AASLD guidelines for treatment of chronic hepatitis B
Potential conflict of interest: Dr. Jonas consults and received grants from Gilead. She received grants from Bristol‐Myers Squibb and Roche. Dr. Chang advises Genentech, Alnylam, and Arbutus. Dr. Terrault consults for Bristol‐Myers Squibb and received grants from Gilead. Dr. Bzowej received grants from Gilead, Synageva, and Ocera. The funding for the development of this Practice Guideline was provided by the American Association for the Study of Liver Diseases. This Practice Guideline was approved by the AASLD on August 1, 2015. This Practice Guideline published with accompanying Reviews by Lok et al., Jonas et al., and Brown et al. See Editorial on Page 31 Objectives and Guiding Principles Guiding Principles This document presents official recommendations of the American Association for the Study of Liver Diseases (AASLD) on the treatment of chronic hepatitis B (CHB) virus (HBV) infection in adults and children. Unlike previous AASLD practice guidelines, this guideline was developed in compliance with the Institute of Medicine standards for trustworthy practice guidelines and uses the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach.1 Multiple systematic reviews of the literature were conducted to support the recommendations in this practice guideline. An enhanced understanding of this guideline will be obtained by reading the applicable portions of the systematic reviews. This guideline focuses on using antiviral therapy in chronic HBV infection and does not address other related and important issues, such as screening, prevention, and surveillance. For broader issues related to diagnosis, surveillance, and prevention as well as treatment in special populations (e.g., liver transplant recipients) that are not addressed by this guideline, the previous AASLD guideline2 and recent World Health Organization (WHO) guideline3 are excellent additional resources. Objectives Guideline developers from the AASLD formulated a list of discrete questions that physicians are faced with in daily practice. These questions were: Should adults with immune active CHB be treated with antiviral therapy to decrease liver‐related complications? Should adults with immune‐tolerant infection be treated with antiviral therapy to decrease liver‐related complications? Should antiviral therapy be discontinued in hepatitis B e antigen (HBeAg)‐positive persons who have developed HBeAg seroconversion on therapy? Should antiviral therapy be discontinued in persons with HBeAg‐negative infection with sustained HBV DNA suppression on therapy? In HBV‐monoinfected persons, does entecavir therapy, when compared to tenofovir therapy, have a different impact on renal and bone health? Is there a benefit to adding a second antiviral agent in persons with persistent low levels of viremia while being treated with either tenofovir or entecavir? Should persons with compensated cirrhosis and low levels of viremia be treated with antiviral agents? Should pregnant women who are hepatitis B surface antigen (HBsAg) positive with high viral load receive antiviral treatment in the third trimester to prevent perinatal transmission of HBV? Should children with HBeAg‐positive CHB be treated with antiviral therapy to decrease liver‐related complications? Target Audience This guideline is intended primarily for health care professionals caring for patients with CHB. Additionally, this guideline may assist policy makers in optimizing the care of individuals living with CHB. Background Burden of Disease Globally, an estimated 240 million persons have CHB with a varying prevalence geographically, highest in Africa and Asia.4 In the United States, the National Health and Nutrition Examination Survey (1999 to 2008) identified approximately 704,000 adults with CHB,5 but with adjustments for hepatitis B infection among foreign‐born persons, the upper estimate of CHB in the United States may be as high as 2.2 million.6 Globally, deaths from cirrhosis and hepatocellular carcinoma (HCC) were estimated at 310,000 and 340,000 per year, respectively.7 To reduce the morbidity and mortality of CHB in the United States and worldwide, there is a need for continued efforts to identify infected individuals through targeted screening, prevent new infections through vaccination, and monitor and treat those at risk for complications of their CHB, including surveillance for HCC.8 Natural History in Adults and Children CHB has been traditionally characterized into four phases (Table 1), reflecting the dynamic relationship between viral replication and evolution and the host immune response. These phases are of variable duration and not every person infected with CHB will evolve through all phases. Given the dynamic nature of CHB infection, serial monitoring of HBV DNA and alanine aminotransferase (ALT) levels is important to characterize the phase of infection. A single ALT and HBV DNA level are insufficient to assign phase of infection and/or need for treatment. Of note, some persons will be in the “gray zones,” meaning that their HBV DNA and ALT levels do not fall into the same of ALT and HBV DNA levels and/or of liver to the phase of infection. In this HBV DNA levels are ALT levels are for and for and are of or The duration of this phase is but in those who are infected there is an of from immune‐tolerant to the HBeAg‐positive HBeAg‐positive ALT and HBV DNA levels in with liver characterize this of is among those infected at a The of from the HBeAg‐positive to phases is HBeAg The of seroconversion from HBeAg to to HBeAg is per in children of and and among adults to and per year, CHB In this HBV DNA levels are low or ALT levels are and is Liver but variable reflecting previous liver the HBeAg‐positive persons who HBeAg will to in the CHB of have or to HBeAg HBeAg‐negative immune those who from HBeAg to to have ALT and high HBV DNA and of may have of HBV replication and of hepatitis of of persons HBV in the or and liver and with HBeAg‐negative CHB to have HBV DNA levels those with HBeAg‐positive CHB and are to a of CHB ALT HBV DNA HBeAg Liver phase million and HBeAg‐positive phase or CHB phase or but variable HBeAg‐negative immune phase or CHB infection is by of with of to of persons with CHB will will to levels of HBV DNA are in the in the of persons of or antiviral therapy, risk of and of liver‐related complications is adults with CHB, of cirrhosis is and among those with risk of is and risk of is and of cirrhosis and (Table HBV DNA ALT and HBeAg are among the important of risk of to HBV DNA levels HBeAg and cirrhosis are of A of risk has been in adults with HBV DNA levels a HBV DNA level is with of cirrhosis and and and of of in Africa HBV DNA ALT levels to HBeAg seroconversion Development of HBeAg‐negative CHB of cirrhosis HBV DNA ALT to HBeAg seroconversion Development of HBeAg‐negative CHB viral infections and viral infections and and of CHB The of persons with CHB a and with special on risk for and of HBV infection and liver of liver and of HBV and for with hepatitis virus hepatitis virus or virus in those at risk (Table to the nature of CHB, the of high HBV DNA level at a single in is and monitoring of is to need for antiviral The upper of for ALT on are from all including those with liver Evaluation of Examination patients of cirrhosis and risk of including HBV DNA to need for or or patients to other of chronic liver liver HBV in those who have not Liver of the of liver is important in antiviral therapy and need for surveillance. Liver an of the of and other of liver and may be for persons who for treatment. liver is as the to the of and to are of hepatitis B may to of by and different for and on ALT levels have been of such as aminotransferase and have in persons with or on the but in and may be in The of antiviral treatment are to decrease the morbidity and mortality related to CHB. The of a sustained suppression of HBV replication has been with of of HBeAg with or of and in liver the was in treatment of CHB, that of DNA the of in the of in persons with of infection, a risk for of infection. an may be by and sustained HBV DNA suppression and a by of including the The is not an are approved for the treatment of adults with CHB in the United States and approved for the treatment of children with CHB (Table are with therapy with all have an excellent a of persons with CHB, including those with cirrhosis and transplant The in for are For persons with the treatment is For persons with treatment of HBV to be with therapy that HBV have and in Adults and Children in in Potential on million in adults and in children to every monitoring for and complications daily daily to levels daily B and levels or to levels daily daily renal at at risk for renal and at bone at and treatment in persons with of or for levels daily daily B at at risk for renal and at bone at and treatment in persons with of or for levels need to be in persons with renal is not approved for children with CHB, but is approved for treatment of chronic hepatitis may using this for children with chronic The duration of treatment in adults is in adults is daily or or in children and at and For children and at the entecavir and and are to the of therapy (Table are on therapy and therapy The of sustained is but this is with of in Adults CHB and Disease HBV DNA HBeAg HBeAg seroconversion 31 HBV DNA of of of DNA for for entecavir and DNA for for entecavir and by of Guideline Development The questions a for by the guidelines are in CHB therapy treatment of CHB, adults therapy treatment of HBeAg‐positive chronic with HBeAg seroconversion on therapy antiviral therapy antiviral therapy of HBeAg‐negative chronic with viral suppression on antiviral therapy antiviral therapy antiviral therapy of CHB on treatment with therapy bone health CHB on treatment with therapy with persistent viremia therapy or therapy HBV of HBeAg CHB with with HBV DNA therapy treatment women with CHB therapy in third trimester treatment CHB in the HBeAg‐positive CHB, therapy treatment HBeAg of A and the of A of AASLD with an with in systematic reviews to the and the systematic the (Table In this the of in is as or low on the of and risk of and The recommendations on the of of and and and are as to patients with or to the of patients and are with the of are to recommendations to to of the questions are as an to this For the questions with and are The the of Study of of when of when (e.g., (e.g., the low of the of a Recommendation of of and and and of the of Recommendation in this the of and a Health care receive the of The be as a policy in The of in this the of but Health care to patients a that is with their using and is a need for and of of CHB The AASLD antiviral therapy for adults with CHB or HBeAg to decrease the risk of liver‐related of of The AASLD or tenofovir as therapy for adults with CHB. of of CHB is by an of ALT or of HBV DNA or The for ALT in adults is for and for is insufficient for or of ALT other ALT The to treat persons with ALT the but of of liver by or is for persons with CHB and cirrhosis HBV DNA of ALT in the to treat persons with CHB but ALT and HBV DNA is with of of treatment of and may to treatment is a risk for of for treatment of liver of HBV DNA be with and the be as a but not for treatment. of antiviral to of therapy in risk in liver‐related in and entecavir as the important was the of with that need to be in between and tenofovir for therapy of treatment (Table is in persons with and of is not in this A therapy with or of antiviral that is in is (Table HBV A and B are to HBeAg and with is for For persons treated with duration is in and is This treatment duration HBeAg seroconversion of and sustained HBV DNA suppression in of persons who HBeAg to The of and has not of or and is not of therapy for therapy is variable and by HBeAg duration of HBV DNA and of in persons with Evaluation for of using or liver is in treatment including duration of with does not the risk of and surveillance for in persons who are at Background CHB is a dynamic characterized by variable of immune that in the development of liver and liver‐related in a of ALT and HBV DNA levels are of risk of liver a of infection, HBV and HBV and The of HBV therapy is to prevent liver‐related morbidity and in the phases of infection positive and of liver and/or and HBV DNA levels with a risk of liver and and The is in A of were to treatment and of or were and were a of provided in persons with and provided in persons with antiviral compared to treatment and compared therapy to treatment. A to antiviral was not to the of per The of was for low to low to of per was per For the of was and The of the treatment in liver‐related and and of risk and among to of the of the therapy to was with risk in cirrhosis in risk and a risk in and and a risk in the of persons with antiviral therapy risk of and liver but not in mortality In by of therapy, and of cirrhosis and but were with of and The for treatment in a person with is the of liver or as by ALT levels or on and/or active HBV of treatment in adults for ALT to ALT and ALT for is that the ALT levels of adults are for and for using ALT for the to treatment of adults with ALT of the for and for is the ALT in the The HBV DNA levels to are on of with from that the risk of liver‐related complications with HBV DNA levels In systematic liver‐related in persons antiviral therapy by HBV DNA level and in Liver are not to treatment of the of previous to treatment is important in treatment duration of therapy, and does not the ALT and HBV DNA at treatment be A high on and on are with of the with treatment seroconversion and HBV DNA such as may be in cirrhosis have high but are in of or and high ALT levels are with and this to be into in are to risk benefit for persons with ALT and HBV DNA (e.g., for HBeAg positive and for HBeAg who are in the “gray for ALT and HBV DNA for treatment to the of of in treatment are is a need for treatment that the HBV to of Adults CHB The AASLD antiviral therapy for adults with immune‐tolerant CHB. of of be by ALT levels for and for women as The AASLD that ALT levels be at every for adults with immune‐tolerant CHB to monitor for to or CHB. of low of The AASLD antiviral therapy in the of adults of with ALT and HBV DNA and liver or of low of or on liver is a to of antiviral therapy, other of liver are Background Natural have a between HBV DNA levels and the development of and of ALT HBV and HBeAg in This the of adults in the immune‐tolerant phase of infection benefit from antiviral Of note, as In using ALT of for and for and is in the of HBeAg‐positive adults with high HBV DNA In persons who their infection at or in the of from immune‐tolerant to phases is is with of in HBeAg‐positive persons with ALT and The is in of in immune‐tolerant adults with ALT ALT for were with treatment duration of for or for with of HBeAg and seroconversion as the antiviral therapy to treatment were the this The were of different antiviral to antiviral therapy in a of HBeAg and seroconversion of by treatment and all that different from The were and the to persons with ALT were low to low are that antiviral therapy is in of and liver‐related in persons with immune‐tolerant CHB. treatment duration for of HBeAg but not and among including persons with ALT The persons with HBeAg‐positive immune active a for antiviral Given the of of benefit to those with ALT of immune‐tolerant the of antiviral therapy, including antiviral and development of Additionally, there are to a for treatment of immune‐tolerant persons with of the of persons with ALT levels and high HBV DNA levels have and/or on liver the of with for adults with an immune‐tolerant but or antiviral therapy is but the of this is of therapy and are to and of antiviral therapy in adults in the immune‐tolerant phase of CHB, in persons with of of HBeAg to on The AASLD that HBeAg‐positive adults cirrhosis with CHB who to on therapy a of treatment of of The of therapy treatment for at of ALT levels and HBV DNA is not a duration of reduce of an is to treat treatment duration and of treatment of and for health risk for liver and of continued antiviral therapy, with and and for with treatment and and These for HBeAg‐positive adults and with cirrhosis who to on who antiviral therapy be every for at for ALT and The AASLD antiviral therapy for HBeAg‐positive adults with cirrhosis with CHB who to on therapy, on for and there is a for treatment of of with cirrhosis who antiviral therapy be (e.g., for every for ALT and may be in persons who have of there is insufficient to treatment for such Background HBeAg and sustained HBV DNA suppression are of antiviral therapy in HBeAg‐positive persons, those of or seroconversion is the of immune of antiviral therapy, persons with HBeAg‐positive immune active who are treated with antiviral therapy may be to treatment of the of HBeAg treatment with antiviral therapy seroconversion is may be an but may not be for all persons to of and need for is health such as or are different in persons who HBeAg seroconversion compared to those who continued antiviral therapy and is the important of or among HBeAg‐positive persons who antiviral therapy compared to those who continued HBeAg compared continued therapy to a of and of ALT and HBeAg that persons who treatment a of viremia and of ALT of the persons who continued treatment either The second a of ALT of in those who in those who continued antiviral The of HBV DNA was in persons who in those who and that of HBeAg was duration of therapy from HBeAg seroconversion to antiviral treatment was to be and In other of HBeAg seroconversion for entecavir was at and for was at The for antiviral therapy is on the of of therapy in of and with the and with antiviral of antiviral therapy may of and risk of liver in with Additionally, the risk of is in persons who are positive those who were and the risk of cirrhosis is in persons with persistent HBeAg A of has been to reduce the risk of HBeAg the duration of HBeAg seroconversion is for HBeAg‐positive persons who to on health such as or in to the duration of of antiviral therapy in persons cirrhosis and impact of antiviral therapy in persons with of in CHB The AASLD antiviral therapy for adults with HBeAg‐negative CHB, there is a for treatment of of A to therapy for HBeAg‐negative adults cirrhosis of and for health risk for liver and of continued antiviral therapy, with and and for with treatment and and in persons with cirrhosis is not to the for and are may be in persons who have of there is insufficient to treatment for such who antiviral therapy be every for at for ALT and therapy is not for persons cirrhosis who are HBeAg with ALT and viremia chronic hepatitis Background The are in HBV DNA do not or viral DNA into the host HBV viremia treatment virus suppression therapy, in some with hepatitis and/or In this antiviral therapy is A previous AASLD hepatitis B practice guideline antiviral therapy for HBeAg‐negative persons was and The is in important such as and among HBeAg‐negative persons who compared to those who continued antiviral were duration of therapy antiviral therapy in HBeAg‐negative an compared treatment duration and were with of viremia in persons treatment viremia in persons with or of four the of treatment in HBeAg‐negative persons with duration of therapy or including and These viremia to level in and ALT in approximately third to of the was in of persons who therapy at of therapy in and in of of therapy in there was in between adults with and in of with cirrhosis in In a from of persons with CHB HBeAg who discontinued therapy from a hepatitis B with the of at 1, and was and there was in the of between persons with and persons with cirrhosis of that virus suppression and ALT may be sustained in of the HBeAg‐negative persons with treatment duration or the of treatment on morbidity and mortality with persistent for and in persons with for treatment of for and Given the health with and antiviral therapy, with duration of are to antiviral therapy be in persons with and treatment for patients on therapy, such as adding or to therapy, are to identify for treatment including levels in the United and and Disease in on Recommendation The AASLD between entecavir and tenofovir of renal and bone of of The do not in renal or bone between persons treated with tenofovir or renal such as renal or have been in In persons on renal including and be treatment and (e.g., at and or high risk for renal In the of other risk for there is insufficient for or monitoring of bone in persons on In of renal and/or tenofovir be discontinued and with an with for previous of be on renal and as by Background and tenofovir are approved as for CHB. tenofovir therapy has been with and chronic with and and on from tenofovir therapy in persons has been with bone and there was risk for or with tenofovir therapy in persons in a systematic and of and have been in persons on HBV infection and liver to the of tenofovir a compared to is the for The of renal and bone for to of treatment was low in a recent with and in bone between and from identified a need for in of persons for renal an approximately a and for The of with approved HBV was in of persons with cirrhosis treated with and risk of was with the of for Liver including and The is in The of tenofovir and entecavir was compared in with of per treatment The of adults with cirrhosis in or of tenofovir or entecavir The second of adults on on in renal and in treatment duration was in In the in and/or between the treatment a in of for tenofovir entecavir a in bone in and adults with an treatment duration of additional in of and in of treated with with an additional of renal in A recent of persons with of low risk for renal and bone was a risk for persons on therapy for the risk was low The duration of in of the with to to in low to low of in the for of renal in persons that persons on tenofovir have renal at with treatment duration and are to renal and bone with therapy, in to and to prevent and of on The AASLD that persons with persistent viremia on entecavir or tenofovir of of of The AASLD of in persons with on entecavir or tenofovir either to antiviral with high to or a second antiviral that of of patients is in those with persistent viremia on antiviral viremia has traditionally been as HBV DNA of treatment. This was by of in and an of antiviral therapy with of antiviral and of the of entecavir and persistent viremia is as a in the of HBV DNA and/or to HBV DNA level of is insufficient to for adding a second or to in of in this may not be viral levels are to is by an in HBV DNA by compared to or HBV DNA in persons on therapy with levels be obtained a therapy may assist with A a for to antiviral with high to or adding a second antiviral with a (Table is insufficient to the risk of viral is to be with antiviral therapy compared to the of HBV DNA monitoring has not been monitoring of HBV DNA levels every HBV DNA is and every for of persistent viremia and For persons on treatment with other tenofovir or viral a to antiviral with high to or the of a second antiviral with a (Table for of tenofovir tenofovir entecavir tenofovir tenofovir and entecavir Background all persons viral suppression on entecavir or tenofovir therapy of those treated with of HBeAg‐positive and of HBeAg‐negative viral For those treated with viral suppression were for HBeAg‐positive persons and for HBeAg‐negative For persons on therapy who to an HBV DNA level of therapy, but do not for is as to a of therapy is The of adding on an additional antiviral therapy to an to antiviral has not been In on antiviral treatment is with viral and a of and was of to continued among persons with persistent the of was low the of persons with persistent viremia who continued entecavir or tenofovir compared to persons who to with high to or a second antiviral with to viral of persons on with persistent viremia viral or on there was support in of either to a or adding a second antiviral with a In a of persons with entecavir treated with tenofovir or tenofovir and the of viral suppression at was and in the In of persons with treated with tenofovir or tenofovir and entecavir for there was in the of viral suppression between the are of insufficient duration to therapy in of risk for with treatment are to care for persons with persistent viremia or on antiviral is to the health of and adding on antiviral need that a in antiviral therapy, and the of different of Adults and The AASLD that adults with compensated cirrhosis and low levels of viremia be treated with antiviral therapy to reduce the risk of of ALT of of and entecavir are of their and risk of with a low to not be the of to is not in persons with compensated but are treatment is not to persons with compensated cirrhosis and low levels of be for a in HBV DNA and/or be either The ALT level in persons is or the ALT levels the of other for ALT is is a for antiviral does not an of treatment. therapy were monitoring every for at for of viral that to with compensated cirrhosis and high HBV DNA levels are treated per recommendations for HBeAg‐positive and CHB with does not the risk of and surveillance for The AASLD that adults with cirrhosis be treated with antiviral therapy of HBV DNA HBeAg or ALT level to decrease risk of liver‐related of of and tenofovir are is in persons with cirrhosis to for liver is in has been with some and persons with cirrhosis may be at of and is with does not the risk of and surveillance for Background The of HBV treatment is to prevent and liver‐related complications through of sustained suppression of In those with and/or on and/or ALT in with HBV DNA the risk of liver‐related complications is highest and the for treatment be persons with cirrhosis but ALT levels and low levels of viremia are at risk is and have that of hepatitis B in viral load to in with an in at a of per in persons with with a viral load between and to be at the highest there is for using antiviral therapy in persons with cirrhosis and low levels of HBV that and liver‐related or a In of persons with cirrhosis HBV DNA and HBeAg at the developed the other in risk was among patients those with HBV DNA