Manrai M, Jha AA, Pachisia AV, Dawra S. Chronic hepatitis B: Is it time for expanded antiviral treatment? World J Virol 2025; 14(3): 103347 [DOI: 10.5501/wjv.v14.i3.103347]
Corresponding Author of This Article
Manish Manrai, Professor, Department of Gastroenterology, Command Hospital, Lucknow Cantt, Lucknow 226002, Uttar Pradesh, India. manishmanrai75@gmail.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Manrai M conceptualized, supervised the review study, and was involved with resources, editing, and validation; Jha AA was involved with resources and writing; Pachisia AV was involved in resources, writing, and editing; Dawra S was involved with resources and writing.
Conflict-of-interest statement: There is no conflict of interest.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Manish Manrai, Professor, Department of Gastroenterology, Command Hospital, Lucknow Cantt, Lucknow 226002, Uttar Pradesh, India. manishmanrai75@gmail.com
Received: November 18, 2024 Revised: May 1, 2025 Accepted: July 11, 2025 Published online: September 25, 2025 Processing time: 313 Days and 14.7 Hours
Abstract
An estimated 3%-4% of people are living with the hepatitis B virus (HBV), and without treatment, the risk of developing cirrhosis and hepatocellular cancer (HCC) is an omnipresent threat. Prevention of HCC is a major challenge, as the association between viral suppression and HCC risk reduction is multifactorial, involving the progressive depletion of hepatocytes through covalently closed circular DNA integration, as well as the prevention of liver fibrosis and cirrhosis. Despite effective and cheap antiviral treatment capable of suppressing HBV replication and thereby cirrhosis and HCC, the current indications for therapy need revision and more research to expand the gamut and treat more infected people. In this review, we discuss the possible expansion of antiviral treatment in chronic hepatitis B to prevent cirrhosis and, importantly, HCC.
Core Tip: An estimated 254 million people, almost 3.3% of the world's population, are estimated to be living with chronic hepatitis B infection. Without therapy, they are at risk of developing cirrhosis and may develop hepatocellular cancer. The prevention of hepatocellular carcinoma is a major challenge. We review the various clinical practice guidelines and consider emerging evidence that will foster research to consider the expansion of treatment indications of chronic hepatitis B.
Citation: Manrai M, Jha AA, Pachisia AV, Dawra S. Chronic hepatitis B: Is it time for expanded antiviral treatment? World J Virol 2025; 14(3): 103347
Chronic hepatitis B (CHB) is estimated to affect 3.3% of the world’s population, and almost 254 million people are living with the hepatitis B virus (HBV). For every 100 persons living with HBV, without treatment, cirrhosis will be seen in one-fourth and hepatocellular cancer (HCC) in ≤ 5 people[1,2]. Prevention of HCC is a major challenge as the association between reduction of HCC risk and viral suppression can be direct, by progressive depletion of hepatocytes with covalently closed circular (ccc) DNA integration, and indirect, by preventing liver fibrosis and cirrhosis[3].
Even though potent, effective, and affordable antiviral treatments for HBV are available to suppress the virus and lower the risk of HCC and cirrhosis, current therapy indications overlook a specific subset of patients at risk for developing cirrhosis and HCC. In this review, we discuss the potential expansion of antiviral treatment in CHB to prevent cirrhosis and, importantly, HCC.
EXISTING HBV GUIDELINES: ASSESSMENT AND MANAGEMENT
The management of “blood-borne viruses” is rapidly changing. Newer biotechnologies for the human immunodeficiency virus (HIV) and novel drugs for the hepatitis C virus (HCV) have raised the hope of containing the HIV and HCV epidemics by 2030[4,5].
Similar targets for HBV have underscored the need to improve screening, expand treatment, and childhood vaccination to prevent the inter- and intra-generational transmission of the virus. Sero-discordance is classically used in the context of HIV to describe a relationship between two people with opposite viral statuses, with the recognition of enhanced risk to the seronegative partner. HBV has not used this, but the rationale remains the same.
Among an estimated 254 million people infected with HBV worldwide, more than 800000 perish[6]. The natural history of chronic HBV infection is worrying, with rates of cirrhosis being 12% to 20%. A fifth of patients could decompensate, and 15% go on to develop HCC[7]
Clinical practice guidelines have been published by the American Association for the Study of Liver Diseases (AASLD)[8] and updated within 2 years[9], European Association for the Study of the Liver (EASL)[10], Asian Pacific Association for the Study of the Liver (APASL)[11], and Indian National Association for Study of the Liver (INASL)[12] provide general recommendations for chronic HBV treatment. The Korean Association for the Study of the Liver (KASL)[13] and the World Health Organization (WHO)[14] have also issued guidelines for the same. We compared the existing guidelines to provide a common platform for the similarities and, more importantly, to highlight the variances between them.
METHODOLOGY FOR DEVELOPMENT OF HBV GUIDELINES
The current standard for developing guidelines for practice is that the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group bases recommendations on the quality of evidence[15]. GRADE offers a structured approach that involves a clear and thorough method for evaluating the quality of evidence. It explicitly weighs the benefits and risks of healthcare interventions, acknowledges the underlying values and preferences shaping recommendations, and assesses whether the intervention is a judicious use of resources.
AASLD issued the guidelines in 2016 following a GRADE-based recommendation on nine questions that physicians routinely encounter[8]. In 2018, AASLD updated the recommendation, but this time, the GRADE system was not followed[9]. Instead, it was developed by consensus of an expert panel. The 2018 guidance article introduced new recommendations not addressed in the 2016 guidelines, covering areas like treatment of individuals with viral co-infections, acute hepatitis B, those receiving immunosuppressive therapy, and transplant recipients. However, these new recommendations in the 2018 update were not based on a systematic review and did not employ the GRADE framework.
The WHO guidelines were created using the GRADE framework and standards[14]. The process began with scoping and planning to determine the most pertinent questions for patients with hepatitis B, particularly in low to middle-income countries. These questions were framed in the population, intervention, comparison, outcomes (PICO) format, with specific outcomes defined for each question. Systematic reviews were conducted to address these PICO questions, and the recommendations were formulated using the GRADE method. KASL[13] also used the GRADE framework, but APASL[11], EASL[10], and INASL[12] did not use the GRADE system and instead relied on an expert panel.
NATURAL HISTORY OF CHB
CHB is a lifelong infection, mostly acquired perinatally or in early childhood. It is characterized by five phases (Table 1). There have been differences in the terminology in various guidelines, but the basic interpretation remains the same in terms of hepatitis B surface antigen (HBsAg) levels, HBV DNA levels, hepatitis B e antigen (HBeAg) positivity, alanine transaminase (ALT), and histology.
Table 1 Comparison of chronic hepatitis B-related terminology and characteristics with natural history.
High HbsAg and DNA levels with HBeAg +ve are Phase 1 [the immune-tolerant (IT) phase] features. The inflammatory activity is assumed to be absent despite the ongoing replication, and the histological activity is expected to be minimal or normal. ALT levels may not indicate inflammatory activity, and several studies have shown a poor correlation between ALT and inflammation[16-18]. Thus, AASLD and KASL decreased the values of ALT in patients with HBV, whereas EASL and APASL continued to use the more traditional values of ALT.
The guidelines also differ in defining expected HBV DNA values in the IT phase. The DNA criteria (> 107) for the IT phase, as per KASL[13] and EASL[10], are different from AASLD (> 106). APASL[11] does not provide a clear-cut-off but favors a range of 1-2 × 106 and states that there is no correlation between fibrosis or inflammation and HBV DNA levels[8]. KASL[13] and EASL[10] recommend that the IT phase needs to have a higher DNA, and keeping it higher only ensures a better follow-up in case the DNA falls and the patient transitions from the IT phase (Phase 1) to the immune active (IA) phase (Phase 2).
Hence, the definition of the IT phase continues to be defined and improved upon, and the consensus regarding ALT and DNA values has still not been reached. There is a relative consensus between the definitions and interpretations of the other three phases (Phases 2, 3, and 4) in the guidelines.
ASSESSMENT OF HBV INFECTION (IT PHASE)
All the existing guidelines have similar recommendations for the assessment of HBV infection, but APASL[11] gives a more detailed guideline for the conduct of biopsy or interpretation of non-invasive tests like transient elastography. The APASL[11] provides guidelines for assessing liver disease, particularly regarding liver fibrosis. A liver stiffness measurement (LSM) below 6 kPa generally indicates the absence of significant liver disease. However, a LSM above 8 kPa suggests significant fibrosis (METAVIR fibrosis score > F2), and a measurement exceeding 11 kPa raises suspicion of cirrhosis. For patients showing signs of significant fibrosis through non-invasive markers—specifically a mean liver stiffness of ≥ 8 kPa (via Fibroscan) or an aspartate aminotransferase to platelet ratio score of ≥ 1.5—APASL recommends considering a liver biopsy. If the biopsy reveals moderate to severe inflammation or significant fibrosis, treatment should then be considered, although APASL notes that the strength of this specific recommendation is weak[11].
APASL[11] is also more detailed in the follow-up of the IT phase of CHB. All the guidelines mention monitoring by serial ALT (3 monthly) and the HBV DNA (6 monthly), along with alpha-fetoprotein (AFP) and ultrasound. In terms of non-invasive assessment of liver fibrosis, all societies recommend an assessment every year, APASL recommends that it should be yearly (if DNA > 2000 IU/L) and once in two years (if DNA < 2000 IU/L).
APASL[11] and KASL[13] have a more aggressive approach and have a low threshold for biopsy. APASL recommends biopsy in patients of IT phase with F2 fibrosis, those with a family history, and those aged more than 35 years. It also recommends a biopsy if the ALT is persistently above normal (even if less than 2 times). KASL has similar indications for biopsy in the IT phase, but they recommend biopsy at an earlier age (30 to 40 years).
CURRENT INDICATIONS FOR TREATMENT OF CHB
Most of the guidelines are in unison for Phase 2 or Phase 4; however, there are subtle differences in the management strategies of the other phases (Phase 1 and Phase 3) of chronic HBV infection (Tables 2, 3, 4, and 5).
Table 2 Management of phases of chronic hepatitis B virus infection.
Table 5 Management of chronic hepatitis B virus infection as per the World Health Organization[14].
Indications for anti-viral therapy in chronic hepatitis B
Evidence of significant fibrosis (≥ F2) based on an APRI score of > 0.5 or a transient elastographic value of > 7 kPa, regardless of DNA
Evidence of cirrhosis (F4) (based on clinical criteria (or an APRI score of > 1, or transient elastography value of > 12.5 kPab), regardless of HBV DNA or ALT levels
HBV DNA > 2000 IU/mL and an ALT level above the ULN on two occasions, 6 months apart
Presence of coinfections (HIV, HDV or HCV); family history of liver cancer or cirrhosis; immune suppression (such as long-term steroids, solid organ or stem cell transplant); comorbidities (such as diabetes or metabolic dysfunction–associated steatotic liver disease); or extrahepatic manifestations (such as glomerulonephritis or vasculitis), regardless of the APRI score or HBV DNA or ALT levels
In the absence of access to an HBV DNA assay persistently abnormal ALT levels (defined as 2 × ULN during a 6- to 12-month period), regardless of APRI score
Almost all societies recommend initiation of treatment if the biopsy shows significant inflammation (> A2) or fibrosis (> F2), but only APASL[11] and KASL[13] lay out specific indications of biopsy in the IT Phase (as explained in the previous section). Initiation of treatment in the IT phase is a new frontier, and biopsy guides the treatment protocol as mentioned above.
INASL[12] additionally recommends that treatment be started in patients with high DNA (> 2000 IU/L) and a family history of cirrhosis or HCC. For patients older than 30 years, EASL[10] and INASL[12] suggest that treatment may be started, whereas AASLD[8] suggests that treatment may be given to patients aged 40 years or more (if they have a high DNA). HBV-related extrahepatic manifestations should be an indication for initiation of therapy, as per INASL[12] and EASL[10] gives it as an optional indication. Other guidelines do not recommend therapy for extrahepatic manifestations alone.
Patients in Phase 3 of infection (inactive CHB) usually do not require any therapy and should be monitored closely for transition to Phase 4. However, APASL[11] recommends that a biopsy should be considered if ALT is raised to 1-2 × times the upper limit of normal (ULN) or if the non-invasive assessment shows significant fibrosis. EASL[10] also recommends a biopsy in such patients. Both guidelines recommend initiation of treatment in the case of significant inflammation (> A2) or fibrosis (> F2). EASL[10] also suggests that patients with extra-hepatic manifestations be treated similarly to their recommendation for Phase 1 disease.
HCC SURVEILLANCE IN CHB
HCC can develop in all stages of HBV infection, and the risk is variable as it is predominantly determined by the patient’s immune response to the infection. Active viral replication and cirrhosis increase the risk of HCC[19].
In untreated patients, the cumulative incidence varies from 8% to 20%, with the annual risk between 2% and 5%[20]. Risk scores, like Guide with Age, Gender, HBV DNA, core promoter mutations, and Cirrhosis score, Chinese University-HCC (CU-HCC), and risk estimation for hepatocellular carcinoma in chronic hepatitis B, have been developed over the years, and various studies have validated the use of these scores[21]. The risk prediction using these scores appears to be more reliable for untreated Asian patients and has limited applicability to Caucasian patients[22].
Despite therapy, HCC remains a major concern for patients with CHB, although the risk is substantially reduced[23]. Oral nucleos(t)ide analogues (NAs) therapy favorably impacts HCC incidence, with the decrease being more evident in patients with baseline cirrhosis[24,25]. Peg interferon-alfa therapy appears to be superior to NA regarding HCC incidence and risk reduction, with the impact being more evident in Asians[20]. Among patients with cirrhosis, the risk of HCC is higher in decompensated cirrhosis with ongoing viremia or in those who fail to achieve a virological response defined as DNA < 20 IU/mL[26]. As undetectable DNA levels can be achieved easily in > 80% of patients over a year on therapy, the risk of HCC is substantially reduced[27].
All guidelines recommend sustained monitoring of patients for the risk of disease progression and development of HCC, with those on treatment being especially monitored for therapy response and adherence. If the patient develops cirrhosis before loss of HBsAg, they remain at risk for HCC and should continue on surveillance. Even in the absence of cirrhosis, HCC may still develop after spontaneous HBsAg loss[28]. The risk is, however, substantially decreased if HBsAg loss is achieved in the absence of fibrosis and/or at a younger age. Hence, HBsAg loss forms a major endpoint in the natural history and treatment objectives (Table 6).
Table 6 Hepatocellular cancer surveillance in chronic hepatitis B.
It is also worth noting that guidelines do vary regarding some specifics. For risk stratification, almost all guidelines recommend multiple risk scores; however, INASL specifically recommends the CU-HCC scores given their simplicity. Similarly, all guidelines mention the concurrent use of ultrasound and AFP during the surveillance program, but INASL only recommends an ultrasound with no added benefit of measuring AFP.
There is a slight discordance amongst the guidelines in the use of contrast-enhanced computed tomography (CECT) during the surveillance. Whereas all guidelines recommend the use of CECT in evaluating a suspicious lesion, APASL[11] recommends a baseline CECT in all cirrhotics and those with a high-risk score. APASL[11] is also more detailed in the frequency of the follow-up. All the guidelines mention a screening evaluation at six-monthly intervals, but APASL[11] recommends a more frequent evaluation (three monthly) for cirrhotics and those with a high-risk score.
ADVANCES IN CLINICAL PRACTICE AND EMERGING DATA IN HBV
As discussed earlier, the main goals in managing CHB include improving liver histology, achieving viral suppression, normalizing ALT levels, and preventing complications such as cirrhosis, liver disease decompensation, and HCC. HBeAg-positive CHB patients are categorized into two main groups: Those with chronic infection (previously called "immune tolerant" or IT) and those with chronic hepatitis (previously called "immune active" or IA, HBeAg-positive). The chronic hepatitis group typically shows abnormal liver histology (indicating ongoing liver damage) and generally has somewhat lower HBV DNA levels when compared to patients in the chronic infection phase. Conventionally, the chronic infection (or "immune-tolerant") phase has been understood as a period marked by high HBV DNA levels and a minimal immune response against the virus. This often results in normal or only mildly elevated ALT levels, which is a liver enzyme that can indicate liver inflammation[29]. Liver histology in this phase generally shows mild necroinflammation, although new evidence suggests that viral integration and cccDNA formation continue during the IT phase[30]. Available tests do not reliably differentiate between patients with no or minimal inflammation. Moreover, patients with chronic hepatitis may harbor replicating or integrated viruses, increasing their risk of HCC[31].
CHB (HBeAg negative) accounts for the majority of hepatitis B infections. The main motive in treating these patients is to achieve either a resolved HBV infection or spontaneous resolution of the infection[32]. Current guidelines generally do not recommend treating HBeAg-negative CHB patients with oral NAs unless specific risk factors are present, such as a significant family history of HCC or an age exceeding thirty or forty years, as per the regional guidelines[4-6]. Conversely, most major guidelines endorse treatment for the IA stage of both HBeAg-positive and HBeAg-negative CHB[32].
Despite these recommendations, a critical objective of HBV treatment—HCC prevention—is often overlooked in patients who are in the "IT" phase. Figure 1 further emphasizes limitations within current guidelines, using "red flags" to highlight areas requiring evidence-based revisions. Since a substantial number of CHB patients remain in the IT phase, they frequently go untreated, which contributes to the perpetuation of ongoing HBV infections.
Figure 1 The natural history of hepatitis B virus presents certain challenges related to clinical management and treatment.
Key concerns include: (1) Variations in hepatitis B virus (HBV) DNA levels during the inactive (immune tolerant) phase, which can lead to missed treatment opportunities; (2) Difficulty in identifying the transition from the inactive (immune tolerant) phase to the active (immune active) phase, increasing the risk of reactivation and clinical flare-ups; and (3) Inadequate follow-up and testing can elevate the risk of undetected hepatocellular carcinoma. These factors emphasize the importance of vigilant monitoring and timely intervention in the management of HBV. IT: Immune tolerant; IA: Immune active; ALT: Alanine aminotransaminase; HCC: Hepatocellular cancer; HBV: Hepatitis B virus; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen.
MANAGEMENT PITFALLS IN EXISTING HBV GUIDELINES
Due to the risk of progression from the IT to IA phase, APASL and EASL have reduced the recommended age limit for starting treatment to over 35 and 30 years, respectively. There are expectations that AASLD may follow APASL and EASL[8,10,11].
During the chronic hepatitis phase, the ALT levels may fluctuate and show a modest correlation with histologic changes of necroinflammation, creating the risk of sampling errors. This is particularly relevant for IT/IA patients, who may be assessed when ALT levels are at a nadir rather than at peak (Table 1). Historically, the upper limit of normal ALT levels has been reduced from less than 50 IU/mL to less than 30 IU/mL in adult males and less than 19 IU/mL in adult females[33]. Fluctuations of ALT are influenced by factors like drug use and alcohol intake, and ALT elevations sustained for 3-6 months typically signal the change from IT to IA phase[32]. This situation is more complicated in patients with low HBV viral loads (< 2000 IU/mL), where normal ALT levels mask IA hepatitis[34].
Interpreting serum HBV DNA levels is also challenging, as there is no clear cut-off for determining treatment eligibility or response. The 2000 National Institutes of Health conference arbitrarily set a threshold of 20000 IU/mL (> 105 copies/mL), but DNA levels fluctuate, making consistent monitoring essential[35].
After HBV infection, over 95% of adults with normal immune function can spontaneously clear the virus, with only a small percentage progressing to chronic infection[36]. For those who develop chronic HBV, age often serves as a useful indicator of the infection’s duration. As the immune system matures, HBV can mutate in response to immune pressure, potentially disrupting immune tolerance at any time. This process can lead to liver inflammation and fibrosis as the immune system attempts to clear the virus[37].
A study involving 253 chronic HBV patients who presented with normal ALT levels revealed a notable association between age and the prevalence of significant liver fibrosis. Specifically, 42% of patients over the age of 40 were found to have significant liver fibrosis. This was a higher proportion compared to 30% of patients under 40 years old in the same study cohort[38,39]. The prevalence of stage 2 Liver fibrosis in those with ALT ≤ 40 U/L was 10%, 33%, and 53% in those aged < 35, 36-50, and over 50 years, respectively. Another study confirmed that age is an independent risk factor for significant liver fibrosis[40,41]. Therefore, age is a critical factor in determining whether to initiate treatment for chronic HBV patients with normal ALT levels.
Expert opinions from AASLD, Sweden, Taiwan, and East Asia all recommend initiating antiviral treatment for patients in the IT phase once they reach 40 years of age[8,42-44]. In the United States, the clinical gastroenterology and hepatology treatment guidelines, along with the APASL, suggest starting treatment at age 35 or older[11,45]. EASL and India’s guidelines are more conservative, recommending antiviral treatment for chronic HBV patients starting at age 30[10,12]. According to Expert Opinion on Expanding Antiviral Treatment of CHB from China, antiviral therapy is advised for individuals over 30 with positive HBV DNA[46].
Current guidelines rely on surrogate markers, such as ALT normalization to indicate the cessation of necroinflammation, and HBV DNA clearance to suggest viral inactivity. Noninvasive tests for liver fibrosis, like Fibroscan, are useful but limited, and liver biopsies are only employed when these tests yield unclear results. Consequently, many individuals eligible for treatment may be missed, leaving them at risk of complications and ongoing transmission (Figure 1).
RISK OF HCC IN IT PHASE
The main obstacle in HBV treatment advancement is the lack of techniques to measure cccDNA directly, as HBeAg, ALT, and HBV DNA levels do not provide any information on cccDNA or HBV genome integration. The REVEAL study from Taiwan demonstrated a strong connection between high HBV DNA and HCC incidence. Among 23820 participants, 4155 were HBsAg-positive, with complete data available for 3653 patients, 94% of whom had ALT levels less than 45 IU/L. Those with consistently high levels of HBV DNA (> 100000 copies/mL) at two time points had the maximum risk of HCC [hazard ratio (HR) = 5.3 95%CI: 2.9-9.7], while those with low HBV DNA levels at all time points had the lowest risk (HR = 1.3 95%CI: 0.5-3.1) over 10.7 years follow up. Importantly, this relationship between HBV DNA and HCC was not dependent on alcohol use, smoking, HBeAg status, ALT level, or cirrhosis. Patients with spontaneous clearance of high HBV DNA levels had an intermediate risk for HCC (HR = 1.9 95%CI: 0.8-4.4) over 11.1 years[47]. These findings strongly suggest that viral replication drives carcinogenesis, making pharmacological virological suppression a key strategy for preventing HCC.
In another study, Kim et al[48] reported that in a Korean population, the cumulative incidence of HCC was significantly higher in the IT group (12.7%) compared to the IA group (6.1%; P = 0.001)[48]. Similarly, the IT group also showed a significantly higher cumulative incidence of death or liver transplantation (9.7%) compared to the IA group (3.4%; P < 0.001)[48]. These findings indicated that untreated patients presumed to be in the IT phase of chronic HBV faced a higher risk of HCC, mortality, and liver transplantation compared to those in the IA phase. However, the absence of strict criteria for defining true IT status rendered the cohort heterogeneous, potentially limiting the reliability of these conclusions.
The ALT levels, commonly used as a marker, do not reliably correlate with liver necroinflammation, HBV mutations, or integration of the HBV genome into hepatocyte DNA[49]. ALT levels also fail to reflect the clonal expansion of hepatocytes that evade natural killer cells and HBV-specific T cell surveillance—processes that remain active even during the IT phase and contribute to the gradual development of HCC. Recent studies show that, contrary to previous beliefs, the IT phase may involve active T cell clones, although their functional activity is reduced[50].
Current guidelines use surrogate markers like normalization of ALT and HBeAg seroconversion as measures of outcome, potentially leaving a significant portion of the IT (at-risk) population untreated. These individuals can continue transmitting the virus and are more likely to develop HCC, especially if they do not adhere to long-term monitoring, including repeated testing, liver biopsies, and follow-ups lasting years or decades[51].
UNDERSTANDING INDETERMINATE PHASE IN CHB
IT and indeterminate phase
Definitions of the IT phase vary globally based on HBV DNA thresholds: > 2 × 107 IU/mL in China[52], > 1 × 107 IU/mL in Europe[10], > 1 × 106 IU/mL in the United States[8], and > 2 × 104 IU/mL per Asia-Pacific Guidelines[11]. These discrepancies lead to significant regional variations in patient classification. AASLD Guidelines[8] define indeterminate CHB patients as those who are HBeAg-negative and HBsAg-positive, have normal ALT (≤ 25 U/L for women, ≤ 35 U/L for men), and HBV DNA levels ≤ 20000 IU/mL.
Key mechanisms underlying immune tolerance include: (1) Persistent cccDNA: HBV cccDNA within hepatocyte nuclei remains stable, complicating complete viral clearance despite antiviral therapy[53,54]; (2) HBV gene variability: Mutations in the pre-S/S region may alter antigenicity, aiding immune evasion[55,56]; (3) Cellular immunity: T-cell mediated immune responses and cytokine production influence immune tolerance[11,57,58]; and (4) Host genetic polymorphisms: Variants in HLA genes (e.g., HLA-DPA1, HLA-DPB) correlate with susceptibility or resistance to chronic infection[59,60].
Some researchers suggest renaming this phase "high replication, low inflammation" due to its minimal immune response, although the "immune-tolerant phase" remains widely used[61,62].
IA and indeterminate phase
CHB progression is not always sequential. Adolescents or adults may bypass immune tolerance, while perinatally infected individuals often have prolonged IT phases[52,62]. The IA phase, also termed HBeAg-positive CHB, is marked by HBeAg presence, elevated HBV DNA, fluctuating or persistently high ALT, and moderate-to-severe necroinflammation or fibrosis[8-10].
Indeterminate CHB patients in this phase typically exhibit HBeAg and HBsAg positivity, HBV DNA levels between 2 × 102 and 2 × 104 IU/mL, and abnormal ALT (≤ 2 × ULN)[9].
Immune-inactive and indeterminate phase
Previously termed the "inactive carrier phase"[8,63], this stage is now recognized as HBeAg-negative chronic HBV infection[10], characterized by HBeAg seroconversion, low or undetectable HBV DNA, normal ALT, and minimal necroinflammation with variable fibrosis[8]. Indeterminate cases include HBeAg-negative patients with either HBV DNA ≥ 2 × 103 IU/mL and normal ALT, or HBV DNA < 2 × 103 IU/mL with elevated ALT[9].
Immune reactivation and indeterminate phase
Spontaneous or post-treatment reactivation, termed HBeAg-negative CHB[9], features anti-HBe positivity, elevated HBV DNA, fluctuating or persistently high ALT, and moderate-to-severe necroinflammation or fibrosis (≥ G2/S2)[8]. Per EASL 2012/2017 Guidelines[10,64,65], spontaneous remission rates in this phase are low.
Indeterminate CHB cases in this phase exhibit: ALT ≥ 2 times ULN with HBV DNA < 2000 IU/mL, or ALT < 2 times ULN with HBV DNA ≥ 2000 IU/mL[9].
The various pros and cons of treating this difficult group of patients have been mentioned in Table 7. The decision for treatment in this phase warrants more convincing data to give way to consensus rather than debate.
Table 7 Management of indeterminate chronic hepatitis B patients: Immune-tolerant and Immune-active.
Phase
Pros of treatment
Cons of treatment
IT
Early viral suppression: Suppresses HBV replication, potentially preventing liver damage, cirrhosis, and HCC[47,48]
Limited immediate benefit: Patients in the IT phase typically have minimal liver damage, so treatment may not provide significant short-term benefits[48,82]
Prevention of carcinogenesis: High HBV DNA levels are linked to increased HCC risk, so early intervention could reduce long-term cancer risk[47]
High cost and long duration: Long-term antiviral therapy can be costly and may require lifelong treatment[11,45]
Reduced Transmission: Lowering viral load during the IT phase can reduce the risk of HBV transmission, important in endemic areas[45]
Treatment resistance: Prolonged antiviral use could lead to drug resistance, reducing effectiveness over time[11,45]
Advances in understanding IT phase: New evidence suggests active immune responses in the IT phase, making treatment potentially more effective than previously thought[57]
Risk of side effects: Antiviral therapy, especially long-term, can cause adverse effects, such as renal toxicity and bone density loss[45,47]
IA
Proven effectiveness: Clear benefits of treatment, including reduced risk of cirrhosis, liver failure, and HCC[45,48]
Side effects: Long-term use of antivirals can lead to renal and bone complications, as well as other side effects[11,45]
While universal immunization can substantially lower the rate of new infections, effectively tackling the significant burden of horizontal transmission necessitates broader access to antiviral therapy. Exceptions have already been made for certain groups, such as individuals under 30, those at risk of mother-to-child transmission during pregnancy, family members of patients with HCC, medical personnel, and individuals on immunosuppression or chemotherapy[8,10,11]. The same principle applies to other high-risk groups, including dialysis patients, military personnel, and residents of care homes, where transmission risks are elevated. A similar approach is seen in HIV treatment, where universal therapy and viral suppression are prioritized to prevent complications and malignancies despite the absence of a cure. The ongoing dilemma is reflected in Table 8, wherein the advantages and the disadvantages have been summarized[66].
Table 8 Pros and cons of expanded hepatitis B treatment in different regions of the world.
Region/Country
Pros of expanded HBV treatment
Cons of expanded HBV treatment
Ref.
United States and Western Europe
Reduces liver cancer (HCC) and cirrhosis risk significantly. Cost-effective long-term due to lower healthcare costs of managing advanced liver disease. High-quality healthcare infrastructure for treatment. National vaccination programs decrease new infections
High upfront costs of expanding treatment programs. A complex treatment regimen requires continuous monitoring. Antiviral drug resistance can develop. Socioeconomic disparities affect access to treatment
Potential to reduce high hepatitis B prevalence (8%-12% in some regions). Cost-effective in preventing liver disease. Availability of generic drugs makes treatment affordable. Could prevent mother-to-child transmission
Limited healthcare infrastructure. Poor access to diagnostic tools. Healthcare worker shortages. High upfront costs for government to scale up treatment
A large reduction in liver cancer cases due to high HBV burden. Government-subsidized treatments improve access. An effective nationwide vaccination program
High cost of treating millions of chronic HBV patients. Disparities between urban and rural healthcare access. Drug adherence and monitoring are challenging in rural areas
Reduces HBV-related mortality in a country with significant disease burden. Affordable generic antivirals are available. National initiatives to improve vaccination rates and awareness
Limited healthcare infrastructure in rural areas. Low awareness about the need for regular treatment. Cultural stigma around liver disease may hinder uptake
High impact due to large HBV burden in the region. Government-funded programs and access to generics lower costs. Reduction in liver cancer and other liver-related mortality
Treatment access is limited in rural and underserved areas - Monitoring and follow-up systems are underdeveloped. High costs of diagnostic tests in some areas
Potential to reduce the growing HBV burden. Generic antivirals are available at lower costs. Could lower healthcare costs related to advanced liver disease
Insufficient healthcare infrastructure in rural areas. Limited access to quality diagnostic and monitoring tools. Economic constraints hinder government spending on healthcare
Moderate HBV prevalence with opportunity for significant impact through expanded treatment. National vaccination programs are already in place. Availability of affordable drugs
Poor healthcare infrastructure in rural areas. Budgetary constraints limit widespread access to treatment. Socioeconomic disparities affect access
High impact potential due to significant HBV burden. Availability of affordable generic treatments. Could reduce complications related to liver disease
Limited diagnostic infrastructure in rural regions. Cultural and religious beliefs may affect treatment adherence. Healthcare costs are a significant burden on government budgets
To support the goal of eliminating CHB, revising treatment guidelines to expand eligibility for therapy is crucial. Current evidence does not allow clear differentiation between the true IT phase of CHB and minimally inflamed IT CHB with normal ALT levels. An invasive biopsy is not recommended for all patients with IT CHB. As the risk of carcinogenesis is well-established for HBV DNA levels exceeding 100000 copies/mL (approximately 2000 IU/mL)[67], it may be appropriate to initiate therapy in adults with HBeAg-positive disease and high viral DNA levels, regardless of ALT levels. Data from Asian cohorts suggest that chronic suppression of HBV DNA is the most effective intervention, and lifelong therapy may be necessary for eligible patients[34,47].
NEED FOR ADOPTION OF NEW HBV BIOMARKERS
Follow-up and adherence are essential even in patients on NA therapy, as they help in preventing complications. Hepatitis B core-related antigen (HBcrAg) is considered a more reliable surrogate marker for cccDNA activity than quantitative HBsAg levels. HBV RNA is another promising biomarker, as it reflects intrahepatic cccDNA transcription and typically declines before HBeAg seroconversion[68]. Although current guidelines use HBeAg seroconversion as a treatment endpoint in HBeAg-positive CHB and HBsAg loss in HBeAg-negative CHB, these markers do not fully capture the persistence of cccDNA or integrated HBV DNA, both of which continue to carry a risk for HCC[69].
Therefore, risk stratification for hepatocarcinogenesis in CHB should be revised to incorporate novel biomarkers such as HBcrAg and HBV RNA, which can help differentiate true viral resolution from mere suppression achieved through antiviral therapy. This is particularly relevant in the IT phase, where elevated levels of HBcrAg or HBV RNA suggest ongoing cccDNA activity and a continued risk of HCC, despite normal ALT levels. Current clinical practice often overlooks key histological subgroups—such as those with minimal inflammation, significant HBV genome integration, or high viral loads—that may still carry a substantial risk for HCC[69].
Measurement of HBcrAg and HBV RNA holds promise for validating cccDNA activity and assessing HCC risk, particularly in patients who are currently considered ineligible for antiviral therapy. Additionally, the rising prevalence of metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and alcohol use complicates the interpretation of elevated transaminase levels, potentially obscuring underlying HBV activity. This is especially significant given the inverse relationship between hepatic steatosis and HBV-related disease activity, alongside the heightened risk of hepatocarcinogenesis in individuals with concurrent HBV and NAFLD[70].
COST-EFFECTIVENESS OF EXPANDED HBV TREATMENT IN HIGH AND LOW-INCOME COUNTRIES
To drive the global elimination of HBV, expanding testing and treatment services in resource-limited regions, particularly sub-Saharan Africa, is essential. However, existing international HBV treatment guidelines involve complex eligibility criteria that rely on diagnostic tests often unavailable in these low-resource settings. Consequently, simplifying the criteria, with a "Treat All" strategy being the most comprehensive option, could offer a practical solution. Despite its potential advantages, such an approach could have considerable economic consequences, especially in a resource-constrained environment (Table 9).
Table 9 Cost-effectiveness of expanded hepatitis B virus treatment in high and low-income countries.
A comprehensive literature review reveals four relevant studies, three examining the cost-effectiveness of a "Treat All" strategy and one evaluating simplified treatment eligibility criteria. Razavi-Shearer and colleagues[71] analyzed the cost-effectiveness of a "Treat All" strategy in the United States, finding an incremental cost-effectiveness ratio (ICER) of $41700 per Disability-Adjusted Life Year (DALY) averted, which falls below the country’s cost-effectiveness threshold of $65850, indicating that the strategy is cost-effective within the United States healthcare context. Sanai and colleagues[72] evaluated a "Treat All" strategy in Saudi Arabia, demonstrating that the approach was cost-effective with an ICER of $22050 per DALY averted, well within the threshold of $66150, which is equivalent to less than three times the gross national income per capita, reflecting high affordability in this upper-middle-income country. Lim et al[73] explored a simplified algorithm in Korea that utilized HBV DNA testing without additional measurements of ALT or HBeAg. They found the simplified approach highly cost-effective, with an ICER of $2583 per DALY averted, against a national threshold of $20000, demonstrating significant economic benefits in this high-prevalence setting. Crossan and colleagues[74] assessed a "Treat All" strategy in the United Kingdom, excluding liver fibrosis assessment. They found the ICER to be £28137 per Quality-Adjusted Life year, exceeding the country’s cost-effectiveness threshold of £20000, suggesting that the strategy may not be economically viable for the United Kingdom under these conditions. While these studies provide useful data, there remains a lack of specific research on the cost-effectiveness of "Treat All" strategies or simplified eligibility criteria in low and middle-income countries, where such approaches might be more impactful but financially challenging to implement due to higher HBV prevalence and limited healthcare budgets.
Nguyen et al[75] in a very recent study from Gambia (West Africa) using a microsimulation model on a closed cohort, assessed the cost-effectiveness of three testing algorithms for selecting HBV-infected patients for antiviral therapy, comparing them to the WHO 2015 treatment guidelines. The evaluated strategies included the EASL conventional criteria, the Treatment Eligibility in Africa for the hepatitis B Virus (TREAT-B) score, which is based on ALT and HBeAg, and a "Treat All" approach for all HBV-infected individuals. Compared with the WHO criteria, TREAT-B resulted in 4877 DALYs averted, and Treat-All resulted in 9352 DALYs averted, whereas the EASL criteria led to an excess of 795 DALYs. TREAT-B was cost-saving, whereas the ICER for "Treat All" (US$2149 per DALY averted) was higher than the cost-effectiveness threshold for The Gambia (0-5 times the country’s gross domestic product per capita: $352). The results indicated that although the "Treat All" strategy might be the most effective, it is unlikely to be cost-effective in The Gambia. A simplified strategy, such as TREAT-B, might be a cost-saving alternative.
CONTRARIAN VIEWPOINT ON TREATMENT EXPANSION IN HBV
The recommendation to extend antiviral therapy to highly replicative phases of CHB, such as the HBeAg-positive, high-DNA IT phase, has encountered considerable resistance. Moreover, current NA therapies result in a very low likelihood of inducing HBeAg seroconversion and HBsAg loss in the IT phase. Chan et al[76] included 126 patients who were HBeAg-positive (mean age: 33 years, 89% were Asian) with HBV DNA > 107 IU/mL and normal ALT, randomized to receive tenofovir disoproxil fumarate (TDF) or TDF emtricitabine for 192 weeks. The study found that HBeAg seroconversion occurred in 3 patients (5%), and no patient lost HBsAg after 192 weeks of treatment. Hence, it is recommended by a few that the IT phase can be monitored and treatment initiated, if they transition to the IA phase or if liver histology has evidence of significant inflammation or fibrosis[77].
The inactive carrier phase is characterized by the absence of HBeAg, consistently normal ALT levels, and low HBV DNA levels (< 2000 IU/mL). Although this phase generally has a more favorable clinical outlook, in a meta-analysis by Raffetti et al[78], some studies have shown that inactive carriers still face a significant risk of HCC and liver-related death compared to individuals not infected with HBV. Additionally, long-term follow-up revealed that inactive carriers have a non-negligible risk of developing HCC and liver-related death. However, most studies indicate that the long-term prognosis of well-defined inactive carriers is comparable to that of the general population controls, with a high HBsAg clearance rate and a low phase transition rate. Therefore, it is recommended that inactive carriers be regularly monitored, with treatment initiated if there is progressive histological evidence or a transition to the IA phase[77,78].
Emerging evidence suggests that a significant portion of CHB patients do not fit neatly into any of the established phases and are therefore classified as being in the indeterminate phase. Current practice guidelines do not recommend antiviral therapy for CHB in this phase[9-11]. A study by Bonacci et al[79] demonstrated that most Caucasian patients in the indeterminate phase experience excellent long-term outcomes without treatment, showing a high rate of HBsAg loss and a low progression to HBeAg-negative CHB. HBV genotype and HBsAg levels may help predict clinical outcomes and improve the classification of indeterminate-phase patients[79]. In a multiethnic North American cohort study of adults with chronic HBV who were not receiving antiviral therapy, the cumulative incidence of adverse clinical outcomes (such as cirrhosis, decompensation, HCC, liver transplantation, and HBV-related death) was only 2% by year 7 in those without cirrhosis at enrolment[80]. Another review found that 43.5%-85% of patients in the indeterminate phase transitioned to the inactive carrier phase, while only 2.2%-15% transitioned to the IA phase, with few developing HCC[81]. These findings suggest that early diagnosis, close monitoring, and timely treatment initiation can help prevent adverse outcomes in indeterminate-phase patients.
One of the primary challenges in managing HBV at the population level is the lack of a curative therapy, which means that sustained viral suppression often requires long-term, and sometimes lifelong, antiviral treatment. A significant concern is the potential emergence of drug-resistant HBV mutants due to extensive use of NA therapy, which can lead to progressive liver fibrosis and decompensation[51,81-93].
OCCULT HBV INFECTION: TO TREAT OR NOT?
Replicable HBV DNA in the liver, even when an individual tests negative for HBsAg in their blood, is called occult HBV infection (OBI). This can occur with or without detectable HBV DNA in the bloodstream. In this particular subset of patients, HBV DNA has reduced replication potential and exists as cccDNA. As a result, the HBV DNA in serum/plasma is often intermittently detected and at a low level of viremia (< 200 IU/mL). OBI can be further subclassified into seropositive and seronegative HBV. Seropositive OBI, which represents approximately 80% of all OBI cases, is typically marked by the presence of anti-HBV surface antigen (anti-HBs) and/or anti-HBV core antigen (anti-HBc) antibodies. Seropositive OBI, which accounts for around 80% of all infections, characteristically has detectable anti-HBs antibodies or anti-HBc antibodies. Seronegative OBI, on the other hand, tests negative for anti-HBc and anti-HBs but has intrahepatic HBV DNA[94]. The cccDNA has a peculiar ability to exist as a chromatized episome in the infected hepatocytes. It has been postulated that epigenetic mechanisms and the host’s immune control are responsible for the non-detection of HBsAg despite the persistence of stable cccDNA[36,95,96]. This biological alteration is clinically pertinent as the cccDNA is fully replicable and may be transmitted through organ transplantation and blood transfusion, manifesting as overt HBV infection in the recipients[97-99].
Moreover, the coexistence of OBI along with other etiologies may exacerbate the progression of underlying liver disease to advanced stages, in addition to the risk of the development of HCC. In clinical practice, it is pertinent to differentiate OBI from ‘S-S-escape mutant infection’ wherein serum HBsAg is undetectable despite the presence of episomal-free HBV genome in the hepatocytes. This phenomenon of ‘false occult HBV’ occurs due to mutations in the pre-S region of the viral genome. False OBI may be seen in up to 40% of patients with OBI[100,101]. There are stark differences in the epidemiology of OBI across the world. These differences have been attributed to the difference in the prevalence of HBV in the general population in defined geographical locations, the efficacy of vaccination programs in different regions, the severity of liver diseases in the general population, and the sensitivity of HBsAg and HBV DNA assays[102,103].
Existing studies have highlighted the increased prevalence of OBI in a cohort of patients with an increased risk of developing HBV: Injectable drug abuse, coinfection with HCV, and individuals on hemodialysis[104-106]. Increased prevalence has also been documented in patients with HCC, liver transplant recipients, and those with NAFLD[107-110]. Classical clinical scenarios wherein reactivation of OBI can lead to overt HBV infection include patients in an immunocompromised state. These can arise secondary to diseases involving the immune system or because of therapeutic modalities that weaken the immune response. Diseases with a high risk of clinical/virological reactivation include hematological malignancies; multiple myeloma, non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and myeloid monoblastic acute leukemia, treatment with immunosuppressive regimens, especially with anti-CD 20 monoclonal antibody (rituximab), patients undergoing hematopoietic stem cell transplantation and liver transplantation involving anti-HBc positive donors (Table 10)[111-113].
Table 10 Highlights the chemotherapeutic drugs associated with a high risk of occult hepatitis B virus infection reactivation.
Cyclophosphamide: Alkylating agent, inhibits protein synthesis by DNA and RNA crosslinking
Hydroxydaunorubicin: Inhibits DNA replication and cell production
Oncovin: Vinca alkaloid, microtubule-disrupting agent. Prednisolone: Suppression of migration of polymorphonuclear lymphocytes and reversal of increased capillary permeability
Individuals undergoing renal transplantation involving anti-HBc positive donors, those with HIV coinfection, rheumatic disorders treated with biological therapy, and those receiving high doses of corticosteroids over a prolonged period carry an intermediate risk of viral reactivation[114,115]. Conditions that carry a low risk of reactivation include individuals undergoing organ transplantation other than hepatic/renal transplant, solid tumors receiving chemotherapy, HCC patients managed with transarterial chemoembolization, and those with inflammatory bowel diseases receiving immunosuppressive therapy[100,116].
VIROLOGICAL PROFILE OF PATIENTS WITH OBI
The detection of anti-HBc in addition to anti-HBs antibodies has been used as a surrogate marker for OBI. Our current understanding of the biological behavior of OBI suggests that patients with anti-HBc/anti-HBs antibodies undergoing immunosuppression tend to experience a progressive decline in the titer of anti-HBs before it finally disappears. This correlates with the reappearance of HbsAg-positive status in individuals who develop clinical/virological reactivation[117-120].
The detection of HBV DNA in the serum of patients with OBI has to be interpreted in light of the fact that the presence of DNA establishes a diagnosis of ‘OBI carrier’. Detection of anti-HBc, although used as a surrogate, is an imprecise method to prove OBI status. The detection of HBV DNA in titers > 200 IU/mL helps to differentiate patients with S escape mutants. This is valuable as the therapeutic approach differs between the above-mentioned (S escape mutants and OBI) subset of patients[121].
At present, antiviral therapy is not recommended for individuals with OBI. However, there is an ardent need to prevent OBI reactivation and, therefore, prevent the development of acute hepatitis in individuals with suppressed immunity.
PREVENTION OF OBI TRANSMISSION
Blood transfusion: Transmission of HBV by OBI-positive blood donors is a major unmet health need, especially in places where anti-HBc and nucleic acid amplification tests are not available. Multiple factors affect the risk of transmission from an OBI-positive donor, notably, the immune status of the recipient and the quantity of plasma transfused. It has been proposed that OBI donors who are anti-HBc positive may be more infectious than those with anti-HBs positive status[122]. Candotti et al[123] have shown that individuals with three negative HBsAg samples and negative HBV DNA, measured by highly sensitive Nucleic Acid Amplification Testing (NAT), can transmit HBV to recipients. They have proposed the revision of the minimum infective dose of HBV DNA from the previous one of 20 IU/mL to 3.0 IU/mL[123]. A recent update of the statements on the clinical and biological impact of OBI has proposed that NAT sensitivity should be lowered from the previous one of 3.4 IU/mL to 0.15 IU/mL[121].
CHRONIC LIVER DISEASE AND OBI
Current evidence dictates the fact that minimal, prolonged inflammation induced by OBI is recognized as a risk factor for the progression of liver disease in patients who are also coinfected with HCV[124-126]. Risk of disease progression has also been documented in patients with other etiological factors, namely alcohol, NAFLD, and cryptogenic cirrhosis[127-129].
HCC AND OBI
Research has highlighted an overwhelming association between OBI and HCC. OBI has been documented in the liver tissue specimens of up to 70% of patients suffering from cryptogenic cirrhosis and HCC[130-132]. A meta-analysis that included 16 studies and 3656 patients has shown an increased risk of HCC in patients with OBI[133]. Evidence also suggests that OBI retains the oncogenic properties similar to an overt HBV infection. Studies involving PCR-based and high-throughput sequencing assays have shown integration of the HBV genome with the host genome in patients with OBI-related HCC[134,135].
Routine prophylactic treatment for OBI is not supported by sufficient evidence; however, treatment may be initiated for individuals at a high risk of reactivation. These high-risk individuals should be screened for serological evidence of OBI: Anti-HBc, anti-HBs, and HBV DNA assay before initiation of immunosuppressive therapy. Monitoring should be continued for months or years after withdrawal of immunosuppressive therapy to screen for viral reactivation, as antibody titers may fall secondary to initiation of therapy. Antiviral drugs should be initiated for OBI individuals, especially those who have tested negative for anti-HBs antibodies. It is recommended that treatment be initiated before the initiation of immunosuppressive therapy and continued for around six months after withdrawal of treatment. Japanese guidelines recommend monthly HBV DNA monitoring during the period of chemotherapy and for one year thereafter. To minimize the risk of blood transfusion-related infection, it is also recommended to use HBV DNA NAT and multivalent anti-HBs antibodies to detect true and false OBI, respectively, while screening for blood donation[136,137].
CONCLUSION
HBV infection is a perplexing entity with myriad clinical, virological, and immunological manifestations. An ever-increasing body of knowledge indicates that the infection may continuously persist in the hepatocytes even when active viral replication is suppressed. There is a dilemma to treat whenever one encounters CHB in the so-called IT phase or indeterminate phase, or for that matter, an OBI. The endpoints of therapy do exist, but whether HCC is being prevented is still debatable, according to the existing guidelines. To add to the complexity, large geographical regions of the world are endemic to HBV with poor healthcare infrastructure. Hence, the treatment protocols must be revised and expanded based on the background of more robust local data. We suggest initiating treatment in IT-phase patients with HBV DNA > 2000 IU/mL and age > 30, using non-invasive fibrosis assessments to identify high-risk individuals, although firm recommendations can only be made after the availability of strong evidence in this regard.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Corresponding Author's Membership in Professional Societies: American College of Gastroenterology, 51519; American Society for Gastrointestinal Endoscopy, 151100; American Gastroenterological Association, 1050754; Indian Society of Gastroenterology, LM001975.
Specialty type: Virology
Country of origin: India
Peer-review report’s classification
Scientific Quality: Grade B, Grade B
Novelty: Grade B, Grade B
Creativity or Innovation: Grade B, Grade B
Scientific Significance: Grade B, Grade C
P-Reviewer: Zeng JQ S-Editor: Liu H L-Editor: Webster JR P-Editor: Yu HG
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