HIV/HCV Co-infection. HIV/HCV Co-infection. Epidemiology. Dr Ranjababu Kulasegaram Guy s & St Thomas Hospital London. Extrahepatic manifestations

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1 HIV/HCV Co-infection Dr Ranjababu Kulasegaram Guy s & St Thomas Hospital London HIV/HCV Co-infection Epidemiology Impact of HIV on HCV Epidemiology Impact of HCV on HIV Management issues Future Extrahepatic manifestations 3 % of the world population UK estimated prevalence 200, ,000 people 0.04% of blood donors % of ANC in London Changing epidemiological pattern incidence (IVDU, Blood) 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 1

2 HIV/HCV Europe 30% of HIV pts are co-infected Germany 15-20% of the 40,000 HIV pts Spain 45% of the 130,000 HIV pts USA 30% of the 800,000 HIV pts» IVDU 60-90%» Blood products prior to %» Sexual transmission <5% Mother to child transmission <6% HIV/HCV 15-20% 4th UK-CAAB Hepatology - Hepatitis Yeung et al 2001 HIV/HCV HIV HCV ss RNA 9000 nt 11 clades chronic infection 100% virions /day integration in host genome ss RNA 9500 nt 6 clades chronic infection 80% no latent form - curable Impact of HIV on HCV 2

3 HIV accelerates HCV liver disease especially when CD4 declines Within yrs of infection 15-25% HIV/HCV cirrhosis % of those without HIV HCC appears to occur at a younger age After shorter duration of HCV infection Swiss Cohort Study Impact of HCV on HIV HCV accelerates the progression of HIV Less likely to achieve CD4 cell increases on HAART (warrants further studies) HCV IgG Ab (EIA-3,RIBA) Assessment HBV, HAV screening and vaccination Management issues HCV RNA and genotyping LFT, coagulation screen, _ fetoprotein U/S scan Liver biopsy 3

4 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 HCV treatment AIMS of treatment Interferon Viral eradication Viral suppression SVR (loss of detectable virus at 24 wks post treatment) improving histology Mid-1980s Antiviral, antiproliferative and antifibrotic activity Glycoproteins produced in vivo by leucocytes in response to viral infection Liver related outcomes Delay cirrhosis, prevent ESLD and HCC Commercially by cell culture or recombinant technology Pegylated interferon reduce clearance -> Longer half life Optimizing Interferon a Kinetics Interferon Serum IFN a Levels (U/mL) optimised IFN a 2nd Dose 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% Time 1 week 4

5 Ribavirin Ribavirin Guanosine nucleoside analogue Drug drug interactions Inhibits intracellular phosphorylation of pyrimidine analogue (AZT, d4t, ddc) Enhances the purines (ddi) - Toxicity 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 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 On HAART and HCV treatment Standard IFN a-2b + RBV as Initial Therapy Drug interactions Anaemia (AZT & ribavirin) Mitochondrial toxicity-lactic acidosis, pancreatitis, lipodystrophy (ddi & ribavirin) Possible reduction in CD4 (due to interferon) Compromise adherence Virologic Response (%) 80% 60% 40% 20% 6% 19% 13% 35% 31% US trial International trial 43% 38% 0% IFN 24 wk IFN 48 wk IFN/RBV 24 wk IFN/RBV 48 wk McHutchison JG et al. NEJM Poynard T et al. Lancet

6 SVR (%) PEG-IFN a-2a (40KD) + RBV Combination Therapy 17 PEG-IFN a-2a (40KD)/PBO IFN a-2b/rbv PEG-IFN a-2a (40KD)/RBV < 2 M > 2 M < 2 M > 2 M Pegylated interferon-a-2a (PEG) + ribavirin (RBV) vs. interferon-a-2a (IFN) + RBV in HCV/HIV co-infection (ACTG A5071) Chung et al Abs LB patients Randomised IFN 6 MIU tiw x 12 weeks then 3 MIU x 36 weeks mg/day RBV escalating to 1 g/day PEG 180 mcg qwk x 48 weeks mg/day RBV escalating to 1 g/day Genotype 1 Genotype 2/3 Hoffmann-La Roche, data on file. Final version X March 2002 PEG + RBV vs. IFN + RBV in HCV/HIV (ACTG A5071) Chung et al Abs LB15 PEG + RBV vs. IFN + RBV in HCV/HIV (ACTG A5071) Chung et al Abs LB15 Percentage <60 IU Proportion HCV RNA <60 IU at week % p= % PEG IFN Ø Total CD4 fell in both arms Ø % CD4 and HIV RNA was unchanged Ø PEG had more grade 4 toxicity (17 vs. 5, p=0.004) Ø Discontinuations were similar in both groups (15% vs. 12%) Ø PEG + RBV was superior in HCV RNA response Ø 133 pts Ø CD4 >100 & VL <10,000 stable on HAART or CD4 >300 off ART Ø HCV RNA Ø Fibrosis score Ø Virologic non responders Liver biopsy histologic response Final version X March 2002 Final version X March 2002 Transplantation Future Is an option in carefully selected patients. HCV specific protease inhibitors Antifibrotic agents Helicase inhibitor Antisense oligonucleotides Ribozymes?Triple therapy Immunotherapy IL-2 ( 2/7 co infected pts SVR) 6

7 Pegylated Interferons 40 kd PEGylated Interferon (Pegasys, Roche) 12 kd PEGylated Interferon (Viraferonpeg/Pegintron TM, Schering Plough) Predictability of Response 12 week predictability with 40 kd Peg IFN a-2a Ribavirin Combination YES 65% All PEG (40kD) Patients + RBV Patients 86% Week 12 PCR < 50 IU/mL or 2 log 10 decline Amplicor 14% 97% NO Safety of Peg IFN alfa-2b (12kD) + RBV Similar to Standard interferon Higher influenza like reactions Substantial injection site reactions SVR NO SVR Manns et al, Lancet Vol 358.Pg