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Lecture on Global Challenges in treatment of Hepatitis C by Dr. Wasim Jafri during the 6th International Infection Control Conference 2006

Lecture on Global Challenges in treatment of Hepatitis C by Dr. Wasim Jafri during the 6th International Infection Control Conference 2006

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DR. SARWAR JEHAN ZUBERI LECTURE DR. SARWAR JEHAN ZUBERI LECTURE Presentation Transcript

  • Goals and Challenges in the Treatment of Hepatitis B Prof Wasim Jafri FRCP, FACP, FACG Chief of Gastroenterology Chairman Department of Medicine Aga Khan University Karachi Sarwar Jahan Zuberi Memorial Lecture
  • DR. SARWAR JEHAN ZUBERI
    • Dr Sarwar Jehan Zuberi graduated from Dow Medical College, Karachi, in 1956 and, after doing a house job in medicine at Jinnah Hospital, Karachi, went to England, where from 1958 to 1965 she worked in various hospitals.
    • In 1965 she went to the United States, where for two years she worked at the Lahey Clinic Foundation, first as a resident and then as a research fellow in gastroenterology.
    • Her initial research interest was in all areas of gastroenterology, but gradually she confined herself to the epidemiology and management of hepatitis.
    • Dr Sarwar Jehan Zuberi began her research career in Pakistan in 1967 as one of the first full time employees of the Medical Research Council, Karachi, and went on to become its head.
    • In 1996, when her contract with the council had ended, she helped in the set up a new medical university in the private sector—Ziauddin Medical University, Karachi.
    • In the seven years of her association with the university MPhil/PhD program in basic sciences and MD/MS programs in clinical disciplines were started.
    • Credit goes to SJZ for guiding the young with planning, conducting, and then publishing their research. In Pakistan, where medical research has not received much support, this was indeed a significant achievement.
    • SJZ was uniquely qualified for the job of research and medical writing.
    • In addition to her background at the research council she had edited the journal of the Pakistan Medical Association for 30 years on a shoestring budget.
    • When she became editor in 1974 the journal was not indexed and it was largely through SJZ’s efforts that in 1978 it became the first medical publication of Pakistan to be indexed.
    • She had more than 250 publications to her credit.
    • Despite arthritis in both knees she was an avid traveler, attending meetings all over the world.
    • She made more than 200 presentations at international and national meetings, and was a much sought after speaker.
    • In the past five years she developed a deep interest in medical ethics, particularly ethics relating to research.
    • In 2004 she was nominated as a member of the National Bioethics Committee set up by the Pakistan Ministry of Health.
    • She was recipient of several national and international awards
  • Model of Natural History of Chronic Hepatitis B D eath Hepatocellular carcinoma Decompensated cirrhosis Cirrhosis Chronic hepatitis Inactive disease Reactivation
  • Primary Goal of Hepatitis B Therapy: Preventing Cirrhosis, HCC, and Death
      • Durable Suppression of HBV Replication
  • Goals of Treatment
    • Prevent long-term clinical outcomes (cirrhosis, HCC, death) by durable suppression of HBV DNA
    • Treatment endpoints in clinical trials and practice
      • Improve liver histology *
      • Decrease serum HBV DNA
      • Decrease or normalize serum ALT
      • Induce HBeAg loss or seroconversion
      • Induce HBsAg loss or seroconversion
    * Clinical trials only; not routinely assessed in practice Conjeevaram HS, Lok AS. J Hepatol. 2003;38:S90-S103.
  • Surrogate Clinical Markers for Hepatitis B Outcomes Prevention of Death, Cirrhosis, and HCC Liver histology
      • Serum HBV DNA
      • ALT
      • Seroconversion
  • Goals of Therapy Two Distinct Patient Populations
    • HBeAg-positive (wild-type)
      • HBeAg loss  seroconversion
      • Durable suppression of HBV DNA to low or undetectable levels
      • Durability of response after seroconversion  80%
    • HBeAg-negative (precore and core promoter mutants)
      • HBeAg seroconversion NOT an endpoint
      • Durable suppression of HBV DNA to low or undetectable levels
      • Relapse common after stopping oral therapy; therapy usually administered long-term
  • Actuarial Survival in End Stage Liver Disease
    • 2 trials studied actuarial survival in end-stage liver disease
    • US study of patients with chronic hepatitis B infection 1
      • N = 379; n = 130 cirrhotic patients
      • Estimated 5-year survival rate for cirrhotic patients, 55% vs 86% for patients with chronic active hepatitis
    • European study of HBsAg-positive cirrhosis 2
      • N = 98; n = 21 patients with hepatic decompensation
      • 5-year survival rate for decompensated patients, 14% vs 84% for patients with compensated cirrhosis
    1. Weissberg et al. Ann Intern Med. 1984;101:613. 2. De Jongh et al. Gastroenterology. 1992;103:1630.
  • HBV and Risk of HCC Yang HI, et al. N Engl J Med. 2002;347:168-174. 12 10 8 6 4 2 0 Percent cumulative incidence 0 1 2 3 4 5 6 7 8 9 10 Year HBsAg(+), HBeAg(+) (RR = 60.2) HBsAg+, HBeAg- (RR = 9.6) HBsAg-, HBeAg-
  • REVEAL: Relationship Between Baseline Viral Load and Cirrhosis
    • Baseline HBV DNA predicted progression to cirrhosis
      • Relationship independent of HBeAg status
    Chen, et al. J Hepatol. 2005:42(Suppl 2):16. * Adjusted for gender, age, anti-HCV levels, smoking, and alcohol use. NS, not significant HBeAg-Positive Patients HBeAg-Negative Patients P Value Adjusted RR* (95% CI) Cases of Cirrhosis Total Patients Serum HBV DNA (copies/mL) < .001 8.6 (6.6 – 11.2) 135 520 ≥ 10 5 < .01 6.2 (1.9 – 19.5) 3 18 ≥ 10 4 to < 10 5 NS 2.6 (0.6 – 10.5) 2 22 < 10 4 < .001 4.9 (3.7 – 6.4) 96 451 ≥ 10 5 < .001 1.9 (1.4 - 2.7) 55 631 ≥ 10 4 to < 10 5 -- 1.0 (reference) 104 2132 < 10 4
  • REVEAL: Relationship Between Baseline HBV DNA Levels and HCC
    • HCC incidence increased with increasing baseline HBV DNA
      • HBV levels independent predictor of HCC in multivariate analysis
    0 200 400 600 800 1000 1200 1400 145 113 315 952 1150 HCC Incidence Rate Per 100,000 Chen, et al. J Hepatol. 2005:42(Suppl 2):16. ≥ 1.1 x 10 6 1.0-9.9 x 10 5 1.0-9.9 x 10 4 300 to < 10 3 < 300 HBV DNA (copies/mL) P Value Adjusted RR (95% CI) < .001 < .001 < .005 NS -- 11.6 (6.7-19.9) 7.2 (4.0-12.9) 2.4 (1.3-4.5) 0.9 (0.5-1.9) 1.0 (ref)
  • REVEAL: Relationship Between Persistent Viremia and HCC Incidence
    • Persistent HBV DNA associated with greater risk of HCC
      • Examined in those with levels ≥ 10 4 copies/mL at baseline (n = 1376)
    0 2.0 x 10 3 4.0 x 10 3 6.0 x 10 3 8.0 x 10 3 1.0 x 10 4 1.2 x 10 4 1473 5882 8730 10,108 HCC Incidence Rate Per 100,000 Chen, et al. J Hepatol. 2005:42(Suppl 2):16. ≥ 10 5 ≥ 10 5 ≥ 10 5 < 10 4 Baseline HBV DNA, copies/mL ≥ 10 5 10 4 to < 10 5 < 10 4 -- Follow-up HBV DNA, copies/mL P Value Adjusted RR (95% CI) < .001 < .001 < .001 -- 9.1 (5.8-14.1) 6.9 (3.4-13.8) 3.6 (1.7-7.6) 1.0 (reference)
  • Hepatitis B Virus Variants
    • Wild type
      • Usual HBeAg(+) hepatitis
    • Precore mutation
      • Abolishes HBeAg production
    • Core promoter mutation
      • Down-regulates HBeAg production
    • Treatment-induced mutations
      • YMDD: induced by lamivudine (  20%/year)
      • N236T and A181V: induced by adefovir
        • 0% at yr 1, 2% at yr 2, 7% at yr 3, and 15% at yr 4
  • HBV Genotypes Epidemiology
    • HBV classified into 8 genotypes (A-H)
      • A: North America, Western Europe, and Africa
      • B and C: Asia, Pakistan
      • D: Southern Europe, Africa, India and Pakistan
      • E: West Africa
      • F: Central and South America and Alaska
      • G: United States, France, and Germany
      • H: Central America
    • B associated with less active disease, slower progression, and lower incidence of HCC than C
    • A and B respond better to IFN than C and D
  • Phases of Chronic Hepatitis B 1. McMahon. Sem Liver Dis. 2004;24(supp 1):17-21. 2. Keeffe et al. Clin Gastroenterol Hepatol. 2004;2:87-106. Normal or minimal inflammation Chronic inflammation Normal or minimal inflammation Liver Histology ALT Levels HBeAg Status HBV DNA Levels (copies/mL) Normal Low (< 10 4 ) Negative Nonreplicative phase (HBsAg Carrier) Elevated High (wild type > 10 5 ; negative > 10 4 ) Positive (wild-type), or Negative (mutants) Immune active phase (Chronic hepatitis B) Phase Normal High (>10 5 ) Positive Immune tolerant phase
  • Dynamics of HBV Replication and Clinical Disease Immune Tolerant Nonreplicative Immune Active
  • AASLD Hepatitis B Treatment Guidelines Lok et al. Hepatology. 2004;39:857-861. Comp: Treat Decomp: Refer for Liver Tx Cirrhosis - +/- Treat Cirrhosis + +/- Follow ≤ 2 x ULN - - Management ALT HBV DNA > 10 5 copies/mL Treat > 2 x ULN + - Treat > 2 x ULN + + HBeAg Follow ≤ 2 x ULN + +
  • Hepatitis B Management Guidelines in the US Keeffe et al. Clin Gastroenterol Hepatol. 2004;2:87-106. Treat Elevated ≥ 10 4 - Consider biopsy; treat if diseased Normal ≥ 10 4 - Follow < 10 4 - Management ALT HBV DNA (copies/mL) Treat Elevated ≥ 10 5 + Consider biopsy; treat if diseased Normal ≥ 10 5 + HBeAg Follow < 10 5 +
  • Hepatitis B Management Guidelines in the US: Cirrhotics Keeffe et al. Clin Gastroenterol Hepatol. 2004;2:87-106. Compensated Decompensated Management Treat ≥ 10 4 HBV DNA (copies/mL) Treat or follow < 10 4 Management Treat carefully with oral antiviral; waitlist for transplant Detectable HBV DNA Follow; waitlist for transplant Undetectable
  • Role of Liver Biopsy in Patients With Normal ALT and High Viral Load 24% 0 10 20 30 40 50 60 70 PNALT (n = 57) ALT 1-1.5 ULN (n = 23) ALT > 1.5 ULN (n = 110) Stage 0 Stage 1 Stage 2 Stage 3 Stage 4 Stage of Fibrosis by ALT Group Patients, % Lai et al. AASLD 2005. Abstract 67571.
  • HBV DNA as a Marker of Efficacy During Treatment of HBV
    • Literature analysis of 26 prospective studies
      • Investigation of the relationship between treatment-induced changes in HBV DNA, histology, other disease activity markers
    • Results
      • Statistically significant and consistent correlations between HBV DNA, histology, biochemical and serologic responses
        • HBV DNA had broader dynamic range than histology
    • Conclusion
      • Treatment-induced reduction in HBV DNA can be used to assess efficacy
      • Treatment goal should be profound and durable suppression of HBV DNA
    Mommeja-Marin H, et al. Hepatology 2003;37:1309-1319.
  • HBeAg Response Correlates With HBV DNA < 10 4 copies/mL
    • US multicenter, open-label follow-up trial (N = 24)
      • Included patients who remained HBeAg(+), HBsAg(+), and HBV DNA(+) on previous LAM treatment
      • Current retreatment: Lamivudine 100 mg/day for up to 18 months  
    • HBV DNA < 10 4 copies/mL correlated with HBeAg seroconversion
      • HBV DNA > 10 4 copies/mL (n = 11)
        • HBeAg seroconversion rate, 0%
      • HBV DNA < 10 4 copies/mL (n = 12)
        • HBeAg seroconversion rate, 50%
    Gauthier et al. JID. 1999;180:1757-1762.
  • HBV DNA and HBeAg Seroconversion at Year 1 in HBeAg(+) Patients HBeAg Seroconversion (Loss), % Log 10 decrease HBV DNA -4 -3.5 -6.5 -6.9 -5.8 17 14 21 21 27 -10 -5 0 5 10 15 20 25 30 35 LAM* ADV 10 † LdT ‡ ETV** PEG-IFN ‡ Data from individual reports, not direct comparisons (different populations, baseline values, HBV DNA assays) Lau et al. N Engl J Med. 2005;352:2682-2695. Dienstag et al. N Engl J Med. 1999;341:1256-1263. Marcellin et al. EASL 2005. Abstract 73. Lai et al. AASLD 2005. Abstract LB01. Chang et al. AASLD 2004. Abstract 70. *Hybridization assay (1.6 pg/mL); † PCR assay (LOQ, 1000 copies/mL); ‡ PCR (LOQ, 200 copies/mL); **PCR assay (LOQ, 300 copies/mL) (32) (23) (26) (22) (30)
  • HBeAg Loss and Seroconversion Over Time With Adefovir Kaplan-Meier estimates of time to confirmed event Marcellin et al. EASL 2005. Abstract 73. HBeAg Seroconversion HBeAg Loss 23% 14% 46% 33% 53% 46% By Wk 48 (n = 171) By Wk 96 (n = 85) By Wk 144 (n = 65) 0 20 40 60 80 100
  • HBeAg+ CHB: Serologic Response to Pegylated Interferon by Genotype
    • N = 307 patients with HBeAg-positive disease
    • Treated with peginterferon alone, or + lamivudine
    • Response to treatment varied by genotype ( P < .01)
    Janssen et al. Lancet. 2005;365:123-129. 103 39 23 90 n 2 25 Genotype D 3 28 Genotype C 9 44 Genotype B 14 47 Genotype A HBsAg Loss, % HBeAg Loss, % HBV Genotype
  • Increased Genotypic Resistance With Long-Term Treatment Adefovir Dipivoxil 1,3 (N236T/A181V) Lamivudine 2 * (M204V/I) 0% 2% 11% 18% 24% 42% 53% 70% 0 20 40 60 80 100 Year 1 Year 2 Year 3 Year 4 Patients, % 29% New data at AASLD Year 5 *Year 5 data not available from this study 1. Qi et al. EASL 2004. Abstract 57. 2. Lai et al. Clin Infect Dis. 2003;36:687. 3. Hadziyannis et al. AASLD 2005. Abstract 72492
  • Less Lamivudine Resistance With Better Early HBV Suppression Yuen et al. Hepatology. 2001; 34:785-791. Patients, % Serum HBV DNA Level at 6 Months (copies/mL) 0 20 40 60 80 100 8% 13% 32% 64% Serum DNA at Month 6 vs Lamivudine Resistance by Month 61 < 200 (n = 12) < 3 log 10 (n = 23) < 4 log 10 (n = 41) > 4 log 10 (n = 118)
  • After 48 weeks, 30% of patients had viral load > 1000 copies/mL 30% HBV DNA > 3 log 10 70% HBV DNA < 3 log 10 Susceptibility at Year 3 According to Year 1 HBV DNA 24 (70.6%) Susceptible 10 (29.4%) Resistant at Wk 144 4 (5.0%) Resistant at Wk 144 76 (95.0%) Susceptible 30% HBV DNA > 3 log 10 70% HBV DNA < 3 log 10 Of this 30%, 10 of 34 (29%) developed ADV-R at Wk 144 Higher HBV DNA at Year 1 Predictive of ADV-R Development by Year 3 Locarnini et al. EASL 2005. Abstract 36.
  • Cross-resistance in the Treatment of Chronic Hepatitis B
    • Lamivudine and entecavir 1,2
      • Through 96 weeks of treatment, no cases of entecavir resistance in nucleoside-naive patients
      • 7% of patients with emerging ETV resistance mutations among lamivudine-refractory patients after 48 weeks
    • Lamivudine and emtricitabine 3
      • In vitro studies show high-level cross-resistance to emtricitabine for 4 major lamivudine-resistance patterns
    • Adefovir and tenofovir 4
      • Phenotypic assays show reduced susceptibility to tenofovir with adefovir mutation N236T
    1. Colonno et al. EASL 2005. Abstract 478. 2. Gish et al. AASLD 2005. 3. Qi et al. EASL 2005. Abstract 57. 4. Yang. 2005;10:625-633.
  • Summary
    • Treatment decisions are individualized based on viral, host and disease state characteristics
    • Liver biopsy is still valuable to identify treatment need especially in normal ALT patients
    • HBV DNA normalization is the optimal surrogate for clinical outcomes
    • HBV DNA < 10,000 copies/mL necessary for HBeAg seroconversion and to reduce risk of resistance
    • Long-term suppression is possible for HBeAg-negative patients
  • US FDA-Approved Therapies for Chronic Hepatitis B March 29, 2005 Bristol-Myers Squibb BARACLUDE ™ Entecavir May 13, 2005 Hoffmann La-Roche Pegasys ® Peginterferon alfa-2a 2002 Gilead Sciences HEPSERA ™ Adefovir dipivoxil 1998 GlaxoSmithKline EPIVIR-HBV ® Lamivudine 1992 Schering Corporation INTRON ® A Interferon alfa-2b Date Approved for Hepatitis B Manufacturer U.S. Trade Name Generic Name
  • Treatment of Chronic Hepatitis B Summary *IFN and LAM – hybridization assay; ADV – PCR assay † Indefinite therapy; **HBeAg seroconversion; ***Undetectable HBV DNA Duration of treatment >>1 yr † >>1 yr † 12 mo e-CHB >1yr >1yr 4–6 mo e+CHB <10% <10% ~20% e-CHB*** 91% 50%–80% 80%–90% e+CHB** Durability of response 51% 60%–70% 60%–70% e-CHB (loss of HBV DNA*) 12% 16%–18% ~18% e+CHB (HBeAg seroconversion) Response in yr 1 ADV LAM IFN Clinical Outcomes
  • Treatment of Chronic Hepatitis B Summary *Based on 1 yr duration of treatment Intermediate* Low* High Costs None yr 1 2% yr 2 7% yr 3 15% yr 4 ~20% yr 1 ~70% yr 5 None Drug resistance – – ++ Contraindications Negligible Negligible Many Side effects Oral Oral Subcutaneous Route Adefovir Lamivudine Interferon Parameter
  • Treatment of Chronic Hepatitis B Summary *PCR assays; † Indefinite therapy; †† 24 weeks post-treatment; **HBeAg seroconversion ***undetectable HBV DNA Lau GK, et al. N Engl J Med. 2005;352:2682; Marcellin P, et al. N Engl J Med. 2004;351:1206; Baraclude package insert, March 2005. Duration of treatment 1 yr >>1 yr † e-CHB 1yr >1 yr e+CHB 19% 48% e-CHB*** 32% 82% e+CHB** Durability of response †† 63% 90% e-CHB (loss of HBV DNA*) 27% 25% 21% 67% e+CHB (HBeAg seroconversion) e+CHB (loss of HBV DNA*) Response in yr 1 Peginterferon Entecavir Clinical Outcomes
  • Treatment of Chronic Hepatitis B Summary *Based on 1 yr duration of treatment High* Intermediate* Costs None None at yr 1 and 2 in naive 6% in LAM-R Drug resistance ++ - Contraindications Many Negligible Side effects Subcutaneous Oral Route Peginterferon Entecavir Parameter
  • Effect of LAM on Disease Progression in CHB and Advanced Fibrosis Time to Disease Progression (months) Placebo (n = 215) Lamivudine (n = 436) Liaw YF, et al. N Engl J Med. 2004;351:1521-1531. 0 6 12 18 24 30 36 Disease Progression (%) Lamivudine Placebo 0 5 10 15 20 25 P = .001
  • Effect of LAM on Incidence of HCC in CHB and Advanced Fibrosis Liaw YF, et al. N Engl J Med. 2004;351:1521-1531. Months Lamivudine Placebo Diagnosis of HCC (%) 0 10 6 0 12 18 24 30 36 P = .047
  • Prevalence of Resistance in Patients Treated with ADV or LAM 24% 80% Locarnini S, et al. J Hepatol. 2005;42(suppl 2):17. ADV (N236T or A181V) LAM 1 (YMDD) Prevalence of Resistance 42% 53% 70% 15% 7% 2% 0% 70% 60% 50% 40% 30% 20% 10% 0% Year 1 Year 2 Year 3 Year 4
  • Summary of Entecavir Viral Resistance Data (Week 48) Conclusion: lamivudine can select for a number of secondary substitutions that can significantly reduce ETV susceptibility and clinical efficacy Colonno RJ, et al. AASLD 2004. Abstract 1146. 1% (2/141) 5.8% (10/172) Lamivudine refractory (rtL180M and/or rtM204V mutations) 0% (n = 679; 354 e+, 325 e – ) 0% (n = 432; 219 e+, 213 e – ) Nucleoside naive Phenotypic Resistance Genotypic Substitutions Group
  • Chronic HBV Infection Proposed Approach to Therapy
    • Adefovir, entecavir or peginterferon alfa-2a *
      • Presence or absence of HBeAg
      • HBV DNA  10 5 cp/mL for HBeAg+ (  10 4 for HBeAg-)
      • Elevated ALT (not > 2-fold), or repeated flares (no need to wait 3-6 months before treating)
      • Presence of chronic hepatitis on biopsy
    • Lamivudine or adefovir, or possibly entecavir
      • Cirrhosis: compensated and decompensated
      • OLT: prophylaxis, and recurrent HBV after OLT
    Updated and modified from: Keeffe EB, Dieterich D, Han S, Jacobson I, Martin P, Schiff E, Tobias H, Wright T. Clin Gastroenterol Hepatol 2004;2:87-106. *PegIFN will likely supplant IFN; ADV or ETV preferred over LAM due to latter’s high rate of resistance
  • Thank you