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Longitudinal renal changes in chronic hepatitis B patients treated with entecavir versus TDF: a REAL-B study

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Abstract

Background and aims

We aimed to compare the longitudinal changes in estimated glomerular filtration rate (eGFR) in chronic hepatitis B (CHB) patients treated with entecavir (ETV) vs. tenofovir disoproxil fumarate (TDF).

Methods

This is a retrospective study of 6189 adult treatment-naïve CHB patients initiated therapy with TDF (n = 2482) or ETV (n = 3707) at 25 international centers using multivariable generalized linear modeling (GLM) to determine mean eGFR (mL/min/1.73 m2) and Kaplan–Meier method to estimate incidence of renal impairment (≥ 1 chronic kidney disease [CKD] stage worsening). We also examined above renal changes in matched ETV and TDF patients (via propensity score matching [PSM] on age, sex, diabetes mellitus [DM], hypertension [HTN], cirrhosis, baseline eGFR, and follow-up duration).

Results

In the overall cohort (mean age 49.7 years, 66.2% male), the baseline eGFR was higher for TDF vs. ETV group (75.9 vs. 74.0, p = 0.009). PSM yielded 1871 pairs of ETV or TDF patients with baseline eGFR ≥ 60 and 520 pairs for the eGFR < 60 group. GLM analysis of the overall (unmatched) cohort and PSM cohorts revealed lower adjusted mean eGFRs in TDF (vs. ETV) patients (all p < 0.01) during 10 years of follow-up. Among PSM eGFR ≥ 60 patients, the 5-year cumulative incidences of renal impairment were 42.64% for ETV and 48.03% for TDF (p = 0.0023). In multivariable Cox regression, TDF vs. ETV (adjusted HR 1.26, 95% CI 1.11–1.43) was associated with higher risk of worsening renal function.

Conclusion

Over the 10-year study follow-up, compared to ETV, TDF was associated with a lower mean eGFR and higher incidence of renal impairment.

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Data available within the article or its supplementary materials.

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Abbreviations

ALT:

Alanine aminotransferase

CHB:

Chronic hepatitis B

CI:

Confidence interval

CKD:

Chronic kidney disease

DM:

Diabetes mellitus

EASL:

The European Association for the Study of the Liver

eGFR:

Estimated glomerular filtration rate

ETV:

Entecavir

HCC:

Hepatocellular carcinoma

HTN:

Hypertension

KDIGO:

Kidney Disease Improving Global Outcomes

NA:

Nucleos(t)ide analogs

PSM:

Propensity score matching

TAF:

Tenofovir alafenamide

TDF:

Tenofovir disoproxil fumarate

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Funding

None.

Author information

Author notes

  1. Lung-Yi Mak and Joseph Hoang have contributed equally.

Authors and Affiliations

  1. Department of Medicine, the University of Hong Kong, Hong Kong SAR, China

    Lung-Yi Mak, Rex Wan-Hin Hui, Vivien Tsui & Man-Fung Yuen

  2. State Key Laboratory for Liver Research, the University of Hong Kong, Hong Kong SAR, China

    Lung-Yi Mak & Man-Fung Yuen

  3. Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA

    Joseph Hoang, Lindsey Trinh, Allen Dao, Ramsey Cheung & Mindie H. Nguyen

  4. Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, South Korea

    Dae Won Jun & Hyunwoo Oh

  5. Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Chien-Hung Chen

  6. Department of Gastroenterology, China Medical University Hospital, Taichung, Taiwan

    Cheng-Yuan Peng

  7. Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    Ming-Lun Yeh, Pei-Chien Tsai, Chung-Feng Huang, Chia Yen Dai, Jee Fu Huang, Wan-Long Chuang & Ming-Lung Yu

  8. Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, China

    Sung Eun Kim

  9. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Daniel Q. Huang, Sabrina Quek, Htet Htet toe Wai Khine & Seng Gee Lim

  10. Division of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore

    Daniel Q. Huang & Seng Gee Lim

  11. Department of Internal Medicine, National Medical Center, Seoul, South Korea

    Jae Yoon Jeong

  12. Department of Internal Medicine, Sanggye Paik Hospital, Inje University Seoul, Seoul, South Korea

    Eileen Yoon

  13. Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University College of Medicine, Seoul, South Korea

    Sang Bong Ahn

  14. San Jose Gastroenterology, San Jose, CA, USA

    Huy Trinh

  15. Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

    Qing Xie

  16. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China

    Grace L. H. Wong

  17. Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan

    Masaru Enomoto & Ritsuzo Kozuka

  18. Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University School of Medicine, Seoul, South Korea

    Jae-Jun Shim

  19. Department of Gastroenterology, Good Gang-An Hospital, Busan, South Korea

    Dong-Hyun Lee

  20. Department of Infection Disease, The Third Hospital of Kumming City, Kumming, People’s Republic of China

    Li Liu

  21. Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Yong Kyun Cho

  22. Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, South Korea

    Soung Won Jeong

  23. Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea

    Hyoung Su Kim

  24. Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, People’s Republic of China

    Rui Huang & Chao Wu

  25. Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan

    Eiichi Ogawa

  26. Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Healthcare, Livermore, USA

    Ramsey Cheung

  27. Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA

    Mindie H. Nguyen

  28. Hepatitis Research Center, College of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan

    Ming-Lun Yeh, Pei-Chien Tsai, Chung-Feng Huang, Chia Yen Dai, Jee Fu Huang, Wan-Long Chuang & Ming-Lung Yu

Authors
  1. Lung-Yi Mak
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  2. Joseph Hoang
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  42. Mindie H. Nguyen
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Contributions

Study concept: MHN. Study supervision: MFY and MHN. Study design: LYM, JH, MFY, MHN. Data analysis: JH and MHN. Drafting of the article: LYM, JH, MFY, MHN. Data collection, data interpretation, review and/or revision of the manuscript: all authors. All authors identified have critically reviewed the paper and approve the final version of this paper, including the authorship statement.

Corresponding authors

Correspondence to Man-Fung Yuen or Mindie H. Nguyen.

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Conflict of interest

CYP: Consulting/ Advisory board member: Abbvie, Bristol Myers Squibb, Gilead Sciences, Roche. DQH: Research grant: Exxon Mobil-NUS Fellowship, NMRC Research Training Fellowship. HT: Research grant: Gilead Sciences, Intercept, Target; Consulting/ advisory board: Gilead Sciences; Speaker fees: Gilead Sciences; Stock ownership: Gilead Sciences. GLHW: Research grant: Gilead Sciences; Consulting/ advisory board: Gilead Sciences, Janssen; Speaker fees: Abbott, Abbvie, Bristol Myers Squibb, Gilead Sciences. DHL: Research grant: Bristol Myers Squibb Korea, Gilead Sciences (Korea), Janssen Korea, Korea Pharma. EO: Speaker fees: Gilead Sciences. CYD: Speaker fees: Abbvie, Merck Sharp and Dohme, Gilead Sciences, Roche, Bristol Myers Squibb. WLC: Consulting: Gilead Sciences, Abbvie, Bristol Myers Squibb, Merck Sharp and Dohme, PharmaEssentia; Speaker fees: Gilead Sciences, Abbvie, Bristol Myers Squibb, Merck Sharp and Dohme, PharmaEssentia. MLY: Research grant: Abbott, Bristol Myers Squibb, Gilead Sciences, Merck Sharp and Dohme; Consulting: Abbvie, Abbott, Ascletis, Bristol Myers Squibb, Gilead Sciences, Merck Sharp and Dohme, Roche; Speaker fees: Abbvie, Abbott, Bristol Myers Squibb, Gilead Sciences, Merck Sharp and Dohme, IPSEN. MFY: Research funding: Assembly Biosciences, Arrowhead Pharmaceuticals, Bristol Myer Squibb, Fujirebio Incorporation, Gilead Sciences, Merck Sharp and Dohme, Springbank Pharmaceuticals, Sysmex Corporation; advisory board member: Abbvie, Arbutus Biopharma, Assembly Biosciences, Bristol Myer Squibb, Dicerna Pharmaceuticals, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, Springbank Pharmaceuticals. MHN: Research grant: Gilead, Vir; Consulting/advisory board: Novartis, Spring Bank, Janssen, Gilead, Exact Sciences, Eli Lilly. All other authors have disclosed no personal conflict of interests in regards to the content of this paper.

Ethics approval

The study was conducted in accordance with the ethics principles of the Declaration of Helsinki in 1975, as revised in 2008, and was approved by the Institutional Review Board of Stanford University and at each participating institution.

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Mak, LY., Hoang, J., Jun, D.W. et al. Longitudinal renal changes in chronic hepatitis B patients treated with entecavir versus TDF: a REAL-B study. Hepatol Int 16, 48–58 (2022). https://doi.org/10.1007/s12072-021-10271-x

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