DOR/ISL Two-Drug Regimen for HIV-1 Is Non-Inferior to BIC/FTC/TAF

The growing emphasis on simplified antiretroviral therapy (ART) regimens for HIV-1 has prompted investigation into two-drug combinations that might retain virologic efficacy while mitigating toxicity and long-term burden.

In a phase 3, randomized, double-blind trial published in Clinical Infectious Diseases in September 2025 evaluated whether 100/0.75mg doravirine/islatravir (DOR/ISL)—an oral, once-daily dual regimen—could match the effectiveness of the three-drug integrase inhibitor-based regimen bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) in previously untreated adults with HIV-1.

Enrollment was halted early due to emerging safety signals regarding lymphocyte and CD4 cell declines associated with the 0.75mg islatravir dose, but the 48-week data remained pivotal in defining the regimen’s comparative efficacy and safety profile.

Here’s a brief overview of the trial.

Virologic Suppression

The study found that at week 48, the DOR/ISL combination demonstrated noninferiority to BIC/FTC/TAF in suppressing HIV-1 RNA to under 50 copies/mL. Virologic suppression was achieved in 88.9 percent of those on DOR/ISL and 88.3 percent on BIC/FTC/TAF, with a treatment difference of 0.5 percent (95 percent CI: –4.7 to 5.6).

Subgroup analyses confirmed similar response rates across sex, age, race, and geographic region. A small drop in performance was observed among participants with baseline viral loads over 100,000 copies/mL treated with DOR/ISL (75.9 percent versus 85.0 percent), but this was within statistical confidence bounds.

Only five participants in total experienced clinically significant confirmed viremia, including one case in the DOR/ISL arm that was associated with nonadherence and emergent resistance mutations.

Immunologic Effects and Treatment Discontinuations

While virologic efficacy was comparable, immunologic endpoints revealed a consistent trend: participants receiving DOR/ISL experienced smaller increases in CD4 counts and more pronounced declines in lymphocyte counts.

Mean CD4 gains were 182 cells/μL with DOR/ISL versus 234 cells/μL for BIC/FTC/TAF (difference –50; 95 percent CI: –79 to –21). Total lymphocyte count changes showed a sharper contrast: +0.01×10⁹/L with DOR/ISL versus +0.21×10⁹/L with BIC/FTC/TAF (difference –0.20; 95% CI: –0.30 to –0.10).

Although infection rates remained similar across groups, the drop in lymphocytes led to more protocol-mandated discontinuations in the DOR/ISL arm (8.7 percent versus 3.7 percent). Notably, the majority of these discontinuations occurred despite values remaining within normal clinical ranges, a reflection of study safety criteria rather than overt immunodeficiency.

Adverse Events and Safety Signatures

Looking at safety, adverse event rates were high in both groups, occurring in over 87 percent of participants, yet generally mild to moderate in severity.

COVID-19 was the most commonly reported adverse event across treatment groups (14.1 percent DOR/ISL versus 16.4 percent BIC/FTC/TAF) and lymphocyte reduction was the most common treatment-related adverse event, with higher rates in the DOR/ISL treatment arm (9.7 percent versus 3.7 percent). DOR/ISL participants also had higher rates treatment-related discontinuations (8.7 percent versus 3.7 percent).

Serious adverse events were balanced across arms and rarely attributed to the study drug. The weight gain observed in both groups was modest and nearly identical (+3.45 kg versus +3.32 kg), and no significant renal impairment was observed.

Despite a greater incidence of lymphocyte-related lab abnormalities in the DOR/ISL group, most changes were not clinically actionable outside the study’s predefined thresholds. The pharmacologic mechanism implicated involves intracellular accumulation of islatravir triphosphate in lymphocytes, potentially impairing DNA polymerase α and slowing cell proliferation.

Programmatic Consequence and Future Directions

Although DOR/ISL (100/0.75 mg) met noninferiority criteria and showed acceptable safety in most respects, concerns over immune cell decline prompted the discontinuation of this dosage combination. A new phase 3 trial is underway testing a lower 0.25 mg dose of islatravir paired with doravirine, informed by modeling and early-phase studies suggesting that reduced exposure may preserve efficacy while avoiding lymphocyte toxicity.

The findings underscore that while two-drug regimens may offer streamlined ART with fewer agents, pharmacologic selectivity and cellular effects require as much scrutiny as virologic control. Future deployment of non-INSTI dual therapy will hinge on balancing these immune safety profiles with the drive toward simplified, tolerable first-line options.

Reference:
Rockstroh JK, Paredes R, Cahn P, et al. Doravirine/Islatravir (100/0.75 mg) Once-Daily Compared With Bictegravir/Emtricitabine/Tenofovir Alafenamide as Initial HIV-1 Treatment: 48-Week Results From a Phase 3, Randomized, Controlled, Double-Blind, Noninferiority Trial. Clin Infect Dis. 2025;81(2):322-332. doi:10.1093/cid/ciaf077