Hepatitis B Treatment & Management

Updated: Oct 20, 2022
  • Author: Nikolaos T Pyrsopoulos, MD, PhD, MBA, FACP, AGAF, FAASLD, FRCP(Edin); Chief Editor: BS Anand, MD  more...
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Approach Considerations

Please note that guidelines for the current diagnostic workup and management of hepatitis B virus (HBV) infection continue to evolve. Clinicians are advised to refer frequently to the most recent recommendations of the American Association for the Study of Liver Diseases (AASLD).

The primary treatment goals for patients with hepatitis B (HBV) infection are to prevent progression of the disease, particularly to cirrhosis, liver failure, and hepatocellular carcinoma (HCC). [2, 41, 59] Risk factors for progression of chronic HBV include the following [2, 41, 59] :

  • Persistently elevated levels of HBV DNA and, in some patients, alanine aminotransferase (ALT), as well as the presence of core and precore mutations seen most commonly in HBV genotype C and D infections

  • Male sex

  • Older age

  • Family history of HCC

  • Alcohol use

  • Elevated alpha-fetoprotein (AFP)

  • Coinfection with hepatitis D (delta) virus (HDV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)

A synergistic approach of suppressing viral load and boosting the patient’s immune response with immunotherapeutic interventions is needed for the best prognosis. [60] The prevention of HCC often includes the use of antiviral treatment using pegylated interferon (PEG-IFN) or nucleos(t)ide analogues. [38]

HBV infection can be self-limited or chronic. [43] No specific therapy is available for persons with acute hepatitis B; treatment is supportive. [43]

Therapy is currently recommended for patients with evidence of chronic active hepatitis B disease (ie, abnormal aminotransferase levels, positive HBV DNA findings, positive or negative hepatitis B e antigen [HBeAg]). Various algorithms have been proposed, such as that by the American Association for the Study of Liver Diseases (AASLD), [41, 61] the European Association for the Study of the Liver (EASL), [62] the Asian Pacific Association for the Study of the Liver (APASL), [63] the Canadian Association for the Study of the Liver (CASL), [64] the National Institute for Health and Clinical Excellence (NICE), [65] Kuo and Gish, [22] and Keeffe et al. [66]

National Institutes of Health recommendations

The National Institutes of Health (NIH) recommends nucleos(t)ide therapy for the treatment of patients with acute liver failure, as well as cirrhotic patients who are HBV DNA positive and those with clinical complications, cirrhosis or advanced fibrosis with positive serum HBV DNA, or reactivation of chronic HBV during or after chemotherapy or immunosuppression. [2] In addition, immunoglobulin and vaccination should be administered to newborns born to women positive for hepatitis B surface antigen (HBsAg). [2, 45, 67]

In general, for hepatitis B e antigen (HBeAg)-positive patients with evidence of chronic HBV disease, treatment is advised when the HBV DNA level is at or above 20,000 IU/mL (105 copies/mL) (or, per the EASL, >2,000 IU/mL [62] ) and when serum ALT is elevated for 3-6 months. [2, 41, 59]

For HBeAg-negative patients with chronic hepatitis B disease, treatment can be administered when the HBV DNA is at or above 2,000 IU/mL (104 copies/mL) and the serum ALT is elevated (ALT levels >20 U/L for females; 30 U/L for males) for 3-6 months.

In patients coinfected with HBV and HIV, initiate therapy against HBV and administer antiretroviral therapy (ART) as well. [45]

The NIH also indicates that immediate therapy is not routinely indicated for patients who have the following [2] :

  • Chronic hepatitis B with high levels of serum HBV DNA but normal serum ALT levels or little activity on liver biopsy (immune-tolerant phase)

  • Low levels of or no detectable serum HBV DNA and normal serum ALT levels (inactive chronically infected/low replicative phase)

  • Positive serum HBV DNA but not HBsAg (latent HBV infection), unless the patient is undergoing immunosuppression

World Health Organization (WHO) recommendations

The 2015 WHO guidelines for the prevention, care, and treatment of persons with chronic hepatitis B infection indicate treatment priority for individuals of all ages who have chronic hepatitis B infection and clinical evidence of compensated/decompensated cirrhosis (or cirrhosis based on APRI [aspartate aminotransferase (AST)-to-platelet ratio index] score >2 in adults), regardless of their levels of ALT or HBV DNA, or their HBeAg status. [59] (Strong recommendation)

Treatment is recommended for adults with chronic hepatitis B infection without clinical evidence of cirrhosis (or based on APRI score ≤2 in adults), but who have all of the following features , and regardless of HBeAg status (strong recommendation) [59] :

  • Are older than 30 years (in particular)
  • Have persistently abnormal ALT levels
  • Have evidence of high-level HBV replication (HBV DNA >20,000 IU/mL). (If HBV DNA testing is unavailable, consider treatment based on persistently abnormal ALT levels alone, regardless of HBeAg status. [Conditional recommendation])

American Association for the Study of Liver Diseases (AASLD) recommendations

The 2016 AASLD guidelines for the treatment of chronic hepatitis B [41] as well as select recommendations from the 2018 AASLD guidance update on the prevention, diagnosis, and treatment of chronic hepatitis B [52] are outlined below and in the Guidelines section.

The AASLD does not recommend  antiviral therapy (indicating it can be deferred) in individuals with all  of the following, regardless of HBeAg status or age (strong recommendation) [59] :

  • No clinical evidence of cirrhosis (or based on APRI score ≤2 in adults)
  • Persistently normal ALT levels
  • Low levels of HBV DNA replication (HBV DNA < 2,000 IU/mL). (If HBV DNA testing is unavailable, treatment can be deferred in HBeAg-positive individuals aged 30 years or younger who have persistently abnormal ALT levels. (Conditional recommendation)]

Adults with immune-active chronic hepatitis B infection (ie, ALT >2 times the upper limit of normal [ULN] or  significant histologic disease and HBeAg negative [HBV DNA >2,000 IU/mL] or HBeAg positive [HBV DNA >20,000 IU/mL]) (Strong recommendations)

Administer antiviral therapy to lower the risk of morbidity and mortality associated with chronic hepatitis B infection.

The recommended initial agent for adults is PEG-IFN, entecavir, or tenofovir.

Adults with immune-tolerant chronic hepatitis B infection (ie, ULNs: ALT levels ≤30 U/L for men and ≤19 U/L for women)

Antiviral therapy is not recommended. (Strong recommendation)

The AASLD suggests obtaining ALT levels at least every 6 months to monitor for potential transition to immune-active or -inactive chronic hepatitis B. (Conditional recommendation)

For select patients older than 40 years, the AASLD suggests antiviral therapy in the setting of normal ALT levels, elevated HBV DNA (≥1,000,000 IU/mL), and significant necroinflammation or fibrosis on liver biopsy specimens. (Conditional recommendation)

Adults with HBeAg-positive immune-active chronic hepatitis B who seroconvert to anti-HBe on nucleos(t)ide analog (NA) therapy (Conditional recommendations)

After a period of treatment consolidation (treatment for ≥12 months in the setting of persistently normal ALT levels and undetectable serum HBV DNA), consider discontinuing NA therapy in noncirrhotic HBeAg-positive adults who seroconvert to anti-HBe while on NA treatment. If antiviral therapy is stopped, monitor the patient every 3 months for a minimum of 1 year for recurrent viremia, ALT flares, seroreversion, and clinical decompensation.

For cirrhotic HBeAg-positive adults who seroconvert to anti-HBe on NA therapy, the AASLD suggests indefinite antiviral therapy owing to the potential for clinical decompensation and death, unless a strong competing rationale for treatment discontinuation exists. If antiviral therapy is stopped, closely monitor these patients for recurrent viremia, ALT flares, seroreversion, and clinical decompensation.

Adults with HBeAg-negative immune-active chronic HBV infection

The AASLD suggests indefinite antiviral therapy for adults with HBeAg-negative immune-active chronic hepatitis B infection, unless there is a competing rationale for treatment discontinuation. (Conditional recommendation) If antiviral therapy is stopped, monitor the patient every 3 months for a minimum of 1 year for recurrent viremia, ALT flares, and clinical decompensation.

Antiviral therapy is not recommended for noncirrhotic individuals who are HBeAg negative and who have normal ALT activity and low-level viremia (< 2,000 U/mL; “inactive chronic hepatitis B”).

Children with chronic hepatitis B infection

For HBeAg-positive children aged 2 years up to 18 years who have both elevated ALT and detectable HBV DNA levels, the AASLD suggests antiviral therapy (IFN-alpha-2b: age ≥1 year; lamivudine, entecavir: age ≥2 year), with the goal of achieving sustained HBeAg seroconversion. (Conditional recommendation) If antiviral therapy is stopped, monitor the child every 3 months for a minimum of 1 year for recurrent viremia, ALT flares, and clinical decompensation.

Antiviral therapy is not recommended for HBeAg-positive children aged 2 years up to 18 years who have persistently normal ALT (conservative value: 30 U/L), regardless of the HBV DNA level. (Strong recommendation)

Individuals with HBV and HCV coinfection [52]

  • Test all HBsAg-positive patients for HCV infection with the anti-HCV test.
  • Those with HCV viremia should receive HCV therapy.
  • HBV treatment is based on levels of HBV DNA and ALT as indicated by the AASLD HBV guideline for monoinfected individuals.
  • HBsAg-positive individuals: At risk for HBV DNA and ALT flares with HCV-DAA (direct-acting antiviral) therapy; monitor HBV DNA levels every 4-8 weeks during treatment and for 3 months posttreatment for individuals who do not meet the treatment criteria according to the AASLD HBV guidelines.
  • HBsAg-negative, anti-HBc-positive individuals with HCV: Low risk of reactivation with HCV-DAA therapy; monitor ALT levels at baseline, treatment completion, and during follow-up; reserve HBV DNA and HBsAg testing for individuals whose ALT levels rise or fail to normalize during treatment or posttreatment

Individuals with HBV and HIV coinfection

In individuals with HBV/human immunodeficiency virus (HIV) coinfection, the AASLD recommends initiating ART in (1) all those with evidence of severe chronic liver disease, regardless of CD4 count, as well as (2) those with a CD4 count of 500 cells/mm3 or below, regardless of their liver disease stage. [59] (Strong recommendation)

Inpatient care

Patients with hepatitis B disease and fulminant hepatic failure should be hospitalized in the intensive care unit (ICU) and be considered for liver transplantation in the event that they do not recover. Any patient with acute HBV disease needs to be treated with first-line oral therapy, such as tenofovir disoproxil fumarate (TDF) or entecavir (ETV).

Patients with acute hepatitis should be monitored with blood tests in order to document biochemical improvement (see Workup).


The recommendations below are from the 2018 AASLD guidance update. [52]

HBsAg-positive patients should receive counseling about the prevention of HBV transmission to others.

Healthcare workers and students who are HBsAg positive can continue with training or practice—unless their job requires they perform exposure-prone procedures. In such situations, these individuals should seek counseling/advice from their institutional expert review panel; they should not perform exposure-prone procedures if their serum HBV DNA level is above 1,000 IU/mL; and they can resume such procedures if their HBV DNA falls and is maintained below 1,000 IU/mL.

Aside from using universal precautions, special arrangements are not indicated for children with HBV in community setting (eg, daycare centers, schools, sports clubs, camps) unless they have a tendency to bite.

HBV-infected individuals are recommended to be abstinent or limit their alcohol use.

To prevent the concurrent development of fatty liver and metabolic syndrome, it is recommended that individuals with HBV optimize their body weight and treatment of metabolic complications (eg, control of diabetes and dyslipidemia).

Dietary limitations

Patients with acute or chronic hepatitis without cirrhosis have no dietary restrictions. For individuals with decompensated cirrhosis (signs of portal hypertension or encephalopathy), the following dietary limitations are indicated:

  • A low-sodium diet (1.5 g/day)

  • High-protein diet (ie, white-meat protein, such as chicken, turkey, or fish)

  • Fluid restriction (1.5 L/day) in cases of hyponatremia


Pharmacologic Management

Currently, pegylated interferon alfa (PEG-IFN-a), entecavir (ETV), and tenofovir disoproxil fumarate (TDF) are the FDA-approved agents in the treatment of hepatitis B disease. These are the main treatment drugs approved globally for this disease, although the use of PEG-IFN-a is limited by its poor tolerability. [3] Ongoing trials are investigating new types of medications, such as tenofovir disoproxil in combination with emtricitabine (FTC). Encapsidation inhibitors, entry inhibitors, TLR7 agonists, and therapeutic vaccines are all in development.

In 2009, international phase III trials with clevudine (l-FMAU) for the treatment of chronic hepatitis B virus (HBV) infection were halted owing to a very high risk of myopathy. [68]

Lamivudine (3TC), telbivudine, and adefovir are of historical interest. Lamivudine and adefovir are either currently considered second- or third-line therapy, or “nonpreferred” treatment. [69]  Telbivudine was withdrawn from the US market in 2016 and from the European Union market in 2020 for commercial reasons; however, it may still be available in other regions.

Approved antiviral therapies

The following are medications approved for the treatment of chronic hepatitis B in adult and/or pediatric patients (adjust all dosing in the setting of renal dysfunction).  [41]

Preferred agents

  • Pegylated interferon (PEG-IFN)-alpha-2a (adults) or IFN-alpha-2b (children) – Adult dose 180 μg weekly; pediatric dose (age ≥ 1 year): 6 million IU/m 2 three times weekly
  • Entecavir – Adult dose: Daily 0.5 mg (lamivudine-/telbivudine-naive persons) or 1 mg (those with lamivudine/telbivudine experience or decompensated cirrhosis); pediatric dose (age ≥ 2 years): Weight-based to 10-30 kg; for children weighing more than 30 kg, use 0.5 mg daily
  • Tenofovir disoproxil fumarate (DF) – Adult and pediatric (aged ≥ 12 years) dose: 300 mg daily
  • Tenofovir alafenamide (AF) – Adult and pediatric (aged ≥ 12 years): 25 mg daily 

Nonpreferred agents

  • Adefovir – Adult and pediatric dose (aged ≥ 12 years): 10 mg daily
  • Lamivudine – Adult dose: 100 mg daily; pediatric dose (aged ≥ 2 years): 3 mg/kg daily (maximum: 100 mg)
  • Telbivudine – Discontinued from United States market in 2016 and from the European Union market in 2020

World Health Organization (WHO) recommendations

First-line antiviral treatment (Strong recommendations)

All individuals aged 12 years or older who are eligible for antiviral therapy are recommended to receive therapy with tenofovir or entecavir, the nucleos(t)ide analogs (NAs) with a high barrier to drug resistance. Entecavir is recommended in children aged 2-11 years.

NAs with a low barrier to drug resistance (lamivudine, adefovir, or telbivudine) are not recommended owing to their potential for drug resistance.

In HBV/human immunodeficiency virus (HIV)-coinfected individuals aged 3 years or older, a fixed-dose combination of tenofovir/lamivudine (or emtricitabine)/efavirenz is the preferred option for initiation of ART.

Second-line antiviral treatment for managing treatment failure (Strong recommendation)

For individuals with confirmed or suspected antiviral resistance (ie, history of prior exposure or primary nonresponse) to lamivudine, entecavir, or adefovir, or telbivudine, the WHO recommends switching to tenofovir.

Specific considerations

Special attention must be given to patients on liver transplantation waitlists. Initiation of treatment with entecavir or tenofovir is of cardinal importance before and after liver transplantation in order to achieve viral suppression and to prevent recurrence of the disease after the procedure. Combination therapy with ETV and TDF or, more rarely, TDF with FTC or 3TC can be considered if drug-resistant mutants are present or for patients with failing first-line therapy.

Caution must also be used with long-term and high-dose administration of adefovir or tenofovir therapy in patients with chronic HBV disease. In a National Institutes of Health (NIH) study, 15% of patients on adefovir or tenofovir for 2-9 years developed proximal renal tubular dysfunction, defined as de novo incidence of 3 of the following 5 features [70] :

  • Hypophosphatemia

  • Hypouricemia

  • Elevated serum creatinine level

  • Proteinuria

  • Glycosuria

Switching to other antiviral agents in the study allowed for partial reversal of the renal tubular dysfunction. [70]

ETV was associated with lactic acidosis in a study of 5 patients with liver failure who had Model for End-Stage Liver Disease (MELD) scores of greater than 20. [71]

In patients with HBV who are coinfected with human immunodeficiency virus (HIV), it may be possible to simplify treatment regimens with agents that have dual effectiveness against both viruses. [45] Hepatitis D (delta) virus (HDV) infection is best treated with PEG-IFN therapy.

Interferon alfa

Interferons are proteins that have antiviral, antiproliferative, and immunomodulatory effects. Published reports indicate that after IFN-a treatment with 5 million U/day or 10 million U 3 times per week subcutaneously (SC) for 4 months, HBV DNA levels and HBeAg become undetectable in 30-40% of patients. [72] In addition, 10% of patients seroconvert from hepatitis B surface antigen (HBsAg) to hepatitis B surface antibody (anti-HBs). Unfortunately, 5-10% of patients relapse after completion of treatment. A transient "flare," (ie, increased serum alanine aminotransferase [ALT] levels during the beginning of treatment) can be identified, and this represents the impact of the activated cytolytic T cells on the infected hepatocytes.

High levels of aminotransferases, a low viral load, and infection with the wild type virus are good prognostic factors for response to IFN-a treatment. However, Asian patients and patients with the precore mutant virus tend to not have a clinical response to IFN-a treatment.

Loss of HBsAg indicates resolution of the HBV infection, acute or chronic, but it is rare in chronic infection. A study by Tseng et al that followed Taiwanese patients with chronic hepatitis B infection who developed spontaneous HBeAg loss (seroconversion) showed that patients with low levels of HBsAg 1 year after their HBeAg seroconversion had a higher probability of loss of HBsAg. [73]


IFN-a therapy has been successful in treating HBV-related glomerulonephritis. A regimen of 5 million units of IFN-a subcutaneously (SC) daily for 4 months has achieved HBsAg seroconversion with improvement of glomerulonephritis. It has also been reported that IFN-a given at a dose of 3 million units 3 times per week led to an improvement of proteinuria only in patients with mesangial proliferative glomerulonephritis, not in those with membranoproliferative glomerulonephritis (MPGN).

Finally, a single case report described the resolution of this complication after liver transplantation. In addition to interferon, antiviral therapy with lamivudine (3TC) has not only been shown to significantly increase the incidences of proteinuria remission and of HBeAg seroconversion but also cause a decline in levels of HBV-DNA in adult patients with HBV-related glomerulonephritis relative to controls. [74]

Polyarteritis nodosa

Small and medium-sized arteries and arterioles are affected in polyarteritis nodosa (PAN). Although corticosteroids and immunosuppressive agents may be beneficial for treating vasculitis, they may potentially have a deleterious effect on the course of hepatitis B liver disease due to viral reactivation, particularly after the withdrawal of treatment.

The antiviral drug adenine arabinoside and IFN-a have been used in conjunction with plasmapheresis and a short course of corticosteroids, with promising results.

The combination of short-term corticosteroids accompanied by plasmapheresis and lamivudine, as used in one study, resulted in 100% clinical recovery and 66% seroconversion, although the number of patients in the trial was relatively small. [75]


Special attention must be given to patients with HBV-decompensated cirrhosis (eg, ascites, encephalopathy) who are taking IFN-a, owing to the fact that, although they occasionally may have a treatment response, these individuals can also deteriorate further.

The adverse effects of IFN-a treatment can sometimes be severe, even devastating. Some patients cannot complete the treatment. A flulike syndrome, myelosuppression (eg, leukopenia, thrombocytopenia), nausea, diarrhea, fatigue, irritability, depression, thyroid dysfunction, and alopecia are among the adverse effects that may occur.

Pegylated IFN-a 2a

PEG-IFN-a 2a has an enhanced half-life relative to the standard IFN-a. Pegylation lowers the rate of absorption following subcutaneous (SC) injection, reduces renal clearance, and decreases the immunogenicity of the interferon.

A 48-week regimen of PEG-IFN-a 2a may induce a 27% rate of HBeAg seroconversion and a 25% rate of loss of HBV DNA. [76] In a study by Lau et al involving a 48-week regimen, after 24 weeks of follow-up the HBeAg seroconversion rate with PEG-IFN-a 2a monotherapy was 32%, compared with 27% in those receiving combination therapy with 3TC and 19% in those receiving 3TC monotherapy. [76]  Other combinations of PEG-IFN-a with NAs have demonstrated safety and improved efficacy as compared to monotherapy regimens. [3]

It appears that patients infected with HBV genotype A or B have a better response to IFN treatment than do patients infected with genotype C or D. This therapy also appears to be more appealing, especially for patients with increased ALT levels.

PEG-IFN-a 2a is also indicated for treatment of chronic hepatitis C, alone or in combination with ribavirin, in patients not previously treated with IFN-a, with compensated liver disease, or with HDV infection. At most, 17% of patients have durable suppression of the virus as defined by undetectable HBV DNA at 5 years posttreatment. [76, 77]


Telbivudine was withdrawn from the United States market in 2016 and from the European Union market in 2020 for commercial reasons. However, it may still be available in other regions.

Telbivudine, a cytosine nucleoside analogue, was a second-line agent (not preferred) used in HBV therapy. [22] This drug was a potent inhibitor of HBV DNA polymerase. Although telbivudine appeared to have slightly more potent antiviral activity than did adefovir and lamivudine, it was more expensive and played a limited role in primary therapy.


Entecavir is a first-line agent in the treatment of hepatitis B. [22] This drug is a potent guanosine analogue inhibitor of the viral polymerase with 1.2% resistance in patients who have no history of previous treatment with nucleos(t)ide analogues and almost 56% resistance in 3TC-resistant patients during a 6-year treatment period. [78]

Advantages of therapy with this agent include potent antiviral activity and a low drug resistance rate, [22] although entecavir has less of a role than other agents in the treatment of 3TC-resistant hepatitis B.

A retrospective study demonstrated that HBV DNA responses at 12 months can potentially be used to evaluate entecavir therapy in nucleos(t)ide analogue ̶ naïve, HBV-infected patients. [79] Investigators reported 3 independent predictors for maintenance of viral suppression among patients on entecavir treatment at 3 years—lower baseline HBV DNA, undetectable HBV DNA at month 12, and negative HBeAg—as well as for the probability of HBeAg-seroconversion and the risk of drug resistance. [79]

HBeAg-positive patients

With regard to the HBeAg-positive population, administration of 0.5 mg of entecavir in patients who were naïve to nucleoside analogues relative to patients who received 100 mg of 3TC for a duration of 48 weeks resulted in histologic improvement in 72% of the entecavir group compared with 62% of the 3TC group. [80] Undetectable serum HBV DNA levels were reported in 67% of entecavir-treated patients, compared with 36% of 3TC-treated patients.

In addition, normalized ALT levels were achieved in 68% of the entecavir group, versus 60% of the 3TC group. [80] The mean reduction in serum HBV DNA from baseline to week 48 was 6.9 log copies/mL (on a base-10 scale) in the entecavir-treated patients, relative to 5.4 log copies/mL in the 3TC-treated patients. HBeAg seroconversion occurred in 21% of patients treated with entecavir and in 18% of patients treated with 3TC. [80]

HBeAg-negative patients

In an HBeAg-negative population, administration of 0.5 mg of entecavir in patients who were naïve to nucleoside analogues compared with patients who received 100 mg of 3TC for a duration of 48 weeks resulted in histologic improvement in 71% of the entecavir group, versus 61% of the 3TC group. [78] Undetectable serum HBV DNA levels were found in 90% of the entecavir-treated patients, versus 72% of the 3TC-treated patients.

Normalized ALT levels were achieved in 78% of the entecavir group, compared with 71% of the 3TC group. [78] The mean reduction in serum HBV DNA levels from baseline to week 48 was 5.0 log copies/mL (on a base-10 scale) in the entecavir-treated patients, versus 4.5 log copies/mL in the 3TC-treated patients. [78]

Long-term (5- and 6-y) data

After up to 5 years (240 wk) of continuous entecavir therapy (1.0 mg qDay) for HBeAg-positive patients, 94% of patients had less than 300 copies/mL of HBV DNA, and 80% had normal ALT levels. [81] An additional 23% of patients achieved HBeAg seroconversion, and 1.4% lost HBsAg. Only 1 patient demonstrated treatment resistance with entecavir through 5 years. [81]

In another study, Schiff et al reported that long-term treatment with entecavir (about 6 y of cumulative therapy [range, 267-297 wk]) in nucleoside-naïve chronic hepatitis B patients with advanced fibrosis or cirrhosis resulted in durable virologic suppression, continued histologic improvement, and reversal of fibrosis/cirrhosis. [82] The patients received entecavir for at least 3 years and had evaluable biopsies at baseline and after long-term treatment.

Lamivudine (3TC)

A nucleoside analogue, 3TC inhibits the viral polymerase. It appears to be effective in patients who do not have a treatment response to IFN-a (eg, patients infected by the precore mutant virus). However, its role in hepatitis B treatment is diminishing as alternate therapies become available [22] ; thus, this agent is a third-line therapy and not preferred.

Other agents, except for adefovir, are superior to 3TC in suppression of viral replication. Another disadvantage to this therapy is its high rate of drug resistance. [22] Relative to other oral treatments, however, 3TC is lower in cost.

Therapy with 3TC has been associated with a 4-log reduction of the viral load. [69, 83, 84, 85] Treatment (100 mg/day) has also been associated with the following:

  • 16-18% seroconversion rate from HBeAg to anti-HBe

  • 30-33% rate of HBeAg loss

  • 40-50% normalization of the value of the aminotransferases

  • 1-2% HBsAg seroconversion rate

The HBeAg seroconversion rate has been shown to possibly increase to 27% after 2 years, 40% after 3 years, and 47% after 4 years of treatment in patients with a viral load of less than 104 pg/mL.

Histologic improvement (ie, reduction of the histologic activity index by >2 points) has been noted in approximately 50% of patients taking 3TC. The adverse effects are negligible, although a transient elevation of aminotransferases can be noticed shortly after starting treatment.

Treatment with 3TC has also been shown to dramatically improve the condition of patients with decompensated disease due to HBV reactivation. Patients with HIV infection and fulminant hepatic failure due to active HBV infection may receive 3TC-only treatment. [45] Those with HIV/HBV coinfection who are eligible for antiretroviral therapy and have less severe hepatic injury should defer the antiretroviral treatment until resolution of the liver injury. [45]

Polyarteritis nodosa

As previously mentioned, the combination of short-term corticosteroids accompanied by plasmapheresis and lamivudine, as used in one study, resulted in 100% clinical recovery and 66% seroconversion in patients with HBV-associated PAN, although the number of patients in the trial was relatively small. [75]

HBV infection prophylaxis in HIV

In patients infected with HIV, antiretroviral therapy regimens containing 3TC or TDF may be prophylactic for HBV infection. A recent analysis examined stocked serum samples from 354 men with HIV who had not been vaccinated against hepatitis B and whose initial serum samples showed no signs of HBV. [86]

All of the patients in the study were men who had sex with men, a population in which hepatitis B infection in the presence of HIV is particularly common. An analysis of the final stocked samples from these patients found that sometime after their first serum samples were obtained, 43 (12%) of the 354 men had become infected with HBV. [86]

The investigators found that the rate of incident HBV infections was lower during periods when antiretroviral regimens using 3TC or TDF were used (0.669 incident infections in 100 person-years) than it was during periods when no antiretroviral therapy was used or when antiretroviral therapy employed neither 3TC or TDF (6.726 and 5.263 incident infections in 100 person-years, respectively). [86]


The emergence of viral variants is the major complication in hepatitis B disease. [87, 88] Approximately 15-30% of patients develop a mutation of the viral polymerase gene (the YMDD variants) after 12 months of treatment with 3TC; approximately 50% develop a mutation after 3 years of treatment with the drug, and as many as 70-100% develop a mutation with long-term therapy. However, continued treatment after the breakthrough with the variant type has been associated with lower HBV DNA levels, less aminotransferase activity, and histologic improvement. For these patients, discontinuation of treatment is accompanied by a reversion to a wild type of HBV and a flare of the disease.

Adefovir dipivoxil

Adefovir is another third-line agent (not preferred) that is indicated for the treatment of chronic hepatitis B disease with evidence of active viral replication, including patients with 3TC-resistant hepatitis B. [22] This agent is a nucleoside analogue, a potent inhibitor of the viral polymerase. The efficacy of adefovir dipivoxil has been tested in HBeAg-positive, HBeAg-negative, and 3TC-resistant patients with encouraging results.

The optimal dose seems to be 10 mg/day [89, 90] ; higher doses are nephrotoxic. The estimated rate of resistance to adefovir and the development of mutations (rtN236T and rtA181V) are approximately 4-6% after 3 years and approximately 30% after 5 years of treatment. [91, 92, 93, 94]

The results of 2 multicenter trials that used adefovir for 48 weeks noted that in HBeAg-positive patients who received 10 mg of adefovir daily, there was a median 3.52-log reduction of the viral load (HBV DNA) level. [89, 90] In 48% of the patients, normalized aminotransferase levels were reported, and histologic improvement was seen in 53% of the patients who received this regimen. [89] The HBeAg seroconversion rate was 12%.

Furthermore, of the HBeAg-negative population, 64% experienced histologic improvement after receiving 10 mg of adefovir for 48 weeks, and 72% had normalized aminotransferase levels. [89, 90] The serum HBV DNA level decreased in 51% of subjects. The outcomes were maintained if treatment was continued for 44 weeks, but the benefits were lost if treatment was discontinued at 44 weeks. [89, 90] The development rate for the resistant mutations rtN236T and rtA181V has been estimated to be around 6%. [90]


Tenofovir may be used as the first-line therapy for treatment-naïve patients. [22] This agent is preferred as an additional therapy in patients with resistance to 3TC, telbivudine, or entecavir. Tenofovir provides more potent antiviral therapy than adefovir, and it can be used as a substitute in patients who do not have an adequate response to adefovir.

Tenofovir is a nucleotide analogue (adenosine monophosphate) reverse transcriptase and HBV polymerase inhibitor. Originally, it was developed in the form of tenofovir disoproxil fumarate (TDF). More recently, a prodrug, tenofovir alafenamide (TAF), was developed. TAF demonstrated greater antiviral efficacy, and improved renal and bone density profile as compared to TDF. [95]

HBeAg-positive naïve patients

In a study that randomized patients to receive either tenofovir DF (300 mg once daily) or adefovir (10 mg once daily) for 48 weeks—with the adefovir-treated patients then switched to tenofovir—79% of the patients who received tenofovir were found to have a viral load below 400 copies/mL, whereas 76% of patients who received adefovir before switching to tenofovir were found to have a viral load below 400 copies/mL. [96]

In addition, 72% of patients in the adefovir arm who were found to have a viral load greater than 400 copies/mL achieved viral suppression after they were switched to tenofovir. For patients who achieved viral suppression on adefovir alone, the effect was maintained after they were switched to tenofovir. [96] Biochemical response was reported in 77% of patients in the tenofovir arm at week 72 and in 61% of those switching from adefovir to tenofovir.

With regard to seroconversion, 26% of patients who received tenofovir seroconverted at week 64, while in the adefovir arm, the observed seroconversion rate was reported as 21%. [96] It is noteworthy to mention that 5% of patients in the tenofovir arm experienced loss of the s antigen.

HBeAg-negative patients

In another report involving patients who were randomized to receive either tenofovir DF (300 mg once daily) or adefovir (10 mg once daily), with all eligible adefovir-treated patients being switched to tenofovir after 48 weeks, 91% of patients receiving tenofovir at 72 weeks of treatment were found to have a viral load below 400 copies/mL, [97] compared with 88% of patients in the adefovir-to-tenofovir arm. All of the adefovir-treated patients who had a viral load below 400 copies/mL at week 48 maintained a viral load below this level after switching to tenofovir. [97] Of the patients in the adefovir arm who did not achieve optimal viral response (that is, those with a viral load >400 copies/mL) by the time they switched to tenofovir, 94% had a viral load below 400 copies/mL by week 72.

Normal ALT levels at week 72 were observed in 79% of patients who initiated therapy with tenofovir and in 77% of patients who switched from adefovir to tenofovir. [97]

HBeAg-negative or -positive patients with chronic HBV

In two double-blind, phase III studies in which patients with HBeAg-negative or HBeAg-positive chronic hepatitis B were randomized to receive tenofovir DF (300 mg) or adefovir (10 mg) in a 2:1 ratio once daily for 48 weeks, Marcellin et al concluded that among patients with chronic hepatitis B, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy and a similar safety profile to adefovir at a daily dose of 10 mg through week 48. [98]

At week 48 in both studies, a significantly higher proportion of patients receiving tenofovir than those receiving adefovir had reached the primary end point (plasma HBV DNA level < 400 copies/mL [69 IU/mL]), and viral suppression occurred in more HBeAg-negative patients in the tenofovir group (93%) than in the adefovir group (63%), as well as in more HBeAg-positive patients receiving tenofovir (76%) than in those receiving adefovir (13%). [98]

Furthermore, significantly more HBeAg-positive patients in the tenofovir group (68%) not only had normalized ALT levels relative to those in the adefovir group (54%), but these individuals also had loss of HBsAg (3% tenofovir group vs 0% adefovir group). [98]

At the end of 48 weeks, none the patients had developed the amino acid substitutions within HBV DNA polymerase that are associated with phenotypic resistance to tenofovir or other drugs used to treat hepatitis B. Tenofovir produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The 2 treatments in both studies had similar safety profiles. [98]

5-Year data

Marcellin et al reported that patients who received tenofovir continuously for 240 weeks had sustained suppression of HBV DNA levels below 400 copies/mL (HBeAg-negative patients: 83%; HBeAg-positive patients: 65%). [65] Patients who were randomized to adefovir and then, at week 48, rolled over to tenofovir for the subsequent 192 weeks also maintained viral suppression (HBeAg-negative patients: 84%; HBeAg-positive patients: 66%).

Of the HBeAg-positive patients who received tenofovir through 240 weeks, 9% experienced s-antigen loss, and 7% seroconverted. The HBeAg loss rate was 46%, and the HBeAg seroconversion rate was 40%. No evidence of resistance to tenofovir emerged over the treatment period. [65]

In addition, 87% of the 348 patients who had paired biopsies at baseline and week 240 experienced an improvement in the overall liver histology, as measured by an improvement of a minimum of 2 points in the Knodell necroinflammatory score without worsening in the Knodell fibrosis score. Of the 96 patients who had cirrhosis (Ishak fibrosis score ≥5) at the start of therapy, 74% experienced regression of cirrhosis. [65]

HBV infection prophylaxis in HIV

As previously mentioned, in patients infected with HIV, antiretroviral therapy regimens containing 3TC or TDF may be prophylactic for HBV infection.


Surgical Intervention

Orthotopic liver transplantation (OLT) is the treatment of choice for patients with fulminant hepatic failure who do not recover and for patients with end-stage liver disease due to hepatitis B disease. The implementation of hepatitis B immunoglobulin (HBIG) during and after the OLT period, and of lamivudine (3TC) or adefovir in the pre- and post-OLT periods, dramatically reduces the recurrence rate of hepatitis B. The current standard is to use HBIG and tenofovir disoproxil fumarate (TDF) or entecavir (ETV). At some centers, HBIG is being stopped at approximately 12 months or sooner; at other centers, HBIG is no longer being used, with the focus on first-line therapy.

For more information, see the Medscape Drugs & Diseases articles Liver Transplants, Liver Transplantation, Transfusion Requirements in Liver Transplantation, and Imaging of Liver Transplantation Complications.


Hepatitis B and Pregnancy

The American College of Obstetricians and Gynecologists (ACOG), the US Preventive Services Task Force (USPSTF), and the World Health Organization recommend routine prenatal screening for hepatitis B surface antigen (HBsAg) in all pregnant women—during every pregnancy—regardless of previous test results or vaccinations. [59, 99, 100]  Pregnant women at risk for hepatitis B infections should be specifically targeted for vaccination. [99] The risk of transmission of hepatitis B associated with amniocentesis is low. WHO further recommends all pregnant women undergo testing at least once for HIV and syphilis in addition to that for HBsAg (especially when there is a ≥2% seroprevalence in the general population) and as early as possible in the pregnancy. [59]

It is recommended that all infants receive their first dose of hepatitis B vaccine as soon as possible after birth (≤24 hours preferred), followed by two or three doses to complete the primary series. [59]

To prevent maternal-fetal HBV transmission, a conditional WHO recommendation is that HBsAg-positive gravida who have an HBV DNA ≥5.3 log10 IU/mL (≥200,000 IU/mL) receive tenofovir prophylaxis beginning the 28th week of pregnancy until at least birth. [101]  TDF should be used rather than TAF due to lack of safety data in pregnancy. [102]  This is in addition to the 3-dose hepatitis B vaccination in all infants, including a timely dose at birth. When antenatal HBV DNA testing is not available, HBeAg testing can be used as an alternative study to determine eligibility for tenofovir prophylaxis to prevent mother-to-child transmission of HBV.

For newborns born to mothers with chronic hepatitis B infection, administer combined immunoprophylaxis with hepatitis B immune globulin (HBIG) and hepatitis B vaccine within 12 hours of birth. [99, 100] Thereafter, these infants should follow the hepatitis B vaccine series as part of the recommended childhood immunization schedule.

Breastfeeding is not contraindicated in women chronically infected with hepatitis B if the infant receives HBIG passive prophylaxis and vaccine active prophylaxis. [99] Mothers with chronic hepatitis B infection are often treated in the third trimester if the serum hepatitis B virus (HBV) DNA level is greater than 106 -108 copies/mL, especially if she is positive for the hepatitis B e antigen (HBeAg).

The 2016 American Association for the Study of Liver Diseases (AASLD) has similar guidelines for the treatment of chronic hepatitis B in pregnant women. [41] The AASLD suggests antiviral therapy to reduce the risk of perinatal HBV transmission in HBsAg-positive pregnant women with an HBV DNA level above 200,000 IU/mL. (Conditional recommendation) Infants of these mothers should receive immunoprophylaxis according to current World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) recommendations.

Therapy for pregnant women with immune-active hepatitis B should be based on the same recommendations as for their nonpregnant counterparts.

Antiviral therapy is not recommended to reduce the risk of perinatal HBV transmission in HBsAg-positive pregnant women whose HBV DNA level is at or below 200,000 IU/mL. (Strong recommendation)



Although a limited number of medications can be used to treat chronic hepatitis B, vaccination is a safe and effective prevention strategy. [103] Universal hepatitis B vaccination programs are ongoing in endemic areas, with encouraging results. In the United States, hepatitis B (HepB) vaccines that consist of a single recombinant hepatitis B surface antigen (HBsAg) produced in yeast include Engerix B, Recombivax HB, and the adjuvanted product Heplisav B. A series of three injections may achieve HBsAg antibody (anti-HBs) levels greater than 10 million IU/mL in approximately 95% of vaccinated individuals.

Immunocompetent individuals who receive the complete 3-dose series are protected indefinitely, and titers are generally not recommended by the Advisory Committee on Immunization Practices (ACIP) except in immunocompromised patients, healthcare workers, infants born to HBsAg-positive mothers, and sexual partners of HBsAg-positive patients. For these groups, antibody titers are recommended within 1-2 months following vaccination, with revaccination for nonresponders. Patients who respond with a positive titer following vaccination are immune and repeat titers are not indicated unless the patient develops immunodeficiency. [36]

In November 2021, the FDA approved PreHevbrio for adults, the first vaccine that contains all three hepatitis B antigens. Approval was based on results from two phase 3 clinical studies (PROTECT and CONSTANT). PreHevbrio elicited higher rates of seroprotection in all study participants aged 18 years and older compared with Engerix B (91.4% vs 76.5%, respectively), including adults aged 45 years and older (89.4% vs 73.1%, respectively). [104, 105]

2018 AASLD recommendations

The following recommendations are from the 2018 AASLD guidance update [52] :

  • Administer HBV vaccines as a 3-dose series at 0, 1, and 6 months (± hepatitis A vaccine). Alternatively, for adults, combination hepatitis A and B vaccine (Twinrix) uses a 4-dose regimen at 0, 7, 21-30 days, and 12 months. A 2-dose series for adults at 0 and 1 months (HEPLISAV-B) is also available.
  • Sexual partners and household contacts of HBV-infected individuals who are negative for HBsAg and anti-HBs should receive HBV vaccination.
  • HBV vaccination is safe in pregnancy, and nonimmune mothers should receive the vaccine series. [106]
  • At delivery, infants born to HBV-infected mothers should receive hepatitis B immunoglobulin (HBIG) and HBV vaccine; thereafter, the recommended vaccination schedule should be completed. Postvaccination testing at age 9-15 months is recommended for infants with HBsAg-positive mothers.
  • Those who should be tested for their response to HBV vaccination 1-2 months after the last vaccine dose is received include healthcare workers, sexual partners of those with chronic HBV, patients on chronic hemodialysis, and immunocompromised patients (eg, HIV patients).
  • Nonresponders to the initial vaccine series: Repeat the 3-dose vaccination series, with a double dose for immunocompromised individuals (eg, cirrhotic patients).
  • Vaccine responders: Annual follow-up testing is recommended for chronic hemodialysis patients.
  • Booster doses or revaccination: Not recommended except if anti-HBs levels remain below 10 mIU/mL after the initial vaccination of infants of HBsAg-positive mothers, in healthcare workers, hemodialysis patients, and immunocompromised patients.


All newborns must be vaccinated against hepatitis B with a 3- or 4-dose series of HepB. For infants born to mothers with active hepatitis B, a passive-active approach (hepatitis B immunoglobulin [HBIG] and vaccination) is recommended.

Children and adolescents who have not been vaccinated as infants should receive a 3-dose series of HepB.


Vaccine options for adults include the following:

  • Heplisav-B/Dynavax (HepB-CpG), a yeast-derived vaccine prepared with a novel adjuvant, administered as a 2-dose series (0, 1 month) [107] (FDA approved November 2017) [108, 109] OR
  • Engerix B, Recombivax HB, or PreHevbrio, administered as a 3-dose series at 0, 1, and 6 months OR
  • Twinrx, combined hepatitis A and hepatitis B vaccine (HepA-HepB), at 0, 1, and 6 months

The following are Advisory Committee on Immunization Practices (ACIP) recommendations for immunizing adults at risk for hepatitis B infection [110] :

  • History of current or recent injection drug use, international travelers to countries with high or intermediate levels of endemic HBV infection (HBsAg prevalence ≥2%)
  • Chronic liver disease (including, but not limited to, hepatitis C infection, cirrhosis, fatty liver disease, alcoholic liver disease, autoimmune hepatitis, and an alanine aminotransferase [ALT] or aspartate aminotransferase [AST] level greater than twice the upper limit of normal)
  • Human immunodeficiency virus infection
  • At risk for infection through sexual exposure (eg, sex partners of HBsAg-positive persons, sexually active persons not in a long-term mutually monogamous relationship, persons seeking evaluation or treatment for a sexually transmitted infection, men who have sex with men)
  • At risk for infection by percutaneous or mucosal exposure to blood (eg, household contacts of HBsAg-positive persons, residents and staff of facilities for developmentally disabled persons, healthcare and public safety personnel with reasonably anticipated risk for exposure to blood or blood-contaminated body fluids, hemodialysis patients and predialysis, peritoneal dialysis, and home dialysis patients)
  • Persons with diabetes mellitus younger than 60 years and persons with diabetes mellitus aged at least 60 years at the discretion of the treating clinician [111]
  • Incarcerated persons
  • Other persons seeking protection from HBV infection (even without acknowledgment of a specific risk factor)

Low response rates and nonresponders

Low vaccination response rates have been associated with obesity, smoking, immunosuppression (eg, hemodialysis), and advanced age. Approximately 25-50% of persons who initially do not have a vaccine response will show a response to one additional vaccine dose, and 50-75% of individuals will have a response to a fourth higher dose of Engerix B or Recombivax HB, or a second 3-dose series.

Postvaccine antibody titers do not need to be obtained in routine vaccinations of children or adults. It is recommended that testing for anti-HBs be obtained 4-12 weeks after vaccination in the following groups [112] :

  • Immunocompromised patients, including those on hemodialysis, HIV patients, and others
  • Infants born to HBsAg-positive mothers
  • Healthcare professionals
  • Sexual partners of HBsAg-positive patients

Nonresponders, (HBsAb levels < 10 IU/L) should be revaccinated with another series of 3-dose hepatitis B vaccine. Consider delaying revaccination for several months after initiation of antiretroviral therapy in patients with CD4 counts below 200 cells/mm3 or those with symptomatic HIV disease. The delay in these individuals is an attempt to maximize the antibody response to the vaccine. [45, 67]

Do not defer vaccination in pregnant patients or patients who are unlikely to achieve an increased CD4 count. [45, 67] Individuals at increased risk of severe complications due to HBV infection include those unlikely to achieve CD4 counts of 200 cells/mm3 or above after antiretroviral therapy (eg, HBV/hepatitis C virus [HCV] coinfection) and HIV-infected pregnant women. [45]

A combined hepatitis A virus (HAV)/HBV vaccine is licensed in many countries and offers the advantage of protection against both of these viruses at the same time. The vaccine seems to be safe, although some questions exist regarding neurologic complications.


Long-Term Monitoring

Individuals with inactive chronic infection with the hepatitis B virus (HBV) should have routine blood tests at least annually to check their aminotransferase levels. Patients with chronic active hepatitis should also undergo blood tests (ie, to evaluate aminotransferase levels, antigen-antibody HBV profile, viral load, and alpha-fetoprotein [AFP] levels). In rare cases, patients may be considered for liver biopsy.

Current guidelines recommend monitoring of HBV DNA and alanine aminotransferase (ALT) levels at least annually; however, a study conducted by Juday et al suggests that adherence falls below recommendations. [113] Expert opinion supports that following the recommended guidelines reduces the risk of disease progression.

Patients with cirrhosis must be monitored for hepatocellular carcinoma (HCC) by having their AFP levels checked every 6-12 months and undergoing surveillance with abdominal ultrasonography. [114] Note, however, that AFP levels have been eliminated from the American Association for the Study of Liver Diseases (AASLD) guidelines. [41, 61]

Monitoring considerations

Physicians should keep the following in mind when managing a patient with hepatitis B:

  • Identify cases of fulminant hepatic failure, and list the patient as a candidate for liver transplantation

  • Monitor individuals with inactive chronic infection for probable disease reactivation

  • Inform the patient's spouse/sexual partners about the infectivity of hepatitis B and their need for screening, possible linkage to care, and possible need for vaccination

  • Monitor patients with cirrhosis and perform HCC surveillance studies (ie, liver ultrasonography) every 6-12 months

  • Place patients with cirrhosis on liver transplantation list when needed

  • Identify hepatitis D (delta) virus (HDV) superinfection in patients with HBV infection

  • Screen for human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV) coinfection

  • Assess for hepatitis A virus (HAV) immunity; if the patient is not immune, provide immunization

Viral reactivation

Hepatitis B virus (HBV) may persist in the blood for decades after clinical recovery from acute hepatitis despite the presence of serum antibodies. Immunosuppressive conditions or drugs may allow dormant HBV to flare or reactivate. Additionally, genetic factors (eg, genetic mutations) may influence the risk for reactivation by affecting hepatitis B core antibody (anti-HBc) response. [115]

Close monitoring during and for several months after therapy with immunosuppressive drugs is appropriate. If reactivation of hepatitis B occurs, stopping the agent and initiating antiviral therapy may be warranted. Various national organizations including the AASLD and the National Institutes of Health (NIH) recommend the use of prophylactic antiviral therapy in inactive HBsAg carriers who are to undergo antineoplastic or immunosuppressive therapy. [2, 61, 115]

Medications that may increase the risk for hepatitis B reactivation include:

  • Anti-CD20 antibodies: Ofatumumab (Arzerra), rituximab (Rituxan)

  • Antineoplastic agents (including methotrexate) [116, 117]

  • Glucocorticoids, especially with abrupt discontinuation [118, 119]

  • Interleukin receptor antagonists: Ustekinumab (Stelara), [120] anakinra (Kineret), tocilizumab (Actemra)

  • Nucleoside and nucleotide therapy, due to immune reconstitution syndrome or discontinuation of antiviral therapy with anti-HBV properties

  • T-cell regulator: Abatacept (Orencia) [121]

  • Tumor necrosis factor (TNF) inhibitors: Infliximab (Remicade), [120] etanercept (Enbrel), [120] adalimumab (Humira), [120] certolizumab pegol (Cimzia), golimumab (Simponi, Simponi Aria)