HBV “Viral Elimination” in the Asia-Pacific region: Current status and challenges

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CURRENT SCENARIO

In the combat against HBV infection, which is endemic in the Asia-Pacific region, we now have universal vaccination to prevent new infection and possess effective antiviral therapy to reduce the risk of developing liver-related morbidity and mortality (acute-on-chronic liver failure, end-stage liver cirrhosis, and HCC) in those patients with chronic hepatitis B (CHB) infection. Cost-effective surveillance using ultrasound with and without alfa-fetoprotein (AFP) in patients with high-risk CHB, for detection of early HCC to enable curative surgical intervention, has also been well established.^1–4 In keeping with this, in 2016, the World Health Assembly approved the World Health Organisation (WHO) Global Health Sector Strategy on HBV, with a goal of “elimination of HBV as a major health threat” by 2030, targeting a 90% reduction in new HBV infection and a 65% reduction in mortality due to HBV.⁵ An update in 2021 further proposed an absolute target of 0.1% or lower for HBV prevalence in children aged 5 years or younger and an annual mortality rate of up to 4 per 100,000.⁶ However, recent data suggested deviation from these goals, with over 890,000 new HBV cases in 2019–2020 and a global HBV-related mortality rate exhibiting minimal change (annualized rate of change < 0.4% between 2015 and 2019⁷).

REDUCING HBV DISEASE BURDEN BESIDES “VIRAL ELIMINATION” SHOULD ALSO BE OUR PRIORITY CONCERN

According to Global Burden of Disease 2019 data,⁷ two-thirds of the HBV-related mortality occurred in Southeast Asia and Western Pacific regions (Table 1). In our opinion, the goal to achieve HBV “viral elimination” in the foreseeable future may be challenged. Instead, viral reduction should be an alternative practical approach to curtail the disease burden related to HBV infection. Universal vaccination for newborns to interrupt perinatal infection, implemented in the late 80s, significantly reduced the prevalence of HBsAg positivity in HBV-endemic regions. The recent addition of tenofovir dipovoxil at 24 weeks of gestation in high-viremia, HBsAg-positive and HBeAg-positive mothers further reduced the risk of mother-to-child HBV transmission without adverse events.⁸ These policies contributed to a one-third decline in all-age prevalence of HBsAg between 1990 and 2019, with a more marked decline of nearly 80% in prevalence in children younger than 5 years (Table 2). Counterfactual estimation suggested that, without universal vaccination, global HBsAg prevalence in 2019 would have been around 5%, suggesting that 85 million cases were prevented.⁷

TABLE 1.

Death counts due to HBV, all ages in 1990, 2015, and 2019, by WHO regions

	1990		2015		2019
Region	Number	%	Number	%	Number	%
Western Pacific region	266,000	50.8	192,000	35.6	206,000	37.1
South-East Asia region	110,000	21.0	172,000	31.9	169,000	30.5
Other regions	146,200	27.9	174,200	32.3	178,900	32.2
Global	524,000	—	540,000	—	555,000	—

Note: Adapted and recalculated from GBD Hepatitis B Collaborators. Global, regional, and national burden of hepatitis B, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Gastroenterol Hepatol. Sep 2022;7(9):796-829⁷ under CC-BY https://creativecommons.org/licenses/by/4.0/.

Abbreviations: GBD, Global Burden of Disease; WHO, World Health Organisation.

TABLE 2.

HBsAg prevalence (%) in all ages and children younger than 5 years in 1990, 2015, and 2019, by WHO regions

	All ages			Reduction
Region	1990, %	2015, %	2019, %	1990–2015, %	2015–2019, %	1990–2019, %
Western Pacific region	10.8	7.7	7.1	28.7	7.8	34.3
South-East Asia region	4.0	3.2	3.1	20.0	3.1	22.5
Global	6.0	4.4	4.1	26.7	6.8	31.7
	Children < 5 years			Reduction
	1990	2015	2019	1990–2015	2015–2019	1990–2019
Western Pacific region	8.3	1.0	0.5	88.0	50.0	94.0
South-East Asia region	2.4	0.6	0.5	75.0	16.7	79.2
Global	4.4	1.2	1.0	72.7	16.7	77.3

Notes: Adapted and recalculated from GBD Hepatitis B Collaborators. Global, regional, and national burden of hepatitis B, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Gastroenterol Hepatol. Sep 2022;7(9):796-829⁷ under CC-BY https://creativecommons.org/licenses/by/4.0/.

Abbreviation: WHO, World Health Organisation.

For the existing CHB patients, the term “viral elimination” is misleading, as HBV is integrated into the host chromosome and intrahepatic cccDNA persists even in patients with CHB with loss of HBsAg and undetectable serum HBV DNA, referred to as a “functional cure.” This is evidenced by the occurrence of hepatitis, hepatic failure, and death due to HBV reactivation in those patients who are HBsAg-negative with past HBV infection when intense immunosuppressive therapy was administered.⁹ As such, a reduction of viral burden in existing patients (by early treatment) should be considered as the major strategy to curb new infections. By contrast, the reduction of HBV disease burden will be facilitated by the appropriate use of effective antiviral therapy, namely high resistant barrier nucleos(t)ide analogs (NAs including tenofovir, entecavir, tenofovir alafenamide) or pegylated interferon or both, which have all been demonstrated to enable a drastic reduction in HBV-related morbidity and mortality with long-term follow-up.^1–4 Thus, the reduction of HBV disease burden besides “viral elimination” should also be strengthened.

MAJOR BARRIERS TO WHO 2030 GOAL OF “VIRAL ELIMINATION “IN THE ASIA-PACIFIC REGION

In real-world clinical practice, 2 major barriers hinder a significant reduction of disease burden due to HBV infection: lack of awareness (among public and policymakers) and under-treatment of those with a risk of developing complications related to HBV infection. It is a great concern to witness the diagnoses of CHB made only when complication has arisen in clinical settings. This is exemplified by the late presentation of HBV-related HCC (usually at an advanced stage when curative surgical resection or ablation could not be performed), as indicated by the high mortality-incidence ratio in places like Hong Kong SAR, China (Table 3).¹⁰ In the Asia-Pacific region, it has been observed that up to half of the patients with CHB diagnosed with HCC were not aware of their HBsAg status, and very few had received any antiviral therapy or regular interval HCC surveillance.^11,12 This clinical scenario did not change significantly over the past 2 decades. Not infrequently, patients with CHB also suffered from acute-on-chronic liver failure due to HBV reactivation during immunosuppressive therapy without concomitant use of pre-emptive NAs.⁹ This reflects the inadequacy of screening and significant under-treatment of patients with CHB.

TABLE 3.

Mortality-to-incidence ratio by age and gender from 2001 to 2019

	ASR mortality		ASR incidence		MIR
Year	Male	Female	Male	Female	Male	Female
2001	26.8	7.8	32.8	7.4	0.82	1.05
2002	26.5	5.9	30.0	7.4	0.88	0.80
2003	25.6	6.8	30.3	8.2	0.84	0.83
2004	24.7	6.6	29.6	7.8	0.83	0.85
2005	24.8	7.2	29.9	8.3	0.83	0.87
2006	23.4	6.8	29.3	8.0	0.80	0.85
2007	23.1	5.9	27.9	7.1	0.83	0.83
2008	22.9	6.3	27.4	7.6	0.84	0.83
2009	21.2	6.7	27.9	7.7	0.76	0.87
2010	21.2	6.5	27.2	8.1	0.78	0.80
2011	21.3	5.9	26.8	7.5	0.79	0.79
2012	18.9	6.5	25.1	6.6	0.75	0.98
2013	19.4	5.6	25.4	6.9	0.76	0.81
2014	19.5	5.7	23.9	6.9	0.82	0.83
2015	18.5	5.4	22.7	6.2	0.81	0.87
2016	18.0	4.9	23.0	5.7	0.78	0.86
2017	17.3	4.9	22.8	5.6	0.76	0.88
2018	16.0	4.5	21.0	5.0	0.76	0.90
2019	16.2	4.1	21.7	5.1	0.75	0.80
2020	15.3	4.4	18.2	5.6	0.84	0.79
Average	20.7	5.8	25.7	6.7	0.81	0.87

Notes: Adapted and recalculated from Surveillance of viral hepatitis in Hong Kong—2021 report. Hong Kong: Department of Health; 2022.¹⁰

ASR (per 100,000 population).

MIR = ASR mortality / ASR incidence.

Abbreviations: ASR, age-standardized rate; MIR, mortality-to-incidence ratio.

Though diagnostic testing for HBV infection has been available since the early 1970s, none of the countries in the Asia-Pacific region, where HBV is endemic, provide universal screening of HBsAg to the public. With the recent availability of low-cost rapid diagnostic tests for HBsAg with negligible false-negative results,¹³ which can be utilized for large-scale screening and diagnosis of HBV infection, only an estimated 15%–30% of chronic HBV infections have been diagnosed.^1,4 Detection of HBsAg in asymptomatic subjects usually relies on institutional recruitment, insurance-supported services, or ad hoc community campaigns. To further decrease global viral and disease burden, it is of paramount importance to identify all patients with CHB infection and timely initiate effective antiviral therapy for them. In the meantime, increasing public awareness to access hepatitis B tests plays a pivotal role in the early detection of hepatitis B and timely linkage to treatment.

In accordance with the existing regional treatment guidelines, it was estimated that less than one-tenth of those patients with CHB indicated for treatment received anti-HBV therapy. There is a recent call to expand treatment criteria beyond existing guidelines to extend therapeutic benefits to more patients with CHB infection. To date, all major regional liver society guidelines identify serum alanine aminotransferase (ALT) as the key indicator for initiating antiviral treatment, but with varying threshold values. The American Association for the Study of Liver Diseases (AASLD) suggests > 2 × upper limit of normal value (35 and 25 U/L for male and female patients)⁴ while WHO recommends >1 × upper limit of normal value (30 and 19 U/L for male and female patients).¹⁴ The Asian Pacific Association for the Study of the Liver (APASL),³ European Association for the Study of the Liver (EASL),² and Chinese Guidelines for the Prevention and Treatment of CHB¹⁵ recommend a 40 U/L ALT cutoff for both male and female patients. All these guidelines also use a HBV DNA cutoff (usually > 2000 IU/mL) to decide treatment candidacy. The Chinese guidelines, however, consider any HBV DNA positivity (with the exclusion of other causes of ALT elevation and certain subgroups of patients with even normal ALT) as candidates for antiviral therapy.¹⁵ Yet, the current ALT threshold with 40 U/L proves an unsuitable indicator for antiviral treatment initiation in HBV-infected patients, as a considerable proportion of them with such levels are noted to have a high degree of liver inflammation and fibrosis, posing an elevated risk for cirrhosis and HCC.¹⁶ Also, patients may develop HCC even when they remain outside the current treatment guidelines.¹⁷ A cost-effectiveness analysis of expanded antiviral treatment for CHB infection, based on decision-tree Markov state-transition model, suggested expanding treatment to HBV-infected patients with ALT thresholds of 30 U/L and 19 U/L for males and females, with 80% treatment coverage for HBsAg-positive individuals aged 18–80 years.¹⁸ This expanded antiviral treatment with a modified ALT threshold, coupled with lower generic drug costs and a revised medical insurance subsidization policy, particularly in HBV-endemic countries like China, could reduce HBV-related complications and deaths to support the global target of 65% reduction in HBV-related death. With the recent surge of prevalence and emerging association of Metabolic dysfunction–associated fatty liver disease as a co-morbidity factor for CHB patients, future treatment guidelines likely need to be modified accordingly¹⁹ (Figure 1).

FIGURE 1.

Proposed strategy for elimination of HBV disease burden. Universal screening for HBsAg positivity with rapid test followed by linkage to care with expanded antiviral treatment criteria. The implementation of this strategy should be evaluated by hard end point including age-standardized mortality and incidence rate of liver cancer. Abbreviation, ALT, alanine aminotransferase.

EARLY TREATMENT OF YOUNGER CHILDREN WITH CHB PROMOTES THE FUNCTIONAL CURE OF THE DISEASE

Active HBV replication in pediatric patients can lead to cirrhosis or HCC, complicating disease resolution in adulthood.²⁰ Guidelines recommend initiating antiviral treatment during the immune clearance phase in children with CHB for better outcomes.²¹ However, over half of the pediatric patients with early HBV infection are in the immune tolerance (IT) phase, considered a “quiescent disease.” Despite conservative recommendations for IT-CHB patients, studies show they are also at risk of progressing to end-stage liver disease.²² Research suggests that children with IT-CHB, especially younger ones, can achieve a functional cure with antiviral treatment.²³ Comprehensive assessments for children with CHB in the IT phase, particularly in younger age groups, are vital for informed clinical decisions.

CONCLUDING REMARKS

In future, the availability of more robust data is essential to formulate effective policies to tackle the heavy disease burden related to HBV in the Asia-Pacific region. As clinicians, health care providers, and public health professionals, we recognize that disease burden might not be accurately reflected by HBsAg prevalence alone, as it varies with the sampled population. For example, in Hong Kong, the HBsAg-positive rate is recently estimated to be 0.9% in blood donors and 1.8% in police workers,¹⁰ but 9.2% in a random households screening.²⁴ Other outcome measures for disease burden, such as end-staged cirrhosis and acute-on-chronic liver failure, are affected by the reporting system in different geographical regions. A better measure of the disease burden related to HBV is probably the age-standardized incidence and mortality related to liver cancer, predominantly associated with CHB, in the cancer registry. Mortality due to liver cancer, often better recorded than incidence, can provide a more accurate estimate of disease burden changes over time in HBV-endemic areas like Hong Kong and mainland China. It will allow one to understand whether the existing measures are adequate to reduce the disease burden. We believe that a collaborative effort of all authoritative liver societies to revise and expand HBV treatment guidelines considering the drastically reduced cost of antiviral therapy, along with universal screening for HBsAg positivity, will contribute to a meaningful reduction in disease burden due to HBV infection in the Asia-Pacific region.