1. HIV/Hepatitis C Co-infection Mark Hull MHSc, FRCPC Clinical Assistant Professor University of British Columbia BC Centre for Excellence in HIV/AIDS February 25 2011

2. Objectives Brief overview of HIV Review natural history of HIV/Hepatitis C co-infection Review indications for hepatitis C treatment in the setting of co-infection Brief overview of current Hepatitis C treatment protocols in setting of co- infection

3. 1981..

4. HIV Replication Cycle Furtado M, et al. N Engl J Med 1999;340:1614-22. Copyright 1999 Massachusetts Medical Society

5. Agent – HIV natural History

6. Total: 33.3 million [31.4 million – 35.3 million] Western & Central Europe 820 000 [720 000 – 910 000] Middle East & North Africa 460 000 [400 000 – 530 000] Sub-Saharan Africa 22.5 million [20.9 million – 24.2 million] Eastern Europe & Central Asia 1.4 million [1.3 million – 1.6 million] South & South-East Asia 4.1 million [3.7 million – 4.6 million] Oceania 57 000 [50 000 – 64 000] North America 1.5 million [1.2 million – 2.0 million] Central & South America 1.4 million [1.2 million – 1.6 million] East Asia 770 000 [560 000 – 1.0 million] Caribbean 240 000 [220 000 – 270 000] Adults and children estimated to be living with HIV  2009 Source: WHO 2011

7. HIV Therapeutic Guidelines 2010 – when to start Recommendation Symptomatic diseaseStart Therapy Asymptomatic CD4 < 500Start Therapy CD4 >500Start for those with: Hepatitis B and C Nephropathy Risk factors for CAD Discordant couples Viral Load > 100,000 CD4 decline >100 in 1 year

8. 164 187 102 181 200 192 87 239 163 97 134 179 97 100 125 123 86 122 103 53 157206 95 72  Review of data from 2003-2005 from 176 sites in 42 countries (N = 33,008)  Since 2000, CD4+ cell count at initiation in developed countries stable at approximately 150-200 cells/mm 3 When to Start: The Real World Egger M, et al. CROI 2007. Abstract 62.

9. Reverse Transcriptase Inhibitors -NRTI - NNRTI Protease Inhibitors Integrase Inhibitors Entry Inhibitors Targets for HIV Inhibition 2010 CCR5 Antagonists

10. Approval of Antiretrovirals: 1987-2006 Figure does not include fixed-dose combinations Slide Courtesy Dr. M. Harris

12. Common First-line agents NNRTI-based: –Efavirenz +tenofovir/emtricitabine (Atripla) –One pill daily PI-based Atazanavir/ritonavir Lopinavir/ritonavir (Kaletra) –Must be combined with 2 NRTI: –+Tenofovir/emtricitabine (Truvada) –+ Abacavir/lamivudine (Kivexa)

13. Improving mortality in the HAART era Adapted from Lohse N, et al. Ann Intern Med 2007;146:87-95 1 0.75 0.5 0.25 0 Probability of Survival Pre-HAART (1995-1996) Early HAART (1997-1999) 25303540455055606570 Survival from age 25 years Age, y Late HAART (2000-2005) Population controls

14. HIV/HCV Epidemiology An estimated 20% of HIV+ individuals are co-infected with HCV in Canada Transmission of HIV and Hepatitis C share common modes of transmission – 1. injection drug use: IDU/former IDU accounted for 56% of Canadian HCV prevalent cases in 2002 Rates of co-infection amongst IDU may be as high as 95% Alter, MJ. J Hepatol 2006;44 (Suppl 1) S6-9.

15. HIV/HCV Epidemiology –2. Sexual transmission –Growing reports of possible sexual transmission of HCV amongst HIV+ MSM populations Higher incidence seen in Swiss cohort study amongst MSM with reports of unsafe sex Rauch, A. CID 2005; 41:395. 10 fold increased incidence in Amsterdam 2000- 2003 Van der Laar, T. JID 2007; 196: 230. Major risk factor among HIV+ patients with acute HCV in Australia 2004-2007 Matthews, G. AIDS 2007;21: 2112.

16. HIV/HCV Epidemiology Sexual transmission cont’d: –Associated with unsafe sex, higher number of concurrent sexual partners –Presence of other sexually transmitted infections

17. HIV and Hepatitis C Interactions HIV has been demonstrated to have a significant impact on HCV infection: –Decreased rates of spontaneous clearance ~10% will clear acute infection –Higher HCV viral loads, regardless of genotype Impacts treatment response

18. HIV and Hepatitis C Interactions HIV impact on HCV infection cont’d more inflammatory activity –47% of co-infected patients vs. 30% in mono- infected with moderate or severe inflammatory activity More extensive fibrosis –60% of co-infected patients with METAVIR fibrosis scores of 2-4 vs. 54% in mono- infected Benhamou, Y. Hepatology 1999;30:1054.

19. HIV and Hepatitis C Interactions HIV impact on HCV infection cont’d Rapid progression to cirrhosis –Mean estimated interval to cirrhosis as short as 6.9 yrs vs. 23.2 yrs Soto, B. J Hepatol 1997;26:1. –Cirrhosis associated with alcohol use, CD4 <200 cells/mm 3, older age at time of HCV infection Benhamou, Y. Hepatology 2001;34:283.

20. HIV and Hepatitis C Interactions HIV impact on HCV infection cont’d This translates into higher risk of decompensated liver disease –Meta-analysis of 8 studies found co-infection had increased risk of 6.14 (95% CI 2.86-13.20) for decompensated liver disease Graham, C. CID 2001; 33:562. Higher rates of hepatocellular carcinoma also seen.

21. HIV and Hepatitis C Interactions Impact of Hepatitis C on HIV –No clear direct effects on HIV disease progression –Increased risk of antiretroviral hepatotoxicity –Treatment of HCV has been shown to decrease this risk Study found 9.3% risk of ARV hepatoxicity in those with response to HCV treatment vs. 37.5% in patients without HCV response Labarga, P. JID 2007;196:670.

22. HIV and HCV Interactions Impact of HAART Control of HIV viremia may lead to slower rates of fibrosis Brau, N. J Hepatol;44:47. HAART associated with decreased rates of liver-related mortality in co-infected patients –285 patients studied between 1990-2002 –Rate of 0.45 vs. 1.70/100 person-years for untreated patients Qurishi, N. Lancet 2003;362:1708.

23. HIV and HCV Interactions –impact of HAART Qurishi, N. Lancet 2003;362:1708

24. HIV and HCV Interactions Impact of HAART cont’d However, as patients live longer, liver-related disease still a primary cause of death in co-infected patients –In the D:A:D HIV cohort 1999-2004, liver failure was the second most common cause of death (AIDS most common) –66% had co-infection with HCV –54.6% of those dying of liver failure had achieved suppressed HIV viral loads, and had CD4 cell count >200 cells/mm 3 Weber, R. Arch Int Med 2006;166:1632.

25. HIV and HCV Interactions Impact of HAART cont’d Cohort data from 1,011 co-infected patients beginning HAART 1999-2005 found that liver disease responsible for 43% of deaths –Factors associated with mortality included baseline fibrosis, lower CD4 cell count response and lack of HCV therapy (OR 11.32) Pineda,.J. J. Hepatology 2007;46:622.

26. Baseline assessment All HIV+ patients should be screened for HCV –HCV Antibody –HCV RNA in pts with risk factors and abnormal liver enzymes and negative Antibody HCV co-infected –confirm HCV RNA positive –Vaccinate for Hepatitis A,B if non-immune –Screen for signs of cirrhosis Pts with cirrhosis need U/S q 6mo (+/- alpha-fetoprotein) referral for gastroscopy for varices

27. Evaluation for HCV treatment Confirm HCV RNA remains positive Identify HCV genotype Screen for other causes of chronic liver disease –Autoimmune hepatitis, Wilson’s disease, hemochromatosis Role of liver biopsy: –Helpful to determine degree of inflammation, fibrosis and necrosis –Helps determine who can defer therapy vs. highlights urgency of treatment in cases of more advanced fibrosis

28. Evaluation for HCV therapy However, up to 20-25% of co-infected patients can have significant fibrosis despite normal liver enzymes –greater reason to consider biopsy Uberti-Foppa, C. JAIDS 2006;41:63.

29. Evaluation for HCV treatment Which to treat first? A moving target… HIV for CD4<500 cells/mm 3 Ideally HCV if CD4>500cells/mm 3 –No drug interactions, improves future ARV tolerance –However, new HIV guidelines recognize benefit of HAART in decreasing progression of HCV: If patient not yet ready for HCV therapy, offer HAART regardless of CD4 cell count!

30. Evaluation for HCV treatment Who should be treated? Dependent on genotype, degree of fibrosis and patient factors BC requires evidence of chronic elevation in ALT: 1.5x ULN –2 elevated levels in 6 months

31. Evaluation for HCV treatment Absolute Contra- indications Relative Contra- indications Pregnancy/refusal to use contraceptives Major depression Major psychosis Strong contra-indications Active autoimmune disease Renal failure Hepatic decompensationPlatelet count < 50,000 Coronary artery diseaseAlcohol abuse

32. Poor Treatment Uptake Unfortunately, many barriers: Underlying alcohol, drug use limit referrals –Few patients eligible eventually receive therapy In a study of 881 HIV+ve patients, 43% found to be co-infected with HCV Only 65 co-infected patients felt to be eligible for HCV treatment, and only 3% of these actually received it Fultz, S. CID 2003;36:1039.

33. Poor Treatment Uptake University based HIV/HCV clinic, Baltimore. 65% not referred for HCV assessment Of those referred only 68% completed pre- treatment evaluation Only 29/277 referred eventually treated. Mehta, S. AIDS 2006;20:2361.

34. HCV Treatment Similar to mono-infection: pegylated interferon and ribavirin Either Pegylated interferon a2a, or a2b may be used. –Peg-INF-alpha 2a 180mg Sc weekly + ribavirin 1000mg (wt 75kg) daily –Peg-INF-alpha 2b 1.5mg/kg Sc weekly + weight based ribavirin 800mg-1400mg daily

35. HCV Treatment - outcomes Source: Soriano, V. AIDS 2007;21:1073 Sustained virologic response = undetectable HCV VL 6 months post treatment

36. HIV/HCV Treatment Length of therapy dependent on genotype and evidence of virologic response: Currently 48 weeks for genotype 1, 24 weeks for genotypes 2,3 for mono-infected previous guidelines have recommended 48 weeks for all genotypes in setting of co- infection – based on APRICOT data Now consider 24 weeks for genotypes 2, 3 if good prognostic features and RVR

37. 2007 HIV-HCV International Guidelines – Response Guided Therapy Source: Soriano, V. AIDS 2007;21:1073

38. HCV Treatment - outcomes This approach has been evaluated in Spanish study of 60 pts: Ven den Eynde, E. CID 2009; 48:1152-9. –Pts with RVR treated 24 weeks –Pts with cEVR treated 48 weeks –Pts with pEVR treated 60 weeks 3 pts Geno 1, 2/3 cleared

39. HCV Treatment - outcomes Better outcomes have been reported for therapy in setting of acute HCV co-infection Australian cohort (n=103) of acute HCV –26% co-infected: –Median duration of infection 30 weeks – Overall SVR was 80% Matthews, G. CID 2009;48:650. Similar results from New York acute cohort –70% SVR Jones LM, 59th AASLD 2008. San Francisco. October 31- November 4, 2008. Abstract 1838.

40. Common Side Effects In clinical trials, 10-14% participants discontinued therapy due to adverse events. –Similar to those experienced by mono- infected patients

41. Common Side Effects Neuropsychiatric symptoms –20-30% patients –Mental health team/consider SSRI Cytopenias –Follow standard guidelines for dose reductions of ribavirin/pegylated interferon

42. HAART and HCV Therapy DDI contra-indicated due to increased toxicity due to ribavirin interactions D4T: increased risks of lactic acidosis while on ribavirin (avoid) AZT: increases risk of anemia (avoid)

43. HAART and HCV Therapy Abacavir: ? interaction with ribavirin with lower HCV SVR –Retrospective review of the RIBAVIC trial: OR 4.92 (95% CI 1.50-16.06) Bani-Sadr, F. JAIDS 2007;45:123. –Not seen in analyses of a cohort treated with weight-based dosing Laufer, N. Antiviral therapy 2008;13:953.

44. HAART and HCV Therapy Interferon leads to decrease in absolute CD4 cell count during therapy –Mean drop of 157 cells/mm 3 in APRICOT trial –But CD4 % stayed stable No clear risk of increased opportunistic infections in patients who began therapy with stable CD4 cell counts Some guidelines suggest starting PCP prophylaxis if CD4 counts drop below 200 cells/mm 3

45. Conclusions HIV/Hepatitis C co-infection common Co-infection associated with increased risk for progression of HCV liver disease –Progression may be alleviated by HAART therapy HCV may increase risk for ARV hepatotoxicity Standard therapy dependent on HCV genotype for duration, and algorithms continue to evolve for co-infected patients