Scientific and Medical Evidence Informing Expansion of HBV Treatment Guidelines

Abstract

Chronic Hepatitis B treatment relies on nucleos(t)ide analog (NA) drugs that suppress hepatitis B virus (HBV) replication, normalize liver enzymes, and slow disease progression with excellent safety. Treatment is not curative, and patients remain at risk of cirrhosis and hepatocellular carcinoma. Treatment guidelines have limited antiviral therapy to individuals with high HBV DNA and elevated liver enzymes or hepatic fibrosis, often requiring longitudinal testing that can be of limited availability in resource-limited settings. Consequently, <3% of people living with HBV infection are receiving antiviral therapy. Guidelines from China and the World Health Organization recently broadened access to NA therapy, but they still do not cover many people who could benefit from NA therapy. Simplifying the guidelines or adopting a “test-and-treat” approach may be superior to current practice. We present the benefits and risks of expanded NA treatment and conclude that the benefits to expanding treatment options greatly outweigh the risks because the pathological process induced by HBV infection are active in individuals outside the treatment guidelines.

Introduction

Chronic hepatitis B (CHB) is a persistent necroinflammatory liver disease caused by chronic hepatitis B virus (HBV) infection. The World Health Organization (WHO) estimated 254 million people were living with CHB infection in 2022, leading to 1.1 million deaths annually from cirrhosis and hepatocellular carcinoma (HCC).¹ CHB is the leading cause of primary liver cancer, leading to ~350,000 HCC deaths yearly, and this number is projected to more than double by 2040.² This underscores the urgent need to address CHB with both existing and novel therapies.

This review commissioned by the International Coalition to Eliminate HBV (ICE-HBV) explores the scientific and medical rationales for expanding antiviral therapy to people living with hepatitis B (PLWHB) who are excluded by current international guidelines. Evidence underlying the patient and public health perspectives on expanding the treatment guidelines is addressed in a companion paper also commissioned by ICE-HBV (reference to be added when available). For the purposes of this review, we define earlier/expanded treatment as: All people living with chronic hepatitis B with any detectable hepatitis B viral DNA in the blood should be considered eligible for treatment with currently available therapeutics, if any one of the following criteria is met: they request treatment, they have a family history of cirrhosis or HCC, they are older than 30 years of age, they have evidence of liver inflammation or liver damage, or they have co-morbidities or other risk factors that support treatment. This definition is not intended to supersede professional medical society or organizational guidelines, but is intended for use in the context of evaluating data, is supported by scientific evidence and expert opinion, and reflects the voices and experiences of PLWHB.³.

We propose that broadening access to the existing front-line nucleo(s)tide analog (NA) drugs and initiating treatment earlier could simplify treatment and significantly reduce CHB-related morbidity and mortality. Whether viewed as “treatment as prevention” or a bridge to a functional cure, this shift in CHB management could help reduce the severe complications associated with CHB and also ease the development of new curative treatments.

Natural history of CHB

Traditionally, CHB has been classified into four disease phases (Figure 1), with treatment reserved for specific phases only. In the first phase, previously termed “immune-tolerant”, but more recently designated hepatitis B e antigen (HBeAg)-positive chronic infection, HBV is usually acquired perinatally or before the age of four and is characterised by high levels of HBV DNA with minimal liver inflammation.⁴ The transition from the HBeAg-positive chronic infection phase is not well understood, but elevation of liver enzymes above the local upper limit of normal (ULN) and reduced viral load are linked to activation of immune responses. The HBeAg-positive chronic hepatitis phase is characterised by overt liver inflammation, which may lead to HBeAg seroconversion and the development of anti-HBe antibodies. During this transition, liver fibrosis can develop, depending on the duration of HBeAg seroconversion and the extent of immune-mediated liver damage. Normalization of liver enzymes and a significant decline in HBV DNA (<2,000 IU/mL), a phase referred to as HBeAg-negative chronic infection, previously known as “inactive carriage”, is believed to mark the end of most immune-mediated liver injury. However, viral escape and the emergence of HBeAg-negative chronic hepatitis signal a new phase of immune-mediated liver damage, associated with more aggressive disease and increased risk of liver fibrosis, cirrhosis, and HCC.^5,6 Indeterminate disease phase refers to PLWHB who fall outside these clinical categorisations, but more often this reflects the dynamic nature of CHB and the limitations of these definitions. Natural history data of CHB are mainly from Asian and Western studies, and little data have been collected in low- and middle-income countries (LMIC), especially in Africa.

Figure 1.

HBV disease phases and presence of key HBV markers in each phase.

Current treatment paradigms

Current preferred oral antiviral therapies are the NAs entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). They reduce viremia to undetectable levels in commercial assays and normalize liver enzymes in most patients, but rarely clear the infection. They have exceptionally low rates of resistance and good safety profiles, and patients on these NAs generally maintain high adherence rates.^4,7 Importantly, long-term NA therapy significantly decreases the risk of HCC and mortality and improves the quality of life for PLWHB.^4,8 NA treatment is available worldwide, and both ETV and TDF are generic and relatively low-cost in many regions. Expanding treatment would not eliminate the need for ongoing monitoring for liver decompensation and HCC, but costs of treating complications from CHB would decline due to their reduced frequency. The effects of expanded treatment on medical costs and quality of life are addressed in the companion paper (reference to be added when available). Thus, NAs provide beneficial management of CHB despite not being curative.

Current American, European, and APASL guidelines require HBV DNA levels >2000 IU/mL and elevated ALT above the local ULN, or evidence of ≥F2 fibrosis for NA treatment eligibility (Table 1).^4,9,10 Accurately defining ≥F2 fibrosis can be challenging with non-invasive tests, but the WHO recently provided a benchmark for this; median liver stiffness >7kPa or APRI >0.5; while these cut-offs are relatively novel, they ensure a low bar is set for treatment initiation. Notwithstanding, these guidelines still require detailed laboratory testing and can be considered complex and restrictive, with the result that they limit access for many patients.

Table 1.

Key criteria for initiating NA treatment for CHB ¹

Panel 1: EASL, AASLD and APASL
HBV DNA>2000 IU/mL
ALT > local ULN
or
Fibrosis ≥ 2
Panel 2: China 2022
Detectable HBV DNA
Elevated transaminases
If normal transaminases, then one or more of:
Family history of cirrhosis
Family history of HCC
Age >30
Fibrosis ≥ 2
Extrahepatic HBV manifestations
Panel 3: WHO 2024
Option 1
Fibrosis ≥ 2
Option 2
HBV DNA>2000 IU/mL
ALT > local ULN
Option 3
One or more of:
Co-infections
Family history of cirrhosis, HCC
Immune suppression
Co-morbidities such as diabetes, metabolic dysfunction associated steatotic liver disease
Extrahepatic HBV manifestations
Option 4 (When DNA testing is unavailable)
ALT persistently above local UNL
Positive HBsAg

¹Extrahepatic HBV manifestations: mixed cryoglobulinemia vasculitis, serum sickness-like syndrome, rheumatoid arthritis, non-rheumatoid arthritis, panarteritis nodosa, glomerulonephropathies, non-Hodgkins lymphoma.

The 2022 Chinese guidelines sought to simplify this process (Table 1).¹¹ They lower the threshold for antiviral therapy initiation by requiring only detectable HBV DNA and elevated alanine transaminase (ALT) levels as the primary criteria for treatment decisions. If ALT levels are normal, antiviral therapy may be initiated if one of the following criteria is met: a family history of cirrhosis or HCC, age >30 years, liver fibrosis ≥F2, or extra-hepatic manifestations of HBV. The new Chinese guidelines still require HBV DNA testing, liver transaminase measurements, and non-invasive markers of fibrosis. This mirrors older guidelines, making them costly and logistically challenging, especially in LMIC. The need for referral, testing, and follow-up before considering therapy complicates the cascade of care (Figure 2). Unlike HCV’s successful point-of-care “test-and-treat” strategy, HBV still relies on a “test-and-refer” model with complex evaluation and treatment processes that are difficult to follow in most resource-limited settings.

Figure 2.

HBV cascade of care with approximate numbers of people at key steps. The icons are from FreePiK.

The 2024 WHO Hepatitis B guidelines also expand treatment and enable simplification by providing four options to initiate therapy (Table 1), (i) Liver fibrosis ≥F2 regardless of HBV DNA or ALT levels; (ii) HBV DNA >2000 IU/mL and ALT>ULN; (iii) Presence of co-infection, family history of cirrhosis or HCC, immune suppression, co-morbidities (diabetes, metabolic dysfunction associated steatotic liver disease) or extrahepatic manifestations; and (iv) ALT levels persistently above the local ULN and positive HBsAg when HBV DNA testing is unavailable.^12,13 Where none of these treatment indications are present, disease monitoring is recommended for those individuals with normal ALT and HBV DNA <2000 IU/mL. This approach balances existing evidence and guideline simplification through bypassing the need for HBV DNA testing in some cases. Consequently, the new WHO guidelines maintain the well-established HBV DNA thresholds >2000 IU/mL and ALT above the local ULN but allow alternate scenarios where HBV DNA testing is unavailable. This reduces barriers to applying the guidelines in resource-limited settings, potentially increasing access to therapy.

Effects of the HBV treatment paradigm on hepatitis elimination goals

The WHO’s Global Health Sector Strategy has defined international goals of viral hepatitis elimination by 2030, targeting reductions in hepatitis-related deaths by 65% and incidence of new hepatitis infections by 90%.¹⁴ The Southeast Asia, West Pacific, and African regions are home to most PLWHB, so the HBV epidemic in these regions provides insight into the effectiveness of the treatment guidelines and their effects on the cascade of care for CHB patients (Figure 2).¹⁵ The WHO data for 2022 reveal that diagnosis of HBV is only 13.4% globally, 25.5% in the West Pacific, 4.2% in Africa, and 2.8% in Southeast Asian regions.¹ Worldwide, only 19.5% of people diagnosed with HBV receive treatment, yielding a net treatment rate of 2.6%.¹ These sobering statistics highlight the unlikeliness of most countries achieving the WHO targets by 2030.

There are four significant barriers to the cascade of care for CHB. First, 87% of PLWHB are not diagnosed.¹ Treating all PLWHB diagnosed with the infection would increase the number of people receiving treatment from 6.6 to 34 million globally, but this is still far short of addressing the current disease burden. Therefore, a large expansion of routine HBsAg screening will be essential to improving care for PLWHB regardless of whether the guidelines are expanded. Second, implementing the current treatment guidelines outside of specialized clinics is challenging because it requires multiple visits to medical facilities and laboratory testing not readily available in many LMICs. Third, centralization of care is an important barrier for millions of people living in many rural areas. Finally, restricting treatment to individuals with high HBV DNA and elevated liver enzymes sharply reduces the number of PLWHB eligible for NA treatment, and also necessitates long-term monitoring of patients and multiple steps to obtain care.

In conclusion, the expanded Chinese and WHO treatment guidelines are a positive step in expanding the pool of PLWHB eligible for NA treatment, but the requirement for HBV DNA testing in most cases complicates implementation and does little to improve the cascade of care. Expanding HBV testing programs is clearly essential to reducing the disease burden from CHB. In addition, consideration should be given to the radical strategy of treating all PLWHB to simplify care and expand treatment rates. The risks and benefits of this approach should be examined through detailed modeling studies.

Shortcomings of the major treatment guidelines in limiting disease progression

The primary aim of antiviral treatment for PLWHB is to mitigate risk of liver disease progression, including HCC development. The risk of developing HCC occurs over long periods of time, complicating how we define PLWHB who could benefit from NAs. For instance, in a prospective observational study of 1192 patients with untreated HBeAg-negative CHB and low HBV DNA levels (mean baseline HBV DNA <10⁴ IU/mL), HBV DNA level correlated with disease progression, but overall disease progression was minimal after seven years, with no changes in fibrosis or HCC incidence.¹⁶ This highlights the difficulty of formally demonstrating the long-term benefits of NA treatment because obtaining such data is often unfeasible for ethical and logistical reasons.

In contrast, several studies have reported significant disease progression in low viraemic patients with essentially normal liver enzymes, HBeAg-negative chronic infection, a phase typically excluded from treatment consideration by society guidelines. One such study noted an HCC incidence of 5% over a mean follow-up of 63 months among 337 treatment-naïve HBeAg-negative chronic infection patients.¹⁷ Another analysis involving 7977 patients in the same disease phase reported that annual cirrhosis and HCC incidence ranged from 0.3–1.3% and 0.04–3.8%, respectively.¹⁸ A study of 1014 untreated HBeAg-negative chronic infection patients observed liver cancer development in 1.1%, over a median follow-up of 42 months. Notably, HCC occurred in 7.7% of the treated patients in the same study, raising questions about the timing of treatment initiation.¹⁹ A recent study found that among treatment-naïve PLWHB who developed HCC, a significant proportion were outside the treatment recommendations of the major liver associations: 64% (APASL), 46% (AASLD), and 34% (EASL).²⁰ A U.S. study following 369 CHB patients over 84 months found 30 who developed HCC and 37 who died of non-HCC liver-related causes. Under existing guidelines, only 20–60% of those who developed HCC and 27–70% of those who died from non-HCC liver conditions would have qualified for antiviral therapy.²¹ Finally, a recent interim analysis of the ATTENTION controlled trial comparing TAF treatment to observation in 734 adults with HBV DNA > 10,000 IU without cirrhosis and with normal or slightly elevated ALT levels was just released. It revealed a significant reduction in a composite endpoint comprised of HCC, death, hepatic decompensation, or liver transplantation in the TAF treatment group.²² Although we acknowledge the limitations of these data, especially the lack of data from LMIC, there is growing consensus that the current treatment paradigm is not serving PLWHB adequately.

HBV replication drives pathogenesis

HBV replicates by reverse transcription in hepatocytes, yielding partially double-stranded DNA that can either be secreted as infectious virions or be transferred intracellularly to the nucleus, where it is converted to the episomal covalently closed circular DNA (cccDNA) that templates viral transcription. Reverse transcription failures yield a duplex linear DNA about 10% of the time. This linear DNA can be randomly inserted into the cellular chromosome, with recombination between the HBV and cellular DNA often occurring very soon after a cell is infected.²³

HBV is non-cytopathic, so CHB stems from inflammation and T cell-mediated hepatocyte killing that is triggered by expression of HBV antigens in hepatocytes.²⁴ Persistent inflammation causes progressive fibrosis, leading in many cases to cirrhosis. Inflammation contributes to HCC development by inducing a mutagenic environment in hepatocytes. HCC is also promoted by the HBV integrants in the cellular genome which accumulate during viral replication and can alter local gene expression, disrupt cancer-associated genes, and promote chromosomal translocations, and which may express the tumor promoting protein HBx.^25,26

NA-based therapies block HBV DNA elongation, which reduces intrahepatic replication intermediates and infectious virions in serum. Benefits from suppressing replication include: i) Limiting infection of new hepatocytes; ii) Reducing over time cccDNA levels and its transcriptional activity; iii) Decreasing new HBV DNA integrations into the host genome by reducing infection of new hepatocytes; iv) Decreasing over time the number of hepatocytes carrying integrated HBV sequences and the number of transcriptionally active integrants, and v) reducing pathogenic intrahepatic inflammation that is a driver of both cirrhosis and HCC development.

NAs reduce infection of new hepatocytes

NA treatment reduces viremia and hence de novo infection events. This was demonstrated experimentally in mice with humanised livers where ETV treatment administered during the spreading phase of the virus blocked the increase of infected, HBcAg+ hepatocytes.²⁷ NA treatment in people with HBeAg-positive or -negative chronic hepatitis was associated with reductions in HBcAg+ cells.²⁸ Intrahepatic levels of HBcAg+ cells correlated with biomarkers indicative of cccDNA such as HBcrAg and circulating HBV RNA, indicating that HBcAg serves as a marker for cccDNA-based infection. This data implies that NA treatment limited the spread and infection of new hepatocytes.

NAs moderately reduce HBV cccDNA and its ability to support viral infection

Although NAs do not directly target the HBV cccDNA transcriptional template, blocking reverse transcription reduces viremia and suppresses maintenance of the nuclear cccDNA pool. Preclinical data suggests that cccDNA is lost both by cell death, with cell death reflected by elevated serum liver enzymes, and during mitosis triggered by compensatory hepatic proliferation.^29,30 The combined effects of suppressing cccDNA replenishment and the reduced hepatocyte turnover during NA therapy resulting in less cccDNA loss are variable among patients, but the balance favors a reduction of the cccDNA pool over time. Indeed, the clinical evidence for NAs reducing the size of the nuclear HBV DNA reservoir in patients is clear.^31,32 Reductions of intra-hepatic cccDNA copy numbers range from 1.0 log₁₀ after 48 weeks to 2.3 log₁₀ after 10 years of NA treatment.^31–34 This is accompanied by reduced numbers of hepatocytes carrying cccDNA, decreased cccDNA transcriptional activity, and increased transcriptionally inactive cccDNA.^35,36 The benefits of these effects for patients will likely increase with the longer treatment duration that would accompany expanded NA treatment for PLWHB.

NAs reduce pathogenic inflammation events that occur throughout the course of CHB

The principal characteristics defining anti-viral immunity in HBV infection are the lack of robust innate immune responses and progressive deficiencies within virus-specific humoral and cellular adaptive immunity in PLWHB. These characteristics can change over time since the immune system changes with age, with changes continuing into adulthood in the form of progressive emergence of systemic low-grade chronic inflammation, alongside a progressive decline in functionality of the immune response. These changes have direct implications for earlier treatment of PLWHB that would accompany expanding the guidelines.³⁷

These age-related changes in the immune system can explain the traditional immune tolerant and immune active phases of CHB (Figure 1), where HBeAg and ALT values exhibit more pronounced alterations in adults compared to children and adolescents.³⁸ However, young individuals with HBeAg-positive chronic infection are not devoid of HBV-specific T cells despite their normal ALT levels. In fact, they exhibit comparatively stronger HBV-specific T cell responses than adult HBeAg-positive chronic hepatitis patients.³⁹

These age-related changes are unsurprising because the naïve T cell repertoire declines and highly differentiated memory T cells with dysregulated properties accumulate with age.⁴⁰ They also demonstrate that ALT cannot be considered as a marker for the presence/absence of HBV-specific immunity in CHB or as a “green light” for initiation of antiviral therapy.

Lysis of HBV-infected hepatocytes by HBV-specific CD8 T cells causes ALT elevations. However, chronic lysis of hepatocytes in adults with CHB primarily results from the activation of non-HBV-specific CD8 T cells, triggering sustained inflammation characterized by recruitment of neutrophils and monocytes.^41,42 Indeed, in CHB patients, the frequency of intrahepatic HBV-specific CD8 T cells is independent of the ALT values and is higher in CHB patients with normal ALT.⁴³

The persistence of hepatic inflammation has additional consequences on HBV immunity. Hepatocyte damage releases amino acid degrading enzymes that indirectly curtail CD8 T cell function.⁴⁴ Inflammatory processes also augment the presence of T regulatory cells (or myeloid suppressor cells, while elevating expression of PD-L1 on hepatocytes and myeloid cells.^5,45,46 Myeloid cells under inflammatory conditions increase production of prostaglandins, a mediator of “liver tolerance” further fostering a liver environment that dampens HBV-specific T cell function.⁴⁷ Sustained liver inflammation also triggers liver fibrosis, which hinders CD8 T cells from reaching infected hepatocytes.⁴⁸

Thus, chronic immune inflammation in the liver directly drives immunopathology, and age-related immune system changes have a profound impact on the immunological profile of CHB patients. NAs decrease cytolysis and liver inflammation, so broadening treatment guidelines to bring more people onto therapy earlier would reduce the steady accumulation of liver damage that characterizes CHB.^4,49 Similarly, an early reduction of HBV replication through NA treatment initiated irrespective of ALT values might prophylactically avoid triggering intrahepatic inflammatory events that make the liver microenvironment less suitable for efficient anti-HBV immune responses and result in better control of HBV replication.

NAs reduce HBV DNA integration

Most HCC tumors carry multiple HBV chromosomal integrations stemming from microhomology-mediated end joining recombination between duplex linear forms of HBV DNA produced by reverse transcription and chromosomal DNA.²⁶ The primary integration sites in the human genome are random, but integrations at a number of chromosomal locations can be selected for during the cellular expansion associated with oncogenesis. The number of tumor integrations correlates with patient mortality, and strong clinical evidence indicates that NA treatment reduces long-term risk of developing an HCC.^26,50

Moreover, clones in the non-tumor tissue carrying integrations are linked to pre-neoplastic lesions.⁵¹ HBV integrations increase over the course of infection through new integrations occurring with new infection events and through clonal expansion of hepatocytes carrying integrations. Indeed, the number of integrations correlates with viral load in HBeAg-negative patients.⁵² This may explain the linear relationship between baseline serum HBV DNA levels and HCC risk, including in treatment-naïve PLWHB with even moderate HBV DNA levels (6–7 log₁₀ IU/mL) who may still face a considerable risk of developing HCC.^53–55

Long-term NA administration has been found to reduce the number and the size of clonally expanded populations of cells that can be traced via analysis of unique integrants in lineages of cells and the number of transcriptionally active viral integrations in CHB patients, presumably in part because integrations are lost as older cells carrying a heavier burden of integrants die.^34,56 Therefore, NA treatment exerts a double protective effect on HCC development by indirectly reducing the oncogenic effects of chronic hepatic inflammation and by suppressing HBV DNA integration.

Risks from long-term NA therapy

Expanded initiation of HBV therapy carries four main risks. First, although ETV, TAF, and TDF are well tolerated, side effects can appear in a minority of patients. These include kidney tubular cell damage with TDF in up to 5% of patients and losses in bone density averaging 2.5% in patients treated with TDF that are absent with TAF, and rare cases of lactic acidosis with ETV that typically resolve upon drug withdrawal.^57,58 Shifting from TDF to ETV or TAF or from ETV to TDF or TAF usually ameliorates these side effects.⁵⁸

Second, patients with high viral loads may be incompletely virally suppressed and run the risk of developing drug-resistant mutants during extended treatment. This risk is negligible for TDF and TAF but five years of treatment with ETV can lead to 0.9% resistance in treatment-naive patients and up to 20% in treatment-experienced patients.^59–62 (Resistance can usually be managed by shifting from ETV to TDF or TAF.

The third risk is over-treatment if benefits to the patients are low. Studies treating individuals with HBeAg-positive chronic infection, who have better preserved immune responses showed low response rates based on HBeAg seroconversion and HBsAg los.^63,64 Studies of antiviral therapy to reduce HCC may show some benefit, but these studies are limited by differing definitions of what was previously referred to as “immune-tolerant” CHB (HBeAg-positive chronic infection) and small study sizes.^65,66 Unfortunately, decades of NA treatment will be needed for effects on HCC to be apparent. Furthermore, we acknowledge that studies designed exclusively to evaluate the impact of treatment in the “immune-tolerant” phase have been disappointing in terms of achieving functional cure and suppressing HBV DNA to undetectable levels. However, we are evaluating evidence regarding broadening treatment and maintaining on-treatment viral suppression to avoid the potential sequelae of untreated CHB.^59,67

Finally, long-term NA therapy is associated with a 25.4% risk of non-adherence, and those who discontinue therapy or are non-compliant risk severe hepatitis flares, liver decompensation and acute-on-chronic liver failure in about in 1.2% and death or transplantation in 0.37% of cases.^7,68 Consequently, early treatment must be coupled with extensive counseling regarding adherence, and support programs for individuals with limited resources should be developed to prevent poverty from interrupting treatment.

Need for better biomarkers to monitor expanded treatment

Evaluating efficacy of NA treatment in a broad spectrum of PLWHB requires understanding of intrahepatic events that occur in response to treatment. This is challenging as circulating biomarkers for intrahepatic forms of HBV are limited. A major obstacle is that HBsAg can be expressed from both integrated HBV DNA and cccDNA.⁶⁹ Therefore, there is a critical need for non-invasive biomarkers to distinguish the integrated HBV DNA burden from the cccDNA burden to inform outcomes from expanding the treatment guidelines.

Emerging surrogate markers for the cccDNA pool and its transcriptional activity (i.e. HBcrAg, serum HBV RNA and HBcAg/phospho-HBcAg) may help measure the pool of functional cccDNA because these markers are preferentially or totally dependent on transcription from the cccDNA.⁶⁸ Monitoring intrahepatic cccDNA with these serum markers in HBeAg+ highly viremic patients would be highly informative, since most of HBV antigens are derived from cccDNA in these individuals. Developing non-invasive biomarkers to distinguish the integrated HBV DNA burden from the cccDNA burden would better inform outcomes from expanding the treatment guidelines in HBeAg-negative patients and would improve assessment of residual cccDNA activity following new therapeutic approaches. ICE-HBV recently released a review of HBV biomarkers.⁷⁰

In terms of immunological biomarkers, quantitative anti-HBcAg may have some prognostic value in the setting of expanded treatment.^71,72 Killing infected hepatocytes releases HBcAg and nucleocapsids, causing expansion and activation of anti-HBcAg producing B cells.^73,74 As a result, anti-HBcAg levels could identify patients with histological inflammation in liver biopsies with normal ALT levels.^75,76 Anti-HBcAg antibody levels drop during NA therapy.⁷⁵ Therefore, anti-HBcAg could be a biomarker for subclinical liver inflammation in HBeAg-positive patients. Because liver inflammation can suppress T cell immunity through mechanisms discussed above, NA therapy in HBeAg-positive patients could suppress subclinical inflammation and benefit HBV-specific T cell function.

Future studies are needed to look at the effects of NA treatment on HBV immunity in younger patients with HBeAg-positive chronic infection. Understanding the effects of NA therapy on immunity and how the immune microenvironment differs in young (<30 years) vs. older patients may permit better tailoring of therapy and may also increase the numbers of younger patients in clinical trials.

Early treatment can help advance drug development

Recent phase 1 or 2 trials aimed at functional cure for CHB, predominantly involving patients in the later phases of disease, have combined NAs with novel direct-acting antivirals (DAAs) and/or immunomodulatory agents.⁷⁷ This raises the question of how earlier NA administration, particularly in highly viremic individuals with HBeAg-positive chronic infection often regarded as difficult to treat, could advance the development of novel combination therapies. Early treatment studies could also provide invaluable evidence supporting early intervention.

Development of curative therapies for CHB faces significant challenges.⁷⁸ Chief among these are the absence of robust efficacy benchmarks and excessively stringent regulatory frameworks pushing for functional cure within relatively short treatment durations.⁷⁸ Notably, Janssen’s recent decision to exit the HBV field after decades of investment highlights these hurdles.

Embracing earlier NA-based therapy may help revitalize the development of novel and potentially curative combination therapies for several reasons. (i) Young individuals with HBeAg-positive chronic infection are more clinically and virologically uniform compared to individuals in advanced stages, such as the HBeAg-negative chronic hepatitis phase. Using this cohort to combine NAs with innovative antiviral and/or immunomodulatory treatments in early trials that involve small numbers of patients may yield richer data and reduce risks in later, more expensive studies. (ii) In young individuals with HBeAg-positive chronic infection, circulating HBeAg and HBsAg are reasonably reliable indicators of cccDNA activity, allowing better evaluation of treatment efficacy using current biomarkers. (iii) Regulators and investors developing curative strategies for CHB require suppression of circulating HBsAg but, as mentioned earlier, serum HBsAg in older CHB patients largely depends on transcription from integrated HBV DNA. The inclusion of younger individuals with HBeAg-positive chronic infection, with reliable cccDNA-based indicators, will benefit all strategies, particularly those like entry inhibitors and capsid assembly modulators (CAM), whose mechanisms do not directly impact HBsAg production. (iv) Younger individuals with HBeAg-positive chronic infection have broader and more functional anti-HBV T cell responses compared to more advanced HBeAg-negative CHB patients, making them more suitable to combination therapies aimed at reversing T cell dysfunction.^79,80

Finally, very few trials involving the combination of NAs with new antivirals or immunotherapeutics have engaged individuals with HBeAg-positive chronic infection and, therefore, it is difficult to gather solid results advocating for early treatment. An illustrative example is an ongoing trial with an ultrapotent CAM termed ALG-000184 that was administered with or without ETV in a small group of HBeAg-positive patients. This combination has shown a reduction in all circulating viral antigens, including HBsAg, suggesting an effect on the cccDNA reservoir. It is noteworthy that the use of this drug combination in more advanced, HBeAg-negative patients might have failed to demonstrate a meaningful reduction in HBsAg, as CAMs cannot affect the transcriptional activity of integrated HBV DNA.⁸¹

Conclusion

The evidence informing expanded NA treatment for CHB is summarized in Table 2. Unfortunately, there are no data available on the impact of expanded NA treatment and long-term outcomes like HCC, and conducting randomized controlled trials comparing antiviral treatment to no treatment under these conditions would be unethical and unfeasible. Furthermore, animal models of persistent HBV infection leading to HCC do not exist. As a result, revisions to current guidelines, particularly those advocating for expanded treatment to curb disease progression and HBV integration-related HCC, must be based on indirect scientific evidence. This manuscript presents the advantages and disadvantages of expanded NA treatment that would include earlier treatment. These data lead us to strongly believe that the benefits far outweigh the drawbacks.

Table 2.

Pros and cons of expanding NA treatment for CHB

Panel 1: Factors in favor
NAs reduce death from CHB NAs suppress HCC development NAs suppress HBV integration into cellular DNA that can be oncogenic People outside current guidelines can develop HCC and may benefit from NA treatment NAs suppress pathogenic hepatic inflammation NAs may enhance intrahepatic HBV immunity, especially in younger people NAs reduce cccDNA levels that drive HBV replication NAs reduce infection of new hepatocytes NAs are well tolerated in the large majority of patients Side effects can be managed by switching the NA employed ETV, TDF, and TAF have very low rates of resistance Drug resistance by switching the NA employed Monitoring can detect flares and guide re-initiation of NA therapy NAs are affordable in most regions of the world Earlier treatment can better identify efficacy of some experimental drugs
Panel 2: Factors against
Lack of extensive clinical data on treating people outside the guidelines may cause over-treatment in some patient populations Kidney or bone pathology can develop in up to 5% of patients on long-term NA therapy Incomplete HBV suppression by NAs can promote resistance evolution, primarily with ETV Significant hepatic flares can occur upon NA withdrawal Costs can be prohibitive for some patients