SUPRESIA VIRALA SUSTINUTA –

MODIFICAREA PROGNOSTICULUI
PE TERMEN LUNG

Dr. Ana-Maria Singeap

Dr. Roxana Livadariu
Prof. Dr. Anca Trifan
SCOALA DE VARA DE GASTROENTEROLOGIE, IASI
CURS INTENSIV HC-VHB, 10 IULIE 2014
HC-VHB
 GLOB = 400.000.000 persoane cu infectie cronica virala B

 1.000.000 decese/ an (insuficienta hepatica, CH-VHB,

hepatom)

 Supravietuire la 2 ani CHC-VHB: 25%

 80% din CHC – sunt pe teren cirotic
 !CHC si in absenta CH; 40% Asia, 5% Europa de Vest

 Supravietuire la 5 ani CH-VHB decompensata: 14-35% /

CH compensata 84%
EVOLUTIA NATURALA A INFECTIEI CU VHB
OBIECTIVELE TRATAMENTULUI ANTIVIRAL
(“ENDPOINTS”)
 Calitatea vietii si supravietuirea
 Prevenirea progresiei bolii catre ciroza, CH
decompensata, CHC si deces

 RASPUNS VIRUSOLOGIC SUSTINUT

 RASPUNS BIOCHIMIC SI VIRUSOLOGIC dupa

seroconversie HBe sau la pacienti Ag HBe negativi

 IDEAL: pierdere Ag HBs +/- seroconversie Ac anti HBs

TIPURI DE RASPUNS
 BIOCHIMIC
 Normalizarea transaminazelor
 SEROLOGIC
 Seroconversie “e”, “s”
 VIRUSOLOGIC
 IFN: ADN-VHB < 2000 UI/ml; mentinere minim 12 luni
posttratament
 AN: ADN-VHB nedetectabil; sustinut – similar
 HISTOLOGIC
 Scaderea activitatii necro-inflamatorii (> 2 puncte in scorul
Knodell sau Ishak) fara agravarea fibrozei
 COMPLET: RVS + pierdere Ag HBs
RASPUNSUL VIRUSOLOGIC SUSTINUT

 Unul dintre OBIECTIVELE PE TERMEN SCURT ale

terapiei antivirale

 INTARZIEPROGRESIA BOLII HEPATICE

 REDUCE COMPLICATIILE HEPATICE

 PRELUNGESTE SUPRAVIETUIREA

 POATE IMBUNATATI PROGNOSTICUL PE TERMEN

LUNG
ADN-VHB – factor de risc
 Risk Evaluation of Viral Load Elevation and Associated
Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV)
study
 Taiwan, studiu de cohorta prospectiv, 23,820 participanti,
3653 Ag HBs +
 Incidenta CHC si cirozei hepatice = semnificativ asociate cu
nivelurile ADN-VHB, in maniera corelata tip “doza-
raspuns” de la nedetectabil (<300 copii/ml) la >1.000.000
copii/ml
 Nivelul ADN-VHB la intrarea in studiu = predictiv pentru
clearance spontan Ag HBe si Ag HBs

 Chen CJ, Yang HI. Natural history of chronic hepatitis B

REVEALed. J Gastroenterol Hepatol. 2011
ALTERNATIVE TERAPEUTICE
IFN / AN
RVS PROGNOSTIC
EFECTUL TERAPIEI ANTIVIRALE
CU INTERFERON
IN INFECTIA CRONICA VIRALA B
Meta-analysis: Reduction in Hepatic Events Following
Interferon-alfa Therapy of Chronic Hepatitis B

 “hepatic events”
Complicatii ale cirozei hepatice
Ascita, EH, SHR, PBS, HD variceala
Cancer hepato-celular
Mortalitate legata de afectiuni hepatice

 11 studii, 975 pacienti tratati/1147 control

 IFN-α 1–24 luni, follow-up 1–13 ani

Wong, Al Pharmacol Therapy 2010
Meta-analysis: Reduction in Hepatic Events Following
Interferon-alfa Therapy of Chronic Hepatitis B

 ↓ riscului global pentru evenimente hepatice cu 45% (RR 0.55, 95%

confident interval or CI 0.43–0.70, P < 0.001)
 ↓ riscului pentru complicatiile cirozei hepatice cu 54% (RR 0.46, 95%
CI 0.32–0.67, P < 0.001
 Responderii la IFN-α : scadere mai importanta a riscului global pentru
evenimente hepatice (RR 0.20, 95% CI 0.05–0.87, P = 0.03) si a riscului
pentru complicatiile cirozei hepatice (RR 0.19, 95% CI 0.09–0.38, P
< 0.001) fata de cei netratati

 “Interferon-alfa treatment reduces the risk of

hepatic events particularly among responders to
treatment”

Wong, Al Pharmacol Therapy 2010

RVS PROGNOSTIC
EFECTUL TERAPIEI ANTIVIRALE
CU ANALOGI NUCLEOS(T)IDICI
IN INFECTIA CRONICA VIRALA B
SUPRESIA VIRALA SI REGRESIA FIBROZEI
Studiu Nr pacienti Ag Regresia fibrozei >1 (%) Scor
HBe fibroza
An 1 3 >5

LAM Dienstag, 2003 30 F+C + - 67 K

11C 73
Rizzetto, 2005 24 F+C - 46 K
6C 50
Schiff, 2008 47 F+C + 49 - I
57 F+C - 53 -
ADV Hadziyannis, 12 F+C - 58, >2 p I
2006 4C 75, 4 p I
ETV Schiff, 2008 46 F+C + 57 I
51F+C - 59
Yokosuka, 2010 13F+C +/- 85 K
Chang, 2010 10 F+C +/- 40 100 I
4C 0 100
TDF Marcellin, 2013 133 F +/- 27 68 I
96 C 74
RVS PROGNOSTIC
TRATAMENTUL ANTIVIRAL IN
CIROZA HEPATICA COMPENSATA
CH COMPENSATA
 RISCUL DECOMPENSARII este mai crescut la pacientii
AND-VHB pozitivi comparativ cu pacientii AND-VHB
negativi
 RR = 4.05, 95%CI: 1.09-15.1

 Studiu de cohorta
 297 pacienti
 Ascita, icter, EH, HDS variceala

Fattovich G, et al. European Concerted Action on Viral Hepatitis (EUROHEP). Effect of

hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study
of 297 patients. Am J Gastroenterol. 2002 Nov;97(11).
LAMIVUDINA IN CH COMPENSATA
 Scorul Child-Pugh:
 Crestere 3,9% pacientii LAM ≠ 7,4% placebo (P = 0.047)

 Rata progresiei bolii:

 Definita ca ↑ cu cel putin 2 puncte a scorului Child –Pugh
 Scadere semnificativa
 7.8% LAM ≠ 18% placebo

 Presiunea portala
 GPVH (gradient de presiune venoasa hepatica)
 ↓ semnificativa la 12 luni de tratament ((14.4 mmHg vs 12.4 mmHg, P =
0.007)

 Liaw YF, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J
Med. 2004
 Manolakopoulos S, et al. Antiviral therapy reduces portal pressure in patients with cirrhosis due to HBeAg-
negative chronic hepatitis B and significant portal hypertension. J Hepatol. 2009
ENTECAVIR IN CH COMPENSATA
 69 pacienti tratati cu ETV
 Biopsie hepatica dupa o perioada medie de
tratament de 6 ani
 88% = reducerea scorului de fibroza Ishak cu ≥ 1
punct, inclusiv toti cei 10 pacienti cu FA sau C la
baseline (Ishak score ≥ 4)
 Chang TT, et al. Long-term entecavir therapy results in the reversal of
fibrosis/cirrhosis and continued histological improvement in patients with chronic
hepatitis B. Hepatology. 2010
TENOFOVIR IN CH COMPENSATA
 641 pacienti
 96 (28%) – ciroza la baseline, cu scor Ishak ≥ 5
 71 (74%) din cei cu ciroza au prezentat ↓ fibrozei
(cu > 1) la 5 ani, nemaifiind cirotici

 Marcellin, Lancet 2013

RVS PROGNOSTIC
TRATAMENTUL ANTIVIRAL IN
CIROZA HEPATICA DECOMPENSATA
 Pacientii cu CH-VHB decompensata:
 In general, [AND-VHB] mai scazut/nedetectabil
 O minoritate [AND-VHB]↑

ISTORIA NATURALA:
 influentata de replicarea virala
 RVS - ↓ necroinflamatiei hepatice si ↓ progresiei fibrozei =
preventia decompensarii

Brown A, Goodman Z Review Hepatitis B-associated fibrosis and fibrosis/cirrhosis

regression with nucleoside and nucleotide analogs Expert Rev Gastroenterol Hepatol.
2012 Apr; 6(2).
CH DECOMPENSATA
 TRATAMENT ANTIVIRAL:
 IFN – acutizari grave, complicatii infectioase
 ANs(t) orali – bine tolerati

 Most clinical guidelines strongly recommend using oral

NAs for patients with decompensated HBV-related
cirrhosis independent of the HBV DNA levels
LAMIVUDINA
 CH decompensata in tratament cu LAM
 69% = ↓ ≥ 3 puncte
 38% = scor Child – Pugh < 7 (status “inactiv” pe lista de
asteptare pentru transplant regionala “United Network of
Organ Sharing”)
 Yao FY, Bass NM. Lamivudine treatment in patients with severely decompensated cirrhosis due to
replicating hepatitis B infection. J Hepatol. 2000 Aug; 33(2):301-7. (San Francisco)

 RISC REZISTENTA (MUTATII YMDD) – RISC IH > la pacientii cu CH decompensata

 DETECTIA PRECOCE A REZISTENTEI (MUTATII YMDD) = SWITCH AGENT
NUCLEOSIDIC
 Di Marco V, et al. HBV-DNA suppression and disease course in HBV cirrhosis patients on long-
term lamivudine therapy. Antivir Ther. 2005;10(3)
ADEFOVIR
 128 pacienti LAM-rezistenti,10 mg/zi
 HBV DNA nedetectabil; 81%
 Imbunatatire scorul Child-Pugh ≥ 90% la 48 saptamani de
tratament
 Schiff, Hepatology 2003

 Studiu de urmarire pe termen lung – 240 de spatmani

 73% - imbunatatirea fibrozei

 Hadziyannis, Gastroenterology, 2006

 Limite:
 20% rezistenta
 Nefrotoxicitate 3%
ENTECAVIR
 70 pacienti cu scor Child-Pugh > 7
 12 luni
 55 pacienti
 ameliorare scor Child-Pugh CTP (8.1 vs 6.6, P < 0.05)
 Ameliorare scor Model for End-Stage Liver Disease (MELD)
(11.1 vs 8.8, P < 0.05)
 Rata cumulativa la 2 ani a incidentei CHC = 6.9%
 Rata cumulativa a decesului = 17%

 These findings suggest that ETV monotherapy improves hepatic

function and provides overall benefits in patients with HBV-
related decompensated cirrhosis.
 Shim, J Hepatol 2010
ENTECAVIR / CONTROL
 Cohorta pacienti tratati ETV 0,5 mg/zi / cohorta pacienti netratati,
supraveghere clinica

 La pacientii cu CH (482 ETV, 69 naivi), pacientii tratati cu ETV au

avut risc scazut pentru (dupa ajustare scor MELD):
 hepatic events (HR = 0.51, 95%CI: 0.34-0.78, P = 0.002)
 HCC (HR = 0.55, 95%CI: 0.31-0.99, P = 0.049)
 liver-related mortality (HR = 0.26, 95%CI: 0.13-0.55, P < 0.001)
 all-cause mortality (HR = 0.34, 95%CI: 0.18-0.62, P < 0.001)

 the risk for hepatic events in the ETV-treated cirrhotic patients who
failed to achieve undetectable HBV DNA levels was comparable
to that in the untreated patients.

Wong, Hepatol 2013

RVS PROGNOSTIC
RASPUNSUL VIRAL SUSTINUT
SI CANCERUL HEPATO-CELULAR
CHC – FACTORI DE RISC
 Ag HBs, AND-VHB si Ag HBe = factori de risc

 Ag HBs – incidenta hepatom:

 40% Asia, 5% Europa de Vest

 Riscul relativ fata de AgHBs – si Ag HBe -

 Ag HBs: 9.6 (95 % C.I, 6.0 to 15.2)
 Ag HBs + Ag Hbe: 60.2 (95% 35.5 to 102.1)
 Yang HI, et al. Taiwan Community-Based Cancer Screening Project Group. Hepatitis B e antigen and the risk of
hepatocellular carcinoma. N Engl J Med. 2002

 AND-VHB > 10.000 copii/ml – factor de risc independent de TGP, Ag HBe sau
ciroza
 Chen CJ, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA
level. JAMA. 2006
 Risc pentru aparitia CHC – inclusiv pacientii
“inactivi”
TRATAMENTUL ANTIVIRAL POST
CHIRURGIE CURATIVA CHC - VHB
 Ag HBs, AND-VHB si Ag HBe = factori de risc pentru CHC- VHB
 TGP↑ si ADN-VHB↑ = asociate cu recurenta dupa chirurgia
curativa

TRATAMENTUL ANTIVIRAL:
 Suprimarea replicarii virale

 Scaderea reactivarii virale perioperatorii

 Scaderea injuriei hepatice

 Conservarea functiei hepatice pre- si postoperator

 Scaderea riscului recurentei CHC

 Post-recurenta, intarzierea afectarii hepatice de catre infectia

virala, crescand sansa terapiilor agresive de salvare
“Unresolved issues and unmet needs”
 …
 …
 10. Assess long-term impact of therapy on the
prevention of cirrhosis and its complications and
HCC
 …
 …

“EASL Clinical Practice Guidelines: Management of chronic

hepatitis B virus infection”, 2012