Research ArticleClinical Studies
Open Access

HB Surface Antigen Level as a Useful Predictor for the Treatment Response to Tenofovir Alafenamide in Nucleoside Analogue Naïve Chronic Hepatitis B

MASAHIRO MATSUI, AKIRA ASAI, KOSUKE USHIRO, KEISUKE YOKOHAMA, SHINYA FUKUNISHI, SOO KI KIM and HIROKI NISHIKAWA
In Vivo March 2023, 37 (2) 726-733; DOI: https://doi.org/10.21873/invivo.13134

Abstract

Aim: To elucidate factors contributing to hepatitis B virus (HBV)-DNA clearance following tenofovir alafenamide (TAF) therapy in nucleoside analogue (NA) naïve patients with chronic hepatitis B (CHB) (n=92, 11 cirrhotic cases). Patients and Methods: The time interval between the start of TAF therapy and first confirmed undetectable HBV-DNA after TAF therapy was calculated. Univariate and multivariate analyses of factors related to undetectable HBV-DNA after TAF therapy were performed. Results: HB envelop antigen seropositivity was found in 12 patients (13.0%). The cumulative undetectable HBV-DNA rate at 1- and 2- year was 74.9% and 90.9%. In the multivariate Cox regression analysis of the undetectable HBV-DNA after TAF therapy, HBsAg level >1,000 IU/ml (p=0.0082, HBsAg level <100 IU/ml as a reference standard) was an independent predictor of the undetectable HBV-DNA after TAF therapy. Conclusion: Baseline higher HBsAg level can be an adverse predictor for the undetectable HBV-DNA after TAF therapy in NA naïve CHB patients.

Key Words:

Chronic hepatitis B (CHB) virus infection is a worldwide public health threat, which leads to considerable liver-related mortality and morbidity (1). World Health Organization reported that in 2019, CHB resulted in an estimated 820,000 deaths, mostly from cirrhosis and hepatocellular carcinoma (2). In recent years, oral antiviral therapy has been increasingly used in the treatment of CHB (1). Nucleoside analogues (NAs) used in oral antiviral therapy include lamivudine, adefovir pivoxil, entecavir (ETV), tenofovir disoproxil (TDF), and their use has dramatically improved the outcome of CHB (3, 4). However, since many CHB patients require lifelong treatment, there has been a need to develop drugs that are potent, safe, and resistant to viral resistance. One of the therapeutic goals during administration of NAs in patients with CHB is achieving hepatitis B virus (HBV)-DNA negativity (5, 6).

Tenofovir alafenamide (TAF), a prodrug of tenofovir like TDF, is more stable in plasma than TDF and has been shown to exhibit equivalent anti-HBV activity at about 10% dose of TDF (7, 8). Two randomized controlled trials [HB envelop (HBe) Ag negative CHB and HBeAg positive CHB] showed that the treatment efficacy (i.e., virological response at 48 weeks of treatment) and incidence of adverse events up to 48 weeks with TAF in patients with CHB were comparable to those with TDF (5, 6). Furthermore, TAF was better than TDF with respect to its effects on bone and renal function (5, 6). TAF has been available in Japan since 2017. Their follow-up study showed that TAF was as effective as TDF in terms of virological response at 96 weeks (9). However, the time of HBV-DNA negativity following TAF therapy varies from case to case. In some cases, HBV elimination is achieved in a relatively short period of time of TAF therapy, while there are cases in which HBV elimination is obtained after prolonged administration of TAF. We believe that the time required for HBV elimination should be taken into consideration. Data on factors contributing to the effectiveness of long-term TAF therapy in patients with CHB are also limited.

In this study, we sought to elucidate factors contributing to the HBV-DNA clearance in patients with CHB receiving TAF therapy without previous NAs therapy.

Patients and Methods

Patients. The subjects were 92 consecutive patients with CHB with no previous history of NA treatment who were introduced to TAF therapy at our hospital between July 2017 and August 2022. TAF therapy (25 mg per day) was determined based on the current Japanese Society of Hepatology guidelines (10). Cirrhosis was determined based on radiological findings. The time interval between the start of TAF therapy and first confirmed undetectable HBV-DNA after TAF therapy was calculated. Univariate and multivariate analyses of factors related to the undetectable HBV-DNA after TAF therapy were performed. During the follow-up period, HBV-DNA level was monitored every 1-3 months. The institutional review board of Osaka Medical and Pharmaceutical University hospital provided ethical approval (approval number: 2022-142). Patient consent was waived due to the retrospective nature of our study.

Blood testing. Quantification of HB surface antigen (HBsAg), HB envelop antigen, HB core-related antigen (HBcrAg) and anti-HBe were determined using enzyme-linked immunosorbent assay (ELISA) or Chemiluminescent Enzyme Immunoassay (Lumipulse System, Fujirebio, Inc. Tokyo, Japan). HBV-DNA level was measured using COBAS TaqMan HBV Test (Roche Diagnostics K.K., Tokyo, Japan). In some cases, iTACT-HBcrAg testing was used (11). The lower detection limit of HBcrAg and iTACT HBcrAg was <3.0 log U/ml and <2.1 log U/ml, respectively.

Statistics. Pearson’s χ-square test was used for between-group comparisons. Kaplan-Meier method was used for the cumulative undetectable HBV-DNA rate after TAF therapy, and the log-rank test was used for testing. Factors with a p-value <0.05 in the univariate analysis were entered into the multivariate analysis (Cox proportional hazard model). The follow-up period was defined as the period from the start of TAF therapy to the date of first confirmed undetectable HBV-DNA after TAF therapy. A p=0.05 was set as the significance level by the JMP ver. 16 (SAS Institute Inc., Cary, NC, USA).

Results

Patients. Patient baseline characteristics (n=92, 43 males) in this study are presented in Table I. The average age was 66 years. Cirrhosis was found in 11 patients (12.0%). HBeAg seropositivity was found in 12 patients (13.0%). Regarding baseline HBsAg level, <100 IU/ml, >100 IU/ml and <1,000 IU/ml, and >1,000 IU/ml was found in 34, 18, and 40 patients, respectively. Regarding baseline HBV-DNA level, >5 log IU/ml and <5 log IU/ml was found in 24 and 68 patients, respectively. Regarding baseline HBcrAg level, <4.0 log U/ml, >4.0 log U/ml and <6.0 log U/ml, and >6.0 log U/ml was found in 73, 8, and 11 patients, respectively. HBV genotype was examined in 48 patients (52.2%). There were three patients with genotype A, three with genotype B and 42 with genotype C.

View this table:
Table I.

Baseline characteristics (n=92).

Relationship between HBcrAg level and HBsAg level. In patients with HBcrAg <4.0 log U/ml (n=73), the proportion of patients with HBsAg level <100 IU/ml, >100 IU/ml and <1,000 IU/ml, and >1,000 IU/ml was 43.8% (32/73), 21.9% (16/73) and 34.3% (25/73), respectively. In patients with 4.0 log U/ml <HBcrAg <6.0 log U/ml (n=8), the proportion of patients with HBsAg level <100 IU/ml, >100 IU/ml and <1,000 IU/ml, and >1,000 IU/ml was 12.5% (1/8), 12.5% (1/8) and 75.0% (6/8), respectively. In patients with HBcrAg >6.0 log U/ml (n=11), the proportion of patients with HBsAg level <100 IU/ml, >100 and <1,000 IU/ml, and >1,000 IU/ml was 9.1% (1/11), 9.1% (1/11) and 81.8% (9/11), respectively (Overall p=0.0137, Figure 1).

Figure 1.
Figure 1.

Relationship between Hepatitis B core-related antigen (HBcrAg) levels and HB surface antigen (HBsAg) levels.

HBcrAg level between patients with positive and negative HBeAg. In patients with HBcrAg <4.0 log U/ml, the proportion of HBeAg-positive patients was 0% (0/73). In patients with 4.0 log U/ml <HBcrAg <6.0 log U/ml, the proportion of HBeAg-positive patients was 37.5% (3/8). In patients with HBcrAg >6.0 log U/ml, the proportion of HBeAg-positive patients was 81.82% (9/11) (Overall p<0.0001, Figure 2A).

Figure 2.
Figure 2.

Hepatis B surface antigen (HBcrAg) levels. (A) HBcrAg levels in patients with HB envelop antigen (HBeAg)-positive and negative patients. (B) HBcrAg levels in cirrhotic and non-cirrhotic patients.

HBcrAg level between cirrhotic and non-cirrhotic patients. In patients with HBcrAg <4.0 log U/ml, the proportion of cirrhotic patients was 9.6% (7/73). In patients with 4.0 log U/ml <HBcrAg <6.0 log U/ml, the proportion of cirrhotic patients was 37.5% (3/8). In patients with HBcrAg >6.0 log U/ml, the proportion of cirrhotic patients was 9.1% (1/11) (Overall p<0.0001, Figure 2B).

Cumulative undetectable HBV-DNA rate after TAF therapy for all cases. During the follow up period, undetectable HBV-DNA was found in 81 patients (88.0%). The median time interval between the start of TAF therapy and first confirmed undetectable HBV-DNA was 91 days. The cumulative undetectable HBV-DNA rate at 1- and 2-year was 74.9% and 90.9%, respectively (Figure 3).

Figure 3.
Figure 3.

Cumulative undetectable hepatitis B virus (HBV)-DNA rate after tenofovir alafenamide (TAF) therapy for all cases.

Cumulative undetectable HBV-DNA rate after TAF therapy according to the HBV status. In patients with and without HBeAg positivity, the cumulative 1- and 2-year undetectable HBV-DNA rate after TAF therapy, was 0% and 48.2%, and 85.7% and 96.4%, respectively (p<0.0001, Figure 4A).

Figure 4.
Figure 4.

Cumulative undetectable Hepatitis B virus (HBV)-DNA rate after tenofovir alafenamide (TAF) therapy according to HBe positivity status (A) and HBV-DNA levels (B).

In patients with HBV-DNA level >5 log IU/ml and <5 log IU/ml, the cumulative 1- and 2-year undetectable HBV-DNA rate after TAF therapy, was 36.2% and 56.2%, and 86.1% and 100%, respectively (p<0.0001, Figure 4B).

In patients with HBsAg level <100 IU/ml, >100 IU/ml and <1,000 IU/ml, and >1,000 IU/ml, the cumulative 1- and 2-year undetectable HBV-DNA rate after TAF therapy, was 88.2% and 100%, 77.8% and 94.4%, 62.4% and 80.4%, respectively (p<0.0001, Figure 5A).

Figure 5.
Figure 5.

Cumulative undetectable Hepatitis B virus (HBV)-DNA rate after tenofovir alafenamide (TAF) therapy according to HB surface antigen (HBsAg) levels (A) and HB core-related antigen (HBcrAg) levels (B).

In patients with HBcrAg level <4.0 log U/ml, >4.0 log U/ml and <6.0 log U/ml, and >6.0 log U/ml, the cumulative 1- and 2-year undetectable HBV-DNA rate after TAF therapy, was 87.8% and 100%, 41.7% and 61.1%, and 9.1% and 48.1%, respectively (p<0.0001, Figure 5B).

Discontinuation of TAF therapy. During the follow up period, no serious adverse events were observed. The discontinuation rate due to side effects of TAF was 0%.

Uni- and multivariate analysis of the undetectable HBV-DNA after TAF therapy. In the univariate analysis of factors associated with the undetectable HBV-DNA after TAF therapy, age ≥65 years (p=0.0010), alanine aminotransferase ≥30 IU/l (p<0.0001), baseline HBV-DNA level >5 log IU/ml (p<0.0001), HBeAg positivity (p<0.0001), HBsAg level (p<0.0001), and HBcrAg level (p<0.0001) were significant factors (Table II). In the multivariate Cox regression analysis of factors associated with the undetectable HBV-DNA after TAF therapy, HBsAg level >1,000 IU/ml (p=0.0082, HBsAg level <100 IU/ml as a reference standard) was an independent predictor of the undetectable HBV-DNA after TAF therapy. While age ³65 years (p=0.0562) and HBcrAg level >6.0 log U/ml (p=0.0524, HBcrAg level <4.0 log U/ml as a reference standard) tended to be significant. Odds ratios in each factor are shown in Table III.

View this table:
Table II.

Univariate analyses of factors linked to undetectable hepatitis B virus-DNA after tenofovir alafenamide therapy.

View this table:
Table III.

Multivariate analyses of factors associated with undetectable Hepatitis B virus (HBV)-DNA after tenofovir alafenamide therapy.

Discussion

Several reports regarding predictors for response to NAs therapy in patients with CHB have been accumulated (12, 13). However, there are few reports regarding predictors for response to NAs in naïve patients with CHB undergoing TAF therapy. As described in the introduction, HBV elimination is achieved in a relatively short period of time after TAF therapy in some cases, while there are cases in which HBV elimination is obtained after prolonged TAF administration. Therefore, the time required for HBV elimination should be taken into consideration, and thus in this study we analyzed the time interval between the start of TAF therapy and the first confirmed undetectable HBV-DNA.

In this study, HBsAg level was an independent predictor of the time period to the undetectable HBV-DNA after TAF therapy. HBsAg is a diagnostic marker of HBV infection, and its quantification is now used to predict the natural course of HBV infection and the response to treatment in patients with CHB (14-16). Clinically, HBsAg level is used as: 1) a predictive marker of disease progression (17); 2) a predictive marker for liver carcinogenesis (18, 19); 3) a predictor of pegylated interferon treatment response (20, 21); 4) an indicator of discontinuation of NAs therapy (22); and 5) a predictor of treatment response during NAs therapy (23-27). In addition, HBsAg well reflects intrahepatic covalently closed circular DNA (cccDNA) levels in patients with CHB (21, 28). Our results show that baseline HBsAg level was an independent predictor for undetectable HBV-DNA after TAF therapy is deemed to be one of the highlighted points. In cases of higher HBsAg levels, the combination of TAF and ETV should also be considered (3). A decrease in HBsAg levels during antiviral therapy for patients with CHB is also an important indicator (3, 29).

Serum HBcrAg is a viral marker developed in Japan, which is measured in combination with HBeAg, HB core antigen and 22kDa precore protein (30, 31). Recently, a highly sensitive HBcrAg assay method “iTACT-HBcrAg”, which is 10 times more sensitive than the conventional method, has been developed and put into practical use (11). Most importantly, it may be a more appropriate and universal marker of HBV proliferative capacity than HBsAg levels, which may not be measurable due to HBV mutations (30, 31). HBcrAg is also a surrogate marker for intrahepatic cccDNA level and a predictor of liver carcinogenesis (19, 28, 32). In the present study, HBcrAg level significantly correlated with HBsAg level and HBeAg positivity, and HBcrAg >6.0 log U/ml was a factor indicating a significant trend toward HBV-DNA negativity after TAF therapy (p=0.0524). HBcrAg level may be a predictor of treatment response during TAF treatment in NAs naïve patients with CHB.

In patients with undetectable HBV-DNA after TAF therapy (81 patients), the median time interval between the start of TAF therapy and first confirmed undetectable HBV-DNA was 91 days, which was relatively shorter than previous reports (5, 6). This may be due in part to the fact that cases of HBV carriers with low viral load who received TAF for reactivation prophylaxis due to the introduction of anticancer therapy or immunosuppressive therapy achieved undetectable HBV-DNA at an early stage. However, presence of cirrhosis or FIB-4 index was not a significant factor in this analysis. Liver disease progression may be less relevant, and HBV-related factors are associated with treatment response. In terms of treatment safety, the discontinuation rate due to serious side effects of TAF was 0% in this study, which is in line with previous reports (5, 6, 9). Indeed, TAF therapy for patients with CHB is safe (33).

There are several limitations to the study. First, our study was a retrospective single center observational study. Second, our study cohort was relatively small (n=92). Third, HBV genotype was not tested for all analyzed patients, contributing to bias. Differences in HBV genotype may affect treatment efficacy (34, 35). Nevertheless, our study denoted that higher baseline HBsAg level was an adverse predictor for undetectable HBV-DNA after TAF therapy in NA naïve patients with CHB.

In conclusion, clinicians should be aware that HBsAg level can be a useful predictor for the undetectable HBV-DNA after TAF therapy in NA naïve patients with CHB.

Acknowledgements

The Authors gratefully thank all medical staff in our department for their help with data collection.

Footnotes

  • Authors’ Contributions

    Data curation, all Authors; Supervision, Hiroki Nishikawa; Writing – original draft, Hiroki Nishikawa and Matsui Masahiro; Writing – review & editing, all Authors; Final approval, all Authors.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare in relation to this study.

  • Received December 24, 2022.
  • Revision received January 2, 2023.
  • Accepted January 4, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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HB Surface Antigen Level as a Useful Predictor for the Treatment Response to Tenofovir Alafenamide in Nucleoside Analogue Naïve Chronic Hepatitis B
MASAHIRO MATSUI, AKIRA ASAI, KOSUKE USHIRO, KEISUKE YOKOHAMA, SHINYA FUKUNISHI, SOO KI KIM, HIROKI NISHIKAWA
In Vivo Mar 2023, 37 (2) 726-733; DOI: 10.21873/invivo.13134
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