By Michael Smith, North American Correspondent, MedPage Today
Published: February 14, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.
A large clinical trial fell short of showing that two commonly used approaches to a first anti-HIV treatment regimen are formally equivalent.
But the two -- based on either the ritonavir-boosted protease inhibitor atazanavir (Reyataz) or the non-nucleoside reverse transcriptase inhibitor efavirenz (Sustiva) -- still appeared to have similar efficacy, according to Eric Daar, MD, of Harbor-UCLA Medical Center in Torrance, Calif., and colleagues.
The failure to reach formal equivalence -- as defined before the study started -- was probably the result of a lower than expected rate of virologic failure two years into the study, Daar and colleagues reported online in Annals of Internal Medicine.
But a post-hoc analysis of the data suggested the probability of remaining free of failure differed by less than 10%, a threshold commonly used for defining equivalence, the researchers argued.
Treatment guidelines for initial HIV therapy suggest two nucleoside reverse transcriptase inhibitors combined with either a non-NRTI, a ritonavir-boosted protease inhibitor, or an integrase inhibitor, the researchers noted.
But there are limited data comparing atazanavir/ritonavir with efavirenz, they noted.
To help fill the gap, they conducted a randomized trial, in which the two lead compounds were added to common, once-daily combinations of nucleoside reverse transcriptase inhibitors -- either abacavir/lamivudine (Kivexa) or tenofovir/emtricitabine (Truvada).
The trial ran from September 2005 to November 2007, with a median of 138 weeks of follow-up, and the primary outcomes were time to virologic failure, safety, and tolerability.
All told, 1,857 patients were randomly assigned to one of the four treatment regimens and 1,331 completed the follow-up.
The primary efficacy hypothesis was that, within each of the NRTI arms, boosted atazanavir would be equivalent to efavirenz, Daar and colleagues noted.
The drugs were specified to be equivalent if a Cox proportional hazards model, using efavirenz as the reference, found the two-sided 95% confidence interval for the hazard ratio to be between 0.71 and 1.40.
But analysis showed:
• Among those randomized to the abacavir/lamivudine arms, the hazard ratio for time to virologic failure was 1.13 with a 95% confidence interval from 0.82 to 1.56. The difference was not statistically significant, at P=0.147.
• For those assigned to the tenofovir/emtricitabine arms, the hazard ratio was 1.01 with a 95% confidence interval from 0.70 to 1.46, which again was not significant, at P=0.37.
Although neither hazard ratio showed a significant difference, "neither met prespecified equivalence boundaries," the researchers reported.
However, analysis also showed that the probability of remaining free of virologic failure at week 96 was 83.4% for boosted atazanavir and 85.3% for efavirenz when they were combined with abacavir/lamivudine. The difference was -1.9 with a 95% confidence interval from -6.8 to 2.9, or 9.7 percentage points.
Values in the tenofovir/emtricitabine arms were 89% for boosted atazanavir and 89.8% for efavirenz, with a difference of -0.8 and a 95% confidence interval from -4.9 to 3.3, or 8.2 percentage points, the researchers reported.
Although the results did not meet the specified equivalence mark, the results suggest "for the first time in a large randomized study" that the two drugs have similar efficacy, the researchers argued.
They also found that safety and tolerability were slightly better for atazanavir than efavirenz when combined with abacavir/lamivudine, but there were no differences when they were combined with tenofovir/emtricitabine.
Daar and colleagues cautioned that when the study started it was not routine practice to test for HLA-B*5701 before using abacavir -- something that might have affected safety and tolerability results.
They also noted that study limitations include baseline drug resistance testing in only 40% to 50% of patients because of changing practices over time, premature unblinding of the NRTIs in the group of patients with high baseline viral loads, and change or discontinuation of the third drug in almost a third of patients.
The study was supported by the National Institute of Allergy and Infectious Diseases, and the National Center for Research Resources. Abbott Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline provided the study medications.
Daar reported financial links with Abbott Laboratories, Merck Laboratories, GlaxoSmithKline, Pfizer, Gilead Sciences, Bristol Myers Squibb, Tibotec, Schering-Plough, and Ardea Biosciences. Several authors reported being employed by the companies that supplied the study drugs.
Primary source: Annals of Internal Medicine
Daar ES, et al "Atazanavir plus ritonavir or efavirenz as part of a three drug regimen for initial treatment of HIV-1: A randomized trial " Ann Intern Med 2011.