[Correspondence] Fibrosis in patients with chronic hepatitis B and minimally raised ALT during tenofovir therapy

We read with interest the Article by Yao-Chun Hsu and colleagues describing a randomised controlled trial in patients with chronic hepatitis B and minimally raised alanine aminotransferase (ALT).Hsu YC Chen CY Chang IW et al.Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial. Several important points warrant further clarification or discussion.First, the proportion of patients given tenofovir disoproxil fumarate who had viral remission at 3 years (63 [85%] of 74) is lower than reported previously (approximately 96% of patients).Marcellin P Zoulim F Hezode C et al.Effectiveness and safety of tenofovir disoproxil fumarate in chronic hepatitis B: a 3-year, prospective, real-world study in France. Second, compared with previous studies of entecavir or tenofovir disoproxil fumarate, the proportion of patients given tenofovir disoproxil fumarate who had regression of fibrosis (12 [16%; 95% CI 9–27] of 73) is substantially lower and the proportion of patients with progression of fibrosis (19 [26%; 17–38]) is markedly higher in the study by Hsu and colleagues (table).Hsu YC Chen CY Chang IW et al.Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial. The effect of treatment on inhibiting fibrosis progression was greater in patients with an Ishak fibrosis stage of less than 3 before treatment than in those with an Ishak stage of 3 or higher before treatment, which contradicts the results of a previous large study of tenofovir disoproxil fumarate treatment over 5 years.Marcellin P Gane E Buti M et al.Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Furthermore, ten (13·7%) of 73 untreated control patients in the studyHsu YC Chen CY Chang IW et al.Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial. developed cirrhosis, which is markedly higher than the 35 (6·9%) of 509 HBeAg-positive and seven (4·0%) of 175 HBeAg-negative patients with chronic hepatitis B who developed cirrhosis during the 3-year follow-up period in the study by Liaw and colleagues.Liaw YF Tai DI Chu CM Chen TJ The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Are there any explanations for these contradictory results? What happened in these patients during follow-up every 12 weeks? Perhaps these results, and even the histology samples, need to be reanalysed, including for co-incidence with other causes of liver fibrosis (eg, steatosis). The rationale that low fibrosis stage before treatment might lead to a higher incidence of fibrosis progression during follow-up is difficult to understand.

TableHistological evidence for regression and progression of fibrosis following antiviral therapy

Data are n/N (%), unless otherwise stated. NA=not applicable.

Finally, the studyHsu YC Chen CY Chang IW et al.Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial. targeted patients who fell in the so-called grey zone of management recommendations among major international guidelines, which was generally defined as patients with a HBeAg-negative status, a HBV DNA concentration of 2000–20 000 IU/mL, and an ALT concentration of less than two-fold the upper limit of normal (ULN), and not those seropositive for HBeAg, or a HBV DNA concentration of more than 5·26 log10 IU/mL, or both.Hsu YC Chen CY Chang IW et al.Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial. As the aim of the study was to inform the decision to start antiviral therapy in so-called grey-zone patients, it is important to focus on HBeAg-negative patients with a HBV DNA concentration of 2000–20 000 IU/mL and a minimally raised ALT concentration (more than one-fold but less than two-fold the ULN) to evaluate the treatment benefit. Patients seropositive for HBeAg, with or without a HBV DNA concentration of more than 20 000 IU/mL, and with an Ishak stage of more than 3 are actually eligible for antiviral therapy according to all guidelines. These issues were not well addressed in the study.Hsu YC Chen CY Chang IW et al.Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial. Why inhibition of fibrosis progression in patients who received tenofovir disoproxil fumarate was only significant in those with a HBeAg-positive status before treatment (odds ratio 0·07 [95% CI 0·01–0·45]) but not in those with a HBeAg-negative status before treatment (0·66 [0·30–1·44], p=0·028) also requires clarification.

In conclusion, the proportions of patients given tenofovir disoproxil fumarate who had progression and regression of fibrosis in this study contradict earlier studies, and the results are insufficient to support their conclusion that tenofovir disoproxil fumarate reduced progression of fibrosis in patients with chronic hepatitis B who have an ALT concentration of less than two-fold the ULN. It is important to clarify the above issues before concluding that treatment should be expanded to all patients with minimally raised ALT.

We declare no competing interests.

References1.Hsu YC Chen CY Chang IW et al.

Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial.

Lancet Infect Dis. 21: 823-8332.Marcellin P Zoulim F Hezode C et al.

Effectiveness and safety of tenofovir disoproxil fumarate in chronic hepatitis B: a 3-year, prospective, real-world study in France.

Dig Dis Sci. 61: 3072-30833.Chang TT Liaw YF Wu SS et al.

Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B.

Hepatology. 52: 886-8934.Marcellin P Gane E Buti M et al.

Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.

Lancet. 381: 468-4755.Liaw YF Tai DI Chu CM Chen TJ

The development of cirrhosis in patients with chronic type B hepatitis: a prospective study.

Hepatology. 8: 493-496Article InfoPublication HistoryIdentification

DOI: https://doi.org/10.1016/S1473-3099(21)00317-0

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ScienceDirectAccess this article on ScienceDirect Linked ArticlesOnce-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial

Tenofovir disoproxil fumarate reduces the risk of progression in liver fibrosis in patients with chronic hepatitis B and minimally raised ALT, but its effect on necroinflammation is non-significant.

Full-Text PDF Fibrosis in patients with chronic hepatitis B and minimally raised ALT during tenofovir therapy – Authors' reply

We are grateful to Wen-Juei Jeng and colleagues for their thoughtful comments, which we address herein. We are confident that the proportion of patients who had viral remission (ie, a hepatitis B virus DNA concentration of <20 IU/mL) in the tenofovir disoproxil fumarate group is correct,1 and we were not surprised to find seemingly different point estimates from other studies, given differences in study design, patient populations, assay sensitivities, attrition during follow-up, and analytical approach, among other factors.

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