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Chronic HBV
Understanding the Updated WHO Guidelines for Chronic HBV Infection

Released: June 12, 2024

Expiration: June 11, 2025

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Key Takeaways
  • The updated World Health Organization hepatitis B virus (HBV) guidelines expand treatment criteria for people with HBV infection to include people with significant fibrosis or cirrhosis and people with HBV DNA >2000 IU/mL and alanine transaminase above the upper limit of normal.
  • Prophylaxis should be an available option for all hepatitis B surface antigen–positive pregnant women to reduce mother-to-child transmission.
  • Universal testing for hepatitis delta virus should be implemented if possible, or at least prioritized for key populations.

This year, the World Health Organization (WHO) updated their hepatitis B virus (HBV) guidelines to address several issues. First and foremost, the updates expand but simplify the guidelines, placing more emphasis on diagnosing and appropriately treating people, with clear risk stratification algorithms to determine the appropriate care for each individual.

The updates also address emerging evidence of epidemiologic shifts, key risk demographics, and the significant rate of mother-to-child transmission, particularly in sub-Saharan Africa.

Finally, the updates address barriers to accessing both treatment and diagnostics, particularly in low- and middle-income countries, with an emphasis on sub-Saharan Africa. So, what are some of the highlights?

Treatment Eligibility
A primary change to the guidelines is expanded eligibility for treatment, with 4 ways that people can meet the criteria for treatment eligibility. Now, treatment is recommended for all adults and adolescents older than 12 years of age with chronic HBV who have any evidence of significant fibrosis or any evidence of cirrhosis, regardless of HBV DNA or alanine aminotransferase (ALT) levels. This includes pregnant people and all women and girls of reproductive age. The WHO recommended definition of significant fibrosis is a disease stage of ≥F2, established by noninvasive surrogate measurements, namely an aspartate aminotransferase to platelet ratio index (APRI) score >0.5 or transient elastography score >7 kPa. Cirrhosis is defined as an APRI score of >1 or transient elastography score >12.5 kPa, regardless of HBV DNA or ALT levels.

People may also be eligible for treatment depending on their viral load. Any individual with HBV DNA >2000 IU/mL and an ALT above the upper limit of normal—30 U/L for men and boys and 19 U/L for women and girls—should receive HBV treatment. For adolescents, determination of whether ALT is above the upper limit of normal should be based on at least 2 test results in a 6- to 12-month period.

In addition, people with evidence of coinfection, family history of liver cancer, concomitant diseases, immunosuppression, diabetes, or extrahepatic manifestations are eligible for treatment, regardless of HBV DNA or fibrosis levels.

Lastly, a conditional recommendation for treatment is possible for people who do not have access to a hepatitis B DNA assay but exhibit persistently abnormal ALT levels, defined as 2 test results above the upper limit of normal during a 6- to 12-month period, regardless of their APRI score.

The evidence for the expanded treatment eligibility came from a systematic review that found much higher rates of disease progression among people with HBV DNA levels >2000 IU/mL or ALT levels greater than the upper limit of normal, compared to people with HBV DNA levels <2000 IU/mL or normal ALT levels. The evidence shows that this particular group would benefit from antiviral therapy.

The preferred first-line therapies remain the same as in the last version of the guidelines: tenofovir disoproxil fumarate (TDF) or entecavir. However, the guidelines now include a new recommendation for combination therapy consisting of tenofovir plus either lamivudine or emtricitabine in settings with limited access to TDF monotherapy.

Mother-to-Child Transmission
With regards to preventing mother-to-child transmission of hepatitis B, the updated guidelines retain the recommendation for TDF prophylaxis (preferably taken from the second trimester of pregnancy until at least delivery or completion of the infant HBV vaccination) for hepatitis B surface antigen (HBsAg)-positive pregnant women with HBV DNA ≥200,000 IU/mL or a positive hepatitis B e-Antigen (HBeAg), in settings where HBV DNA and e antigen testing is readily available. However, to address barriers to accessing HBV DNA testing and HBeAg serology testing that may prevent otherwise eligible women from obtaining prophylaxis, a new recommendation gives all HBsAg-positive pregnant women the option to take antiviral prophylaxis, should they choose to (again, preferably from the second trimester of pregnancy until at least delivery or completion of the infant HBV vaccination).

Point-of-Care Diagnostics
Although point-of-care diagnostics for HBV DNA testing is still an emerging field, the updated guidelines also address this topic, as well as the concept of reflex testing. Now, the guidelines recognize that point-of-care HBV DNA testing is an alternative to lab-based DNA testing that can improve identification of treatment-eligible people. That is, if HCPs can reflex from a positive HBsAg assay to an HBV DNA quantification, this logistically will allow us to identify more people who require treatment and improve our ability to link them to care and treatment.

Hepatitis Delta Virus
As the epidemiology of hepatitis delta virus (HDV) remains elusive, the revised guidelines also recommend universal testing for hepatitis D for all people with chronic HBV infection and for people who are HBsAg positive. In resource-limited settings where anti-HDV antibody testing is not feasible, testing should be prioritized for specific populations, such as people who are from HDV endemic countries, people at higher risk of HDV infection (men who have sex with men, people who inject drugs, sex workers, hemodialysis recipients, or people living with HIV or HCV), individuals who have frequent close contact with people who have HDV infection, and those with advanced liver disease.

Depending on the estimate, there may be up to 12 million individuals with hepatitis D infection, putting them at significantly higher risk of developing liver complications. Implementation of this universal HDV testing or increasing HDV testing in specific populations can improve diagnosis and linkage to care for these individuals.

Which Guidelines to Follow?
So, should HCPs follow the WHO guidelines or wait for their respective national guidance to change? I believe that there is a trend towards lowering the thresholds for treatment, as seen in the American Association for the Study of Liver Diseases 2018 Hepatitis B Guidance, and the 2023 Chinese Society of Hepatology/Infectious Diseases clinical practice guidelines. The WHO guidance provides even more evidence-based recommendations for lower thresholds for treatment.

Ideally, there would be a curative HBV therapy that we could prescribe for all people with HBV infection. Since that is not yet a reality, HCPs ultimately must utilize their best judgement to recommend therapies that suppress viral replication and reduce morbidity and mortality while awaiting the development of a curative therapy.

Altogether, the updated WHO guidance and expanded treatment criteria should increase the number of people with HBV infection who receive treatment. Simplifying the criteria for pregnant women to be eligible for prophylaxis should decrease mother-to-child transmission. Point-of-care HBV DNA testing, as well as reflex testing for both HBV and HDV, will allow us to be able to better identify people with these infections and more readily link these individuals to care.

Your Thoughts?
How have the updated guidelines changed how you approach HBV care and management? Leave a comment to join the discussion!