Withdrawal of Long-Term Nucleotide Analog Therapy in Chronic Hepatitis B: Outcomes From the Withdrawal Phase of the HBRN Immune Active Treatment Trial

Jordan J. Feld*, Abdus S. Wahed, Michael Fried, Marc G. Ghany, Adrian M. Di Bisceglie, Robert P. Perrillo, Mandana Khalili, Xue Yang, Steven H. Belle, Harry L.A. Janssen, Norah Terrault, Anna S. Lok

*Corresponding author for this work

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INTRODUCTION:Withdrawal of nucleos(t)ide analog therapy is increasingly being evaluated in chronic hepatitis B infection as a strategy to induce hepatitis B surface antigen (HBsAg) loss. The Hepatitis B Research Network Immune-Active Trial evaluated treatment with tenofovir (TDF) for 4 years ± an initial 6 months of peginterferon-α (PegIFN) (NCT01369212) after which treatment was withdrawn.METHODS:Eligible participants (hepatitis B e antigen [HBeAg]-/anti-HBe+, hepatitis B virus [HBV] DNA <103IU/mL, no cirrhosis) who discontinued TDF were followed for at least 1 year with optional follow-up thereafter. Retreatment was based on predefined criteria.RESULTS:Among 201 participants who received 4 years of treatment, 97 participants (45 TDF and 52 TDF + PegIFN arm, 79 Asian) discontinued TDF. HBsAg loss occurred in 5 participants, 2 within 25 weeks and 3 within 89-119 weeks postwithdrawal (cumulative rate 4.3% by 2 years). Alanine aminotransferase (ALT) flares (>5× upper limit of normal) after TDF withdrawal occurred in 36 (37.1%) participants and occurred more frequently and earlier in those HBeAg- compared with HBeAg+ at treatment initiation. ALT flares were associated with older age and higher HBV DNA pretreatment and at the visit before the flare. ALT flares were not significantly associated with HBsAg decline or loss but were associated with immune active disease at 1 year (70.6% vs 11.9%, P < 0.0001) and 2 years (66.7% vs 25.9%, P = 0.03) postwithdrawal. Treatment reinitiation was required in 13 (13.4%) participants, and 13 others remained in a sustained inactive carrier state by the end of the study follow-up. No criteria reliably predicted safe treatment withdrawal.DISCUSSION:Results from this trial do not support TDF withdrawal as a therapeutic strategy. HBsAg loss was infrequent within 2 years of stopping long-term TDF. If withdrawal is considered, HBV DNA should be carefully monitored with reinitiation of therapy if levels rise above 4 log10IU/mL to reduce the risk of ALT flares, as they were not associated with subsequent HBsAg decline or loss.

Original languageEnglish
Pages (from-to)1226-1236
Number of pages11
JournalAmerican Journal of Gastroenterology
Issue number7
Publication statusPublished - 1 Jul 2023

Bibliographical note

Funding Information:
Financial support: 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), Jordan J. Feld MD MPH (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. 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 (CTSA Grant Number UL1TR000004), Michael W. Fried, MD (CTSA Grant Number UL1TR001111), and Anna Suk-Fong Lok (CTSA Grant Number UL1RR024986 and U54TR001959.) Additional support was provided by Gilead Sciences and Roche Molecular Systems through Cooperative Research and Development Agreement (CRADA) with the NIDDK and Roche/Genentech through a Clinical Trials Agreement (CTA) with the NIDDK.

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