New WHO hepatitis B treatment guidelines: look to Ethiopia

Abstract

An estimated 296 million people are living with chronic hepatitis B virus (HBV) infection and nearly 1 million people die each year from its complications.1WHOHepatitis B fact sheet.http://www.who.int/mediacentre/factsheets/fs204/en/Date: 2019Date accessed: September 15, 2022Google Scholar In 2016, WHO endorsed a plan to eliminate viral hepatitis as a public health threat by 2030, but few countries in sub-Saharan Africa are on track to achieve this goal. HBV elimination will require improved infant vaccination coverage to reduce new infections, and universal access to HBV testing and treatment, which effectively reduces the risk of HBV-related complications and death. Sub-Saharan Africa has the highest prevalence of HBV infection globally, yet only 0·1% of patients with chronic HBV infection receive antiviral treatment.2WHOGlobal Progress Report on HIV, viral hepatitis and sexually transmitted infections, 2021. World Health Organization, Geneva2021Google Scholar WHO issued its first HBV treatment guidelines in 2015, when treatment was recommended to patients with clinically diagnosed cirrhosis, patients with aspartate aminotransferase to platelet ratio index (APRI) >2, or those aged 30 years or older with abnormal alanine aminotransferase and HBV viral load >20 000 IU/mL.3WHOGuidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. World Health Organization, Geneva2015Google Scholar The WHO guidelines were soon adopted as national treatment guidelines in many countries in sub-Saharan Africa, despite the scarcity of local data to back these guidelines up. Indeed, nearly all data used to inform international HBV guidelines are from cohorts of Asian patients, for whom environmental exposures, endemic infections, and host and viral genetic factors differ substantially from those of patients in sub-Saharan Africa. The absence of data from sub-Saharan Africa was also acknowledged as a substantial knowledge gap in the WHO 2015 guidelines. In 2015, a group of researchers and clinicians (the EthNoHep group) established a pilot HBV treatment programme at a public hospital in Addis Ababa, Ethiopia. A total of 1303 patients were enrolled and followed up, and antiviral treatment was prescribed to those who had signs of liver injury. This cohort has been a valuable source of information about HBV infection and antiviral treatment efficacy in sub-Saharan Africa. In a landmark study, the authors compared the WHO treatment criteria with a gold standard (namely the European criteria) and found that the WHO criteria only detected half of the patients in need of treatment.4Aberra H Desalegn H Berhe N et al.The WHO guidelines for chronic hepatitis B fail to detect half of the patients in need of treatment in Ethiopia.J Hepatol. 2019; 70: 1065-1071Summary Full Text Full Text PDF PubMed Scopus (25) Google Scholar After excluding patients with decompensated cirrhosis, only 25·7% of patients in need of therapy were detected with the WHO criteria. In 2020, researchers and clinicians in eight different countries in sub-Saharan Africa decided to merge data on more than 3500 patients with HBV to create a strong evidence base for treatment recommendations on the continent. This network (HEPSANET) recently published its first joint article focusing on the accuracy of APRI and other non-invasive fibrosis markers.5Johannessen A Stockdale AJ Henrion M et al.Diagnostic performance of non-invasive fibrosis markers for chronic hepatitis B in sub-Saharan Africa: a Bayesian individual patient data meta-analysis.medRxiv. 2022; (published online March 18.) (preprint).https://doi.org/10.1101/2022.03.18.22272415Google Scholar The authors found that the WHO recommended APRI threshold of 2 had a very poor sensitivity (16·5%) to detect cirrhosis, rendering it virtually useless as a diagnostic tool. The authors identified new and improved cirrhosis thresholds to optimise the performance of APRI, suggesting a rule-in threshold of 0·65 and a rule-out threshold of 0·36. In 2021–22, the EthNoHep group—in close collaboration with the Federal Ministry of Health (FMoH)—launched an HBV scale-up treatment programme in Ethiopia. Four hospitals outside the capital were selected and a simplified treatment protocol was developed (table), based on local data from the pilot HBV treatment programme and results from the HEPSANET collaboration. Criterion I is uncontroversial and in line with all international guidelines. Criterion II is based on the rule-in cirrhosis threshold identified in the recent HEPSANET study. Criterion III is based on local data from the Ethiopian pilot programme in which alanine aminotransferase >40 U/L was associated with disease progression;6Johannessen A, Pripp AH, Desalegn H, Aberra H, Gundersen SG, Berhe N. The TREAT-B score predicts disease progression in Ethiopian patients with chronic hepatitis B. International Viral Hepatitis Elimination Workshop; Dec 4–5, 2020 (abstr 11).Google Scholar this is also in line with the recent TORCH-B study where the authors found an increased risk of fibrosis progression in untreated patients with viral load >2000 IU/mL and minimally raised alanine aminotransferase (40–80 U/L).7Hsu Y-C Chen C-Y Chang I-W et al.Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial.Lancet Infect Dis. 2021; 21: 823-833Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar Criterion IV is added since African patients appear to be at higher risk of hepatocellular carcinoma.8Yang JD Mohamed EA Aziz AO et al.Characteristics, management, and outcomes of patients with hepatocellular carcinoma in Africa: a multicountry observational study from the Africa Liver Cancer Consortium.Lancet Gastroenterol Hepatol. 2017; 2: 103-111Summary Full Text Full Text PDF PubMed Scopus (107) Google ScholarTableTreatment eligibility criteria in the hepatitis B scale-up programme, EthiopiaTreatment criteriaIClinically diagnosed cirrhosisIIAPRI >0·7IIIALT >40 U/L and HBV viral load >2000 IU/mLIVHCC in first-degree relative and HBV viral load >2000 IU/mLAPRI=aspartate aminotransferase to platelet ratio index. ALT=alanine aminotransferase. HBV=hepatitis B virus. HCC=hepatocellular carcinoma. Open table in a new tab APRI=aspartate aminotransferase to platelet ratio index. ALT=alanine aminotransferase. HBV=hepatitis B virus. HCC=hepatocellular carcinoma. The close collaboration between academia, clinicians, and the FMoH in Ethiopia can be an example for other countries in the battle against the HBV epidemic. Indeed, in the revised 2022 National HBV guidelines, Ethiopia has adopted the simplified treatment criteria from the EthNoHep group. The FMoH has shown leadership and flexibility in this process, which is key to achieve the elimination goals. WHO has forecasted a revision of their hepatitis B treatment guidelines shortly, and we strongly urge the WHO hepatitis team to take novel data from sub-Saharan Africa into account in this process. Otherwise, the new WHO guidelines might end up just as irrelevant. We declare no competing interests.

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