Hepatitis C Presentation, CDC, 2014
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CDC PUBLIC HEALTH GRAND ROUNDS The 25th Anniversary of the Discovery of the Hepatitis C Virus Looking Back to Look Forward June 17, 2014 1 The Epidemiology of Hepatitis C How Did We Get Here? John W. Ward, MD Director, Division of Viral Hepatitis National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention 2 Key Contributors to the Discovery of HCV Harvey Alter 3 Daniel Bradley Discovery of Hepatitis C Virus (HCV) Discovered in 1989, RNA virus, family Flaviviridae 9,600 nucleotide genome-single polyprotein Structural proteins Non-structural proteins - viral replication and targets of therapy High genetic diversity leads to intra-host variants “quasispecies” 7 major genotypes that predict treatment response Genotype 1 accounts for ~ 70% of infections in US No vaccine candidates for licensure Serine protease RNA helicase Lindenbach BD, Fields Virology 2001. Simmonds P, Hepatology 1995. Irshad M, Hepatogastroenterology 2010. Manos MM, J Med Virol 2012. 4 Global Burden of HCV Infection, 2005 135 million persons living with HCV 500,000 deaths per year HCV: Hepatitis C virus. Estimated from: Hanafiah K, Hepatology 2012. Lozano R, Lancet 2012. 5 Prevalence of Current HCV Infection Among Persons in the United States Prevalence in United States ~3 million NHANES prevalence estimate 2.7 million individuals (2.2-3.2 million) 1.0% (0.8%-1.2%) Civilian, non-institutionalized populations Non-NHANES prevalence estimate 360,000-840,000 22%-52% of those incarcerated Homeless or incarcerated persons NHANES: National Health and Nutrition Examination Survey. Denniston M, Ann Int Med 2014. Chak E, Liver Int 2011. 6 Impact of Prevention Measures on HCV in United States 20 18 1986 Indirect blood screening for HCV and HIV prevention measures 16 14 12 10 8 6 4 Anti-HCV test licensed 1992 1992199219 Needlestick Safety Discovery and Prevention Act of HCV 2001 1 111989 2 0 Year 22,000 new cases reported in 2012 Jagger J, J Infect Dis Pub Health 2008. Ward JW. Clin Liver Dis, 2013. CDC.gov/hepatitis 7 Recent Increases in HCV Infection Between 2007 and 2012 50% increase in case reporting 200% increase in 17 states Risk factors ~ 70% persons who inject drugs Previous oral prescription narcotic use Equally male to female Young, ages 18 to 29 years Rural and suburban White PWID: Persons who inject drugs. 8 CDC unpublished data. HCV Transmission Among Persons Who Inject Drugs (PWID) Transmission risks Injection duration Injection frequency Equipment sharing, not just sharing needles HIV HCV HCV prevalence 27 to 51% Incidence declined in response to harm reduction for HIV (e.g., syringe access programs) Burt, J Urban Health 2007. Garfein R, J Urban Health 2013. Keen L, Addict Behav 2014. Amon JJ, Clin Infect Dis 2008 Kwon J, AIDS 2009. 9 Other Modes of HCV Transmission Accidental needle stick in healthcare setting HCV risk is 1.3%, HIV risk is 0.3% 18 healthcare-associated outbreaks from 2008 to 2013 223 cases involving over 90,550 at-risk persons notified Non-injecting drug use (e.g., intranasal cocaine use) Perinatal-infants born to HCV infected mothers ~4% risk if mother infected with HCV ~25% risk if mother co-infected with HCV and HIV Sexual transmission is rare HIV infected MSM at highest risk Miscellaneous reported Unregulated tattooing MSM: Men who have sex with men. 10 Scheinmann, Drug and Alcohol Dependence 2006. Weinbaum, MMWR 2003. Gough, BMC Public Health 2010. Mast, J Infect Dis, 2005. Marincovich B, Sex Transm Infect 2003. Yaphe S, Sex Transm Inf 2012. Bottieau, Eurosurveillance 2010. Ackerman Z, J Viral Hepat 2000. Tohme RA, CID 2012. MMWR 2001. CDC/hepatitis.gov Natural History of HCV Infection In 20 years, 15-30% progress to cirrhosis Progression accelerated by HIV, HBV, alcohol use, and fatty liver 20 years Liver Transplant or Early Death HIV: Human immunodeficiency virus. HBV: Hepatitis B virus. Hepatocellular carcinoma = Liver cancer. Decompensated Cirrhosis = End stage liver disease. 11 Ly KN, Clin Infect Dis. 2014. Mahajan R, CID 2014 . Mortality from HCV is Increasing From 1999 to 2010, HCV deaths increased by 50% In 2010, 16,600 deaths Mean age at death was 59 years Two-fold increased mortality risk Black non-Hispanic American Indian/Alaskan Natives Mortality is under estimated Only 33% of liver-related deaths among HCV infected persons are reported on Vital Records At least 45-60% are not aware of their HCV infection Ly KN, Clin Infect Dis 2014. Mahajan R, CID 2014 . 12 The Silent Growing Burden of Hepatitis C in the United States Number of People Of 2.7 million HCV-infected people from NHANES 1.47 million will develop decompensated cirrhosis (DCC) 350,000 will develop hepatocellular carcinoma (HCC) 900,000 will die from HCV-related complications 40,000 Deaths 35,000 30,000 DCC 25,000 HCC 20,000 15,000 10,000 5,000 0 Year NHANES: Nutritional Health DCC: Liver failure. HCC: Liver cancer. 13 Rein D, Dig Liver Dis 2010. Six-fold higher prevalence than other US adults 3.39% vs 0.55% Of all HCV infected US adults, 81% were born in this cohort Of all HCV-related deaths in US, 73% were born in this cohort 1988–1994 1999–2002 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 0 10 20 30 40 50 7.0 1945 70 1965 6.0 1988–1994 1999–2002 5.0 4.0 3.0 2.0 1.0 0.0 1910 1920 1930 1940 1950 1960 Year of Birth Smith, AASLD Liver Meeting 2011. Armstrong, Ann Int Med 2006. Kramer, Hepatology 2011. Ly, Ann Int Med 2012. 14 60 Age at Time of Survey, y Proportion Anti-HCV-Positive, % Historical high incidence Proportion Anti-HCV-Positive, % The Birth Cohort: People Born during 1945 to 1965 1970 1980 1990 One time Testing for HCV for Persons Born 1945-1965 Recommended by CDC in 2012 and USPSTF in 2013 Screening recommendation is solely based on year of birth, not on risk factors Clinicians may be reluctant to ask about risks Patients may be reluctant to disclose or may not recall risks Persons found to be HCV infected need to link to care and treatment 15 USPSTF: U.S. Preventive Services Task Force. MMWR Aug 2012. Moyer VA, Ann Int Med 2013. Shehab TM, J Viral Hepat 2001. Shehab TM, Am J Gastroenterol 2003. Serrante JM, Fam Med 2008. Shehab TM, Hepatology 1999. Roblin, Am J Man Care 2011. Spradling, Hepatology 2012. Zapata, Ann Hepatology 2010. Napper, AIDS Behav 2010. Haley, Preven Med 2002. Torrone, AIDS Pat Care 2010. Rein D, Ann Int Med 2012. Eckman, CID, 2013. McEwan, Hepatology 2013. McGarry, Hepatology 2012. Liu S, Plos One 2013. Continued Risk-based Recommendations for HCV Screening Risk-based screening Major risk-past or present injection drug use Other risks Received blood/organs prior to June 1992 Received blood products made prior to 1987 Ever on chronic hemodialysis Infants born to HCV-infected mothers Intranasal drug use Unregulated tattoo History of incarceration Medical Persistently elevated ALT HIV USPSTF: U. S. Preventive Services Task Force. ALT: Alanine transaminase. 16 MMWR Aug 2012. Moyer VA, Ann Int Med 2013. Benefits of Birth Cohort Testing The Birth Cohort urgently needs to be identified to allow them the opportunity to be diagnosed and treated Reduces risks of all-cause mortality by 50% Reduces risks of hepatocellular carcinoma by 70% Rein D, Ann Int Med 2012. Eckman, CID, 2013. McEwan, Hepatology 2013. McGarry, Hepatology 2012. Liu S, Plos One 2013. 17 HCV Testing Cost Effectiveness Cost per Quality Adjusted Life Year Gained 60,000 50,000 40,000 HCV Therapy 2014* HCV Therapy 2012 30,000 20,000 10,000 0 *CDC unpublished data. TVR: Telapravir. http://www.prevent.org/National-Commission-on-Prevention-Priorities/Rankings-of-Preventive-Services-for-the-US-Population.aspx Rein D, Ann Int. Med 2012. 18 Improving the Continuum of Care for HCV Management ~ 3 million persons living with HCV in the United States Current cure rates need to improve 120% 100% 80% 50% 60% 38% 23% 40% 11% 20% 6% 0% All HCV infected anti-HCV tested HCV care SVR: Sustained viral response. Holmberg S, NEJM 2013. 19 HCV RNA Treated SVR Where Are We Now? The burden of HCV-related disease is large Reports of new HCV infections are increasing CDC and USPSTF recommend HCV testing for persons Born during 1945 to 1965 Who inject drugs, past or present Others at risk At least half of HCV-infected person are unaware of status Access to HCV testing, care, and treatment must improve for patients to benefit from advances in therapy 20 Know More Hepatitis Campaign Times Square, May 2014 21 Hepatitis C: The Curative Era David Thomas, MD Stanhope Bayne Jones Professor of Medicine Chief of Infectious Diseases Johns Hopkins School of Medicine 22 Hepatitis C Treatment Responses Non-Response, Relapse, Sustained Viral Response HCV RNA serum levels Non-Response (Null) Treatment Non-Response (Partial) Relapse Interval Sustained Viral Response (SVR) Non-Response Relapse SVR AASLD HCV Treatment Guidelines, www.aasld.org 23 SVR is Considered Cure Reinfection is Uncommon Percent with 5-year SVR 5-year estimate of continued sustained viral response: 99.2% (95% CI 98.1%-99.7%) N=636 SVR: Sustained viral response Swain, Gastro 2010. Manns, J Viral Hep 2014. 24 SVR is Considered Cure Reduction in Liver Failure Van der Meer, JAMA 2012. Backus, Clin Gastro 2011. Imazeki, Hepatology 2003. Shiratori, Ann Intern Med 2005. Veldt, Ann Intern Med 2007. Berenguer, Hepatology 2009. 25 SVR is Considered Cure Reduction in Hepatocelluar Carcinoma Van der Meer, JAMA 2012. Backus, Clin Gastro 2011. Imazeki, Hepatology 2003. Shiratori, Ann Intern Med 2005. Veldt, Ann Intern Med 2007. Berenguer, Hepatology 2009. 26 SVR is Considered Cure Reduction in All-Cause Mortality Van der Meer, JAMA 2012. Backus, Clin Gastro 2011. Imazeki, Hepatology 2003. Shiratori, Ann Intern Med 2005. Veldt, Ann Intern Med 2007. Berenguer, Hepatology 2009. 27 Key Therapeutic Milestones in Reaching the Curative Era of HCV FDA Approval of HCV Treatments 1991 Interferon (IFN) 1998 IFN and ribavirin 2001 Pegylated IFN 2011 Boceprevir and telaprevir 2013 Sofosbuvir and simeprevir 28 Thomas, Nat Med 2013. High Rate of SVR Sofosbuvir, PegIFN, and Ribavirin for 12 weeks Percent maintaining SVR 12 weeks after end of therapy 100 98 92 90 87 87 Non-CC Black 91 80 80 70 60 50 40 30 20 10 0 F0-3 F4 IL28B CC PegIFN; pegylated interferon. F0-3: Stages of liver fibrosis from none to moderate. F4: Severe liver fibrosis. Non-CC: Individuals with either CT or TT IL28-genotype. 29 Lawitz, NEJM 2013. Latino High Rate of SVR for Genotype 1 HCV Ledipasvir (LDV) and Sofosbuvir (SOF) LDV/SOF naive F0-2, naive SVR12 Non-VF Relapse 100% Percent maintaining SVR 12 weeks after end of therapy LDV/SOF prior treatment, 20% cirrhosis SVR12 Non-VF Relapse 100% 90% 80% 80% 70% 60% 60% 50% 40% 40% 30% 20% 20% 10% 0% 0% LDV/SOF 8W, 215 LDV/SOF/R 8W, 216 LDV/SOF 12W, 216 LDV/SOF LDV/SOF/R LDV/SOF LDV/SOF/R 12W, 109 12W, 111 24W, 109 24W, 111 SVR12: Sustained Viral Response for 12 weeks. Non-VF: Non-virologic treatment failure. 8W: 8 weeks of therapy. 12W: 12 weeks of therapy. 24W: 24 weeks of therapy. R: Ribavirin. 30 Kowdley NEJM 2014. Afdhal, NEJM 2014. SVR with 6 weeks of Sofosbuvir, Ledipasvir, and GS-9669 or GS-9451 SVR12 Relapse Percent maintaining SVR 12 weeks after end of therapy 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% SOF/LDV 8W N=20 SOF/LDV/9669 6W N=20 SOF/LDV/9451 6W N=20 SVR12: Sustained Viral Response at 12weeks. SOF: Sofosbuvir. LDV: Ledipasvir. 8W: 8 weeks. 6W: 6 weeks. 31 Kohli, Poster 27LB, Conference on Retroviruses and Opportunistic Infections 2014. NCT01431898. NCT01805882. Fewer Adverse Events with Newer Therapies Events Telaprevir, Peg, R n=292 Boceprevir, Peg, R n=205 Serious adverse event (SAE) 132 (45%) 67 (33%) Premature discontinuation 66 (23%) 54 (26%) Discontinuation due to SAE 43 (15%) 15 (7%) 6 (2%) 6 (3%) 14 (5%) 0 LDV-SOF x 8 wk n=215 LDV-SOF RBV x 8 wk n=216 Serious adverse event (SAE) 4 (2%) 1 (<1%) Discontinuation due to SAE 0 1 (<1%) Hepatic decompensation Serious rash Events Peg=Pegylated interferon. R=Ribavirin. LDV=Ledipasvir. SOF=Sofosbuvir. 32 Hezode J Hepatol 2013. Knowdley, NEJM 2014. Rapid Progress in Interferon-sparing HCV Treatment Genotype 1 *Simeprevir and sofosbuvir (not FDA approved, filed) *Sofosbuvir and ribavirin (alternative) Sofosbuvir and ledipasvir (filed) ABT 450/r, ombitasvir, dasabuvir, +/- ribavirin (filed) Daclatasvir and asunaprevir (filed) MK5172, MK8742, +/- ribavirin (phase 3) Genotype 2 and 3 *Sofosbuvir and ribavirin *the individual components of these regimens are already available in June 2014. 33 Expert Guidelines for HCV Screening, Management and Treatment Copyright © 2014 by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. 34 Evaluating the Cost Effectiveness of New Therapies In 2011, average wholesale acquisition costs of drugs alone were $32,000 to over $100,000 Quality adjusted life years for those regimens considered reasonable New regimens are $100,000 to $175,000 in US Incremental cost benefits have been demonstrated Evaluating cost effectiveness of new regimens also has to reflect the increased efficacy of the treatment (cost/cure) 35 Rein Ann Intern Med 2012 and unpublished data. Younoussi, J Hepatol 2014. Hagan, Hepatology 2014. Linas, AIDS 2014. Deuffic-Burban, J Hepatol 2014. Brogan, Plos One 2014 . Steady Progress in Treatment Efficacy Has Increased the Proportion of Persons Who Are Cured All oral PegIFN, RBV, and protease inhibitor PegIFN and ribavirin IFN and ribavirin IFN 36 Thomas, Nat Med 2013. Greater Uptake Will Maximize Potential Global Impact 135 million 2013 % cured 2011 2004 Lack of expanded use in infected people 1998 1991 % treated 37 Thomas, Nat Med 2013. Conclusions: HCV Curative Era HCV can be cured Curing HCV reduces mortality and morbidity Curing HCV reduces the risk of HCV transmission Major challenges to global control are screening and testing and lack of treatment access 38 Steps Toward Ending Hepatitis C in the US Phillip Coffin, MD, MIA Director of Substance Use Research San Francisco Department of Public Health University of California San Francisco 39 Essential Goals to Eliminate HCV Prevent sequelae of advancing liver disease in those already infected Baby Boomers, born 1945-1965 Many don’t know they are infected Prevent new or “incident” infections Persons who inject drugs (PWID) Unsafe healthcare practices Sexual exposures in immunocompromised individuals 40 Continuum of Care Model for HIV Primary Prevention Screening and Testing Diagnosis Management Linkage Treatment Engagement / Retention Engagement / Retention Adapted from: Das M, Conference on Retroviruses and Opportunistic Infections 2014. 41 Virologic Suppression Long-term Reduction in Prevalence and Incidence of HIV Continuum of Care Model for HCV Primary Prevention – Syringe Exchange, Condoms, Substance Use Treatment Screening and Testing Diagnosis Management Linkage Treatment Engagement / Retention Cure Engagement / Retention HCV screening test Screening tests would be opt-out EHR designed to have automated reminders Healthcare-level tracking to ensure baby boomers get screened Adapted from: Das M, Conference on Retroviruses and Opportunistic Infections 2014. 42 Long-term Decrease in Prevalence and Incidence of HCV Continuum of Care Model for HCV Screening and Testing Diagnosis Management Linkage Treatment Engagement / Retention Cure Engagement / Retention Long-term Decrease in Prevalence and Incidence of HCV RNA confirmatory testing Staging of fibrosis Simplify two-step process of screening then RNA confirmatory through reflexive testing Healthcare level systems could match positive screens to ensure follow-up testing Public health systems cannot track follow-up testing, negative test results not reportable Evaluate effectiveness of screening efforts by comparing to stage of fibrosis at diagnosis Adapted from: Das M, Conference on Retroviruses and Opportunistic Infections 2014. 43 Continuum of Care Model for HCV Screening and Testing Diagnosis Management Linkage Treatment Engagement / Retention Cure Engagement / Retention Long-term Decrease in Prevalence and Incidence of HCV Screening for syndemics, Vaccination, Risk-reduction counseling, Evaluation for treatment including liver function, Genotyping Patient management should include referral to substance use disorder treatment and brief alcohol interventions Healthcare-level systems could track serial ALT to ensure periodic evaluation is done ALT: Alanine transaminase. Syndemic infections include Hepatitis A, Hepatitis B and HIV. Adapted from: Das M, Conference on Retroviruses and Opportunistic Infections 2014. 44 Continuum of Care Model for HCV Screening and Testing Diagnosis Management Linkage Treatment Engagement / Retention Cure Engagement / Retention Long-term Decrease in Prevalence and Incidence of HCV Serial RNA measurements Historically, treatment uptake was major barrier New regimens should improve treatment uptake New barriers such as cost and access may limit potential impact of new regimens Interventions could address these new barriers If negative RNA results were reportable, public health systems could track SVR SVR: Sustained viral response. 45 Adapted from: Das M, Conference on Retroviruses and Opportunistic Infections 2014. Continuum of Care Model for HCV Screening and Testing Diagnosis Management Linkage Treatment Engagement / Retention Sustained viral response (SVR) is monitored through repeated negative RNA results over time Healthcare systems could track this data Public health systems cannot track unless negative RNA results become reportable Adapted from: Das M, Conference on Retroviruses and Opportunistic Infections 2014. 46 Cure Engagement / Retention SVR vs. re-infection monitoring through RNA measurements Long-term Decrease in Prevalence and Incidence of HCV Potential Reduction in HCV-Related Liver Deaths from Expanded Screening and Treatment Regimens Annual number of HCV-related liver deaths / 2008 U.S. adult population 40000 Old regimens and old screening Old regimens and new screening New regimens and old screening New regimens and new screening 35000 30000 25000 20000 15000 10000 2015 5 2020 10 2025 15 2030 20 2035 25 Years after intervention Coffin, CID 2012 (modified for new treatment regimens, direct-acting agents). 47 2040 30 Potential Reduction in HCV-Related Liver Deaths by Treatment Strategy based on Liver Fibrosis Annual number of HCV-related liver deaths / 2008 U.S. adult population 40000 Old regimens and old screening New Rx limited to F4 New Rx limited to F3-4 New Rx limited to F2-4 New Rx all stages, new screening 35000 30000 25000 20000 15000 10000 2015 5 2020 10 2025 2030 2035 15 20 25 Years after intervention F2-F4: Stages of liver fibrosis including moderate (F2), severe (F3), and cirrhosis (F4) Coffin, CID 2012 (modified for novel direct-acting agents). 48 2040 30 Expanding Treatment in Primary Care to Meet Demand New therapies are 8-12 weeks, all-oral, with minimal side effects HCV specialists 2,335 US-based AASLD members in 2010 Only 5,200 unique prescribers of HCV therapeutics for January-March 2014 Primary care & other providers 209,000 practicing PCPs in 2010 Similar SVR with ECHO support for IFN-based Rx 9,000 IDSA members in 2013 49 AASLD: American Association for the Study of Liver Diseases. IDSA: Infectious Diseases Society of America. IFN: Interferon. ECHO: Extension for Community Healthcare Outcomes. Rustgi, Hepatology 2008. Arora, NEJM 2011. Centers for Medicare and Medicaid. Strategies to Prevent New Infections of HCV Major risk factor for new infections is IV drug use Largest numbers of new infections are in PWIDs Strategies to reduce HCV in PWIDs Syringe access programs and education programs Treatment as Prevention (TasP) Medication-assisted treatment for substance use disorder Low threshold methadone treatment programs Vaccine research Early Phase 2 stages PWIDs: Persons who inject drugs 50 Syringe Access Programs Impact On HCV Prevalence and Incidence Impact on Prevalence NSP: Needle & syringe program. Kwon J, AIDS 2012. 51 Impact on Incidence Treatment as Prevention (TasP) for HCV Interrupt Secondary Transmission Maximize Impact on Incidence Target active injectors Social network-based recruitment strategy PWID in high prevalence areas Optimize treatment delivery Patient navigation programs Conditional cash transfer programs Directly observed therapy 52 Potential Impact of Treatment as Prevention based on Prevalence Prevalence in many US cities falls close to 50%-65% Treating just 8% of active injectors per year would reduce prevalence by 50% to 90% in 15 years MartinHepatology 2013. 53 Value of Comprehensive Prevention: TasP, Syringe Access and Opioid Substitution TasP: Treatment as prevention. OST: Opioid substitution treatment. HCNSP: Syringe access programming. Martin, Clinical Infectious Diseases 2013. 54 Concerns and Research Needs for HCV TasP Acceptability of new treatments to PWIDs Impact of acute infection on treatment and transmission Drug resistance archiving Efficacy of behavioral interventions to reduce reinfection 55 To Reduce and Perhaps Eliminate HCV Increase priority – widen public recognition of urgency of action Increase screening – follow USPSTF recommended screening Improve testing algorithm – simplify HCV screening and diagnosis Enhance surveillance – change policies to improve utility of data Expand clinical workforce – allow for primary care management Increase treatment availability – modify treatment regimens Reduce payer restrictions – increase number of therapeutics 56 CDC PUBLIC HEALTH GRAND ROUNDS The 25th Anniversary of the Discovery of the Hepatitis C Virus Looking Back to Look Forward 57