Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection

Hepatitis B virus (HBV) infection poses a significant challenge to public health, resulting in chronic liver diseases and contributing to an estimated 820,000 deaths in 2019, primarily from cirrhosis and liver cancer. The World Health Organization (WHO) estimated that 296 million individuals were living with chronic hepatitis B (CHB) in 2019, with a disproportionately high prevalence in low- and middle-income countries. The WHO Africa, Southeast Asia, and Western Pacific regions accounted for 88% of the global burden.

The majority of CHB cases stem from mother-to-child transmission, occurring either at birth or shortly after that, leading to a high rate of chronic infection. Substantial strides have been made in combating perinatal HBV transmission through universal infant immunization programs, particularly with the timely administration of the hepatitis B birth dose, which has proven highly effective in curbing new infections among children. Nonetheless, as of 2022, global hepatitis B birth-dose coverage stood at only 45%, with the lowest coverage observed in the WHO African Region at 18%.

For individuals with CHB infection, nucleoside analog treatments such as tenofovir and entecavir, as currently recommended, offer high efficacy in delaying cirrhosis progression, reducing hepatocellular carcinoma (HCC) incidence, and enhancing long-term survival. However, a significant gap persists in testing and treatment. In 2019, merely 10% of the estimated 296 million individuals with CHB had received a diagnosis, with only 2% undergoing treatment. Addressing this gap and advancing towards elimination objectives will necessitate a radical simplification of treatment criteria and care pathways to surmount barriers to accessing hepatitis B testing and treatment.

In 2015, the World Health Organization (WHO) released its initial comprehensive guidelines concerning the prevention, care, and treatment of individuals with chronic hepatitis B (CHB). Subsequently, in 2017, WHO issued guidelines focusing on testing for viral hepatitis B and C. In 2021, WHO released guidelines addressing the prevention of mother-to-child transmission of HBV through antiviral prophylaxis during pregnancy. Since the publication of the 2015 guidelines, numerous significant advancements have emerged.

These advancements include new research findings on various fronts:

• The diagnostic accuracy of non-invasive tests for liver disease staging, including cut-off values for identifying significant fibrosis or cirrhosis.
• The regional variations in the natural progression of CHB and the effectiveness of antiviral therapy are based on different HBV DNA and ALT levels.
• Comparative assessments of the efficacy and safety of combination therapies such as tenofovir with lamivudine or emtricitabine and the prodrug tenofovir alafenamide fumarate (TAF) compared to standard tenofovir.
• The diagnostic capabilities and impact of point-of-care HBV DNA viral load testing technologies.
• Strategies for testing hepatitis D virus co-infection and the effectiveness of reflex testing approaches for HBV DNA and hepatitis D infection.
• Evaluations of different service delivery models for CHB care and treatment and their impacts across the care continuum.

Furthermore, there are opportunities to broaden the utilization of antiviral prophylaxis to prevent mother-to-child transmission, especially in alignment with the global initiative for the triple elimination of HIV, hepatitis B, and syphilis.

Introduction: Goals and Objectives for the Guidelines

The objective of the 2024 guidelines is to provide updated, evidence-informed recommendations on key priority topics. These encompass broadened and simplified treatment criteria not only for adults but also for adolescents, extending eligibility for antiviral prophylaxis to pregnant women to hinder the transmission of HBV from mother to child, enhancing HBV diagnostics by utilizing point-of-care HBV DNA viral load testing and reflex approaches to HBV DNA testing, as well as determining the appropriate individuals to test for and the methodologies for testing hepatitis D virus (HDV) infection.

The focal points included:

• Broadened treatment qualification for adults and adolescents and updated thresholds for non-invasive tests to diagnose significant fibrosis or cirrhosis.
• Extended use of antiviral prophylaxis for pregnant women who test positive for hepatitis B surface antigen (HBsAg).
• Enhancement of HBV diagnostics, incorporating the utilization of point-of-care (POC) HBV viral load testing, reflex viral load testing, and protocols for testing hepatitis D virus (HDV) infection (identification of individuals to test and methodologies for testing).
• Streamlined approaches for service delivery.

Implementation of Recommendations

1. Non-Invasive Assessment of Liver Disease Stage

1.1. Recommendations
Existing and maintained recommendation (1)

APRI (aspartate aminotransferase-to-platelet ratio index) is recommended as the preferred non-invasive test to assess for the presence of significant fibrosis or cirrhosis among adults in resource-limited settings. Transient elastography (FibroScan®) may be a preferable non-invasive test in settings where it is available, and the cost is not a major constraint (strong recommendation, moderate-certainty evidence).

New recommendation (for non-invasive test thresholds (APRI and transient elastography) to establish the presence of significant fibrosis (≥F2) or cirrhosis (F4)) Evidence of significant fibrosis (≥F2) should be based on an APRI score of >0.5 or transient elastography value of >7.0 kPa, a and cirrhosis (F4) should be based on clinical criteria (oran APRI score of >1.0 or transient elastography (FibroScan®) value of >12.5 kPaa). (Adults: strong recommendation, moderate-certainty evidence; adolescents: strong recommendation, low-certainty evidence)

2. Who to Treat Among People with Chronic Hepatitis B (CHB)

2.1. Recommendations

New recommendations – who to treat
Treatment is recommended for all adults and adolescents (aged ≥12 years) with CHBa (including pregnant women and girls and non-pregnant women of reproductive age) with:

• Evidence of significant fibrosis (≥F2) based on an APRI score of >0.5 or transient elastography value of >7 kPa or evidence of cirrhosis (F4) (based on clinical criteria (or an APRI score of >1 or transient elastography value of >12.5 kPab), regardless of HBV DNA or ALT levels.
  (adults: strong recommendation, moderate-certainty evidence; adolescents: strong recommendation, low-certainty evidence)

OR

• HBV DNA >2000 IU/mL and an ALT level above the upper limit of normal (ULN) (30 U/L for men and boys and 19 U/L for women and girls). For adolescents, this should be based on ALT>ULN on at least two occasions in a 6- to 12-month period. (adults: strong recommendation, high-certainty evidence [HBV DNA >20 000 IU/mL] and low certainty evidence [HBV DNA 2000–20 000,]; adolescents: conditional recommendation, low-certainty evidence)

 OR

• Presence of coinfections (such as HIV, hepatitis D, or hepatitis C); family history of liver cancer or cirrhosis; immune suppression (such as long-term steroids, solid organ or stem cell transplant); comorbidities (such as diabetes or metabolic dysfunction––associated steatotic liver disease); or extrahepatic manifestations (such as glomerulonephritis or vasculitis), regardless of the APRI score or HBV DNA or ALT levels.
  (adults: strong recommendation, moderate-certainty evidence; adolescents: conditional recommendation, low-certainty evidence)

OR

In the absence of access to an HBV DNA assay:

• Persistently abnormal ALT levels (defined as two ALT values above the ULN at unspecified intervals during a 6- to 12-month period), regardless of APRI score. (adults and adolescents: conditional recommendation, very-low-certainty evidence)

3. First-Line Antiviral Therapies for CHB (adults, adolescents, and children)

3.1. Recommendations
Existing and maintained recommendations (1)
Nucleoside analogues with a low genetic barrier to resistance (lamivudine, adefovir, or telbivudine) can lead to drug resistance and are not recommended.
(strong recommendation, moderate-certainty evidence)

Updated recommendation

For all adults, adolescents, and children (two years or older) for whom antiviral therapy is indicated, the nucleos(t)ide analogues that have a high genetic barrier to drug resistance – tenofovir disoproxil fumarate (TDF) or entecavir (ETV) are recommended as preferred regimens.
TDF + lamivudine (3TC) or TDF + emtricitabine (FTC) are recommended as alternative regimens (where TDF monotherapy is not available). (strong recommendation, moderate-certainty evidence)

New recommendation
Entecavir (ETV) or tenofovir alafenamide fumarate (TAF) (if available) are recommended for people with established osteoporosis and/or impaired kidney function, as well as for children (ETV for those aged two years or older) or adolescents (TAF for those aged 12 years or older as an alternative regimen) for whom antiviral therapy is indicated.
(strong recommendation, moderate-certainty evidence)

4. Preventing Mother-to-Child Transmission of Hepatitis B using Antiviral Prophylaxis

4.1. Recommendations

Antiviral prophylaxis among pregnant women and adolescent girls (3)

Updated recommendation
In settings where HBV DNA or HBeAg testing is available, prophylaxis with tenofovir disoproxil fumarate (TDF) is recommended for all HBV-positive (HBsAg-positive) pregnant women with HBV DNA ≥200 000 IU/mL or positive HBeAg (preferably from the second trimester of pregnancy until at least delivery or completion of the infant HBV vaccination series), to prevent the mother-to-child transmission (MTCT) of HBV. (strong recommendation, moderate-certainty evidence)

New recommendation

In settings where neither HBV DNA nor HBeAg testing is available, prophylaxis with tenofovir disoproxil fumarate (TDF)c for all HBV-positive (HBsAg-positive) pregnant women may be considered (preferably from the second trimester of pregnancy until at least delivery or completion of the infant HBV vaccination series), to prevent MTCT of HBV. 
(conditional recommendation, low-certainty evidence)

All interventions should be given in addition to at least three doses of hepatitis B vaccination for all infants, including a timely birth dose.

Existing and maintained recommendations
Immunization (1)

1. All infants should receive their first dose of hepatitis B vaccine as soon as possible after birth, preferably within 24 hours.
2. Delivery of the hepatitis B vaccine within 24 hours of birth should be a performance indicator for all immunization programs. Reporting and monitoring systems should be strengthened to improve the quality of data on the birth dose.
3. The birth dose should be followed by two or three additional doses to complete the primary immunization series.

HBsAg testing among pregnant women and adolescent girls (2)

All pregnant women should be tested for HIV, syphilis, and hepatitis B surface antigen (HBsAg) at least once and as early as possible during their pregnancy.
(strong recommendation, low-certainty evidence)

5. Who to Treat and What Antiviral Drugs to use for Adolescents and Children with CHB

5.1. Recommendations: Who to Treat Among Adolescents
New recommendations
Treatment is recommended for all adolescents (aged 12–17 years) with CHBa (including pregnant and non-pregnant adolescent girls of reproductive age) with:

• Evidence of significant fibrosis (≥F2) based on clinical criteria or an APRI score of >0.5 or transient elastography value of >7 kPa or evidence of cirrhosis (F4) based on clinical criteria (or an APRI score of >1 or transient elastography value of >12.5 kPa), regardless of HBV DNA or ALT levels.
  (adolescents: strong recommendation, low-certainty evidence)

OR

• HBV DNA >2000 IU/mL and an ALT level above the ULN (30 U/L for boys and men and 19 U/L for girls and women). For adolescents, ALT>ULN at least twice in a 6- to 12-month period.
  (adolescents: conditional recommendation, low-certainty evidence)

OR

• Presence of coinfections (such as HIV, HDV, and HCV), family history of liver cancer or cirrhosis, immune suppression (such as long-term steroids, solid organ or stem cell transplant), comorbidities (such as diabetes, metabolic dysfunction–associated steatotic liver disease and iron overload secondary to treatment for disorders of the blood) or extrahepatic manifestations (such as glomerulonephritis or vasculitis), regardless of APRI score, HBV DNA, or ALT level.
  (adolescents: conditional recommendation, low-certainty evidence)

OR

• Persistently abnormal ALT levels (without access to an HBV DNA assay), regardless of APRI score. 
  (adolescents: conditional recommendation, very-low-certainty evidence)

No recommendation – who to treat among children aged 2–11 years old

5.2. Recommendations – What Antivirals to Use in Adolescents and Children
Existing and maintained recommendations (from WHO 2015 HBV guidelines)
Nucleoside analogues with a low barrier to resistance (lamivudine, adefovir, or telbivudine) that can lead to drug resistance are not recommended. 
(strong recommendation, moderate certainty of evidence)

Updated recommendation

For all adults, adolescents, and children (two years or older) for whom antiviral therapy is indicated, the nucleos(t)ide analogues that have a high genetic barrier to drug resistance – tenofovir disoproxil fumarate (TDF) or entecavir (ETV) are recommended as preferred regimens. TDF + lamivudine (3TC) or TDF + emtricitabine (FTC) are recommended as alternative regimens (where TDF monotherapy is not available). 
(strong recommendation, moderate-certainty evidence)

New recommendation
Entecavir (ETV) or tenofovir alafenamide fumarate (TAF) (if available) are recommended for people with established osteoporosis and/or impaired kidney function, and for children (ETC for those aged two years or older) or adolescents (TAF for those aged 12 years or older as alternative regimen), for whom antiviral therapy is indicated. (strong recommendation, moderate-certainty evidence)

6. Second-Line Antiviral Therapies for Managing Treatment Failure

6.1. Recommendations
Existing and maintained recommendation
Among people with evidence of treatment failure due to confirmed or suspected antiviral resistance (based on history of previous exposure or primary non-response) to lamivudine, entecavir, adefovir or telbivudine, switching to tenofovir disoproxil fumarate is recommended. Tenofovir alafenamide may be considered as an alternate regimen, if available.
(strong recommendation, low-certainty evidence)

7. Measuring HBV DNA to Guide Treatment Eligibility and Monitor the Response

7.1. Recommendations
Existing and maintained recommendation
Laboratory-based HBV DNA assays (1,2): Directly following a positive HBsAg serological test result, the use of HBV DNA nucleic acid testing (NAT) (quantitative or qualitative) is recommended as the preferred strategy to assess viral load level for treatment eligibility and to monitor treatment response.
(strong recommendation, moderate-certainty evidence)

New recommendation

Point-of-care (POC) HBV DNA assays: POC HBV DNA nucleic acid testing (NAT) assays may be used as an alternative to laboratory-based HBV DNA testing to assess the HBV DNA level used to determine treatment eligibility and monitor treatment response.
(conditional recommendation, low-certainty evidence)

8.  HBV DNA Reflex Testing

8.1 Recommendations

New recommendation

Reflex HBV DNA testing for those testing positive for HBsAg may be an additional strategy to promote linkage to care and treatment. This can be achieved through either laboratory-based reflex HBV DNA testing using a sample already in the laboratory or clinic-based reflex testing in a healthcare facility through immediate sample collection following a positive HBsAg rapid diagnostic test (RDT).
(conditional recommendation, low-certainty evidence)

9. Hepatitis D Virus (HDV) Testing: Who to Test for HDV Infection

9.1 Recommendations

New recommendations

For people with CHB, serological testing for anti-HDV antibodies may be performed for all HBsAg-positive individuals as the preferred approach to scale up access to HDV diagnosis and linkage to care. 
(conditional recommendation, very-low-certainty evidence)

In settings in which a universal anti-HDV antibody testing approach is not feasible because laboratory capacity or other resources are limited, testing for anti-HDV may be given priority in specific populations of HBsAg-positive individuals, including the following:

• People born in HDV-endemic countries, regions, and areas;
• People with advanced liver disease, those receiving hepatitis B treatment, and those with features suggesting HDV infection (such as low HBV DNA with high ALT levels);
• People considered to have an increased risk of HDV infection, including hemodialysis recipients, people living with HCV or HIV infection, people who inject drugs, sex workers, and men who have sex with men.

(conditional recommendation, very-low-certainty evidence)

10. How to Test for HDV Infection: Testing Strategy and Choice of Serological and NAT Assays

10.1. Recommendations

New Recommendation

People with CHB (HBsAg positive) may be diagnosed with hepatitis D by using a serological assay to detect total anti-HDV followed by a NAT to detect HDV RNA and active (viraemic) infection among those who are anti-HDV positive. Assays should meet minimum quality, safety, and performance standards.
(conditional recommendation, low-certainty evidence)

11. How to Test for HDV: Laboratory-Based Reflex Testing

11.1. Recommendations
New recommendation
Reflex testing for anti-HDV antibody testing following a positive HBsAg test result and HDV RNA testing (where available) following a positive anti-HDV antibody test result may be used as an additional strategy to promote diagnosis.
(conditional recommendation, low-certainty evidence)

12. Monitoring for Treatment response among people with CHB receiving treatment or not yet receiving treatment

12.1. Recommendations
Existing and maintained recommendations from the 2015 hepatitis B guidelines
Monitoring for people receiving treatment
For people receiving treatment, the following are recommended to be monitored at least.
Annually:

• Non-invasive tests (APRI score or transient elastography) to assess stage of disease and
• Progression of fibrosis or cirrhosis, and
• ALT levels (and AST for APRI), HBV DNA levels (when HBV DNA testing is available), HBsAgb and HBeAg/anti-HB.
• Treatment adherence should be monitored regularly and at each visit.

(strong recommendation, moderate-certainty evidence)

13. Monitoring the Safety of Nucleoside Analogues

13.1. Recommendations
Existing and maintained recommendations from the 2015 hepatitis B guidelines

• Before initiating antiviral therapy, people’s baseline risk for renal dysfunction may be assessed, and baseline renal function was measured.
• People receiving long-term tenofovir disoproxil fumarate therapy may be monitored annually for renal function, and children’s growth may be monitored carefully.

(conditional recommendation, very-low-certainty evidence)

14. Surveillance for hepatocellular carcinoma (HCC) among people with CHB

14.1.  Recommendations
Existing and maintained recommendations (1)

Routine surveillance for HCC with abdominal ultrasound and alpha-fetoprotein testing every six months is recommended for:

• People with cirrhosis, regardless of age or other risk factors; 
  (strong recommendation, moderate-certainty evidence)
• People with a family history of HCC; and
  (strong recommendation, moderate-certainty evidence)
• If there is no family history of HCC or evidence of cirrhosis, people older than 40 years (a lower age may apply depending on the regional incidence of HCCa) and with HBV DNA level >20,000 IU/mL (if HBV DNA testing is available).
  (conditional recommendation, low-certainty evidence)

15. When to Stop and Restart Antiviral Therapy

15.1. Recommendations
Existing and Maintained Recommendations from the 2015 Hepatitis B Guidelines
Lifelong nucleos(t)ide analogue therapy

All people with cirrhosis, based on clinical evidence (or APRI or transient elastography score) require lifelong treatment with nucleos(t)ide analogues and should not discontinue antiviral therapy because of the risk of reactivation, which can cause an acute hepatitis flare.
(strong recommendation, moderate-certainty evidence)

Discontinuation

Antiviral therapy is lifelong. Discontinuing nucleos(t)ide analogue therapy may be considered exceptionally for:

• People without clinical evidence of cirrhosis (or based on a non-invasive test score – APRI or transient elastography);

and

• Who can be followed carefully after discontinuation and long term for reactivation;

and

• If there is evidence of HBeAg loss and seroconversion to anti-HBe (for people initially HBeAg-positive) and after completing at least one additional year of treatment,

and

• This is associated with persistently normal ALT levels and undetectable HBV DNA levels (if HBV DNA testing is available).

If HBV DNA testing is unavailable, discontinuing nucleos(t)ide analogue therapy may be considered for people with evidence of persistent HBsAg loss and after completing at least one additional year of treatment, regardless of previous HBeAg status.
(conditional recommendation, low-certainty evidence)

Retreatment

Relapse is common after stopping therapy with nucleos(t)ide analogues. Retreatment is recommended if there are consistent signs of reactivation:

• HBsAg or HBeAg becomes positive,
• ALT levels increase, or
• HBV DNA becomes detectable again (if HBV DNA testing is available).

(strong recommendation, low-certainty evidence)

Management Considerations for Specific Populations

A holistic strategy for managing chronic hepatitis B (CHB) encompasses various measures aimed at preventing the spread of hepatitis B, screening for coinfections with HIV, hepatitis C, and hepatitis D, as well as addressing comorbidities. This approach involves administering HBV vaccination, general care, and treatment. Additionally, management should cater to the specific needs of various CHB populations, such as individuals coinfected with HIV, HDV, or HCV, those experiencing advanced or decompensated liver disease, including extrahepatic manifestations, as well as children, adolescents, pregnant women, and individuals who engage in drug injection.

^{Note: The 2024 recommendations focus on testing and case-finding for HDV infection. WHO recognizes that the HDV treatment landscape is rapidly evolving. Until recently, PEG-IFNα had been the only treatment option for CHD but had poor treatment outcomes, a significant side effect profile, and many contraindications. WHO continues to monitor the outcomes of ongoing HDV treatment trials and will consider formal recommendations on treatment when further evidence becomes available.}

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References

1. Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection by World Health Organization (WHO). Published on March 29, 2024. Available at: https://iris.who.int/bitstream/handle/10665/376353/9789240090903-eng.pdf?sequence=1
2. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. Geneva: World Health Organization; 2015 (https://apps.who.int/iris/handle/10665/154590, accessed 5 February 2024).
3. Guidelines on hepatitis B and C testing. Geneva: World Health Organization; 2017 (https://apps.who.int/iris/ handle/10665/254621, accessed 5 February 2024).
4. Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. Geneva: World Health Organization; 2018 (https://apps.who.int/iris/handle/10665/273174, accessed 5 February 2024).
5. WHO handbook for guideline development. 2nd ed. Geneva: World Health Organization; 2014 (https://apps.who.int/ iris/handle/10665/145714, accessed 5 February 2024).

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