1 / 70

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.

maris-koch
Download Presentation

HCV and HBV co-infections

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related