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HIV and Hepatitis C and B Co-Infection

HIV and Hepatitis C and B Co-Infection. Debika Bhattacharya, MD, MS UCLA Center for Clinical AIDS Research & Education Assistant Clinical Professor of Medicine David Geffen School of Medicine at UCLA. Overview. Epidemiology Natural history of HCV Diagnosis Treatment. J.B. ’ s story.

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HIV and Hepatitis C and B Co-Infection

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  1. HIV and Hepatitis C and B Co-Infection Debika Bhattacharya, MD, MS UCLA Center for Clinical AIDS Research & Education Assistant Clinical Professor of Medicine David Geffen School of Medicine at UCLA

  2. Overview • Epidemiology • Natural history of HCV • Diagnosis • Treatment

  3. J.B.’s story • J.B was recently diagnosed with HIV and HCV. • He used to inject drugs and have unprotected sex with men most of whom were HIV+, but hasn’t used injection drug in 2 years and is now in a monogamous relationship with a male HIV-negative partner over the last year. • “What is hepatitis C and how did I get it ?”

  4. What should you tell him? • Hepatitis C is a virus and you probably contracted it by sharing needles but may have acquired it through sex. • Hepatitis C is a flesh-eating bacteria and you contracted it by drinking contaminated water • I don’t know—I fell asleep during those talks

  5. What should you tell him? • Hepatitis C is a virus and you probably contracted it by sharing needles but may have acquired it through sex. • Hepatitis C is a flesh-eating bacteria and you contracted it by drinking contaminated water • I don’t know—I fell asleep during those talks

  6. Hepatitis C: A Global Health Problem >184 Million (M) Carriers Worldwide Far East Asia >50 million Eastern Europe >10 million Western Europe >10 million United States >4 M South/Southeast Asia >60 million Africa >33 M Americas >12 M Australia >0.6 million MohdHanafiah K et al. Hepatology. 2013;57(4):1333-42.

  7. Prevalence of HCV Among Persons with HIV in the US Courtesy Sylvestre Thomas D. Hepatology. 2002;36:S201-S209.

  8. HIV/HCV Overview • Epidemiology • Prevalence • Transmission • Prevention • HCV genotypes • Natural history of HCV • Diagnosis • Treatment

  9. How do you get hepatitis C? Injecting drug use 60% Sexual 15% Transfusion 10% (before screening) Occupational 4% Other 1%* Unknown 10% * Nosocomial; iatrogenic; perinatal Source: Centers for Disease Control and Prevention Source: Sentinel Counties, CDC

  10. Sexual Transmission HETEROSEXUAL HIV-INFECTED MSM Prevalence of 6-15.7% (East Coast, Australia, SF, Europe)3-7 Estimated incidence rates of 0.83-0.87 per 100 person-years8,9 aOR of 4.5-5.7 for HCV infection compared to HIV-uninfected MSM8,10-11 • Prevalence estimates of 2-10% • Monogamous couples in Italy1 • 3 infections • 0.37 per 1000 persons-years • Phylogenetic analysis: discordant virus • HCV Partners Study (Northern California)2 • HCV prevalence among partners of 4% (n=20), 11 discordant virus • maximum incidence rate of HCV transmission by sex was 0.07% per year (95% CI 0.01-0.13) 1Vandelli C, et al. Am J Gastroenterol 2004, 2Terrault et al, Hepatology 2013, 3Garg et al, CID 2013, 4Wandeler et al, CID 2012, 5Raymond et al, Sex Transm Dis2012, 6Matser et al, PLoS One 2013, 7Matthews et al, CID2011, 8Van de Laar et al, JID 2007, 9Ghosn Sex Transm Infect 2006, 10Richardson et al, JID 2008; 11Hammer Sex Transm Dis 2003

  11. Risk Factors for Sexual Transmission • Traumatic sexual practices (anal mucosal damage) – fisting, sex toys, bleeding • Multiple partners, group sex • Non-injection drug use, particularly stimulant use • Genital ulcer disease Van de Laar et al, AIDS 2010 Yaphe et al, Sex Transm Infect 2012

  12. How can you prevent hepatitis C? • Do not reuse or share syringes, needles, water, or drugworks. • Do not share personal care items that might have blood i.e. toothbrushes and razors • Consider health risks of tattoos and body-piercing • Use condoms www.cdc.gov Hepatitis C Fact Sheet 2008

  13. You will not get hepatitis C through: • Breastfeeding • Sneezing • Hugging or kissing • Coughing • Sharing eating utensils or drinking glasses • Food or water • Casual contact www.cdc.gov Hepatitis C Fact Sheet 2008

  14. HIV/HCV Overview • Epidemiology • Prevalence • Transmission • HCV genotypes • Natural history of HCV • Diagnosis • Treatment

  15. J.B’s story • J.B.’s doctor also told him that he has genotype 3 disease • “Why does it matter what type of hepatitis C I have?”

  16. HCV genotypes:“Know your genotype” • HCV genotypes 1-6 • Genotypes 1-3 most common in US • Geographic Distribution

  17. HCV genotypes • Differ in Treatment Responses • Genotype 3 • Lower likelihood of achieving cure • Even with newer antiviral agents • Genotypes 1,2 • Higher likelihood of achieving cure • Genotype 1 • Subtype matters; 1a vs 1b

  18. HIV/HCV Overview • Epidemiology • Natural history of HCV • How HIV impacts hepatitis C • Disease Progression • Diagnosis • Treatment

  19. Natural History of Hepatitis C Most patients with chronic HCV infection are asymptomatic Acute Hepatitis C 10-20 years Chronic Hepatitis 75%-85% Cirrhosis 20% Hoofnagle JH Hepatology. 1997;26 (suppl 1): 15S-20S Di Bisceglie, Hepatology, 2000

  20. Sequelae of HCV Infection • FibrosisCirrhosisLiver failure • Decompensated liver disease: ascites, variceal bleeding, hepatic encephalopathy • Hepatocellular carcinoma (HCC) • Death– increased mortality from both liver and non-liver diseases

  21. HIV/HCV Overview • Epidemiology • Natural history of HCV • How HIV impacts hepatitis C • Disease Progression • Diagnosis • Treatment

  22. HIV accelerates natural history of HCV • HIV accelerates rate of liver fibrosis progression • 2.9 times higher in HIV/HCV co-infection1 • Progression to cirrhosis occurs in • 15%-25% of HIV/HCV coinfected patients • 3%-6% of HCV mono-infected patients2-3 • Time to progression • 6 to 10 years in HIV/HCV coinfected individuals4 • 20 to 30 years in HCV mono-infected patients 1. CDC. MMWR. 2004;53(RR-15):49-53 2. Verucchi Infection. 2004;33:33-46. 3. Khalili M, GastroenterolClin N Am. 2004;33:479-496. 4. Chun S, Clin Liver Dis. 2005;9:525-533

  23. Mortality by HCV status with AIDS Dx in cART era In adjusted analysis: 50% increased risk of death with chronic HCV compared to HCV negative (RR 1.5, 95% CI 1.2-1.9) 20% = liver-related deaths Proportion of deaths related to CVD, AIDS, non-AIDS cancers similar Chronic Cleared No HCV Branch et al, CID 2012;55(1):137–44: Longitudinal Studies of the Ocular Complications of AIDS Cohort

  24. HIV/HCV Overview • Epidemiology • Natural history of HCV • Diagnosis • Treatment

  25. HIV/HCV Overview • Epidemiology • Clinical Course of HCV • Diagnosis • Who should get tested? • HCV antibody and virologic testing • Liver biopsy • Noninvasive markers • Treatment

  26. Who should get tested for hepatitis C?CDC guidelines1 • Individuals with HIV • Individuals with hepatitis B • Individuals with a history of injection drug use • received a blood transfusion or solid organ transplant before July, 1992 • were a recipient of clotting factor(s) made before 1987 • have ever been on long-term kidney dialysis • have evidence of liver disease (e.g., persistently abnormal ALT levels) Additional Recommendations2: 1945-1965 Birth Cohort • Prevalence of anti-HCV among persons born from 1945 to 1965 is 3.25%, 5x higher than among adults born in other years • Adults born during this time should receive one-time testing for HCV regardless of prior HCV exposure risk 1. http://www.cdc.gov/hepatitis/hcv/guidelinesc.htm 2. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6104a1.htm

  27. HIV/HCV Overview • Epidemiology • Clinical Course of HCV • Diagnosis • Who should get tested? • Types of blood tests: antibody and virus • Liver biopsy • Noninvasive markers • Treatment

  28. Hepatitis C Diagnosis:Blood Tests to detect presence of HCV • 1. Antibody • 2. Virus

  29. Hepatitis C TestingAntibody Test • Antibody test (EIA) • Indicates past or active infection • Unlike hepatitis B, presence of antibodies does not indicate immunity • Mean time to seroconversion: 10 weeks • 98% sensitive and specific

  30. Special considerations for hepatitis C antibodytesting in HIV infection • Individuals who may not have HCV antibodies • CD4<200 • Acute HCV

  31. HCV Ab test less sensitive in HIV+ patients • Up to 19% of HIV+ individuals with chronic hepatitis C have negative HCV Ab titers1 • CD4 count below 200 cells/mm3 (OR 2.80)2 • HCV RNA PCR (viral load) testing is indicated if chronic hepatitis C suspected • Unexplained transaminitis • History of IDU • George, et al. JAIDS 2002;31:154-162 • G Chamie, XVI International AIDS Conference. Toronto, August 13-18, 2006. Abstract WEPE0046/13774.

  32. Hepatitis C Testing:Virus TestPCR • HCV RNA test (PCR) • Confirms active infection, infectivity to others • Quantitative or qualitative RNA tests exist; the former is more often used because it provides a potentially useful viral load measurement

  33. HIV/HCV Overview • Epidemiology • Clinical Course of HCV • Diagnosis • HCV Ab testing • Liver biopsy and noninvasive markers • Treatment

  34. How do we measure how much liver disease (fibrosis) a patient has? • LIVER BIOPSY • Has been considered the gold standard • Subject to sampling error • Consider quality of biopsy specimen • NON-INVASIVE MEASURES • Blood: perform well at extremes (minimal vs advanced fibrosis), not in mid ranges • FIB-4: age, plt, ALT, AST; validated for HIV/HCV • FibroSURETM: alpha2 macroglobulin, alpha2 globulin, gamma globulin, apolipoprotein A1, GGT, total bilirubin • APRI: AST-to-platelet ratio index; lower accuracy in HIV/HCV coinfection • Transient elastography (FibroScan) • LIVER ULTRASOUND – 88% sensitivity, 82-95% specificity for cirrhosis

  35. Stage 0 Stage 1 Stage 2 Few septa No Fibrosis Portal Fibrosis Stage 3 Stage 4 Numerous septa Cirrhosis Histologic Staging

  36. HIV/HCV Overview • Epidemiology • Clinical Course of HCV • Diagnosis • Treatment

  37. The Good News DAAs 2013 100 2011 90+ PegIFN 2001 RBV 80 Standard IFN 70+ 1998 55 60 1991 SVR (%) 42 39 40 34 16 20 6 0 DAA + RBV ± PegIFN IFN 12 mos IFN/RBV 6 mos IFN/RBV 12 mos PegIFN 12 mos PegIFN/ RBV 12 mos IFN 6 mos PegIFN/ RBV/ DAA Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD.

  38. HCV Life Cycle and DAA Targets Receptor bindingand endocytosis Transportand release Fusion and uncoating LD LD Translation andpolyprotein processing ER lumen Virionassembly (+) RNA LD NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside Membranousweb RNA replication ER lumen NS5A inhibitors Block replication complex formation, assembly RNA replication Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

  39. Successful HCV treatment reduces risk of death and liver complications in HIV-infected persons Overall deaths Liver-related deaths Event –free survival SVR = sustained virologic response Overall deaths 9.2% non-SVR vs 1.3% SVR Liver-related deaths 5.7% vs 0.5% Berenguer et al, CID 2012;55:728-36

  40. J.B.’s StoryJ.B. wants to start treatment.What can you tell him? A. JB may clear the virus from his system B. JB doesn’t need to worry about side effects with his HIV medications C. There is no treatment for JB D. There may be newer, more effective treatment for JB

  41. J.B.’s StoryJ.B. wants to start treatment.What can you tell him? A. JB may clear the virus from his system B. JB doesn’t need to worry about side effects with his HIV medications C. There is no treatment for JB D. There may be newer, more effective treatment for JB

  42. HIV/HCV Overview • Epidemiology • Natural history of HCV • Diagnosis • Treatment

  43. Pegylated interferon and ribavirin (PR) • Has been the standard of care for HIV-infected patients (and until 2011, for HCV monoinfected patients) • Inadequate response rates in HIV • Genotype 1: 14-29% SVR • Genotype 2/3: 44-73% SVR Chung RT et al, NEJM 2004; TorrianiFJet al, NEJM 2004; Carrat F et al, JAMA 2004

  44. FDA-approved agents for HCV (as of September 2014) • Interferon (pegylated, consensus, standard) • Ribavirin (with interferon) • HCV protease inhibitors: • Boceprevir with PR • Telaprevir with PR • Simeprevir with PR • HCV nucleotide polymerase inhibitor: • Sofosbuvir (with PR for GT1/4 and with RBV for GT 2/3)

  45. Improved overall SVR rates

  46. Simeprevir and SofosbuvirTreatment-Naïve and Null Responders (COSMOS) SMV (PI) + SOF (Nuc) + RBV 12 wks SMV (PI) + SOF (Nuc) 12 wks 100 96 96 100 93 • 78% GT1a • 40% Q80K • 79% non-CC • 47% F4 • 54% Null 80 • 78% GT1a • 50% Q80K • 94% non-CC • All nulls 60 SVR4 (%) SVR12 (%) 40 20 26/27 13/14 26/27 14/14 0 F0-F2 Fibrosis F3/F4 Fibrosis Jacobson I, et al. AASLD 2013. Abstract LB-3.

  47. Phase III Studies of Sofosbuvir (Nuc) + Ledipasvir (NS5A) ± RBV in GT1 HCV ION-1*: GT1 treatment-naive pts (16% cirrhotic): SOF/LDV FDC ± RBV for 12 wks ION-3: GT1 treatment-naive pts: SOF/LDV FDC ± RBV for 8 or 12 wks ION-2: GT1 treatment-experienced pts (20% cirrhotic): SOF/LDV FDC ± RBV for 12 or 24 wks SOF/LDV FDC + RBV SOF/LDV FDC 99 99 98 97 96 100 95 94 93 94 80 60 SVR12 (%) 40 20 209/214 211/217 102/109 107/111 108/109 110/111 202/215 201/216 206/216 n/N = 0 8 Wks 12 Wks 12 Wks 24 Wks 12 Wks *24-wk arms not yet reported. Press release. These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data.

  48. HIV/HCV: SOF/LDV

  49. HCV treatment for HIV-infected persons • HCV treatment should be considered in ALL HIV-infected persons • In those with CD4<200 cells/cmm and not on ART, can consider delaying HCV therapy until CD4 improved on ART • In those with CD4> 500 cells/cmm and HIV treatment naïve, can consider deferring ART until completion of HCV treatment (pill burden, drug interactions, toxicities) DHHS Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, March 28, 2012

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