SAN FRANCISCO – When treating patients with chronic hepatitis B, two antiviral agents are not necessarily better than one, according to the results of an international randomized trial called BE-LOW.

About 80% of patients achieved viral suppression regardless of whether they received entecavir alone or entecavir combined with tenofovir, with no significant difference between groups, Dr. Anna S. Lok reported at the annual meeting of the American Association for the Study of Liver Diseases.

"The combination did not provide an overall benefit compared to the entecavir monotherapy; however, it may provide incremental benefit in HBeAg-positive patients with a baseline viral load of more than 10⁸ IU/mL."

However, combined therapy was more efficacious than monotherapy among the subset of patients who were hepatitis B e antigen (HBeAg) positive and had a high viral load at baseline.

"The combination did not provide an overall benefit compared to the entecavir monotherapy; however, it may provide incremental benefit in HBeAg-positive patients with a baseline viral load of more than 10⁸ IU/mL," she commented. "It is possible that there may be some clinical settings in patients with high viral load in which rapid viral decline is important, where combination therapy may have a role."

An attendee asked whether the better response with the combination in those HBeAg-positive patients might have been due to the tenofovir alone. "Obviously, the limitation of this study was that there was no tenofovir monotherapy group, so we don’t know," Dr. Lok replied. "Maybe this would be just because of tenofovir and we don’t need the combination."

The trial tested combination therapy for several reasons. "Entecavir and tenofovir are both potent antiviral agents with nonoverlapping resistance profiles, and they are also generally very well tolerated. Combination therapy may provide additive or synergistic antiviral activity and reduce the risk of resistance development," she explained. "But this potential benefit has not yet been confirmed, and the safety of the combination also needs to be established."

Patients were eligible for the phase IIIb trial if they were aged 16 years or older, had been hepatitis B surface antigen (HBsAg) positive for at least 24 weeks, and had not previously received a nucleoside or nucleotide analogue.

"Because one of the purposes was to determine if combination therapy might have a preferential advantage in patients with high baseline hepatitis B virus (HBV) DNA, the study was designed to cap the number of HBeAg-negative patients at 30% to enrich for patients with high baseline viral load," noted Dr. Lok, who is director of clinical hepatology at the University of Michigan, Ann Arbor.

In all, 384 patients were randomized in balanced fashion to open-label treatment with entecavir (Baraclude) alone or entecavir at the same dose combined with tenofovir (Viread).

The patients had a mean age of 39 years. Roughly half of the patients were white and the other half were Asian. Seventy percent were HBeAg positive.

About 7% of patients in the monotherapy group and 12% of patients in the combination therapy group discontinued treatment before 96 weeks. "In the majority of the patients who came off treatment, it was because of loss to follow-up. There were some patients who discontinued because of adverse events, but those adverse events were not related to renal side effects or anything significant – they were more sort-of constitutional symptoms," Dr. Lok said.

In a modified intention-to-treat analysis, in which patients lost to follow-up were considered not to have achieved suppression, the 96-week rate of viral suppression (HBV DNA less than 50 IU/mL), was 76.4% with entecavir alone and 83.2% with entecavir plus tenofovir, not a statistically significant difference. The results were essentially the same in a per-protocol analysis.

However, in the HBeAg-positive subset of patients, the rate was higher with the combination therapy (80.4% vs. 69.8%, P = .046), and further analysis showed that this difference was solely due to a higher rate among those who had a high viral load at baseline, with an HBV DNA of at least 10⁸ IU/mL (78.8% vs. 62.0%).

For other end points in the trial population overall, there were numerical trends actually favoring monotherapy when it came to rates of alanine aminotransferase normalization, HBeAg loss, and HBeAg seroconversion.

The rate of virologic breakthrough was 1.0% with the monotherapy and 3.6% with the combination therapy. There were no cases of genotypic resistance specific for the study drugs in either group.

"Safety was also very comparable between the two groups," Dr. Lok reported, with similar rates of serious adverse events.

Three patients in the monotherapy group developed hepatocellular carcinoma, compared with none in the combination therapy group. In all three cases, HBV DNA was undetectable at the time of the cancer diagnosis.

Dr. Lok reported that she is an adviser or reviewer for Bristol-Myers Squibb, Gilead, Merck, Roche, Abbott, Bayer, and GlaxoSmithKline, and that she receives research or grant support from Bristol-Myers Squibb, Gilead, Merck, Roche, and GlaxoSmithKline.

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