Integrase Versus Protease Inhibitors In Advanced HIV Disease

Key Takeaways

• Across planned analyses, the bictegravir-based regimen matched the comparator on the primary composite endpoint and met the trial's noninferiority threshold.
• Grade 2 or higher drug-related adverse events were less frequent with bictegravir/emtricitabine/tenofovir alafenamide, while serious adverse events and discontinuations were similar between groups.
• Twelve deaths occurred overall, were unevenly distributed between groups, and were considered unrelated to study drugs; the authors described the bictegravir-based regimen as preferred in this population on the basis of non-inferior efficacy with fewer adverse events.

In therapy-naive adults with advanced HIV disease, the LAPTOP trial found the 48-week composite outcome in 22% receiving bictegravir/emtricitabine/tenofovir alafenamide and 32% receiving darunavir/cobicistat/emtricitabine/tenofovir alafenamide. The adjusted hazard ratio was 0.70, with a 95% CI of 0.48 to 1.00, in this initial-treatment comparison across seven European countries. The comparison met the prespecified noninferiority criterion at 48 weeks.

LAPTOP was an open-label, multicenter, non-inferiority trial conducted across Spain, France, Italy, Germany, Belgium, Ireland, and the UK. Participants were therapy-naive adults with advanced HIV disease, randomly assigned 1:1 to the two regimens, with allocation stratified by country and baseline CD4 cell count. 447 participants were enrolled. Among the 442 treated participants, the median CD4 count was 41 cells/μL; 358 were male, 84 were female, and ethnicity was reported as 276 White, 83 Black, and 83 other. Treatment lasted 48 weeks, adverse events were assessed at eight visits, and the comparison tested initial integrase versus boosted protease therapy in advanced disease.

The primary endpoint was time to the first specified virological or clinical event in both the modified intention-to-treat and per-protocol populations. For the 48-week primary outcome, noninferiority required the upper 95% confidence limit for the hazard ratio to remain below 1.606, equivalent to a 12% cumulative-probability difference. The modified intention-to-treat analysis included all randomly assigned participants who received study drug. In that population, the adjusted hazard ratio was 0.70, and the per-protocol analysis was similar at 0.69. Both confidence intervals ranged from 0.48 to 1.00, keeping the result consistent across the planned analyses.

Grade 2 or higher drug-related adverse events occurred in 16 of 220 participants, or 7%, in the bictegravir/emtricitabine/tenofovir alafenamide group. They occurred in 32 of 222 participants, or 14%, in the darunavir/cobicistat/emtricitabine/tenofovir alafenamide group, with p=0.043. Serious adverse events and adverse events leading to discontinuation did not differ between groups. The safety difference reflected fewer drug-related events rather than differences in serious events or discontinuations.

Twelve deaths occurred during the study, with nine in the bictegravir/emtricitabine/tenofovir alafenamide group and three in the darunavir/cobicistat/emtricitabine/tenofovir alafenamide group. Investigators reported that these deaths were not related to the study drugs.

The authors concluded that the bictegravir-based regimen remained non-inferior and was associated with fewer adverse events, and described it as a preferred first-line option in this population. Over 48 weeks, the balance was noninferior efficacy with fewer drug-related adverse events in adults with advanced HIV disease.