Tratamentul actual al hepatitei cronice cu virus B

01.03.2011, 01:00
Asist. univ. Dr. Ioan Ancua, medic primar medicin intern, specialist reumatologie, doctor n medicin; Clinica de Medicin Intern i Reumatologie a Spitalului Dr. Ion Cantacuzino, U.M.F. Carol Davila Bucureti

Articol preluat din publicatia Medicina Moderna, 2010; 17(3):126-9 pentru sectiunea EMC medicina familiei, luna martie 2011. Rezumat. Hepatita cronica B este o infectie Abstract. Chronic hepatitis B virus (HBV) virala hepatica cu o lunga si complexa evolutie infection has a complex and long natural n timp cu forme clinice asimptomatice sau history, ranging from asymptomatic chronic severe. Tratamentul are ca scop reducerea hepatitis to severe liver disease.i1] The progresiei bolii. Terapiile actuale pentru HVB indications for treatment should ideally be inhiba replicarea virala, asociindu-se cu tailored to prevent or reduce progressive ameliorarea nivelului seric al disease. Antiviral therapy for HBV alaninaminotransferazei (ALT) si a activitatii suppressed viral replication with necroinflamatorii. De asemenea n cazul accompanying improvement in serum cirozelor hepatice terapia antivirala creste alanine aminotransferase (ALT) levels and supravietuirea. Modificarile majore ale terapiei hepatic necroinflammatory disease. de prima linie n HVB pentru toate categoriile de Furthermore, treatment of cirrhosis or pacienti fac cuprinsul acestui articol. advanced stages of the disease improves clinical outcomes associated with advanced disease, providing a proof of principle that antiviral therapies improve survival. Major advances in the efficacy of treatment for HBV infection have been made, and recommended first-line therapies are the topic of this review. Cuvinte-cheie: hepatit cronic, virus B, Keywords: chronic B hepatitis, treatment tratament Tratamentul hepatitei cronice cu virus B nelegerea fazelor de evoluie a HVB permite alegerea unei terapii corecte astfel nct aceasta s fie eficient n determinarea remisiei bolii i absenei apariiei rezistenei. Controlul bolii este esenial ca factor de prognostic pe termen lung, avnd n vedere c boala nu este vindecabil cu arsenalul terapeutic actual. Scopurile terapiei este, n primul rnd, prevenirea complicaiilor pe termen lung (ciroz hepatic, insuficien hepatic i carcinomul hepatic primitiv), ceea ce depinde de gradul de supresie a replicrii virale.

 Endpointul primar Scderea nivelului seric al ADN HVB (sczut sau nedetectabil) Endpointurile secundare Scderea sau normalizarea ALT Seroconversia sau dispariia AgHBe Seroconversia sau dispariia AgHBs Ameliorarea histologic (valabil n studii clinice dar neaplicabil ca monitorizare n practica curent. Mijloacele terapeutice actuale sunt reprezentate n tabelul I.

Alegerea terapiei de prim intenie depinde de fazele de evoluie n care este diagnosticat bolnavul, precum i de o serie de ali factori: Statusul AgHBe(AgHBe pozitiv sau negativ) Genotipul HVB Nivelul viremiei (ADN HVB seric) Nivelul seric al ALT Prezena sau absena cirozei Comorbiditi (boala cardiac ischemic, depresie, insuficiena renal) Factorii care influeneaz rspunsul la tratament sunt durata terapiei, eficacitatea terapiei alese i rezistena la terapie.

Tratamentul hepatitei cronice cu virus B (AgHBe+) Criteriile de indicaie a terapiei antivirale sunt prezena replicrii virale i a citolizei hepatice. Se trateaz cazurile cu ADN HVB > 20,000ui/ml (100000copii/ml) i ALT > 2 x ULN. Durata tratamentului este de 6 luni dup apariia seroconversiei AgHBe. Indicaia de biopsie o au cazurile cu vrst >40ani, cu ALT normale i ADN HVB>20,000ui/ml la care exist antecedente heredocolaterale de carcinom hepatic primitiv. Pentru cazurile n care PBH deceleaz activitate necroinflamatorie sever sau fibroz la stadiul de puni de fibroz portoportal, se ia n discuie tratamentul. Cazurile cu ALT normale i ADN HVB>20,000ui/ml se vor monitoriza la 3-6 luni din punct de vedere al ALT i dac apare citoliz acestea vor fi tratate. Medicaia utilizat este unul dintre ageni urmtori, n monoterapie: peginterferon alfa2S, lamivudina, adefovirul i entecavirul. Se consider un rspuns complet scderea ADN VHB cu 2-3log10 fa de viremia iniial. Pentru cazurile cu ADN VHB Tratamentul hepatitei cronice B (AgHBe-) Ca i n cazul hepatitei cronice B AgHBe +, criteriile de indicaie pentru terapia antiviral sunt prezena replicrii virale i a citolizei hepatice. Se trateaz cazurile cu ADN VHB>2000ui/ml(10000copii/ml) i ALT>1-2xULN. Valorile date se explic prin faptul c n aceast faz de evoluie a bolii replicarea virusului B cu AgHBe- este mult mai sczut. Cazurile cu ADN VHB 2000ui/ml i cu ALT normale se vor monitoriza la 6-12 luni i se va lua n discuie biopsia n aceleai condiii ca la cazurile AgHBe pozitive. Medicaia utilizat este peginterferon alfa-2S, lamivudina, adefovirul, entecavirul. Se consider un rspuns complet scderea ADN VHB cu 1log10 fa de viremia iniial. Durata tratamentului este de 12 luni cu peginterferon alfa-2a i indefinit n timp cu analogi nucleotidici. Tratamentul antiviral in cazul cirozelor cu virus hepatitic B Pentru ciroza hepatic compensat, indicaie de tratament antiviral au cazurile cu ADN HVB > 2000ui/ml, indiferent de prezena AgHBe i de nivelul ALT. Nu se trateaz cazurile cu viremie nedetectabil. Medicaia utilizat este lamivudina, adefovirul i entecavirul. Medicaia antiviral utilizat n hepatita cronic cu HVB Interferonul alfa/2a i 2b. Ambele molecule au fost aprobate de FDA n 1991, dar astzi este utilizat pe scar larg interferonul pegylat alfa 2 (Pegasys) datorit convenienelor de administrare i a rezultatelor. n cazurile Ag HBe+, interferonul pegylat alfa/2a produce o seroconversie de aproximativ 30% dup 1 an de tratament, comparativ cu o rat de seroconversie de 12-23% la terapia cu analogi nucleotidici. Extensia terapiei la 2 ani ridic rata de seroconversie la 40%. Un alt avantaj al terapiei cu interferon pegylat alfa/2a este seroconversia AgHBs ntre 3-8% dup 1 an de tratament (comparativ cu

La cazurile cu AgHBe- terapia cu interferon pegylat alfa/2a reduce nivelul seric al ADN VHB i circa 20% din bolnavi rmn nedetectabili la 4 ani de la terminarea terapiei. Cazurile cu recdere la interferon alfa/2a vor fi tratate cu analogi nucleotidici, dar acetia sunt de introdus numai dup ncercarea realizrii clereance-ului viral cu interferon pegylat alfa/2a timp de 48 de sptmni. Lamivudina a fost introdus n 1990 i este la ora actual cea mai folosit. Problema de baz a tratamentului cu lamivudin este apariia mutaiilor YMDD compensatorii la codonul rtV173L i/sau rtL180M, care restabilesc fitnessul viral. Lamivudina nu este indicat n terapia de lung durat ca prim linie terapeutic, dezvoltarea rezistenei fiind de 23% din cazuri dup 1 an, 46% la 2 ani, mergnd pn la 65-71% dup 5 ani de tratament. Lamivudina este un analog cu barier genetic joas. Doza uzual este de 100mg/zi Adefovirul are un profil al rezistenei i al supresiei virale mai bun ca al lamivudinei. Doza uzual este de 10 mg/zi i principala reacie advers este nefrotoxicitatea. Adefovirul are o rat de rspuns (ADN HVB seric nedetectabil) ntre 20-50% la 1 an. Rezistena genotipic este de 4% la 4 ani la cei cu ADN VHB Entecavirul n doz de 0,5 mg/zi determin viremie nedetectabil la 67 % din cazurile AgHBe+ i la pn 90% din cazurile AgHBe-, comparativ cu 36% respectiv 72% ct se obine cu lamivudin. Rata de seroconversie a AgHBe+ a fost de 18-21% comparativ cu lamivudina. Cazurile cu recdere i cu lipsa seroconversiei AgHBe dup 1 an de tratament, vor fi tratate cu 1mg/zi. Rezistena este de 1,2% la 5 ani, entecavirul fiind un agent cu barier genetic nalt. Este nevoie de 3 mutaii ale ADN polimerazei, din care 2 comune cu lamivudin (M204V/I+L180M) plus mutaia n poziia 169, 202, 250 specific entecavirului ca molecul. Cazurile rezistente la lamivudin dezvolt rezisten la entecavir n 35% din cazuri. Paradigma este c se poate asocia entecavirul cu lamivudin la cazurile cu rezisten la lamivudin. Se obin rezulate mai bune dect dac se face switch-ul pe adefovir sau tenofovir. Telbivudina permite n 60 % din cazuri obinerea viremiei nedetectabile dup 1 an de tratament, la doza de 600mg/zi. Viremia este nedetectabil la 1 an n 60% din cazurile AgHBe+ i n 90% dintre cazurile AgHBe-. Rata de seroconversie a AgHBe este de 31% la 2 ani comparativ cu 26 % pentru lamivudin. Profilul de rezisten genotipic este ntre 2-5%, la 1 an de tratament, dar cu o cretere major 11-25% dup sptmna 104 de tratament, la cazurile cu viremie detectabil la sptmna 24. Pentru cei cu viremie nedetectabil la 24 de sptmni, rezistena este de 2-4%. Telbivudina nu este de prim linie terapeutic din aceste motive, fiind un analog cu barier genetic joas. Rezistena viral. Consecinele clinice ale apariiei rezistenei la analogi nucleotidici sunt scderea ratei de seroconversie a AgHBe+ cu alterarea aspectului histologic hepatic i eventual decompensare la pacienii cu ciroz constituit. Exist o corelaie ntre gradul de inhibare a replicrii virale de ctre analogul nucleotidic i apariia rezistenei. Supresia replicrii virale complete sau pn la nivele ct mai apropiate de limita de detecie a ADN VHB nu confer apariia rezistenei. O supresie moderat a ADN VHB are mari anse de apariie a rezistenei virale. Capacitatea de inhibare a replicrii virale a analogilor nu este cheia obinerii susinute a rspunsului virusologic. Rezistena viral este legat de bariera genetic a analogului nucleotidic folosit. Bariera genetic se definete ca fiind numrul de mutaii din locusuri specofoce ale ADN/polimerazei care restabilesc fitnessul viral (scparea de sub supresia dat de analog i reluarea replicrii virale). Cu ct

numrul de mutaii necesar n gena ADN polimerazei pentru restabilirea fitness-ului viral este mai mare, cu att bariera genetic a analogului nucleotidic respectiv este mai nalt. Astfel lamivudina i telbivudina au barier genetic joas i rate crescute de apariie a rezistenei. Entecavirul este cel mai potent, avnd barier genetic nalt, ca i adefovirul. Noiunile de rezisten utilizate sunt date n tabelul II: Tabel II .Nomenclatorul rezistenei virale. Lipsa scderii ADN VHB cu 1 log10 la 6 luni de tratament Creterea cu 1 log10 a ADN VHB la 2 determinri Breakthrough viral diferite i la pacient compliant Rezistena Detectarea mutaiilor n ADN polimeraz, mutaii care genotipic confer rezistena Rezistena Scderea n vitro susceptibilitii unui analog la un pacient fenotipic compliant Breakthrough Creterea ALT n timpul terapiei biochimic Rezistena primar Monitorizarea rezistenei virale se realizeaz prin determinarea simultan a ALT i ADN VHB la 6 luni pentru cazurile de hepatit cronic B i la 3 luni pentru cirozele cu virus hepatitic B. Managementul rezistenei este redat n tabelul III . Se ine cont de rezistena ncruciat i de bariera genetic a analogului nucleotidic. Tabel III : Managementul rezistenei HVB a agenii antivirali.

Monitorizarea terapiei cu analogi nucleotidici Tratamentul odat nceput, se monitorizeaz la 24 de sptmni prin prisma ALT i ADN VHB. 1. Dac exist viremie nedetectabil (rspuns complet) cu analogul ales, se va continua cu acesta i se vor face monitorizrile de ALT i ADN VHB la fiecare 6 luni. 2. Dac ADN VHB este >2000 ui/ml (10.000 copii/ml) (rspuns inadecvat) se va aduga un analog cu barier genetic nalt la cel deja folosit i se va monitoriza ADN VHB la 3 luni. 3. Dac ADN HVB este 60-2000 ui/ml (rspuns incomplet) se va proceda n felul urmtor: - n cazul folosirii unui analog cu barier genetic joas se va aduga un al doilea cu barier genetic nalt i fr rezisten ncruciat.

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