Chronic hepatitis B: Prevent, diagnose, and treat before the point of no return

Abstract

Hepatitis B remains a significant global health challenge, contributing to substantial morbidity and mortality. Approximately 254 million people worldwide live with Chronic hepatitis B (CHB), with the majority of cases occurring in sub-Saharan Africa and the Western Pacific regions. Alarmingly, only about 13.4% of the individuals infected with this disease have been diagnosed, and awareness of hepatitis B virus (HBV) infection status is as low as 1% in sub-Saharan Africa. In 2022, CHB led to 1.1 million deaths globally. The World Health Organization (WHO) has set a target of eliminating hepatitis B as a public health concern by 2030; however, this goal appears increasingly unattainable due to multiple challenges. These challenges include low vaccination coverage; a large number of undiagnosed cases; a low proportion of patients eligible for treatment under current guidelines; limited access to healthcare; and the costs associated with lifelong treatment. Treatment of HBV can yield significant clinical benefits within a long window of opportunity. However, the benefits of therapy are markedly diminished when the disease is detected at the advanced cirrhosis stage. This editorial aim to highlight the current challenges in hepatitis care and the necessary steps to achieve the WHO's hepatitis elimination goals for 2030.

Key Words: Chronic hepatitis B; Hepatitis B virus; Cirrhosis; Decompensation; Hepatocellular carcinoma

Core Tip: Hepatitis B remains a significant global health challenge. Despite ongoing efforts by the World Health Organization to eliminate hepatitis B as a public health concern by 2030, the situation on the ground is dire, with only about 13% of those infected diagnosed and merely 2.6% receiving treatment. In sub-Saharan Africa, awareness of hepatitis B virus infection is alarmingly low (1%), and many cases are identified only at the stage of cirrhosis, when the benefits of therapy are significantly reduced. This editorial aim to elucidate the challenges and explore potential strategies to improve the quality of care for such patients.

INTRODUCTION

Chronic hepatitis B (CHB) is a major public health issue, leading to cirrhosis and hepatocellular carcinoma (HCC). Globally, CHB affects 254 million people, with 65% residing in the African and Western Pacific regions[1]. Most of this global burden is attributed to mother-to-child and horizontal household transmission among children. Neonatal transmission is a significant cause of endemic hepatitis B in East Asia and Africa, where the prevalence of CHB exceeds 8%[2]. Although the incidence of new infections has decreased after introducing the hepatitis B vaccine, the overall prevalence of hepatitis B virus (HBV) has not declined significantly[1]. We recently reviewed a prospective cohort study conducted in Eastern Ethiopia by Ismael et al[3], which assessed the clinical characteristics and efficacy of antiviral therapy in 193 patients with CHB. Remarkably, one-third of the patients were found to have cirrhosis at presentation, with the majority in the decompensated stage. These patients with decompensated cirrhosis exhibited a very high 6-month mortality rate despite receiving tenofovir disoproxil fumarate (TDF) therapy. In contrast, early initiation of TDF effectively suppressed viremia, improving liver fibrosis markers[3]. This study underscores the inadequate hepatitis B care facilities in a country with an intermediate-to-high prevalence of hepatitis B, delaying initiation of antiviral therapy and unfavorable outcomes. These findings also emphasize the need to strengthen national programs in endemic countries for preventing and controlling the HBV. Against this backdrop, we aim to highlight the current challenges in hepatitis care, the natural history of CHB, the importance of early initiation of antiviral therapy, and the steps to achieve the World Health Organization (WHO) hepatitis elimination goals for 2030.

BURDEN OF CHB AND ITS NATURAL PROGRESSION

According to the WHO hepatitis report for 2024, the global seroprevalence of Hepatitis B surface antigen (HBsAg) is 3.8%, with approximately 254 million people living with CHB in 2022. Hepatitis B resulted in an estimated 1.1 million deaths in 2022, primarily from cirrhosis and HCC. The burden of CHB is predominantly concentrated in the WHO Western Pacific and African regions[4]. The age-standardized death rate globally was 4.03 per 100000 population but exceeded 10 per 100000 in many highly endemic countries[5]. Despite a reduction in global mortality from HBV-related HCC, the total number of deaths increased by 23%, likely due to the ageing population living with HBV infection[6].

CHB can naturally progress to liver cirrhosis, hepatic decompensation, and HCC (Figure 1). In HBeAg-positive patients, the progression to cirrhosis occurs at an annual rate of 2% to 5.5%, increasing to 8% to 20% over five years. HBeAg-negative patients progress to cirrhosis more rapidly, with a yearly rate of 8% to 20%[7]. The natural course of cirrhosis is characterized by a protracted silent compensated phase, followed by a more progressive phase after the first decompensation. The first decompensation is a critical prognostic watershed, as the median survival of cirrhosis patients significantly decreases from 8–12 years to just 1–2 years[8]. Overall, 16% of HBV cirrhosis patients experience hepatic failure within five years[7].

Figure 1 Diagrammatic representation of natural history of hepatitis B virus infection in human beings. Approximately, 8% to 20% of patients with chronic hepatitis B progressed to cirrhosis over 5 years. The natural course of cirrhosis is characterized by a protracted silent compensated phase to a more progressive phase following the first decompensation. A timely institution of antiviral therapy leads to significant regression of hepatic fibrosis as well as reversal of cirrhosis from compensated stage.

THERAPEUTIC BENEFITS AND CONCERNS

Once a patient is diagnosed with CHB, ensuring the best possible care is necessary to improve overall outcomes. Current clinical guidelines recommend antiviral treatment for patients with CHB exhibiting active viral replication and/or significant liver injury or fibrosis. Antiviral therapy has been shown to decrease the risk of disease progression, prevent or reverse liver fibrosis, and reduce the development of HCC (Table 1)[9-11]. Treatment of CHB can yield significant clinical benefits within a long window of opportunity, extending up to the compensated cirrhosis stage. However, as demonstrated in the current study, a consistent mortality benefit is not observed in the decompensated cirrhosis stage. Antiviral therapy significantly slows liver disease progression in non-cirrhotic CHB patients. A meta-analysis of 59 studies provides moderate-quality evidence that antiviral therapy in immune-active CHB patients significantly reduces the risks of cirrhosis, decompensation, and HCC[12]. In the multicenter TORCH-B trial, liver fibrosis progressed in 26% of patients in the TDF group compared to 47% in the placebo group. Additionally, necroinflammation progressed in 7% of the TDF group vs 16% of the placebo group[13]. All major guidelines now recommend antivirals for patients with significant viremia (> 2000 IU/mL), even with minimally elevated alanine aminotransferase (ALT).

Table 1 Impact of Antiviral therapy on outcomes of patients with advanced stages of chronic hepatitis B.

Ref.	Study design	Drug/duration	HBV patients number	Baseline cirrhosis	Main results
Fontana et al[18], 2002	Prospective	Lamivudine for 16 months	154	154 (DC)	78% had very high mortality due to complications of liver failure
Dienstag et al[38], 2003	Prospective	Lamivudine, 3 years	63	11	Cirrhosis regressed in 8 of 11 patients (73%)
Hadziyannis et al[37], 2006	Prospective	Adefovir, up to 240 weeks	125	4	58% had reversal of bridging fibrosis/cirrhosis; 3 had cirrhosis reversal
Schiff et al[39] 2008	Randomized	Entecavir/lamivudine for 48 weeks	1633	245	71% of Entecavir and 61.5% of lamivudine group showed fibrosis regression
Das et al[40], 2010	Retrospective-prospective	Lamivudine/adefovir	151	151 (DC)	Better 5 year survival rate in treated patients for > 6 months
Andersen et al[41], 2011	Prospective	Nucleoside(tide) analogues, 50.5 months	66	53	26 (49%) had regression of cirrhosis
Marcellin et al[9], 2013	Randomized	TDF/adefovir for 48 weeks then open-label TDF	641	96	71 of 96 (74%) became non-cirrhotic at 5 years
Du et al[42], 2013	Prospective	Lamivudine/adefovir for 44.5 months	48	33	23 (69%) patients had reversal of cirrhosis
Srivastava et al[43], 2013	Prospective	TDF 2 years	96	96 (DC)	MELD score of > 20 a/w 58 fold increased mortality
Papatheodoridis et al[16], 2018	Multicenter prospective	TDF/entecavir for 6 years	1951	526	Significant improvement in overall survival
Hsu et al[13] 2021	Randomized	TDF for 3 years	73	00	16%- reduced fibrosis, 58% non- progression
Desalegn et al[44], 2019	Prospective	TDF for 2 years	276	35 (DC)	24 fold increase in mortality if decompensated cirrhosis
Ismael et al[3], 2024	Prospective	TDF	193	35 (DC)	60% of all death occurred due to decompensated liver disease with in first 6 months

HBV: Hepatitis B virus; DC: Decompensated cirrhosis; TDF: Tenofovir disoproxil fumarate; MELD: Model for end-stage liver disease.

A meta-analysis of 17 studies conducted in Africa found that 4%–13% of CHB patients had already developed cirrhosis at diagnosis[14]. However, even in compensated cirrhosis, treatment-induced viral suppression can lead to regression of cirrhosis. A systematic review by Manne et al[15] reported that a median of 70% (range: 33% to 80%) of patients with compensated HBV cirrhosis (n = 463) experienced cirrhosis regression. In a recent multicenter prospective study of 1951 CHB patients with or without cirrhosis receiving entecavir or TDF for six years, the 1-, 5-, and 8-year cumulative probabilities of overall survival were 99.7%,95.9% and 94.1%[16]. Hepatic decompensation typically has poor five-year survival rates of 14%–35%[17]. In a study by Fontana et al[18], 78% of deaths in decompensated cirrhosis patients treated with antiviral drugs occurred within the first six months due to liver complications. Notably, 80% of these patients had a very good virological response, suggesting that survival in decompensated HBV cirrhosis may correlate with HBV replication status in less advanced cirrhosis (Child's B) but not in more advanced cirrhosis (Child's C). In cirrhosis patients, the five-year risks of developing hepatic decompensation and HCC are 20%–23% and 6%–15%, respectively[19,20]. In patients with decompensated HBV cirrhosis, the estimated survival rates on TDF were 75.9%, 72.1%, and 70.1% at 6, 12, and 24 months, respectively, in a cohort study. Conversely, the corresponding survival rates in patients with compensated cirrhosis were 100.0%, 100.0%, and 98.4%. The decompensation of cirrhosis was the strongest predictor of mortality in this cohort, increasing the risk of death 24-fold, even with antiviral therapy[21]. In CHB, the risk of HCC varies significantly by disease stage and treatment status[22]. A retrospective cohort study of 6914 CHB patients revealed an 8-year cumulative HCC incidence of 20.13% in untreated individuals vs 4.69% in those treated with TDF[23]. Additionally, a 384-week follow-up study by Kim et al[11] reported an annual HCC incidence of 0.28% in non-cirrhotic patients and 0.65% in cirrhotic patients[11]. This underscores the importance of early and sustained antiviral therapy in managing CHB to improve long-term liver health outcomes.

A meta-analysis in 2021 estimated that approximately 20% of individuals with HBV infection globally meet the eligibility criteria for antiviral therapy[24]. However, data from the global hepatitis report for 2024 indicate that only 2.6% of individuals living with HBV infection received treatment. The low treatment rate for HBV infection stems from multiple gaps in healthcare systems. Current guidelines rely on categorizing HBV infection into distinct phases in its natural history to guide antiviral treatment decisions. However, many patients in clinical practice may not fit into these predefined phases. In a study by Huang et al[25], 39% of patients in an untreated CHB cohort did not fit into a specific phase. These indeterminate patients had a 14-fold increased risk of HCC compared to those in the inactive phase. The updated WHO 2024 hepatitis B guidelines now extend treatment eligibility to all adults and adolescents (≥ 12 years), increasing the proportion of eligible patients to at least 50%.

HBsAg clearance rate is very low with the current nucleoside/nucleotide analogues (NAs) therapy[26]. Interestingly, some studies have reported that peginterferon (PegIFNα) add-on or switch therapy increases the HBsAg clearance rate for HBeAg-negative CHB patients previously treated with NAs, particularly for those with lower HBsAg levels[27,28]. In one study, NAs-treated HBeAg-negative CHB patients with HBsAg levels < 1500 IU/mL and HBV DNA < 100 IU/mL, PegIFNα-2b add-on therapy achieved HBsAg clearance in 50.93% and HBsAg seroconversion in 48.15% at week 48. Patients with baseline HBsAg < 100 IU/mL achieved the highest HBsAg clearance rate of 60.87% at week 48[28]. Recently, a five-year update of the Everest Project, a multicenter real-world study in China evaluating the efficacy of PegIFNα therapy in NA-suppressed HBeAg-negative CHB patients, was presented at the 33^rd annual meeting of the Asian Pacific Association for the Study of the Liver 2024. A total of 23412 HBeAg-negative patients with HBV DNA < 100 IU/mL and HBsAg ≤ 1500 IU/mL were recruited over five years. The HBsAg loss rates were 22.72%, 28.72%, and 31.43% at 24, 36, and 48 weeks, respectively, according to per-protocol analysis. Factors predicting higher HBsAg loss included lower baseline HBsAg levels, reduced HBsAg levels at 12 and 24 weeks, ALT flare at the 12-week mark, younger age, and female gender. These emerging data may influence future guidelines for CHB treatment, as achieving a functional cure would significantly decrease the risk of cirrhosis or HCC.

SHORTCOMINGS IN THE CARE OF HEPATITIS B

To decrease the global burden of HBV, interrupting mother-to-child transmission is crucial. The currently available vaccine is highly effective, preventing 90%–95% of infections. However, only 45% of newborns receive the birth dose within 24 hours. By the end of 2018, 189 countries had included HBV vaccination in their infant programs[29]. However, in the WHO African region, only 14 of 47 countries had introduced the birth dose by 2021, resulting in an estimated coverage of just 18%. Furthermore, diagnosing CHB can be challenging due to its often asymptomatic nature. The underdiagnosis of CHB is concerning, as it leads to late presentations with cirrhosis and decompensation. In resource-limited settings, public health facilities often lag behind guideline recommendations. Presently, only about 13.4% of those infected have been diagnosed, a figure that is alarmingly lower in sub-Saharan Africa, where awareness of HBV infection status is as low as 1%[1]. Low awareness among the public and healthcare providers exacerbates underdiagnosis, while limited healthcare access and inadequate screening programs further impede early detection, highlighting the multifaceted difficulties in identifying and managing CHB effectively[30].

WHO HEPATITIS B ELIMINATION TARGET 2030

In October 2015, the WHO global health sector strategy on viral hepatitis outlined a plan to eliminate viral hepatitis as a public health problem by 2030, targeting a 90% reduction in incidence and a 65% reduction in mortality from 2015 baseline levels[31,32]. In 2022, the WHO expanded its hepatitis elimination program to include specific absolute targets by 2030. However, despite ongoing efforts, progress toward the 2030 hepatitis B elimination targets has been insufficient. According to 2020 data from the Polaris Observatory, no countries are on track to meet all the targets. Projections suggest that if the issues of underdiagnosis and undertreatment are not addressed, global mortality from hepatitis B will rise by 39%, from 850,300 deaths in 2015 to 1109500 deaths in 2030[13]. Achieving sustainable development goals requires treating an estimated 40 million people with hepatitis B by the end of 2026[1].

THE WAY FORWARD

To overcome the aforementioned challenges and reach the goal of eliminating hepatitis B, we must focus on five key approaches: (1) Enhancing screening services to identify patients; (2) Increasing knowledge and awareness among healthcare and social-service providers, as well as the public, particularly those at risk; (3) Expanding HBV vaccine coverage; (4) Improving viral hepatitis services and access to affordable treatment; and (5) Reducing behaviors related to hepatitis B transmission.

Universal infant vaccination is the cornerstone of strategies to eliminate HBV and is recommended for all countries, regardless of infection prevalence or income status[33]. Prenatal screening for HBV in all pregnant women is essential. Mothers who test positive for HBsAg and have serum HBV DNA levels exceeding 200000 IU/mL should receive antiviral therapy in the third trimester to prevent immunoprophylaxis failure. In resource-limited settings, point-of-care tests such as HBsAg and HBeAg can serve as alternatives to HBV DNA quantification for initiating antiviral prophylaxis[34]. Enhancing access to birth centers for pregnant women can facilitate the administration of the HBV vaccine birth dose within the first 24 hours. Emerging data support universal screening and catch-up vaccination for susceptible adults, indicating that this strategy is likely cost-effective in reducing HBV-related morbidity and mortality. However, further evidence is needed to determine whether catch-up vaccination is a resource-efficient approach, particularly in low-income countries[35]. Alongside vaccination, administering antiviral treatment to patients at risk of spreading HBV can help protect susceptible individuals from infection. This 'treatment as prevention' approach could be particularly effective in curbing HBV transmission in regions with high endemicity, where both active and past infections are common[36]. Integrating screening programs with medical care is essential for identifying undiagnosed patients and motivating them to pursue treatment.

CONCLUSION

Controlling HBV infection is a critical global health priority that demands a comprehensive and multifaceted strategy, including enhanced screening, diagnosis, and treatment efforts. Currently, only about 13% of the individuals infected with this disease have been diagnosed, and only 2.6% have received treatment. CHB is not only preventable but also treatable, with excellent outcomes achievable through the timely initiation of therapy[9,37-42]. Diagnosing HBV at advanced stages of liver disease is concerning, as it leads to poor outcomes[3,18,43,44]. There is an unmet need to deliver high-quality health services for hepatitis B care. Important approaches may include enhancing screening services to identify patients, increasing public awareness about HBV, decentralizing testing and treatment services to primary health facilities to improve access, promoting adherence to long-term antiviral therapy, and fostering community engagement to enhance care delivery and support for patients. Collectively, these strategies can improve the detection and treatment of hepatitis B, ensuring comprehensive and accessible care for all affected individuals.