Hepatitis B Elimination Globally: The Answer May Not Be the Same for Everyone

Abstract

While progress has been made toward global elimination of hepatitis B virus, many countries lag behind. A one-size-fits-all approach is not practical to address HBV. Rather, the approach should be tailored to local prevalence, risk factors, and available resources.

In 2016, the World Health Organization (WHO) established a Global Health Sector Strategy for the elimination of viral hepatitis globally by 2030 [1]. Specific to hepatitis B virus (HBV), these goals include:

• 90% reduction in incident cases (and <0.1% prevalence among children under age five).

• Diagnosis of 90% of all cases.

• Treatment of 80% of eligible individuals.

• 65% reduction in mortality.

• 90% coverage of the standard three-dose infant vaccine series, HepB3.

• 90% coverage of HBV birth-dose vaccine (HepB-BD) to prevent vertical transmission.

• 100% screening of donated blood.

• 90% safe injection practices.

When these goals were set in 2016, global prevalence of HBV, measured by HBV surface antigen (HBsAg) positivity, was 3.9% (95% CI: 3.4–4.6%); it has only declined slightly, to 3.2% (95% CI: 2.7–4.0%), according to 2022 modeling estimates by the Polaris Observatory [2, 3]. Progress has been made among children ≤5 years: HBV prevalence has decreased by 50%, from 1.4% (95% CI: 1.2–1.6%) in 2016 to 0.7% (95% CI: 0.6–1.0%) in 2022 [2, 3]. Despite this progress, childhood HBV remains a threat, and persists well above the goal of 0.1% prevalence. Also important to consider is differential risk by geographical location, with children living in sub-Saharan Africa, Oceania, and Central and South Asia most at risk for infection.

Integral to childhood HBV elimination efforts is vaccination, where progress has been virtually non-existent: coverage with HepB3 only slightly increased from 2016 to 2022, from 85% to 87% globally, while receipt of timely HepB-BD remained stagnant at 46% [2, 3]. HepB-BD coverage is lowest in the sub-Saharan African region, where only one in five infants (in 14 of 47 countries) receive HepB-BD [4].

Finally, progress in the realm of diagnosis and treatment has been dismal. As of 2022, only 34 million of an estimated 254 million infected individuals (13.4%) have been diagnosed with HBV and only 6.7 million HBV + individuals (2.6%) received antiviral treatment [2, 3, 5]. In response, the WHO has recently amended guidelines to expand treatment [6], although notably these guidelines only apply to adults and adolescents over age 12.

The reality of the current status of HBV is that, without major progress, elimination goals will not be achievable until 2090 [7]. In light of progress—or lack thereof—toward HBV elimination, what can be done toward achieving elimination goals? The following strategies should be considered, combined, and tailored to the specific needs of a given region of the world.

1. Improve routine vaccination coverage

• Prevention is the mainstay of HBV elimination. HepB3 has been available in many parts of the world since the 1980s. However, progress has been slower in areas of the world where vaccine introduction was delayed. For example, the Democratic Republic of Congo (DRC) did not officially introduce the pentavalent vaccine including HepB until 2007; current national coverage of HepB3 is a mere 65% compared to global coverage of 85% [8]. To compound low coverage, HepB3 vaccine effectiveness is estimated to be low among African children, with 56.95–89.23% achieving protective HBV surface antibody levels (10 mIU/mL) at 1–3 months post-HepB3 vaccination in recent systematic reviews [9, 10]. HIV exposure is an established risk factor for hypo-responsiveness to vaccines such as HepB [10], but other factors may be at play and should be further explored to maximize protection against HBV. Alongside efforts to improve vaccine coverage, the scientific community must come together to better understand why some children do not have robust responses to HepB3 vaccine.

• 2. Increase screening in pregnancy and prevention of vertical transmission

• HBV vertical transmission, from birthing person to their infant, is entirely preventable through a two-pronged approach of antiviral prophylaxis in pregnancy and infant birth-dose vaccination. Birth-dose vaccination ideally includes both HepB-BD and immunoglobulin (HBIG); however, HBIG coverage is only 13% globally [3], and it is unrealistic to expect HBIG coverage for all HBV-exposed infants due to cost and storage issues. Unfortunately, the first step in the prevention of vertical transmission—testing of pregnant individuals to know their HBV status—is not standard practice in some areas of the world, particularly in sub-Saharan Africa [11]. Furthermore, HBV DNA testing was previously recommended in order to identify individuals at high risk of transmitting the virus to their infants [12]. This testing is not only unaffordable but oftentimes inaccessible for people living in resource-limited settings. Novel approaches adopted by the Ministry of Health of Malawi and under investigation by researchers in DRC (NCT05705427) include a prophylaxis-for-all approach, in which all pregnant individuals positive by HBsAg testing receive antiviral prophylaxis, and/or use of novel markers for high-risk HBV such as an HBcrAg rapid diagnostic test (RDT) [13]. A prophylaxis-for-all approach is more practical and cost-effective than the standard approach to the prevention of vertical in resource-constrained settings, and an HBcrAg-RDT approach may be even more affordable, according to a recent cost-effectiveness analysis conducted in Burkina Faso [13]. With the advent of new WHO HBV treatment guidelines in March 2024, prophylaxis is now recommended for all HBsAg + pregnant individuals in settings where HBV DNA is inaccessible [6]. This paradigm shift will surely prevent hundreds of thousands of cases of vertical transmission, and findings of ongoing research will be needed to support the prophylaxis-for-all approach.

• Integral to the prevention of vertical transmission is incorporation of HepB-BD into the national vaccination schedule; coverage of HepB-BD is lowest in the WHO African region. While many countries have committed to adoption of HepB-BD, there is no time to wait; thankfully HBV researchers and nonprofit organizations have jointly voiced the urgent need for improved access to this cancer-preventing and life-saving vaccine [14, 15].

• 3. Identify and treat those with chronic HBV

• Simplification of treatment guidelines for HBV, as recently undertaken by the

  WHO [6], should greatly improve the number of individuals who qualify for antiviral treatment. However, these new guidelines do not solve the issues of limited access to diagnostics and antivirals, as well as the need for ongoing monitoring while on treatment, that hinder progress. Some researchers and clinicians have advocated for universal treatment for HBsAg-positive individuals, which is cost-effective in modeling studies [16], but remains controversial and requires further investigation. In the case of prophylaxis-for-all in pregnancy (Point #2 above), 2024 WHO treatment guidelines recommend that postpartum individuals of childbearing age remain on treatment if indicated so as to prevent transmission in subsequent pregnancies [6], an important but often overlooked aspect of care. Furthermore, where HBV DNA testing is readily available, pregnant individuals who test positive for HBsAg should ideally have reflex testing to HBV DNA to determine the need for antiviral prophylaxis as early as possible in pregnancy. Reflex HBV DNA testing is not routine practice but could improve time to initiation of therapy so that the window for perinatal prevention is not missed, as highlighted in the 2024 WHO treatment guidelines [6]. As high-prevalence HBV countries create and/or amend their national hepatitis elimination plans, cost and availability of diagnostic tests and antiviral treatment must be considered first and foremost.

• 4. Prioritize known effective public health prevention strategies

• As evident in the 2016 Global Health Sector Strategy on hepatitis elimination [1], public health prevention strategies such as screening of blood products, use of clean needles, and sterilization of medical equipment are important to prioritize alongside other measures. Because HBV is highly infectious in blood and bodily fluids, remaining viable on surfaces for at least seven days, submicroscopic exposure may lead to horizontal transmission from person to person. A recent household-based study of horizontal transmission of HBV in Kinshasa, DRC investigated common household objects such as shared nail clippers or hair salons as potential sources of infection [17]. Improved understanding of routes of horizontal transmission can lead to improved public health prevention strategies such as sterilization of shared personal and medical equipment.

• 5. Adopt a tailored approach based on national and sub-national prevalence

• As with many health prevention strategies, a one-size-fits-all approach is neither reasonable nor effective. National and sub-national estimates of HBsAg positivity can vary greatly. For instance, a recent analysis of national survey samples in the DRC revealed an overall HBsAg-positive prevalence of 1.2%, but with wide geographical variation, from 0% in the capital city of Kinshasa to 5.7% in more remote regions (https://www.medrxiv.org/content/10.1101/2024.06.12.24308840v1). Differential adoption of testing, treatment, and vaccination strategies may be at play to explain this variation, as could cultural practices such as circumcision and/or scarification. Regional variation is important to consider, not only in large countries such as DRC (the 11th largest country in the world) but also across smaller regions and communities.

• Furthermore, approaches will differ by continent, local transmission patterns, and available resources. In Southeast Asian countries, where vertical transmission is the predominant route of acquisition of HBV among children, recent focus centered around improving HepB-BD coverage has been successful, improving from 34% in 2016 to 54% in 2019 [18]. In contrast, horizontal transmission predominates in sub-Saharan Africa and thus strategies should include prevention of ongoing household and community spread. In summary, recommendations must be tailored, combined, and adjusted to the unique needs and resources available in various parts of the world.

• 6. Reconsider elimination goals

• In evaluating progress toward the 2030 hepatitis elimination goals, one must consider whether these metrics are appropriate in the first place. To this effect, in 2020 Polaris Observatory Collaborators recommended that WHO pursue simplified elimination targets that are based on absolute rather than relative measures [19]. These recommendations have been adopted by the WHO as of 2023; for instance, rather than a 65% reduction in mortality from HBV, a reduction to 6 per 100 000 deaths may be not only more achievable but more relevant from a clinical and public health perspective [20]. Varying absolute targets for elimination must be considered in light of different needs and resources throughout various parts of the world.

In conclusion, global elimination of HBV is within reach. In order to achieve elimination goals outlined by the WHO, global leaders and organizations must combine and adapt known effective prevention strategies to their unique circumstances. Working together in international collaborations, we continue the battle toward a world free of HBV.

Notes

Financial support . PT is funded by grants from the NIH (K08AI148607) and the Doris Duke Foundation, outside of this work.

Potential conflicts of interest . All authors: No reported conflicts.

Data availability . All data included in this manuscript are referenced above and readily available.

Supplement sponsorship . This article appears as part of the supplement “Viral Hepatitis Elimination in Infants, Children, and Pregnant Women,” sponsored by Gilead Sciences.