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Clinical Advances in Diagnosis, Treatment and Outcome of Hepatitis A, B and C Marc Ghany, M.D. LDB, NIDDK, NIH Demystifying Medicine May 19th, 2009
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Case Presentation A 21 year old male college student presents with abdominal pain, nausea, loss of appetite, yellowing of the skin and darkening of his urine x 2 days. On physical exam he is jaundiced, tender to palpation in the right upper quadrant and his liver is enlarged.
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Some More History… On further questioning: He admits to recent travel to Mexico one month prior to his getting ill He reports eating street food Having a one night relationship with someone he met while on vacation Drinking 6-7 drinks on most nights He denied using acetaminophen (Tylenol), herbal preparations or using injection drugs
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Pertinent Laboratory Results Serum ALT: 1200 IU/ml Serum AST: 1121 IU/ml Serum Alkaline phosphatase 120 IU/ml Total Bilirubin: 7.3 mg/dL Direct Bilirubin: 6.0 mg/dL Abdominal Ultrasound: Enlarged, homogenous appearing liver; No biliary obstruction
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Overview of Hepatitis A, B and C HAVHBVHCV GenomeRNA +sense, single stranded DNA Partially double stranded RNA +sense, single stranded SourceStoolBlood TransmissionEntericPercutaneous/ permucosal Incubation period (days) 15-4530-18015-160 Risk for chronic hepatitis NoYes Risk for HCCNoYes PreventionPre/postexposure prophylaxis Blood donor screening; risk behavior modification
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He Asks “What’s Wrong with Me? How Do We Diagnose Hepatitis A, B or C?
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0123 4561224 IgM anti-HAV Total anti-HAV ALT Jaundice Fecal HAV HAV RNA Months after exposure Normal Serologic Course of Hepatitis A
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Jaundice HBeAg anti-HBe Total anti-HBc IgM anti-HBc anti-HBs HBsAg 0481216 20 242832 36 52100 HBV DNA Weeks after exposure Serologic Course of Hepatitis B
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Jaundice Time after Exposure anti-HCV ALT Normal 012345 61234 YearsMonths HCV RNA Serologic Course of Hepatitis C
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He Asks “Could This Have Been Prevented?” Prevention of hepatitis A Passive immunization with immunoglobulin Pre-exposure prophylaxis –Provides 3-5 months protection –95% effective Post-exposure prophylaxis –>85% effective Active Immunization –2 commercially available vaccines (HAVRIX and VAQTA) –94-100% effective –Safe
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Persons For Whom Hepatitis A Vaccine is Recommended People traveling to or working in countries that have high or intermediate endemicity of infection Men who have sex with men Illicit drug users People who have occupational risk factors for infection People who have clotting factor disorders
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Prevention of hepatitis B Passive immunization-HBIG –immunization Postexposure prophylaxis (perinatal, sexual, household contact of acute case, inadvertent percutenous/permucosal exposure) Active immunization –Two yeast-derived vaccines available –80-95% effective
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Persons For Whom Hepatitis B Vaccine is Recommended People with occupational risk Clients and staff of institutions for the developmentally disabled Hemodialysis patients Recipients of clotting factor concentrates Household contacts and sex partners of HBV carriers Adoptees from countries where HBV is endemic International travelers Injection drug users Sexually active men and women Inmates of long-term correctional facilities
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Prevention of hepatitis C Immunoglobulin ineffective No vaccine available
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The Case Continues… In 4 weeks his jaundice resolves, he feels better and his liver associated enzymes (ALT and AST) improve but have not quite returned to normal He is lost to follow-up
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Scenario 1 He returns to your office 5 years later. He feels well but he went for a physical exam prior to getting life insurance and was denied because of elevated liver associated enzymes. Blood tests reveal the following: HBsAg positive; HBeAg positive; HBV DNA 5 x10 8 copies/ml Serum ALT 150, AST 125 Total bilirubin 1.0, albumin 4.2 g/dl
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Outcome of CHB by phases ALT HBV-DNA 10 9 –10 10 10 7 –10 8 <10 5 >10 5 HBeAg - positive CHBHBeAg – negative CHB Immune escape reactivation inactive carrier state Immune tolerance Immune clearance Immune control immuno activeminimally active low replicative state high replicative state
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Who To Treat?
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Lok AS, et al. Hepatology. 2007;45:507-539. HBeAg Positive HBeAg Negative ALT 2 x ULN Monitor patientHBV DNA > 20,000 IU/mL HBV DNA < 2000 IU/mL HBV DNA ≥ 20,000 IU/mL Treat if persistentMonitor patientTreat if persistent ALT 1-2 x ULN HBV DNA > 20,000 IU/mL Consider biopsy if persistent or > 40 yrs; treat if needed HBV DNA 2000-20,000 IU/mL Consider biopsy; treat if needed ALT 2 x ULN AASLD Guidelines for Initiation of Treatment in Chronic Hepatitis B
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Definitions of Response Virological Full: Decrease in HBV DNA to levels that are undetectable by sensitive PCR assay e.g. < 60 IU/mL Partial: Decrease in HBV DNA by at least 2 logs and to less than 20,000 IU/mL Primary non-response: Decrease in HBV DNA by <2 logs Serological HBeAg seroconversion: Loss of HBeAg with gain of anti-HBe HBsAg seroconversion: Loss of HBsAg with gain of anti-HBs
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Definitions of Response Biochemical Normalization of serum ALT level Histological Decrease in hepatic necroinflammatory score by at least 2 points with no worsening in fibrosis score Complete response Combined biochemical, virological,serological (loss of HBsAg) and histological
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What to Treat With
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1992 2009 and beyond… IFN alfa ADV LdT LAM “The New Era” Oral therapy 1998 2002 2005 ETV PegIFN alfa-2a Combination Rx? 2006 Therapy for Chronic Hepatitis B: 2009 2008 TDF
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Factors Influencing Choice of Therapy Age of patient HBeAg status of patient Stage of disease Co-infection with other hepatotrophic viruses or HIV-1 Presence of co-morbid conditions Efficacy and side effects of therapy Costs associated with therapy Patient’s preference
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Decision to treat IFN (PegIFN alfa-2a) Nucleos(t)ide analogues The First Decision: Choosing What to Treat With
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Advantages and Disadvantages of PegIFN ProCon Finite course of therapySubcutaneous administration No resistanceAdverse effects Higher rate of HBeAg loss at 1 year vs oral drugs HBeAg loss “catches up” with > 1 year oral drugs; prolonged IFN use not feasible Potential for HBsAg clearance with short duration therapy HBsAg clearance also occurs with oral agents
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Favorable predictors of response –Genotype A or B > C or D –Low HBV DNA –High ALT Specific patient demographics –Generally young persons Young woman wanting future pregnancy –Absence of comorbidities Patient preference Concomitant HCV infection Concomitant HIV infection and no indication for HAART When to Consider PegIFN
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Lok AS, et al. Hepatology. 2007;45:507-539. *By PCR based assay (LLD ~ 50 IU/mL) except for some LAM studies. 40-44 21 67 25 69 Patients With Undetectable HBV DNA (%) 60 0-16 Not head-to-head trials; different patient populations and trial designs 76 Virologic Response in HBeAg+ Patients (Undetectable* HBV DNA at Wk 48-52 ) 100 80 60 40 20 0 LAMADVETVLdTTDFPeg- IFN Peg- IFN + LAM PLB
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27* *Response 6 months after stopping treatment. Lok AS, et al. Hepatology. 2007;45:507-539. Heathcote EJ, et al. AASLD 2007. Abstract LB6. Virologic Response in HBeAg+ Patients (HBeAg Seroconversion at Wk 48-52) Patients Achieving HBeAg Seroconversion (%) 100 80 60 40 20 0 LAMADVETVLdTTDFPeg- IFN Peg- IFN + LAM PLB 16-21 12 21 32* 4-6 27 24 22 21 Not head-to-head trials; different patient populations and trial designs
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Chang TT, et al. J Gastro Hepatol. 2004;19:1276-1282. Lok AS et al. Gastroenterol. 2003;125:1714-1722. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Chang TT, et al. Hepatology. 2006;44(suppl 1):229A. Marcellin P, et al. N Engl J Med. 2003;348:808-816. Marcellin P, et al. Hepatology. 2006;44(suppl 1):548A. Lai CL, et al, Hepatology. 2005;42(suppl 1):748A. Lai CL, et al. Hepatology. 2006;44(suppl 1):222A. Han S, et al. AASLD 2007. A938. HBeAg Seroconversion With Extended Treatment 50 47 40 29 22 0 20 40 60 LAMADV ETVLdT 12345 Years of Therapy Patients (%) 80 100 47 37 31 21 0 20 40 60 80 100 48 12 0 20 40 60 80 100 23 29 12345 Years of Therapy Patients (%) 0 20 40 60 80 100 Patients (%) Not head-to-head trials; different patient populations and trial designs TDF 21 30 12345 Patients (%) 0 20 40 60 80 100
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Virological Response in HBeAg+ Patients (HBsAg Loss at Week 48-52) 3% 0-1% 0% 2% 3% PegIFNPegIFN & LAM ADVLAMETVTDF Lau GKK, NEJM 2005;352:2682; Marcellin P NEJM 2003;348:808; Chang TT NEJM 2006;354:1001; Marcellin NEJM 2008;359:2442
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Lamivudine Therapy Maintained Response and Breakthrough HBeAg HBsAg HBeAg HBV DNA (-) Nl ALT Lamivudine HAI PreRx:14/3Yr 4:1/0Yr 1:3/1 ALT HBV DNA Anti-HBe Liver Bx
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Lamivudine Therapy: Sustained Response HBsAg Lamivudine HBV DNA HBeAg Anti-HBs 1/113/3 Biopsy scores 3/3 ALT
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Antiviral Resistance
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*Defined as < 2 log reduction in serum HBV DNA after 6 months of therapy. Adapted from Lok AS, et al. Hepatology. 2007;45:507-539. Log HBV DNA 0.0 -2.0 -3.0 -4.0 +1.0 1 log Antiviral Drug Genotypic resistance Primary nonresponse* Secondary treatment failure Time 2 log Antiviral Treatment Failure in HBV
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Rates of Genotypic Resistance Nucleos(t)ide Naïve Patients Percent Lai CL N Engl J Med 1998;341:339:61-68; Lok AS. Gastroenterology. 2003;125:1714-1722; Dienstag JL N Engl J Med 1999;341:1256-1263; Westland C. Hepatology 2003; 38:96-103; Hadziyannis S. Gastroenterology. 2006;131(6):1743-51; Colonno RJ Hepatology. 2006;44:1656-1665; Lai CL. N Engl J Med. 2007;20;357:2576-88; Heathcote EJ. Hepatology. 2007;46:LB6; Gilead Sciences
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End points of therapy HBeAg+: -IFN / PegIFN: Loss of HBeAg -Nucleosides: HBeAg loss ?HBeAg seroconversion Loss of HBsAg HBeAg-: -Undetectable HBV DNA by PCR assay and normal ALT Loss of HBsAg
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Scenario 2 He returns to your office 5 years later He feels well but he went for a physical exam prior to getting life insurance and was denied because of elevated liver associated enzymes Blood tests reveal the following: Anti-HCV positive; HCV RNA level 3.5 x 10 6 copies/ml; genotype 1b Serum ALT 150, AST 125 Total bilirubin 1.0, albumin 4.2 g/dl
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Distribution of HCV Genotypes in the U.S. Gt 1 (78%) Gt 2 (13.5%) Gt 3 (5.5%) Gt 4 (1%)Gt 6 (2%) Nainan OV Gastroenterology 2006;131:478-84
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Sources of Infection in Persons with Hepatitis C Sexual 24% HD* 1% Unknown 12% Injection drug use 54% Transfusion 1% Source: MMWR April 2007 Nosocomial 8% *Hemodialysis
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Hepatitis C Virus Infection Natural History Stable 80% (68%) HCC Liver failure 25% (4%) Slowly progressive 75% (13%) Resolved 15% (15%) Acute HCV Cirrhosis 20% (17%) Chronic HCV 85% (85%) HCC, hepatocellular carcinoma
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Who To Treat?
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Therapy of Hepatitis C: Current Indications Age above 18 years HCV RNA in serum Raised serum aminotransferases Liver biopsy showing fibrosis or moderate-to-severe necrosis and inflammation No contraindications Based upon Recommendations from the 2002 NIH Consensus Development Conference: “Management of Hepatitis C”
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Outcomes of Therapy of Chronic Hepatitis C Virological Response is defined by absence of HCV RNA from serum using a sensitive method (<50 IU/ml) On treatment: End-of-Treatment Virological Response Virological Non-Response (NR) Off Treatment: Relapse Sustained Virological Response (SVR)
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CHRONIC HEPATITIS C Virological Responses 0 1 2 3 4 5 6 7 -8-4-204812162024324048526072 Weeks After Start of Therapy Undetectable Peginterferon and Ribavirin Non-Response SVR Relapse ETR
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What to Treat With
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Optimal Therapy of Hepatitis C: 2009 Combination Therapy Peginterferon (by injection) alfa-2a 180 g weekly alfa-2b 1.5 g/kg weekly Ribavirin (by mouth) 800 to 1400 mg in two divided doses daily For 24 to 48 weeks
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16% 54% 6% Progress in Therapy of Hepatitis C 34% 42% 39% 1995 2001 1991 1995 1998 2002 2001 Ribavirin Peginterferon Standard Interferon 69% Telapravir 2009
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Frequency of Virologic Responses to Peginterferon and Ribavirin Shiffman et al NEJM 2007;357:124-134; Ferenci J Hepatol 2005;43:425-433
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SVR is Associated with Lower Rates of Liver Related Complications and HCC Liver related complicationsHCC Bruno et al Hepatology 2007;45:579
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