1. HIV and Hepatitis C Co-infection Amy Kindrick, M.D., M.P.H. San Francisco AIDS ETC National HIV/AIDS Clinical Consultation Center February 12, 2002

2. The Hepatitis C Virus

3. Is There Only One Kind of Hepatitis?

4. HCV Infection: Epidemiology Major healthcare problem worldwide 70%–90% of HCV-infected patients develop chronic disease ~50 million infected worldwide –~5 million in Europe –~4 million in USA Contributes to ~12,000 deaths/yr

5. <1 % 1–2.4 % 2.5–4.9 % 5–10 % > 10 % No data available HCV Has Broad Global Prevalence

6. Hepatitis C Virus Infection U.S. Overall antibody prevalence 1.8% –64% positive for HCV RNA –Estimated 2.7 million persons chronically infected Parenteral transmission route –Current risk of transfusion about 1 in 1,000,000

7. How Is HCV Transmitted? Infected blood –Needlestick –Needle sharing –Transfusion ?Infected body fluids –Amniotic fluid –Breast milk

8. Who Should Be Tested? Drug users Recipients of blood products or organ transplant before 1992 Long-term partners of infected individuals Persons with occupational exposures Children born to HCV-infected mothers HIV-infected individuals

9. Consider Testing For Persons with tattoos or body piercing Persons with multiple sexual partners Tissue transplant recipients

10. HCV Diagnosis Enzyme immunoassays (EIA) –Initial screening test for patients with liver disease –False positives in low risk patients –Occasional false negatives, esp. With HIV+ Recombinant immunoblot assays (RIBA) –Confirmatory test if EIA positive in low risk pt HCV RNA by PCR –Confirmatory if RIBA is “indeterminant”

11. Hepatitis C Virus Infection: Diagnosis HCV antibody HCV viral load HCV genotype Liver function tests Liver biopsy is gold standard for assessing disease status –ALT and AST do not predict liver histology –HCV RNA does not predict liver histology or outcomes

12. Hepatitis C Virus Infection Incubation period 2-26 weeks Acute infection may be asymptomatic Natural history variable –Chronic infection in 70-75% –Cirrhosis in 10% to 20% of chronically infected Develops in 15-25 years –Hepatocelluar carcinoma in 1% to 5% after 20 years 1% to 4% per year once cirrhosis is established –Extrahepatic manifectations Arthritis Glomerulonephritis Mixed cryoglobulinemia

15. Vaccinate, Vaccinate, Vaccinate

17. Acute Hepatitis C

18. Chronic HCV Infection With Cirrhosis

19. Stigmata of Chronic Liver Disease

20. Mixed Cryoglobulinemia

21. Esophageal Varices

22. Hepatocellular Carcinoma

24. HCV/HIV Co-infection: General Issues U.S. Prevalence 40% to 60% –Varies geographically –Varies by HIV risk behavior Major transmission routes are transfusion and IDU Sexual and vertical transmission are rare Coinfection may enhance –Sexual transmission of HIV –Vertical transmission of HCV

25. Diagnosis of HCV in HIV-infected Patients Co-infection may reduce sensitivity of HCV antibody test (EIA or RIBA) –Measure HCV RNA by PCR or bDNA if history or clinical symptoms are suggestive

26. Patients With HCV and HIV: Key Points 30% of patients with HIV also have HCV  Mortality from HCV proportional to  mortality from HIV Natural history more fibrotic in coinfected patients

27. Impact of HIV on HCV HIV infection worsens HCV-related liver disease (in pre-HAART era) –ALT levels higher –Fibrosis more severe –Cirrhosis, liver failure, and HCC more common –Death rates higher –Vertical HCV transmission enhanced

28. Impact of HCV on HIV Impaired Th1 function in HIV infection affects appropriate immune response to HCV Conflicting clinical results More rapid progression to AIDS or death for HCV genotype 1 Increasing HIV RNA and decreasing CD4 more likely in co-infected pts

29. AIDS Incidence by HCV Genotype in Greek Hemophiliacs With HCV/HIV 0.25 0.5 0.75 P=0.002 Genotype 1 Other genotypes 0 1.0 4812160 After HIV seroconversion (yr) Probability of developing AIDS Conclusion: Genotype 1 is associated with faster progression to AIDS

30. Are There Any Treatments for Hepatitis C?

31. HCV Treatment Rationale Treatment may improve HCV outcomes –Decrease fibrosis –Increase T-cell responsiveness to HCV antigens –Decrease rate of fatal hepatocellular carcinomas Treatment may improve HIV outcomes –Reduce hepatic toxicity of ARVs

32. HCV Treatment Options Interferon monotherapy –Sustained response rates similar to HCV- infected alone 8% - 44% –Minimal correlation with CD4 counts Interferon-ribavirin combination therapy –Trials ongoing –Preliminary findings encouraging

34. Treatment of HCV in HIV+ Patients Soriano et al. Clin Infect Dis 1996;23:585 Patients (%) n=80 5 MU TIW 3 mo, Responder 3 MU 9 mo Complete response Sustained response 32.5% 22.5%

35. Interferon-Ribavirin Therapy Cohort study with 37 pts 84% of patients on HAART with stable HIV disease –Median baseline CD4 343 –Median baseline HIV RNA < 400 c/mL 59% on combination therapy 41% on IFN monotherapy

36. Interferon-Ribavirin Therapy: Interim Results Analysis of 27 patients at 12 weeks of treatment –50% of combo arm had undetectable HCV RNA vs 9% on mono arm –No significant change in HIV RNA Similar results in NYC cohort on HAART –Absolute CD4 count drop (529 to 277) without change in CD4 %

37. Interferon-Ribavirin Toxicity Flu-like symptoms Depression Leukopenia Anemia ? Reduced effectiveness of ARV therapy with ribavirin –May inhibit intracellular AZT and d4T phosphorylation

38. What About OTC Medications?

39. Conclusions Natural course of chronic HCV accelerated by concurrent HIV infection Coinfected patients with stable HIV and good clinical, functional status should be considered for treatment New treatment options for chronic HCV should be urgently explored

40. HCV Future Treatment Options HCV-specific viral enzyme inhibitors –Helicase –Protease –RNA polymerase Internal ribosomal entry site inhibitors Antisense nucleotides Vaccination

41. Case 1 39 y/o HIV-infected man –HIV+ in 5/98 –PCP in 12/98 –Elevated LFTs and HCV antibody + in 12/98 –Began HAART in 1/99 d4T, 3TC, NVP Labs –ALT 100-200 u/l (2-4x ULN) –CD4 300 (from 80), HIV RNA <400

42. Case 1: Antiretroviral Treatment d4T, 3TC, NVP (transaminitis) d4T, 3TC, ABC (worsening transaminitis) ARVs stopped (transaminitis resolved) d4T, 3TC, NLF (transaminitis)

43. Case 1: Management Challenge Stop ARVs and treat HCV Continue ARVs and treat HCV Continue ARVs and biopsy liver

44. Case 2 34 y/o HIV-infected man –HIV+ in 1991 –H/O IDU and alcohol use –Persistent transaminitis (ALT 160-280) –Negative HBV and HCV serologies –HCV RNA > 1,000,000 c/mL

45. Case 2: Diagnosis Liver biopsy –Fibrous expansion of portal areas, portal inflammation, piecemeal necrosis, activity in >2/3 of lobules

46. Case 2: HIV Therapy Initial CD4 50, HIV RNA 100,000 6/98 d4T, 3TC, ADF (renal toxicity) 8/98 ABC, 3TC, NLF, EFV 11/98 NLF stopped for rash 12/98 transaminitis 3/99 all ARVs stopped (despite VL>1 mil) 6/99 d4T, 3TC, ABC, NLF (jaundice)

47. Case 2: Management Challenge Hold ARVs until LFTs normalize, then restart with different agents Stop ARVs and treat HCV Continue ARVs and treat HCV

48. Consultation Services for Clinicians Caring for Patients with HIV/AIDS Local expert clinicians Regional and local AIDS Education and Training Centers National HIV Telephone Consultation Service (Warmline) –(800) 933-3413 National Clinicians’ Post-Exposure Prophylaxis Hotline (PEPline) –(888) HIV-4911

49. National HIV/AIDS Clinicians’ Consultation Center A Joint Program of UCSF and San Francisco General Hospital Supported by HRSA and CDC http://www.ucsf.edu/hivcntr PEPLine (888) 448-4911 Warmline (800) 933-3413