Doravirine/Islatravir for Initial HIV Therapy: A Two-Drug Strategy in a Three-Drug World

At CROI 2026, much of the discussion around antiretroviral therapy focused on long-acting agents and treatment optimization in experienced populations. Yet another important presentation turned to the starting point of care: initial therapy in people newly diagnosed with HIV.

In the Phase 3 study MK-8591A-053, investigators compared the investigational once-daily two-drug regimen doravirine/islatravir (DOR/ISL 100/0.25 mg) with the established three-drug single-tablet regimen bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) in treatment-naïve adults.

The central question was straightforward but clinically relevant: can a non-INSTI two-drug regimen deliver virologic efficacy comparable to one of the most widely used integrase inhibitor–based standards?

Study Population and Design

The trial enrolled 536 participants across 116 sites in 20 countries, creating a geographically diverse and contemporary cohort. Recruitment spanned Latin America, North America, Africa, Europe, and Asia/Pacific regions. Median age was 32 years, and 25% of participants were female at birth. Viral diversity was notable, with subtype B accounting for approximately 53% of infections, subtype C 19%, and non-B/non-C strains 28%.

Clinical presentation at baseline reflected real-world variability. Median CD4 count was 370 cells/mm³, and 17% of participants had CD4 counts below 200 cells/mm³. Viral burden was substantial: median HIV-1 RNA was approximately 55,000 copies/mL, 37% had levels exceeding 100,000 copies/mL, and 10% were above 500,000 copies/mL. These are populations in which durability and resistance barriers are tested early.

Participants were randomized in a double-blind design to receive either DOR/ISL or BIC/FTC/TAF. The primary endpoint was HIV-1 RNA <50 copies/mL at Week 48 using the FDA Snapshot approach, with a prespecified noninferiority margin of −10%.

Virologic Outcomes at Week 48

At Week 48, 91.8% of participants receiving DOR/ISL achieved HIV-1 RNA <50 copies/mL, compared with 90.6% in the BIC/FTC/TAF arm. The treatment difference was 1.2% (95% CI −3.7, 6.2), meeting the statistical criteria for noninferiority.

Efficacy was consistent across subgroups, including those with high baseline viral load, low CD4 counts, and across viral subtypes. Discontinuations due to lack of efficacy were uncommon: four in the DOR/ISL group and two in the comparator arm.

From a virologic standpoint, the two-drug regimen performed comparably to a modern three-drug integrase inhibitor–based standard.

Resistance Profile

Treatment-emergent resistance was observed in two of 269 participants (<1%) in the DOR/ISL group. In both cases, reverse transcriptase mutations associated with doravirine resistance were detected, including substitutions such as Y188L and V106A. Phenotypic testing demonstrated high-level resistance to doravirine, while susceptibility to islatravir was maintained.

In one case, plasma drug concentrations suggested possible incomplete adherence early in treatment; in the other, drug levels were detectable at study visits. No corresponding resistance signal was reported in the BIC/FTC/TAF arm.

Although rare, these findings underscore a principle inherent to two-drug strategies: the genetic barrier to resistance depends heavily on adherence and on the resistance profile of each component.

Immune Recovery and Safety

Immune reconstitution was similar between groups. At Week 48, mean CD4 count increased by 218 cells/mm³ in the DOR/ISL arm and 226 cells/mm³ in the BIC/FTC/TAF arm, with no clinically meaningful difference.

Safety outcomes were broadly comparable. Any adverse event occurred in 84.8% of participants receiving DOR/ISL and 88.0% receiving BIC/FTC/TAF. Serious adverse events were reported in 8.2% and 7.1%, respectively. Discontinuations due to adverse events were infrequent in both arms.

Two drug-related serious adverse events occurred in the DOR/ISL group — one case of drug reaction with eosinophilia and systemic symptoms (DRESS) and one drug-induced liver injury that did not meet Hy’s law criteria. Three hepatitis B infections were observed in the DOR/ISL arm among participants without baseline hepatitis B immunity; one individual transitioned to BIC/FTC/TAF with subsequent resolution of infection. Two deaths occurred in the comparator arm and were not considered drug-related.

Weight and Metabolic Considerations

Weight gain was similar between regimens. At Week 48, mean weight increased by 3.6 kg in the DOR/ISL group and 3.9 kg in the BIC/FTC/TAF group. The between-group difference of −0.3 kg (95% CI −1.5, 0.9) was not statistically significant.

In practical terms, the non-INSTI two-drug regimen did not demonstrate a metabolic advantage over integrase inhibitor–based therapy during the first year.

Expanding First-Line Options

Doravirine is an established non-nucleoside reverse transcriptase inhibitor, while islatravir represents a nucleoside reverse transcriptase translocation inhibitor with multiple mechanisms of action, including inhibition of translocation and delayed chain termination. The combination offers a mechanistically distinct alternative to integrase-based regimens.

The Week 48 results demonstrate that DOR/ISL (100/0.25 mg) is noninferior to BIC/FTC/TAF for initial treatment of HIV-1, with high rates of viral suppression, comparable immune recovery, and a similar safety profile.

These findings do not displace integrase inhibitor–based therapy as a standard of care. Rather, they broaden the therapeutic landscape. In contemporary HIV medicine, flexibility is increasingly important. Not every patient requires the same mechanism, and not every clinical situation favors an integrase-based approach.

The value of this study lies in diversification. It confirms that a non-INSTI two-drug regimen can achieve control comparable to a three-drug standard in a globally representative, treatment-naïve population.

In an era where treatment goals remain unchanged — durable viral suppression, immune recovery, and long-term safety — expanding validated options is itself progress.