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Abstract Details
Withdrawal of Long-Term Nucleotide Analog Therapy in Chronic Hepatitis B: Outcomes From the Withdrawal Phase of the HBRN Immune Active Treatment Trial
Am J Gastroenterol. 2023 May 5. doi: 10.14309/ajg.0000000000002176. Online ahead of print.
1Toronto Centre for Liver Disease, University of Toronto University Health Network, Toronto, Ontario, Canada.
2Department of Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
3Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
4Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
6Liver Diseases Branch, NIDDK, NIH, Bethesda, Maryland, USA.
7Department of Medicine, St. Louis University School of Medicine, St. Louis, Michigan, USA.
8Department of Medicine, Baylor Scott and White Medical Center, Dallas, Texas, USA.
9Department of Medicine, University of California San Francisco, San Francisco, California, USA.
10Department of Medicine, University of Southern California, Los Angeles, California, USA.
11Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Abstract
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tenofovir (TDF) for 4 years ± an initial 6 months of peginterferon-α (PegIFN) (NCT01369212) after which treatment was withdrawn.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 <10 3 IU/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 log 10 IU/mL to reduce the risk of ALT flares, as they were not associated with subsequent HBsAg decline or loss.
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