Efficacy and safety of switching to once-daily oral doravirine plus raltegravir in virologically suppressed people with HIV-1: a randomized, open-label, multicentre phase 2 study (DORAL)

Abstract Background We evaluated the efficacy and safety of a once-daily oral two-drug regimen (2DR) combining doravirine and raltegravir in virologically suppressed people with HIV (PWH). Methods DORAL is a multicentre, open-label, randomized phase II trial conducted in France, Italy, and Spain. Virologically suppressed adults receiving stable antiretroviral therapy (ART), naïve to doravirine and without raltegravir resistance, were randomized (2:1) either to switch immediately to doravirine (100 mg) plus raltegravir (1200 mg) or to continue baseline ART until week 48 before switching to doravirine plus raltegravir. The primary endpoint was virological failure (VF; confirmed plasma HIV-1-RNA ≥50 copies/mL) at week 48. Secondary endpoints included maintenance of virological suppression through W96, immunological outcomes, safety, and pharmacokinetics in a genital sub-study. Results Among 114 participants (median age, 57 years; median CD4 count, 700 cells/mm3; median duration of virological suppression, 10 years), one VF occurred by week 48 in the immediate-switch group (1.3%; 95% CI, 0.0–6.9); none occurred in the delayed-switch group. No additional VF was observed through week 96. Immunological parameters remained stable during follow-up. Three adverse events considered related to doravirine and raltegravir led to treatment discontinuation. One grade 3 adverse event (anxiety), considered related to study treatment, was reported. In the genital sub-study, drug concentrations exceeded inhibitory thresholds in most samples, with infrequent detection of low-level seminal HIV-1-RNA. Conclusions This proof-of-concept phase II switch trial supports the feasibility of a once-daily doravirine plus raltegravir 2DR in selected PWH, particularly when minimizing drug-drug interactions or avoiding NRTI exposure is a priority.