Update on HIV-HCV Epidemiology and Natural History

Update on HIV-HCV Epidemiology and Natural History Jennifer Price, MD Assistant Clinical Professor of Medicine University of California, San Francisco

Learning Objectives Upon completion of this presentation, learners should be better able to: Describe the burden of liver disease related to HCV among HIV-infected individuals Identify the factors influencing liver disease progression among HIV-HCV coinfected patients

Faculty and Planning Committee Disclosures Please consult your program book. Off-Label Disclosure There will be no off-label/investigational uses discussed in this presentation.

Causes of Death Among HIV+ 40% 35% 30% 25% 20% Chronic viral hepatitis 15% 10% 5% 0% AIDS Liver Cardiac Cancer Other Causes of death in 33,308 HIV+ adults followed prospectively 1999-2008 in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. Adapted from D:A:D Study Group.AIDS 2010, 24: 1537-1548

Chronic HCV Epidemiology Worldwide: ~3% (170 million) chronically infected Global prevalence varies depending on area Up to 20% in highly endemic areas such as Nile Delta 5 million are HIV-HCV coinfected United States: 1.3-1.9% (2.7-3.9 million) chronically infected with HCV 8% are HIV-infected 25-30% of HIV+ in US are also HCV+: prevalence varies by transmission risk factor WHO: http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index4.html#incidence; CDC: http://www.cdc.gov/hepatitis/statistics/index.htm; Lavanchy D. Clin Microbiol Infect. 2011;17:107-115. Ghany, et al. Hepatology.2009;49:1335-1337.

Global Prevalence of HCV 2.9% 2.0-2.9% 1.0-1.9% <1.0% No data http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/hepatitis-c.htm

Global Prevalence of HCV 1>2,3 1>2>3 1>3>2 2>1 4 3>1,2 1>2>6 2.9% 2.0-2.9% 1.0-1.9% <1.0% No data 5 1>3,6>2 1>2,3 http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/hepatitis-c.htm

Which of the following is the most efficient mode of HCV transmission? 1. Heterosexual contact 2. Injection drug use 3. Maternal-child transmission 4. Male homosexual contact

Transmission of HCV Transfusion (before screening) 10% Other* 5% Unknown 10% Sexual 15% Injection drug use 60% * Iatrogenic; health-care work; perinatal Mother-child transmission 2-5% if mother is HCV-monoinfected and 5 x higher if mother is HIV- HCV-coinfected CDC: http://www.cdc.gov/hepatitis/hcv/strategy/nathepcprevstrategy.htm; Yeong et al.. Hepatology. 2001;34(2):223. Mast et al.. J Infect Dis. 2005;192:1880-1889

Anti-HCV+, % Prevalence of HIV-HCV by HIV Risk Factor 100 85.1% 90 80 70 60 50 40 30 20 10 0 Injection Drug Use 14.3% Heterosexual Contact Sulkowski and Thomas. Ann Intern Med. 2003;138:197-207 9.8% Male Homosexual Contact 45.1% Entire Cohort

Reported cases/100,000 population 3 Incidence of Acute HCV by Age Group- United States, 2000-2010 2.5 2 1.5 1 0 19 yrs 20 29 yrs 30 39 yrs 40 49 yrs 50 59 yrs 60 yrs 0.5 0 Year Source: National Notifiable Diseases Surveillance System (NNDSS)

Acute HCV Among HIV+ MSM 2004/2005: Clusters of acute HCV in HIV+ MSM reported in Northern Europe Ulcerative STI s more common in HCV incident cases Molecular genetics more similar to each other than in IDU-associated HCV isolates Linkages made to high-risk sexual behavior (fisting, group sex, traumatic and receptive intercourse) and recreational (not-injected) drugs Browne et al. Sex Transm Infect 2004; 80:326 327. Gilleece et al. J Acquir Immune Defic Syndr 2005; 40:41 46. Gambotti, et al. Euro Surveill 2005; 10:115 117. Ghosn, et al. HIV Med 2004; 5:303 306. Gotz et al. AIDS 2005; 19:969 974. Luetkemeyer et al. J Acquir Immune Defic Syndr 2006; 41:31 36. Fierer, et al. J Infect Dis 2008; 198:683 686.

Acute HCV Among HIV+ MSM Clusters of acute HCV among HIV+ MSM reported in both US and Australia Northern Europe cohort studies suggests increased HCV incidence since 2000 Short time frame (<2 years) between HIV diagnosis and HCV seroconversion Browne et al. Sex Transm Infect 2004; 80:326 327. Gilleece et al. J Acquir Immune Defic Syndr 2005; 40:41 46. Gambotti, et al. Euro Surveill 2005; 10:115 117. Ghosn, et al. HIV Med 2004; 5:303 306. Gotz et al. AIDS 2005; 19:969 974. Luetkemeyer et al. J Acquir Immune Defic Syndr 2006; 41:31 36. Fierer, et al. J Infect Dis 2008; 198:683 686.

ALT (IU/L) Course of Acute HCV Infection 1000 800 600 400 HCV RNA positive Anti-HCV Symptoms 200 0 0 2 4 6 8 10 12 24 1 2 3 4 5 6 Weeks Months Time After Exposure 7 Normal ALT Hoofnagle, Hepatology. 1997;26:15S. Carithers, et al. Semin Liver Dis. 2000;20:159-171. Pawlosky, Hepatology. 2002;36(suppl 1):S65-S73. NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002.

HIV impacts which of the following among HCV-infected individuals? 1. Clearance of acute HCV infection 2. Progression to cirrhosis 3. Survival after development of cirrhosis 4. Graft and patient survival after liver transplant 5. All of the above

Natural History of HCV Lower rates of spontaneous clearance Acute HCV Resolved 15-40% Chronic HCV 60-85% Stable 85-90% Cirrhosis 10-15% Slowly progressive 75% HCC Liver failure 25% (2-4%) NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002.

Percent Influence of HIV on Spontaneous Clearance of HCV 16 13.8% 14 12 10 8 8.3% 8.6% 6 5.0% 4 2 0 HIV Negative HIV+ (CD4 500) HIV+ (CD4 200-500) HIV+ (CD4 <200) Thomas et al. JAMA 2000; 284:450-456.

Natural History of HCV Acute HCV Resolved 15-40% Stable 85-90% Chronic HCV 60-85% Cirrhosis 10-15% Accelerated fibrosis progression Increased risk of cirrhosis, liver decompensation Slowly progressive 75% HCC Liver failure 25% (2-4%) NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002.

Increased Risk of Cirrhosis and ESLD Due to HIV-HCV Coinfection Makris (UK) Soto (Spain) Pol (France) Benhamou (France) Combined Histologic Cirrhosis Relative Risk Decompensated Liver Disease Eyster (USA) Telfer (UK) Makris (UK) Lesens (Canada) Combined Relative Risk.76 1.0 2.07 10.83 HCV HIV-HCV Only.61 1.0 6.14 10 HCV HIV-HCV Only Graham et al.. Clin Infect Dis. 2001;33:562-569.

Incidence density rate of HCC, cases per 1000 person years Hepatocellular Carcinoma in HIV-HCV Coinfected Patients 2.5 2 1.5 1 0.5 0 Merchante et al. Clin Infect Dis. 2013;56:143-150. Ioannou et al. Hepatology. 2013;57: 249-257.

Natural History of HCV Acute HCV Resolved 15-40% Chronic HCV 60-85% Stable 85-90% Cirrhosis 10-15% Slowly progressive 75% HCC Liver failure 25% (2-4%) Liver Transplant Death Shorter survival after decompensation

Survival (%) HIV-HCV Coinfected Patients with Decompensated Cirrhosis Shorter Survival 100 80 60 40 20 0 HCV-monoinfected 5-Year Cumulative Survival 91 50 Decompensation Compensated Retrospective study of 1,037 HCV monoinfected and 180 HIV-HCV coinfected subjects with decompensated cirrhosis Median survival HCV monoinfected: 48 months HIV-HCV coinfected: 16 months Relative risk of death HIV: 2.26 [1.51-3.38] Fattovich et al. Gastroenterology. 1997;112:463-472. Pineda et al. Hepatology. 2005;41:779-789

Natural History of HCV Acute HCV Resolved 15-40% Chronic HCV 60-85% Stable 85-90% Cirrhosis 10-15% Slowly progressive 75% HCC Liver failure 25% (2-4%) Liver Transplant Poorer outcomes after liver transplant Death

Patient Survival Patient Survival Liver Transplant and HIV-HCV Graft and patient survival is decreased among HCV+ transplant recipients. Further reduced among HIV-HCV coinfected recipients HCV HCV p=0.0065 HIV-HCV p<0.001 HIV-HCV Spain Multi-site study HIV-HCV: n=84 US Multi-site study HIV-HCV: n=89 Miro et al, A J Transplant 2012; 12:1866-1976. Terrault, et al. Liver Transpl. 2012; 18:716-26.

Which of the following factors has NOT been associated with higher risk of cirrhosis in HCV-infected individuals? A. HCV Genotype B. Alcohol use C. Marijuana use D. Post-menopausal status E. Older age at time of HCV exposure

Risk Factors for Disease Progression in HCV-monoinfection Alcohol use Daily marijuana use Elevated BMI, obesity, insulin resistance Longer duration of infection Age >40 at time of infection Male gender, post-menopausal women Host genetic factors Organ transplantation Coinfections: HBV, HIV, Schistosomiasis Poynard, et al. Lancet 1997;349:825-32; Mathurin, et al. Hepatology 1998; 27:868-72. Benhamou, et al. Hepatology 1999; 30:1054-8; Kamal, et al. Hepatology 2006;43:771-779. Asselah, et al. Gut 2006; 55:123-130. Ishida, et al. Clin Gastro Hepatology 2008;6:69-7.

Predictors of Severe Liver Fibrosis in HIV-HCV Coinfected Patients Variable OR (95% CI) Age at biopsy >35 years 2.95 (2.08-4.18) Alcohol >50 g/day 1.61 (1.1-2.35) CD4 count <500 cells/mm 3 1.49 (1.06-2.08) Male sex 1.26 (0.94-2.06) 914 HIV-HCV coinfected patients with elevated ALT who underwent liver biopsy between 1992-2002 Route of transmission, HCV genotype, HCV viral load, and ART were not associated with liver fibrosis severity Martin-Carbonero, et al. Clin Infect Dis. 2004;38:128-133.

Alcohol and Liver Disease in HIV+ Patients Percent of deaths due to ESLD Percent of ESLD deaths with history of excessive alcohol* 60 100 100% 40 44% 31% 80 60 56% 62% 20 0 22% 2% 40 20 0 21% Salmon-Ceron. J Hepatol. 2005; 42:799-805. *men >30 g/day, women >20 g/day

Hepatic Steatosis is Common in HIV- HCV Coinfected Patients Prevalence estimates range from 23-72% Factors associated with increased prevalence of hepatic steatosis in HIV-HCV coinfected patients: Variable OR (95% CI) BMI 1.13 (1.07, 1.19) Diabetes Mellitus 2.32 (1.32, 4.07) Elevated ALT 1.28 (1.02, 1.61) Fibrosis 1.67 (1.20, 2.34) Necroinflammation 1.72 (1.11, 2.67) Machado, et al. Hepatology. 2010; 52:71-78.

Ishak Fibrosis Units/yr Ishak Fibrosis Units/yr Impact of ART on Fibrosis Progression Rate (FPR) in HIV-HCV 0.22 0.2 0.22 0.2 CD4 <500/mm 3 CD4 500/mm 3 0.18 0.18 0.16 0.16 0.14 0.14 0.12 0.12 0.1 0.1 0.08 HIV- HIV RNA <400 HIV RNA 400-99K HIV RNA 100K 0.08 HIV RNA <400 HIV RNA 400 HIV RNA <400 HIV RNA 400 FPR similar among HIV-HCV coinfected patients with suppressed HIV replication on ART and HCV-monoinfected FPR accelerated among HIV viremic patients with CD4 counts < 500/mm 3 Brau, et al. J Hepatol. 2006;44:47-55.

Impact of ART on Survival with Decompensated Cirrhosis Prospective study of 153 HIV-HCV coinfected subjects with decompensated cirrhosis Median survival: 13 months Independent predictors of mortality: Variable HR (95% CI) Child-Pugh score 1.22 (1.08-1.37) Encephalopathy 2.45 (1.41-4.27) CD4 count <100 cells/µl 2.48 (1.52-4.06) HAART during following up 0.57 (0.34-0.95) Cumulative 3-year survival: 18% off HAART, 40% on HAART Merchante, et al. AIDS.2006;20:49-57.

Impact of HIV on HCV Disease Progression in the ART-Era HIV-HCV HCV Predicted fibrosis scores +/- HIV holding constant race, sex, alcohol use, BMI, HBsAg status, HCV RNA level HIV-HCV have liver fibrosis equivalent to HCV-mono 9.2 yrs older on average Kirk, et al. Ann Intern Med. 2013; Feb 26 [Epub ahead of print].

Summary HCV coinfection is common among HIV+ Prevalence varies by population HIV+ MSM are new high risk group HIV influences the natural history of HCVrelated liver disease Beneficial impact of potent ART

Summary Other modifiable risk factors include: Alcohol abuse Marijuana use Obesity and insulin resistance