 150 mg fiecare (1.200 mg bid) sau
4 capsule amprenavir bid de 150 mg fiecare (600 mg bid) plus 100 mg
ritonavir bid sau 8 capsule amprenavir qd de 150 mg fiecare (1.200 mg qd)
plus 200 mg ritonavir qd.
Amprenavir ar trebui administrat cu cel putin o ora inainte sau dupa antacide
sau didanozina. Ajustarea dozelor (masurati nivelele plasmatice!) ar trebui
luata in considerare in combinatie cu lopinavir.
Surse Internet:
USA: Capsule: http://hiv.net/link.php?id=61, Solutie:
http://hiv.net/link.php?id=62, Combinatie cu ritonavir:
http://hiv.net/link.php?id=63
Bibliografie:
Atazanavir (AZV)
Atazanavir este primul PI cu administrare o data pe zi, si are o putere
antivirala care ar trebui sa fie comparata cu nelfinavir. In comparatie cu PI
stimulate, atazanavir este usor mai slab, dar are un profil lipidic favorabil.
Daca acest lucru va avea vreun efect asupra lipodistrofiei trebuie inca
demonstrat.
Efecte secundare: Cresteri relativ frecvente ale bilirubinei, care pana acum
nu au limitat tratamentul. Diaree in aproximativ 30%. In plus, greturi,
varsaturi, cefalee, dureri abdominale. Aceste tulburari se rezolva de obicei in
decursul primelor saptamani de tratament. In contrast cu alte PI: nici o
dislipidemie. Efectul asupra lipodistrofiei ramane necunosct.
Bibliografie:
272
http://www.retroconference.org/2002/Abstract/13619.htm
2. Murphy R et al. Switch to atazanavir from nelfinavir associated with
cholesterol
and triglyceride improvement:12 week results from BMS AI424-
044. Fourteenth International AIDS Conference, Barcelona, abstract
LbPeB9013, 2002. http://hiv.net/link.php?id=65
3. Piliero P, Cahn C, Pantaleo G, et al. Atazanavir: A Once-Daily Protease
Inhibitor with a Superior Lipid Profile: Results of Clinical Trials Beyond
Week 48. Abstract 706, 9th CROI 2002, Seattle, USA.
http://63.126.3.84/2002/Abstract/13827.htm
4. Preston S, Piliero P, O’Mara E, et al. Evaluation of steady-state interaction
between atazanavir and efavirenz. Abstract 443, 9th CROI 2002, Seattle,
USA. http://63.126.3.84/2002/Abstract/13543.htm
5. Robinson BS, Riccardi KA, Gong YF, et al. BMS-232632, a highly potent
HIV protease inhibitor that can be used in combination with other available
antiretroviral agents. Antimicrob Agents Chemother 2000, 44:2093-
2099. Original-Artikel:
http://aac.asm.org/cgi/content/full/44/8/2093?view=full&pmid=10898681
6. Squires KE, Thiry A, Giordano M, for the AI424-034 International Study
Team. Atazanavir QD and efavirenz QD with fixed-dose ZDV+3TC:
Comparison of antiviral efficacy and safety through wk 24 (AI424-034).
Abstract H-1076, 42nd ICAAC 2002, San Diego, USA.
Combivir ®
Mod de prezentare: Tablete continand 150 mg lamivudina si 300 mg
zidovudina.
Producator: GlaxoSmithKline
Surse Internet:
USA: http://hiv.net/link.php?id=68
273
Delavirdine (DLV)
Delavirdina (DLV)
Delavirdina este foarte rar utilizata, datorita metodei de dozare nepractice si
interactiunilor medicamentoase, si a fost complet marginalizata de celelalte 2
NNRTI nevirapine si efavirenz. Totusi, medicamentul prezinta un anumit
potential teoretic. Este destul de bine tolerat (nu exista hepatotoxicitate, nu
exista probleme la nivelul SNC), si creste nivelele de indinavir si saquinavir.
Daca ar exista mai multe date disponibile, delavirdina ar putea fi o alternativa
la ritonavir pentru stimulare. Prezinta obisnuita rezistenta incrucisata pentru
NNRTI.
Mod de prezentare:
Tablete 100 mg
Tablete 200 mg
Producator: Pfizer
274
mialgiei si artralgiei, delavirdina ar trebui intrerupta. Greturi, transaminaze
crescute.
Surse Internet:
USA: http://hiv.net/link.php?id=178
Bibilografie:
275
Didanozina (ddI)
Mod de prezentare:
Tablete tamponate: 25 mg, 50 mg, 100 mg, 200 mg
Capsule EC: 125 mg, 200 mg, 250 mg, 400 mg
2 g/100 ml pudra cu uz pediatric
4 g/200 ml pudra cu uz pediatric
Doza orala: 400 mg qd (greutate corporala > 60 kg) sau 250 mg qd (greutate
corporala < 60 kg). Didanozina trebuie administrata pe stomacul gol, cu cel
putin 2 ore dupa sau 1 ora inainte de masa.
276
Initial, monitorizarea lunara a amilazei, sangelui, transaminazelor, bilirubinei.
Pacientii ar trebui informati asupra riscului de pancreatita. Didanozina ar
trebui intrerupta daca exista suspiciune de pancreatita, fara reluare ulterioara.
Surse Internet:
USA: http://hiv.net/link.php?id=86
Bibliografie:
Efavirenz (EFV)
Efavirenz este un NNRTI frecvent folosit, cu putere antiretrovirala
necontestata. Are multiple efecte secundare la nivelul SNC, pentru care
patogeneza nu este suficient inteleasa. Interactiunile medicamentoase au fost
documentate pentru o varietate de medicamente mai des prescrise
pacientilor HIV.
Mod de prezentare:
Capsule 50 mg
Capsule 100 mg
Capsule 200 mg
277
Capsule 600 mg
Surse Internet:
USA: http://hiv.net/lik.php?id=88
Bibliografie:
278
withdrawal induced by efavirenz in drug users with hiv infection and
undergoing
chronic methadone treatment. AIDS Res Hum Retroviruses
2002, 18: 341-2.
2. Casado JL, Moreno A, Hertogs K, Dronda F, Moreno S. Extent and
importance
of cross-resistance to efavirenz after nevirapine failure. AIDS
Res Hum Retroviruses 2002, 18: 771-5.
http://amedeo.com/lit.php?id=12167268
3. Clotet B. Quality of life, emotional status, and adherence of HIV-1-
infected patients treated with efavirenz versus protease inhibitorcontaining
regimens. J Acquir Immune Defic Syndr 2002, 29: 244-53.
http://amedeo.com/lit.php?id=11873073
4. Estrada V, De Villar NG, Larrad MT, et al. Long-term metabolic
consequences
of switching from protease inhibitors to efavirenz in therapy for
HIV-infected patients with lipoatrophy. Clin Infect Dis 2002, 35: 69-76.
http://amedeo.com/lit.php?id=12060877
5. Fundaro C, Genovese O, Rendeli C, Tamburrini E, Salvaggio E.
Myelomeningocele
in a child with intrauterine exposure to efavirenz. AIDS
2002, 16: 299-300.
6. Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus
zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus
zidovudine
and lamivudine in the treatment of HIV-1 infection in adults.
Study 006 Team. N Engl J Med 1999, 341:1865-73.
http://amedeo.com/lit.php?id=10601505
Emtricitabin (FTC)
279
Doza orala: 200 mg qd
Efecte secundare: Rare. Cel mai frecvent dureri de cap (cefalee), greturi,
efecte gastrointestinale.
Bibliografie:
280
Indinavir (IDV)
Un PI eficient si bine cercetat, folosirea caruia este usor limitata datorita
problemelor localizate la nivelul pielii, rinichilor si problemelor intestinale.
Exista rezistente incrucisate multiple la alte PI, dar medicamentul are o buna
penetrare la nivelul SNC. Astazi, indinavir este in general folosit cu stimulare
cu ritonavir, care simplifica dozarea.
Mod de prezentare:
Capsule 200 mg
Capsule 333 mg
Capsule 400 mg
Producator: Merck
Fara stimulare cu ritonavir: 800 mg tid (2 capsule 400 mg tid) cu o ora inainte
sau 2 ore dupa mese. Functie hepatica afectata: 600 mg tid (3 capsule 200
mg tid).
Un sindrom sicca (sindrom Sjogren) apare relativ frecvent (piele uscata, gura
uscata, ochi); unghii incarnate si paronichie; rar alopecie. Hiperbilirubinemie
asimptomatica.
Surse Internet:
USA: http://hiv.net/link.php?id=102
Bibliografie:
282
7. Gallego O, de Mendoza C, Perez-Elias MJ, et al. Drug resistance in
patients
experiencing early virological failure under a triple combination including
indinavir. AIDS 2001, 15: 1701-1706.
http://amedeo.com/lit.php?id=11546946
8. Gatell JM, Lange J, Arnaiz JA, et al. A randomized study comparing
continued
indinavir (800 mg tid) vs switching to indinavir/ritonavir (800/100
mg bid) in HIV patients having achieved viral load suppression with indinavir
plus 2 nucleoside analogues The BID Efficacy and Safety Trial
(BEST). Abstract WeOrB484, XIII International AIDS Conference 2000,
Durban, South Africa.
9. Gerstoft J, Dragstedt UB, Cahn P. Final analysis of a randomised trial to
evaluate safety and efficacy of indinavir/ritonavir versus saquinavir/
ritonavir in adult HIV-1 infection: the MaxCmin1 trial. Abstract 2853,
ICAAC 2002, San Diego, USA.
10. Gulick RM, Mellors JW, Havlir D, et al. 3-year suppression of HIV viremia
with indinavir, zidovudine, and lamivudine. Ann Intern Med 2000;133:35-
9. Abstract: http://amedeo.com/lit.php?id=10877738
11. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two
nucleoside analogues plus indinavir in persons with HIV infection and
CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997,
337:725-33. http://amedeo.com/lit.php?id=9287227
12. Kirk O, Mocroft A, Pradier C, et al. Clinical outcome among HIV-infected
patients starting saquinavir hard gel compared to ritonavir or indinavir.
AIDS 2001, 15: 999-1008. http://amedeo.com/lit.php?id=11399982
13. Kopp JB, Falloon J, Filie A, et al. Indinavir-associated interstitial nephritis
and urothelial inflammation: clinical and cytologic findings. Clin Infect Dis
2002, 34: 1122-8. http://amedeo.com/lit.php?id=11915002
14. Lacarelle B. High indinavir Cmin is associated with higher toxicity in
patients
on indinavir-ritonavir 800/100 mg twice-daily regimen. J Acquir Immune
Defic Syndr 2002, 29: 374-7.
http://amedeo.com/lit.php?id=11917242
15. Nolan D, Upton R, McKinnon E, et al. Stable or increasing bone mineral
density in HIV-infected patients treated with nelfinavir or indinavir. AIDS
2001, 15: 1275-1280. http://amedeo.com/lit.php?id=11426072
16. Noor MA, Lo JC, Mulligan K, et al. Metabolic effects of indinavir in healthy
HIV-seronegative men. AIDS 2001, 15: F11-F18.
http://amedeo.com/lit.php?id=11399973
17. Squires KE, Gulick R, Tebas P, et al. A comparison of stavudine plus
lamivudine versus zidovudine plus lamivudine in combination with indinavir
in antiretroviral naive individuals with HIV infection: selection of thymidine
analog regimen therapy (START I). AIDS 2000, 14: 1591-600.
http://amedeo.com/lit.php?id=10983646
283
18. Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus
zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus
zidovudine
and lamivudine in the treatment of HIV-1 infection in adults.
Study 006 Team. N Engl J Med 1999, 341:1865-73.
http://amedeo.com/lit.php?id=10601505
19. Voigt E, Wickesberg A, Wasmuth JC, et al. First-line ritonavir/indinavir
100/800 mg twice daily plus nucleoside reverse transcriptase inhibitors in
a German multicentre study: 48-week results. HIV Med 2002, 3:277-282.
http://amedeo.com/lit.php?id=12444946
Lamivudine (3TC)
Medicament bine tolerat, dar dezvoltare rapida a rezistentei. Lamivudine este
frecvent folosit drept component al tabletelor cu combinatie fixa. Combivir ®
si Trizivir ®. Este eficient de asemenea impotriva virusului hepatitei B.
Mod de prezentare: Epivir ®: tablete 150 mg; tablete 300 mg; 10 mg/ml
solutie orala, 240 ml
Combivir ®: Tablete continand 150 mg lamivudine si 300
mg zidovudine.
Trizivir ®: Tablete continand 150 mg lamivudine si 300
mg zidovudine si 300 mg abacavir.
Clasa: NRTI
Producator: GlaxoSmithKline
Doza orala Epivir ®: 300 mg qd sau 150 mg bid. Este necesara ajustarea
dozei la un clearance redus al creatininei:
284
Clearance-
ul Doza
creatininei
(ml/min)
30–49 150 mg qd
15–29 150 mg prima doza, apoi 100 mg qd
5–14 150 mg prima doza, apoi 50 mg qd
<5 50 mg prima doza, apoi 25 mg qd
Surse Internet:
USA: Epivir®: http://hiv.net/link.php?id=49, Combivir®:
http://hiv.net/link.php?id=50, Trizivir®: http://hiv.net/link.php?id=51
Bibliografie:
1. Demeter LM, Hughes MD, Coombs RW, et al. Predictors of virologic and
clinical outcomes in HIV-1-infected patients receiving concurrent treatment
with indinavir, zidovudine, and lamivudine. Ann Intern Med 2001,
135: 954-964. http://amedeo.com/lit.phpid=11730396
2. Jankelevich S, Mueller BU, Mackall CL, et al. Long-term virologic and
immunologic responses in HIV type 1-infected children treated with indinavir,
zidovudine, and lamivudine. J Infect Dis 2001, 183: 1116-1120.
http://amedeo.com/lit.phpid=11237839
285
3. Kirkland LR, Fischl MA, Tashima KT, et al. Response to
lamivudinezidovudine
plus abacavir twice daily in antiretroviral-naive, incarcerated
patients with HIV infection taking directly observed treatment. Clin Infect
Dis 2002, 34: 511-8. http://amedeo.com/lit.phpid=11797179
4. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, et al.
Lamivudinezidovudine
combination for prevention of maternal-infant transmission of
HIV-1. JAMA 2001, 285: 2083-93. http://amedeo.com/lit.phpid=11311097
5. Miller V, Stark T, Loeliger AE, Lange JM. The impact of the M184V
substitution
in HIV-1 reverse transcriptase on treatment response. HIV Med
2002, 3:135-45. http://amedeo.com/lit.php?id=12010361
6. Sension MG, Bellos NC, Johnson J, et al. Lamivudine 300 mg QD versus
continued lamivudine 150 mg BID with stavudine and a protease inhibitor
in suppressed patients. HIV Clin Trials 2002, 3:361-70.
http://amedeo.com/lit.php?id=12407485
7. Thabut D, Thibault V, Benhamou Y, et al. Successful control of
subfulminant
hepatitis related to lamivudine- resistant hepatitis B virus in an HIVinfected
patient. AIDS 2001, 15: 2463-4.
Lopinavir (LPV)
Kaletra ® este un PI foarte eficient si relativ bine tolerat. Kaletra este un
medicament ideal pentru terapia de salvare, pentru ca are o putere uimitoare
la pacientii cu experienta in PI cu multiple mutatii de rezistenta. Ramane de
dovedit daca Kaletra ® este superior celorlalte PI stimulate in terapia initiala
sau nu. Dezavantajele includ nivele lipidice extrem de mari si interactiuni
medicamentoase.
Pastrati la rece!
Producator: Abbott
286
Indicatii: Infectia HIV
Cand este folosit cu rifabutin, doza de rifabutin ar trebui redusa cu 75%, adica
150 mg qd la fiecare 2 zile.
Surse Internet:
USA: http://hiv.net/link.php?id=116
Bibliografie:
1. Benson CA, Deeks SG, Brun SC, et al. Safety and antiviral activity at 48
weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside
reversetranscriptase
inhibitors in HIV type 1--infected protease inhibitor--
experienced patients. J Infect Dis 2002, 185: 599-607.
http://amedeo.com/lit.php?id=11865416
287
2. Clarke S, Mulcahy F, Bergin C, et al. Absence of opioid withdrawal
symptoms in patients receiving methadone and the protease inhibitor
lopinavir-ritonavir. Clin Infect Dis 2002, 34: 1143-5.
http://amedeo.com/lit.php?id=11915005
3. Eyer-Silva WA, Neves-Motta R, Pinto JF, Morais-De-Sa CA. Inflammatory
oedema associated with lopinavir-including HAART regimens in advanced
HIV-1 infection: report of 3 cases. AIDS 2002, 16: 673-4.
4. Kempf DJ, Isaacson JD, King MS, Brun SC, Xu Y, Real K et al.
identification
of genotypic changes in human immunodeficiency virus protease that
correlate with reduced susceptibility to the protease inhibitor lopinavir
among viral isolates from protease inhibitor- experienced patients. J Virol
2001, 75: 7462-9. http://amedeo.com/lit.php?id=11462018
5. Khanlou H, Graham E, Brill M, Farthing C. Drug interaction between
amprenavir
and lopinavir/ritonavir in salvage therapy. AIDS 2002, 16: 797-8.
6. Lascoux AS, Lesprit P, Bertocchi M, Levy Y. Inflammatory oedema of the
legs: a new side-effect of lopinavir. AIDS 2001, 15: 819.
7. Molla A, Mo H, Vasavanonda S, Han L, Lin CT, Hsu A et al. In vitro
antiviral
interaction of lopinavir with other protease inhibitors. Antimicrob
Agents Chemother 2002, 46: 2249-53.
http://amedeo.com/lit.php?id=12069982
8. Prado JG, Wrin T, Beauchaine J, Ruiz L, Petropoulos CJ, Frost SD et al.
Amprenavir-resistant HIV-1 exhibits lopinavir cross-resistance and reduced
replication capacity. AIDS 2002, 16: 1009-17.
http://amedeo.com/lit.php?id=11953467
9. Walsmley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir
for the initial treatment of HIV infection. N Engl J Med 2002, 346:
2039-46. http://amedeo.com/lit.php?id=12087139
Nelfinavir (NFV)
Un PI relativ bine tolerat si bine investigat, dar este mai putin puternic decat
PI stimulate. Un regim PI bazat pe Nelfinavir este mai putin puternic (potent)
decat regimurile NNRTI. Principalele probleme sunt reprezentate de povara
crescuta a medicatiei si diareea frecventa. Datorita profilului de rezistenta
favorabil (dupa esecul tratamentului cu nelfinavir, alte PI pot inca sa fie
eficiente), este potrivit ca PI de linie I.
288
Clasa de medicamente: Inhibitor de proteaze
Producator: Roche
Surse Internet:
USA: http://hiv.net/link.php?id=118
Bibliografie:
1. Albrecht MA, Bosch RJ, Hammer SM, et al. Nelfinavir, efavirenz, or both
after the failure of nucleoside treatment of HIV infection. N Engl J Med
2001, 345: 398-407. http://amedeo.com/lit.php?id=11496850
2. Fitzgibbon JE, Gaur S, Walsman SM, et al. Emergence of drug resistance
mutations in a group of HIV-infected children taking nelfinavircontaining
regimens. AIDS Res Hum Retroviruses 2001, 17: 1321-8.
http://amedeo.com/lit.php?id=11602042
3. Mortier E, Pouchot J, Vinceneux P, Lalande M. Ergotism related to
interaction
between nelfinavir and ergotamine. Am J Med 2001, 110: 594.
289
4. Phanuphak P. Dose-escalating study of the safety and pharmacokinetics
of nelfinavir in HIV-exposed neonates. J Acquir Immune Defic Syndr
2002, 29: 455-63. http://amedeo.com/lit.php?id=11981361
5. Resch W, Ziermann R, Parkin N, Gamarnik A, Swanstrom R.
Nelfinavirresistant,
amprenavir-hypersusceptible strains of HIV type 1 carrying an
n88s mutation in protease have reduced infectivity, reduced replication
capacity. J Virol 2002, 76: 8659-66.
http://amedeo.com/lit.php?id=12163585
6. Walsmley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir
for the initial treatment of HIV infection. N Engl J Med 2002, 346:
2039-46. http://amedeo.com/lit.php?id=12087139
Nevirapine (NVP)
Comentarii/ Avertizari:
Folositi cu atentie in disfunctie hepatica (determinati nivelele plasmatice).
Contraindicat pentru co-medicatia cu rifampicin, ketoconazol, St. John’s wort
si pilula.
Derivati de Azole: fluconazol ar trebui folosit pentru tratamentul antimicotic.
Ajustarea dozei in combinatie cu
Indinavir: cresteti doza de indinavir pana la 1.000 mg tid.
Metadona: daca apar simptome determinate de abstinenta doza s-ar
putea sa fie nevoie sa fie marita.
Lopinavir: posibila cresterea dozei de Kaletra ® pana la 4 capsule bid
(masurati nivelele plasmatice!).
Surse Internet:
USA: http://hiv.net/link.php?id=121
Bibliografie:
1. Antinori A, Baldini F, Girardi E, et al. Female sex and the use of antiallergic
agents increase the risk of developing cutaneous rash associated
with nevirapine therapy. AIDS 2001, 15: 1579-81.
http://amedeo.com/lit.php?id=11504993
2. Clarke SM, Mulcahy FM, Tjia J, et al. Pharmacokinetic interactions of
nevirapine and methadone and guidelines for use of nevirapine to treat
Injection drug users. Clin Infect Dis 2001, 33.
http://amedeo.com/lit.php?id=11568856
3. Conway B, Wainberg MA, Hall D, et al. Development of drug resistance
in patients receiving combinations of zidovudine, didanosine and nevirapine.
AIDS 2001, 15:1269-74. http://amedeo.com/lit.php?id=11426071
4. Domingo P, Matias-Guiu X, Pujol RM, et al. Switching to nevirapine
decreases
insulin levels but does not improve subcutaneous adipocyte
apoptosis in patients with highly active antiretroviral therapy-associated
lipodystrophy. J Infect Dis 2001, 184: 1197-201.
http://amedeo.com/lit.php?id=11598845
5. Fagot JP, Mockenhaupt M, Bouwes-Bavinck JN, et al. Nevirapine and the
risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. AIDS
2001, 15:1843-1848. http://amedeo.com/lit.php?id=11579247
6. Fätkenheuer G, Romer K, Kamps R, Salzberger B, Burger D.
Pharmacokinetics
of amprenavir and lopinavir in combination with nevirapine in
highly pretreated HIV-infected patients. AIDS 2001, 15: 2334-5.
7. Gonzalez de Requena D, Nunez M, Jimenez-Nacher I, Soriano V. Liver
toxicity caused by nevirapine. AIDS 2002, 16: 290-1.
http://amedeo.com/lit.php?id=11807315
8. Martinez E, Blanco JL, Arnaiz JA, et al. Hepatotoxicity in HIV-1-infected
patients receiving nevirapine-containing antiretroviral therapy. AIDS
2001, 15: 1261-1268. http://amedeo.com/lit.php?id=11426070
9. Mirochnick M, Siminski S, Fenton T, Lugo M, Sullivan JL. Nevirapine
pharmacokinetics in pregnant women and in their infants after in utero
exposure. Pediatr Infect Dis J 2001, 20: 803-5.
http://amedeo.com/lit.php?id=11734746
10. Negredo E, Cruz L, Paredes R, et al. Virological, immunological, and
clinical impact of switching from PIs to nevirapine or to efavirenz in patients
with HIV infection and long-lasting viral suppression. Clin Infect Dis
292
2002, 34: 504-10. http://amedeo.com/lit.php?id=11797178
11. Rey D, L'Heritier A, Lang JM. Severe ototoxicity in a health care worker
who received postexposure prophylaxis with stavudine, lamivudine, and
nevirapine after occupational exposure to HIV. Clin Infect Dis 2002, 34:
418-419.
12. Sinkala M, Stout JP, Vermund SH, Goldenberg RL, Stringer JS. Zambian
women's attitudes toward mass nevirapine therapy to prevent perinatal
transmission of HIV. Lancet 2001, 358: 1611-2.
http://amedeo.com/lit.php?id=11716891
13. Suzuki K, Kaufmann GR, Mukaide M, et al. Novel deletion of hiv type 1
reverse transcriptase residue 69 conferring selective high-level resistance
to nevirapine. AIDS Res Hum Retroviruses 2001, 17: 1293-6.
http://amedeo.com/lit.php?id=11559430
14. Van der Valk M, Kastelein JJ, Murphy RL, et al. Nevirapine-containing
antiretroviral therapy in HIV-1 infected patients results in an antiatherogenic
lipid profile. AIDS 2001, 15: 2407-2414.
http://amedeo.com/lit.php?id=11740191
15. Veldkamp AI, Weverling GJ, Lange JM, et al. High exposure to nevirapine
in plasma is associated with an improved virological response in
HIV-1-infected individuals. AIDS 2001, 15: 1089-1095.
http://amedeo.com/lit.php?id=11416710
16. Wit FW, Wood R, Horban A, et al. Prednisolone does not prevent
hypersensitivity
reactions in antiretroviral drug regimens containing abacavir
with or without nevirapine. AIDS 2001, 15: 2423-2429.
http://amedeo.com/lit.php?id=11740193
Ritonavir (RTV)
Datorita efectelor secundare gastrointestinale, doza terapeutica de ritonavir
este cu greu acceptabila si rareori prescrisa. In orice caz, ritonavir a devenit
un medicament important pentru stimularea altor inhibitori de proteaze. In
aceste combinatii, cand se folosesc doze mai reduse, efectele secundare ale
293
ritonavirului sunt tolerabile. Trebuie luate in considerare numeroase
interactiuni medicamentoase.
Producator: Abbott
Doza orala: In cazurile rare, in care se foloseste ritonavirul ca unic PI, doza
de 600 mg bid (cresteti doza in decursul a 2 saptamani: 300 mg bid in zilele
1-2, 400 mg bid in zilele 3-5, 500 mg bid in zilele 6-13).
Folosirea optima a ritonavirului, in orice caz, este pentru stimularea altor PI!
Doze zilnice in combinatie cu
Saquinavir (Fortovase ® sau Invirase ®):
100 mg ritonavir + 1.000 mg saquinavir bid
Sau
400 mg ritonavir bid + 400 mg saquinavir bid
Indinavir (Crixivan ®):
100 mg ritonavir bid + 800 mg indinavir bid
Sau
400 mg ritonavir bid + 400 mg indinavir bid
Amprenavir (Agenerase ®):
100 mg ritonavir bid + 600 mg amprenavir bid
Sau
200 mg ritonavir qd + 1.200 mg amprenavir qd
Lopinavir (Kaletra ®): Combinatie fixa, vezi lopinavir.
294
Ar trebui avuta grija si nivelele plasmatice masurate atat pentru ritonavir si
(daca este posibil) pentru urmatoarele co-medicatii: Metadona,
imunosupresoare (ciclosporine, tacrolimus), antibiotice macrolide
(eritromicina, claritromicina), steroizi, antagonisti de calciu, antidepresoare
triciclice, alte antidepresoare (fluoxetine, paroxetine, sertraline), neuroleptice
(haloperidol, risperidone, thioridazine), medicamente antimicotice
(ketoconazol, itraconazol), carbamazepina, tolbutamida, rifabutin, teofilina si
warfarina.
Surse Internet:
USA: http://hiv.net/link.php?id=31
Bibliografie:
1. Benson CA, Deeks SG, Brun SC, et al. Safety and antiviral activity at 48
weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside
reversetranscriptase
inhibitors in HIV type 1--infected protease inhibitor--
experienced patients. J Infect Dis 2002, 185: 599-607.
http://amedeo.com/lit.php?id=11865416
2. Cameron DW, Heath-Chiozzi M, Danner S, et al. Randomised
placebocontrolled
trial of ritonavir in advanced HIV-1 disease. Lancet 1998,
351:543-9. http://amedeo.com/lit.php?id=9492772
3. Cameron DW, Japour AJ, Xu Y, et al. Ritonavir and saquinavir combination
therapy for the treatment of HIV infection. AIDS 1999, 13: 213-24.
http://amedeo.com/lit.php?id=10202827
4. Clarke S, Mulcahy F, Bergin C, et al. Absence of opioid withdrawal
symptoms in patients receiving methadone and the protease inhibitor
lopinavir-ritonavir. Clin Infect Dis 2002, 34: 1143-5. Abstract:
http://amedeo.com/lit.php?id=11915005
5. Deeks SG, Grant RM, Beatty GW, et al. Activity of a ritonavir plus
saquinavir-
containing regimen in patients with virologic evidence of indinavir or
ritonavir failure. AIDS 1998, 12: F97-102.
http://amedeo.com/lit.php?id=9677159
6. Duval X, Lamotte C, Race E, et al. amprenavir inhibitory quotient and
virological response in HIV-infected patients on an amprenavir-containing
salvage regimen without or with ritonavir. Antimicrob Agents Chemother
2002, 46: 570-4. http://amedeo.com/lit.php?id=11796381
7. Kempf DJ, Marsh KC, Kumar G, et al. Pharmacokinetic enhancement of
inhibitors of the HIV protease by coadministration with ritonavir. Antimicrob
Agents Chemother 1997, 41:654-60.
http://amedeo.com/lit.php?id=9056009
8. Kirk O, Mocroft A, Pradier C, et al. Clinical outcome among HIV-infected
295
patients starting saquinavir hard gel compared to ritonavir or indinavir.
AIDS 2001, 15: 999-1008. http://amedeo.com/lit.php?id=11399982
9. Moreno S, Podzamczer D, Blazquez R, et al. Treatment of tuberculosis in
HIV-infected patients: safety and antiretroviral efficacy of the concomitant
use of ritonavir and rifampin. AIDS 2001; 15: 1185-7.
10. Saah AJ, Winchell GA, Nessly ML, Seniuk MA, Rhodes RR, Deutsch PJ.
Pharmacokinetic profile and tolerability of indinavir-ritonavir combinations
in healthy volunteers. Antimicrob Agents Chemother 2001, 45: 2710-5.
http://amedeo.com/lit.php?id=11557459
11. Sadler BM, Piliero PJ, Preston SL, Lloyd PP, Lou Y, Stein DS.
Pharmacokinetics
and safety of amprenavir and ritonavir following multiple-dose,
co-administration to healthy volunteers. AIDS 2001, 15:1009-18.
http://amedeo.com/lit.php?id=11399983
12. Spiegel M, Schmidauer C, Kampfl A, Sarcletti M, Poewe W. Cerebral
ergotism under treatment with ergotamine and ritonavir. Neurology 2001,
57:743-4.
13. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus
nelfinavir
for the initial treatment of HIV infection. N Engl J Med 2002, 346:
2039-46. http://amedeo.com/lit.php?id=12087139
14. Wensing AM, Reedijk M, Richter C, Boucher CA, Borleffs JC. Replacing
ritonavir by nelfinavir or nelfinavir/saquinavir as part of HAART leads to
an improvement of triglyceride levels. AIDS 2001, 15:2191-3.
Saquinavir (SQV)
Unul din primele PI, si, singurul cu 2 forme de prezentare disponibile. Relativ
“benign” (bine tolerat cu exceptia problemelor gastrointestiale, nu exista
probleme serioase pe termen scurt). Povara a medicatiei intolerabila daca nu
este stimulat. Datorita biodisponibilitatii reduse, forma de prezentare a fost
imbunatatita de la Invirase ® la Fortovase ®, care din pacate este mai putin
bine tolerata. Conform datelor recente, Invirase ®, care aproape a fost
abandonata, este la fel de eficienta cand este stimulata cu ritonavir. Destul de
straniu, Invirase ® este semnificativ mai scumpa. Rezistenta incrucisata cu
alte PI este frecventa.
296
Clasa de medicamente: Inhibitori de proteaze
Surse Internet:
USA: http://hiv.net/link.php?id=132
Bibliografie:
Stavudine (d4T)
Stavudine este un analog de timidine ca si zidovudine. Tolerabilitatea
subiectiva este buna; medicamentul a fost considerat mult timp cel putin
echivalent zidovudinei. Indrumarile mai noi sunt mai precaute, datorita
neuropatiei si datelor legate de toxicitatea mitocondriala (lipoatrofie, acidoza
lactica), in special la combinarea cu didanosine. Noi capsule de 75 mg si 100
mg vor deveni disponibile in scurt timp, permitand dozarea/ administrarea o
data – zilnic.
Mod de prezentare:
Capsule 15 mg, 20 mg, 30 mg, 40 mg
1 mg/ml solutie orala, 200 ml
Capsule cu eliberare treptata, 37,5 mg, 50 mg, 75 mg, si 100 mg, disponibile
mai tarziu in 2003
298
Doza orala: 40 mg bid ( greutate corporala > 60 kg), sau 30 mg bid ( greutate
corporala < 60 kg). in insuficienta renala:
Surse Internet:
USA: http://hiv.net/link.php?id=80
Bibliografie:
T-20 (Enfuvirtide)
T-20 este prototipul unei noi clase de medicamente – inhibitori de intrare.
Este bine tolerat, dar poate fi administrat numai ca injectie. Va fi important
pentru terapia de salvare in viitor.
300
dureri si discomfort, indurare, eritem, noduli si chisturi, prurit si echimoze
(schimbati locul de injectare).
Reactiile de hipersensibilitate au fost asociate cu T-20 (<1%) si au reaparut la
reluarea administrarii medicamentului. Simptomele unei reactii alergice pot
include urticarie, febra, greturi si varsaturi, frisoane, rigiditate, hipotensiune si
transaminaze serice crescute.
Bibliografie:
301
Tenofovir (TDF)
Producator: Gilead
302
Urmeaza sa se realizeze studii controlate ale utilizarii tenofovirului in sarcina.
In studiile pe maimute, tenofovir era eficient in profilaxia transmiterii SIV, dar
a determinat de asemenea tulburari de crestere.
Surse Internet:
USA: http://hiv.net/link.php?id=134
Bibliografie:
Doza orala: Tipranavir este testat in studiile Phase III in doza de 500 mg bid
plus 200 mg ritonavir bid.
Bibliografie:
304
antiretroviral-naive HIV-1-infected patients. Abstract 673, 7th CROI, San
Francisco, USA. http://www.retroconference.org/2000/abstracts/673.htm
Trizivir ®
Aceasta combinatie a dus la o reducere semnificativa a poverii
medicamentelor. Este cea mai simpla combinatie tripla disponibila in prezent.
Vezi de asemenea medicamentele zidovudine, lamivudine si abacavir.
Mod de prezentare:
Tablete continand 150 mg lamivudine si 300 mg zidovudine si 300 mg
abacavir.
Producator: GlaxoSmithKline
Surse Internet:
USA: http://hiv.net/link.php?id=51
Bibliografie:
305
vs indinavir-lamivudine-zidovudine in antiretroviral-naive HIVinfected
adults: A randomized equivalence trial. JAMA 2001, 285: 1155-
63. http://amedeo.com/lit.php?id=11231744
4. Vibhagool A, Cahn P, Schechter M, et al. Abacavir/Combivir (ABC/COM)
is comparable to Indinavir/Combivir in HIV-1-infected antiretroviral therapy
naïve adults: preliminary results of a 48-week open label study
(CNA3014). Abstract 63, 1st IAS Conference on HIV Pathogenesis and
Treatment 2001, Buenos Aires, Argentina.
Zalcitabine (ddC)
Unul din primele medicamente antiretrovirale. In prezent, este folosit foarte
rar datorita dozarii complicate, riscului de polineuropatie si rezistentei
incrucisate cu didanosine. Este posibil sa fie mai putin puternic decat
didanosine si stavudine.
Mod de prezentare:
Tablete 0,375 mg
Tablete 0,75 mg
306
Doza orala: 0,75 mg tid. Ajustarea dozei pentru insuficienta renala:
Clearance al creatininei de 40 pana la 10 ml/min: 0,75 mg bid, CrCl < 10
ml/min: 0,75 mg qd.
Surse Internet:
USA: http://hiv.net/link.php?id=84
Bibliografie:
Zidovudine (AZT)
Cel mai vechi si mai bine investigat medicament HIV. Datorita efectelor
secundare gastro-intestinale si mielotoxice, medicamentul nu a fost la moda o
perioada. Totusi, ramane un component important al multor regimuri HAART
chiar si azi, in particular pentru ca are o buna penetrare la nivelul SNC si o
toxicitate mitocondriala relativ redusa (tolerabilitate buna pe termen lung!).
Mod de prezentare:
Retrovir ®: capsule 100 mg, 250 mg, 300 mg
10 mg/ml sirop, 240 ml
Fiole 20 ml (intravenos), 10 mg/ml
307
Combivir ®: tablete continand 300 mg zidovudine si 150 mg lamivudine.
Producator: GlaxoSmithKline
Doze: 250 mg bid sau 200 mg tid. Pentru Combivir ® si Trizivir ® 300 mg bid.
Clearance al creatininei sub 20 ml/min: 300 pana la 400 mg zilnic.
Hemodializa: 300 mg zilnic. Insuficienta hepatica: 100 mg tid.
Surse Internet:
Bibliografie:
t.i.d. abbr. Latin ter in die (three times a day)- de trei ori pe zi
U U
bid abbr. Latin bis in die twice a day- de doua ori pe zi.
310
HIV Medicine 2003 – www.HIVMedicine.com
311