Background
Hepatitis B is the necrosis and inflammation of hepatocytes caused by infection of the liver by an enveloped DNA virus, hepatitis B virus (HBV). Chronic hepatitis B (CHB), defined as persistent positive hepatitis B surface antigen for 6 months or more, is a major public health problem with approximately 240 million chronically infected individuals worldwide, especially in low- and middle-income countries (LMICs). The major complications of chronic hepatitis B are cirrhosis and hepatocellular carcinoma (HCC). These complications occur in approximately 20% to 30% of chronically infected patients, and approximately 650,000 people die from chronic hepatitis B each year. Most patients are unaware of their hepatitis B infection and therefore may be in a progressive stage of the disease by the time they are seen. Universal hepatitis B vaccination programs for infants, including the first dose at birth, have been effective in reducing the incidence and prevalence of hepatitis B in many hepatitis B endemic countries. However, these programs can only affect hepatitis B virus infection-related deaths after decades of implementation.
About this guideline
This guideline is the first WHO guideline for the prevention, care and treatment of people with chronic hepatitis B.
The guideline recommendations are structured along a continuum of care for patients with chronic hepatitis B, from initial assessment of disease stage and indication for treatment, initiation of first-line antiviral therapy, monitoring of disease progression, drug toxicity and hepatocellular carcinogenesis, to switching to second-line agents in case of treatment failure. The recommendations cover adult patients of all ages and races.
The guidelines recommend the use of simple, non-invasive diagnostic methods to assess the stage of liver disease and indications for treatment; prioritize treatment of patients with progressive liver disease and those at high risk of death; and recommend the preferred high resistance barrier nucleoside (acid) analogs tenofovir and entecavir (entecavir for children 2-11 years of age) as first- and second-line therapy. The guidelines recommend lifelong treatment for patients with cirrhosis, along with regular monitoring for disease progression, drug toxicity, and hepatocellular carcinoma.
In addition, the guidelines emphasize the management of special populations, including patients co-infected with HIV, hepatitis C virus (HCV) and hepatitis D virus (HDV), children and adolescents, and pregnant women. The guidelines highlight established WHO recommendations for prevention of hepatitis B virus transmission, particularly those related to prevention of hepatitis B infection in the perinatal and early childhood periods through infant hepatitis B vaccination programs.
The recommendations in the guidelines offer opportunities to save lives, improve clinical outcomes for people with chronic hepatitis B, reduce hepatitis B morbidity and transmission, and reduce discrimination against patients, but they also present practical challenges for policymakers and program implementers in low- and middle-income countries. The guidelines also include a chapter on how to apply the core recommendations to national programs in health systems, emphasizing the decision-making and planning processes necessary to establish hepatitis treatment programs, taking into account factors such as hepatitis B prevalence, health system service capacity, laboratory testing services, supply systems for drugs and other supplies, available funding, ethics, and human rights.
Assess liver disease staging with non-invasive diagnostics at baseline and during follow-up
APRI (aspartate aminotransferase [AST]-platelet ratio index) is recommended as the preferred noninvasive diagnostic method for assessing the presence of cirrhosis (APRI score >2) in adults in resource-limited areas. Transient elastography (e.g., FibroScan) or liver fibrosis testing may be the preferred noninvasive diagnostic method in areas where this equipment is available and economically feasible. (conditional recommendation, low quality evidence)
People with chronic hepatitis B who do and do not require treatment
Population requiring treatment
Those requiring priority treatment.
All adults, adolescents, and children with chronic hepatitis B with evidence of compensated or decompensated cirrhosis (or an APRI score >2 in adult patients), regardless of alanine aminotransferase level, hepatitis B e antigen status, or hepatitis B virus DNA level, need treatment. (Strongly recommended, moderate quality evidence)
Treatment is recommended for adult chronic hepatitis B patients without evidence of cirrhosis (or adult patients with an APRI score ≤2) who are >30 years of age and who also have persistently elevated alanine aminotransferase and evidence of active hepatitis B virus replication (hepatitis B virus DNA >20 000 IU/mL), regardless of their hepatitis B e antigen. (Strongly recommended, moderate quality evidence)
If hepatitis B virus DNA is not detectable: treatment may also be considered regardless of hepatitis B e antigen status, provided there is persistent elevation of alanine aminotransferase. (conditional recommendation, low-quality evidence)
Current recommendations for patients co-infected with hepatitis B/HIV.
For hepatitis B/HIV co-infected patients: all those with evidence of severe chronic liver disease need to start antiviral therapy regardless of their CD4 cell count; and all those with a CD4 cell count ≤500 cells/mm3 need to start antiviral therapy regardless of the stage of their liver disease. (Strongly recommended, low quality evidence)
Those who do not require treatment but need continued monitoring
Patients without clinical evidence of cirrhosis (or adult patients with an APRI score ≤ 2), with persistently normal alanine aminotransferase and low levels of hepatitis B virus replication (hepatitis B virus DNA < 2000 IU/mL) do not require immediate treatment regardless of hepatitis B e antigen status or age. (Strongly recommended, low quality grade)
If hepatitis B viral DNA is not detectable: hepatitis B e antigen-positive patients younger than 30 years of age with persistently normal alanine aminotransferase may defer treatment (conditional recommendation, low-quality evidence)
Ongoing monitoring is required in all patients with chronic hepatitis B, especially in those who do not currently meet the above indications for treatment or do not require treatment criteria to determine the need for future antiviral therapy to prevent the development of progressive liver disease. This includes.
Patients younger than 30 years of age without cirrhosis, with hepatitis B viral DNA levels >20 000 IU/mL and persistently normal alanine aminotransferase.
Patients who are negative for hepatitis B e antigen, are younger than 30 years of age, do not have cirrhosis, and have hepatitis B viral DNA levels that fluctuate between 2,000 and 20,000 IU/mL or intermittently elevated alanine aminotransferase.
If hepatitis B viral DNA is not detectable: patients younger than 30 years of age without cirrhosis and with persistently normal alanine aminotransferase, regardless of hepatitis B e antigen status.
First-line antiviral therapy for chronic hepatitis B
Tenofovir or entecavir, nucleoside (acid) analogs with a high resistance barrier, are recommended for all adults, adolescents, and children >12 years of age with chronic hepatitis B for whom antiviral therapy is indicated. entecavir is recommended for children 2-11 years of age. (Strongly recommended, moderate quality evidence)
Nucleoside analogs with low resistance barriers (lamivudine, adefovir, telbivudine) cause drug resistance and are therefore not recommended (strong recommendation, moderate quality evidence)
Current recommendations for patients with hepatitis B/HIV co-infection
Tenofovir + lamivudine (or emtricitabine) + efavirenz fixed-dose combination is recommended as the starting antiviral regimen for adults, adolescents, and children aged 3 years and older with hepatitis B/HIV coinfection (strong recommendation, moderate quality evidence)
Second-line antivirals in case of treatment failure
Switch to tenofovir is recommended for patients with confirmed or suspected resistance to lamivudine, entecavir, or telbivudine (e.g., history of prior drug use or primary nonresponse). (Strongly recommended, low quality evidence)
When to stop treatment
Lifetime nucleoside analogue therapy
All patients with clinical evidence-based cirrhosis (or adult patients with an ARPI score >2) require lifelong nucleoside (acid) analogue therapy, which cannot be discontinued due to the risk of relapse and the serious slow-onset acute liver injury that can result if relapse occurs. (Strongly recommended, low quality evidence)
Discontinuation
Discontinuation of nucleoside analogue therapy may be considered only in the following special circumstances.
Patients without clinical evidence of cirrhosis (or adult patients with an APRI score ≤ 2)
and are able to undergo close long-term follow-up to monitor for active disease
and have a hepatitis B e antigen conversion and serologic conversion to hepatitis B e antibody (in patients with initial hepatitis B e antigen positivity) followed by at least 1 year of consolidation therapy
and both persistent normal alanine aminotransferase and persistent hepatitis B viral DNA below the detection limit (if hepatitis B viral DNA levels can be detected)
If hepatitis B viral DNA is not detectable: patients with persistent negative hepatitis B surface antigen who have been on treatment for at least 1 year may be considered for discontinuation of nucleoside analogue therapy, regardless of their pretreatment hepatitis B e antigen status (conditional recommendation, low quality evidence)
Re-treatment
Relapse may occur after discontinuation of nucleoside analogs. Re-treatment is recommended if there is evidence of re-active virus (hepatitis B surface antigen or hepatitis B e antigen turning positive, elevated alanine aminotransferase levels, or hepatitis B viral DNA is detectable again (if hepatitis B viral DNA is detectable). (Strongly recommended, low quality evidence)