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In Vitro and In Vivo Renoprotective Effects of Telbivudine in Chronic Hepatitis B Patients Receiving Nucleotide Analogue

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Abstract

Aim

Renal toxicity of adefovir disoproxil (ADV) and tenofovir disoproxil fumarate (TDF) is a significant concern in chronic hepatitis B (CHB) patients. Early observational clinical data suggested that telbivudine (LdT) might have renoprotective effects.

Methods

In this prospective study, consecutive CHB patients on combined lamivudine (LAM) + ADV/TDF were switched to LdT + ADV/TDF at recruitment and were followed up for 24 months. Estimated glomerular filtration rate (eGFR) was calculated with the modification of diet in renal disease equation. The effects of LdT on cell viability and expression of kidney injury or apoptotic biomarkers were investigated in cultured renal tubular epithelial cell line HK-2.

Results

Thirty-one patients (median age 55 years, 90.3% male) were recruited (54.8% TDF: 45.2% ADV). Serum HBV DNA was undetectable at all time points. Median eGFR was 70.2 (IQR 62.6–77.9) and 81.5 (IQR 63.6–99.1) mL/min/1.73 m2 at baseline and 24 months, respectively (p < 0.001). Downstaging of chronic kidney disease was observed in eight (25.8%) patients and was more common in ADV-treated compared to TDF-treated patients (7/8 vs. 1/17, p = 0.011; OR 16, 95% CI 1.643–155.766, p = 0.017). In vitro data showed that adding LdT to ADV or TDF was associated with improved cell viability and lower expression of injury and apoptotic biomarkers compared with ADV or TDF alone. Treatment was prematurely discontinued in four(12.9%) patients due to myalgia.

Conclusions

Clinical and in vitro data suggest that LdT has renoprotective effects in patients on long-term ADV/TDF treatment. LdT may be considered as an adjuvant therapy in this special group of patients with renal impairment (NCT03778567).

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Funding

This study was sponsored by Novartis Pharmaceuticals (Hong Kong) Limited, which was not involved in the study design and execution, data analyses, and writing of manuscript. The in vitro studies were supported by the Hong Kong Society of Nephrology Research Grant 2017 awarded to Mr. Paul Lee and Dr. Desmond Yap, and the Hong Kong College of Physicians Young Investigator Research Grant 2016 awarded to Dr. Desmond Yap.

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Author notes

  1. Lung-Yi Mak and Sze-Hang Liu have contributed equally to the study.

Authors and Affiliations

  1. Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road 102, Pokfulam, Hong Kong

    Lung-Yi Mak, Sze-Hang Liu, Desmond Yat-Hin Yap, Wai-Kay Seto, Danny Ka-Ho Wong, James Fung, Tak-Mao Chan, Ching-Lung Lai & Man-Fung Yuen

  2. State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong

    Wai-Kay Seto, Danny Ka-Ho Wong, James Fung, Ching-Lung Lai & Man-Fung Yuen

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  1. Lung-Yi Mak
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Correspondence to Man-Fung Yuen.

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Conflict of interest

WK Seto is an advisory board member of Gilead Sciences and Bristol-Myers Squibb and received speaker fees from Gilead Sciences, Bristol-Myers Squibb, and Novartis. J Fung received research funding from Novartis. CL Lai received speaker fees from Bristol-Myers Squibb, Novartis and Gilead Sciences, and is an advisory board member of Gilead Sciences. MF Yuen received speaker fees from GlaxoSmithKline, Bristol-Myers Squibb, Novartis, and Gilead Sciences; and received research funding and is an advisory board member of Bristol-Myers Squibb, Novartis, and Gilead Sciences. The remaining authors have no conflict of interest.

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Mak, LY., Liu, SH., Yap, D.YH. et al. In Vitro and In Vivo Renoprotective Effects of Telbivudine in Chronic Hepatitis B Patients Receiving Nucleotide Analogue. Dig Dis Sci 64, 3630–3641 (2019). https://doi.org/10.1007/s10620-019-05717-0

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