Chronic Hepatitis B: management update. E.O.Ogutu Department of clinical medicine & therapeutics, University of Nairobi. Physicians meeting,kisumu 2011.
Background epidemiology Chronic hepatitis B (CHB) is an important public health problem & a leading cause of liver related morbidity & mortality worldwide (Lee WM, Hepatitis B virus infection. N Engl. J. Med. 1997, 337: 1733 1745) In the USA an estimated 1.25 million individuals (0.4%) of the population are infected with hepatitis B virus. ( McQuillan GM et al Am J. Public Health 1999,89:14 18) In Kenya the HBsAg carrier rate is about 10%(Okoth e tal)
CHB: Disease progression If unrx. individuals with hepa s B are at risk of developing: Liver cirrhosis Hepatic decompensation HCC Cumulative rate of morbidity & mortality from cirrhosis & HCC is highest in those who acquire HBV infection as neonates or in early childhood. (Lee WM. N. Engl. J Med. 1997, 337: 1733 1745)
CHB: Natural history/phases of HBV infection Immune tolerance Immune clearance Inactive carrier Resolution Reactivation (Chu CM et al. Current hepatitis reports 2004:3:123 131 Yim HJ. Et al. Hepatology 2006;43:s173 s181.)
CHB: What defines the Phases. Immune tolerance: ALT: Normal or minimally HBV DNA: High levels >20,000 Iu/ml (> 10 5 copies/ml) HBeAg +ve., anti. Hbe ve. Liver Histology: Minimal activity: absent or scant fibrosis
CHB: What defines the Phases. Immune tolerance phase Note : Acquisition of HBV at birth or early childhood is associated with: a long latency period of immune tolerance, which might last for 2 3 decades before immune clearance, characterized by HBeAg seroconversion to antibody to HBeAg ( anti. Hbe) Late acquisition is associated with a very short immune tolerance phase or none at all. (Chu CM et al. Current hepatitis reports 2004:3:123 131 ( Lai CL et al Ann Intern Med 2007;147:58 61)
CHB: What defines the Phases. Immune clearance: ( HBeAg +ve CHB) ALT: Persistently or intermi ently Serum HBV DNA > 20,000 Iu/ml Liver histology: Active with necroinflammation score 4. HBsAg +ve. >6months
CHB: What defines the Phases. Inactive carrier:( HBsAg > 6months) HBsAg +ve. & IgG anti HBc +ve ALT normal HBV DNA low or undetectable ( <2000Iu/ml.) HBeAg ve. anti. Hbe +ve. Liver histology: Inactive with minimal fibrosis & necroinflamation score <4.
CHB: What defines the Phases. Reactivation HBeAg ve. CHB, ant. HBe +ve. & HBsAg +ve. HBV DNA ( > 2000 Iu/ml) ALT Fluctua ng Resolution (HBsAg ve.) ALT : Normal HBeAg ve. Anti Hbe +ve. HBV DNA ve. In serum, Low levels might be detected in the liver, in form of covalently closed circular DNA (cccdna) Liver histology inactive.
CHB: Risk factors for disease progression Viral factors HBeAg +ve :Hazard ratio(hr) 4.2 HBV DNA level > 2000Iu/ml: HR 2.7 >20,000Iu/ml: HR 8.9 10.7 Host factors: Male gender: HR 3.0 Advanced age(>35): HR 3.6 8.3 Alcohol consumption: HR 2.6 Cigarette smoking HR 1.7
CHB: Risk factors for disease progression Other factors: Co infection with HCV,HDV,or HIV HBV genotype: Worse with genotype C Presence of HBV precore & especially core promoter mutation ALT elevation: ( Severity & Frequency )
CHB: Patient evaluation: History: e.g. F/H of :HBV infection, liver cancer Risk factors for co infection Alcohol use
CHB( HBsAg +ve >6months): Patient evaluation: Laboratory: Liver biochemistry (ALT, Albumin, PTI) Anti. HBc. ( IgG, IgM) HBeAg, anti HBe Markers of HBV replication: (HBV DNA) Check for co infection: HCV(anti HCV), HDV( anti HDV) HAV(IgM. anti HAV) HIV HBV Genotype in selected cases. TBC & Urinalysis & U/E + creatinine. Alfa feto protein
CHB: Patient evaluation: Imaging Abdominal ultrasound CT scan MRI Fibroscan: If available: Evaluates degree of fibrosis Liver biopsy
CHB: Patient evaluation: Liver biopsy: Indications: Pa ents with intermi ent or persistent in ALT Pts. With elevated serum HBV DNA (HBeAg +ve. >20,0000Iu/ml: HBeAg ve: >2000Iu/ml.) but normal ALT particularly if >35yrs of age Mass lesion
ALT: CHB: Patient evaluation: Practical points. NOTE : Cut off level of upper limit of normal in pts. With CHB is lower than for commercial level. Males: 30 Iu/ml Females: 19 Iu/ml
CHB: Patient evaluation: Practical points. HBV DNA: Serum HBV DNA must be done in all pts. With CHB It is a direct measure of viral replication It characterizes the state of replication It predicts the risk of cirrhosis, liver decompensation & HCC. This is x4 fold if HBeAg is +ve. (Liaw YF et al Liver Int 2006;26:23 29, de Jorgh FE et al Gastroenterology 1992;103:1630 1635) ( 1Iu/ml = 5 6 copies/ml )
CHB: Patient evaluation: Practical points. HBV Genotype Influences : +ve progression of disease Risk of HCC Response to therapy Genotype B: Associated with early HBeAg seroconversion at an early age Genotype C: Associated with severe disease progression & HCC Genotype A&B: Associated with better response to therapy ( Pegylated INF but not Nucleos(t)ide analogue)
CHB: Interpretation of serological tests:(some aspects) Chronic hepatitis HBsAg +ve > 6 months & IgG anti HBc +ve. The onset of CHB infection is marked by continual presence of HBsAg, High serum levels of HBV DNA & +ve HBeAg in serum.
CHB: Interpretation of serological tests:(some aspects) Occult hepatitis HBsAg ve, IgG anti HBc +ve. HBV DNA +ve at low levels <2000Iu/ml Resolved hepatitis: HBsAg ve., anti HBs +ve. anti HBc +ve. Vaccinated recipient: HBsAg ve. anti HBs +ve, anti HBc ve., (Emmet B Keeffe et al.clinical Gastroenterology & hepatology 2008;6:1315 41)
CHB: Goal of Therapy 1. Eliminate or significantly suppress the replication of CHB (HBV DNA suppression to possible lowest level) This leads to : ALT normalization & histological improvement THUS Prevent the progression of liver disease to cirrhosis, decompensation, HCC (Emmet B Keeffe et al.clinical Gastroenterology & hepatology 2008;6:1315 41)
CHB: Goal of Therapy 2. HBeAg loss with seroconversion to anti Hbe. in pts. Who are HBeAg +ve at the initiation of Rx. The complete HBeAg seroconversion indicates a high likelihood that the benefit will persist once the patient is off therapy. Note: continue Rx. For at least 6months after seroconversion if on NA. (Emmet B Keeffe et al.clinical Gastroenterology & hepatology 2008;6:1315 41) (Lok As Hepatology 2009;50:661 662)
CHB: Goal of Therapy 3. HBsAg loss: This would be a Rx. End point in pts. Who are HBeAg ve at the initiation of therapy However this is rarely achieved, hence an unrealistic goal. Thus pts who are HBeAg ve should be treated for life if on NA (Emmet B Keeffe et al.clinical Gastroenterology & hepatology 2008;6:1315 41) (Lok As Hepatology 2009;50:661 662)
CHB: Drug therapy What drugs are available: 7 drugs are currently available Interferon α 2b 5 10 mu/dose x3/wk. Peg Interferon α 2a 180µg s/c/wk. Lamivudine 100mg P.O. OD Adefovir 10mg/day PO OD Entecavir 0.5mg 1.0mg/day PO, OD Telbivudine 600mg OD PO Tenofovir 300mg OD PO (Lok AS et al Hepatol 2009; 50: 661 662)
CHB: Drug therapy What is the current recommended 1 st. Line therapy: Peg Interferon alfa 2a Exception: Pregnancy, chemotherapy prophylaxis,decompensated cirrhosis, acute infection Entecavir Tenofovir (EASL. J hepatol 2009;50:227 242, Liaw F et al Hepatol int. 2008; 2: 263 283, Lok AS et al Hepatol 2009;50: 661 662)
CHB: Drug therapy NOTE: Lamivudine : Has been removed from the list of preferred 1 st. Line drugs because of high rate of resistance (Keeffe EB,et al Clin Gastroenterol Hepatol 2006;4:936 962; Lai CL et al N Engl J Med 2007;357:2576 2588; Keeffe EB et al Clin Gastroenterol Hepatol 2008;6:1315 1341 )
CHB: Who to treat 1. Pt. Who is HBsAg With: HBV DNA 20,000 Iu/ml & Normal ALT Should have a liver biopsy done particularly if >30yrs. Of age If histology is: Stage 2 &/or grade 2 necroinflammation. TREAT NOTE: Pt.<30yrs. Liver biopsy is optional as is in immune tolerance phase of infection & is unlikely to have significant disease & responds poorly to Rx.
CHB: Who to treat 2. ALT > ( 1 2 xuln) with: HBV DNA 20,000 Iu/ml ( HBeAg +ve.) 2000Iu/ml (HBeAg ve.) TREAT even without liver biopsy
CHB: Who to treat 3. HBeAg +ve or ve with : underlying cirrhosis or HIV co infection TREAT If HBV DNA 2000Iu/ml
CHB: Who not to treat. 1. High HBV DNA & Normal ALT Particularly if <35yrs of age: They tend to be in immune tolerance phase, thus have minimal disease activity on liver biopsy. Those >35yrs. Do liver biopsy & Rx. If significant stage & / or grade NOTE: Always consider ALT levels in conjunction with serum HBV DNA & Pts. Age.
CHB: Treatment end point: Nucleoside/Nucleotide analougue 1. HBeAg +ve: Rx. Until : HBeAg seroconversion + Undetectable HBV DNA by PCR Then continue for a further 6 12 months. Rx. For life if no sero conversion 2. HBeAg ve: HBV DNA undetectable, ALT normal HBsAg loss end point is rare so is unrealistic Hence Rx. Is life long
CHB: Treatment end point: Peg Interferon Duration is 1yr. Effect continues after stopping Rx. NOTE: Despite prolonged HBV DNA suppression relapse is common unless there is loss & seroconversion of HBsAg This effect is better with PEG Interferon> NA.
CHB: When to consider PEG INF Favourable predictors of response: Lower baseline HBV DNA < 10 9 copies/ml High ALT Genotype A&B
CHB: When to consider PEG INF Specific patient demographics Young ( particularly females intending to be pregnant in the near future) Absence of Comorbidities Patient preference Concomitant HCV infection
CHB: When not to consider PEG INF Patients with Cirrhosis, particularly when decompensated Pregnancy Immunosuppressed pts. Lange CM et al Hepatology 2009;50:2001 2006 Lok AS et al Hepatology 2010;52:743 47
Cumulative rates of resistance with oral agents in Nucleos(t)ide naive pts. Drug Resistance Rate 1 st. Generation Yr1 Yr2 Yr3 Yr4 Yr5 Lamivudine 24% 38% 49% 67 70% 2 nd. Generation Adefovir 0% 3% 11% 18% 29% Telbivudine 4% 17% 3 rd. Generation Entecavir 0.2% 0.5% 1.2% 1.2% 1.2% Tenofovir 0% 0% 0% EASL J Hepatol. 2009; 50: 227 242, Healthcole E et al AASLD 2009; Abstract 48
None exists Resistance:Pegylated INF
CHB: Management of antiviral resistance Lamivudine Restance: Add adefovir OR tenofovir Stop LAM & switch to Tenofovir/Emtricitabine. Adefovir Resistance Add LAM OR Entecavir Stop adefovir & switch to Tenofovir/Emtricitabine
CHB: Management of antiviral resistance Entecavir Resistance: Switch to Tenofovir *Tenofovir/Emtritabine Telbivudine Resistance: Add adefovir or Tenofovir Stop Telbuvidine & switch to *Tenofovir/Emtricitabine Lok AS Hepatology 2010;52:743 747
CHB: Management of antiviral resistance NOTE: Ac vity of Entecavir is in LAM/Telbuvidine resistance Ac vity of Tenofovir is in Adefovir resistance Lok AS Hepatology 2010;52:743 747
CHB: Management of antiviral Tenofovir: No resistance resistance HIV co infected Pts. Use Tenofovir/Emtricitabine ( Truvada) Lok AS et al Hepatol 2009;50:61 62
CHB: Management of antiviral resistance When possible, it is most beneficial to use the most potent nucleos(t)ide analogue that posses the lowest risk of genotype resistance as initial therapy for pts. With nucleos(t)ide naive disease. The development of resistance is associated with loss of initial response & HBV DNA rebound which is followed by biochemical breakthro, & eventual reversion of histological improvement.
Pegylated Interferon Entecavir Tenofovir CHB:1 o Drugs Tenofovir/Emtricitabine (TRUVADA) in HBV/HIV co infected pt.
CHB: Special Population Groups. Cirrhosis: Compensated: Viral load 2000Iu/ml Preferred therapies: Entecavir & tenofovir NAs preferred over IFN as the latter can be associated with hepatic flares Long term Rx. Preferred Lok As et al Hepatology 2009; 50:661 662
CHB: Special Population Groups. Decompensated Cirrhosis R x. If there is any detectable HBV DNA Tenofovir or Entecavir monotherapy (Alt. LAM or Telbuvidine + Adefovir or Tenofovir) Liver transplant INF is C/I Life long Rx. Is recommended Lok AS et al. Hepatology 2009;50:661 662
CHB: Special Population Groups. HBV/HIV Co infected HBV Rx.Indicated BUT HIV (HAART) not indicated HBeAg ve.: Adefovir 10mg OD HBeAg +ve : Consider PEG INF IF Fails Adefovir Choose drug (NA) with no effect on HIV Telbivudin not recommended because of HBV resistance rate Lok As et al Hepatology 2009;50:661 667
CHB: Special Population Groups. HBV/HIV Co infection HAART Indicated BUT HBV Rx. Not indicated: Choose anti HIV drugs with no effect on HBV
CHB: Special Population Groups. HBV/HIV Co infection HAART & HBV ( HBV DNA 2000Iu/ml) treatment Indicated. Choose drug with dual activity Preferred: Tenofovir + LAM or Emtricitabine Entecavir not recommended as is associated with induction of HIV resistant mutation
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