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Chronic hbv infection diagnosis and management dr neeraj nagaich

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  • single dose of HBIG (0.06 ml/kg or 5.0 ml for adults) as soon as possible and within 24 hours if possible. (0.5 ml) IM within 12 hours of birth. HepaGam B 312 units/mL
  • The United States Department of Health and Human Services (DHHS)
  • Transcript

    • 1. Chronic HEPATITIS B Infection Diagnosis and management Dr NEERAJ NAGAICH Dept of gastroenteroloy SMS medical college jaipur.
    • 2. A world-wide public health problem• Three quarters of the world’s 5.2 billion people live in endemic regions• Nearly 75% of chronic carriers are Asian.• HBV is 100 times more contagious than HIV.
    • 3. A world-wide public health problem• Established cause of chronic hepatitis and cirrhosis.• 2nd most important carcinogen behind tobacco.• cause of up to 80% of Hepatocellular carcinomas.
    • 4. Geographic Distribution of Chronic HBV Infection HBsAg Prevalence ≥8% - High 2-7% - Intermediate <2% - Low
    • 5. Hepatitis B Immunopathogenesis
    • 6. Natural History
    • 7. Outcome Of Acute Hepatitis B
    • 8. Natural history >90% of ChildrenAcute HBV Infection Chronic HBV Infection <5% of Adults 10% of Children 30-40% Risk 95% of Adults Hepatocellular Recovery Cirrhosis Carcinoma (HCC)Protective Immunity Transplant or Death
    • 9. Phases of Infection
    • 10. Phases of Chronic HBV Infection
    • 11. Whom to screen ``` wi• Patients with elevated liver enzymes• Patients with HCC, Cirrhosis ,liver fibrosis• Immigrants from areas of high HBV prevalence• Families , household members and sexual contacts of HBV + person• Patients in psychiatric institutions, residents of welfare institutions and mentally disabled• Homo/Bisexuals and person having multiple sexual partners• Active and ex drug user• Dialysis patients• HCV or HIV infected persons
    • 12. Whom to screen…• Recipients of organ transplant before and after transplant• Blood and organ donors• All medical personnels• All pregnant women• Patients before and during immunosuppressive or chemotherapy therapy• New borne to HBsAg + ve mothers
    • 13. Diagnosis
    • 14. Diagnosis
    • 15. Interpretation of Hepatitis B PanelHBsAg HBsAg negative negativeantiHBc antiHBc positive immune due to natural infection negative susceptibleantiHBs positive antiHBs negativeHBsAg negativeantiHBc negative immune due to vaccineantiHBs positiveHBsAg positiveantiHBc ( total ) positive acutely infectedIgM antiHBc positiveantiHBs negativeHBsAg positiveantiHBc ( IgG) positive chronicallyIgM antiHBc negative infectedantiHBs negativeHBsAg negative 1.resolution of chronic infection 2. “window period” infectionantiHBc ( IgG) positive 3. false-positive anti-HBcantiHBs negative 4. active infection with waning HBsAg
    • 16. Treatment
    • 17. Goals of HBV Therapy•HBV infection cannot eliminated or “cured”•The clinical goal of HBV treatment (primary goal ) Prevention or reversal of complications /deaths suppress HBV replication and achieve a target HBV DNA <10-15 IU/mL Can allow biochemical remission and prevent further liver injury
    • 18. Goals of HBV TherapyIn HBeAg-positive patients (cont) HBeAg loss and seroconversionIn HBeAg-positive and HBeAg-negative patients HBsAg loss and seroconversion is ultimate form of HBV treatment success Best predictor of durable viral suppression Strongest indicator of best longterm outcome, lowest risk of cirrhosis and liver cancer Not achieved by the majority of patients Histological Improvement
    • 19. Options in treatment
    • 20. Evolution of Approved HBV Therapy Over Time Peginterferon alfa-2a Lamivudine Entecavir Tenofovir 1990 1990 1998 1998 2002 2005 2005 2006 2008 2008Interferon alfa-2b Adefovir Telbivudine
    • 21. Recommendations for Treatment Initiation in HBeAg-Positive Patients AASLD 2007[1] US Algorithm 2008[2] EASL 2009[3] HBV DNA, IU/mL > 20,000 > 20,000 ≥ 2,000 ALT, x ULN* >2 >1 >1 Moderate/severe necroinflammation Disease stage/grade and/or significant fibrosis ADV,† ETV, ETV, TDF, ETV, TDF, First-line therapy pegIFN pegIFN pegIFN Criteria for HBV DNA, ALT and disease stage/grade must all be met – If not, guidelines recommend monitoring and consideration of treatment based on individual’s age, health status, and stage of infection/disease 1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 3. EASL HBV Guidelines. J Hepatology. 2009;50:227-242.
    • 22. Recommendations for Treatment Initiation in HBeAg-Negative Patients AASLD 2007[1] US Algorithm 2008[2] EASL 2009[3] HBV DNA, IU/mL > 20,000‡ > 2000 ≥ 2000 ALT, x ULN* 1 to > 2 >1 >1 Moderate/severe necroinflammation Disease stage/grade and/or significant fibrosis ADV,† ETV, ETV, TDF, ETV, TDF, First-line therapy pegIFN pegIFN pegIFN  Criteria for HBV DNA, ALT and disease stage/grade must all be met – If not, guidelines recommend monitoring and consideration of treatment based on individual’s age, health status, and stage of infection/disease1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 3.EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242.
    • 23. Special Populations That Should Also Be Considered for HBV TreatmentRegardless of HBV DNA and ALT levels • Patients with rapid deterioration of liver function • Patients with compensated cirrhosis If DNA > 2,000 IU/mL, regardless of ALT • Patients with decompensated cirrhosis (IFN contraindicated) • Recurrent HBV infection post liver transplantation • HBV carriers undergoing immunosuppressive or cytotoxic chemotherapy
    • 24. Factors Associated With Choosing Nucleos(t)ides as Initial Therapy Favorable predictors of response High ALT Low HBV DNA (baseline and on treatment) Specific patient demographics Older people Patient preference Concomitant HIV infection No HCV coinfection
    • 25. Selecting Between Recommended First Line Nucleos(t)ide and Interferon Therapy Nucleos(t)ides Interferon-Based TherapyFeature Pro Con Pro Con Long term/Administration Oral Finite duration Subcutaneous indefinite Low durable ratesAntiviral activity High DNA suppression Very lowResistance No resistance† Rare renal toxAdverse events Minimal Substantial* with nucleotideHBeAg loss and HBeAg loss ↑ Lower rates vs. Higher rates vs HBeAg loss ≠ HBVclearance over time IFN nucles(t)ides DNA suppressionHBsAg loss and Higher and High rates (select Low rates in general Low ratesclearance earlier events† populations) patient groups May induce HIVOther Anti HIV (TDF) resistance Anti HCV/HDV (TDF/ETV)
    • 26. Selecting a First-line Nucleos(t)ide
    • 27. Factors Driving Selection of Initial Nucleos(t)ide Safety Efficacy (potency) Barrier to resistance (durability)
    • 28. Efficacy (Potency)
    • 29. Undetectable* HBV DNA in HBV Patients After 1 Year of Treatment Not head-to-head trials; different patient populations and trial designs HBeAg Positive HBeAg Negative 100 100 90 88 91 Undetectable* HBV DNA (%) 80 76 80 67 60 60-73 60 60 51-63 40-44 40 40 20 13-21 20 0 0 LAM ADV ETV LdT TDF LAM ADV ETV LdT TDF *By PCR-based assay (LLD ~ 50 IU/mL) except for some LAM studies.Lok A, et al. Hepatology. 2007;45:507-539. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242 .
    • 30. HBeAg Loss/Seroconversion in HBeAg- Positive Patients After 1 Year of Treatment Not head-to-head trials; different patient populations and trial designsHBeAg Loss/Seroconversion (%) HBeAg Loss HBeAg Seroconversion 100 100 80 80 60 60 40 32 40 24 26 23 22 22 21 21 20 20 12-18 NR 0 0 LAM ADV ETV LdT TDF LAM ADV ETV LdT TDFLau GK, et al. N Engl J Med. 2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2003;348:808-816 Chang TT, et al. NEngl J Med. 2006;354:1001-1010. Lai CL, et al. N Engl J Med. 2007;357:2576-2588. Marcellin P, et al. N Engl J Med.2008;359:2442-2455.
    • 31. Normalization of ALT and Histological Improvement After 1 Year of Treatment HBeAg Positive Outcome, % LAM ADV ETV LdT TDF Normalization of ALT 41-75 48 68 77 69 Histological improvement 49-56 53 72 65 74 HBeAg Negative Outcome, % LAM ADV ETV LdT TDF Normalization of ALT 60-79 72 78 74 77 Histological improvement 60-66 64 70 67 72Lai CL, et al. N Engl J Med. 1998;339:61-68. Dienstag JL, et al. N Engl J Med. 1999;341:1256-1263.Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Lai CL, et al.N Engl J Med. 2007;357:2576-2588. Marcellin P, et al. N Engl J Med. 2003;348:808-816. Marcellin P, et al.2008;359:2442-2455.
    • 32. Resistance andTreatment Durability
    • 33. Cumulative Rates of Resistance With Oral Agents in Nucleos(t)ide-Naive Patients LAM ADV ETV LdT TDF 100 80 70 67Patients (%) 60 49 40 38 29 24 18 20 17 11 4 3 0.5 0 0.2 0 0 1.2 1.2 1.2 1.2 0 1 2 3 4 5 6 Year
    • 34. Summary of Potency and Genetic Barrier to ResistanceLAM and LdT Potent agents with low genetic barriers and high rates of resistanceADV Less potent agent with low pharmacologic barrier with intermediate rate of resistanceETV Potent agent with high pharmacologic and genetic barriers and low rates of resistanceTDF Potent agent with high pharmacologic and low rates of resistance, genetic barrier not yet defined
    • 35. Proposed Special Populations for Combination TherapyCirrhosis (especially decompensated) High risk of hepatitis flare with emergence of resistanceHIV/HBV coinfection Drugs with dual antiviral activity must be used in combination to prevent drug resistancePreexisting resistance Rates of infection with resistant virus low but increasingNo data showing benefit of combination therapy vs. monotherapy with newermore potent agents in treatment naïve patients
    • 36. Summary of FDA Approved Oral HBV Treatments*Approximate and relative.† Number of mutations needed for primary antiviral drug resistance.‡ Only includes reported adverse events that may differ in historical incidence associatedwith LAM and, therefore, potentially affecting selection vs other agents. Pancreatitis hasbeen reported as a class effect and all agents have to be dose adjusted for renalinsufficiency.§ From HIV databases
    • 37. Summary: Selecting the Best Nucleos(t)ide for Initial Therapy• Use nucleos(t)ides as monotherapy with •Highest antiviral potency and genetic barrier to resistance •Low incidence of resistance over time •LAM/LdT/ADV not generally recommended as first-line therapy • Combination therapy may be considered in patients where avoiding resistance is especially important •Consider individual patient characteristics in relation to safety •Comorbidities (ie, compromised renal function) •Coinfections (ie, anti-HIV activity of agents) •Conception planning
    • 38. Tenofovir Disoproxil Fumarate
    • 39. Tenofovir vs Adefovir comparison of results at week 48 HBeAg +ve HB e Ag –ve Tenofovir Adefovir Tenofovir Adefovir 300 mg 10 mg 300 mg 10 mg 176 patients 90 patient 250 Patient s 125 patientsHBV DNA 76% 13% 93% 63%<400 copies /mlALT 68% 54% 76% 77%NormalizationHBeAg 21 18 -- --SeroconversionHistological 74 68 72 69Response≥ 2 log fall KS
    • 40. Regression of Fibrosis on ADV 1 year ADV Fibrosis = 5/6 5 years ADV Fibrosis = 3/6Patient 1566 (year 5 cohort)
    • 41. Selecting an Interferon-Based Initial HBV Treatment
    • 42. Factors Associated With Choosing Interferon for Initial Therapy Favorable predictors of response Genotype A or B > C or D Low HBV DNA (baseline and on treatment) High ALT (baseline) Specific patient demographics Younger people Young woman wanting future pregnancy Patient preference No coinfection with HIV Concomitant HCV infection
    • 43. PegIFN Treatment-Associated Adverse EffectsPatients should be carefully monitored for adverse eventsMost common adverse events: flu-like symptoms (fever, chills, headache, malaise, and myalgia) as well as psychological impairmentIncidence/Severity Increase in Depression Fatigue Anxiety Flu-like symptoms 0 1 2 3 4 Months Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
    • 44. Peglfa-2a vs LAM vs Combination at EOT (48 Weeks) in HBeAg-Positive Patients PegIFN 180 µg (n = 271) PegIFN + LAM (n = 271) LAM 100 mg (n = 272) 100 86 80 69 62Patients (%) 62 60 52 46 40 39 40 30 27 24 27 25 20 22 20 0 HBeAg HBeAg HBV DNA HBV DNA ALT Seroconversion Loss < 105 copies/mL < 400 copies/mL Normal (~ 20,000 IU/mL) (~ 80 IU/mL)  Lau GK, et al. N Engl J Med. 2005;352:2682-2695.
    • 45. HBeAg Seroconversion After EOT (Week 48) 100 90 Off-Treatment Follow-up (Week 72)HBeAg Seroconversion (%) 80 70 60 P < .001 50 40 P = .023 32 30 27 20 19 10 0 PegIFN PegIFN + LAM LAM (n = 271) (n = 271) (n = 272)
    • 46. Viral Suppression in HBeAg-NegativePatients After PegIFN-2a ± LAM Treatment 100 90 Patients with HBV DNA ≤ 400 copies/mL (%)* 80 70 60 50 40 30 20 18 17 13 13 10 0 1 2 3 4 Years After Therapy Completed*~ 80 IU/mL, missing data considered a nonresponse. Marcellin P, et al. AASLD 2006. Abstract. 972. Marcellin P, et al. EASL 2007. Abstract 53. Marcellin P, et al. EASL 2008. Abstract 103.
    • 47. Early HBsAg Kinetics Are Predictive of Long-term PegIFN Treatment Success•HBsAg decrease at Week 12 associated withsubsequent sustained treatment response in bothHBeAg-positive or HBeAg-negative patients•Suggests that HBsAg monitoring could bebeneficial in identifying •Patients likely to respond favorably in the long term •Patients likely to be nonresponders •Who might benefit from an alternative treatment approach Lau GK, et al. APASL 2009. Abstract PE083. Moucari R, et al. Hepatology. 2009;49:1151-1157. Brunetto MR, et al. Hepatology. 2009;49:1411-1150. Moucari R, et al. J Hepatol. 2009;50:1084-1092. Perillo RP. Hepatology. 2009;49:1063-1065.
    • 48. Summary of PegIFN alfa- 2a as Initial Therapy•Advantages:• finite duration of treatment, durable response in a subsetof responding patients; lack of viral resistancedevelopment•Disadvantages:•administered by subcutaneous injections; associated withsignificant toxicities in most patients•HBeAg and HBsAg seroconversion rates, tolerability, andlikelihood of response to treatment vs nucleos(t)ides allplay a role decision•HBsAg kinetics may offer a early idea of the likelihood ofresponse
    • 49. Other Factors to Consider When Initiating First-line Treatment
    • 50. Recommendations for HBV-Infected Women Who Desire PregnancyWomen with mild liver disease, low viremia Pregnancy before treatmentWomen with moderate liver disease, no cirrhosis Treatment before pregnancy; if response, stop treatment before pregnancyWomen with advanced liver disease Treatment before and during pregnancy; continue treatment after deliveryWomen with mild liver disease, very high viremia Treatment in last trimester with “B” category drug Wedemeyer H, et al. Dtsch Med Wochenschr. 2007;132:1775-1782. EASL HBV Guidelines. J Hepatol. 2009;50:227-242.
    • 51. Dialysis and Renal Transplantation Patients ADV and TDF have been linked to worsening renal function and should be used with caution in renally impaired patients No specific renal toxicity associated with entecavir Dose-adaptation should be used with any agent TDF can be used if dose adjustments are made in response to changes in GFR Monitoring of renal function before and during therapy particularly important.
    • 52. post-exposure prophylaxis
    • 53. Recommended post-exposure prophylaxis for exposure to HBV Vaccination and antibody Treatment response status of Source HBsAg Source HBsAg exposed workers Source unknown +ev -ve HBIG x 1 and initiate Initiate HB vaccine Initiate HB vaccine Unvaccinated HB vaccine series series series Previously vaccinated Known responder No treatment No treatment No treatment HBIG X 1 and initiate No treatment If known high risk Known revaccination source, treat as non-responder* or HBIG X 2 if source were HBsAg positive Test exposed person No treatment Test exposed person Antibody for anti-HBs for anti-HBs response 1. If adequate, no 1. If adequate, no treatment is treatment is unknown necessary. necessary. 2. If inadequate*, 2. If inadequate*, administer administer vaccine HBIG x 1 and booster and vaccine booster. recheck titer in 1-2 months. Source: MMWR, June 29 2001, vol 50, RR-11, p22* A non-responder is a person with inadequate levels of serum antibody to HBsAg (I.e., anti-HBs <10 mIU/mL).
    • 54. Take home message• Suspect and Diagnose.• Initial evaluation includes education o Family and contacts should be tested• Monitor as status changes over time• Selection of patients to treat o Individualize treatment decisions o Change if no/ poor response• Long term monitoring o HCC, special populations, reactivation.
    • 55. Take home messagePrevention is better than cure.
    • 56. THANK YOU
    • 57. Outcomes of chronic Hepatitis Binfection
    • 58. A liver biopsy is indicated in the following scenarios : HBeAg-negative and HBV DNA ≥ 20,000 IU/ml andALT < 2x ULN HBeAg-negative and HBV DNA = 2,000–19,999IU/ml HBeAg-positive and HBV DNA ≥ 20,000 IU/ml andALT < 2x ULN and age ≥ 40
    • 59. Comparison of the drugs used in treatment-naive patients with chronic hepatitis B 100 100Cost /Y 36,500 73,000 1,09500 41,400
    • 60. On interferon alpha therapy:Primary non-response is defined asless than 1 log10 IU/ml decrease in HBV DNA level frombaseline at 3 months of therapy. Virological response is defined as an HBV DNAconcentration of less than 2000 IU/ml at 24 weeksof therapy. Serological response is defined by HBe eroconversionin patients with HBeAg-positive CHB.
    • 61. On NUC therapy:Primary non-response is defined asless than 1 log10 IU/ml decrease in HBV DNA level frombaseline at 3 months of therapy.Virological response is defined as undetectableHBV DNA by real-time PCR assay within 48weeks of therapy. Partial virological response is defined as a decreasein HBV DNA of more than 1 log10 IU/ml butdetectable HBV DNA by real-time PCR assay.
    • 62. Monitor HBV patients who are not in treatment.HBeAg(+) and treatment not indicated: ALT every 3–6 months if WNL; ALT every 1–3 months if 1–2x ULN. HBV DNA viral load every 6–12 months. Liver biopsy if ALT ≥ 2x ULN for 6 months, or if ALT 1–2x ULN for6 months and age ≥ 40.HBeAg(–) and treatment not indicated: ALT every 3 months for 1 year; then every 6–12 months. HBV DNA viral load if ALT > 1–2x ULN. Liver biopsy if persistent ALT elevation or HBV DNA ≥ 2,000 IU/ml.
    • 63. Monitor patients on treatment.Monitoring schedule for Nucleos(t)ide Analogues: ALT and AST levels every 3–6 months HBeAg every 3–6 months (in patients who are HBeAg(+) at start oftreatment) HBsAg every 6–12 months (in patients who are HBeAg(–) at start oftreatment) HBV DNA viral load every 3 months during first year of therapy; thenevery 6 months Serum creatinine every 12 weeks while taking adefovir or tenofovirMonitoring schedule for Interferon alfa:
    • 64. HCV co-infected patientsHBV DNA level is often low or is undetectable and HCV isresponsible for the activity of chronic hepatitis in most patients.patients should receive pegylated interferon alpha withribavirin as for HCV .SVR rates for HCV are broadly comparable with HCVmonoinfected patients .potential risk of HBV reactivation during or after clearance ofHCV that must then be treated with NUCs
    • 65. HIV co-infected patientsHIV-positive patients with CHB are at increased riskof cirrhosis . Treatment of HIV may lead to flaresof hepatitis B due to immune restitution.The indications for therapy are the same as in HIV-negativepatients,it is recommended that most coinfected patients besimultaneously treated for both HIV and HBV de novo. Tenofovir and emtricitabine (FTC) together, plusa third agent active against HIV, are indicated.
    • 66. Acute severe hepatitis 95–99% of adults with acute HBV infection will recoverspontaneously and seroconvert to anti- HBs without anti-viraltherapy.Some patients with fulminant hepatitis or severe protractedsubacute hepatic necrosis may benefit from NUC treatment.potent drugs with a high barrier to resistance, i.e. entecaviror tenofovir, should be used.The duration of treatment is not established.(at least 3 months after seroconversion to anti-HBs or at least 6months after Hbe Seroconversion is recommended)