Randomized Trial of Tenofovir With or Without Peginterferon Alfa Followed by Protocolized Treatment Withdrawal in Adults With Chronic Hepatitis B

Abstract

Hepatitis B surface antigen (HBsAg) loss is associated with improved long-term outcomes of patients with chronic hepatitis B but is infrequently achieved with current monotherapies. We assessed whether combination strategies that included treatment withdrawal enhanced HBsAg loss. METHODS:A randomized (1:1) trial of tenofovir disoproxil fumarate (TDF) for 192 weeks with or without peginterferon (PegIFN) alfa-2a for the first 24 weeks, followed by withdrawal of TDF at week 192 with 48 weeks of off-treatment follow-up to week 240. The primary end point was HBsAg loss at week 240. RESULTS:Of 201 participants (52% HBeAg positive, 12%/6% genotype A/A2, 7% cirrhosis) randomized to TDF 1 PegIFN (n 5 102) or TDF alone (n 5 99), 6 participants had lost HBsAg at the end of the treatment phase (week 192), 5 (5.3%) in the combination group, and 1 (1.0%) in the TDF alone group (P 5 0.09). By week 240, 9 participants had cleared HBsAg, 5.3% in combination, and 4.1% in monotherapy arms (P 5 0.73). HBsAg decline and loss occurred earlier with TDF 1 PegIFN than TDF, with a ‡1-logIU/mL qHBsAg decline by week 24 in 28% in TDF 1 PegIFN compared with 6% in TDF (P 5 0.04). HBsAg loss occurred in 7 of 12 (58%) with hepatitis B virus subgenotype A2 (all HBeAg positive) compared with only 2 of 189 (1%) with other hepatitis B virus genotypes and in 8 of 93 (8.6%) HBeAg positive vs 1 of 87 (1.1%) HBeAg negative. DISCUSSION:PegIFN combined TDF followed by protocolized TDF withdrawal led to earlier but not higher percentages of HBsAg clearance. Pretreatment HBeAg positivity and subgenotype A2 were strongly associated with HBsAg clearance.

Safety and yield of percutaneous liver biopsy in adults and children with chronic hepatitis B: Results from a prospective, multicenter study

“… 23 For example, among 281 participants screened for an HBRN clinical trial, 11 were excluded for mild liver disease, potentially sparing these individuals long-term treatment (at least in the near term). 24 Therefore, we recommend that practitioners and patients with CHB should not hesitate to undergo percutaneous liver biopsy when clinically indicated to inform medical decision-making.…”

Aiming for Functional Cure With Established and Novel Therapies for Chronic Hepatitis B

“…(38) A recent study from the Hepatitis B Research Network of 201 patients with CHB also reported a higher rate of HBsAg loss of 4.4% at 192 weeks among patients treated with TDF in combination with PEG-IFNα (24 weeks) versus 1.0% among those treated with TDF alone, although statistically insignificant (P = 0.20). (39) Cumulatively, these data suggest that PEG-IFNα plus NA de novo combination therapy increases rates of HBsAg loss compared with NA alone and potentially PEG-IFNα monotherapy also, although the enhancement may be more pronounced with newer NAs (e.g., TDF). Therefore, PEG-IFNα remains a therapeutic option, as it is the only well-characterized, approved immunomodulator capable of improving serological response from a finite duration compared with long-term NA therapy.…”

Association of Alanine Aminotransferase Flares to Hepatitis B Surface Decline During Tenofovir Alone or With Pegylated Interferon Alfa

“…Participants were enrolled in the Hepatitis B Research Network trial (8). Serum samples were analyzed for quantitative assessments of HBsAg (qHBsAg) by the Elecsys II platform (Roche Molecular Systems, Branchburg, NJ, lower limit of 0.05 IU/mL) at a central virology laboratory.…”

“…The Hepatitis B Research Network recently reported the findings of a chronic hepatitis B (CHB) treatment trial comparing either 24 weeks of PegIFN combined with tenofovir disoproxil fumarate (TDF) or TDF monotherapy (8). Tenofovir was given for 192 weeks in both treatment arms (8). As a reduction in serum HBsAg concentration occurred in a substantial number of cases during treatment, this secondary analysis of the clinical trial was conducted to evaluate whether the magnitude of treatment-induced ALT flares was associated with the degree of HBsAg decline.…”

“…The Hepatitis B Research Network recently reported the findings of a chronic hepatitis B (CHB) treatment trial comparing either 24 weeks of PegIFN combined with tenofovir disoproxil fumarate (TDF) or TDF monotherapy (8). Tenofovir was given for 192 weeks in both treatment arms (8).…”