Gastroenterology

Gastroenterology

Volume 143, Issue 3, September 2012, Pages 619-628.e1
Gastroenterology

Original Research
Clinical—Liver
Efficacy of Entecavir With or Without Tenofovir Disoproxil Fumarate for Nucleos(t)ide-Naïve Patients With Chronic Hepatitis B

The data in this manuscript were presented at the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (Presidential Plenary Session III), November 2011, San Francisco, CA.
https://doi.org/10.1053/j.gastro.2012.05.037Get rights and content

Background & Aims

Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are potent antiviral agents that might have additive or synergistic antiviral activity in treatment of patients with chronic hepatitis B (CHB). We compared the efficacy and safety of ETV monotherapy with those of a combination of ETV and TDF.

Methods

We performed a randomized, open-label, multicenter, superiority study of 379 nucleos(t)ide-naïve patients with hepatitis B e antigen (HBeAg)-positive (n = 264) or HBeAg-negative (n = 115) CHB. Subjects were given ETV 0.5 mg (n = 182) or a combination of ETV 0.5 mg and TDF 300 mg (n = 197) for 100 weeks.

Results

At week 96, comparable proportions of patients in each study arm achieved the primary end point of a level of hepatitis B virus (HBV) DNA <50 IU/mL (83.2% vs 76.4%; P = .088). Among HBeAg-positive patients, a greater proportion given combination therapy achieved levels of HBV DNA <50 IU/mL than those given ETV alone (80.4% vs 69.8%; P = .046). However, this difference was observed only in patients with baseline levels of HBV DNA ≥108 IU/mL (79% vs 62%) and not in those with baseline levels of HBV DNA <108 IU/mL (83% in both arms). Rates of HBeAg loss and HBeAg seroconversion were comparable between groups, whereas the rate of alanine aminotransferase normalization was greater in the ETV monotherapy group. No HBV variants associated with ETV or TDF resistance were detected. Safety profiles were consistent with previous reports of ETV or TDF monotherapy.

Conclusions

The antiviral efficacy of ETV monotherapy is comparable to that of ETV plus TDF in a mixed population of nucleos(t)ide-naïve patients with CHB (70% HBeAg positive). The combination therapy could provide an incremental benefit to HBeAg-positive patients with baseline levels of HBV DNA ≥108 IU/mL. Clinical trial information: ETV-110, the BE-LOW study; NCT00410072.

Section snippets

Study Design

This was a randomized, open-label, multicenter, phase 3b superiority study (ETV-110, the BE-LOW study; NCT00410072) in NA-naïve HBeAg-positive or HBeAg-negative patients with CHB. Patients were randomized 1:1 to receive ETV 0.5 mg plus TDF 300 mg once daily or ETV 0.5 mg once daily for 100 weeks, with the primary end point measurement at week 96. To test whether patients with high viral load might derive greater benefit from combination therapy, the total number of HBeAg-negative patients was

Patient Population

Of the 384 patients randomized in this study, 379 were treated with ETV plus TDF (n = 197) or ETV alone (n = 182) (Figure 1 and Supplementary Figure 1). More patients in the combination arm than in the monotherapy arm discontinued therapy before week 96 (23 [11.6%] vs 12 [6.5%]), but this difference was not statistically significant (P = .11). The most common reasons for treatment discontinuation were lost to follow-up (ETV + TDF, 6; ETV, 7) and adverse events (ETV + TDF, 5; ETV, 2). At the end

Discussion

In this study, which included a mixed population of NA-naïve HBeAg-positive and HBeAg-negative patients with compensated CHB, the antiviral efficacy of ETV monotherapy was comparable to that of ETV plus TDF. At week 96, combined treatment with ETV plus TDF did not result in a higher proportion of patients with an HBV DNA level <50 IU/mL, ALT normalization, HBeAg loss, or HBeAg seroconversion compared with ETV monotherapy. When the responses of HBeAg-positive and HBeAg-negative patients were

Acknowledgments

In addition to the authors, the BE-LOW Study Group consists of the following principal investigators: Frank Anderson (Canada), Peter Angus (Australia), Giorgio Antonucci (Italy), David Bernstein (United States), Fernardo Bessone (Argentina), Marc Bourliere (France), Maurizia R. Brunetto (Italy), Olivier Chazouilleres (France), Sing Chan (United States), Hugo Cheinquer (Brazil), Gourdas Choudhuri (India), Douglas Dieterich (United States), Paul Desmond (Australia), Chundamannil Eapen (India),

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      A total of 250 CHB cases treated either with TDF (n = 140) or ETV (n = 110) for at least 24 months were screened for the study and evaluated. All patients with CHB of age more than 18 years, hepatitis B surface antigen (HBsAg) seropositivity for more than 6 months and pretreatment serum HBV-DNA level > 2 x 105 IU/ml and ALT > 2 x ULN in HBeAg seropositive cases; HBV DNA > 2 x 104 IU/ml and ALT > 2 x ULN in case of HBeAg-negative cases (as per AASLD guidelines (6)) with compensated liver function as defined by serum total bilirubin level ≤2.5 mg/dL, serum albumin level ≥3 g/dL and international normalized ratio ≤1.5 were included in the study.8 Those cases who were previously treated with nucleos(t)ide or IFN, patients with decompensated cirrhosis, history of coinfection with hepatitis C, D or HIV, having history of any other liver disease such as alcoholic liver disease, nonalcoholic fatty liver disease or autoimmune liver disease, HCC, patients with incomplete treatment record and nonadherence to treatment were excluded from the study.

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    Editorial support was provided by Articulate Science and funded by Bristol-Myers Squibb.

    Conflicts of interest The authors disclose the following: Anna S. Lok has received research grants from Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Roche, and Merck and has served as ad hoc advisor for Bristol-Myers Squibb, Gilead, GlaxoSmithKline, and Roche. Ulus S. Akarca is an advisory board member of Bristol-Myers Squibb, Gilead, and MSD and a consultant for Gilead. Adrian Gadano has provided consultancy services for Bristol-Myers Squibb. François Habersetzer has received lecture fees, consulting fees, and investigator fees from Bristol-Myers Squibb and Gilead. William Sievert is a member of Australian Advisory Boards for Bristol-Myers Squibb and Gilead. Meghan Lovegren, David Cohen, and Cyril Llamoso are employees of Bristol-Myers Squibb. The remaining authors disclose no conflicts.

    Funding Supported by Bristol-Myers Squibb.

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