HEPATITIS C: GENOTYPES IN U.S. GENOTYPE 1A 37% GENOTYPE 1B 30% GENOTYPE 2 10% GENOTYPE 3 6% OTHER OR MIXED 9% INDETERMINATE 5%
Sources of Infection for Hepatitis C Previously Acquired (<1990s) Transfusion 10% Sexual 18% Other 1%* Unknown 9% Injection Drug Use 68% Unknown 10% Other 1%* Sexual 15% Injection Drug Use 60% * Other includes nosocomial, iatrogenic, perinatal Occupational 4% Occupational 4% Newly Acquired (1995-2000) Sources: Based on Sentinel Counties, NHANES III
Sexual Transmission CDC estimates risk between spouses: ~ 3% CDC estimates risk between spouses: ~ 3% Most share other HCV risk factors Most share other HCV risk factors Italian study: Italian study: Both partners (+) in 32/311 (10.3%) of couples Both partners (+) in 32/311 (10.3%) of couples Infected couples shared risk factors Infected couples shared risk factors 8 had same strain 8 had same strain Stroffolini Am J Gastro 2001
HCV PREVALENCE BY SELECTED GROUPS IN U.S. Hemophilia Injecting drug users Surgeons Hemodialysis Average Percent Anti-HCV Positive Gen population adults Military personnel STD clients Pregnant women
Future Prevalence of HCV 0 1.0 2.0 3.0 4.0 19601970198019902000201020202030 Years Prevalence of HCV Infection Percent Armstrong GL, Alter MJ, McQuillan GM, Margolis HS. The past incidence of hepatitis C virus infection: Implications for the future burden of chronic liver disease in the United States. Hepatology. 2000;31:777-782. Individuals infected at any time Individuals infected for > 20 years
HCV Testing Routinely Recommended Based on increased risk for infection Ever injected illegal drugs Received clotting factors made before 1987 Received blood/organs before July 1992 Ever on chronic hemodialysis Evidence of liver disease Based on need for exposure management Healthcare, emergency, public safety workers after needle stick/mucosal exposures to HCV-positive blood Children born to HCV-positive women Adapted from Hepatitis Slide Kit http://www.cdc.gov/ncidod/diseases/hepatitis/slideset. Accessed 01/18/03.
Routine HCV Testing Not Recommended (Unless Risk Factor Identified) Health-care, emergency medical, and public safety workers Pregnant women Household (non-sexual) contacts of HCV- positive persons General population Adapted from Hepatitis Slide Kit http://www.cdc.gov/ncidod/diseases/hepatitis/slideset. Accessed 01/18/03.
HCV RNA Serologic Pattern of Acute HCV Infection with Progression with Recovery 12345 6 123 4 0 Months Years Titer Time after Exposure ALT anti-HCV Normal Symptoms +/- Adapted from MMWR 1998; 47(No. RR19)
Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection Normal HCV RNA Symptoms +/- 12345 6 123 4 0 Months Years Titer Time after Exposure ALT anti-HCV Adapted from MMWR 1998; 47(No. RR19)
Histological Data: Normal vs. Elevated ALT Normal ALT ML Shiffman et al. J Infect Dis. 2000; 182:1595-1601. Elevated ALT Portal No Fibrosis Mild Cirrhosis Bridging 23% 40% 6% 6% 26% Portal NoFibrosis Mild Cirrhosis Bridging 19% 19% 22% 16% 24%
Stage 0 Stage 2 Stage 3 Stage 4 CIRRHOSIS DIAGNOSING CIRRHOSIS LIVER BIOPSY ALL OF THESE PATIENTS MAY HAVE THE SAME ALT
Pegylated Interferon Two brands of Peg-INF Two brands of Peg-INF Weight based Weight based Standard dose Standard dose Administered once a week Administered once a week
Pegylated Interferon Side Effects: Side Effects: Fevers, chills, sweat, muscle aches, fatigue, weight loss, hair loss Fevers, chills, sweat, muscle aches, fatigue, weight loss, hair loss Neutropenia, thrombocytopenia Neutropenia, thrombocytopenia Psychiatric Disorders Psychiatric Disorders Thyroid abnormalities Thyroid abnormalities Worsening of: Worsening of: Diabetes Diabetes Autoimmune conditions Autoimmune conditions Decompensation of liver disease Decompensation of liver disease
Ribavirin Taken twice a day Taken twice a day Side Effects Side EffectsAnemiaRash Can’t be used in the setting of renal dysfunction Can’t be used in the setting of renal dysfunction Warning: Warning: Severe birth defects Severe birth defects 2 types of birth control 2 types of birth control
Contraindications to Treatment Advanced liver disease Advanced liver disease Child’s B-C cirrhosis Child’s B-C cirrhosis Severe psychiatric disease Severe psychiatric disease Severe cardiac/pulmonary disease Severe cardiac/pulmonary disease Pregnancy Pregnancy Severe neutropenia, thrombocytopenia Severe neutropenia, thrombocytopenia Renal failure Renal failure
Old HCV Therapy Treatment response: Treatment response: SVR (sustained virologic response) SVR (sustained virologic response) HCV RNA negative 6 months after d/c of therapy HCV RNA negative 6 months after d/c of therapy Relapser Relapser HCV RNA negative at the end of treatment, but + 6 months after end of treatment HCV RNA negative at the end of treatment, but + 6 months after end of treatment Non-responder Non-responder Never achieved negative HCV RNA Never achieved negative HCV RNA
Undetectable Non-responsive Relapse SVR Weeks HCV RNA (log IU/mL) 02448-8 Genotype 2/3 Virological Responses to Interferon-Based Therapy Adapted from Lindsay KL. Hepatology. 2002;36:S114-S120. Genotype 1 PEG-IFN and RBV
HEPATITIS C: PREDICTORS OF RESPONSE TO THERAPY Genotype (2, 3 > 1) Viral load (< 2 million) Lower body weight Decreased fibrosis Female Age < 40 Absence of co-infection Race
Genotype 1, >2M copies 51% Non-1, <2M copies 8% Non-1, >2M copies 19% Genotype 1, <2M copies 22% Genotypes and Viral Titer: US Patients Adapted from McHutchison JG et al. N Engl J Med. 1998;339:1485-1492.
Week 4 Week 12 Week 24 Partial Null Week HCV RNA (-) SVR (% Ferenci P, et al. J Hepatology. 2005;43(3):425-433. % of Treated Patients Achieving Undetectable HCV RNA at Various Time Points Rate of SVR
SVR Rates with PEG-IFN /RBV According to Genotype Genotype Non-1 Genotype 1 Strader DB et al. Hepatology. 2004;39:1147-1171. SVR (%) 42%-46%42%-46% 76%-82% 76%-82%
Treatment of Hepatitis C in African Americans: SVR Virological Response Rates (%) 1. Muir AJ et al. N Engl J Med 2004;350:2265-2271. 2. Jeffers LJ et al. Hepatology 2004;39:1702-1708. 12 n=100 n=78n=28 Peg-IFN -2b Peg-IFN -2a
100 75 50 25 0 European- Americans African- Americans HispanicsCombined T/T T/C C/C SVR (% of Patients) Reprinted by permission from Macmillan Publishers Ltd: Ge D, et al. Nature. 2009;461(7262):399-401. Copyright 2009. Genotype: P<0.0001P=0.002P=0.004P<0.0001
80 70 60 50 40 30 20 10 SVR (%) 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 rs1297980 C-allele frequency African-Americans (n=61) Hispanics (n=16) European-American (n=271) East Asians (n=107) Ge D, et al. Nature. 2009;461(7262):399-401.
Peg-INF/Ribavirin/Protease Inhibitor Only approved for Genotype 1 Only approved for Genotype 1 Very little benefit shown for genotype 2/3 Very little benefit shown for genotype 2/3 Not FDA approved for post-transplant recipients Not FDA approved for post-transplant recipients Not studied in co-infected populations (HBV, HIV) Not studied in co-infected populations (HBV, HIV)
Protease Inhibitors MUST NEVER be taken as monotherapy MUST NEVER be taken as monotherapy MUST be taken every 8 hours MUST be taken every 8 hours Imperative that patient’s are compliant Imperative that patient’s are compliant Success of therapy can be predicted by prior response to therapy Success of therapy can be predicted by prior response to therapy Relapsers do better than non-responders Relapsers do better than non-responders
Incivek (Telaprevir) Taken for the first 12 weeks of treatment Taken for the first 12 weeks of treatment Taken with fatty foods Taken with fatty foods Side effects Side effects Rash Rash Anemia Anemia Anal pruritus Anal pruritus
Victrelis (Boceprevir) Started 4 weeks after starting pegylated interferon/ribavirin Started 4 weeks after starting pegylated interferon/ribavirin Taken during the rest of treatment Taken during the rest of treatment Side effects: Side effects: Anemia Anemia Nausea/vomiting Nausea/vomiting
SUMMARY (1) Hepatitis C is prevalent Hepatitis C is prevalent Multiple genotypes with geographic distribution Multiple genotypes with geographic distribution Recognize risk factors Recognize risk factors The presence of Hepatitis C viral RNA indicates active infection The presence of Hepatitis C viral RNA indicates active infection Can range from spontaneous clearance to cirrhosis necessitating liver transplant Can range from spontaneous clearance to cirrhosis necessitating liver transplant
SUMMARY (2) Liver biopsy is the best predictor of prognosis Liver biopsy is the best predictor of prognosis Genotype, viral load and IL28b are best predictors of response to therapy Genotype, viral load and IL28b are best predictors of response to therapy Interferon in combination with ribavirin and protease inhibitors are the standard of care for genotype 1 (protease inhibitors not necessary in genotypes 2/3) Interferon in combination with ribavirin and protease inhibitors are the standard of care for genotype 1 (protease inhibitors not necessary in genotypes 2/3) Next advance will be polymerase inhibitors Next advance will be polymerase inhibitors