Compare HBV relapse rates in patients who discontinue tenofovir disoproxil fumarate or tenofovir alafenamide fumarate

doi:10.21203/rs.3.rs-1353362/v1

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Compare HBV relapse rates in patients who discontinue tenofovir disoproxil fumarate or tenofovir alafenamide fumarate

https://doi.org/10.21203/rs.3.rs-1353362/v1

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Background/purpose: Clinical relapse occurred majorly within the first six months after stopping tenofovir disoproxil fumarate (TDF) in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients. However, the incidence and relapse pattern in patients stopping Tenofovir alafenamide fumarate (TAF), a prodrug of tenofovir which more concentrated in hepatocyte, is unknown.

Methods: HBeAg-negative CHB patients stopping TDF (off-TDF) or switch to TAF more than 3 months (off-TAF) before discontinuation from two medical centers were recruited. The propensity score-matching method (PSM) was used by creating a ratio of 1:3 between the off-TAF group versus the off-TDF group to adjust age, sex, HBV genotype, cirrhosis, HBV DNA at entry, treatment and consolidation duration and end-of-treatment (EOT) HBsAg.

Results: After PSM, 60 off-TAF and 180 off-TDF patients were analyzed. In off-TDF group, the cumulative rates of virological and clinical relapse at 52 weeks were 75.4% and 57.4%, respectively, and were 90.8% and 63.6% in off-TAF group, respectively. Patients in off-TAF group had significantly higher virological relapse rates than those in off-TAF group (p = 0.031), but not clinical relapse (p = 0.418). Multivariate cox regression analysis showed that off-TAF group was an independent factor of virological relapse, but not clinical relapse. Retreatment rate and severity of clinical relapse and hepatic decompensation rate were comparable between off-TDF and off-TAF groups

Conclusions: Off-TDF group had a higher virological relapse rate than off-TAF group in HBeAg-negative CHB patients. However, the difference of clinical relapse pattern and severity was not clinically important between two groups.

clinical relapse

chronic hepatitis B

cirrhosis

decompensation

hepatitis B surface antigen

hepatitis B e antigen

nucleos(t)ide analogues

propensity score matching

retreatment

virological relapse

Nucleos(t)ide analogues (NAs) have become the cornerstone of treatment for chronic hepatitis B (CHB) as they effectively suppress hepatitis B virus (HBV) replication and reduce hepatic inflammation. Entecavir and tenofovir disoproxil fumarate (TDF) are preferred potent drugs with effective viral suppression, optimal resistance profiles and are used as a first-line therapy and the cornerstone of CHB treatment for chronic hepatitis B (CHB) [1–3]. However, patients rarely achieve hepatitis B surface antigen (HBsAg) loss during treatment [4, 5]. Finite Nucleos(t)ide analogues (NAs) therapy has therefore become widely accepted for non-cirrhotic HBeAg negative chronic hepatitis B(CHB) patients, with the emerging concept of “to-Stop-to-Cure” for the significant increased incidence of functional cure [6, 7].

In recent studies shown that HBV relapse occurred in 40–50% of patients stopping entecavir or TDF therapy 7–9], which occurred much earlier after cessation of TDF therapy than cessation of entecavir therapy in hepatitis B e antigen (HBeAg)-negative patients [1013]. Tenofovir alafenamide fumarate (TAF), a prodrug of tenofovir with higher plasma stability and lower renal and bone toxicity than TDF [14], has been reported to achieve similar antiviral efficacy and better renal safety compared to TDF [1517]. Whether the HBV relapse rate or pattern are different in patients cessation of TAF comparing to those off-TDF remains unknown. In previous pilot study, the off-therapy relapse pattern was in accordance with of the NA at time of discontinuation rather than the start of treatment [18]. This study aims to investigate the incidence and timing of off-therapy relapse between HBeAg-negative CHB patients stopping TDF monotherapy (off-TDF) and those switch from TDF to TAF more than 3 months prior to discontinuation (off-TAF) after propensity score matching.

Patients recruitment

Fig 1 shows the flow chart of patients enrolled in this study. The patients who enrolled in this study were prospectively followed-up with retrospective assays from two tertiary hospitals located in Northern and Southern part of Taiwan (Linkuo and Kaohsiung Chang Gung Memorial Hospital). The study subjects included 508 (CGMH-KH: 228, CGMH-LK: 288) HBeAg negative CHB patients who received TDF treatment from 2011 to 2019. In addition, 60 (CGMH-KH: n=31. CGMH-LK: n=29) HBeAg-negative CHB patients who received TDF at the start treatment and switching to TAF until to end of treatment for at least 12 weeks (median: 54, range 20-103 weeks) were recruited. All patients were HBeAg seronegative before and throughout TDF or TAF therapy. The reasons of switching to TAF were due to new drug available and safety concern, but not due to neither suboptimal virological suppression nor viral breakthrough. All patients fulfilled the antiviral-agent stopping criteria of APASL of 2012 [19]. The APASL 2012 guidelines suggested NA discontinuation in HBeAg-negative CHB patients may be considered if patients had three times of undetectable HBV DNA with 6 month apart [19]. During the study period, Taiwan's National Health Plan reimbursed patients for 3 years of NAs therapy. Most patients stopped either ETV or TDF therapy according to the criteria of Taiwan's National Health Plan to avoid bearing the expense of the drug. The patients and clinical physician determined whether shorter or prolonged treatments were prescribed. Patients were excluded if they had evidence of autoimmune hepatitis, alcoholic liver disease, or positive markers of human immunodeficiency virus, hepatitis C virus, or hepatitis D virus. Patients who had received immunosuppressive therapy or chemotherapy were excluded. Patients who had achieved HBsAg loss prior to Nuc cessation were also excluded. All patients enrolled in this study had post-treatment follow-up for at least 6 months.

The propensity score-matching method (PSM) was used by creating a ratio of 1:3 between the off-TAF group versus the off-TDF groupto adjust age, sex, HBV genotype, cirrhosis, HBV DNA at entry, treatment and consolidation duration and end-of-treatment (EOT) HBsAg. After PSM, 60 and 180 patients in the off-TAF and off-TDF groups were included in this study. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the appropriate institutional review committee. All patients provided written informed consent, and the study was approved by the Research Ethics Committees of Chang Gung Memorial Hospital.

Methods

Off-therapy follow-up and laboratory assessment

After NA cessation, the patients were followed up every month during the first three months and every 3 months thereafter until their last hospital visit or the time of retreatment. During the increase alanine aminotransferase (ALT) level, especially > two times upper limit of normal (X ULN), weekly to biweekly monitoring was suggested till the descending of ALT for close monitoring and identification of early signs of decompensation [19]. HBV DNA was assessed every 1-3 months in the first year and every 3-6 months thereafter. Additional HBV DNA was assessed when virological or clinical relapse was found. Serum HBsAg quantification was carried out using stored serum at baseline and at the end of treatment in those lack prospectively assessed due to not routine reimbursed by Taiwan’s health insurance policy.

Definition of HBV relapse and criteria of retreatment

Virological relapse was defined as the reappearance of serum HBV DNA levels ≥ 2000 IU/mL after stopping NA therapy. Clinical relapse was defined as an episode of ALT elevation >2X ULN plus HBV DNA ≥2000 IU/mL after cessation of NA therapy [19]. The consolidation duration was calculated from the first demonstration of undetectable HBV DNA to the end of treatment.

The criteria for retreatment in Taiwan's National Health Plan are an ALT ≥ 2× ULN twice 3 months apart and HBV DNA ≥ 2000 IU/mL in HBeAg-negative patients without cirrhosis. The criteria for retreatment are HBV DNA ≥ 2000 IU/mL in patients who fulfilled the diagnosis of cirrhosis according to either histology or repeated ultrasounds suggestive of cirrhosis and clinical features, such as splenomegaly and gastroesophageal varices. The criteria for retreatment of decompensated patients were total biliruin ≥ 2 mg/dL or prothrombin time prolongation ≥ 3 seconds, regardless of HBV DNA levels.

Serology

The presence of HBsAg, HBeAg, and anti-hepatitis C virus antibodies was determined using commercial assay kits (HBsAg EIA, Abbott, North Chicago, IL; HBeAg EIA, Abbott; anti-HCV, EIA 3.0, Abbott). HBsAg titers were quantified using Elecsys HBsAg II Quant reagent kits (Roche Diagnostics, Indianapolis, IN) according to the manufacturer’s instructions with a lower limit of detection of 0.05 IU/ml. Serum HBV DNA was quantified using the COBAS TaqMan HBV test (CAP-CTM; Roche Molecular Systems, Inc., Branchburg, NJ, USA) with a lower limit of detection of 20 IU/ml.

HBV genotyping

The HBV genotypes in sera were determined by restriction fragment length polymorphism analysis of the S-gene sequence, which was amplified by polymerase chain reaction with nested primers, as described previously [20].

Statistical analysis

Data are presented as the mean ± standard deviation or median (range) for normal and non-normal distributed continuous variables, respectively, while categorical variables presented as number of cases (proportions). To compare values between the two groups, the chi-squared or Fisher’s exact tests were applied to analyze categorical variables, and the student’s t test or Mann-Whitney U test were used for normal or non-normal continuous variables, respectively. The Kaplan-Meier analysis with a log-rank test was used to compare the cumulative incidences of post-treatment virological and clinical relapse between the off-TAF and off-TDF groups. Cox proportional hazards regression models with the forward method were performed to identify independent factors associated with post-treatment virological and clinical relapse using the variables which appear to be significant in the univariate analysis (<0.05) or clinical significance will be entered into multivariate analysis for adjustment. All statistical tests were two-sided with significance determined at a P-value of 0.05.

The propensity score-matching method was used to reduce the significant differences in clinical features between the off-TAF and off-TDF at a 1:3 ratio, including adjusting age, gender, HBV genotype, NA-naïve, baseline HBV DNA, treatment and consolidation duration, and HBsAg levels at the end of treatment (EOT). Caliper matching was performed on the propensity score (nearest available matching). Pairs (discontinuing and continuing groups) on the propensity score logit were matched to within a range of 0.2 SD [21,22]. All statistical analysis were done by SPSS 22.0.

Clinical characteristics of the study population

The clinical features of Off-TAF and Off-TDF groups after propensity score matching are shown in Table 1. There was no significant difference in clinical feathers and HBsAg levels between two groups. The median times of post-treatment follow-up in Off-TDF and Off-TAF groups were 78 weeks (range: 32–390 weeks) and 40 weeks (range 26–96 weeks), respectively (p < 0.001).

Table 1

Clinical characteristics of study population
	Off-TAF group n = 60	Off-TDF group n = 180	p value
Age (years)	53.1 ± 8.2	53.9 ± 10.6	0.593
Sex (male: female)	48:12	146:34	0.850
ALT (U/L)	366.4 ± 645.5	348.8 ± 453.6	0.816
Total bilirubin (mg/dL)	1.59 ± 2.26	1.42 ± 1.40	0.486
HBV DNA (log IU/mL)	6.32 ± 1.19	6.35 ± 1.54	0.879
Cirrhosis (%)	7 (11.7%)	29 (16.1%)	0.404
HBV genotype B C	45 (75%) 15 (25%)	137 (76.1%) 43 (23.9%)	0.862
Treatment duration (weeks)	166.4 ± 40.3	160.3 ± 31.3	0.224
Consolidation duration (weeks)	131.1 ± 36.5	123.4 ± 34.9	0.146
NA-naïve status	29 (52.6%)	81 (57.0%)	0.654
HBsAg at baseline (log IU/mL)	3.16 ± 0.75	3.15 ± 0.82	0.967
HBsAg at the end of treatment (log IU/mL)	2.42 ± 0.76	2.37 ± 0.86	0.694
ALT, alanine aminotransferase; HBV, hepatitis B virus, HBsAg: hepatitis B surface antigen; HBeAg, hepatitis B e antigen; NA, nucleoside analogues; TAF, Tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate.

Incidence and predictors of post-treatment virological relapse and clinical relapse

Of the 180 CHB patients in the TDF group, the cumulative rates of virological relapse at 13, 26, 52 and 104 weeks were 39.4%, 61.7%, 75.1% and 83.5%, and the clinical relapse rates were 26.1%, 45.6%, 57.4% and 67.6%, respectively. In the off-TDF group, the median times of virological and clinical relapse were 13 weeks (range: 4-138 weeks) and 16 weeks (range 5-264 weeks), respectively.

Of the 60 CHB patients in the TDF with switching to TAF (off-TAF) group, the cumulative rates of virological relapse at 13, 26, and 52 weeks were 48.3%, 76.7%, and 90.8%, and the clinical relapse rates were 33.3%, 53.4%, and 63.6%, respectively. In the TDF with switching to TAF group, the median times of virological and clinical relapse were 12 weeks (range: 4–49 weeks) and 12 weeks (range: 8–67 weeks), respectively. Patients who discontinued TDF with switching to TAF therapy had significantly higher virological relapse rates than those who discontinued TDF therapy (p = 0.031). There was no significant difference in the clinical relapse rate between two groups (p = 0.418).

Predictors of post-treatment virological and clinical relapse at 52 weeks after NAs cessation.

Because the number of cases of post-treatment follow up duration more than one year was limited in TDF with switching to TAF group, we analyzed the predictors of virological and clinical relapse rates at 52 weeks after cessation of TDF with or without switching to TAF therapy. Patients who discontinued TDF with switching to TAF therapy had significantly higher virological relapse rates than those who discontinued TDF therapy (p = 0.029) (Fig. 2a). There was no significant difference in the clinical relapse rate between two groups (p = 0.541) (Fig. 2b). Multivariate analysis showed that off-TAF group, cirrhosis and higher EOT HBsAg were independent factors of virological relapse, and cirrhosis, higher HBV DNA at baseline and EOT HBsAg levels were independent factors of clinical relapse at 52 weeks after cessation of TDF with or without switching to TAF therapy (Tables 2 and 3).

Table 2

Factors predictive of virological relapse within 52 weeks
Variables	Univariate analysis		Multivariate analysis
Variables	HR (95% CI)	p value	HR (95% CI)	p value
Age (per year)	1.006 (0.992–1.020)	0.392
Sex (Male vs. female)	0.814 (0.570–1.162)	0.257
Cirrhosis, yes vs. no	1.508 (1.020–2.230)	0.040	1.590 (1.074–2.351)	0.020
Off-TAF vs. Off- TDF groups	1.420 (1.031–1.954)	0.032	1.400 (1.017–1.928)	0.039
ALT (per U/mL)	1.000 (1.000–1.000)	0.739
Total bilirubin (per mg/dL)	0.950 (0.867–1.041)	0.270
HBV DNA (per log IU/mL)	1.087 (0.987–1.197)	0.092
HBV genotype (C vs. B)	0.914 (0.646–1.292)	0.609
NA-naïve status	1.309 (0.985–1.739)	0.064
HBsAg at baseline (per log IU/L)	1.140 (0.959–1.356)	0.137
HBsAg at the end of treatment (per log IU/L)	1.415 (1.173–1.707)	< 0.001	1.420 (1.177–1.713)	< 0.001
Treatment duration (per week)	1.000 (0.996–1.004)	0.977
Consolidation duration (per week)	0.997 (0.993–1.001)	0.186
TAF duration Off-TDF group (reference) n = 180 Off-TAF group < 52 weeks, n = 23 Off-TAF group ≥ 52 weeks, n = 37	1 1.217 (0.760–1.949) 1.579 (1.077–2.314)	0.413 0.019
ALT, alanine aminotransferase; CI, confidence interval; HR, Hazard ratio; HBV, hepatitis B virus, HBsAg: hepatitis B surface antigen; NA, nucleoside analogues; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate

Table 3

Factors predictive of clinical relapse within 52 weeks
Variables	Univariate analysis		Multivariate analysis
Variables	HR (95% CI)	p value	HR (95% CI)	p value
Age (per year)	1.008 (0.992–1.025)	0.322
Sex (Male vs. female)	1.259 (0.811–1.953)	0.305
Cirrhosis, yes vs. no	1.763 (1.151–2.701)	0.009	1.775 (1.158–2.721)	0.008
Off-TAF vs. Off- TDF groups	1.125 (0.770–1.644)	0.544
ALT (per U/mL)	1.000 (0.999-1.000)	0.233
Total bilirubin (per mg/dL)	0.916 (0.807–1.039)	0.172
HBV DNA (per log IU/mL)	1.178 (1.051–1.320)	0.005	1.162 (1.036–1.303)	0.010
HBV genotype (C vs. B)	0.996 (0.674–1.742)	0.985
NA-naïve status	1.371 (0.985–1.907)	0.061
HBsAg at baseline (per log IU/L)	1.228 (1.002–1.505)	0.048
HBsAg at the end of treatment (per log IU/L)	1.322 (1.061–1.646)	0.013	1.306 (1.053–1.620)	0.015
Treatment duration (per week)	1.002 (0.997–1.006)	0.490
Consolidation duration (per week)	0.997 (0.992–1.002)	0.317
TAF duration Off-TDF group (reference) n = 180 Off-TAF group < 52 weeks, n = 23 Off-TAF group ≥ 52 weeks, n = 37	1 1.035 (0.592–1.808) 1.191 (0.751–1.889)	0.905 0.457
ALT, alanine aminotransferase; CI, confidence interval; HR, Hazard ratio; HBV, hepatitis B virus, HBsAg: hepatitis B surface antigen; NA, nucleoside analogues; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate

There was no significant difference in virological relapse (p = 0.539 and p = 0.078, respectively) and clinical relapse (p = 0.591 and p = 0.405, respectively) at 3 and 6 months after NA cessation between off-TDF and off-TAF groups.

In the univariate analysis, the duration of TAF therapy ≧ 52 weeks (not < 52 weeks) in off-TAF group was a significant predictor of virological relapse compared with off-TDF group. However, the duration of TAF therapy was not an independent factor of virological and clinical relapse (Tables 2 and 3).

Incidence and predictors of retreatment at 52 weeks after NAs cessation.

Of the 180 and 60 CHB patients in the off-TDF and off-TAF groups, 64 and 19 received retreatment at 52 weeks of cessation of TDF or TAF therapy, respectively. The cumulative incidences of retreatment at 52 weeks were 35.8% and 38.3% in the off-TDF and off-TAF groups, respectively. Only higher HBV DNA level at baseline was independent factor of retreatment (Hazard ratio (HR): 1.315, 95% confidence incidence: 1.127–1.534, p = 0.001). There was no significant difference in retreatment rate between the two groups (p = 0.929).

Severity of clinical relapse and hepatic decompensation between off-TDF and off-TAF groups

Among the 130 clinical relapsers in off-TDF and 38 in off-TAF groups, 47 (36.1%) and 20 (52.6%) occurred within the 3 months and 83 (63.8%) and 33 (86.8%) occurred within 6 months from discontinuation. The median peak ALT level at time of relapse between off-TDF and off-TAF were 471.5 versus 397.5 (U/L), p = 0.643. The severity of ALT flares between off-TDF and off-TAF groups were listed as Table 4. There was no significant difference in severity of ALT flares between off-TDF and off-TAF groups. We defined hepatic decompensation as total bilirubin > 3.5 mg/dL (more than 2.5 times the upper limit of normal (1.4 mg/dL)) and prolonged PT > 3 seconds, or INF > 1.5 according to APASL guideline of 2015 [23]. There was no significant difference in the rate of hepatic decompensation between the two groups (Table 4). No patient died in both groups after timely retreatment.

Table 4

Highest ALT levels and hepatic decompensation upon clinical relapse
	Off-TAF group (n = 38)	Off-TDF group (n = 130)	p value
ALT ≥ 200 U/L, n (%)	28 (73.7%)	100 (76.9%)	0.680
ALT ≥ 400 U/L, n (%)	19 (50%)	78 (60%)	0.312
ALT ≥ 1000 U/L, n (%)	5 (13.2%)	16 (12.3%)	0.902
Hepatic decompensation, n (%)	2 (5.3%)	5 (3.8%)	0.701
ALT, alanine aminotransferase; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate.

Predictors Of Post-treatment Hbv Relapse In Off-taf Groups

In 60 patients with TDF switching to TAF therapy, univariate analysis showed that no any significant factor could predict virological relapse. In contrast, univariate analysis showed that higher HBV DNA at baseline and EOT HBsAg levels were significant factors for clinical relapse (Supplementary Table 1). Multivariate analysis showed that only HBV DNA at baseline (HR: 1.358, 95% CI: 1.067–1.729, p = 0.013) was an independent factor of clinical relapse. The duration of TAF therapy was not a significant predictor of virological or clinical relapse. Furthermore, there was no significant different in virological relapse (p = 0.343) and clinical relapse (p = 0.737) between patients with TAF treatment ≥ 52 weeks and < 52 weeks.

Recent studies showed that HBV relapse occurred much earlier after cessation of TDF therapy than cessation of entecavir therapy in HBeAg-negative patients [10, 11, 13, 24]. The real mechanism remains uncertain in spite of recent immunological studies suggesting that the HBV specific CD8 + T cell phenotype may be different between nucleotide analogue (adefovir) and nucleoside analogue (entevavir) therapy (25). TAF is a new prodrug of tenofovir that enables more efficient delivery into hepatocyte with a lower dose than with TDF [14]. In primary human hepatocyte, TAF resulted in high level of the pharmacological active metabolite tenofovir diphosphate (TFV-DP) with half-life (t_1/2) of TFV-DP to be > 24 hours. In animal study using beagle dogs [26], more efficient hepatic delivery by TAF was noted than that by TDF with the apparent t_1/2 of hepatic TFV-DP > 20 hours. Thus, it has been speculated that those stopping TAF may have decreased relapse rate or deferred relapse timing than that off-TDF. In Taiwan, TAF has been reimbursed since May, 2019. Hence it is difficult for us to recruit mono-TAF treated patients who had already treated for 3 years and planned to discontinue TAF. In recent pilot study comparing relapse pattern between mono-entecavir or mono-TDF treated and switch-ETV or switch-TDF populations, the off-therapy relapse pattern goes along with the later NA rather than that at start of treatment [18]. Based on these evidences, it is reasonable that the relapse pattern in those starting with TDF whom later switching to TAF more than 3 months may be same as those using mono-TAF.

Our current study is the first report showing that higher virological relapse rate in the off-TAF group was noted than that in the off-TDF group. There was no significant difference in the clinical relapse rate between the two groups. Due to the follow-up duration in off-TDF group is much longer than that in off-TAF group, it is more reasonable to compare the event incidence within 52 weeks between off-TAF and off-TDF groups. In this current study, univariate analysis also showed that off-TAF group had a higher rate of virological relapse than off-TDF group (p = 0.029). There was no significant difference in the rates of clinical relapse and retreatment between the two groups. Our result also showed that the difference in virological relapse rate between the two groups was observed after 6 months off-therapy, but not as early as 3 or 6 months after treatment. Multivariate analysis showed that TDF with switching to TAF groups was an independent predictor associated with virological relapse, but not clinical relapse or retreatment. Furthermore, patients who received longer duration of TAF therapy (≥ 52 weeks) in off-TAF group seemed to be associated with higher virological relapse rate than those in off-TDF group. Although the duration of TAF therapy is not an independent predictor of virological relapse, it is worthy to note that patients who discontinued TAF monotherapy might be associated with higher virological relapse rate than those who discontinued TDF monotherapy. Our study suggests that the longer half-life in hepatocyte of TFV-DP in off-TAF patients did not yield higher durability of off-NA response, standing for the minimal correlation between the half-life of drug and off-therapy outcome. However, we could not explain the real mechanism why virological relapse rate was higher in TAF switch group. The key reason for why off-TAF and off-TDF which both relapse timing being much earlier than those off-entecavir may be the different influence of intrahepatic active metabolite (tenofovir diphosphate) and triphosphate of entecavir metabolites on the duration of reverse transcriptase inhibition. Another possible reason is that those stopping entecavir required longer time to rebuild the transcriptional active covalently closed circular DNA (cccDNA) to a threshold level to elicit relapse or flare [27]. We would suggest that patients who discontinued TAF monotherapy should be monitored closely first 3 or 6 months in HBeAg-negative CHB patients, even who fulfilled the antiviral-agent stopping criteria. Further studies are needed to confirm this important issue after cessation of TAF monotherapy.

This study has some limitations. First, the treatment assignments were not randomized. However, we used the propensity score-matched method to reduce the significant differences in baseline and on-treatment factors between the two groups. The TDF with switching to TAF group was an independent factor associated with an increased rate of virological relapse after adjusting for risk factors. Second, the number of cases of TDF with switching to TAF group was not large enough for further stratification analysis to investigate whether they exist differences in certain subgroups such as higher or lower pretherapy HBV DNA or EOT HBsAg. Third, the number of cases of TDF with switching to TAF group is limited in HBeAg-positive patients. Thus, we did not compare the HBV relapse rate between the off-TDF and off-TAF groups in HBeAg-positive patients. Forth, the off-therapy follow-up duration was not long enough in the off-TAF group, which we could not report the long-term outcome, including HBsAg loss rate, in these patients over 52 weeks of follow-up. Thus, our findings worth to be validated by another large prospective cohort study or randomized trial.

In conclusion, the virological relapse rate was higher in off-TAF group compared with in off-TDF group in HBeAg-negative CHB patients. In contrast, clinical relapse incidence and pattern, retreatment rate and severity of clinical relapse and hepatic decompensation were comparable between off-TDF and off-TAF groups in HBeAg-negative CHB patients. Therefore, the difference of HBV relapse was not clinically important between two groups. The off-therapy follow-up protocol in off-TAF patients shall be adhered to that in the current off-TDF patients which closely and stringent monitoring in the first 6 months after discontinuation is warranted for patients’ safety.

ALT, alanine aminotransferase; CHB, chronic hepatitis B; CR, clinical relapse; EOT, end-of-treatment; HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; NA, nucleoside analogues; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate; ULN, upper limit of normal

Data Availability: Data available upon requested to corresponding authors

Animal Research (Ethics): Not applicable

Consent to Participate (Ethics): Not applicable

Consent to Publish (Ethics): Not applicable

Plant Reproducibility: Not applicable

Clinical Trials Registration: Not applicable

Author Contribution: Conceptualization: Chien-Hung Chen; Methodology: Chien-Hung Chen and Wen-Juei Jeng; Formal analysis and investigation: Chien-Hung Chen and Wen-Juei Jeng, Writing - original draft preparation: Chien-Hung Chen; Writing - review and editing: Chien-Hung Chen and Wen-Juei Jeng; Funding acquisition: Chien-Hung Chen and Wen-Juei Jeng; Resources: Tsung-Hui Hu, Yen-Chun Liu, Jing-Houng Wang, Chao-Hung Hung, Sheng-Nan Lu, Rong-Nan Chien Supervision: Chien-Hung Chen.

Conflict of Interest: Chien-Hung Chen, Wen-Juei Jeng, Tsung-Hui Hu, Yen-Chun Liu, Jing-Houng Wang, Chao-Hung Hung, Sheng-Nan Lu, Rong-Nan Chiendeclare that they have no conflict of interest.

Funding: This study was financially supported by grants NMRPG8G6102 from the Ministry of Science and Technology and CMRPG8F0222, CMRPG3K0842, CMRPG3L0881from the Chang Gung Memorial Hospital, Taiwan.

Ethics approval: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (Chang Gung Memorial Hospital (IRB No.: 202002188B0 and IRB 202000151B0) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study.

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Compare HBV relapse rates in patients who discontinue tenofovir disoproxil fumarate or tenofovir alafenamide fumarate

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Abstract

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Introduction

Patients And Methods

Results

Clinical characteristics of the study population

Incidence and predictors of post-treatment virological relapse and clinical relapse

Severity of clinical relapse and hepatic decompensation between off-TDF and off-TAF groups

Discussion

Abbreviations

Declarations

References

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