INTRODUCTION — Hepatitis B virus (HBV) is a double-stranded DNA virus belonging to the family of hepadnaviruses. HBV infection is a global public health problem. It is estimated that there are more than 250 million HBV carriers in the world, of whom approximately 600,000 die annually from HBV-related liver disease.
The following topic review will summarize issues related to the management of HBV infection. The recommendations below are generally consistent with guidelines from the European Association for the Study of the Liver (EASL) guidelines, Asian-Pacific Association for the Study of the Liver guidelines, and American Association for the Study of Liver Diseases (AASLD) Practice Guidelines [1-3]. Clinical decisions regarding individual patients should be based upon patient-specific clinical information and test results.
Topic reviews that discuss the management of pregnant women and children with HBV infection, as well as the data supporting this section, are presented separately.
●(See "Hepatitis B and pregnancy".)
●(See "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents" and "Management of hepatitis B virus infection in children and adolescents".)
●(See "Hepatitis B virus: Case studies".)
●(See "Pegylated interferon for treatment of chronic hepatitis B virus infection".)
●(See "Entecavir in the treatment of chronic hepatitis B virus infection".)
●(See "Tenofovir and adefovir for the treatment of chronic HBV infection".)
ACUTE INFECTION — The diagnosis of acute HBV infection is based upon the detection of hepatitis B surface antigen (HBsAg) and immunoglobulin M (IgM) antibody to hepatitis B core antigen (anti-HBc) (table 1A-B and figure 1). Treatment of acute HBV depends upon the clinical setting. However, appropriate measures should be taken to prevent infection in all exposed contacts, and hepatitis B immune globulin and hepatitis B vaccine should be administered to all household and sexual contacts who are not known to be immune. (See "Epidemiology, transmission, and prevention of hepatitis B virus infection", section on 'Prevention'.)
For most patients, treatment is mainly supportive. The likelihood of liver failure from acute HBV is less than 1 percent, and in immunocompetent adults, the likelihood of progression to chronic HBV infection is less than 5 percent . There are known subgroups of patients whose prognosis is relatively worse (eg, patients who are immunocompromised, have concomitant infection with hepatitis C or human immunodeficiency virus [HCV or HIV], have preexisting liver disease, or are older adults), but the role of antiviral therapy for such patients remains unsettled since few studies have addressed its benefits during acute infection.
As a general rule, we treat patients with a severe or a protracted course (eg, those who develop a coagulopathy [international normalized ratio (INR) >1.5], those with persistent symptoms or marked jaundice [bilirubin >3 mg/dL] for more than four weeks after presentation) . We also treat patients with acute liver failure due to HBV to reduce the likelihood of reinfection post-liver transplant, should a liver transplant become necessary.
For those who require treatment, tenofovir or entecavir are acceptable options given as monotherapy. Treatment can be stopped after confirmation that the patient has cleared HBsAg (two consecutive tests four weeks apart). Lamivudine or telbivudine can also be used, as the duration of treatment is generally short. However, since severe exacerbations of chronic HBV in previously undiagnosed patients can be difficult to differentiate from acute HBV, tenofovir or entecavir are preferred. Adefovir is not typically used because of its weak antiviral activity, and interferon should be avoided because of the risk of bacterial infections and a further increase in hepatic necroinflammation in patients with severe hepatitis or acute liver failure.
CHRONIC HEPATITIS B — The diagnosis of chronic HBV infection is based upon the persistence of hepatitis B surface antigen (HBsAg) for greater than six months. A number of risk factors for HBV infection have been identified, providing a rationale for screening (table 2 and table 3) [3,5-7]. A more detailed discussion of screening and diagnosis of HBV is found elsewhere. (See "Hepatitis B virus: Screening and diagnosis" and "Hepatitis B virus immunization in adults".)
The management of chronic HBV infection is complex and depends upon multiple factors including clinical variables (eg, the presence or absence of liver inflammation and/or cirrhosis), the patient's immunologic response to infection (eg, hepatitis B e antigen [HBeAg] status), virologic factors (eg, the HBV viral load and genotype), and risk factors for disease progression (eg, age >40 and family history of hepatocellular carcinoma).
General approach — The initial evaluation of patients with chronic HBV infection should include (table 4):
●A history and physical examination, emphasizing: risk factors for coinfection with hepatitis C virus (HCV), hepatitis delta virus (HDV), and/or HIV; use of alcohol; family history of HBV infection and hepatocellular carcinoma (HCC); and signs and symptoms of cirrhosis.
●Laboratory tests, including: a complete blood count with platelets, liver chemistry tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, alkaline phosphatase, albumin), international normalized ratio (INR), and tests for HBV replication (HBeAg, antibody to HBeAg [anti-HBe], HBV DNA). Testing for immunity to hepatitis A virus (HAV) with HAV immunoglobulin G (IgG) antibody should be performed in patients who are not known to be immune.
●Evaluation for other causes of liver disease (eg, hemochromatosis, HCV, HDV) by testing for iron, total iron binding capacity, ferritin, and HCV antibody in all patients. For HDV, we screen patients with a history of injection drug use and those who migrated from countries where HDV is prevalent (eg, Southern or Eastern European countries); however, other experts suggest one-time screening for HDV in all patients with chronic hepatitis B. (See "Pathogenesis, epidemiology, natural history, and clinical manifestations of hepatitis D virus infection".)
●Screening for HIV infection in those who have not undergone routine screening, and in those persons with ongoing risk factors for HIV (eg, injection drug use, multiple sexual exposures, men who have sex with men). (See "Screening and diagnostic testing for HIV infection".)
●Screening for HCC if indicated. (See "Surveillance for hepatocellular carcinoma in adults".)
●Screening for fibrosis using noninvasive tests (eg, vibration-controlled transient elastography, serum fibrosis panel) or liver biopsy. Noninvasive assessments of liver fibrosis, notably measurements of liver stiffness, are increasingly used instead of liver biopsies; however, liver stiffness can be influenced by inflammation as well as fibrosis, and therefore, liver stiffness measurements may overestimate liver fibrosis in patients with a high ALT (more than 100 units/L) . (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations" and "Noninvasive assessment of hepatic fibrosis: Ultrasound-based elastography" and 'Role of liver biopsy' below.)
Role of liver biopsy — Most patients will not need a liver biopsy. However, a liver biopsy may be useful in the following scenarios:
●Patients who have persistently elevated ALT but persistently low HBV DNA to exclude other causes of liver disease.
●Patients who do not meet criteria for treatment but are at risk for having histologically active or advanced liver disease that would benefit from treatment. These include patients who have ALT levels that are normal or mildly elevated (<2 x the upper limit of normal [ULN]), an HBV viral load that is persistently elevated (eg, >6 months), and one of the following risk factors:
•Age >40 years.
•A family history of HCC.
An elevated HBV DNA is considered >2000 international units/mL (104 copies/mL) for HBeAg-negative patients or >20,000 international units/mL (>105 copies/mL) for HBeAg-positive patients.
A normal serum ALT level alone in patients with active viral replication does not predict mild or normal histologic findings [9,10]. As an example, one report found that up to 37 percent of patients with persistently normal ALT and HBV DNA levels >10,000 copies/mL (approximately >2000 international units/mL) had significant fibrosis and inflammation on liver biopsy. On subgroup analysis, most such patients had an ALT in the high range of normal and were older than 40 years of age. By contrast, two studies in patients in the immune tolerant phase of chronic HBV infection found that despite high HBV DNA levels, most patients had no or minimal fibrosis [11,12].
The decision to obtain a liver biopsy should be made on a case-by-case basis in consultation with a specialist in liver diseases. More detailed information on the approach to liver biopsy is presented elsewhere. (See "Approach to liver biopsy".)
Indications for antiviral therapy — The decision to initiate treatment is primarily based upon the presence or absence of cirrhosis, the ALT level, and the HBV DNA level (table 5). However, there are additional indications for patients with certain concurrent conditions, such as malignancy and pregnancy. (See 'Patients receiving immunosuppressive therapy' below and 'Pregnant women' below and 'Patients with hepatocellular carcinoma' below.)
Patients who are deemed not to be treatment candidates at presentation, and those who decide to defer treatment, should undergo monitoring of liver biochemical tests, HBV DNA, and HBeAg status since liver disease and/or HBV replication may become active later. The frequency of monitoring is described in the table (table 4). These patients should also undergo HCC surveillance if indicated. (See 'Screening for hepatocellular carcinoma' below.)
Our approach is consistent with recommendations from the American Association for the Study of Liver Diseases (AASLD) . The AASLD, European Association for the Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL) guideline recommendations are very similar. However, there are minor differences related to the year of publication, the prevalence of HBV infection within the population, and the availability of resources .
Acute liver failure or decompensated cirrhosis — Patients with life-threatening liver disease secondary to HBV should initiate antiviral therapy. This includes patients with acute liver failure (eg, fulminant acute HBV, severe exacerbation of chronic HBV), as well as those with decompensated cirrhosis and a detectable HBV DNA by polymerase chain reaction (PCR) assay (regardless of the ALT level) . Such patients should also be evaluated for liver transplant. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients".)
Nucleos(t)ide analog treatment has been shown to stabilize liver disease, and in some cases reverse liver failure [15,16]. Antiviral treatment also reduces the risk of recurrent HBV should these patients require liver transplantation. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients".)
Compensated cirrhosis — Patients with compensated cirrhosis and an HBV DNA >2000 international units/mL (>104 copies/mL) should be treated with antiviral therapy regardless of the HBeAg status or the serum ALT level (table 5). Treatment should be considered even if HBV DNA levels are lower than 2000 international units/mL, since there are data showing that patients with cirrhosis and low HBV DNA levels have a higher risk of hepatocellular carcinoma than those with undetectable HBV DNA levels .
Patients without cirrhosis
HBeAg-positive (immune active phase) — For HBeAg-positive patients without cirrhosis, treatment should be initiated when the HBV DNA is >20,000 international units/mL (>105 copies/mL) and the ALT is >2 x ULN (table 5) . The ULN should be considered 35 U/L for males and 25 U/L for females; these levels should be used rather than individual laboratory cut-off levels. Treatment should be delayed for three to six months in newly diagnosed HBeAg-positive patients with compensated liver disease to determine whether spontaneous HBeAg seroconversion will occur. (See "Hepatitis B virus: Clinical manifestations and natural history", section on 'Phases of chronic HBV infection'.)
Patients with chronic hepatitis whose serum ALT is persistently below 2 x ULN can be observed, considering treatment if and when the serum ALT becomes higher (table 4). Exceptions to this rule include: those who have recurrent hepatitis flares that fail to clear HBeAg, patients with icteric flares, those with active or advanced histologic findings (such as moderate/severe inflammation or bridging fibrosis/cirrhosis) or advanced fibrosis on noninvasive tests such as elastography, patients with extrahepatic manifestations (eg, HBV-related polyarteritis nodosa), patients above the age of 40 who remain HBeAg-positive with persistently high HBV DNA levels, those with a family history of HCC (there is a lower threshold for HBV DNA and ALT in these patients), and health care providers performing exposure-prone procedures (as required by local guidelines). (See "Epidemiology, transmission, and prevention of hepatitis B virus infection", section on 'Health care providers'.)
Although treatment can lead to virus suppression in HBeAg-positive patients with normal ALT (immune tolerant phase), the likelihood of HBeAg seroconversion on treatment is low, and HBV DNA rebounds to baseline levels when treatment is stopped. The poor results are true for monotherapy as well as combination therapy with two nucleos(t)ide analogs or a nucleos(t)ide analog and pegylated interferon (PegIFN) [18-20]. In addition, despite high HBV DNA levels, the risk of HCC during follow-up to 10 years is low . Thus, the benefits of long-term treatment in such patients, most of whom are young and Asian with perinatally acquired HBV infection, must be balanced against the risks of drug resistance, side effects, and costs, particularly since some of these individuals will undergo spontaneous HBeAg seroconversion and remain in remission for many years afterwards.
HBeAg-negative chronic hepatitis — Treatment may be initiated immediately once a diagnosis of HBeAg-negative chronic hepatitis (ALT >2 x ULN and HBV DNA >2000 international units/mL) is established because sustained remission is rare in the absence of treatment. However, delaying treatment for two to three months to allow patients to understand the disease, the need for long-term (and often lifelong) treatment, and the importance of adherence is reasonable in patients with no evidence of cirrhosis. We follow the AASLD recommendations that define the ULN for ALT as 35 U/L for males and 25 U/L for females, rather than using individual laboratory cut-off levels .
For those with an ALT <2 x ULN, serial follow-up is needed to differentiate an inactive carrier state from HBeAg-negative chronic hepatitis because of the fluctuating course of HBeAg-negative chronic hepatitis. Liver biopsy should be considered in HBeAg-negative patients who have serum HBV DNA levels >2000 international units/mL and normal or mildly elevated ALT to determine if treatment is warranted. Alternately, noninvasive tests such as elastography may be used to assess fibrosis stage. Patients with low HBsAg levels (<1000 international units/mL) are more likely to be in the inactive phase than those with higher HBsAg levels.
Patients receiving immunosuppressive therapy — Antiviral therapy should be administered to most patients with chronic HBV prior to initiating immunosuppressive therapy, regardless of the HBV DNA or aminotransferase levels. Such patients are at risk for HBV reactivation if they receive immunosuppressive therapy. The level of risk is influenced by the type of immunosuppressive agent that is used. Prophylactic antiviral therapy may also be indicated in HBsAg-negative, anti-HBc-positive patients receiving potent immunosuppressive therapy such as anti-CD20. A detailed discussion of prophylactic antiviral therapy is presented elsewhere. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
Pregnant women — For pregnant women, the indications for antiviral therapy are generally the same as those for patients who are not pregnant. However, women with high viral loads (>2 x 105 international units/mL) should initiate therapy in the late second or early third trimester, even if the aminotransferase levels are normal, to prevent transmission to their child. The management of HBV in pregnancy is presented in a separate topic review. (See "Hepatitis B and pregnancy".)
Patients with hepatocellular carcinoma — All patients with hepatocellular carcinoma (HCC) should be treated with a nucleos(t)ide analog (eg, tenofovir or entecavir). Treatment with nucleos(t)ide analogs can reduce the risk of HCC recurrence, particularly late recurrence (>2 years after initial diagnosis), and improve the prognosis of HBV-related HCC after curative therapy. This approach was supported in a meta-analysis that included 15 studies with 8060 patients where the recurrence rate was significantly decreased among those who received treatment (one-year recurrence: risk ratio [RR] 0.41, 95% CI 0.28-0.61; three-year recurrence: RR 0.63, 95% CI 0.43-0.94) .
Patients with hepatitis C coinfection — Patients who have coinfection with HBV and HCV are at risk for HBV reactivation if they are being treated for HCV with direct-acting antiviral therapy and are not receiving treatment for HBV .
●For HBsAg-positive patients who meet criteria for antiviral treatment of HBV (table 5), HBV treatment should be initiated prior to or at the same time as HCV therapy. For those who do not meet criteria for HBV therapy, the HBV DNA levels should be monitored at regular intervals (eg, every four weeks) during and for up to 12 weeks after HCV therapy. HBV therapy should be initiated if HBV DNA levels meet criteria for treatment.
●For HBsAg-negative, hepatitis B core antibody-positive patients, the risk of HBV reactivation during HCV direct-acting therapy is low. Monitoring of ALT is recommended, and if the ALT increases during treatment, HBV markers (HBsAg and HBV DNA) should be tested.
More detailed discussions of the management of HCV infection are found elsewhere. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Monitoring during antiviral therapy'.)
Antiviral therapy — The goals of antiviral therapy are suppression of HBV DNA, loss of HBeAg (in patients who were initially HBeAg-positive), and loss of HBsAg. A sustained viral response, particularly in those who clear both HBeAg and HBsAg, is almost invariably accompanied by normalization of serum ALT, a decrease in necroinflammatory activity, and over time, a decrease in fibrosis as well. Antiviral treatment can also reduce the risk of long-term complications from chronic HBV (eg, liver failure and hepatocellular carcinoma) as well as the transmission of HBV to others. For some patients, immediate antiviral therapy is indicated, whereas for others, treatment may be deferred with careful monitoring. (See 'Indications for antiviral therapy' above.)
Overview of antiviral agents — Treatment strategies for chronic HBV typically include PegIFN or nucleos(t)ide analogs (eg, entecavir and tenofovir) (table 5) . Investigational treatments can be considered in selected patients where such protocols are available. In addition, new strategies for the treatment of HBV continue to be developed. (See "Combination therapy for chronic hepatitis B virus infection".)
The following discussion provides an overview of the different agents in nonpregnant adults. More detailed discussions of how to select a regimen and the use of these agents for the treatment of children and pregnant women are found elsewhere. (See 'Choice of initial agent' below and 'Persistent viremia/breakthrough infection' below and "Hepatitis B and pregnancy" and "Management of hepatitis B virus infection in children and adolescents", section on 'Choice of treatment'.)
Interferon — The main role of interferon is primarily treatment of young patients with well compensated liver disease who do not wish to be on long-term treatment. Among HBeAg-positive patients, HBV genotype A (and to a less extent, genotype B), as well as low HBV DNA and high ALT levels are predictive of response to interferon therapy.
The advantages of interferon compared to nucleos(t)ide analogs are its finite duration of treatment, the absence of selection of resistant variants, and a higher rate of HBeAg loss and HBsAg loss compared to the same duration of nucleos(t)ide analog therapy. On the other hand, side effects from interferon are troubling for many patients, and (less commonly) can be severe. Furthermore, interferon should not be used in pregnant women and patients with decompensated disease or compensated cirrhosis and portal hypertension. (See "Pegylated interferon for treatment of chronic hepatitis B virus infection", section on 'Whom to treat'.)
Interferon alfa is administered by subcutaneous injection. The preferred formulation is peginterferon alfa-2a, which should be administered as 180 mcg once weekly for 48 weeks for HBeAg-positive or HBeAg-negative chronic HBV . A more detailed discussion of interferon for the treatment of chronic HBV is found elsewhere. (See "Pegylated interferon for treatment of chronic hepatitis B virus infection".)
Nucleos(t)ide analogs — Several nucleos(t)ide analog agents are available. The predictors of response depend in part upon the HBeAg-status of the patient:
●For HBeAg-positive patients, the likelihood of a virologic response (HBV DNA suppression) to nucleos(t)ide analogs is independent of ALT levels and HBV genotype; however, the serologic response (HBeAg clearance), like interferon, is higher in those with elevated serum aminotransferases [26,27]. As a general rule, treatment with any of these drugs does not result in higher rates of HBeAg seroconversion compared with no treatment in those who have a serum ALT ≤2 x ULN. (See 'HBeAg-positive (immune active phase)' above.)
In patients with high HBV DNA levels, it takes more time for HBV DNA to become undetectable after initiating nucleos(t)ide analogs. For such patients, the HBV DNA often remains detectable after one and sometimes two years of treatment; however, treatment with the same nucleos(t)ide analog as monotherapy is appropriate as long as HBV DNA levels continue to decline and the nucleos(t)ide analog has a high barrier to resistance. The management of persistent viremia is discussed below. (See 'Persistent viremia/breakthrough infection' below.)
●For HBeAg-negative patients, prediction of response (eg, HBsAg loss or sustained virologic response after discontinuation of treatment) is less precise. Because of the need for long-term treatment, therapy is recommended only for those with persistent or intermittent elevation in ALT and/or substantial histologic abnormalities (moderate/severe inflammation or bridging fibrosis/cirrhosis) or advanced fibrosis based on elastography. (See 'HBeAg-negative chronic hepatitis' above.)
The available agents include:
●Entecavir – The main advantages of entecavir are its potent antiviral activity and low rate of drug resistance in patients who are nucleos(t)ide-naïve (approximately 1 percent with up to five years of treatment). However, entecavir should not be used for patients with lamivudine-resistant HBV, since resistance has been observed in up to 50 percent of lamivudine-refractory patients after five years of treatment. (See "Entecavir in the treatment of chronic hepatitis B virus infection".)
Entecavir is administered orally. The dose should be adjusted for patients with reduced kidney function (table 6).
•For nucleoside-naïve adults and adolescents older than 16, the recommended dose is 0.5 mg once daily.
•The dose should be increased to 1 mg daily for those with decompensated liver disease.
The dose should also be increased to 1 mg daily if it is used for patients who have been treated with lamivudine in the past; however, for such patients, tenofovir is preferred. (See 'Persistent viremia/breakthrough infection' below.)
●Tenofovir – Tenofovir can be used as first-line therapy in treatment-naïve patients and also in those who have had prior exposure, or developed drug resistance, to other nucleos(t)ide analogs (eg, lamivudine). In clinical trials of patients receiving tenofovir disoproxil fumarate (TDF), no signature mutation for tenofovir resistance has been identified, even among those who have been treated for up to eight years. (See "Tenofovir and adefovir for the treatment of chronic HBV infection", section on 'Risk of resistance'.)
There are two formulations of tenofovir, TDF and tenofovir alafenamide. For most patients, we recommend tenofovir alafenamide (25 mg daily) rather than TDF (300 mg daily), if available. For those who were originally started on TDF, we generally suggest switching to tenofovir alafenamide, particularly in older patients and those with risk factors for renal impairment or osteoporosis. Although there is more experience with TDF compared with tenofovir alafenamide, tenofovir alafenamide appears to be equally effective and is associated with less renal and bone toxicity [28-31]. (See "Tenofovir and adefovir for the treatment of chronic HBV infection", section on 'Safety'.)
The use of tenofovir and the choice of tenofovir formulation in patients with reduced kidney function and in patients with decompensated cirrhosis are discussed below. In addition, until more data are available, tenofovir alafenamide should be avoided in pregnant women. (See 'Choice of initial agent' below.)
●Lamivudine – The main advantages of lamivudine are its lower cost compared with the other oral agents and the many years of experience confirming its safety. However, lamivudine should not be used, given the high rate of drug resistance, unless entecavir or tenofovir is not available. (See "Entecavir in the treatment of chronic hepatitis B virus infection" and "Tenofovir and adefovir for the treatment of chronic HBV infection".)
Lamivudine (or the closely related agent emtricitabine) may still have a role in patients coinfected with HIV when used as part of an antiretroviral regimen that contains a second drug with anti-HBV activity, such as tenofovir. A detailed discussion of the treatment of HBV in HIV-infected patients is found elsewhere. (See "Treatment of chronic hepatitis B in patients with HIV".)
The recommended dose of lamivudine for adults with normal renal function without concomitant HIV infection is 100 mg daily. Dose adjustment is required in those with decreased renal function (table 6). For patients with HIV, a higher dose (lamivudine 300 mg once daily) is used as part of an HIV antiretroviral regimen. (See "Treatment of chronic hepatitis B in patients with HIV", section on 'Preferred regimens'.)
●Adefovir – The most important role of adefovir is in the treatment of patients with lamivudine-resistant HBV, preferably in combination with other agents. However, this role has been replaced by tenofovir, which is more potent and effective when used as monotherapy. If used, adefovir is administered orally, and the dose is 10 mg daily. Patients with impaired renal function should have the dosing interval adjusted (table 6).
Virus suppression is slow at the approved dose, and up to 25 percent of patients experience minimal or no viral suppression. Adefovir at high doses has been associated with nephrotoxicity. At the approved dose of 10 mg daily, a reversible increase in serum creatinine has been reported in 3 to 9 percent of patients after four to five years of treatment. Adefovir resistance was not detected after one year of treatment, but the rate of drug resistance has been reported to be as high as 29 percent after five years of treatment. (See "Tenofovir and adefovir for the treatment of chronic HBV infection", section on 'Adefovir'.)
●Telbivudine – Telbivudine is administered orally. The recommended dose is 600 mg once daily. Dose should be adjusted in patients with impaired renal function. This agent is no longer manufactured in the United States.
Telbivudine appears to have slightly more potent antiviral effects compared with lamivudine and adefovir. In addition, telbivudine has been reported to produce mild improvements in renal function due to an unidentified mechanism . Despite these potential benefits, we generally do not recommend this agent given the increased risk of drug resistance and other adverse events (eg, myopathy and peripheral neuropathy) compared with alternative antiviral agents.
Cost-effectiveness — The cost-effectiveness of various treatment strategies for chronic HBV is incompletely understood as many cost-effectiveness analyses were conducted before approval of peginterferon, entecavir, TDF, and tenofovir alafenamide. Furthermore, the cost of generic nucleos(t)ide analogs is markedly reduced and highly variable in different countries. However, a cost-effectiveness analysis using data from Hong Kong suggests that PegIFN may be the most cost-effective treatment for HBeAg-positive patients, especially if a 12-week stop rule is used, whereas entecavir is more cost-effective for HBeAg-negative patients .
Choice of initial agent
Approach for most patients — For most treatment-naïve patients, either tenofovir or entecavir is preferred because they both are well tolerated, have potent antiviral activity, and have a low risk of selecting for drug-resistant virus. We avoid monotherapy with lamivudine, adefovir, or telbivudine given the high risk of developing resistance with long-term use and, in the case of adefovir, its weak antiviral activity. (See 'Overview of antiviral agents' above.)
PegIFN is also an option for select immunocompetent patients without cirrhosis. However, given the increased risk of adverse events with this agent compared with nucleos(t)ide analogs, it is typically reserved for those who desire a finite duration of treatment (eg, young adults and women planning to conceive in the future), particularly if they are HBeAg positive, are infected with HBV genotype A, and if a week 12 stop rule will be applied. A detailed discussion of interferon therapy for treatment of hepatitis B is presented separately. (See "Pegylated interferon for treatment of chronic hepatitis B virus infection".)
Considerations for select patients
●Patients with cirrhosis – Tenofovir or entecavir can be used for patients with cirrhosis. We generally prefer entecavir for patients with decompensated cirrhosis who are treatment-naïve. Such patients are at risk for acute kidney injury secondary to the hepatorenal syndrome, and entecavir has not been shown to be nephrotoxic, whereas TDF has been associated with reduced kidney function. Tenofovir alafenamide is an alternative agent, but efficacy and safety data in patients with decompensated liver disease are lacking. Lactic acidosis has been reported in patients with severe liver dysfunction receiving entecavir ; however, this is likely a class effect of nucleos(t)ide analogs. Several larger studies did not observe any clinical cases of lactic acidosis, but lactate levels were not monitored in those studies. Treatment of such patients should be coordinated with a transplant center. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients".)
In general, there is no evidence that initiating combination therapy with two nucleos(t)ide analogs (eg, entecavir and TDF) is superior to monotherapy. Although combination therapy results in more rapid viral suppression in patients with high baseline HBV DNA, it has not been determined whether accelerating viral suppression improves clinical outcomes. A discussion of combination therapy is found elsewhere. (See "Combination therapy for chronic hepatitis B virus infection".)
For patients with decompensated cirrhosis, interferon is contraindicated . Interferon may be used with caution in patients with compensated cirrhosis, normal hepatic synthetic function, and minimal or no evidence of portal hypertension, but nucleos(t)ide analogs are safer. (See 'Nucleos(t)ide analogs' above and 'Interferon' above.)
●Pregnancy – For pregnant women who require treatment, we prefer TDF rather than other antiviral agents. Interferon is contraindicated in such patients, and we do not use tenofovir alafenamide or entecavir given the lack of sufficient safety data. A detailed discussion of the management of HBV and pregnancy is presented separately. (See "Hepatitis B and pregnancy".)
●Patients with reduced kidney function – For patients with chronic HBV and reduced kidney function, the choice of agent depends in part upon the creatinine clearance and if the patient is on dialysis (table 6). As examples:
•For patients with a creatinine clearance (CrCl) <60 mL/min, TDF should be avoided, if possible.
•For patients with a CrCl >15 mL/min, either entecavir or tenofovir alafenamide can be used. An advantage of tenofovir alafenamide over entecavir is that the dose does not need to be adjusted for renal function.
•For patients with a CrCl <15 mL/min, tenofovir alafenamide should be avoided in patients who are not on dialysis given the lack of pharmacokinetic data in this population; for such patients, entecavir (with the dose modified for the degree of renal insufficiency) can be used.
•Entecavir, tenofovir alafenamide, and TDF can all be administered to patients on hemodialysis with appropriate dose adjustments.
Information on the dosing of antiviral agents in patients with reduced kidney function can be found in the table (table 6) and in the drug information topics within UpToDate. More detailed discussions of the renal toxicity associated with tenofovir are presented in separate topic reviews. (See "Tenofovir and adefovir for the treatment of chronic HBV infection", section on 'Renal insufficiency and renal tubular dysfunction' and "Overview of antiretroviral agents used to treat HIV", section on 'Tenofovir'.)
●Other considerations – Treatment considerations for patients with breakthrough infection and those who require preemptive antiviral therapy to prevent HBV reactivation are discussed in detail elsewhere. (See 'Persistent viremia/breakthrough infection' below and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
Monitoring on therapy — To monitor the response to nucleos(t)ide therapy we measure:
●HBV DNA every three months until undetectable for at least two consecutive visits. We then decrease the frequency to every six months.
●Aminotransferases every three months. The frequency can be decreased to every six months in patients with an undetectable HBV DNA or normalized ALT.
●HBeAg and anti-HBe every 12 months in patients who are HBeAg positive to determine if seroconversion has occurred. If HBeAg seroconversion has occurred, we repeat the HBeAg and anti-HBe to confirm the result.
●HBsAg should be tested yearly in patients with undetectable HBV DNA.
In addition, we monitor for adverse reactions to the antiviral medications. If TDF or adefovir are used, creatinine and phosphate should be monitored every three to six months. For those with decompensated cirrhosis, the creatinine should be monitored more frequently (eg, every one to three months). The frequency of monitoring can be reduced (but not eliminated) if tenofovir alafenamide is used, although there are no clear guidelines. Monitoring creatinine every 12 months is reasonable for patients at low risk of renal impairment.
For patients who receive interferon, monitoring the response to therapy and adverse events is discussed elsewhere and is summarized in the table (table 7). (See "Pegylated interferon for treatment of chronic hepatitis B virus infection", section on 'Monitoring'.)
Duration and treatment endpoints — Patients receiving interferon therapy receive a finite duration of therapy of 48 weeks. (See 'Interferon' above and "Pegylated interferon for treatment of chronic hepatitis B virus infection".)
The optimal duration of therapy for the oral drugs is not well established. Most patients receiving nucleos(t)ide analog therapy will require at least four to five years of treatment, and some may require indefinite treatment (table 5). In a systematic review that included 1716 patients with chronic HBV who discontinued oral therapy (of whom 18 percent had cirrhosis), virologic remission, defined as HBV DNA <20,000 international units/mL, was maintained in 50 percent of patients after 12 months, 39 percent after 24 months, and 38 percent after 36 months . Remission rates were lower using more stringent definitions, but were higher in HBeAg-positive patients who discontinued treatment after HBeAg seroconversion and additional consolidation therapy. The presence of HBV RNA in serum at the end of treatment may be a predictor of viral rebound when treatment is discontinued ; however, this test is not yet clinically available, and this finding needs to be validated.
Long-term treatment is particularly important for patients with cirrhosis. This was illustrated in a retrospective cohort study of 263 patients with chronic HBV (94 with cirrhosis) who discontinued lamivudine after being treated for a hepatitis flare . Patients were treated for a median duration of 12 months, and over half required retreatment after lamivudine was discontinued. When compared with those without cirrhosis, patients with cirrhosis were significantly more likely to require retreatment (64 versus 47 percent) and/or experience a clinical relapse (76 versus 60 percent).
Patients without cirrhosis
●HBeAg-positive chronic hepatitis – The endpoint of treatment for HBeAg-positive patients is HBeAg seroconversion (ie, HBeAg undetectable and the development of hepatitis B e antibodies confirmed by testing on two occasions at least two months apart). For patients being treated with nucleos(t)ide analogs, a prolonged duration of therapy is often required since HBeAg seroconversion only occurs in about 40 percent of patients after five years of treatment (table 5) [39-41].
Treatment should be continued for at least 12 more months to reduce the rate of relapse after HBeAg seroconversion has been confirmed . Patients who discontinue treatment should be closely monitored as viral relapse may lead to hepatitis flares and hepatic decompensation. For patients without cirrhosis, the ALT, HBV DNA, and HBeAg should be monitored every one to three months for at least one year.
Because relapse can occur even after completion of 12 months consolidation treatment following HBeAg seroconversion, an alternative is to continue treatment until HBsAg loss, but this would mean most patients will have to be on lifelong treatment.
●HBeAg-negative chronic hepatitis – We discontinue treatment in patients with HBeAg-negative hepatitis without cirrhosis if they have confirmed loss of HBsAg on two occasions at least six months apart (table 5). The APASL guidelines suggest 12 months of consolidation therapy after HBsAg loss unless anti-HBs seroconversion has occurred . However, only a small minority of patients (approximately 5 percent) lose HBsAg after five years of continued therapy.
Our approach for those who remain HBsAg positive is as follows:
•Preferred approach – For most patients who remain HBsAg positive, we continue treatment indefinitely, since almost all patients will experience a virologic relapse after therapy is stopped. In a systematic review that evaluated the duration of HBV DNA suppression after treatment discontinuation in 17 studies of HBeAg-negative patients who achieved virologic remission while on therapy, the probability of having virologic remission 12 months after discontinuing treatment was 51 percent when remission was defined as HBV DNA <20,000 international units/mL . When more stringent criteria were used (eg, HBV DNA <200 international units/mL), the probability of being in remission 12 months after stopping treatment was only 29 percent. In one study, virologic relapse rates (HBV DNA >200 international units/mL) were reported to be as high as 90 percent 24 months after therapy was discontinued . Although those receiving tenofovir appear to have virologic relapse sooner than those receiving entecavir, the risk of relapse is the same at 12 months . (See "Entecavir in the treatment of chronic hepatitis B virus infection", section on 'Risk of relapse after discontinuing entecavir'.)
•Patients who are unable/do not want to continue life-long therapy – For patients without cirrhosis or advanced fibrosis who are unable to or do not want to continue life-long therapy because of its associated risk of adverse events or cost, a trial of treatment discontinuation may be reasonable for those who:
-Have had HBV DNA suppression to undetectable levels by PCR assays for >3 years;
-Agree to close monitoring for at least one year (a monthly liver panel and testing for HBV DNA every three months for the first six months; a liver panel and HBV DNA testing every three months for the next six months). Monitoring can be decreased to every 6 to 12 months thereafter for patients who remain in an inactive carrier state. This approach is consistent with guideline recommendations from the EASL  and the APASL .
For such patients, we review the risks and benefits of stopping treatment. We explain that several studies have evaluated the risk of virologic and clinical relapse in HBeAg-negative patients who have achieved virologic suppression for several years but continue to have detectable HBsAg [42-47]. While studies indicate that viral relapse (detection of HBV DNA by PCR assay) is nearly universal when the nucleos(t)ide analog is stopped prior to HBsAg clearance, regardless of specific patient characteristics , not all patients will experience clinical relapse (HBV DNA >2000 international units/mL and ALT >2 x ULN). In one study that evaluated 21 patients who stopped nucleos(t)ide analog therapy, 63 percent did not reinitiate therapy after almost three years of follow-up because they had an HBV DNA <2000 international units/mL or HBsAg loss . Patients who have received a longer duration of therapy (eg, >24 versus <24 months) are less likely to develop a flare [13,36].
Withdrawal of therapy may even result in higher rates of HBsAg clearance than continuation of treatment, although some patients may experience a flare of their HBV [44,45,48]. In a randomized trial in Europe that included 178 HBeAg-negative patients without cirrhosis who had HBV DNA suppression for ≥4 years on nucleos(t)ide analog therapy, HBsAg loss was observed at 96 weeks after randomization in 8 of the 79 patients (10 percent) who discontinued treatment and 0 of 79 who continued treatment; however, 35 percent of those who discontinued therapy experienced ALT flares, and 14 percent resumed treatment . Similarly, in a retrospective study of 1541 HBeAg-negative patients from North America, Europe, and Asia who discontinued nucleos(t)ide analog therapy (23 percent of whom were HBeAg positive at the start of treatment), the cumulative HBsAg loss was 14 percent after four years, with 50 percent having resumed treatment by year 4 . White individuals were six times more likely to lose HBsAg, while patients ≥50 years of age were more likely to resume treatment. In this study, 15 (1 percent) of patients experienced hepatic decompensation and 12 died; of these 12, 9 were liver related. These data indicate that, in select patients (HBeAg-negative and no cirrhosis), discontinuation of nucleos(t)ide analog therapy after ≥4 years of therapy may be associated with a higher rate of HBsAg loss, more so in White than in Asian patients, but over time, many will develop clinical relapse necessitating resumption of treatment.
Several new HBV markers including quantitative HBsAg level, HBV RNA level, and hepatitis B core related antigen (HBcrAg) level have been shown to be predictive of sustained clinical remission or HBsAg clearance after withdrawal of nucleos(t)ide analogs [37,45,50]. If a quantitative HBsAg level is obtained, a low level (<100 international units/mL) at the time of treatment withdrawal is the best marker of HBsAg clearance. Assays for HBV RNA and HBcrAg are not standardized and are not available clinically.
Patients with cirrhosis — For patients with cirrhosis, lifelong therapy with oral agents is typically administered to reduce the risk of clinical decompensation if a relapse occurs. Therapy should be continued even with those who are HBeAg-positive and have seroconverted to anti-HBe on nucleos(t)ide therapy, as well as those with decompensated cirrhosis who have resolution of cirrhosis complications on treatment.
Although it is possible that treatment may be discontinued in those with compensated cirrhosis who have lost HBsAg, or those who have documentation of cirrhosis regression by histology or noninvasive assessment of liver fibrosis, there is insufficient evidence to guide treatment decisions for this group of patients.
Persistent viremia/breakthrough infection — The management of patients with persistent viremia depends upon the viral load and the initial antiviral agent that was used. As examples:
After interferon therapy — Patients who failed to respond to interferon therapy (ie, failure to achieve HBeAg seroconversion six months posttreatment for HBeAg-positive patients or failure to achieve HBV DNA <2000 international units/mL six months posttreatment for HBeAg-negative patients) can be treated with any of the nucleos(t)ide analogs with the expectation of a similar response as treatment-naïve patients. Because most patients require a long duration of treatment, entecavir or tenofovir is preferred. (See 'Nucleos(t)ide analogs' above.)
While receiving tenofovir or entecavir — For patients receiving tenofovir or entecavir, the AASLD considers an initial virologic response as an undetectable HBV DNA after 96 weeks of treatment. Although most HBeAg-negative patients have undetectable HBV DNA after 48 weeks of treatment, some HBeAg-positive patients with high baseline HBV DNA may remain viremic at week 96.
For patients who remain viremic after 96 weeks, or have breakthrough infection (an increase in serum HBV DNA by >1 log10 [10-fold] from nadir or after HBV has been undetectable), we verify medication adherence since tenofovir- or entecavir-resistant virus rarely occurs in treatment-naïve patients. This is in contrast to patients receiving therapy with nucleos(t)ide analogs with a low barrier to resistance, such as lamivudine, adefovir, and telbivudine. (See 'While receiving other nucleos(t)ide analogs' below.)
In patients who are adherent, we do not modify our therapy if there is persistent viremia as long as the HBV DNA levels are low (ie, <200 international units/mL) and continue to decrease . However, we obtain resistance testing if the HBV DNA has plateaued after 96 weeks of treatment or if there is virologic breakthrough.
For those failing entecavir, we add tenofovir until the HBV DNA becomes undetectable; at that point, we discontinue entecavir and treat with tenofovir alone. Some providers increase the dose of entecavir from 0.5 to 1.0 mg daily, but there are very little data to support whether this accelerates HBV DNA suppression. Other providers switch to tenofovir without an overlap period since data suggest that monotherapy with TDF has similar efficacy compared with combination therapy (ie, TDF plus entecavir) . For those failing tenofovir, we add entecavir until the HBV DNA becomes undetectable; at that point, we discontinue tenofovir. Information on the individual agents is found above. (See 'Nucleos(t)ide analogs' above.)
While receiving other nucleos(t)ide analogs — Although nucleos(t)ide analogs with a low barrier to resistance (eg, lamivudine, adefovir, or telbivudine) are not generally recommended for initial therapy, these agents are sometimes used in settings where cost is a consideration. Patients receiving these agents should be switched to tenofovir if possible, particularly if the HBV DNA remains >4 log10 international units/mL after 12 months or the patients develop confirmed breakthrough infection (an increase in serum HBV DNA by >1 log10 [10-fold] from nadir or >2 log10 international units/mL after HBV had been undetectable). Tenofovir monotherapy is effective in suppressing HBV replication in patients who have lamivudine-, telbivudine-, or adefovir-resistant virus. By contrast, there is a high risk of entecavir resistance developing in patients with pre-existing drug-resistant virus after lamivudine or telbivudine treatment. An overview of the different nucleos(t)ide agents is found above. (See 'Nucleos(t)ide analogs' above.)
Therapy should be changed promptly once virologic breakthrough is confirmed to prevent a biochemical breakthrough. This is particularly important in those with worsening liver disease, decompensated cirrhosis, recurrent HBV after transplantation, or immunosuppression.
Testing for antiviral drug-resistant variants is desirable but not essential for most patients. However, resistance mutation testing should be obtained to guide selection of salvage therapy if the patient received sequential nucleos(t)ide analog therapy. As an example, for patients with adefovir-resistant virus, we add entecavir to tenofovir if viral suppression is slow (eg, HBV DNA >10,000 international units/mL after three months). Although TDF has been found to be effective in suppressing adefovir-resistant HBV, the efficacy is lower in patients with double mutations (A181T/V and N236T). (See "Tenofovir and adefovir for the treatment of chronic HBV infection", section on 'Adefovir resistance'.)
Counseling and prevention
●Alcohol use – Heavy use of alcohol (>40 g/day for men and >20 g/day for women) has been associated with worsening liver disease and an increased risk of hepatocellular carcinoma. Although the exact amount of alcohol that can be safely consumed is unclear, advising patients to be completely abstinent is reasonable in those who have cirrhosis. (See "Hepatitis B virus: Clinical manifestations and natural history".)
●Immunizations – Patients with chronic HBV should receive appropriate immunizations, particularly hepatitis A vaccination. (See "Immunizations for patients with chronic liver disease".)
●Preventing transmission to others – Carriers of HBV should be counseled regarding the risk of transmission to others (table 8A-B). Patients should be advised regarding prevention of sexual transmission (ie, vaccination of spouses and steady sex partners in individuals with monogamous partners, and safe sex practice including use of condoms in subjects with multiple partners), perinatal transmission, and risk of environmental exposure from blood. (See "Epidemiology, transmission, and prevention of hepatitis B virus infection".)
Screening for hepatocellular carcinoma — Periodic screening for hepatocellular carcinoma (HCC) should be performed in select patients with chronic HBV. Screening should be performed regardless of antiviral therapy.
Several different guidelines provide recommendations for HCC screening [1-3,52]. We perform ultrasound screening (with or without screening for alpha-fetoprotein) every six months for:
●All HBsAg-positive patients with cirrhosis
●HBsAg-positive adults at high risk for HCC
•Asian men over 40 years of age
•Asian women over 50 years of age
•Persons with a first-degree family member with a history of HCC
•Persons with HDV
A more detailed discussion of screening for HCC is presented in a separate topic review. (See "Surveillance for hepatocellular carcinoma in adults".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of hepatitis B" and "Society guideline links: Diagnosis of hepatitis B".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Hepatitis B (The Basics)")
●Beyond the Basics topic (see "Patient education: Hepatitis B (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Hepatitis B virus (HBV) is a double-stranded DNA virus belonging to the family of hepadnaviruses. It is estimated that there are more than 250 million HBV carriers in the world, of whom approximately 600,000 die annually from HBV-related liver disease. (See 'Introduction' above.)
●Acute HBV infection – The diagnosis of acute HBV infection is based upon the detection of hepatitis B surface antigen (HBsAg) and IgM antibody to hepatitis B core antigen (anti-HBc). For most patients, treatment is mainly supportive. The likelihood of liver failure from acute HBV is less than 1 percent, and in immunocompetent adults, the likelihood of progression to chronic HBV infection is less than 5 percent. However, preventive measures (eg, hepatitis B immune globulin and hepatitis B vaccine) should be administered to all household and sexual contacts who are not known to be immune. (See 'Acute infection' above.)
●Chronic HBV infection – The diagnosis of chronic HBV infection is based upon the persistence of HBsAg for more than six months. The management of chronic HBV infection is complex and depends upon multiple factors including clinical variables (eg, the presence or absence of liver inflammation and/or cirrhosis), the patient's immunologic response to infection (eg, hepatitis B e antigen [HBeAg]), virologic factors (eg, HBV viral load and genotype), and risk factors for disease progression (eg, age >40, family history of hepatocellular carcinoma) (table 4). (See 'Initial evaluation' above.)
●Antiviral therapy for chronic HBV – Antiviral agents for chronic HBV include pegylated interferon (PegIFN) or nucleos(t)ide analogs (eg, entecavir and tenofovir). The goals of antiviral therapy are suppression of HBV DNA, loss of HBeAg (in patients who were initially HBeAg-positive), and loss of HBsAg. (See 'Overview of antiviral agents' above.)
•When to initiate treatment – The decision to initiate treatment is primarily based upon the presence or absence of cirrhosis, the alanine aminotransferase (ALT) level, and the HBV DNA level (table 5). There are additional indications for patients with certain concurrent conditions, such as malignancy and pregnancy. Patients who are not deemed to be treatment candidates at presentation, and those who decide to defer treatment, should undergo monitoring of liver biochemical tests, HBV DNA, and HBeAg status since liver disease and/or HBV replication may become active later (table 4). (See 'Indications for antiviral therapy' above.)
•Choice of agent – For treatment-naïve patients who initiate therapy, we generally administer a nucleos(t)ide analog. We recommend tenofovir or entecavir rather than other nucleos(t)ide analogs (Grade 1B). Tenofovir and entecavir have potent antiviral activity and are at low risk of selecting for drug-resistant virus. PegIFN may also be reasonable as an initial agent for certain treatment-naïve patients without cirrhosis, particularly if they have genotype A infection and/or they do not wish to be on long-term treatment. However, PegIFN is typically associated with more side effects compared with nucleos(t)ide analogs. (See 'Choice of initial agent' above.)
For most patients who are initiating therapy with tenofovir, we recommend tenofovir alafenamide (25 mg daily), if available, rather than tenofovir disoproxil fumarate (TDF) (300 mg daily) (Grade 1B). Although there is more experience with TDF, tenofovir alafenamide appears to be equally effective and is associated with less renal and bone toxicity. In addition, for most patients who were originally started on TDF, we suggest switching to tenofovir alafenamide (Grade 2B). (See 'Nucleos(t)ide analogs' above and 'Choice of initial agent' above.)
There are special treatment considerations when choosing an antiviral agent for patients with decompensated cirrhosis or reduced kidney function and for women who are pregnant. (See 'Choice of initial agent' above and "Hepatitis B and pregnancy".)
•Patient monitoring – Patients should be monitored while on therapy to assess for virologic response and medication toxicity. Most patients receiving nucleos(t)ide analog therapy will require at least four to five years of treatment, and some may require indefinite treatment (table 5). (See 'Monitoring on therapy' above and 'Duration and treatment endpoints' above.)
●Patients with persistent viremia – The management of patients with persistent viremia or breakthrough infection on therapy depends upon the viral load and the antiviral agent that was used.
•Tenofovir- or entecavir-resistant virus is unlikely to emerge in treatment-naïve patients, and most cases of treatment failure are due to poor adherence. However, on rare occasion, a patient may need to be transitioned to an alternative agent. (See 'While receiving tenofovir or entecavir' above.)
•By contrast, drug-resistant virus is likely to develop in patients failing therapy with nucleos(t)ide analogs, such as lamivudine, adefovir, or telbivudine. For patients with persistent viremia or breakthrough infection on one of these agents, we recommend tenofovir rather than entecavir (Grade 1B). Tenofovir is effective in suppressing HBV replication in this setting, whereas entecavir should generally be avoided since there is a high risk of entecavir resistance developing in patients with pre-existing drug-resistant virus after lamivudine or telbivudine treatment. (See 'While receiving other nucleos(t)ide analogs' above.)
●Patient counseling – Patients with chronic HBV should receive counseling on ways to prevent worsening liver disease (eg, avoid alcohol use, hepatitis A vaccination) and to reduce transmission to others. In addition, screening for hepatocellular carcinoma is indicated for certain high-risk patients. (See 'Counseling and prevention' above and 'Screening for hepatocellular carcinoma' above.)
3 : Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
5 : A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults.
6 : A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents.
7 : Recommendations for identification and public health management of persons with chronic hepatitis B virus infection.
8 : Evaluation of alanine transaminase and hepatitis B virus DNA to predict liver cirrhosis in hepatitis B e antigen-negative chronic hepatitis B using transient elastography.
10 : Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT.
11 : Chronic hepatitis B virus carriers in the immunotolerant phase of infection: histologic findings and outcome.
12 : Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase.
15 : Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy.
16 : Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using a matched, untreated cohort.
17 : Hepatocellular carcinoma risk in chronic hepatitis B virus-infected compensated cirrhosis patients with low viral load.
18 : Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA.
19 : Combination of Entecavir/Peginterferon Alfa-2a in Children With Hepatitis B e Antigen-Positive Immune Tolerant Chronic Hepatitis B Virus Infection.
20 : Entecavir and Peginterferon Alfa-2a in Adults With Hepatitis B e Antigen-Positive Immune-Tolerant Chronic Hepatitis B Virus Infection.
21 : Extremely low risk of hepatocellular carcinoma development in patients with chronic hepatitis B in immune-tolerant phase.
22 : Evaluation of Antiviral Therapy Performed after Curative Therapy in Patients with HBV-Related Hepatocellular Carcinoma: An Updated Meta-Analysis.
23 : Evaluation of Antiviral Therapy Performed after Curative Therapy in Patients with HBV-Related Hepatocellular Carcinoma: An Updated Meta-Analysis.
24 : Antiviral therapy for chronic hepatitis B viral infection in adults: A systematic review and meta-analysis.
26 : Pretherapy alanine transaminase level as a determinant for hepatitis B e antigen seroconversion during lamivudine therapy in patients with chronic hepatitis B. Asian Hepatitis Lamivudine Trial Group.
28 : Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial.
29 : Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial.
30 : Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial.
31 : Tenofovir alafenamide for hepatitis B virus infection including switching therapy from tenofovir disoproxil fumarate.
32 : Potential benefit of telbivudine on renal function does not outweigh its high rate of antiviral drug resistance and other adverse effects.
33 : Cost effectiveness of response-guided therapy with peginterferon in the treatment of chronic hepatitis B.
34 : Review article: long-term safety of nucleoside and nucleotide analogues in HBV-monoinfected patients.
35 : Long-term efficacy and safety of lamivudine, entecavir, and tenofovir for treatment of hepatitis B virus-related cirrhosis.
37 : Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound.
38 : Clinical events after cessation of lamivudine therapy in patients recovered from hepatitis B flare with hepatic decompensation.
39 : Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy.
41 : Entecavir safety and effectiveness in a national cohort of treatment-naïve chronic hepatitis B patients in the US - the ENUMERATE study.
42 : Significance of definitions of relapse after discontinuation of oral antivirals in HBeAg-negative chronic hepatitis B.
43 : Distinct Relapse Rates and Risk Predictors After Discontinuing Tenofovir and Entecavir Therapy.
44 : Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study.
45 : Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B.
46 : Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study.
47 : Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients.
51 : Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial.
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