Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

acute HBV infection

1st line – supportive care

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ACUTE
|
acute HBV infection
1st line – 

supportive care

More than 95% of immunocompetent individuals with acute infection will achieve seroconversion with appearance of antibody to hepatitis B surface antigen in the absence of treatment. Therefore, supportive care is usually all that is needed in most patients.[2][38]

Consider – antiviral therapy + assess for liver transplantation

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ACUTE
|
acute HBV infection
Consider – 

antiviral therapy + assess for liver transplantation

Additional treatment recommended for SOME patients in selected patient group

Initiate antiviral therapy in patients with acute liver failure or in those who have a severe, protracted course (i.e., total bilirubin level >51.3 micromoles/L (>3 mg/dL), international normalised ratio >1.5, encephalopathy, or ascites).[2][38]

Simultaneously, assess the patient for the need for liver transplantation, as there is a high risk of mortality in patients with liver failure who do not undergo a transplant.[2][38]

Entecavir, tenofovir alafenamide, and tenofovir disoproxil are the drugs of choice. Continue treatment until hepatitis B surface antigen clearance is confirmed, or indefinitely in patients who undergo liver transplantation.[2][38]

Primary options

entecavir: children: consult specialist for guidance on dose; adults: 0.5 mg orally once daily

OR

tenofovir disoproxil: children: consult specialist for guidance on dose; adults: 300 mg orally once daily

OR

tenofovir alafenamide: children: consult specialist for guidance on dose; adults: 25 mg orally once daily

ONGOING

chronic HBV infection: adult non-pregnant without co-infection or cirrhosis

1st line – antiviral therapy

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ONGOING
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chronic HBV infection: adult non-pregnant without co-infection or cirrhosis
1st line – 

antiviral therapy

Initiate antiviral therapy in patients with immune-active chronic hepatitis B virus (HBV) infection (i.e., elevated alanine aminotransferase [ALT] levels ≥2 the upper limit of normal [ULN] or evidence of histological disease with elevated HBV DNA levels >2000 IU/mL if hepatitis B e antigen [HBeAg] negative, or >20,000 IU/mL if HBeAg positive). Consider antiviral therapy in patients >30 to 40 years of age (age cut-off depends on guideline) or with a family history of hepatocellular carcinoma if ALT levels are <2 ULN and below HBV DNA thresholds.[2][38] Antiviral therapy is generally not recommended in patients with immune-tolerant or immune-active chronic HBV infection.

Entecavir, tenofovir disoproxil or tenofovir alafenamide, or peginterferon alfa 2a are the recommended first-line drugs. Tenofovir alafenamide or entecavir are preferred in patients who are at risk of renal dysfunction or bone disease. There is some data to suggest that switching tenofovir disoproxil to tenofovir alafenamide can be done without a loss of efficacy in patients who are virally suppressed.[105]​​[106]​​​ Five-year data from two randomised controlled trials found comparable efficacy between tenofovir alafenamide and tenofovir disoproxil (switching to tenofovir alafenamide after 2 or 3 years), with high rates of viral suppression and no resistance documented. Improved bone and renal safety with tenofovir alafenamide was maintained over the five years, and improvements were seen in the comparison group after switching.[107]​​

No treatment shows superiority over another in terms of risk reduction of hepatic decompensation.[2][38]​ Meta-analyses give conflicting results on the risk of HCC due to the patient populations included and differences in study inclusion criteria. Some have found that tenofovir disoproxil was associated with a significantly lower risk of HCC compared with entecavir, particularly in patients who were HBeAg-positive.[110]​​[111]​​​ However, others have found no significant difference between tenofovir disoproxil fumarate and entecavir in their association with incident HCC.[112][113][114]​​​​ Tenofovir disoproxil was associated with a lower risk of recurrence and mortality after resection or ablation of HCC compared with entecavir.[115]​​[116]​​

Treatment course is variable. The treatment course of peginterferon alfa 2a is 48 weeks. Consider stopping oral antiviral therapy in HBeAg-positive patients who seroconvert to antibody to HBeAg during therapy after a consolidation period (i.e., 12 months of persistently normal ALT levels and undetectable serum HBV DNA). Some experts treat until hepatitis B surface antigen loss occurs. Continue treatment indefinitely in HBeAg-negative patients, unless there is a compelling reason to stop.[2][38]

Primary options

entecavir: 0.5 mg orally once daily

More

OR

tenofovir disoproxil: 300 mg orally once daily

OR

tenofovir alafenamide: 25 mg orally once daily

OR

peginterferon alfa 2a: 180 micrograms subcutaneously once weekly for 48 weeks

chronic HBV infection: adult non-pregnant with cirrhosis

1st line – antiviral therapy

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ONGOING
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chronic HBV infection: adult non-pregnant with cirrhosis
|
with compensated cirrhosis
1st line – 

antiviral therapy

Initiate antiviral therapy in patients with low-level viraemia (i.e., hepatitis B virus [HBV] DNA levels <2000 IU/mL), regardless of alanine aminotransferase levels. Treat patients with high-level viraemia as you would for patients with immune-active chronic HBV infection.[2][38]

Entecavir, tenofovir disoproxil, and tenofovir alafenamide are the recommended first-line drugs. Peginterferon alfa 2a may only be considered in patients who do not have portal hypertension.[2][38][121]​ There is no optimal length of treatment.

Monitor patients (at least every 3 months for 1 year) after stopping therapy to check for viral rebound that could lead to decompensation.[2][38]​​​​​​​ Discontinuation of antiviral therapy in these patients was associated with a high-risk of relapse (virological relapse 55%, clinical relapse 44%), but the incidence of adverse events was generally low and controlled. The rate of HCC after discontinuation of antiviral therapy was 9%.[122]​​

Primary options

entecavir: 0.5 mg orally once daily

More

OR

tenofovir disoproxil: 300 mg orally once daily

OR

tenofovir alafenamide: 25 mg orally once daily

Secondary options

peginterferon alfa 2a: 180 micrograms subcutaneously once weekly

1st line – antiviral therapy

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ONGOING
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chronic HBV infection: adult non-pregnant with cirrhosis
|
with decompensated cirrhosis
1st line – 

antiviral therapy

Initiate antiviral therapy as soon as possible. Antiviral therapy has been shown to improve outcomes (e.g., improved liver function, increased survival, and increased transplant-free survival) in patients with decompensated cirrhosis, especially with early treatment.[2][38]

Entecavir (administered at a higher dose than the dose used for other patients) and tenofovir disoproxil are the recommended first-line drugs. Tenofovir alafenamide can be considered in patients in whom tenofovir disoproxil or entecavir are not an option (e.g., patients with renal dysfunction or bone disease).[2][38]Peginterferon alfa 2a is contraindicated in these patients due to safety concerns.[123]

Lifelong treatment is recommended, regardless of alanine aminotransferase or hepatitis B virus (HBV) DNA levels, or hepatitis B e antigen status.[2][38]

Monitor patients closely for the development of lactic acidosis and renal dysfunction.[2][38] Lactic acidosis has been associated with use of entecavir and tenofovir, and the risk is increased in patients with decompensated cirrhosis.[124]

Primary options

entecavir: 1 mg orally once daily

OR

tenofovir disoproxil: 300 mg orally once daily

Secondary options

tenofovir alafenamide: 25 mg orally once daily

Consider – assess for liver transplantation

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ONGOING
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chronic HBV infection: adult non-pregnant with cirrhosis
|
with decompensated cirrhosis
Consider – 

assess for liver transplantation

Additional treatment recommended for SOME patients in selected patient group

In patients with chronic HBV and decompensated cirrhosis, referral to a liver transplantation centre is necessary.

chronic HBV infection: adult non-pregnant with HIV co-infection

1st line – antiviral therapy

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ONGOING
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chronic HBV infection: adult non-pregnant with HIV co-infection
1st line – 

antiviral therapy

Initiate antiretroviral therapy (ART), regardless of CD4 cell count, according to current local HIV guidelines and under specialist guidance. The ART regimen should include drugs that are active against both viruses, with two drugs that have activity against HBV. The preferred regimen should include tenofovir disoproxil or tenofovir alafenamide plus emtricitabine or lamivudine as the backbone. In patients already on ART, review the regimen to make sure it includes drugs with HBV activity.[2][38][126] See HIV infection.

chronic HBV infection: adult non-pregnant with hepatitis C co-infection

1st line – antiviral therapy

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ONGOING
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chronic HBV infection: adult non-pregnant with hepatitis C co-infection
1st line – 

antiviral therapy

Initiate antiviral therapy in patients with detectable hepatitis C virus (HCV) RNA levels. If hepatitis B virus (HBV) DNA levels are also detectable, treatment is determined by HBV DNA and alanine aminotransferase levels. HBV antiviral therapy should be started concurrently with direct-acting antiviral therapy (DAA) for HCV, according to current local hepatitis C guidelines and under specialist guidance.[2][38] See Hepatitis C.

Monitor HBV DNA levels every 4-8 weeks during treatment (and for 3 months after treatment) as hepatitis B surface antigen-positive patients are at risk of hepatitis B reactivation with HCV DAA therapy.[2][38]

chronic HBV infection: adult non-pregnant with hepatitis D co-infection

1st line – antiviral therapy

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ONGOING
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chronic HBV infection: adult non-pregnant with hepatitis D co-infection
1st line – 

antiviral therapy

Peginterferon alfa 2a (or bulevirtide in locations where it is available) is the treatment of choice in patients with elevated hepatitis D virus (HDV) RNA and alanine aminotransferase levels. If hepatitis B virus (HBV) DNA levels are elevated, entecavir, tenofovir disoproxil, or tenofovir alafenamide can be added.[2][38]​ Refer patient to a specialised centre that offers access to experimental therapies for HDV infection. See Hepatitis D.

chronic HBV infection: adult pregnant or breastfeeding

1st line – antiviral therapy

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ONGOING
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chronic HBV infection: adult pregnant or breastfeeding
1st line – 

antiviral therapy

Antiviral therapy prophylaxis is recommended in all hepatitis B surface antigen-positive pregnant women, with an hepatitis B virus (HBV) DNA level >200,000 IU/mL or positive hepatitis B e antigen (HBeAg), to reduce the risk of perinatal transmission (in settings where HBV DNA or HBeAg testing is available). Pregnant women with immune-active chronic HBV infection should be treated the same as non-pregnant adults.[2][38][64][66]​​​​​​​​ Peripartum antiviral prophylaxis has been shown to be highly effective at reducing the risk of mother-to-child transmission, with no increased risk of infant or maternal safety outcomes.[129]​ However, one Cochrane review found no evidence to demonstrate or disprove any benefit for antiviral therapy for the prevention of mother-to-child transmission of hepatitis B virus in HIV-positive pregnant women with hepatitis B co-infection.[130]

Tenofovir disoproxil is the preferred drug to minimise the risk of viral resistance during treatment, and shows high efficacy in preventing perinatal transmission. It is usually started in the second trimester or at 28-32 weeks' gestation (depending on guidelines) and discontinued at birth to 3 months postnatally or upon completion of the infant HBV vaccination series.[2][38][64]​​ Reviews have shown that tenofovir disoproxil significantly reduces the rate of mother-to-child transmission, and is considered safe for the mother and baby.[131]​​[132]​​[133]​​​​​ Tenofovir alafenamide may become an option as evidence emerges.[134]​​

Lamivudine can be given during the third trimester of pregnancy, and demonstrates safety and reduction in perinatal and intra-uterine transmission of HBV when given with neonatal hepatitis B vaccine and hepatitis B immunoglobulin.[135][136][137][138][139]

Women who become pregnant while receiving peginterferon alfa 2a or entecavir should be switched to a safer regimen.

Breastfeeding is not contraindicated. Breastfeeding of infants born to HBsAg-positive mothers should be encouraged unless there are contraindications or the mother presents with cracked nipples and/or the infant has oral ulcers and the mother has detectable HBV DNA.[66]​​[141]​​ Antivirals are minimally excreted in breast milk and are unlikely to pose a significant risk to the infant; however, the risks associated with low-level exposure are unknown.[2][38]

Primary options

tenofovir disoproxil: 300 mg orally once daily

Secondary options

lamivudine: 100 mg orally once daily

Consider – delivery via caesarean section

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ONGOING
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chronic HBV infection: adult pregnant or breastfeeding
Consider – 

delivery via caesarean section

Additional treatment recommended for SOME patients in selected patient group

Caesarean section delivery may be considered to reduce the risk of mother-to-child transmission.[140]

The American College of Obstetricians and Gynecologists (ACOG) suggest that caesarean delivery be reserved for obstetric indications for caesarean delivery.[66]

European guidelines do not recommend caesarean section to reduce the risk of mother-to-child transmission in HBsAg-positive women. However, caesarean section may be considered in Asian HBeAg-positive women with a high HBV DNA titre who have not received antiviral therapy during pregnancy. Recommendations for patients with HDV co-infection are the same as those with HBV infection.[141]

chronic HBV infection: children

1st line – supportive care

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ONGOING
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chronic HBV infection: children
1st line – 

supportive care

Generally chronic hepatitis B runs an asymptomatic course in children, and a conservative approach is acceptable, owing to a paucity of clinical data and therapeutic options.

Consider – antiviral therapy

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ONGOING
|
chronic HBV infection: children
Consider – 

antiviral therapy

Additional treatment recommended for SOME patients in selected patient group

Consider antiviral therapy in hepatitis B e antigen (HBeAg)-positive children ≥2 years of age who have elevated alanine aminotransferase levels (>1.3 times the upper limit of normal for at least 6 months) and measurable HBV DNA levels. HBV DNA levels are generally very high in children. Therapy may be deferred until other aetiologies of liver disease and spontaneous HBeAg seroconversion are excluded in patients with HBV DNA levels <10⁴ IU/mL.[2] Treatment should be initiated by a provider experienced in treating children with hepatitis B virus (HBV).

The treatment course for peginterferon alfa 2a is 48 weeks in children. The duration of treatment that has been studied for oral antivirals is 1 to 4 years. However, HBeAg seroconversion may be used as a therapeutic endpoint for oral antivirals, continuing for a further 12 months of consolidation (as in adults).[2]

Primary options

entecavir: children ≥2 years of age: consult specialist for guidance on dose

OR

tenofovir disoproxil: children ≥2 years of age: consult specialist for guidance on dose

OR

tenofovir alafenamide: children ≥6 years of age: consult specialist for guidance on dose

OR

peginterferon alfa 2a: children ≥3 years of age: consult specialist for guidance on dose

Secondary options

lamivudine: children ≥2 years of age: consult specialist for guidance on dose

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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