Discontinuation of nucleos(t)ide analog therapy in hepatitis B e antigen-negative non-cirrhotic chronic hepatitis B patients: A real-life study

Abstract

BACKGROUND

The discontinuation of nucleos(t)ide analog (NUC) therapy remains controversial in hepatitis B e antigen-negative chronic hepatitis B (CHB) patients who have not attained hepatitis B surface antigen loss.

AIM

To assess re-treatment rates and risk factors in non-cirrhotic hepatitis B e antigen-negative CHB patients after the cessation of NUC.

METHODS

Demographic, clinical, and laboratory data were prospectively collected before to and following the discontinuation of NUC.

RESULTS

Eighty-seven patients were included in the follow-up from January 2015 to September 2025; 57 were male, with a mean age of 41.3 ± 10.8 years old. The baseline median values of alanine aminotransferase (ALT) and hepatitis B viral deoxyribonucleic acid (DNA) were 87 IU/L and 37211 IU/mL, respectively. The median histologic fibrosis score was 2. The median length of treatment and consolidation therapy was 69 months and 46 months, respectively. The median duration of follow-up following the cessation of therapy was 39 months. Of the 56 patients deemed qualified for assessment based on the suggested re-treatment criteria, 29 (51.7%) underwent re-treatment. The median duration until relapse was 11 months. The cumulative virological relapse rates, defined as HBV DNA over 2000 IU/mL, were 25%, 52%, 58%, and 61% at 6 months, 12 months, 24 months, and 36 months, respectively. The cumulative retreatment rates at 6 months, 12 months, 24 months, and 36 months were 19%, 25%, 28%, and 35%, respectively. Thirty-eight patients (43%) returned to NUC treatment after an average interval of 9 months (range 1 months to 42 months). The risk factors influencing clinical relapse in patients included gender, baseline HBV DNA levels, treatment method, and ALT and aspartate aminotransferase levels at the end of treatment, Ishak fibrosis score > 2, and at the conclusion of treatment. In multivariate analysis, Ishak fibrosis score > 2 is the unique factor for retreatment.

CONCLUSION

In resource-constrained areas, discontinuing NUC may be considered for early-stage patients with low baseline hepatitis B viral DNA and ALT levels after a lengthy consolidation treatment. A higher pretreatment liver biopsy fibrosis score predicts relapse.

Key Words: Hepatitis B; Treatment; Discontinuation; Relapse; Re-treatment

Core Tip: Prolonged therapy remains the recommended method for patients with chronic hepatitis B. Nonetheless, concerns about treatment adherence and economic strain, particularly in resource-constrained areas, combined with research indicating that virological and clinical remission persists in non-cirrhotic patients after treatment cessation, prompted the development of nucleos(t)ide analog cessation guidelines for specific patients. However, the discontinuation of nucleos(t)ide analog is still a contested question. The median duration until recurrence was 11 months. The cumulative virological relapse rates, defined as chronic hepatitis B deoxyribonucleic acid over 2000 IU/mL, were 25%, 52%, 58%, and 61% at 6 months, 12 months, 24 months, and 36 months, respectively. The cumulative retreatment rates at 6 months, 12 months, 24 months, and 36 months were 19%, 25%, 28%, and 35%, respectively. Histologic fibrosis score > 2 is the unique factor for retreatment.

INTRODUCTION

Chronic hepatitis B (CHB) infection represents a major public health concern around the world[1]. Despite the efficacy of immunization campaigns[2], it remains a significant cause of end-stage liver disorders, impacting around 400 million individuals globally[3]. In fact, the primary cause in low-income areas, resulting in approximately 750000 death yearly from hepatitis B viral (HBV)-related chronic liver disorders[4]. Long-term administration of nucleos(t)ide analog (NUC) with a high genetic barrier, such as tenofovir or entecavir, results in the lowering of HBV replication, enhancement of liver histopathology, decreased risk of cirrhosis and hepatocellular carcinoma (HCC), and improved survival rates overall[1].

As NUCs target the last stage of the viral cycle and have no direct effect on covalently closed circular deoxyribonucleic acid (DNA), patients infrequently achieve hepatitis B surface antigen (HBsAg) deletion[5]. Prior research has shown that the annual rate of effective recovery (HBsAg loss) ranges from approximately 0.5% to 2.3%. Consequently, in contemporary clinical practice, the majority of patients with CHB must persist with NUC therapy for life once initiated. The prolonged duration of NUC treatment raises issues regarding economic costs, the potential for resistance development, compliance, and side effects. Some investigations have indicated that virological and biochemical responses are maintained, liver histology remains stable, and the risk of HCC does not escalate following the discontinuation of antiviral therapy[1,6,7]. The newly revised CHB guidelines progressively recommend for the potential discontinuation of NUC in select individuals. Therefore, the discontinuation of HBV therapy was initially recommended by the Asian-Pacific Association for the Study of the Liver (APASL), and treatment cessation guidelines for patients with hepatitis B e antigen (HBeAg)-negative CHB were established in the 2008 APASL, addressing concerns over cost and resistance[8].

The current European guidelines recommend that NUC may be stopped prior to loss of HBsAg in certain, non-cirrhotic, HBeAg-negative patients who maintain sustained virological suppression for a minimum of 3 years and will receive continuous follow-up monitoring[9]. Nonetheless, a considerable percentage of patients may have relapse following discontinued use of NUC; the precise conditions for discontinuation, the ideal off-treatment monitoring, and the standards for retreatment remain unclear[10-13].

This prospective study aimed to evaluate the long-term outcomes of discontinuing NUC therapy in a group of non-cirrhotic individuals with HBeAg-negative CHB. Our primary objective was to evaluate the percentage of patients who continue off the therapy, achieve HBsAg clearance after a minimum of three years of follow-up and analyze virological and/or clinical relapse rates, risk factors for re-treatment, and re-evaluate the retreated patients.

MATERIALS AND METHODS

Patients and study design

In this prospective, single-center, and observational study. we included 87 eligible and agreed patients with HBeAg-negative CHB who discontinued NUC therapy between 2015 and 2025, followed up in the Department of Gastroenterology in Department of Gastroenterology, Mohamed Seghir Nekkache, Algiers 16000, Algeria. NUC treatment was discontinued in accordance with the European Association for the Study of the Liver (EASL) hepatitis B guideline[9], NUC therapy may be discontinued for patients with HBeAg-negative CHB after a minimum of 3 years of treatment, provided that undetectable HBV-DNA is confirmed on three different times, 6 months apart. All patients underwent a liver biopsy prior to the initiation of NUC therapy.

The patients underwent follow-up at scheduled appointments. During each visit, biochemical tests including aspartate aminotransferase (AST), alanine aminotransferase (ALT), total and direct bilirubin, urea, creatinine, albumin, and electrolytes were conducted, along with a virological profile (HBsAg, HBeAg, anti-Hbe, HBV-DNA), international normalized ratio, alpha-fetoprotein measurement, and full blood count. Additionally, screening for HCC was conducted via abdominal ultrasonography every 3 months to 6 months. Informed written consent was acquired from all participants prior to their inclusion in the study. This study was approved by the hospital ethics committee, which functions in accordance with the Declaration of Helsinki.

Inclusion and exclusion criteria

The participants were over 18 years old with well-documented HBeAg-negative CHB prior to the commencement of antiviral treatment and met the following criteria: (1) HBsAg positive, HBeAg negative, and anti-HBe positive for a minimum of 6 months prior to the initiation of NUC treatment and at the time of NUC cessation; (2) Uninterrupted NUC therapy for no less than 4 years, with the final 2 years consisting of either entecavir (ETV) or tenofovir disoproxil fumarate (TDF) monotherapy; (3) Serum HBV DNA undetectable during treatment for at least 3 years; (4) Absence of advanced liver disease at the commencement of NUC therapy, characterized by an Ishak staging score of < 4 and/or liver stiffness of < 10 kilopascal as measured by transient elastography (FibroScan). Participants having a history of hepatic decompensation (ascites, encephalopathy, serum bilirubin > 2 mg/dL, variceal hemorrhage), signs of HCC, co-infection (human immunodeficiency virus or hepatitis C virus), pregnancy, and those on simultaneous immunosuppression were excluded.

Definitions of relapse and retreatment decision

Virological relapse was defined as HBV-DNA levels greater than 2000 IU/mL at one time during off-treatment follow-up. Biochemical relapse was characterized by ALT over twice the upper limit of normal (ULN) during one time of discontinued treatment follow-up, while clinical relapse was defined as the concurrent presence of HBV-DNA above 2000 IU/mL and ALT beyond twice the ULN[8].

A sustained response was defined by HBV-DNA levels under 2000 IU/mL and persistently normal ALT levels during the follow-up after therapy cessation.10. The duration of consolidation treatment was defined as the period following the achievement of undetectable HBV-DNA and normalization of ALT in HBeAg-negative CHB patients[3]. ALT exceeding 10 times the ULN or ALT surpassing 5 times the ULN in conjunction with total bilirubin greater than 2 mg/dL and/or prothrombin time prolongation following the cessation of medication has been classified as a substantial flare in prior studies[14]. In the follow-up period post-treatment discontinuation, we employed the identical retreatment criteria and recommenced treatment with the agreement of both the physician and the patient.

Statistical analysis

All data were analyzed with the statistical software SPSS 25 (International Business Machines Corporation, NY, United States). Continuous variables are expressed as mean ± SD or median ± IQR. The comparison of continuous variables between two patient groups was conducted using the t-test or Mann-Whitney test. The Wilcoxon matched-pairs signed-rank test was employed to compare continuous variables across multiple time points for the same individuals. Categorical variables were presented as frequencies and percentages. Comparisons between categorical variables were conducted using the corrected χ²d test or the two-sided Fisher’s exact test. Kaplan-Meier estimates of the cumulative chance of relapse or retreatment were calculated and analyzed using the log-rank test. Cox regression analysis was utilized to develop predictive models. P value below 0.5 were deemed statistically significant.

RESULTS

Baseline data

A total of 87 patients were included in the study. All of the patients tested negative for HBeAg at the initiation of NUC therapy. A liver biopsy was conducted on all patients prior to the introduction of treatment. The median Ishak fibrosis scores from liver biopsies of patients prior to initiating NUC treatment was 2 (range 0-3). Upon cessation of treatment, all patients’ HBV-DNA levels were below the detectable lower limit. The median age was 40 years (range 18 years to 67 years), with 57 individuals (65%) identifying as male. Patients were monitored for a median period of 38 months (range 36 months to 48 months). The median length of treatment was 84 months (range 38 months to 132 months), while the median length of consolidation was 68 months (range 34 months to 130 months). Upon discontinuation, 79 patients were administered entecavir, and 8 were taking tenofovir. Mean variation in pretreatment HBV-DNA value was 3.72 (3.21-13.2) log10 IU/mL, while pretreatment mean ALT level was 87 U/L (44 U/L to 321 U/L). Clinical features of the patients at NUC discontinuation (n = 87) are illustrated in Table 1. In four patients, ALT levels were below the norm at the commencement of NUC therapy. During the pretreatment follow-up, the ALT measurement of these patients fluctuated between elevated and normal ranges. Consequently, NUC initial rates were utilized as a reference. The status of patients whose treatment was discontinued and who were subsequently followed up untreated is depicted a column chart in Figure 1. During the follow-up process, 32 patients out of 87 patients (36%) underwent re-treatment, while 2 patient discontinued follow-up. The HBV-DNA (log10) levels (median IQR range) of untreated patients at follow-up are illustrated.

Figure 1 Long-term outcomes and related factors of hepatitis B e antigen negative chronic hepatitis B after nucleos(t)ide analog discontinuation. A: Cumulative rates of hepatitis B e antigen-negative chronic hepatitis B patients, who remained without retreatment after nucleos(t)ide analog discontinuation; B: The cumulative percentages of patients classified as inactive carriers (hepatitis B viral deoxyribonucleic acid < 2000 IU/mL and alanine aminotransferase < upper limit of normal); C: Factors affecting the persistence of hepatitis B viral deoxyribonucleic acid > 2000 IU/mL. UNC: Nucleos(t)ide analog.

Table 1 Characteristics of the 87 non-cirrhotic patients with hepatitis B e antigen-negative chronic hepatitis B at the discontinuation of nucleos(t)ide analog treatment, n (%).

Variable (n = 87)
Age		40.63 (18-67)
Male		57 (65.51)
BMI (kg/m2)		23.81 (18-41)
ALT (IU/L)		87.32 (65-378)
AST (IU/L)		78.21 (44-321)
Albumin (g/dL)		39.24 (32-64)
DNA HBV (IU/L)		37211 (3210-132000)
Ishak fibrosis	F2	51 (58.62)
	F3	36 (41.37)
NUC therapy	Entecavir	79 (90.80)
	Tenofovir	8 (9.20)
Time to undetectable HBV DNA (year)		5.83 (3-11)
Consolidation therapy duration (months)		46.2 (37-87)
Stiffness	< 7 kPa	21 (24.37)
	7 kPa to 9.5 kPa	66 (75.63)
HBsAg	≤ 100 IU/mL	16 (18.31)
	101 IU/mL to 1000 IU/mL	42 (48.27)
	≥ 1000 IU/mL	29 (33.33)

BMI: Body mass index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; DNA: Deoxyribonucleic acid; HBV: Hepatitis B viral; NUC: Nucleos(t)ide analog; HBsAg: Hepatitis B surface antigen.

Virological and biochemical relapses

The cumulative virological relapse rates, defined as HBV DNA over 2000 IU/mL, were 25%, 52%, 58%, and 61% at 6 months, 12 months, 24 months, and 36 months, respectively. Serum HBV DNA levels exceeding 20000 IU/mL were detected in 8%, 21%, 28%, and 28% of patients at 6 months, 12 months, 24 months, and 36 months, respectively. The aggregate biochemical relapse rates, characterized as ALT exceeding the ULN, were 2%, 28%, 32%, and 34% at 6 months, 12 months, 24 months, and 36 months, respectively. Consequently, ALT levels above 2 × ULN were 2%, 23%, 27%, and 27% at 6 months, 12 months, 24 months, and 36 months, respectively. Patients exhibiting combined ALT levels exceeding the upper limit of normal (ULN) and HBV DNA levels surpassing 2000 IU/mL or 20000 IU/mL during the 3 months to 48 months follow-up period were observed at rates of 25% to 61% and 8% to 28%, respectively. Consequently, patients exhibiting combined ALT levels exceeding 2 × ULN and HBV DNA levels greater than 2000 IU/mL or 20000 IU/mL demonstrated rates of 2% to 34% and 2% to 22% across the 6 months to 36 months follow-up period. Cumulative rates of biochemical, virological, or combination relapse are presented in Table 2.

Table 2 Cumulative rates of virological, biochemical or combined relapse in 87 non-cirrhotic patients with hepatitis B e antigen-negative chronic hepatitis B who discontinued nucleos(t)ide analog therapy, n(%).

Discontinuation of NUCs (n = 87)	HBV DNA > 200 IU/mL	HBV DNA > 2000 IU/mL			HBV DNA > 20000 IU/mL
	ALT = ULN	ALT = ULN	ALT > ULN	ALT > 2ULN	ALT = ULN	ALT > ULN
6 months	36	25	2	2	8	2
12 months	63	52	28	23	21	18
24 months	65	58	32	27	28	22
36 months	68	61	34	27	28	22

NUCs: Nucleos(t)ide analogues; HBV: Hepatitis B viral; DNA: Deoxyribonucleic acid; ALT: Alanine aminotransferase; ULN: Upper limit of normal.

Retreatment rates

The cumulative retreatment rates at 6 months, 12 months, 24 months, and 36 months were 19%, 25%, 28%, and 35%, respectively (Figure 1A). Thirty-eight patients (43%) returned to NUC treatment after an average interval of 9 months (range 1 months to 42 months). Among the 38 patients who met the criteria for resuming NUC treatment, 8 experienced flares with ALT exceeding 10 times the upper limit of normal (one of whom had baseline HBsAg levels below 10 IU/mL), one exhibited ALT greater than 5 times the upper limit of normal and total bilirubin of 2.6 mg/dL, 4 had ALT exceeding 3 times the upper limit of normal and HBV DNA greater than 100000 IU/mL, and 3 had ALT above the upper limit of normal and HBV DNA exceeding 2000 IU/mL on three consecutive visits.

All patients showed biochemical and virological responses following re-treatment with ETV or TDF, attaining undetectable serum HBV DNA and normalized ALT levels within the initial six months; however, none achieved HBsAg elimination. Of the residual 36 patients (41%), regular follow-up without therapy initiation has been maintained for over 36 months, with 25 of these patients having ≥ 60 months of follow-up. The cumulative percentages of patients classified as inactive carriers (HBV DNA < 2000 IU/mL and ALT < ULN) at 6 months, 12 months, 24 months, and 36 months were 71%, 68%, 50%, and 42%, respectively (Figure 1B). In the follow-up, HBV DNA levels diminished progressively after an average of 20 months ± 16 months to < 2000 IU/mL, with nine patients achieving undetectable HBV DNA 32 months ± 10 months post-peak. Additionally, four patients had a loss of HBsAg, with one demonstrating HBV DNA levels above 100000 IU/mL throughout follow-up.

Following the cessation of NUC treatment, HBsAg levels were < 100 IU/mL in 16 patients (18%), 100 IU/mL to 1000 IU/mL in 42 patients (48%), and > 1000 IU/mL in 29 patients (34%). Of the 49 untreated patients, 10 (22%) exhibited HBsAg levels below 100 IU/mL, 21 (44%) had HBsAg levels between 100 IU/mL and 1000 IU/mL, and 18 (36%) presented with HBsAg levels over 1000 IU/mL. During follow-up, one of the 38 patients (2%) and three of the 49 patients (6%) who did not receive retreatment lost HbsAg.

Re-treatment’s risk factors

The univariate analysis indicated that, with the exception of ALT levels and AST at three months of treatment, all aforementioned measures were risk factors for re-treatment. A multivariate logistic regression model was analyzed using variables identified as significant in the univariate analysis. The risk factors influencing clinical relapse in patients included gender, baseline HBV DNA levels, treatment method, and ALT and AST levels at cessation of treatment, Ishak fibrosis score > 2, and at the conclusion of treatment. In multivariate analysis, Ishak fibrosis score > 2 is the unique factor for retreatment (Figure 1C, Table 3). The relapsers were categorized into subgroups based on the timing of their relapses for additional study. Despite the results being insignificant, the duration of consolidation therapy was greater in the group that relapsed after 6 months compared to the group that relapsed within 6 months.

Table 3 Logistic regression analysis of the factors affecting the persistence of hepatitis B viral-deoxyribonucleic acid > 2000 IU/mL.

Factors	OR (95%CI)	P value
Age	1.01 (0.91, 1.89)	0.762
Gender (male)	1.86 (0.98, 2.29)	0.289
BMI	0.98 (0.71, 1.38)	0.891
ALT	1.78 (0.78, 1.98)	0.871
AST	1.45 (0.89, 1.87)	0.091
Albumin	0.88 (0.67, 0.92)	0.421
HBV DNA	1.23 (0.87, 1.89)	0.213
Fibrosis score > F2	3.68 (0.32, 16.89)	0.011
Stiffness (FibroScan)	0.91 (0.87, 1.03)	0.367
HBsAg at the end of NUC therapy	2.89 (0.87, 8.45)	0.228

OR: Odds ratio; CI: Confidence interval; BMI: Body mass index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; HBV: Hepatitis B viral; DNA: Deoxyribonucleic acid; HBsAg: Hepatitis B surface antigen; NUC: Nucleos(t)ide analogues.

DISCUSSION

Prolonged therapy remains the recommended method for patients with CHB. Nonetheless, concerns about treatment adherence and economic strain, particularly in resource-constrained areas, combined with research indicating that virological and clinical remission persists in non-cirrhotic patients after treatment cessation, prompted the development of NUC cessation guidelines for specific patients[6-9,14-16]. However, the discontinuation of NUC is still a contested question.

In this study we evaluated a cohort of 87 non-cirrhotic patients with HBeAg-negative CHB who stopped NUCs monotherapy and were followed for more than 3 years after NUC discontinuation. Different criteria for stopping treatment are established by guidelines for patients HBeAg-negative patients. The APASL stated that patients who received NUCs therapy for at least two years and had undetectable HBV-DNA levels in their serum three times with a 6 months interval could have their treatment discontinued, while the EASL stated that this would be feasible after at least three years of virological suppression. Conversely, the American Association for the Study of Liver Diseases advises that antiviral medication may be terminated solely in individuals who have achieved HBsAg clearance[3,9,14].

Our solid long-term prospective data unequivocally demonstrated that it is safe and possible for CHB patients without severe liver disease to stop receiving effective long-term NUC medication. None of the patients exhibited symptoms of hepatic failure or decompensation, and all retreated patients achieved remission immediately after the re-initiation of ETV or TDF. No instances of HCC development were observed during the follow-up period. Consequently, our findings unequivocally substantiate the most recent recommendations of the European guidelines, which propose that NUC discontinuation may serve as a novel approach to the treatment of non-cirrhotic HBeAg-negative CHB patients who have experienced long-term (> 3 years) on-therapy virological suppression and will be subjected to rigorous post-NUC observation[14].

Our data indicates that retreatment launched in over fifty percent of patients after 36 months to 48 months of follow-up. Lower retreatment rates were reported by three prospective studies that included Caucasian populations with HBeAg-negative CHB. The authors of the “Finite” study, which used different criteria for retreatment and relapse, reported that 8 (38%) of 21 participants restarted NUC during the 36 months follow-up period[17]. The “daratumumab + bortezomib” study[12], which used similar retreatment criteria, reported cumulative re-treatment rates of 26% at 12 months off-therapy. A study indicated a retreatment rate of 54%[18]. Retreatment rates may be explained by population heterogeneity, study size, varying definitions and criteria of retreatment, and disparities in long-term follow-up. Additional clinical research focusing on retreatment criteria is necessary to enhance patient management during follow-up.

Prior research has demonstrated that virological relapse happened in over fifty percent of individuals within the initial 6 months to 12 months post-treatment cessation[9,11,19]. At the 12 months and 24 months follow-up intervals, 85% and 90% of our patients exhibited HBV DNA levels over 2000 IU/mL, whereas 53% and 67% demonstrated HBV DNA levels surpassing 20000 IU/mL at least once during the visits. Significantly, 13 patients of the 29 patients who did not undergo retreatment exhibited serum HBV DNA levels exceeding 20000 IU/mL at least once, which subsequently diminished to below 2000 IU/mL with extended follow-up; six of these 13 patients (four with HBV DNA peaks exceeding 100000 IU/mL) attained undetectable HBV DNA, with two of them (one with a peak exceeding 100000 IU/mL) achieving HBsAg loss. The aforementioned highlights the fluctuating trajectory of HBV DNA post-discontinuation and the importance of meticulous monitoring; the dilemma between patient safety and the postponement of early retreatment to enhance HBsAg loss rates presents a clinical challenge that can be addressed through adherence to established retreatment criteria. Our data indicate that one third of the patients maintain HBV DNA levels below 2000 IU/mL and exhibited normal ALT levels at the three-year follow-up. The patient demographics (age, gender) and disease metrics such as ALT or HBV DNA levels, serum albumin, or platelet count at the commencement of NUC treatment were not predictive of outcomes following NUC cessation, based on an analysis of a subgroup of 39 patients with available laboratory screening data at the initiation of NUC treatment (data not shown); the sole determinant was the level of fibrosis.

The present emphasis of hepatitis B management research is to enhance the rates of HBsAg loss, which represents the nearest state of clinical cure for HBV. This research shown that the frequencies of HBsAg loss in HBeAg-negative individuals rose from 7% in the first 12 months to 20% at 36 months following the cessation of treatment. The predicted rate of HBsAg loss at 12 months post-treatment is approximately 10% to 20% according to several reports[19-21]. Research has shown that HBsAg levels at the conclusion of therapy may serve as a valuable predictor for determining the cessation of treatment. Proposed levels of 100 IU/mL, 120 IU/mL, 200 IU/mL, and 1000 IU/mL lack widespread consensus[20,22,23]. In our investigation, HBsAg levels below 100 IU/mL could forecast HBsAg loss. Regrettably, HBsAg levels below 100 IU are observed in quite a tiny fraction of patients (14%) undergoing NUC treatment, hence this cannot serve as the sole criterion for determining the cessation of NUC medication. The identification of relapse predictors is highly significant, necessitating more investigation into the interplay between clinical and immunological variables in forecasting off-treatment relapse or response. Our study posits that the elevated rate of HBsAg loss in patients who discontinued NUC treatment, relative to those who continued treatment, aligns with recent controlled research on the cessation of TDF therapy in HBeAg-negative patients without severe liver disease[17]. Consequently, discontinuing NUC therapy in HBeAg-negative non-cirrhotic patients, especially those with low HBsAg levels, may constitute a strategy for achieving a functional cure.

An additional important thing to clarify is the ideal timing for re-treatment, should it be deemed required. The EASL guideline has established the re-treatment method for patients who have ceased treatment, in conjunction with HBV-DNA levels exceeding 2000 IU/mL and ALT levels above the ULN. Numerous criteria and methodologies have been emphasized in research on this matter. In many studies, re-treatment commenced when HBV-DNA levels exceeded 2000 IU/mL, irrespective of ALT elevation[24,25]. Conversely, Papatheodoridis et al[20] investigation identified a distinct pattern for re-treatment. It is advised that severe flares, such as ALT over 10 times the upper limit of normal or ALT exceeding 5 times the ULN in conjunction with bilirubin levels exceeding 2 mg/dL (predominantly direct) and/or an extension of prothrombin time, should be re-treated. Furthermore, prolonged elevation of ALT beyond the upper limit of normal and HBV DNA exceeding 2000 IU/mL for a duration of at least 3 months to 6 months, indicative of chronic mild to severe liver disease activity, necessitates treatment[15]. In an Asian research, only 11.7% of patients exhibited a doubling of ALT levels, whereas 91.4% experienced virological relapse. The majority of patients in this study group underwent re-treatment, resulting in a very low rate of functional cure[26]. According to Hadziyannis et al[19], in their seminal work, the cessation of adefovir treatment in 33 HBeAg-negative patients resulted in virological relapse in all patients and biochemical relapse in 76% of them from the first month onward. In this trial, patients did not resume treatment immediately upon relapse and remained to be monitored, leading to HBsAg reduction in 39% of the patients. Consequently, it is reasonable to conclude that isolated virologic relapse without the danger of decompensation does not constitute a suitable rationale for resuming medication.

At present, vigilant monitoring following the cessation of treatment appears to be the most critical factor for identifying probable adverse outcomes and implementing prompt interventions[12]. Considering the studies indicating a higher frequency of virological and biochemical relapses in HBeAg-negative patients post-treatment cessation, our cohort of HBeAg-negative patients was monitored meticulously, particularly during the initial 3 months to 6 months, with supplementary follow-ups arranged as needed. The dispute centers on whether the expense of rigorous follow-up surpasses that of NUCs. Additional concerns requiring attention in subsequent research include the optimal timing for retreatment initiation and the identification of relapses that are advantageous vs those that risk decompensation. A systematic evaluation indicated that the incidence of hepatic decompensation following the termination of NUC ranged from 0.8% to 3%[11]. which is deemed acceptable. The primary limitation of our investigation was the absence of HBV genotype determination, as most prior studies did not demonstrate a significant correlation between genotype determination and relapses throughout the treatment-free follow-up period[21,27]. The comparison with the cohort of patients undergoing NUC treatment lacks a controlled analysis, as the results for this population were retrospectively gathered during a different timeframe.

CONCLUSION

Using predetermined criteria for retreatment, we found that half of our patients who stopped successful NUC therapy after a median of more than three years did not require retreatment; nearly one-third of them experienced a functional cure, and one-third were inactive. In resource-constrained areas, discontinuing NUC may be considered for early-stage patients with low baseline HBV DNA and ALT levels after a lengthy consolidation treatment. A higher pretreatment liver biopsy fibrosis score predicts relapse. Our findings and the idea of discontinuing treatment in HBeAg-negative hepatitis B patients should be considered in the upcoming period of clinical research for HBV, both when designing clinical studies and when evaluating response rates.