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Viral Hepatitis: Prevention and Control Mark Sulkowski, MD Professor of Medicine Medical Director, Viral Hepatitis Center Divisions of Infectious Diseases and Gastroenterology/ Hepatology Johns Hopkins Medical Institutions Baltimore Maryland USA Viral Hepatitis: Prevention and Control The US Perspective HCV Prevention Policy Development Institute of Medicine AASLD/ Trust for America’s Health Report HHS Plan for Viral Hepatitis Prevention “Development of a vaccine that prevents new HCV infections remains a high priority task.” Acute HCV infection continues to occur in the United States • Sexual Transmission of Hepatitis C Virus Among HIVInfected Men Who Have Sex with Men --- New York City, 2005--2010 • Acute Hepatitis C Virus Infections Attributed to Unsafe Injection Practices at an Endoscopy Clinic --Nevada, 2007 • Hepatitis C Virus Infection Among Adolescents and Young Adults --- Massachusetts, 2002--2009 MMWR May 16, 2008 / 57(19);513-517; MMWR July 22, 2011 / 60(28);945-950; MMWR; May 6, 2011 / 60(17);537-541 Since 2007, more Americans die from HCV than HIV infection • National multiple-cause mortality data Mortality rates of HBV, HCV, and HIV; United States 1999-2007 'By 2007 hepatitis C-associated deaths had overtaken HIV as a cause of mortality in the United States. To achieve declines in mortality similar to those seen with HIV will require new policy directions and commitment to detect and link infected persons to care and successful treatment‘ • Co-morbidities associated with increased odds ratio of mortality – – Alcohol related (4.6;HCV and 3.7;HBV) HIV co-infection (1.8;HCV and 4.0;HBV) Holmberg SD , et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 243 Future Burden of Hepatitis C Related Morbidity and Mortality in the US • Markov model of health outcomes • Of 2.7 M HCV infected persons in primary care — 1.47 M will develop cirrhosis — 350,000 will develop liver cancer — 897,000 will die from HCV-related complications • Incur expenses — $24.7 productivity losses — $179.53 per person in primary care — $33.3 billion medical costs 1 Rein et al Dig Liver Dis 2010 Treatment of chronic hepatitis can save lives SVR for HCV reduces HCC, ESLD, and death Survival in HCV GT 1 VA members after treatment Backus Clin Gastro 2011; Imazeki Hepatology 2003; Shiratori Ann Intern Med 2005; Veldt et al Ann Intern Med 2007; Berenguer Hepatology 2009; HCV treatment with IFN/RBV is not effective due to contraindications: National VA cohort Kramer et al. J Hepatol. 2011 Jul 12. [Epub ahead of print] HCV treatment: Injection drug users SH Mehta, et al. J Community Health 33 (2008), pp. 126–133 Birth Cohort Screening to be adopted in the US --July 2012 1999-2002 NHANES 6% 5% 4% 3% 2% 1% Age Group (years) Armstrong et al. Ann Intern Med, 2006 55+ 50-54 45-49 40-44 35-39 0% 20-34 Overall 4.3% Men 6.2% Blacks 9.4% Black men 13.6% Women 6-19 65.6% born in 1945-1964 Men 7% ALL - 8% Prevalence of an -HCV HCV prevalence - chronic 1.3% (3.2 mil) DHHS/CDC Response ~ 2012 • July 2012: Revise CDC guidelines to promote early detection • • • • Confirm active HCV infection (HCV PCR, core antigen) Routine and periodic testing of persons with transmission risks ( e.g. IDU) Routine one –time testing of subpopulations of high prevalence [e.g., birth cohort 1946-1964] ) of HCV disease – Integrate HCV and HIV screening in STD clinics, drug outreach, prisons, • Improve training of clinicians in viral hepatitis screening, management, and care • Support models and standards of care that promote linkage of HCV screening with medical management and treatment services Brown H, J Clin Gastroenterol 2008 US Investment in Viral Hepatitis Lags Far Behind Edlin Nature 2011 Viral Hepatitis: Prevention and Control The Global Perspective HBV and HCV is a leading cause of death: A global perspective 7 5 HIV HBV + HCV Measles RSV, Rota Flu Dengue 4 HPV Log10 Global Death Rate 6 3 2 1 Tobacco Malaria Road accidents Non-HIV TB Hospital infection Suicide West Nile SARS Ebola Polio Hanta vCJD Caused by Viruses Other Causes Global Death Rate Adapted by permission from Macmillan Publishers Ltd: Nature Medicine. Weiss RA, et al;10(12 suppl):S70-S76, copyright 2004. Burden of Chronic Viral Hepatitis HCV HBV 350,000,000 infected Cirrhosis Chronic hepatitis 170,000,000 infected HCC www.ncbi.nlm.nih.gov; Yu X Virology 2007 Burden of Chronic Viral Hepatitis HCV HBV Chronic hepatitis Cirrhosis 446,000 deaths HCC Perz, J Hepatol 2006; www.ncbi.nlm.nih.gov; Yu X Virology 2007 Burden of Chronic Viral Hepatitis HCV HBV Chronic hepatitis Cirrhosis Perz J Hepatol 2006; www.ncbi.nlm.nih.gov; Yu X Virology 2007 HCC 483,000 deaths Burden of Chronic Viral Hepatitis 929,000 Deaths/year HCV HBV Chronic hepatitis Cirrhosis HCC WHO 2008; Perz J Hepatol 2006; www.ncbi.nlm.nih.gov; Yu X Virology 2007 Worldwide HCV Prevalence Hepatitis C Deaths (2008) Hepatitis B Deaths (2008) Absolute Poverty (< 2 dollars day) Prevention: Unsafe health-care injections • World wide, unsafe injections account for an estimated: Dangerous practices at Las Vegas endoscopy clinic called 'baffling' – 30% of hepatitis B infections – 24% of hepatitis C infections – 27% of liver cancer – 24% of liver cirrhosis deaths http://www.who.int/healthinfo/global_burden_disease/GlobalHealthRisks_report_part2.pdf Prevention: Injection drug use Global Heroin Use (UNDOC) Prevention: HBV vaccine • WHO position paper on Hepatitis B vaccines • Infant programs in 177 countries – 69% of 2008 birth cohort received 3 doses • Only 27% within 24 hours – All infants should receive their first dose as soon as possible after birth (< 12) Decreased Incidence of HCC in Hepatitis B Vaccinees: A 20-Year Follow-up Study Group Personyears No. of HCCs RR (95% CI) 1.00 (referent) No Vaccine 78,496,404 444 Vaccine 37,709,340 64 Chang M-H, et al J Natl Cancer Inst 2009 0.31 (0.24 -0.41) Can we make an effective HCV vaccine? • Challenges parallel to HIV – Highly diverse virus – Unsafe to use live attenuated or killed virus – Vectors to deliver viral antigens in a system that induces robust innate and adaptive immune responses • Preexisting vector immunity limits responses rs12979860 C IL-28B allele associated with higher probability of natural clearance of HCV Thomas DL, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009; 461(7265):798 Protection from Persistent HCV p = 0.001 compared to initial infection Osburn et. al. Gastroenterolgy 2010;138:315–324 (P =.001) Shorter duration of viremia during reinfection Osburn et. al. Gastroenterolgy 2010;138:315–324 Preventing pre-existing anti-vector immunity from limiting vaccine efficacy • Okairos search for novel adenoviral strains in chimpanzees worldwide • Goals: Discover adenoviral vectors that are • Highly immunogenic • Easily manufactured to high titers • Not stimulating cross reactive immunity (humans rarely exposed) • Success: • Adenoviruses derived from chimpanzees (ChAd) differ from human adenovirus primarily in hexon (surface) proteins, making Ab cross reactivity low • many are highly immunogenic HCV Vaccine Healthy Volunteer Trial • AdCh3NS and Ad6NS are highly potent (> 1400 SFU/million PBMC; IFN- ELISpot) following a single injection. • At the highest dose all individuals responded to vaccination. • The majority of subjects developed responses against multiple HCV proteins. • Polyfunctional CD4 and CD8+ T cells are induced. • AdCh3NS and Ad6NS are safe and well tolerated at all tested doses. Barnes et. al. Science Translational Medicine 2012 HLA class-I pentamer (KLSGLGINAV) High frequencies of HCV Specific CD8 T cells 10 5 10 0% 10 5 4 10 10 3 10 2 0 7.18% 10 5 4 10 10 3 10 2 0 0 10 2 10 3 10 4 10 5 0.83% 10 5 4 10 10 3 10 2 0 0 10 2 10 3 10 4 10 5 6.24% 10 5 4 10 4 10 3 10 3 10 2 10 2 0 0 10 2 10 3 10 4 10 5 1.52% 0 0 10 2 10 3 10 4 10 5 0 10 2 10 3 10 4 10 5 CD8+ % Pentamer positive CD8 (KLSGLGINAV) 10 B 1 0.1 0.01 4 weeks post prime Ad1 prime (TW4 or 8) (TW0) Barnes et. al. Science Translational Medicine 2012 Ad2 boost (TW 8 or 24) 4 weeks post boost (TW 12 or 28) Final time point (TW 36 or 52) HCV Prophylactic Vaccine Based on Sequential Use of AdCh3and MVA with NS • Cross reactivity of AdCh3 with human antiadenovirus Abs is 12% • MVA boosts well in Phase I trials • Double-blinded, randomized, placebocontrolled two stage study. • Subjects: HCV Ab and RNA negative, active IDU’s at high risk for HCV, 18 -45 y.o. • Two Sites (UCSF, JH) W0 W8 AdCh3 2.5 x1010vp MVA 1.8x108pfu W = week W50 = test immune response HCV treatment: Heterogeneity in Europe J Hepatol. 2008 Oct;49(4):528-36. HCV Treatment: Limited availability in many regions Progress toward HCV eradication will be limited by delivery Thomas Lancet 2010 Improvements in HCV Detection, Care and Therapy Needed to Reduce Future Increases in HCV Mortality -8% -18% Deaths -37% Deuffic-Burban, J Viral Hepatitis 2007. Difficult challenges to addressing the global burden of disease due to viral hepatitis • Societal – – – – Poverty Competing priorities (e.g., HIV, malaria, Tb) Indifference (e.g., IDUs) Health systems – reimbursement; doctors • Individual – Medical and psychiatric comorbidities – Indifference (asymptomatic disease) • Therapeutic – – – – Cost Toxicity Effectiveness Delivery (injection, cold-chain packaging ) Geopolitical Solutions are needed • HIV is well funded because there is political will – – – – public health importance economic impact celebrities advocacy groups Expanding Global Update of HIV Treatment HIV related mortality was reduced in countries with PEPFAR programs Bendavid Ann Intern Med 2009 Global AIDS-related Deaths Estimated number of AIDS-related deaths with and without antiretroviral therapy, globally, 1996–2008 3.0 Number (millions) 2.5 2.0 1.5 1.0 0.5 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Year No antiretroviral therapy At current levels of antiretroviral prophylaxis UNAIDS: 2009 AIDS epidemic update; UNAIDS.org Prevention and control depends on political and societal commitment • Prevention – Safer needle use, no reuse, and/or abuse – Vaccine • Control – Detection – Treatment can cure infected individuals • Safe, oral therapies • Lower cost – Treatment can reduce transmission by curing active IDUs