2EPIDEMIOLOGY Highly endemic in Southeast Asia Materno-fetal transmission in these areas90% transmission if E antigen positive as opposed to 15-20% if E antibody positiveLow incidence since routine screening of blood donors since 1970In U.S , high risk sexual behaviour and IV drug useNo source of infection in 15%
3Natural course of infection Fulminant hepatits in 1%Only 20% survival in fulminant hepatitis, in the absence of liver transplantationHBV carriers: Normal lfts, asymptomatic1-5% become chronically infected30% of above will develop cirrhosis85% , five year survival for compensatec cirrhosis15% , five survival with decompensation
4MOLECULAR BIOLOLGY OF HEP B VIRUS DNA virusGenotypes A-H ( A has best response to IFN )Genotype A is predominant in the U.SReplicationE- AntigenRTcoresurfaceX ProteinPolymeraseCarcinogenesisSurface Antigen
5MOLECULAR BIOLOGY OF HEPATITIS B VIRUS Hepatitis Surface antigen mutationAfter liver transplantationWith chronic Hepatitis Immune globulin administratonResult in recurrence of infectionHep Surface Antigen NegSurface antibody pos (from vaccination)DNA PCR positive
6MOLECULAR BIOLOGY OF HEPATITIS B VIRUS Hepatitis B Pre-Core mutationLoss of E antigenCan cause fulminant hepatitisMay reduce response to InterferonSurface antigen posE antigen negativeE antibody negativePCR positiveHepatitis B Polymerase mutationSeen with treatment with polymerase inhibitors like lamivudine, adefovir etcCalled YMDD mutation
7Hepatitis B virus: Clinical Features and Diagnosis Chike Anusionwu, M.DGI Fellow, PGY 409/23/09
8Clinical Features Incubation period: few wks-6mths (60-90days) Factors that reduce the IPCoinfection: HCV, HDV, HIVUnderlying liver diseaseIP depends on the amount of replicating virus in the inoculum
9Clin Features of Acute infection Acute infections are heralded by a serum sickness-like prodrome of fever, arthralgias/arthritis, and rash, which is most commonly maculopapular or urticarial, in 10% to 20% of patients.This prodrome results from circulating HBsAg-anti-HBs complexes that activate complement and are deposited in the synovium and walls of cutaneous blood vessels.These features generally abate before the manifestations of liver disease and peak serum aminotransferase elevations are observed.Jaundice develops in only about 30% of patients.
10CF of Acute Infections/Labs Clinical symptoms and jaundice generally disappear after 1-3mths, but some pts have prolonged fatigue even after serum ALT levels return to nml.Elev serum ALT levels and serum HBsAg titers decline and disappear together, and in approximately 80% of cases, HBsAg disappears by 12wks after the onset of illness.In 5-10% of cases, HBsAg is cleared early and is no longer detectable by the time the patient first presents to a healthcare provider.Persistence of HBsAg after 6mths implies development of a carrier state, with only a small likelihood of recovery during the next 6-12 mths.Delayed clearance of HBsAg has been reported to be preceded by a decline in HBsAg titers.
11LabsSerum aminotransferase levels of 1000 to 2000 U/L are typical, with ALT being higher than AST levels.In patients with icteric hepatitis, the rise in serum bilirubin levels often lags behind that in ALT levels.The peak ALT level does not correlate with prognosis, and the PT is the best indicator of prognosis.After clinical recovery from acute hepatitis B and HBsAg seroconversion, HBV DNA often remains detectable in serum as determined by a PCR assay.
12Fulminant Hep B Fulminant hepatitis occurs in <1% of cases. Fulminant hepatitis B generally occurs within 4wks of the onset of symptoms and is associated with encephalopathy, multiorgan failure, and a high mortality rate (>80%) if not treated by liver transplantation.Patients >40 years appear to be more susceptible than younger persons to "late-onset liver failure," in which encephalopathy, renal dysfunction, and other extrahepatic complications of severe liver insufficiency become manifest over the course of several months.The pathogenic mechanisms of fulminant hepatitis are poorly understood but are presumed to involve massive immune-mediated lysis of infected hepatocytes.This proposed mechanism may explain why many patients with fulminant hepatitis B have no evidence of HBV replication in serum at presentation.
13Chronic Hep B Hx of acute infection is often lacking Asymptomatic Commons sxs: fatigue, poor appetite and malaise. RUQ pain may occur but is low grade.When superimposed on cirrhosis, reactivation of HBV infection may be assoc with jaundice and signs of liver failure.Features of decompensated cirrhotic Hep B include; spider angiomata, ascites, peripheral edema,hypoAlb, prolonged PT, AST>ALT
14Extrahepatic manifestations Pathogenesis is unclear but likely involves an aberrant immunologic response to extrahepatic viral proteins.Often in assoc with circulating immune complexes that activate serum complement.Examples:ArthritisDermatitisPolyarteritis nodosaGlomerulonephritisEssential mixed cryoglobulinemiaType II(polyclonal IgG and monoclonal IgM)Type III (polyclonal IgG and RF)
15Histopathologic Features Chr HBV infxnmononuclear cell infiltration in the portal triadsNO steatosisGround glass hepatocytesChr Hep C has steatosis
16DiagnosisHBsAg appears in serum 2-10wks after HBV exposure, before sxs or labs changes.In self limiting acute hepatitis, HBsAg disappears in 4-6mths.Persistence of HBsAg >6mths Chr HBVSeveral weeks later, anti-HBs appearspersists for life and provide longterm immunityCoexistence of HBsAg and anti-HBs occurs in 25%.Implies chronic HBV and not acute HBV
17DiagnosisWindow period (several wks-mths)– b/w disappearance of HBsAg and appearance of anti-HBs. Check IgM anti-HBcAnti-HBc is detectable in acute and chronic infective states.In an acute infection,anti-HBc can linger in serum up to 4-6mths.
18Clinical significance of isolated anti-HBc Isolated anti-HBc has a prevalence of 1-4%, in nonendemic areas.Clinical scenarios:during the window period of acute hepatitis B, when anti-HBc is predominantly of the IgM classmany years after recovery from acute hepatitis B, when anti-HBs has fallen to undetectable levelsas a false-positive serologic test resultafter many years of chronic infection, when the HBsAg titer has fallen below the level of detectionin persons who are coinfected with HCVand, rarely, as a result of varying sensitivity of HBsAg assays.Evidence for coinfection with HCV has been demonstrated in up to 60% of persons in whom anti-HBc is the only marker of HBV
19Isolated anti-HBcPCR testing of sera with isolated anti-HBc have shown HBV DNA in 0-30%As a result, the patients are infective.E.g, anti-HBc testing of blood donors prevents some cases of post-transfusion hepatitis B.The risk of transmission of HBV infection from a liver donor with isolated anti-HBc has been found to be as high as 50-70% in some series.
20HBeAg A viral protein found in serum early furing acute infection. HBeAg reactivity usually disappears at or soon after the peak in serum aminotransferase levelspersistence of HBeAg 3 or more months after the onset of illness indicates a high likelihood of transition to chronic HBV infection.HBeAg in serum of an HBsAg carrier indicatesgreater infectivityhigh level of viral replicationthe need for antiviral therapy.
21HBeAg Most HBeAg-positive patients have active liver disease. The exceptions areHBeAg-positive childrenyoung adults with perinatally acquired HBV infxn, who usually have normal serum ALT levels and minimal inflammation of the liver.Seroconversion from HBeAg to anti-HBe is assoc withreduction in serum HBV DNA levels of 3 log10 copies/mL or greaterremission of liver disease.Some patients, however, continue to have active liver disease and detectable HBV DNA in serum because of low levels of wild-type virus or the selection of precore or core promoter mutations that impair HBeAg secretion.
22HBV DNACan be measured in serum with qualitative or quantitative assaysThe clinical utility of testing for serum HBV DNA has been hampered by the absence of a licensed test in the US as well as an accepted international reference standard.A number of non-PCR-based assays are available.are less sensitive than the PCR-based onestheir results correlate with clinical response to antiviral therapyseveral of the currently available antiviral therapies were licensed on the basis of clinical trials in which these assays were used.Use of these less sensitive non-PCR-based assays has several shortcomingsMost clinical laboratories use one of several commercially available PCR assaysNon-PCR based assays sens: copies/mlPCR asays sens: 102 copies or less/ml
23HBV DNA Measurement of serum HBV DNA is used to evaluate a patient's candidacy for antiviral therapyto monitor response during treatment.Pts with high serum HBV DNA levels at baseline respond less to therapy with conventional interferon than pts with low levels.The use of solution hybridization testing, a baseline HBV DNA level of 200 pg/mL (roughly equivalent to 56 million copies/mL on a PCR assay) or greater has been found to be associated with a very low rate of response to standard interferon.
24HBV DNAIn contrast, baseline serum HBV DNA levels have not been shown to correlate with response to nucleoside analog therapybecause of the more potent inhibition of viral replication by these agents.Monitoring of HBV DNA levels during therapy allows one to predictthe likelihood of HBeAg clearance.The likelihood of relapse after treatment is discontinuedDevelopment of resistance to lamivudineReappearance of HBV DNA in serum during treatment suggests that drug resistance has occurred.
25Testing for HBV DNAQualitative PCR is a more sensitive method of detecting HBV DNA than quantitative PCR.Small amts of HBV DNA can be detected in serum and peripheral mononuclear cells, years after recovery from acute hepatitis B.Even after disappearance of HBsAg and apparent loss of HBV DNA from serum in patients with chronic hepatitis B, small amounts of HBV DNA persist in liver tissue and peripheral mononuclear cells years later.Detection of HBV DNA in serum by a qualitative PCR assaybefore liver transplantation may identify patients who are at increased risk of apparent de novo hepatitis after transplantationmay pinpoint HBV as the cause of liver disease in HBsAg-negative patients.in diagnosing patients with fulminant hepatitis B, who frequently have cleared HBsAg by the time they seek medical attention.
29Diagnostic criteria Chronic hepatitis B 1. HBsAg-positive 6 months 2. Serum HBV DNA 20,000 IU/mL, lower values 2, ,000 IU/mL are often seen in HBeAg-negative chronic hepatitis B 3. Persistent or intermittent elevation in ALT/AST levels 4. Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation
30Diagnostic criteria Inactive HBsAg carrier state 1. HBsAg-positive 6 months2. HBeAg–, anti-Hbe+3. Serum HBV DNA 2,000 IU/mL4. Persistently normal ALT/AST levels5. Liver biopsy confirms absence of significant hepatitis
31Liver Biopsy Role in management in hepatitis B The purpose of a liver biopsy is to assess the degree ofliver damage and to rule out other causes of liver disease.Liver biopsy is most useful in persons who do not meetclear cut guidelines for treatment .Recent studies suggest that the upper limits of normal for ALT and AST should be decreased to 30 U/L for men and 19U/L for women.HBV infected patients with ALT values close to the upper limit of normal may have abnormal histology and can be at increased risk of mortality from liver disease especially those above age 40.
32Patients that should be considered for treatment of hepatitis B Patients with HBeAg-positive ALT greater than 2 times normal or moderate/severe hepatitis on biopsy, and HBV DNA >20,000 IU/mL.
33Medications for hepatitis B treatment First-line oral antiviral medications-tenofovir (viread) mg-entecavir, (baraclude) 0.5mg-interferon (for patients without cirrhosis)Second-line oral antiviral medications.-adeofovir (hepsera) 10mg-lamividine (epivir, 3TC) 100mg-telbivudine (tyzeka) 600mgOther: Emtricitabine (Emitriva, FTC) and Truvada (in combination with tenofovir, approve for HIV treatment
34Serum HBV DNA levels of 20,000 IU/mL and elevated ALT levels : -entecavir, tenofovir, or peginterferon alfa-2a might be considered as first-line options;High levels of serum HBV DNA and/or normal levels of ALT:-given that response to interferon-based therapy is low in this population, however, entecaviror tenofovir would be preferred
35Emtricitabine (emtriva, FTC) It is a potent inhibitor of HIV and hep BIt approved for HIV treatment as emtriva and as Truvada (in combination with tenofovir as a single pill)
36Duration of treatment● IFN-alpha: 16 weeks ● PegIFN-alpha: 48 weeks ● LAM/ADV/ETV/LdT/TDF: minimum 1 year, continue for at least 6 months after HBeAg seroconversion
37Important points about Duration of treatment Hbe Ag-positive patients continue to be treated after HBeAg seroconversion as long as HBV DNA levels are decreasing and until the HBV DNA levels are undetectable by PCR. Treatment then should be continued for an additional 12 months.In patients who undergo HBeAg seroconversion but who still havedetectable but stable HBV DNA levels, treatment should becontinued for 6 months; seroconversion should be documentedagain, and then consideration should be given to stoppingtreatment in patients without cirrhosis. Patients who relapsecan be re-treated.HBeAg-positive patients who fail to lose HBeAg should be treated long-term because the chance of HBeAg seroconversion increases with time, and there is a high risk of recurring viremia if therapy is stopped in the absence of HBeAg seroconversion.
38End-point of treatment Seroconversion from HBeAg to anti-HBe
39Patients who failed to achieve primary response Patients who failed to achieve primary response as evidenced by <2 log decrease in serum HBV DNA level after at least 6 months of NA therapy should be switched to an alternative treatment or receive additional treatment.
40Recommendations for Treatment: HBeAg-Positive CHB HBV DNA ALT Treatment strategy <20,000 Normal No treatment Monitor every 6–12 mo Consider therapy if significant histologic disease, even if low level replication
41Recommendations for Treatment: HBeAg-Positive CHB HBV DNA ALT Treatment strategy >20,000 Normal Consider liver biopsy particularly if patient is 35–40 y; treat if disease; in the absence of biopsy examination, observe increase in ALT levels
42Recommendations for Treatment: HBeAg-Positive CHB HBV DNA ALT Treatment strategy>20, Elevated Entecavir, tenofovir, or peginterferon alfa-2a preferred
43Duration of therapyHBeAg-positive patients continue to be treated after HBeAg seroconversion as long as HBV DNA levels are decreasing and until the HBV DNA levels are undetectable by PCR.Treatment then should be continued for an additional 12 months.In patients who undergo HBeAg seroconversion but who still have detectable but stable HBV DNA levels, treatment should be continued for 6 months then consideration should be given to stopping treatment in patients without cirrhosis. Patients who relapse can be re-treated.
44Duration of therapyHBeAg-positive patients who fail to lose HBeAg should be treated long-term because the chance of HBeAg seroconversion increases with time, and there is a highrisk of recurring viremia if therapy is stopped in the absence of HBeAg seroconversion
45Recommendations for Treatment: HBeAg-Negative CHB HBV DNA ALT Treatment strategy <2000 Normal No treatment; majority are inactive HBsAg carriers Monitor every 6–12 mo Consider therapy if significant histologic disease, even if low level replication
46Recommendations for Treatment: HBeAg-Positive CHB HBV DNA ALT Treatment strategy >2000 Normal Consider liver biopsy particularly if patient is 35–40 y; treat if disease; in the absence of biopsy examination, observe increase in ALT levels
47Recommendations for Treatment: HBeAg-Positive CHB HBV DNA ALT Treatment strategy> Elevated Entecavir, tenofovir, or peginterferon alfa-2a preferredLong-term treatment required for oral agents
48Duration of therapy for HBeAg-negative patients HBeAg-negative patients who are receiving therapy should be monitored every 6 months.The duration of therapy with peginterferon remains unclear, although longer treatment (12 months) appears to be more beneficial in terms of sustained virologic response off treatment than do shorter periods of treatment.Entecavir, tenofovir, and telbivudine need to be given for the long term;
49Monitoring Virologic Response and Management of Resistance to Oral Antiviral Therapy Prolonged antiviral therapy is associated with the development of antiviral resistance.The long term rates of resistance are highest for lamivudine (65%–70% at4–5 years), intermediate for telbivudine (25% in HBeAg-positivepatients and 11% in HBeAg-negative patients at 2 years),lower for adefovir (29% at 5 years),and lowest for entecavir in the absence of prior lamivudine resistance (1.2% at 5 years) and for tenofovir in treatment-naïve patients (0% at 1 year).The development of resistance is associated with loss of initial response and HBV DNA rebound →biochemical breakthrough→reversion of histologic improvement and in some cases, resistance leads to progressive liver disease
50On-Treatment Monitoring Serum HBV DNA levels should be monitored at 12 weeks to determine primary treatmentfailure (HBV DNA decline of <1 log10 IU/mL) and at 24 weeks to confirm adequate virologic suppression by antiviral therapy.At 24 weeks, virologic response should be categorized as complete, partial, or inadequate, according to the following definitions:-complete, HBV DNA level 60 IU/mL;-partial, HBV DNA level 60 to 2000 IU/mL; and inadequate, HBV DNA level 2000 IU/mL
52Recommendation for all cases of HBV resistance The recommendation for all cases of HBV resistance is to use add-on therapy with a drug in another class, while continuing therapy with the original drug, or to switch to another drug within that same class but one that is more potent
53Management of Antiviral-Resistant HBV Prevention ● Avoid unnecessary treatment ● Initiate treatment with potent antiviral that has low rate of drug resistance or with combination therapy ● Switch to alternative therapy in patients with primary non-response Monitoring ● Test for serum HBV DNA (PCR assay) every 3-6 months during treatment ● Check for medication compliance in patients with virologic breakthrough ● Confirm antiviral resistance with genotypic testing
54Management of Antiviral-Resistant HBV TreatmentLamivudine-resistance → Add adefovir or tenofovirStop lamivudine, switch to Truvada in HIVAdefovir-resistance → Add lamivudineStop adefovir, switch to Truvada in HIVSwitch to or add entecavirEntecavir-resistance → Switch to tenofovir or TruvadaTelbivudine-resistance→ Add adefovir or tenofovirStop telbivudine, switch to Truvada
55Treatment of Cirrhotic (HBeAg-Positive or HBeAg-Negative) HBV DNA Cirrhosis Treatment strategy <2000 Compensated Might choose to treat or observe Entecavir or tenofovir preferred >2000 Compensated Entecavir or tenofovir are first-line options Long-term treatment required, and combination therapy might be preferred
56Treatment of Cirrhotic (HBeAg-Positive or HBeAg-Negative) HBV DNA Cirrhosis Treatment strategy Any detectable Decompensated Combination with lamivudine, or possibly entecavir, plus tenofovir preferred Long-term treatment required, and combinationtherapy might be preferred Wait list for liver transplantation