March 24, 2014
Primary results from the ACTG 5257 study shifted the assumed relative parity between three of the preferred first-line combinations in US DHHS guidelines. Raphael Landovitz from University of California Los Angeles, presented results at CROI 2014 from this large randomised open label study with over 1800 treatment naive participants. 
The study was designed based on a hypothesis of equivalence for the three groups, with 90% power to define any pair-wise comparison.
Equivalence was defined based on cumulative incidence of events at 96 weeks if the 97.5% CI for results fell within +/-10% margin. Superiority required the upper limit of the 97.5% CI to be greater than 10% and the lower limit greater than zero. All three study groups used tenofovir/FTC as background. Atazanavir/r (300 mg/100 mg) and darunavir/r (800 mg/100 mg) were dosed once-daily and raltegravir (400 mg) was twice-daily.
Overall, the study performed better than the study projections, with lower rates of virological (25% vs 16%) and tolerability (10% vs ~7%) failure and less loss-to-follow-up (12% vs 5%), in the projected vs actual rates, respectively. While all arms performed well, significant differences were seen for some comparisons in the primary endpoint of time to virological failure or cumulative time to discontinuation due to toxicity.
Baseline characteristics were well balanced between arms. Mean age was 37 years and 24% of participants were women. Ethnicity was 42% black, 36% white, and 22% Hispanic. Median CD4 and viral load were 308 cells/mm3 (IQR 170-425, with 30% <200) and 4.6 log copes/mL (IQR 4.1-5.1, with 30% >100,000, including 7% >500,000), respectively.
Approximately 8% of patients were lost to follow up over two years, with 92% of patients in the 96 week analysis.
Viral suppression to <50 copies/mL was achieved by 88%, 94% and 89% (ITT analysis, tolerability change allowed) and 63%, 80% and 73% (ITT analysis, off-ART = failure) of the atazanavir/r, raltegravir and darunavir/r arms respectively.
In pairwise comparisons, equivalence was demonstrated for the three regimens: atazanavir/r vs raltegravir (difference 3.4%; 97.5% CI: -0.7%, 7.4%); atazanavir/r vs darunavir/r (diference -2.2%; 97.5% CI: -6.7%, 2.3%), and darunavir/r vs raltegravir (difference 5.6%; 97.5% CI: 1.3%, 9.9%).
In the analysis of cumulative incidence of tolerability failure, darunavir/r and raltegravir were non-inferior (difference 3.6%; 97.5% CI: 1.4%, 5.8%). However, atazanavir/r was inferior to both darunavir/r (difference 9.2%; 97.5% CI 5.5%, 13%) and raltegravir (difference 13%; 97.5% CI: 9.4%, 16%).
This was driven by side effects that are already well-described with 16% vs 1% vs 5% in the atazanavir/r, raltegravir and darunavir/r arms respectively stopping treatment for this reason (n = 25 vs 2 vs 14 for gastrointestinal; 47 vs 0 vs 0 for increased bilirubin/jaundice and 4 vs 0 vs 0 for kidney stones). Of the 47 cases of jaundice/bilirubin, 8 were early switches and 30 were already virologically suppressed to <50 copies/mL.
Approximately 75-80% of patients with virological failure had results from genotype testing, with primary mutations (mainly M184V and other NRTIs) detected in 2.8%, 3.3% and 2.0% of the atazanavir/r, raltegravir and darunavir/r arms, respectively. However, 11/18 patients with detected resistance in the raltegravir group, had integrase mutations, with or without additional NRTIs.
Results were also presented for two tolerability substudies. Both PI/r arms had significantly higher increases in LDL-cholesterol and trgilycerides (p<0.001), unlinked to ritonavir exposure.
Approximate CD4 increases were similar between arms (+284 (IQR 270, 300), though slightly, non-statistically, lower with darunavir/r (+256, IQR 240, 271).
This was a very large study and this may mean that some of the statistically significant findings might be less important clinically. The dataset is also likely to lead to numerous future analyses, relating to cardiovascular, metabolic, skeletal, lipids, biomarkers, behavior, adherence and key subgroup differences.
While the incidence of atazanavir-related side-effects occurred at a similar rate to that reported in phase 3 studies the other discontinuations occurred at a lower rate than the study expected.
Unless stated otherwise, references are to the Programme and Abstracts of the 21st Conference on Retroviruses and Opportunistic Infections (CROI), 3-6 March 2014, Boston.