Randomized trial of 192 weeks of tenofovir with or without peginterferon alfa for the first 24 weeks followed by protocolized withdrawal in adults with chronic hepatitis B
About 5% in Randomized Trial Lose HBsAg After Long-Term TDF Stops
AASLD The Liver Meeting Digital Experience, November 13-16, 2020
Mark Mascolini
After 240 weeks of follow-up, 4.5% of people with chronic HBV treated for 192 weeks with tenofovir disoproxil fumarate (TDF) alone lost hepatitis B surface antigen (HBsAg), compared with 5.7% who combined 192 weeks of TDF with 24 weeks of peginterferon alfa 2a (PegIFN), a nonsignificant difference [1]. The proportion who lost hepatitis B e antigen (HBeAg) was 41% with TDF alone versus 61% with combined therapy, a difference that stopped short of statistical significance (P = 0.06).
Researchers who conducted this randomized parallel-group trial [2] noted that loss of HBsAg, indicating functional cure of chronic HBV infection, has become a frequent goal of anti-HBV therapy. People who lose HBsAg run a low risk of HBV disease progression. Treatment with nucleos(t)ides like TDF is limited by the need for long-term use and a low rate of HBsAg loss, especially in HBeAg-negative people. (HBsAg indicates current HBV infection; HBeAg indicates replicating, transmissible HBV.)
This trial aimed to assess the safety and efficacy of 192 weeks of TDF alone or with 24 weeks of PegIFN followed by structured withdrawal of TDF in participants with immune-active chronic HBV infection. The trial focused on participants in the Hepatitis B Research Network (HBRN), which has 21 clinical sites in the United States and 1 in Canada. Participants had to be at least 18 years old and free from antiviral therapy for at least 24 weeks before entering the trial. They could be HBeAg-positive or negative but could not have HIV, HCV, or HDV infection.
Researchers randomized participants 1-to-1 to take TDF alone for 192 weeks or TDF for 192 weeks plus PegIFN for 24 weeks. At week 192 participants could stop TDF if their HBV DNA lay below 1000 IU/mL for the previous 24 weeks, if they were HBeAg-negative and anti-HBe positive, and if they did not have cirrhosis. During the withdrawal phase, participants had to restart TDF if certain signals of liver disease progression arose. Follow-up continued until week 240, when the primary outcome was HBsAg loss.
The study included 102 people randomized to TDF alone and 99 randomized to dual therapy. Of the 102 TDF-alone participants, 96 got evaluated for TDF withdrawal at week 96, 51 stopped TDF (53% of 96), and 96 completed the study to week 240. Of the 99 people in the dual-therapy group, 92 got evaluated for TDF withdrawal, 60 stopped TDF (65% of 92), and 92 completed the study. Among those eligible for TDF withdrawal, 30% in the TDF-alone group and 39% in the dual-therapy group met criteria for inactive chronic HBV infection, a nonsignificant difference (P = 0.39).
Median age stood at 41 in both treatment groups. The TDF-alone group had a slightly lower proportion of women (30% vs 40%) and a barely lower proportion of Asians (80% vs 86%). Similar proportions in the TDF-alone and dual-therapy groups tested positive for HBeAg at the initial study visit (53% and 49%), and initial HBV DNA levels were similar in the two groups (medians of 6.7 and 6.3 log IU/mL).
In an intention-to-treat analysis after 240 weeks, 4 people (4.5%) in the TDF-alone group and 5 (5.7%) in the dual-therapy group lost HBsAg, a small and nonsignificant difference (P = 0.74). Cumulative incidence of HBsAg loss over 240 weeks did not differ by treatment group (P = 0.92). At the 240-week point, a slightly lower proportion in the TDF-alone group than in the dual-therapy group lost HBeAg (41% vs 61%), though that difference fell shy of statistical significance (P = 0.06). The two treatment groups differed little at week 240 in proportions with a normal alanine aminotransferase (ALT) (61% and 64%), HBV DNA below 20 IU/mL (51% and 53%), and HBV DNA below 1000 IU/ml plus a normal ALT (45% and 49%).
Throughout the study, 11% taking TDF alone and 7% taking TDF plus PegIFN had a serious adverse event. The proportion of participants with an ALT flare was marginally lower in the TDF-alone group (24% vs 31%). Most flares in the TDF-alone group (70%) came when TDF stopped, and most in the dual-therapy group (58%) came during dual therapy (the first 24 weeks).
The researchers suggested these results can inform the long-term management of chronic HBV infection until more effective therapies become available.
References
1. Terrault N, Lok AS, Wahed A, et al. Randomized trial of 192 weeks of tenofovir with or without peginterferon alfa for the first 24 weeks followed by protocolized withdrawal in adults with chronic hepatitis B. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 19.
2. ClinicalTrials.gov. Combination therapy of pegylated interferon alfa-2a and tenofovir versus tenofovir monotherapy in chronic hepatitis B (HBRN). ClinicalTrials.gov identifier NCT01369212. https://clinicaltrials.gov/ct2/show/NCT01369212作者: StephenW 时间: 2020-11-15 12:57