1. 4th UK-CAAB - Hepatitis coinfection HIV/HCV Co-infection Dr Ranjababu Kulasegaram Guy’s & St Thomas’ Hospital London

2. 4th UK-CAAB - Hepatitis coinfection

3. HIV/HCV Co-infection Epidemiology Impact of HIV on HCV Impact of HCV on HIV Management issues Future

4. 4th UK-CAAB - Hepatitis coinfection Epidemiology

5. 4th UK-CAAB - Hepatitis coinfection 3 % of the world population UK estimated prevalence 200,000-400,000 people 0.04% of blood donors 0.4-0.6% of ANC in London Changing epidemiological pattern – incidence (IVDU, Blood)

6. 4th UK-CAAB - Hepatitis coinfection Extrahepatic manifestations Dermatological- PCT, lichen planus Renal- MPGN Haematology- Essential mixed cryoglobulinaemia B cell lymphoma Endocrine – Type 2 Diabetes Autoimmune, peripheral neuropathy, PAN,uveitis, corneal ulceration, sialadenitis

7. 4th UK-CAAB - Hepatitis coinfection

8. 4th UK-CAAB - Hepatitis coinfection HIV/HCV Europe 30% of HIV pts are co-infected Germany15-20% of the 40,000 HIV pts Spain45% of the 130,000 HIV pts USA30% of the 800,000 HIV pts »IVDU 60-90% »Blood products prior to 1985 85% »Sexual transmission <5% Mother to child transmission <6% HIV/HCV 15-20% Yeung et al 2001 Hepatology

9. 4th UK-CAAB - Hepatitis coinfection HIV/HCV HIV ss RNA 9000 nt 11 clades chronic infection 100% 10 9 -10 10 virions /day integration in host genome HCV ss RNA 9500 nt 6 clades chronic infection 80% 10 11 -10 12 no latent form - curable

10. 4th UK-CAAB - Hepatitis coinfection Impact of HIV on HCV

11. 4th UK-CAAB - Hepatitis coinfection

12. 4th UK-CAAB - Hepatitis coinfection

13. HIV accelerates HCV liver disease especially when CD4 declines Within 10-15 yrs of infection 15-25% HIV/HCV cirrhosis 2.6-6.5% of those without HIV HCC appears to occur at a younger age After shorter duration of HCV infection

14. 4th UK-CAAB - Hepatitis coinfection

15. Impact of HCV on HIV

16. 4th UK-CAAB - Hepatitis coinfection Swiss Cohort Study HCV accelerates the progression of HIV Less likely to achieve CD4 cell increases on HAART (warrants further studies)

17. 4th UK-CAAB - Hepatitis coinfection Management issues

18. 4th UK-CAAB - Hepatitis coinfection Assessment HCV IgG Ab (EIA-3,RIBA) HBV, HAV screening and vaccination HCV RNA and genotyping LFT, coagulation screen, α fetoprotein U/S scan Liver biopsy

19. 4th UK-CAAB - Hepatitis coinfection Liver biopsy Not yet a reliable non-invasive test to assess liver fibrosis Neither HCV RNA nor level of ALT correlates well with liver inflammation and fibrosis

20. 4th UK-CAAB - Hepatitis coinfection HCV treatment

21. 4th UK-CAAB - Hepatitis coinfection AIMS of treatment Viral eradication SVR (loss of detectable virus at 24 wks post treatment) Viral suppressionimproving histology Liver related outcomes Delay cirrhosis, prevent ESLD and HCC

22. 4th UK-CAAB - Hepatitis coinfection Interferon Mid-1980s Antiviral, antiproliferative and antifibrotic activity Glycoproteins produced in vivo by leucocytes in response to viral infection Commercially – by cell culture or recombinant technology Pegylated interferon – reduce clearance -> Longer half life

23. 4th UK-CAAB - Hepatitis coinfection Time Serum IFN  Levels (U/mL) “optimised” IFN  Optimizing Interferon  Kinetics 1 week 2nd Dose

24. 4th UK-CAAB - Hepatitis coinfection Interferon Flu-like symptoms – transient Fatigue, apathy, alopecia Bone marrow suppression Hypothyroidism, Hyperthyroidism Depression, irritability Severe-seizure,cardiac,renal failure,pulmonary fibrosis,retinopathy,hearing impairment in <2%

25. 4th UK-CAAB - Hepatitis coinfection Ribavirin Guanosine nucleoside analogue Drug – drug interactions Inhibits intracellular phosphorylation of pyrimidine analogue (AZT, d4T, ddC) Enhances the purines (ddI) - Toxicity

26. 4th UK-CAAB - Hepatitis coinfection Ribavirin Dose dependent haemolysis –Hb start to drop after the first week and stabilise by week 4 of therapy ( mean drop 2.9g/dl) EPO Rash, pruritus, teratogenicity, insomnia, cardiovascular deterioration, cough and dyspnoea

27. 4th UK-CAAB - Hepatitis coinfection When to treat? Treat HCV before HIV treatment? Likely to help avoid Hepatotoxicity Less drug interactions – toxicity (TDM), adherence Response to HAART – better immune reconstitution

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29. On HAART and HCV treatment Drug interactions Anaemia (AZT & ribavirin) Mitochondrial toxicity-Lactic acidosis, pancreatitis, lipodystrophy (ddI & ribavirin) Possible reduction in CD4 (due to interferon) Compromise adherence

30. 4th UK-CAAB - Hepatitis coinfection Standard IFN  -2b + RBV as Initial Therapy 20% 40% 60% 80% IFN 24 wk IFN 48 wk IFN/RBV 24 wk IFN/RBV 48 wk Virologic Response (%) McHutchison JG et al. NEJM. 1998. Poynard T et al. Lancet. 1998 6% 13% 31% 38% 19% 35% 43% 0% US trial International trial

31. 4th UK-CAAB - Hepatitis coinfection PEG-IFN  -2a (40KD) + RBV Combination Therapy 17 44 56 13 33 41 58 65 81 40 59 74 0 20 40 60 80 100 < 2 M copies/mL > 2 M copies/mL < 2 M copies/mL > 2 M copies/mL PEG-IFN  -2a (40KD)/PBO IFN  -2b/RBV PEG-IFN  -2a (40KD)/RBV Genotype 1Genotype 2/3 Hoffmann-La Roche, data on file. SVR (%)

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35. Transplantation Is an option in carefully selected patients.

36. 4th UK-CAAB - Hepatitis coinfection Future HCV specific protease inhibitors Antifibrotic agents Helicase inhibitor Antisense oligonucleotides Ribozymes ?Triple therapy Immunotherapy IL-2 ( 2/7 co infected pts SVR)

37. 4th UK-CAAB - Hepatitis coinfection Pegylated Interferons 40 kD PEGylated Interferon (Pegasys ®, Roche) 12 kD PEGylated Interferon (Viraferonpeg/Pegintron TM, Schering Plough)

38. 4th UK-CAAB - Hepatitis coinfection Predictability of Response

39. 4th UK-CAAB - Hepatitis coinfection 12 week predictability with 40 kD Peg IFN  -2a Ribavirin Combination All PEG (40kD) Patients + RBV Patients 65% YES 86% SVR 97% NO 14% NO SVR Week 12 PCR < 50 IU/mL or 2 log 10 decline Amplicor®

40. 4th UK-CAAB - Hepatitis coinfection Safety of Peg IFN alfa-2b (12kD) + RBV Similar to Standard interferon Higher influenza like reactions Substantial  injection site reactions Manns et al, Lancet Vol 358.Pg 958 - 965