HEPATITIS BHEPATITIS B

EPIDEMIOLOGYEPIDEMIOLOGY

• Highly endemic in Southeast AsiaHighly endemic in Southeast Asia• Materno-fetal transmission in these areasMaterno-fetal transmission in these areas• 90% transmission if E antigen positive as 90% transmission if E antigen positive as

opposed to 15-20% if E antibody positiveopposed to 15-20% if E antibody positive• Low incidence since routine screening of Low incidence since routine screening of

blood donors since 1970blood donors since 1970• In U.S , high risk sexual behaviour and IV In U.S , high risk sexual behaviour and IV

drug usedrug use• No source of infection in 15%No source of infection in 15%

Natural course of infectionNatural course of infection

• Fulminant hepatits in 1%Fulminant hepatits in 1%• Only 20% survival in fulminant hepatitis, in Only 20% survival in fulminant hepatitis, in

the absence of liver transplantationthe absence of liver transplantation• HBV carriers: Normal lfts, asymptomaticHBV carriers: Normal lfts, asymptomatic• 1-5% become chronically infected1-5% become chronically infected• 30% of above will develop cirrhosis30% of above will develop cirrhosis• 85% , five year survival for compensatec 85% , five year survival for compensatec

cirrhosiscirrhosis• 15% , five survival with decompensation15% , five survival with decompensation

MOLECULAR BIOLOLGY OF HEP MOLECULAR BIOLOLGY OF HEP B VIRUSB VIRUS• DNA virusDNA virus

• Genotypes A-H ( A has best response Genotypes A-H ( A has best response to IFN )to IFN )

• Genotype A is predominant in the U.SGenotype A is predominant in the U.S

core surface X Protein Polymerase

E- Antigen

Surface Antigen

Carcinogenesis

Replication

RT

MOLECULAR BIOLOGY OF MOLECULAR BIOLOGY OF HEPATITIS B VIRUSHEPATITIS B VIRUS

• Hepatitis Surface antigen mutationHepatitis Surface antigen mutation– After liver transplantationAfter liver transplantation– With chronic Hepatitis Immune globulin With chronic Hepatitis Immune globulin

administratonadministraton– Result in recurrence of infectionResult in recurrence of infection

•Hep Surface Antigen NegHep Surface Antigen Neg

•Surface antibody pos (from vaccination)Surface antibody pos (from vaccination)

•DNA PCR positiveDNA PCR positive

MOLECULAR BIOLOGY OF MOLECULAR BIOLOGY OF HEPATITIS B VIRUSHEPATITIS B VIRUS• Hepatitis B Pre-Core mutationHepatitis B Pre-Core mutation

– Loss of E antigenLoss of E antigen– Can cause fulminant hepatitisCan cause fulminant hepatitis– May reduce response to InterferonMay reduce response to Interferon

• Surface antigen posSurface antigen pos• E antigen negativeE antigen negative• E antibody negativeE antibody negative• PCR positivePCR positive

• Hepatitis B Polymerase mutationHepatitis B Polymerase mutation– Seen with treatment with polymerase inhibitors Seen with treatment with polymerase inhibitors

like lamivudine, adefovir etclike lamivudine, adefovir etc– Called YMDD mutationCalled YMDD mutation

Hepatitis B virus:Hepatitis B virus:Clinical Features and Clinical Features and

DiagnosisDiagnosis

Chike Anusionwu, M.DChike Anusionwu, M.D

GI Fellow, PGY 4GI Fellow, PGY 4

09/23/0909/23/09

Clinical FeaturesClinical Features

• Incubation period: few wks-6mths Incubation period: few wks-6mths (60-90days)(60-90days)

• Factors that reduce the IPFactors that reduce the IP– Coinfection: HCV, HDV, HIVCoinfection: HCV, HDV, HIV– Underlying liver diseaseUnderlying liver disease

Clin Features of Acute Clin Features of Acute infectioninfection• Acute infections are heralded by a serum sickness-Acute infections are heralded by a serum sickness-

like prodrome of fever, arthralgias/arthritis, and like prodrome of fever, arthralgias/arthritis, and rash, which is most commonly maculopapular or rash, which is most commonly maculopapular or urticarial, in 10% to 20% of patients.urticarial, in 10% to 20% of patients.

• This prodrome results from circulating HBsAg-anti-This prodrome results from circulating HBsAg-anti-HBs complexes that activate complement and are HBs complexes that activate complement and are deposited in the synovium and walls of cutaneous deposited in the synovium and walls of cutaneous blood vessels.blood vessels.

• These features generally abate before the These features generally abate before the manifestations of liver disease and peak serum manifestations of liver disease and peak serum aminotransferase elevations are observed.aminotransferase elevations are observed.

• Jaundice develops in only about 30% of patients. Jaundice develops in only about 30% of patients.

CF of Acute Infections/LabsCF of Acute Infections/Labs• Clinical symptoms and jaundice generally disappear after 1-Clinical symptoms and jaundice generally disappear after 1-

3mths, but some pts have prolonged fatigue even after 3mths, but some pts have prolonged fatigue even after serum ALT levels return to nml.serum ALT levels return to nml.

• Elev serum ALT levels and serum HBsAg titers decline and Elev serum ALT levels and serum HBsAg titers decline and disappear together, and in approximately 80% of cases, disappear together, and in approximately 80% of cases, HBsAg disappears by 12wks after the onset of illness.HBsAg disappears by 12wks after the onset of illness.

• In 5-10% of cases, HBsAg is cleared early and is no longer In 5-10% of cases, HBsAg is cleared early and is no longer detectable by the time the patient first presents to a detectable by the time the patient first presents to a healthcare provider. healthcare provider.

• Persistence of HBsAg after 6mths implies development of a Persistence of HBsAg after 6mths implies development of a carrier state, with only a small likelihood of recovery during carrier state, with only a small likelihood of recovery during the next 6-12 mths. the next 6-12 mths.

• Delayed clearance of HBsAg has been reported to be Delayed clearance of HBsAg has been reported to be preceded by a decline in HBsAg titers. preceded by a decline in HBsAg titers.

LabsLabs• Serum aminotransferase levels of 1000 to 2000 U/L Serum aminotransferase levels of 1000 to 2000 U/L

are typical, with ALT being higher than AST levels.are typical, with ALT being higher than AST levels.• In patients with icteric hepatitis, the rise in serum In patients with icteric hepatitis, the rise in serum

bilirubin levels often lags behind that in ALT levels. bilirubin levels often lags behind that in ALT levels. • The peak ALT level does not correlate with The peak ALT level does not correlate with

prognosis, and the PT is the best indicator of prognosis, and the PT is the best indicator of prognosis.prognosis.

• After clinical recovery from acute hepatitis B and After clinical recovery from acute hepatitis B and HBsAg seroconversion, HBV DNA often remains HBsAg seroconversion, HBV DNA often remains detectable in serum as determined by a PCR assay.detectable in serum as determined by a PCR assay.

Fulminant Hep B Fulminant Hep B • Fulminant hepatitis occurs in <1% of cases. Fulminant hepatitis occurs in <1% of cases. • Fulminant hepatitis B generally occurs within 4wks of the Fulminant hepatitis B generally occurs within 4wks of the

onset of symptoms and is associated with encephalopathy, onset of symptoms and is associated with encephalopathy, multiorgan failure, and a high mortality rate (>80%) if not multiorgan failure, and a high mortality rate (>80%) if not treated by liver transplantation. treated by liver transplantation.

• Patients >40 years appear to be more susceptible than Patients >40 years appear to be more susceptible than younger persons to "late-onset liver failure," in which younger persons to "late-onset liver failure," in which encephalopathy, renal dysfunction, and other extrahepatic encephalopathy, renal dysfunction, and other extrahepatic complications of severe liver insufficiency become manifest complications of severe liver insufficiency become manifest over the course of several months.over the course of several months.

• The pathogenic mechanisms of fulminant hepatitis are The pathogenic mechanisms of fulminant hepatitis are poorly understood but are presumed to involve massive poorly understood but are presumed to involve massive immune-mediated lysis of infected hepatocytes. immune-mediated lysis of infected hepatocytes.

• This proposed mechanism may explain why many patients This proposed mechanism may explain why many patients with fulminant hepatitis B have no evidence of HBV with fulminant hepatitis B have no evidence of HBV replication in serum at presentation. replication in serum at presentation.

Chronic Hep BChronic Hep B• Hx of acute infection is often lackingHx of acute infection is often lacking• AsymptomaticAsymptomatic• Commons sxs: fatigue, poor appetite and Commons sxs: fatigue, poor appetite and

malaise. RUQ pain may occur but is low grade.malaise. RUQ pain may occur but is low grade.• When superimposed on cirrhosis, reactivation of When superimposed on cirrhosis, reactivation of

HBV infection may be assoc with jaundice and HBV infection may be assoc with jaundice and signs of liver failure. signs of liver failure.

• Features of decompensated cirrhotic Hep B Features of decompensated cirrhotic Hep B include; spider angiomata, ascites, peripheral include; spider angiomata, ascites, peripheral edema,hypoAlb, prolonged PT, AST>ALTedema,hypoAlb, prolonged PT, AST>ALT

Extrahepatic manifestationsExtrahepatic manifestations• Pathogenesis is unclear but likely involves an Pathogenesis is unclear but likely involves an

aberrant immunologic response to extrahepatic aberrant immunologic response to extrahepatic viral proteins. viral proteins.

• Often in assoc with circulating immune Often in assoc with circulating immune complexes that activate serum complement. complexes that activate serum complement.

• Examples:Examples:– ArthritisArthritis– DermatitisDermatitis– Polyarteritis nodosaPolyarteritis nodosa– GlomerulonephritisGlomerulonephritis– Essential mixed cryoglobulinemiaEssential mixed cryoglobulinemia

– Type II(polyclonal IgG and monoclonal IgM)Type II(polyclonal IgG and monoclonal IgM)– Type III (polyclonal IgG and RF)Type III (polyclonal IgG and RF)

Histopathologic FeaturesHistopathologic Features

• Chr HBV infxnChr HBV infxn– mononuclear cell infiltration in the portal triadsmononuclear cell infiltration in the portal triads– NO steatosisNO steatosis– Ground glass hepatocytesGround glass hepatocytes

DiagnosisDiagnosis• HBsAg appears in serum 2-10wks after HBsAg appears in serum 2-10wks after

HBV exposure, before sxs or labs changes.HBV exposure, before sxs or labs changes.• In self limiting acute hepatitis, HBsAg In self limiting acute hepatitis, HBsAg

disappears in 4-6mths.disappears in 4-6mths.• Persistence of HBsAg >6mthsPersistence of HBsAg >6mths Chr HBV Chr HBV• Several weeks later, anti-HBs appearsSeveral weeks later, anti-HBs appears

• persists for life and provide longterm immunitypersists for life and provide longterm immunity

• Coexistence of HBsAg and anti-HBs occurs Coexistence of HBsAg and anti-HBs occurs in 25%. in 25%.

• Implies chronic HBV and not acute HBVImplies chronic HBV and not acute HBV

DiagnosisDiagnosis• Window period (several wks-mths)– Window period (several wks-mths)–

b/w disappearance of HBsAg and b/w disappearance of HBsAg and appearance of anti-HBs. Check IgM appearance of anti-HBs. Check IgM anti-HBcanti-HBc

• Anti-HBc is detectable in acute and Anti-HBc is detectable in acute and chronic infective states.chronic infective states.

• In an acute infection,anti-HBc can In an acute infection,anti-HBc can linger in serum up to 4-6mths.linger in serum up to 4-6mths.

Clinical significance of isolated anti-Clinical significance of isolated anti-HBcHBc• Isolated anti-HBc has a prevalence of 1-4%, in nonendemic Isolated anti-HBc has a prevalence of 1-4%, in nonendemic

areas.areas.• Clinical scenarios:Clinical scenarios:

– during the window period of acute hepatitis B, when anti-HBc during the window period of acute hepatitis B, when anti-HBc is predominantly of the IgM classis predominantly of the IgM class

– many years after recovery from acute hepatitis B, when anti-many years after recovery from acute hepatitis B, when anti-HBs has fallen to undetectable levelsHBs has fallen to undetectable levels

– as a false-positive serologic test resultas a false-positive serologic test result– after many years of chronic infection, when the HBsAg titer has after many years of chronic infection, when the HBsAg titer has

fallen below the level of detectionfallen below the level of detection– in persons who are coinfected with HCVin persons who are coinfected with HCV– and, rarely, as a result of varying sensitivity of HBsAg assays.and, rarely, as a result of varying sensitivity of HBsAg assays.

• Evidence for coinfection with HCV has been demonstrated Evidence for coinfection with HCV has been demonstrated in up to 60% of persons in whom anti-HBc is the only in up to 60% of persons in whom anti-HBc is the only marker of HBV marker of HBV

Isolated anti-HBcIsolated anti-HBc• PCR testing of sera with isolated anti-HBc PCR testing of sera with isolated anti-HBc

have shown HBV DNA in 0-30%have shown HBV DNA in 0-30%• As a result, the patients are infective.As a result, the patients are infective.• E.g, anti-HBc testing of blood donors E.g, anti-HBc testing of blood donors

prevents some cases of post-transfusion prevents some cases of post-transfusion hepatitis B.hepatitis B.

• The risk of transmission of HBV infection The risk of transmission of HBV infection from a liver donor with isolated anti-HBc from a liver donor with isolated anti-HBc has been found to be as high as 50-70% in has been found to be as high as 50-70% in some series.some series.

HBeAgHBeAg• A viral protein found in serum early furing acute infection.A viral protein found in serum early furing acute infection.

• HBeAg reactivity usually disappears at or soon after the HBeAg reactivity usually disappears at or soon after the peak in serum aminotransferase levelspeak in serum aminotransferase levels

• persistence of HBeAg 3 or more months after the onset of persistence of HBeAg 3 or more months after the onset of illness indicates a high likelihood of transition to chronic illness indicates a high likelihood of transition to chronic HBV infection.HBV infection.

• HBeAg in serum of an HBsAg carrier indicates HBeAg in serum of an HBsAg carrier indicates – greater infectivitygreater infectivity– high level of viral replicationhigh level of viral replication– the need for antiviral therapy. the need for antiviral therapy.

HBeAgHBeAg• Most HBeAg-positive patients have active liver disease.Most HBeAg-positive patients have active liver disease.• The exceptions areThe exceptions are

– HBeAg-positive childrenHBeAg-positive children– young adults with perinatally acquired HBV infxn, who usually have young adults with perinatally acquired HBV infxn, who usually have

normal serum ALT levels and minimal inflammation of the liver.normal serum ALT levels and minimal inflammation of the liver.

• Seroconversion from HBeAg to anti-HBe is assoc withSeroconversion from HBeAg to anti-HBe is assoc with– reduction in serum HBV DNA levels of 3 log10 copies/mL or greaterreduction in serum HBV DNA levels of 3 log10 copies/mL or greater– remission of liver disease. remission of liver disease.

• Some patients, however, continue to have active liver Some patients, however, continue to have active liver disease and detectable HBV DNA in serum because of low disease and detectable HBV DNA in serum because of low levels of wild-type virus or the selection of precore or core levels of wild-type virus or the selection of precore or core promoter mutations that impair HBeAg secretion. promoter mutations that impair HBeAg secretion.

HBV DNAHBV DNA• Can be measured in serum with qualitative or quantitative Can be measured in serum with qualitative or quantitative

assaysassays• The clinical utility of testing for serum HBV DNA has been The clinical utility of testing for serum HBV DNA has been

hampered by the absence of a licensed test in the US as hampered by the absence of a licensed test in the US as well as an accepted international reference standard. well as an accepted international reference standard.

• A number of non-PCR-based assays are available. A number of non-PCR-based assays are available. – are less sensitive than the PCR-based onesare less sensitive than the PCR-based ones– their results correlate with clinical response to antiviral therapytheir results correlate with clinical response to antiviral therapy– several of the currently available antiviral therapies were several of the currently available antiviral therapies were

licensed on the basis of clinical trials in which these assays licensed on the basis of clinical trials in which these assays were used. were used.

• Use of these less sensitive non-PCR-based assays has Use of these less sensitive non-PCR-based assays has several shortcomingsseveral shortcomings

• Most clinical laboratories use one of several commercially Most clinical laboratories use one of several commercially available PCR assays available PCR assays

HBV DNAHBV DNA• Measurement of serum HBV DNA is usedMeasurement of serum HBV DNA is used

– to evaluate a patient's candidacy for antiviral therapyto evaluate a patient's candidacy for antiviral therapy– to monitor response during treatment. to monitor response during treatment.

• Pts with high serum HBV DNA levels at baseline Pts with high serum HBV DNA levels at baseline respond less to therapy with conventional respond less to therapy with conventional interferon than pts with low levels.interferon than pts with low levels.– The use of solution hybridization testing, a baseline HBV DNA The use of solution hybridization testing, a baseline HBV DNA

level of 200 pg/mL (roughly equivalent to 56 million copies/mL level of 200 pg/mL (roughly equivalent to 56 million copies/mL on a PCR assay) or greater has been found to be associated on a PCR assay) or greater has been found to be associated with a very low rate of response to standard interferon.with a very low rate of response to standard interferon.

HBV DNAHBV DNA• In contrast, baseline serum HBV DNA levels have In contrast, baseline serum HBV DNA levels have

not been shown to correlate with response to not been shown to correlate with response to nucleoside analog therapynucleoside analog therapy– because of the more potent inhibition of viral replication by because of the more potent inhibition of viral replication by

these agents. these agents.

• Monitoring of HBV DNA levels during therapy Monitoring of HBV DNA levels during therapy allows one to predictallows one to predict– the likelihood of HBeAg clearance.the likelihood of HBeAg clearance.– The likelihood of relapse after treatment is discontinuedThe likelihood of relapse after treatment is discontinued– Development of resistance to lamivudineDevelopment of resistance to lamivudine

• Reappearance of HBV DNA in serum during Reappearance of HBV DNA in serum during treatment suggests that drug resistance has treatment suggests that drug resistance has occurred.occurred.

Testing for HBV DNATesting for HBV DNA• Qualitative PCR is a more sensitive method of Qualitative PCR is a more sensitive method of

detecting HBV DNA than quantitative PCR. detecting HBV DNA than quantitative PCR.

• Small amts of HBV DNA can be detected in serum Small amts of HBV DNA can be detected in serum and peripheral mononuclear cells, years after and peripheral mononuclear cells, years after recovery from acute hepatitis B.recovery from acute hepatitis B.– Even after disappearance of HBsAg and apparent loss of HBV Even after disappearance of HBsAg and apparent loss of HBV

DNA from serum in patients with chronic hepatitis B, small DNA from serum in patients with chronic hepatitis B, small amounts of HBV DNA persist in liver tissue and peripheral amounts of HBV DNA persist in liver tissue and peripheral mononuclear cells years later.mononuclear cells years later.

• Detection of HBV DNA in serum by a qualitative PCR Detection of HBV DNA in serum by a qualitative PCR assayassay– before liver transplantation may identify patients who are at before liver transplantation may identify patients who are at

increased risk of apparent de novo hepatitis after transplantationincreased risk of apparent de novo hepatitis after transplantation– may pinpoint HBV as the cause of liver disease in HBsAg-may pinpoint HBV as the cause of liver disease in HBsAg-

negative patients.negative patients.– in diagnosing patients with fulminant hepatitis B, who frequently in diagnosing patients with fulminant hepatitis B, who frequently

have cleared HBsAg by the time they seek medical attention. have cleared HBsAg by the time they seek medical attention.

In SummaryIn Summary

Table summaryTable summary

Hepatitis BHepatitis B

Waheed GulWaheed Gul

GI FellowGI Fellow

Diagnostic criteriaDiagnostic criteriaChronic hepatitis BChronic hepatitis B

1. HBsAg-positive 6 months1. HBsAg-positive 6 months

2. Serum HBV DNA 20,000 IU/mL, lower 2. Serum HBV DNA 20,000 IU/mL, lower values 2,000- 20,000 IU/mL are often seen values 2,000- 20,000 IU/mL are often seen in HBeAg-negative chronic hepatitis Bin HBeAg-negative chronic hepatitis B

3. 3. Persistent or intermittent elevation Persistent or intermittent elevation in ALT/AST levelsin ALT/AST levels

4. Liver biopsy showing chronic hepatitis 4. Liver biopsy showing chronic hepatitis with moderate or severe with moderate or severe necroinflammationnecroinflammation

Diagnostic criteriaDiagnostic criteriaInactive HBsAg carrier stateInactive HBsAg carrier state

• 1. HBsAg-positive 6 months1. HBsAg-positive 6 months

• 2. HBeAg–, anti-Hbe+2. HBeAg–, anti-Hbe+

• 3. Serum HBV DNA 2,000 IU/mL3. Serum HBV DNA 2,000 IU/mL

• 4. 4. Persistently normal ALT/AST Persistently normal ALT/AST levelslevels

• 5. Liver biopsy confirms absence of 5. Liver biopsy confirms absence of significant hepatitissignificant hepatitis

Liver BiopsyLiver BiopsyRole in management in Role in management in hepatitis Bhepatitis B• The purpose of a liver biopsy is to assess the The purpose of a liver biopsy is to assess the

degree ofdegree ofliver damage and to rule out other causes of liver liver damage and to rule out other causes of liver disease.disease.

• Liver biopsy is most useful in persons who do Liver biopsy is most useful in persons who do not meetnot meetclear cut guidelines for treatment clear cut guidelines for treatment ..

• Recent studies suggest that the upper limits of Recent studies suggest that the upper limits of normal for ALT and AST should be decreased to 30 normal for ALT and AST should be decreased to 30 U/L for men and 19U/L for men and 19U/L for womenU/L for women..

• HBV infected patients with ALT values close to the HBV infected patients with ALT values close to the upper limit of normal may have abnormal histology upper limit of normal may have abnormal histology and can be at increased risk of mortality from liver and can be at increased risk of mortality from liver disease especially those above age 40. disease especially those above age 40.

Patients that should be Patients that should be considered for treatment of considered for treatment of hepatitis Bhepatitis B

Patients with HBeAg-positivePatients with HBeAg-positive

ALT greater than 2 times normal ALT greater than 2 times normal

or or

moderate/severe hepatitis on moderate/severe hepatitis on biopsy, biopsy,

and and

HBV DNA >20,000 IU/mLHBV DNA >20,000 IU/mL. .

Medications for hepatitis B Medications for hepatitis B treatmenttreatment• First-line oral antiviral medications First-line oral antiviral medications

-tenofovir (viread) -tenofovir (viread) 300 mg 300 mg -entecavir, (baraclude)-entecavir, (baraclude) 0.5mg0.5mg-interferon (for patients without cirrhosis)-interferon (for patients without cirrhosis)

• Second-line oral antiviral medications.Second-line oral antiviral medications.--adeofovir (hepsera)adeofovir (hepsera) 10mg 10mg -lamividine (epivir, 3TC)-lamividine (epivir, 3TC) 100mg100mg-telbivudine (tyzeka)-telbivudine (tyzeka) 600mg600mg

• Other: Other: Emtricitabine (Emitriva, FTC) and Emtricitabine (Emitriva, FTC) and Truvada (in combination with tenofovir, approve Truvada (in combination with tenofovir, approve for HIV treatmentfor HIV treatment

• Serum HBV DNA levels of 20,000 Serum HBV DNA levels of 20,000 IU/mL and elevated ALT levelsIU/mL and elevated ALT levels : :-entecavir, tenofovir, or peginterferon -entecavir, tenofovir, or peginterferon alfa-2a might be considered as first-line alfa-2a might be considered as first-line options;options;

• High levels of serum HBV DNA High levels of serum HBV DNA and/or normal levels of ALT:and/or normal levels of ALT:--given that response to interferon-given that response to interferon-based therapy is low in this population, based therapy is low in this population, however, entecavirhowever, entecaviror tenofovir would be preferred or tenofovir would be preferred

Emtricitabine (emtriva, FTC)Emtricitabine (emtriva, FTC)

• It is a potent inhibitor of HIV and hep It is a potent inhibitor of HIV and hep BB

• It approved for HIV treatment as It approved for HIV treatment as emtriva and as Truvada (in emtriva and as Truvada (in combination with tenofovir as a combination with tenofovir as a single pill)single pill)

Duration of treatmentDuration of treatment

● ● IFN-alpha: 16 weeksIFN-alpha: 16 weeks

● ● PegIFN-alpha: 48 weeksPegIFN-alpha: 48 weeks

● ● LAM/ADV/ETV/LdT/TDF: LAM/ADV/ETV/LdT/TDF:

minimum 1 year, continue for at minimum 1 year, continue for at least 6 least 6 months after HBeAg months after HBeAg seroconversionseroconversion

Important points about Important points about Duration of treatmentDuration of treatment• Hbe Ag-positive patients continue to be treated after HBeAg Hbe Ag-positive patients continue to be treated after HBeAg

seroconversion as long as HBV DNA levels are decreasing and seroconversion as long as HBV DNA levels are decreasing and until the HBV DNA levels are undetectable by PCR. Treatment until the HBV DNA levels are undetectable by PCR. Treatment then should be continued for an additional 12 months.then should be continued for an additional 12 months.

• In patients who undergo HBeAg seroconversion but who still In patients who undergo HBeAg seroconversion but who still havehavedetectable but stable HBV DNA levels, treatment should bedetectable but stable HBV DNA levels, treatment should becontinued for 6 months; seroconversion should be documentedcontinued for 6 months; seroconversion should be documentedagain, and then consideration should be given to stoppingagain, and then consideration should be given to stoppingtreatment in patients without cirrhosis. Patients who relapsetreatment in patients without cirrhosis. Patients who relapsecan be re-treated. can be re-treated.

• HBeAg-positive patients who fail to lose HBeAg should be HBeAg-positive patients who fail to lose HBeAg should be treated long-term because the chance of HBeAg treated long-term because the chance of HBeAg seroconversion increases with time, and there is a high risk of seroconversion increases with time, and there is a high risk of recurring viremia if therapy is stopped in the absence of recurring viremia if therapy is stopped in the absence of HBeAg seroconversion.HBeAg seroconversion.

End-point of treatmentEnd-point of treatment

• Seroconversion from HBeAg to anti-Seroconversion from HBeAg to anti-HBeHBe

Patients who failed to Patients who failed to achieve primary responseachieve primary response

• Patients who failed to achieve Patients who failed to achieve primary response as evidenced by primary response as evidenced by <2 log decrease in serum HBV DNA <2 log decrease in serum HBV DNA level after at least 6 months of NA level after at least 6 months of NA therapy should be switched to an therapy should be switched to an alternative treatment or receive alternative treatment or receive additional treatment.additional treatment.

Recommendations for Recommendations for Treatment: HBeAg-Positive Treatment: HBeAg-Positive CHBCHBHBV DNAHBV DNA ALT ALT Treatment Treatment

strategystrategy

<20,000 <20,000 Normal Normal No treatmentNo treatment

Monitor every 6–12 moMonitor every 6–12 mo

Consider therapy ifConsider therapy ifsignificant histologic significant histologic

disease, even if lowdisease, even if lowlevel replicationlevel replication

Recommendations for Recommendations for Treatment: HBeAg-Positive Treatment: HBeAg-Positive CHBCHBHBV DNAHBV DNA ALT ALT Treatment Treatment

strategystrategy

>20,000 >20,000 Normal Normal Consider liver biopsy Consider liver biopsy

particularly if patient is particularly if patient is 35–40 y; treat if disease; 35–40 y; treat if disease; in the absence of biopsyin the absence of biopsy

examination, observe examination, observe increase in ALT levelsincrease in ALT levels

Recommendations for Recommendations for Treatment: HBeAg-Positive Treatment: HBeAg-Positive CHBCHBHBV DNAHBV DNA ALT ALT

Treatment strategyTreatment strategy

• >20,000 >20,000 Elevated Entecavir, Elevated Entecavir, tenofovir, tenofovir, or or peginterferon alfa-2a peginterferon alfa-2a preferredpreferred

Duration of therapyDuration of therapy

• HBeAg-positive patients continue to be HBeAg-positive patients continue to be treated after HBeAg seroconversion as long treated after HBeAg seroconversion as long as HBV DNA levels are decreasing and until as HBV DNA levels are decreasing and until the HBV DNA levels are undetectable by the HBV DNA levels are undetectable by PCR. PCR. Treatment then should be continued for an Treatment then should be continued for an additional 12 months. additional 12 months.

• In patients who undergo HBeAg In patients who undergo HBeAg seroconversion but who still have detectable seroconversion but who still have detectable but stable HBV DNA levels, treatment should but stable HBV DNA levels, treatment should be continued for 6 months then be continued for 6 months then consideration should be given to stopping consideration should be given to stopping treatment in patients without cirrhosis. treatment in patients without cirrhosis. Patients who relapse can be re-treated. Patients who relapse can be re-treated.

Duration of therapyDuration of therapy

• HBeAg-positive patients who fail to HBeAg-positive patients who fail to lose HBeAg should be treated long-lose HBeAg should be treated long-term because the chance of term because the chance of HBeAg seroconversion increases with HBeAg seroconversion increases with time, and there is a hightime, and there is a high

risk of recurring viremia if therapy is risk of recurring viremia if therapy is stopped in the absence of HBeAg stopped in the absence of HBeAg seroconversionseroconversion

Recommendations for Recommendations for Treatment: HBeAg-Negative Treatment: HBeAg-Negative CHBCHBHBV DNAHBV DNA ALT ALT Treatment Treatment

strategystrategy<2000 <2000 Normal Normal No treatment; majority No treatment; majority

are inactive HBsAg are inactive HBsAg carriers carriers

Monitor every 6–12 moMonitor every 6–12 moConsider therapy ifConsider therapy ifsignificant histologic significant histologic disease, even if lowdisease, even if low

level replicationlevel replication

Recommendations for Recommendations for Treatment: HBeAg-Positive Treatment: HBeAg-Positive CHBCHBHBV DNAHBV DNA ALT ALT Treatment Treatment

strategystrategy

>2000 >2000 Normal Normal Consider liver biopsy Consider liver biopsy

particularly if patient is particularly if patient is 35–40 y; treat if disease; 35–40 y; treat if disease; in the absence of biopsyin the absence of biopsy

examination, observe examination, observe increase in ALT levelsincrease in ALT levels

Recommendations for Recommendations for Treatment: HBeAg-Positive Treatment: HBeAg-Positive CHBCHBHBV DNAHBV DNA ALT ALT Treatment Treatment

strategystrategy

• >2000 >2000 Elevated Entecavir, Elevated Entecavir, tenofovir, tenofovir, or or peginterferon alfa-2a peginterferon alfa-2a preferredpreferred

Long-term treatment Long-term treatment required for oral agents required for oral agents

Duration of therapy for Duration of therapy for HBeAg-negative patients HBeAg-negative patients

• HBeAg-negative patients who are receiving HBeAg-negative patients who are receiving therapy should be monitored every 6 months. therapy should be monitored every 6 months.

• The duration of therapy with peginterferon The duration of therapy with peginterferon remains unclear, although longer treatment remains unclear, although longer treatment (12 months) appears to be more beneficial in (12 months) appears to be more beneficial in terms of sustained virologic response off terms of sustained virologic response off treatment than do shorter periods of treatment than do shorter periods of treatment.treatment.

• Entecavir, tenofovir, and telbivudine need to Entecavir, tenofovir, and telbivudine need to be given for the long term;be given for the long term;

Monitoring Virologic Response Monitoring Virologic Response andandManagement of Resistance to Management of Resistance to OralOralAntiviral TherapyAntiviral Therapy• Prolonged antiviral therapy is associated with the Prolonged antiviral therapy is associated with the

development of antiviral resistance. development of antiviral resistance. • The long term rates of resistance are highest for The long term rates of resistance are highest for

lamivudine (65%–70% atlamivudine (65%–70% at4–5 years), intermediate for telbivudine (25% in HBeAg-4–5 years), intermediate for telbivudine (25% in HBeAg-positivepositivepatients and 11% in HBeAg-negative patients at 2 years),patients and 11% in HBeAg-negative patients at 2 years),lower for adefovir (29% at 5 years),and lowest for lower for adefovir (29% at 5 years),and lowest for entecavir in the absence of prior lamivudine resistance entecavir in the absence of prior lamivudine resistance (1.2% at 5 years) and for tenofovir in treatment-naïve (1.2% at 5 years) and for tenofovir in treatment-naïve patients (0% at 1 year).patients (0% at 1 year).

• The development of resistance is associated with loss of The development of resistance is associated with loss of initial response and initial response and HBV DNA reboundHBV DNA rebound → →biochemical biochemical breakthroughbreakthrough→→reversion of histologic improvementreversion of histologic improvement and in some cases, and in some cases, resistance leads to resistance leads to progressive liver diseaseprogressive liver disease

On-Treatment On-Treatment MonitoringMonitoring• Serum HBV DNA levels should be monitored Serum HBV DNA levels should be monitored

at 12 weeks to determine primary treatmentat 12 weeks to determine primary treatmentfailure (HBV DNA decline of <1 log10 IU/mL) failure (HBV DNA decline of <1 log10 IU/mL) and at 24 weeks to confirm adequate and at 24 weeks to confirm adequate virologic suppression by antiviral therapy. virologic suppression by antiviral therapy.

• At 24 weeks, virologic response should be At 24 weeks, virologic response should be categorized as complete, partial, or categorized as complete, partial, or inadequate, according to the following inadequate, according to the following definitions: definitions: -complete, HBV DNA level 60 IU/mL; -complete, HBV DNA level 60 IU/mL; -partial, HBV DNA level 60 to 2000 IU/mL; -partial, HBV DNA level 60 to 2000 IU/mL; and inadequate, HBV DNA level 2000 IU/mLand inadequate, HBV DNA level 2000 IU/mL

Recommendation for all Recommendation for all cases of HBV resistancecases of HBV resistance

• The recommendation for all cases of The recommendation for all cases of HBV resistance is to use add-on HBV resistance is to use add-on therapy with a drug in another class, therapy with a drug in another class, while continuing therapy with the while continuing therapy with the original drug, or to switch to another original drug, or to switch to another drug within that same class but one drug within that same class but one that is more potentthat is more potent

Management of Antiviral-Management of Antiviral-Resistant HBVResistant HBV

PreventionPrevention● ● Avoid unnecessary treatmentAvoid unnecessary treatment● ● Initiate treatment with potent antiviral that has low Initiate treatment with potent antiviral that has low rate of drug resistancerate of drug resistanceor with combination therapyor with combination therapy● ● Switch to alternative therapy in patients with Switch to alternative therapy in patients with primary non-responseprimary non-responseMonitoringMonitoring● ● Test for serum HBV DNA (PCR assay) every 3-6 Test for serum HBV DNA (PCR assay) every 3-6 months during treatmentmonths during treatment● ● Check for medication compliance in patients with Check for medication compliance in patients with virologic breakthroughvirologic breakthrough● ● Confirm antiviral resistance with genotypic testingConfirm antiviral resistance with genotypic testing

Management of Antiviral-Management of Antiviral-Resistant HBVResistant HBV

TreatmentTreatmentLamivudine-resistance →Lamivudine-resistance → Add adefovir or tenofovirAdd adefovir or tenofovir Stop lamivudine, switch to Stop lamivudine, switch to Truvada in HIV Truvada in HIV Adefovir-resistance →Adefovir-resistance → Add lamivudineAdd lamivudine Stop adefovir, switch to Stop adefovir, switch to Truvada in HIV Truvada in HIV Switch to or add entecavirSwitch to or add entecavirEntecavir-resistance →Entecavir-resistance → Switch to tenofovir or Switch to tenofovir or TruvadaTruvadaTelbivudine-resistance→Telbivudine-resistance→ Add adefovir or tenofovirAdd adefovir or tenofovirStop telbivudine, switch to Stop telbivudine, switch to TruvadaTruvada

Treatment of Cirrhotic Treatment of Cirrhotic (HBeAg-Positive or HBeAg-(HBeAg-Positive or HBeAg-NegativeNegative))HBV DNA HBV DNA Cirrhosis Cirrhosis Treatment strategyTreatment strategy<2000 <2000 Compensated Compensated Might choose to Might choose to

treat or observe treat or observe Entecavir or Entecavir or tenofovir preferredtenofovir preferred

>2000 >2000 Compensated Compensated Entecavir or tenofovir areEntecavir or tenofovir arefirst-line optionsfirst-line optionsLong-term treatmentLong-term treatmentrequired, and required, and

combinationcombinationtherapy might be therapy might be

preferredpreferred

Treatment of Cirrhotic Treatment of Cirrhotic (HBeAg-Positive or HBeAg-(HBeAg-Positive or HBeAg-NegativeNegative))HBV DNA HBV DNA Cirrhosis Cirrhosis Treatment strategyTreatment strategyAny detectable Decompensated Any detectable Decompensated Combination Combination

withwithlamivudine, or possiblylamivudine, or possiblyentecavir, plus tenofovirentecavir, plus tenofovirpreferredpreferredLong-term treatment Long-term treatment required, required,

and and combinationtherapy combinationtherapy might be might be preferredpreferred

Wait list for liverWait list for livertransplantationtransplantation