What DOR/ISL Noninferiority Means for First-Line HIV Care

New phase 3 data presented at CROI 2026 position the investigational doravirine/islatravir (DOR/ISL) regimen as a potentially practice-changing alternative to integrase inhibitor–based standard-of-care therapy in treatment-naïve adults with HIV-1. In a large, randomized study of more than 500 participants, DOR/ISL demonstrated noninferior efficacy to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), achieving high rates of virologic suppression across key subgroups, including patients with high baseline viral loads and low CD4 counts. These findings are notable given the long-standing dominance of integrase strand transfer inhibitor (INSTI)-based regimens in first-line therapy.

Equally important, the safety and tolerability profile of DOR/ISL at 48 weeks closely mirrored that of BIC/FTC/TAF. Rates of drug-related adverse events and discontinuations were low and comparable between arms, helping to address earlier concerns surrounding islatravir, particularly related to lymphocyte declines. The absence of new safety signals in both treatment-naïve and switch populations further reinforces confidence in the regimen’s clinical viability.

Together, these efficacy and safety findings suggest that DOR/ISL could expand the therapeutic landscape beyond INSTI-based approaches, offering clinicians greater flexibility in tailoring initial therapy. For patients who may not be ideal candidates for integrase inhibitors—or for whom long-term toxicity considerations are paramount—this regimen introduces a compelling alternative with a novel mechanism of action. While longer-term data will be critical, these results mark an important step toward diversifying first-line HIV treatment strategies.