Mixed Outcomes in Tenofovir Trial for Chronic Hepatitis B

Emily Willingham

November 15, 2020

About one-third of patients with chronic hepatitis B maintained a profile consistent with inactive disease 1 year after withdrawal from treatment in the randomized HBRN trial, which compared tenofovir with and without pegylated interferon (PEG-IFN). The two treatment groups, however, had similarly low rates of hepatitis B surface antigen (HBsAg) loss, the trial's primary end point.

Norah Terrault

The successful withdrawals could inform discussions with patients who are "very motivated to have a finite treatment course," said investigator Norah Terrault, MD, from the University of Southern California in Los Angeles. The results might "help patients in talking about expectations," she said, because "there's a one in three chance they won't go back on treatment" if they meet specific metrics.

In HBRN, the metrics for withdrawal from treatment after 192 weeks included low levels of viral DNA (<1000 IU/mL) for at least 24 weeks, no cirrhosis, negative week 144 test results for the hepatitis B envelope antigen (HBeAg), and week 180 conversion to anti-HBe positivity.

Of 102 patients who received tenofovir monotherapy for 192 weeks and who completed the trial, 51 met these criteria. After withdrawal from treatment, 30% still had DNA levels below 1000 IU/mL and normal alanine aminotransferase (ALT) at week 240, which is consistent with inactive chronic hepatitis B.

Of the 99 participants in the combination group — who received PEG-IFN for the first 24 of 192 weeks in addition to tenofovir — 60 met the withdrawal criteria at 192 weeks. At week 240, 39% of this withdrawal group still had DNA and ALT values consistent with inactive disease.

Rates of HBsAg loss, which signals functional cure, were low in the two groups, however. At week 240, fewer patients in the tenofovir monotherapy group tested negative for HBsAg than in the tenofovir plus PEG-IFN combination group, but the difference was not significant (4.5% vs 5.7%).

The timing of HBsAg loss differed between the groups. In the combination group, the loss largely occurred before treatment withdrawal, likely because of the antiviral effects of interferon, Terrault told Medscape Medical News. In the monotherapy group, the loss occurred after 192 weeks, possibly reflecting the immunologic consequences of treatment withdrawal, she added.

The timing of ALT flares also differed between groups. In the combination group, 58% of flares occurred during the 24-week PEG-IFN period. In the monotherapy group, 70% of flares occurred after tenofovir was stopped at 192 weeks.

The flare picture is a tricky one, said Terrault. The episodes might be a positive factor in HBsAg loss, but severe flares carry a risk for decompensation. Good predictors of the severity of flares are lacking, she said, and "that is the hurdle" to finding a balance with these tradeoffs.

"Partially a Failure and Partially a Success"

The findings are "partially a failure and partially a success," said Robert Gish, MD, from Loma Linda University of Health in California, who was not involved in the study.

The low rates of HBsAg loss and the similarity between the two treatment groups represent the failure, he explained. The success is for the patients who were HBeAg-positive when the study began because they had high HBeAg loss rates in both the monotherapy and combination groups (41% vs 61%; P = .06).

Loss of HBeAg was numerically higher in the combination group because of the interferon effect. That could be viewed as a "subjective benefit" of PEG-IFN, even though the difference wasn't statistically significant, said Gish.

The low rates of HBsAg loss could relate to two features of the patient profile, he explained. At study entry, the participants had moderately high levels of quantitative HBsAg and were predominately of Asian ancestry, which are predisposing factors for limited HBsAg loss.

Previous studies have suggested that peak HBsAg loss could take 2 to 3 years to develop after treatment withdrawal in a trial population. In the HBRN trial, rates almost 1 year after withdrawal are similar to 1-year rates from other studies, Terrault said. How these results for HBsAg loss in the two treatment groups will look at the 3-year mark is not known.

The trial design standardized withdrawal protocol and the length of time patients were on treatment before withdrawal was attempted, which are strengths of this study, said Terrault. And "a triumph of this study is execution of a standard for nucleic acid treatment in a protocolized way, followed by withdrawal. That is something we are happy about."

Terrault reports receiving institutional grant support from Roche/Genentech and Gilead Sciences. Gish reports receiving research support from Gilead Sciences and serving as a consultant and on advisory boards for several pharmaceutical companies.

The Liver Meeting Digital Experience 2020: American Association for the Study of Liver Diseases (AASLD): Abstract 0019. Presented November 14, 2020.

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