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HIV and Hepatitis C Virus Co-infection

HIV and Hepatitis C Virus Co-infection. Kara Chew, MD, MS UCLA Center for Clinical AIDS Research & Education Assistant Clinical Professor of Medicine David Geffen School of Medicine at UCLA. Overview. The Basics Epidemiology Natural history of HCV Diagnosis Treatment. 0.

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HIV and Hepatitis C Virus Co-infection

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  1. HIV and Hepatitis C Virus Co-infection Kara Chew, MD, MS UCLA Center for Clinical AIDS Research & Education Assistant Clinical Professor of Medicine David Geffen School of Medicine at UCLA

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

  3. 0 WHAT IS HEPATITIS C? WHAT ORGAN DOES IT INFECT?

  4. Hepatitis C Virus (HCV) • Single-stranded, positive-sense RNA virus • Flaviviridaefamily • Infects hepatocytes (liver cells) • Causes acute and chronic infection Image from chop.edu

  5. HIV VS HCV Adapted from CCO slideset, S. Ray 2011

  6. HCV Genome • 9.6 kb genome with a single ORF • Single polyprotein co- and post-translationally processed by cellular and viral proteases • 3 structural, 6 NS proteins, and p7 Poenisch and Bartenschlager, SeminLiv Dis 2010

  7. HCV Life Cycle HEPATOCYTE

  8. HEPATITIS C EPIDEMIOLOGY

  9. HOW BIG OF A PROBLEM IS HEPATITIS C? DOES IT AFFECT MORE OR FEWER PEOPLE THAN HIV?

  10. The Burden of Hepatitis C • ~170 million chronically infected worldwide1 • 2.4-3.9 million in the U.S. (NHANES, 1999-2002- excludes incarcerated and homeless and those on active military duty)2 • Other estimates of up to 5.2 million in the U.S3 • Leading indication for liver transplantation in the U.S. 1WHO, J ClinPharmacol 2004;44:20-9 2Armstrong et al, Ann Intern Med 2006;10:705-714 3Chak et al, Liver International 2011; 31:1090-1101

  11. The Global Burden of HCV Holmberg, CDC Yellow Book 2012

  12. HCV is underdiagnosed • In U.S. and Europe, ~3/4 of infections in “Baby Boomers” (born 1945-1965) • High endemicity in other countries • Foreign-born in U.S. may not be appropriately tested based on lack of traditional (U.S.) risk factors • Homeless adults in LA: community-based probability sample of 534 adults • 26.7% tested HCV positive (ELISA +/- RIBA) • 46.1% unaware of having HCV Alter, World J Gastroenterol 2007;13:2436-41 Gelberg et al, Pub Health Rep 2012

  13. HOW IS HEPATITIS C TRANSMITTED? CAN HEPATITIS C BE TRANSMITTED SEXUALLY?

  14. HCV Transmission • Bloodborne virus • ROUTES OF TRANSMISSION • In developed countries today, IDU • In developing countries: unsafe injections in healthcare settings, unscreened blood transfusions, IDU • Increasing sexual transmission in HIV+ MSM Averhoffet al, CID 2012;55(S1):S10–15 CDC/MMWR 2011;60:945-76 Wandeleret al, CID 2012;e-pub 8/2012

  15. 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

  16. 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

  17. 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

  18. 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

  19. Natural History of Hepatitis C infection

  20. WHAT ARE THE SIGNS AND SYMPTOMS OF ACUTE HEPATITIS C INFECTION AND HOW COMMON ARE THEY?

  21. Symptoms of Acute HCV Infection • Often asymptomatic • Symptoms in 20-30% • Fatigue • Jaundice • Abdominal pain • Poor appetite • Symptom onset on average 4-12 (range 2-24) weeks from exposure

  22. WHAT ARE THE LONG-TERM COMPLICATIONS OF HEPATITIS C INFECTION?

  23. 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

  24. Sequelae of HCV Infection Image from www.news-medical.net

  25. Natural History of HCV Infection 20-30 years Often asymptomatic Hoofnagleet al, Hepatology. 1997 Di Bisceglie et al, Hepatology, 2000

  26. Risk of death is increased with HCV Infection Prospective HCV-monoinfected cohort Adjusted Hazard Ratio (AHR) for death, HCV+ vs HCV-: All-cause death 1.89 (1.66-2.15) Hepatic diseases 12.48 (9.34-16.66) Extrahepatic 1.35 (1.15-1.57) Circulatory diseases 1.50 (1.10-2.03) Renal disease (2.77 (1.49-5.15) Lee et al, JID 2012;206:469-77

  27. HOW DOES HAVING HIV INFECTION AFFECT HEPATITIS C-ASSOCIATED LIVER DISEASE?

  28. HIV/HCV Co-infection • ~30% of HIV-infected persons in the U.S. and Europe are coinfected with HCV1 • Liver disease accelerated2 – 3x greater risk of progression to cirrhosis or decompensated liver disease • ART seems to slow progression, but not fully3 • Increased mortality (vs HCV and HIV monoinfection)4 • Unrelated to HIV disease progression • Possible increased risk of mother-to-child HCV transmission5 1Mohsen et al, Gut 2002; 51:601–8, 2Graham et al, CID 2001;33:562-9,3Weber et al, Arch Intern Med 2006;166:1632-41, 3Kitahata et al, NEJM 2009;360:1815-26, 4Chen et al, CID 2009; 49:1605-15, 4Branch et al, CID 2012; e-pub 4/24/12, 4Hernando et al J Hepatol 2012, e-pub, 5Gibb et al, Lancet 2000; 356:904-7

  29. 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

  30. How to prevent liver disease progression • Treat HIV • Avoid alcohol • Avoid smoking cigarettes • Avoid marijuana • Treat and vaccinate for co-infections (e.g. hepatitis A and hepatitis B) • Weight loss may help

  31. Hepatitis C Testing

  32. Which of the following is the recommended test for HCV screening? • Anti-HCV antibody (enzyme immunoassay or enhanced chemiluminescence immunoassay) • HCV RNA PCR (quantitative or qualitative) • HCV recombinant immunoblot assay (RIBA)

  33. A patient tests anti-HCV antibody positive. What is the next step? • Tell him he has chronic hepatitis C infection • Tell him he may have hepatitis C infection and needs additional testing, repeat the anti-HCV antibody to confirm • Tell him he may have hepatitis C infection and needs additional testing, check an HCV RNA PCR

  34. How do we measure how much liver disease (fibrosis) a patient has? • LIVER BIOPSY • Preferred if available • 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 • Now FDA-approved in the U.S. • LIVER ULTRASOUND – 88% sensitivity, 82-95% specificity for cirrhosis

  35. Hepatitis C Treatment

  36. 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% Berengueret al, CID 2012;55:728-36

  37. How do we measure HCV treatment response? • Sustained virologic response (SVR) = undetectable HCV viral load 24 weeks after end of HCV treatment • SVR12 (undetectable HCV viral load at 12 weeks after end of treatment) used in many clinical trials as the primary endpoint now • Think of SVR as “Cure”

  38. Pegylated interferon and ribavirin (PEG/RBV) • 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

  39. New Drug Targets: Direct-Acting Antivirals (DAAs) NS3/4A PROTEASE INHIBITORS NS5A INHIBITORS NS5B POLYMERASE INHIBITORS Nucleotides and Non-nucleosides Shimakami et al CurrOpinPharmacol 2009

  40. Expanding treatment options • Boceprevir and telaprevir (each given with PEG/RBV) FDA-approved in 2011 for treatment of HCV-monoinfected persons • Used off-label for HIV/HCV co-infected – phase III trials ongoing • Treatment of HIV-infected with HCV DAAs mostly via clinical trials • Phase III trial data for HIV/HCV still mostly with peginterferon/ribavirin-based regimens • Interferon-sparing regimens coming • Goals: Improved response rates, shorter courses, less toxicity

  41. Boceprevir + PEG/RBV in Genotype 1 HIV/HCV Coinfected Patients • Untreated HCV genotype 1 • 97% with HIV RNA < 50 copies/mL • - NNRTIs, zidovudine, didanosine not permitted • 4 week PR lead-in, then BOC 800 mg po TID + PEG 2b + weight-based ribavirin (WBR) or placebo + PR x 44 wks • 85% F0-F2 • 78% genotype 1a • Discontinued due to adverse effects: 20% (B/PR) vs 9% (PR) • HIV-1 RNA breakthrough: 3/64 BOC/PR, 4/34 PR Sulkowski M et al, Lancet Infect Dis, 2013;13(7):597-605

  42. Study 110: Telaprevir Plus PEG/RBV in Genotype 1 HIV/HCV-Coinfected Patients • Untreated HCV genotype 1 • TVR or placebo + PEG 2b + RBV (800 mg/d) x 12 weeks, then 36 weeks PR • ART: NONE or (EFV or ATV/r) + TDF + (3TC or FTC) • If on EFV, TVR dose 1125 mg po q8h (vs 750 mg po q8h) • 70% white • 12% bridging fibrosis or cirrhosis • 68% genotype 1a • D/C due to AEs: 8% (T/PR) vs 0% (PR) • - No severe rash Slide 44 of 83 Dieterich D, et al, CROI 2012, Seattle, WA, Abstract 46; Sulkowski, M, et al, Ann Intern Med, 2013;159(2):86-96

  43. HCV Protease Inhibitor Resistance • Barrier to resistance lower in subtype 1a than 1b • Baseline prevalence of resistance-associated variants (RAVs) 0.3-2.8% in untreated subjects • RAVs associated with virologic breakthrough or failure • Extensive cross-resistance between BOC and TVR (and other PIs) Sarrazin C et al, J Hepatol 2011; 2012;56 Suppl 1:S88-100

  44. Comparison of HCV DAAs Sarrazin C et al, J Hepatol 2011; 2012;56 Suppl 1:S88-100; Poordad and Dietrich, JVH 2012;19:449-464

  45. WHICH HIV PATIENTS SHOULD BE CONSIDERED FOR HEPATITIS C TREATMENT?

  46. HCV treatment for HIV-infected persons • HCV treatment should be considered in ALL HIV-infected persons • In those with CD4<200 cells/cmmand 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

  47. Treat now or wait? Factors to consider • Fibrosis stage • Treatment history (prior response to peginterferonalfa and ribavirin, PR): naïve, relapser, partial responder, null responder • Other characteristics predicting PR response: HCV viral load, IL28B • Treatment options (considering drug-drug interactions, interferon tolerability, pending FDA approval for new DAAs, clinical trials)

  48. HIV/HCV resources for patients and educators • CDC - HIV and Viral Hepatitis:http://www.cdc.gov/hiv/resources/factsheets/hepatitis.htm • VA resources for the public: http://www.hepatitis.va.gov/patient/index.asp http://www.hepatitis.va.gov/patient/diagnosis/ coinfection-index.asp • DHHS guidelines on HIV-1 treatment:http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf

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