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HCV and HBV co-infections

HCV and HBV co-infections. Sanjay Bhagani Royal Free Hospital London EACS Advanced Course 2008. Causes of Liver Disease in HIV Infection. Mortality of HIV-infected patients in France (GERMIVIC Study Group). Rosenthal et al. AASLD 2004; Abstract 572. Overlapping HCV & HIV Epidemics.

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HCV and HBV co-infections

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  1. HCV and HBV co-infections Sanjay Bhagani Royal Free Hospital London EACS Advanced Course 2008

  2. Causes of Liver Disease in HIV Infection

  3. Mortality of HIV-infected patients in France (GERMIVIC Study Group) Rosenthal et al. AASLD 2004; Abstract 572.

  4. Overlapping HCV & HIV Epidemics 25% of HIV 10 million HIV HCV 40 million 175 million

  5. Reports of acute HCV in HIV+ MSM across Europe Danta et al. AIDS 2007; 21: 983-991. Gambotti et al. Euro Surveill 2005; 10: 115-117. Ghosn et al. Sex Transm Infect 2006; 82: 458-460 ; 40: 41-46. Serpaggi et al. AIDS 2006; 20: 233-240.Vogel M et al. J Viral Hepat 2005; 12: 207-211

  6. Risk Factors for Acute HCV in MSM High-risk practices Shared implements Sexual practice Drug practice Group Sex Internet ‘Club drugs’ STI Danta et al, AIDS 2007

  7. Is HCV Viraemia after SVR Following Initial Infection Re-infection or Relapse? Phylogenetic Tree Constructed from Analysis of Paired Samples (red) Compared with Genebank Samples (black) Jones et al. CROI 2008;Oral Abstract 64LB.

  8. Effect of HIV/HCV co-infection on hepatic fibrosis progression (Benhamou et al 1999) Fibrosis grade Fibrosis progression influenced by • CD4 cell count (< 200 cells/microlitre) • Age at infection ( > 25 years) • Male sex • Alcohol consumption ( > 50g/d)

  9. Progression to cirrhosis 1.00 4682 patients 0.83 HIV-HCV Alcohol HBV Haemochromatosis HCV Steatosis BMI>25 2PBC 0.67 0.50 Hazard function 0.33 0.17 0.00 0 20 40 60 80 Age in years Poynard, T. et al., (2003) A comparison of fibrosis progression in chronic liver disease. Journal of Hepatology 38:257-265

  10. HIV/HCV - Cirrhosis and survival Pineda et al. Hepatology 2005

  11. Overall and Liver-related Mortality - effect of HAART A) Overall-Mortality B)Liver-related-Mortality 1,1 1,1 P<0.018 P<0.0001 Patients with HAART Patients with HAART ,9 ,9 Patients with ART untreated Patients Cumulative survival Cumulative survival ,7 ,7 ,5 ,5 Patients with ART untreated Patients ,3 ,3 6000 0 1000 2000 3000 4000 5000 0 1000 2000 3000 4000 5000 6000 Observation time[days]] Observation time[days]] Patients under observation: HAART-group: 93 79 33 - - - ART-group: 55 46 30 15 9 1 Untreated-group: 137 94 49 37 32 27 Patients under observation: HAART-group: 93 79 33 - - - ART-group: 55 46 30 15 9 1 Untreated-group: 137 94 49 37 32 27 Qurishi N et al. Lancet, 2004

  12. Interactions were not significant between drug CLASS and CO (p=0.800) 40 30 % Patients with LEE 20 10 0 NNRTI PI Mixed BPI NRTI Overall N arms1174129 314 10 4 11 6 553253 3518 N patients581 1242 2705 2038 1055 7621 244 737 2321 630 572 4504 337 505 384 1408 483 3117 Drug Class All Patients HCV Co-inf HIV Only % LEE by co-infection status • Benhamou Y, Mats V, Walcak D. Systemic overview of HAART associated liver enzyme elevations in patients infected with HIV and co-infected with HCV. CROI 2006;#88

  13. Treating HCV in HIV-infected patients • HAART treated HIV patients live longer • Faster progression to liver cirrhosis • Increased mortality due to end stage liver disease • Higher risk of hepatotoxicity following treatment with ART drugs • Risk of hepatotoxicity reduced with successful HCV erradication

  14. Response to PegIFN and Ribavirin in HIV/HCV co-infected patients

  15. Acute HCV/HIV: Overall virological responses: 133 = 56 89 95 99 85 3rd Int HIV/Hepatitis co-infection meeting, Paris 2007

  16. Host Acute infection Younger age Lack of stage 3/4 fibrosis Ethnicity Low BMI Lack of hepatic steatosis High CD4 % Lack of insulin resistance Virus Genotypes 2/3 Low viral loads Predictors of response

  17. APRICOT: Baseline CD4+ Count and Efficacy of Peg-IFN alpha-2a Plus RBV • Retrospective analysis of HIV/HCV-coinfected patients treated with peg-IFN alpha-2a + RBV in APRICOT • SVR rates analyzed in overall population and within genotypes according to baseline CD4+ cell count quartiles (Q1-Q4) • Rate of SVR varied according to CD4+ cell percentage quartile in genotype 1 but not in genotypes 2/3 Q1 (2.5% to 19%) 100 Q2 (19.1% to 25.0%) 73 80 69 62 60 Pts With SVR (%) Q3 (25.0% to 32.1%) 47 34 40 27 29 Q4 (32.1% to 69.3%) 16 20 0 Gt 1 (n = 150) Gt 2/3 (n = 78) Dieterich D, et al. ICAAC 2006. Abstract H-1888.

  18. APRICOT: SVR rates according to exposure Genotype 1 recipients of peginterferon alfa-2a plus ribavirin 50 39% 40 29% SVR rate (%) 30 20 11% 10 n = 176 62 114 0 Allpatients <80/80/80exposure* ≥80/80/80exposure *Patients violated the rule if ≥1 of the three targets were not achieved Opravil M, et al. 45th ICAAC 2005; Abstract 2038

  19. Why lower response rates to anti-HCV therapy in HIV+ patients? • Useoflowerdoses of RBV in most trials • More advanced fibrosis grade • Higher rate of steatosis (NRTIs, PIs) • Unfavourable baseline HCV virological features • Higher discontinuation due to side effects • Lower initial HCV-RNA clearance • Higher relapse rates

  20. Viral Dynamic response to interferon and ribavirin Pawlotsky Hepatology 2002; 32(4)

  21. APRICOT PPV 82% NPV 79% RIBAVIC PPV 97.5% NPV 81.3% PRESCO Lack of RVR independent predictor of relapse Crespo M et al. G3 patients with RVR low rates of relapse with 24 weeks of therapy ROMANCE G2/3 patients without RVR need longer Rx (48 weeks) Does RVR predict response?(week 4 undetectable HCV RNA)

  22. How can we maximise response to therapy?

  23. Zidovudine: impact on HCV treatment Alvarez D et al. 12th Conference on Retroviruses and Opportunistic Infections (Abstract #: P-192). Boston, MA USA, February 22–25, 2005

  24. AZT ddI d4T anemia hepatic pancreatitis weight decomp. & lactic acidosis loss  mitochondrial DNA synthesis  lactate Interactions between RBV & nucleoside analogues Blanco et al. NEJM 2002; 347: 1287

  25. Abacavir and SVR Vispo et al, 3rd Int. HIV/hepatitis Conference, Paris 2007. Abs 46

  26. PRESCO G1,4 Follow-up N=192 G1,4 N=45 Follow-up Peg-IFN + RBV 1000-1200 mg/day G2,3 Follow-up N=96 G2,3 N=56 Follow-up 84 72 60 48 96 24 36 12 0 Study weeks Only patients who achieved EVR (>2 log drop in HCV-RNA at week 12) continued treatment. Study Design n=389

  27. Importance of weight-based Ribavirin(1000mg <75kg/1200mg >75kg) Soriano, et al. AIDS 2007. 21: 1073-89

  28. Treatment of Chronic HCVExtending Therapy 80 EOT 60 61 SVR 52 % HCV RNA (-) 40 45 Extending the duration of therapy reduced relapse from 47% to 13% 32 20 0 48 72 Weeks of Treatment Sanchez-Tapias et al. AASLD 2004. Abstract 126.

  29. PRESCO G 2/3 82% Short arm Extended arm G 1/4 67% 53% 64 46 31% 59 24 No. of patients (389) 192 45 96 Voluntary withdrawals (64) 15 (8%) 36 (80%) 4 (4%) 9 (16%) Results (On Treatment analysis) p=0.04 p=0.004 56

  30. New oral small molecule ARVs in development for the treatment of HCV Drug name Drug class Preclinical Phase I Phase II Phase III X MK-0608 (Merck) Nucleoside polymerase inhibitor X R7128 (Pharmasset & Roche) Nucleoside polymerase inhibitor X NIM811 (Novartis) Cyclophilin inhibitor X ITMN-191 (InterMune & Roche) Protease inhibitor X MK-7009 (Merck) Protease inhibitor X BI12202 (Boehringer) Protease inhibitor X BI 1220 (Boehringer) Nucleosite polymerase inhibitor X Nucleoside polymerase inhibitor R1626 (Roche) X Cyclophilin inhibitor DEBIO-025 (Debiopharm) X Telaprevir (Vertex Pharmaceuticals) X Protease inhibitor X Boceprevir (Schering-Plough) Protease inhibitor X Protease inhibitor TMC435350 (Tibotec & Medivir) Adapted from Manns MP et al. Nat Rev Drug Discovery. 2007;6:991-1000.

  31. TELAPREVIR: PROVE 2SVR 2) S26 • Dusheiko et al .Treatment of chronic hepatitis C with telaprevir in combination with peginterferon alfa 2a with or without ribavirin: further interim analysis results of the PROVE2 study. J Hepatology 2008; 48 (suppl)

  32. Take home messages: • HIV/HCV co-infection is common • Increasing incidence of acute HCV • ESLD major cause of morbidity/mortality • Early HAART beneficial • Avoid d-thymidine analogues/AZT • Treat HCV with PegIFN and Ribavirin • Best results if HCV treated in the acute phase • Maximal doses of Ribavirin (1000/1200mg) • Avoid AZT, d4T and DDI, • ?Avoid Abcavir • EPO and G-CSF – avoid dose reductions

  33. Take home messages: • Duration of therapy individualised • Genotype • Pre-Rx viral load • Fibrosis stage • RVR/EVR • No role for maintenance low-dose IFN • Give some thought to hepatic steatosis • New anti-HCV drugs (STAT-Cs!) will be available in the future… • …be careful out there….!!!

  34. W12 W48 W72 W4 W24 Proposed optimal duration of HCV therapy in HCV/HIV-coinfected patients. G2/3 24 weeks therapy* HCV-RNA neg G1/4 48 weeks therapy G2/3 HCV-RNA neg G1/4 72 weeks therapy > 2 log drop in HCV-RNA HCV-RNA pos Stop HCV-RNA pos < 2 log drop in HCV-RNA Stop * In patients with baseline low viral load and minimal liver fibrosis. EACS Guidelines 2008

  35. Overlapping HBV & HIV Epidemics 5–15% of HIV 4 million HIV HBV HBsAg+ 40 million 400 million

  36. Geographic Distribution of Chronic HBV Infection HBsAg Prevalence ≥8% –High 2–7% – Intermediate <2% – Low

  37. Hepatitis B Disease Progression Clearance 5%-10% of chronic HBV-infected individuals1 Liver Cancer (HCC) 30% of chronic HBV-infected individuals1 Liver Transplantation Acute Infection Death Chronic Infection Cirrhosis • >90% of infected children progress to chronic disease • <5% of infected immunocompetent adults progress to chronic disease1 Liver Failure (Decompensation) Chronic HBV is the 6th leading cause of liver transplantation in the US 4 23% of patients decompensate within 5 years of developing cirrhosis 3 1. Torresi, J, Locarnini, S. Gastroenterology. 2000. 2. Fattovich, G, Giustina, G, Schalm, SW, et al. Hepatology. 1995. 3. Moyer, LA, Mast, EE. Am J Prev Med. 1994. 4. Perrillo, R, et al. Hepatology. 2001.

  38. Phases of chronic HBV Infection • Immune tolerant phase • High levels of HBV DNA • Very little inflammation • Chronic hepatitis • HBeAg positive • High levels HBV DNA, inflammation/progressive fibrosis • HBeAg negative • Low levels HBV DNA, progressive inflammation and fibrosis • Inactive HbsAg carrier state (non replicative phase) • HBeAg negative, low/absent HBV DNA, no inflammation/fibrosis

  39. Emergence of the e-negativePrecore Mutant HBeAg+ HBeAg / anti-HBe Anti-HBe+ HBV-DNA (wild) HBV-DNA (mutant) Transaminases Chronic hepatitis mild Chronic moderate to severe hepatitis Cirrhosis & hepato- cellular carcinoma HBV wild-type clearance Continued HBV precore mutant replication HBV tolerance Years 0 5 10 15 20 Carman WF et al Viral Hepatitis. Scientific Basis and Clinical Management. NY: Churchill Livingstone; 1993:121.

  40. Geographical distribution of HBV genotypes A to H North Europe Mediterranean Africa India & USA - A basin - D E & D A E & D A Far East B & C Rare types: F – Latin America G –France, USA H –Mexico, Latin America

  41. Hepatitis B SerologyIsolated HBcAb+ • HIV negative • 50% true positive HBcAb • <2% with detectable serum HBV DNA • HIV positive • 60-90% true positive HepBcAb • Many with detectable HBV DNA (~15% at RFH) • ~40% with necro-inflammation on liver biopsy • Isolated anti-HBc more common in HIV/HCV • Implications for 3TC based HAART and vaccination strategies • Hofer, Euro J Clinical Micro 1998. Ghandi, CID. June 15, 2003. Nebya, BHIVA 2006

  42. HIV/HBV Coinfection • Increased incidence of chronic HBV in HIV+ patients (Lazizi JID 1988). Will vary greatly with subpopulation • HIV+ pts 3-6x more likely to develop chronic HBV than HIV- (Bodsworth JID 1991) • HBeAg and HBV DNA higher levels in HIV+ but AST/ALT lower (Perillo 1986) • Increased hepatic fibrosis • Decreased spontaneous seroconversion (Krogsgaard 1987) or seroreversion of prior HBV infection with loss of anti-HBs and return of HBsAG (Waite AIDS 1988) • Atypical serologies: anti-HBc may indicate chronic infection (Hofer 1998)

  43. Liver Mortality Rate (per 1000 PY)MACS Thio et al. Lancet 2004

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