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AASLD 2011: Adding Tenofovir to Entecavir Offers No Additional Benefit for Hepatitis B Patients

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Dual therapy using entecavir (Baraclude) plus tenofovir (Viread) did not work better than entecavir alone in a 3-year study of previously untreated chronic hepatitis B patients, according to a presentation at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2011) last week in San Francisco.

Several nucleoside/nucleotide analog drugs are approved for treatment of chronic hepatitis B virus (HBV) infection. HBV can develop resistance that makes these drugs less effective, especially when they are used alone.

Anna Lok and fellow investigators with the international BE-LOW study evaluated whether combination therapy with entecavir plus tenofovir would have additive antiviral activity or prevent resistance better than entecavir alone.

This open-label multicenter study included 379 nucleoside/nucleotide-naive chronic hepatitis B patients. About 70% were men and the average age was 40 years; approximately half were white and half Asian. About 70% were hepatitis B "e" antigen (HBeAg) positive, the rest HBeAg negative; the average baseline HBV viral load was 7.5 log IU/mL.

Participants were randomly assigned to received 0.5 mg once-daily entecavir plus 300 mg once-daily tenofovir, or else the same dose of entecavir alone, both for 100 weeks. The primary endpoint was the proportion of patients with undetectable HBV DNA (< 50 IU/mL) at week 96. Discontinuation of therapy prior to week 96 were considered treatment failure.

Results

  • Overall, at 96 weeks, 83% of patients in the entecavir/tenofovir combination arm achieved HBV DNA < 50 IU/mL compared with 76% in the entecavir monotherapy arm, not a statistically significant difference.
  • Among HBeAg positive patients, more people in the entecavir/tenofovir arm achieved undetectable HBV DNA than in the entecavir monotherapy arm (80% vs 70%, respectively), a difference that just reached statistical significance.
  • Further analysis showed that this difference was apparent in only HBeAg positive people with high baseline HBV DNA ³100 million IU/mL (79% vs 62%, respectively), but not those with lower baseline viral load (83% in both arms).
  • Among HBeAg negative patients, virological response rates were also similar (90% vs 91%, respectively).
  • Fewer participants in the combination therapy arm experienced alanine aminotransferase (ALT) normalization (69% vs 82%).
  • HBeAg seroconversion was also less likely in the entecavir/tenofovir arm (22% vs 33%).
  • Virological breakthrough occurred in 4% of entecavir/tenofovir recipients and 1% of entecavir monotherapy recipients.
  • However, no entecavir or tenofovir drug resistance mutations were detected in either arm.
  • Rates of adverse events and serious adverse events were comparable in the combination therapy and entecavir monotherapy arms.
  • However, more patients discontinued treatment prematurely in the combination therapy compared with the monotherapy arm (3% vs 1%).
  • Notably, just 2% of combination entecavir/tenofovir recipients and 3% of entecavir monotherapy recipients experienced serum creatinine increases (≥ 0.3 mg/dL), a possible indicator of kidney impairment, which is a potential toxicity of tenofovir.

"At week 96, both treatment arms (entecavir monotherapy and entecavir + [tenofovir] combination therapy) showed comparable antiviral efficacy in a mixed population (70% HBeAg positive) of nucleoside analog-naive chronic hepatitis B patients," the researchers concluded. "Both treatments were well tolerated with comparable safety profiles."

However, they added, the combination of entecavir plus tenofovir "may provide incremental benefit in HBeAg positive patients with baseline viral load ≥ 108 IU/mL."

"In these 96-week data comparing entecavir monotherapy to combination of entecavir plus tenofovir, we found that combination therapy did not result in statistically significant difference in virologic response compared to entecavir monotherapy," Lok said in a press release issued by entecavir manufacturer Bristol-Myers Squibb. "The BE-LOW study data confirmed the results of previous studies showing limited or no benefit of combination therapy compared to monotherapy for treatment-naive patients with chronic hepatitis B."

Investigator affiliations: University of Michigan, Ann Arbor, MI; Pacific Health Foundation, San Jose, CA; Institute of Infectious and Tropical Disease, University of Brescia, Brescia, Italy; Department of Gastroenterology, Ege University, Izmir, Turkey; Sección Hepatología, Hospital Italiano de Buenos Aires-Argentina, Ciudad de Buenos Aires, Argentina; Service d’Hépato-gastroentérologie, Nouvel Hôpital Civil, Strasbourg, France; Department of Medicine, Monash University, Melbourne, Victoria, Australia; Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Research and Development, Bristol-Myers Squibb Company, Wallingford, CT.

11/15/11

Reference

AS Lok, HN Trinh, G Carosi, et al. Entecavir (ETV) monotherapy for 96 weeks is comparable to combination therapy with ETV plus tenofovir (TDF) in nucleos(t)ide-naive patients with chronic hepatitis B (CHB): the BE-LOW study. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 223.

Other Source

Bristol-Myers Squibb. Phase IIIb Comparison of Baraclude (entecavir) Monotherapy Versus BARACLUDE Plus Tenofovir Combination Shows No Statistical Difference Between Study Arms. Press release. November 8, 2011.