Approach
The main goal of treatment is to improve survival and quality of life by preventing disease progression and the development of complications. Specific management depends on whether the infection is acute or chronic. Acute infection is almost always treated with supportive care alone, although antiviral therapy may be required in select patients. Chronic infection is treated with long-term antiviral therapy. Some patients may require liver transplantation.
Treatment of acute infection
More than 95% of immunocompetent adults with acute infection will achieve seroconversion with the appearance of antibodies to hepatitis B surface antigen (anti-HBs) in the absence of treatment. Therefore, supportive care is usually all that is needed in most patients.[2][38]
Some patients may require antiviral therapy. Initiate treatment 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 (INR) >1.5, encephalopathy, or ascites). Entecavir, tenofovir alafenamide, and tenofovir disoproxil are the drugs of choice in patients with acute infection; peginterferon is contraindicated. Continue treatment until hepatitis B surface antigen (HBsAg) clearance is confirmed, or indefinitely in patients who undergo liver transplantation. 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]
There is currently no evidence of benefit of any pharmacological treatment in acute hepatitis B virus (HBV) infection.[99]
Treatment of chronic infection: general principles
The need for antiviral therapy in patients with chronic HBV infection is based on alanine aminotransferase (ALT) levels, serum HBV DNA levels, and severity of liver disease, and regular monitoring is important to determine the phase of infection. Additional factors that should be considered before starting treatment include the patient’s age, likelihood of response, potential adverse events, family history of hepatocellular carcinoma (HCC), and extrahepatic manifestations.[2][38]
Who to treat
The World Health Organization (WHO) recommends initiating antiviral therapy in all adults (including pregnant women) and adolescents ≥12 years of age with:[64][Evidence B]
Evidence of significant fibrosis or cirrhosis (based on transient elastography or aspartate aminotransferase-to-platelet ratio index scores), regardless of HBV DNA or ALT levels; OR
HBV DNA level >2000 IU/mL and an ALT level above the upper limit of normal (ULN). For adolescents this should be based on ALT level > ULN on at least two occasions in a 6-12-month period; OR
Presence of: coinfections (e.g., HIV, hepatitis C, hepatitis D); family history of liver cancer or cirrhosis; immunosuppression (e.g., solid organ or stem cell transplant, long-term corticosteroid use); comorbidities (e.g., diabetes, metabolic dysfunction-associated steatotic liver disease); or extrahepatic manifestations (e.g., vasculitis, glomerulonephritis) - regardless of aminotransferase-to-platelet ratio index score, HBV DNA, or ALT levels; OR
Persistently abnormal ALT levels (i.e., two ALT values above the ULN at unspecified intervals during a 6-12 month period) in the absence of access to an HBV DNA assay, and regardless of aminotransferase-to-platelet ratio index score.
If ALT levels are persistently normal, HBV DNA is <2000 IU/mL, and there is an absence of coinfections, comorbidities, immunosuppression, extrahepatic manifestations, and a family history of liver cancer or cirrhosis, treatment may be deferred.[64]
Evidence is insufficient to support using these treatment eligibility criteria in children aged 2-11 years. Treatment in this age group is generally offered on a case-by-case basis to selected children (e.g., presence of cirrhosis, advancing liver fibrosis, persistent hepatitis flare, or comorbidities).[64]
Goals of treatment
The ultimate goal of treatment is amelioration of hepatic dysfunction and the development of a disease-free state, marked by seroconversion of HBsAg-positive to HBsAg-negative and production of anti-HBs.
Treatment can sometimes lead to hepatitis B e antigen (HBeAg) loss and HBeAg seroconversion to antibody to HBeAg (anti-HBe) in HBeAg-positive chronic HBV patients. However, overall eradication of HBV is rare with currently available treatments, so the primary goal of therapy in most patients with chronic HBV infection is sustained and durable suppression of serum HBV DNA to undetectable levels.
The degree of HBV DNA suppression is inversely related to the emergence of drug-related resistance. Therefore, greater suppression of serum HBV DNA is better for the long-term outcomes without producing resistance to the virus. Prolonged suppression may reduce the rate of cirrhosis, hepatic failure, and HCC in patients with chronic HBV, but does not completely eliminate the risk.[100][101][102][103] However, there are no randomised controlled trials to support this as such trials would be prohibitively expensive and take 20-30 years.
Antiviral therapies
There are several agents used for the treatment of chronic HBV, including peginterferon alfa 2a, nucleoside analogues (e.g., entecavir), and nucleotide analogues (e.g., tenofovir disoproxil or tenofovir alafenamide).[104]
Nucleoside/nucleotide analogues with a high generic barrier to drug resistance (e.g., tenofovir disoproxil, entecavir) are preferred options. Nucleoside analogs with a low genetic barrier to resistance (e.g., lamivudine, adefovir) are not generally recommended as they can lead to drug resistance.[64]
Tenofovir alafenamide is more stable in plasma compared to tenofovir disoproxil and therefore delivers the active metabolite to hepatocytes more efficiently. This allows a lower dose to be used resulting in less systemic exposure and a decreased risk of renal and bone toxicity. 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] Entecavir may also be used in patients with established osteoporosis and/or renal impairment.[64][Evidence B]
While peginterferon is typically administered for a pre-set duration, the nucleoside/nucleotide analogues are given until specific end points are achieved, which may mean long-term therapy. For HBeAg-positive patients, viral suppression can be sustained with currently approved treatments in 50% to 90% of patients if treatment is stopped after HBeAg seroconversion.[108] However, in HBeAg-negative patients, relapse occurs frequently, even when HBV DNA is suppressed to undetectable levels for more than 1 year, making end points for treatment unclear, and lifelong therapy may be required. Dose of nucleoside/nucleotide analogues should be adjusted based on renal function, and renal function should be monitored during treatment.[2]
Guidelines for the treatment of chronic HBV constantly evolve, particularly with the advent of new and highly potent antiviral drugs that have a lower risk of resistance.
The recommendations in this topic, including antiviral regimens, are based mainly on guidelines published by the American Association for the Study of Liver Diseases in 2018, and the European Association for the Study of the Liver published in 2017.[2][38]
More recent guidelines published by the WHO continue to support the use of entecavir, tenofovir disoproxil, and tenofovir alafenamide, but also recommend alternative regimens for certain situations.[64]
Guidelines may differ in different countries, and local guidelines should be consulted.[109]
Treatment of chronic infection: without cirrhosis
The need to start treatment depends on the phase of infection.
Immune-active chronic HBV infection
Initiate antiviral therapy in patients with elevated ALT levels ≥2 the ULN or evidence of histological disease with elevated HBV DNA levels >2000 IU/mL (if 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 HCC if ALT levels are <2 ULN and below the HBV DNA thresholds.[2][38]
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. Combination therapy with peginterferon alfa 2a and a nucleoside/nucleotide analogue is not recommended due to the lack of safety and efficacy data.[2][38]
No treatment shows superiority over another in terms of risk reduction of hepatic decompensation.[2][38] Meta-analyses give conflicting results on 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, a meta-analysis found no significant difference between tenofovir disoproxil 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]
Choice of treatment also depends on patient-specific factors including: desire for finite therapy; anticipated tolerability of potential adverse effects; presence of comorbidities (e.g., peginterferon is contraindicated in autoimmune disease, severe cardiac disease, uncontrolled seizures, uncontrolled psychiatric disease, cytopenia); previous history of lamivudine resistance (e.g., entecavir is not recommended in these patients); HBV genotype; costs; and family planning factors.[2][38] Factors that predict a response to interferon include baseline ALT >5 times ULN, baseline HBV DNA <20,000,000 IU/mL, and HBV genotype A or B.[117]
Treatment course is variable. Peginterferon alfa 2a has a finite treatment course of 48 weeks. The duration of nucleotide/nucleoside analogue therapy is variable, and depends on HBeAg status and HBV DNA suppression. Consider stopping treatment in HBeAg-positive patients who seroconvert to anti-HBe during therapy after a consolidation period (i.e., 12 months of persistently normal ALT levels and undetectable serum HBV DNA). Some experts treat until HBsAg loss occurs. Continue treatment indefinitely in HBeAg-negative patients, unless there is a compelling reason to stop treatment after carefully weighing the risks and benefits.[2][38]
In patients with confirmed viral breakthrough, consider either switching to another antiviral drug with a high barrier to resistance, or adding a second antiviral with a complementary resistance profile. There is currently insufficient evidence to recommend one approach over the other.[2]
Monitor patients who stop treatment every 3 months for at least 1 year for viraemia, ALT flares, seroconversion, and clinical decompensation.[2]
Immune-tolerant chronic HBV infection
Antiviral therapy is not recommended in patients with immune-tolerant chronic HBV infection (i.e., HBeAg positive, serum HBV DNA >1 million IU/mL, normal or persistently elevated ALT and/or aspartate aminotransferase levels), except in people >40 years of age with normal ALT levels, elevated HNV DNA, and a liver biopsy showing significant necro-inflammation or fibrosis. Assess ALT levels at least every 6 months to monitor for potential transition to immune-active or immune-inactive chronic HBV infection.[2]
Immune-inactive chronic HBV infection
Antiviral therapy is not recommended in patients who are HBeAg negative with normal ALT levels and low-level viraemia (i.e., HBV DNA level <2000 IU/mL).[2]
Treatment of chronic infection: with cirrhosis
All patients with compensated or decompensated cirrhosis require treatment, regardless of ALT levels. Treatment improves survival and reduces liver-related morbidity and mortality by preventing liver failure or requirement for liver transplantation.
Compensated cirrhosis
Initiate antiviral therapy in patients with low-level viraemia (i.e., HBV DNA levels <2000 IU/mL), regardless of ALT levels, to reduce the risk of decompensation. Treat patients with high-level viraemia as you would for patients with immune-active chronic HBV infection.[2][38] Studies have shown that suppression of HBV DNA levels can halt the natural progression of liver disease to decompensated cirrhosis, and in some circumstances, show improvements in liver histology.[118][119][120]
Entecavir, tenofovir disoproxil, and tenofovir alafenamide are the recommended first-line drugs due to their potency and minimal risk of adverse effects, decompensation, and resistance. While peginterferon alfa 2a is not contraindicated in these patients, nucleoside/nucleotide analogues are considered safer. 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]
Decompensated cirrhosis
Initiate antiviral therapy as soon as possible and assess the patient for liver transplantation. 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 has not been studied in these patients, but 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. High rates of serious adverse events, including sepsis and the risk of hepatic decompensation, have been reported.[123]
Lifelong treatment is recommended, regardless of ALT or HBV DNA levels, or HBeAg 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]
Treatment of chronic infection: with co-infections
HIV infection
HBV has no significant effect on the natural history of HIV infection, but HIV infection and its treatment may profoundly affect the natural history of HBV. Reactivation of HBV may occur in HIV infection.[125]
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 2 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] Decisions about the best treatment regimen should be made in conjunction with an HIV specialist.
See HIV infection.
Hepatitis C virus infection
Initiate antiviral therapy in patients with detectable hepatitis C virus (HCV) RNA levels. If HBV DNA levels are also detectable, treatment is determined by HBV DNA and ALT 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]
Monitor HBV DNA levels every 4 to 8 weeks during treatment (and for 3 months after treatment) as HBsAg-positive patients are at risk of hepatitis B reactivation with HCV DAA therapy.[2][38]
The rate of reactivation is higher with patients receiving DAA therapy compared with those receiving interferon-based therapy for the treatment of hepatitis C.[127]
See Hepatitis C.
Hepatitis D virus infection
Fulminant hepatitis is usually seen in patients with HBV and hepatitis D virus (HDV) co-infection.[128] Refer patient to a specialised centre that offers access to experimental therapies for HDV infection. Peginterferon alfa 2a (or bulevirtide in locations where it is available) is the treatment of choice in patients with elevated HDV RNA and ALT levels. If HBV DNA levels are elevated, entecavir, tenofovir disoproxil, or tenofovir alafenamide can be added.[2][38]
See Hepatitis D.
Treatment of chronic infection: special patient groups
Pregnancy
Antiviral prophylaxis is recommended in all HBsAg-positive pregnant women with an HBV DNA level >200,000 IU/mL or positive HBeAg to reduce the risk of perinatal transmission (in settings where HBV DNA or HBeAg testing is available).[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]
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.
Pregnant women with immune-active chronic HBV infection should be treated the same as non-pregnant adults.
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 titer who have not received antiviral therapy during pregnancy. Recommendations for patients with HDV co-infection are the same as those with HBV infection.[141]
Breast-feeding
Breast-feeding is not contraindicated.[2][38] Breast-feeding 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. Breast-feeding after proper neonatal immunoprophylaxis does not increase transmission rates compared with non-breastfeeding, according to one systematic review.[142]
Children
Chronic hepatitis B runs an asymptomatic course in most children. Generally, a conservative approach for HBV therapy is acceptable, owing to a paucity of clinical data and therapeutic options. Treatment should be initiated by a provider experienced in treating children with HBV. Follow-up of children with chronic HBV to adulthood is important.[2][38]
Consider antiviral therapy in HBeAg-positive children aged ≥2 years who have elevated ALT levels (>1.3 times the ULN 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]
Entecavir, tenofovir disoproxil, and lamivudine are approved for use in children ≥2 years of age. Tenofovir alafenamide is approved for children ≥6 years of age. Peginterferon alfa 2a is approved for use in children aged ≥3 years of age.
The treatment course for peginterferon alfa 2a is 48 weeks in children. The duration of treatment that has been studied for oral antivirals is 1-4 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]
Combination therapy with interferon and nucleoside/nucleotide analogues has been shown to be more effective than interferon monotherapy in children in terms of serological response and viral suppression. However, guidelines do not recommend combination therapy, and more studies are needed.[143]
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