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Management & prevention of HBV infection

Management & prevention of HBV infection. Elias S. , MD. Initial Evaluation. Hx and P/E Risk factors for coinfection HCV/HIV Use of alcohol Family Hx of HBV infection or liver D. Lab tests CBC AST, ALT, bil., ALP, Albumin, PT HBeAg, Anti-HBe, HBVDNA

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Management & prevention of HBV infection

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  1. Management & prevention of HBV infection Elias S. , MD

  2. Initial Evaluation • Hx and P/E • Risk factors for coinfection HCV/HIV • Use of alcohol • Family Hx of HBV infection or liver D. • Lab tests • CBC • AST, ALT, bil., ALP, Albumin, PT • HBeAg, Anti-HBe, HBVDNA • Anti-HCV, Anti-HDV • ? Liver biopsy • ? Screening for HCC

  3. Indications of Rx • HBeAg+ve cases • ALT - >2x ULN Exeptions:  Advanced Histologic findings Age>40 with high HBVDNA P’ts with recurrent Hepatitis flare • Newly diagnosed cases with compensated liver disease Delay Rx for 3-6 months(to give time for spont. Seroconversion) • HBeAg-ve cases • HBVDNA > 10 copies/ml with ALT- >2x ULN • Advanced liver disease

  4. Rx Goals – End points • Durable supression of serum HBVDNA  <100,000 copies/ml • HBeAg seroconversion (HBeAg+ve p’ts) • Normalization of serum ALT • Amelioration of Hepatic dysfunction • ? True cure of infection(loss of HBsAg, complete disappearance of the virus) Impractical

  5. ?Tenofovir ?Emtricitabine Telbivudine Clevudin Valtrocitabine Agents for Rx of HBV infection • Interferon alpha • Lamivudine • Adefovir • Entecavir • Factors determining the choice of agents • Serum HBVDNA , ALT level • Liver Histology • Availability, Cost • Age, comorbid condition

  6. Guidelines of Management • American association for the study of liver disease • Asian-Pacific association for the study of liver • European association for the study of liver • Generally – similar • Differences – in availability of agents • Common recommendations • Rx : If – HBVDNA >10 copies/ml ALT > 2x P’ts with histologically moderate to sever hepatitis • INFa – as alternative to nucloside analogs • Nucloside analogs- for decompemsated LD. • No recommendation on combination therapy

  7. Interferon alpha • Licenced by FDA in 1992 • Direct immunomodulatory properties • Augments CD8+ CTL activity by enhancing MCH-I Ag  HBVDNA • Finite duration of Rx (4-6 months) • More durable off-Rx response • No associated drug resistance • Disadvantages: • Side effects(fever,thrombocytopenia Myalgia, depression) • flares with HBeAg seroconversion • Contraindicated in Decompensated liver D. •  cost

  8. Standard INFa – 16wksAdult dose: 5MU/d or 10MU 3x/wk S.C • Efficacy • Meta Analysis, Multiple studiescomparing INFa with Placebo inHBeAg+ve P’ts (Rx3-6 months)

  9. Pegylated INF alfa-2a 24-48wks Adult dose : 180 microg./wk Efficacy • Pegylated INF Vs Lamivudine(adult p’ts with compensated ch.HBVrandomly assigned,( Rx for48wks then off-Rx followup for 24 wks)

  10. Lamivudine • Approved for Rx of HBV in 1998 • Blocks viral replication by inhibiting reverse transcriptase • Well tolerated, safe • Rx for 12 months is associated with: HBeAg loss  30% of P’ts HBeAg seroconversion  15-20% Normalization of ALT  50-70% Histologic improvement  50-60% • Low cost • Can be used in decompensated liver D.

  11. Lamivudine cont…. • Succesful Rx relies on adequate host immune response • Strong correlation b/n HBeAg clearanceand elevated pre-Rx ALT • Retrospective study ALT HBeAg clearance >5x 65% 2-5x 26% <2x 5%

  12. Lamivudine Cont…. • Disadvantage: • Development of drug resistance • By the end of 1 year –in 15-20% of p’ts 2yrs - 40% 4yrs - 67% • Relapse – breakthrough infections • Add adefovir!

  13. Lamivudine Cont… • Dose: 100mg/day p.o. • In HBV/HIV coinfection – 150 bid • dose in p’ts with renal insufficiency • ?Duration of therapy  minimum – 1yr • HBeAg+ve cases • Check HBeAg &HBeAb at 1yr • If seroconversion – Rx for 6more months • If no seroconversion – continue Rx. check Q 3-6 months • Check HBVDNA – Q 3 months • HBeAg-ve p’ts • Optimal duration of Rx not clear • Relapse – more common • Rx beyond 1yr - rate of response resistance

  14. Adefovir (Dose: 10mg po/day) • Approved in 2002 • Inhibits viral polymerase • Less potent than lamivudine • Advantage: • Low rate of drug resistance(suitable as 1st line therapy for HBeAg-ve cases) • Active against lamivudine resistant HBV • Disadvantage: • Slow viral supression • Potentially nephrotoxic

  15. Entecavir ( dose: 0.5mg/day) • Approved in 2005 • Selectively inhibit HBVDNA polymerase • More potent than lamivudine • Effective against lamivudine resistant strains • Drug resistance – rare • More important role in 1° Rx HBV inf. • Rx of p’ts with decompensated liver D. • Disadvantage: cost

  16. Relative antiviral potencies • Level of HBDNA supression

  17. Summary of management

  18. Combination therapy • Combination of nucleoside analogues • In vitro data & animal model study ?efficacy ?prevent/delay emergence of resistance • Clinical trials: Lamivudine+Adefovir Lamivudine + Telbivudine no additive benefit over monotherapy! • Concerns: Added cost,toxicity theoritical multidrug resistance • INFa + Nucloside analoge • Several clinical trials  +ve additive effect • One study: loss of HBeAg 1yr 26wk off-Rx polygated INF+ Lamivudine44% 35% Polygated INF + Placebo29% 36%

  19. ? Antiviral Rx for acut HBV infection  Sever protracted course Persistent Sx with marked jaundice for > 4wks HBeAg remain detectable for >10-12wksReactivation of infection in p’ts receiving immunosupressive therapy Fulminant hepatitis (to  post-liver transplant reinfection) Immunocompromized Pre existing liver disease Coinfection(Hep.C,D)  Elderly

  20. Novel Therapies • Augmenting immune response • Thymosine-alpha-1 (thymine-derived peptide) • Enhances T-cell maturation & function • Approved in some countries • TH1 cytokines (IL-12,IL-18) cellular response • Selective targeting of liver • Anti-sense approaches • Anti-sense molecules/ribozymes to prevent transcription and translation of HBVDNA &HBVRNA • Therapeutic vaccines • S and pre-S Ag vaccines • T-cell vaccines

  21. Prevention • 2 types • Passive immunization(using HBIG) • Immediate,short lived protection • Safe (rare anaphylactic Rxn) • Used for potexposure prophylaxis • Active immunization (using HBsAg) • Longterm immunity • Recombirax-HB, Engerix-B (by DNA recombinant technology)

  22. Hepatitis B vaccine • IM,Deltoid M. • Primarly given to high risk groups • Induce production of Anti-HBs • Anti-HBs >100mu/Ml100% protection • Titer steadily drops over 1-2yrs • to non protective level over 5-10yrsin 25-50% recipients“ strong immunologic memory” • 5-8% - non responders • No side effects • Schedule – 0,1,6 months • dose – in P’ts undergoing Hemodialysis immunocompromized obesity, extreme age, CLD • ? Booster dose

  23. Post-exposure prophylaxis • Infants born to HBsAg+ve mother • HBIG 0.5ml IM with in 12 hrs • Vaccine 0,1,6 months • After exposure to a known HBsAG+vesource (percutaneous, ocular, mucus m.) • Previously vaccinated • Known responder – No Rx • Known non-responder: • HBIG - 2doses 1month apart • HBIG – 1dose + revaccination • Ab response unknown: test for Anti-HBs • If adequate(>10mu/ml) – No Rx • If inadequate – HBIG + Booster dose

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