Research summary

Integrase Inhibitor Regimen Demonstrates Non-Inferiority, Fewer Adverse Events in Advanced HIV Disease

Edited by:
Anthony Calabro, MA

Key Highlights

  • In the LAPTOP trial, bictegravir/emtricitabine/tenofovir alafenamide was non-inferior to darunavir/cobicistat/emtricitabine/tenofovir alafenamide for the composite endpoint of virological or clinical events at 48 weeks.
  • Virological failure was lower in the integrase inhibitor group (11%) than in the boosted protease inhibitor group (21%).
  • Drug-related adverse events (grade ≥2) occurred in 7% of participants in the integrase inhibitor group vs 14% in the boosted protease inhibitor group.
  • Twelve deaths occurred, none deemed related to study treatment.

In a large, investigator-initiated, open-label, multicenter, non-inferiority trial, researchers found that in adults with advanced HIV disease, an integrase inhibitor–based regimen was non-inferior to a boosted protease inhibitor regimen for a composite virological and clinical endpoint and was associated with better virological efficacy and fewer drug-related adverse events.

Published in The Lancet Infectious Diseases, the Late Presenter Treatment Optimisation (LAPTOP) trial examined antiretroviral therapy (ART) performance specifically in adults with advanced HIV disease—a population underrepresented in prior randomized trials. Advanced HIV disease remains common globally and is associated with markedly higher morbidity and mortality. Investigators evaluated whether a regimen containing the integrase inhibitor bictegravir could match or improve upon outcomes observed with a boosted protease inhibitor regimen, given the high genetic barrier to resistance offered by both approaches.

Researchers enrolled ART–naïve adults across 56 sites in seven European countries. Eligible participants had untreated HIV-1 infection with advanced disease characteristics, including CD4 counts below 100 cells/μL, AIDS-defining illness, severe bacterial infection with low CD4 count, or ongoing opportunistic infection treatment. Participants were randomised 1:1 to receive either bictegravir/emtricitabine/tenofovir alafenamide or darunavir/cobicistat/emtricitabine/tenofovir alafenamide for 48 weeks. The primary composite endpoint included virological failure or clinically relevant adverse outcomes, assessed using modified intention-to-treat and per-protocol analyses. Non-inferiority was defined by an upper 95% CI hazard ratio margin of less than 1.606.

Study Findings

Of the 447 randomized individuals, 442 received at least one study dose (median CD4 count 41 cells/μL; 59% with AIDS-defining conditions). By week 48, the composite primary outcome occurred in 22% of participants receiving the integrase inhibitor regimen and 32% receiving the boosted protease inhibitor regimen (adjusted HR 0.70; 95% CI 0.48–1.00), demonstrating non-inferiority. Virological failure was significantly lower in the integrase inhibitor group (11% vs 21%; HR 0.54; P = .013). Early viral suppression findings favored the integrase inhibitor regimen, with more participants achieving <50 copies/mL at weeks 4, 8, and 12.

CD4 recovery was substantial in both groups, with no significant differences in reaching CD4 counts >200 cells/μL. Rates of IRIS, hospitalizations, and serious adverse events were comparable. Overall adverse events (grade ≥2) were lower with the integrase inhibitor regimen (adjusted incidence rate ratio 0.82; P = 0.0024). Drug-related grade ≥2 events were also lower in this group (7% vs 14%). Twelve deaths occurred (nine integrase inhibitor, three boosted protease inhibitor), none attributed to study medications.

Clinical Implications

According to the study authors, these findings support the use of integrase inhibitor–based regimens as preferred first-line therapy in advanced HIV disease. The authors noted that non-inferiority, improved virological outcomes, and fewer drug-related adverse events align with global treatment trends favoring high genetic barrier integrase inhibitors. They also indicated that the absence of treatment-related deaths and similar rates of clinical events between groups underscore the safety of both regimens.

Still, the authors noted several study limitations. For example, the study findings may not fully apply to settings with different burdens of opportunistic disease and that enrollment was delayed due to the COVID-19 pandemic. They identified several additional limitations, including the open-label design, which could influence adverse event reporting; the modest duration of follow-up, which limits long-term assessment; and the exclusion of participants with tuberculosis or cryptococcal meningitis, which affects applicability to those groups.

Expert Commentary

“These findings support high-barrier integrase inhibitor-based regimens as preferred evidence-based first-line therapy in advanced HIV disease, in line with global ART trends,” the researchers concluded.

Reference
Behrens GMN, Assoumou L, Liegeon G, et al. Integrase versus protease inhibitor therapy in advanced HIV disease (LAPTOP): a multicountry, randomised, open-label, non-inferiority trial. Lancet Infect Dis. 2025. doi:10.1016/S1473-3099(25)00681-4