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Symptoms of Liver Disease During Tenofovir Therapy With or Without Peginterferon: Results from the Hepatitis B Research Network Immune Active Trial

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Abstract

Aims

Evaluate patient-reported liver symptoms during treatment for chronic hepatitis B viral (HBV) infection and associations between changes in symptoms and levels of alanine aminotransferase (ALT) and viral markers.

Methods

Data from 200 participants in the Hepatitis B Research Network Immune Active Trial who completed symptom assessments were analyzed. Patients were treated with tenofovir, with or without peginterferon (TDF + PegIFN vs. TDF alone) for 192 weeks. Participants completed a Symptom Checklist at baseline and every 4–12 weeks. A total symptom score was created, ranging from 0 (none) to 40 (severe). The SF-36 was completed every 48 weeks. Associations of symptom scores with ALT and viral markers were evaluated at baseline and end of treatment.

Results

Participants were 65% male, 83% Asian, with a mean age of 42. Baseline symptoms were mild (median = 2, range 0–25) and associated with baseline ALT, HBV DNA levels and HBeAg + status. Patients on TDF alone experienced a more rapid and greater improvement in symptoms, but by week 192, symptom improvement was similar in both groups (54% vs 36%). Symptom improvements correlated with ALT and HBV DNA, most markedly among those with symptoms at baseline. Most patients (4 out of 6) who achieved HBsAg loss experienced symptom improvements. Overall, SF-36 scores did not change with treatment.

Conclusions

Reduction in ALT and HBV DNA levels with therapy are associated with significant improvement in liver symptoms such as fatigue and pain over the liver, especially among those with higher ALT, HBV DNA, symptoms and HBeAg + status prior to treatment.

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Abbreviations

HBRN:

Hepatitis B research network

NIDDK:

National Institute of Diabetes and Digestive and Kidney Diseases

NIH:

National Institutes of Health

HBV:

Hepatitis B virus

ALT:

Alanine aminotransferase

HBsAg:

Hepatitis B surface antigen

HBeAg:

Hepatitis B e antigen

PegIFN alfa:

Peginterferon

TDF:

Tenofovir disoproxil fumarate

FDA:

Food and Drug Administration

PRO:

Patient-related outcome

HRQOL:

Health-related quality of life

IA:

Immune active

PCS:

Physical component summary

MCS:

Mental component summary

APRI:

Asparate aminotransferase platelet ratio index

ULN:

Upper limit of the normal range

qHBsAg:

Quantitative HBsAg concentration

qHBeAg:

Quantitative HBeAg concentration

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Acknowledgments

We wish to acknowledge the contributions of all members and important contributors of the Hepatitis B Research Network (HBRN: Supporting information) and to people living with chronic hepatitis B who participated in HBRN studies. Tenofovir (Viread®) was kindly provided by Gilead Sciences, Foster City, CA, PegIFN-alfa2a (Pegasys®) by Roche Genentech, San Francisco, CA, and assays for HBV DNA by Roche Diagnostics, Indianapolis, IN. These entities had no role in study design, data collection, data analysis or interpretation or the writing of this report.

Funding

The HBRN was funded as a Cooperative Agreement between the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the following investigators: Lewis R. Roberts, MB, ChB, PhD (U01-DK082843), Anna Suk-Fong Lok, MD (U01-DK082863), Steven H. Belle, PhD, MScHyg (U01-DK082864), Kyong-Mi Chang, MD (U01-DK082866), Michael W. Fried, MD (U01-DK082867), Adrian M. Di Bisceglie, MD (U01-DK082871), William M. Lee, MD (U01-DK082872), Harry L. A. Janssen, MD, PhD (U01-DK082874), Daryl T-Y Lau, MD, MPH (U01-DK082919), Richard K. Sterling, MD, MSc (U01-DK082923), Steven-Huy B. Han, MD (U01-DK082927), Robert C. Carithers, MD (U01-DK082943), Mandana Khalili, MD (U01-DK082944), an interagency agreement with NIDDK: Lilia M. Ganova-Raeva, PhD (A-DK-3002-001) and support from the intramural program, NIDDK, NIH: Marc G. Ghany, MD and David E. Kleiner, National Cancer Institute, NIH. Additional funding to support this study was provided to Kyong-Mi Chang, MD, the Immunology Center, (NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases P30DK50306, NIH Public Health Service Research Grant M01-RR00040), Richard K. Sterling, MD, MSc (UL1TR000058, NCATS (National Center for Advancing Translational Sciences, NIH), Mandana Khalili, MD, MPH (CTSA Grant Number UL1TR000004), Michael W. Fried, MD (CTSA Grant Number UL1TR001111), and Anna Suk-Fong Lok (CTSA Grant Number UL1RR024986, U54TR001959.) Additional support was provided by Gilead Sciences, Inc. and Roche Molecular Systems through Cooperative Research and Development Agreements (CRADAs) with the NIDDK, and Roche/Genentech through a Clinical Trials Agreement (CTA) with the NIDDK. Mandana Khalili was also in part supported by NIAAA (grant number K24AA022523). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Donna M. Evon

  2. Departments of Epidemiology and Biostatistics, University of Pittsburgh, Pittsburgh, USA

    Hsing-Hua S. Lin

  3. Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, USA

    Hsing-Hua S. Lin

  4. Department of Medicine, University of California at San Francisco, San Francisco, USA

    Mandana Khalili

  5. Department of Biostatistics, University of Pittsburgh, Pittsburgh, USA

    Abdus S. Wahed

  6. Toronto Centre for Liver Disease, University of Toronto, Toronto, Canada

    Colina Yim

  7. Department of Internal Medicine, University of Michigan, Ann Arbor, USA

    Robert J. Fontana

  8. Liver Disease Research Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), National Institutes of Health (NIH), Bethesda, USA

    Jay H. Hoofnagle

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  1. Donna M. Evon
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for the Hepatitis B Research Network (HBRN)

Contributions

(i) Guarantor of the article: D.M.E. (ii) Specific author contributions: Performed the research: D.E., H.-H.S.L., M.K., R.J.F., C.Y., A.S.W., J.H.H. Collected and analysed the data: D.E., H.-H.S.L., M.K., R.J.F., C.Y., A.S.W., J.H.H. Designed the research study: D.E., H.-H.S.L., A.S.W., J.H.H. Contributed to writing the manuscript: D.E., H.-H.S.L., M.K., R.J.F., C.Y., A.S.W., J.H.H. Contributed to the design of the study: D.E., H.-H.S.L., A.S.W., J.H.H. (iii) All authors have approved the final version of this manuscript.

Corresponding author

Correspondence to Donna M. Evon.

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Conflict of interest

Donna Evon has received research grant funding (to her institution) from Gilead Sciences Inc and Merck Sharp and Dohme. Mandana Khalili received research grant funding (to her institution) from Gilead Sciences Inc and Intercept Pharmaceutical and has served as a scientific consultant for Gilead Science. Robert Fontana has received research support from Gilead, BMS, and Abbvie and provides consulting to Alynam. Colina Yim has received speaker’s honorarium from Abbvie Canada, and consulting fees from Abbvie Canada and Lupin Pharma Canada. Hsing-Hua S. Lin, Abdus S. Wahed, and Jay H. Hoofnagle have no conflict of interests to disclose.

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Evon, D.M., Lin, HH.S., Khalili, M. et al. Symptoms of Liver Disease During Tenofovir Therapy With or Without Peginterferon: Results from the Hepatitis B Research Network Immune Active Trial. Dig Dis Sci 68, 4499–4510 (2023). https://doi.org/10.1007/s10620-023-08108-8

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