Introduction: The Evolving Landscape of HIV Maintenance
The management of HIV-1 has undergone a paradigm shift over the last decade, moving from complex multi-pill regimens to highly effective single-tablet regimens (STRs). While integrase strand-transfer inhibitor (INSTI)-based therapies, such as the combination of bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF), currently represent the gold standard for many patients, the clinical community continues to seek alternative strategies. This pursuit is driven by the need for personalized medicine, the management of long-term metabolic or weight-related side effects associated with some INSTIs, and the desire to minimize cumulative drug exposure through two-drug regimens (2DRs).
The recent Phase 3 trial published in The Lancet by Colson and colleagues provides critical evidence for a novel 2DR consisting of doravirine, a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), and islatravir, the first nucleoside reverse transcriptase translocation inhibitor (NRTTI). This study evaluates the efficacy and safety of switching virologically suppressed adults from the robust B/F/TAF regimen to this new fixed-dose combination.
Highlights of the Phase 3 Trial
– The doravirine (100 mg) and islatravir (0.25 mg) fixed-dose combination met the primary endpoint of non-inferiority compared to B/F/TAF at 48 weeks.
– The safety profile of the doravirine-islatravir regimen was comparable to the current standard-of-care, with low rates of discontinuation due to adverse events.
– This study reinforces the viability of two-drug regimens as a potent maintenance strategy, specifically providing an option that avoids integrase inhibitors for those who require or prefer an alternative.
Background: The Rationale for Doravirine and Islatravir
Doravirine has established itself as a potent NNRTI with a superior resistance profile compared to first-generation agents in its class and a favorable lipid profile. Islatravir represents a novel class of antiretrovirals; as an NRTTI, it works through multiple mechanisms, including the inhibition of reverse transcriptase by preventing nucleotide translocation.
One of the most significant aspects of islatravir is its high potency and long half-life, which allows for lower dosing. In previous developmental phases, islatravir was investigated at higher doses, but concerns regarding a decrease in total lymphocyte and CD4+ T-cell counts led to the selection of the 0.25 mg dose used in this Phase 3 trial. The combination of these two agents aims to provide a high barrier to resistance while maintaining a minimalist drug burden.
Study Design and Methodology
This Phase 3, multicentre, randomised, controlled, double-blind, non-inferiority trial (NCT05630755) was designed with rigorous clinical standards. It spanned 49 sites across Australia, Chile, Israel, Japan, the UK, and the USA, ensuring a diverse geographic and demographic cohort.
Participant Selection
Eligible participants were adults (18 years or older) with HIV-1 who had achieved stable virological suppression (HIV-1 RNA <50 copies per mL) for at least three consecutive months while on a B/F/TAF regimen. Crucially, participants had to have no history of treatment failure or known resistance to doravirine.
Randomization and Masking
Participants were randomly assigned in a 2:1 ratio to either switch to the oral fixed-dose combination of doravirine (100 mg) and islatravir (0.25 mg) or to continue their current B/F/TAF therapy. The double-blind nature of the study, where participants, investigators, and sponsor personnel were masked to the treatment allocation, preserved the integrity of the safety and efficacy data through the 48-week primary analysis.
Endpoints
The primary efficacy endpoint was the proportion of participants with a viral load of 50 copies per mL or higher at week 48, determined by the US FDA snapshot approach. The non-inferiority margin was set at 4%, a standard threshold for modern antiretroviral switch trials.
Key Findings and Statistical Analysis
Between February and November 2023, 514 participants were randomized, and 513 received treatment (342 in the switch group, 171 in the continuation group). The study population was notably inclusive, with 31% Black or African American and 23% Hispanic or Latino participants, addressing a historical gap in clinical trial representation.
Efficacy Results
At the 48-week mark, the doravirine and islatravir combination demonstrated clear non-inferiority to B/F/TAF.
– In the doravirine/islatravir group, 5 of 342 participants (1.5%) had a viral load ≥50 copies per mL.
– In the B/F/TAF group, 1 of 171 participants (0.6%) had a viral load ≥50 copies per mL.
– The treatment difference was 0.9% (multiplicity-adjusted 95% CI -1.9 to 2.9). Because the upper bound of the 95% CI (2.9%) was well below the pre-specified 4% margin, non-inferiority was successfully established.
Safety and Tolerability
The safety data showed that the new combination was well-tolerated. Adverse events (AEs) occurred in 74.6% of the switch group compared to 71.3% of the B/F/TAF group. Most AEs were mild to moderate. Treatment-related AEs were similar (10.2% vs 9.4%), and the rate of serious adverse events was actually lower in the switch group (4.4%) than in the B/F/TAF group (6.4%). Discontinuations due to AEs remained low in both arms (2.9% vs 1.8%), and no deaths occurred during the study period.
Expert Commentary: Clinical Implications
The success of the doravirine/islatravir combination is significant for several reasons. First, it validates the move toward 2-drug regimens that exclude both integrase inhibitors and tenofovir alafenamide (TAF). While TAF is generally well-tolerated, some patients experience weight gain or metabolic shifts; having a TAF-free, INSTI-free option is a valuable addition to the clinician’s toolkit.
Mechanistic Insights
The use of 0.25 mg of islatravir is a key takeaway. Following earlier concerns about lymphopenia at higher doses, this trial confirms that the 0.25 mg dose maintains potent antiviral activity without the adverse hematological effects seen previously. The synergy between doravirine and islatravir provides a high genetic barrier, which is essential for the long-term success of any 2-drug maintenance therapy.
Study Limitations
While the 48-week results are promising, long-term data (96 weeks and beyond) will be necessary to confirm the durability of this regimen and to monitor for any delayed toxicities. Additionally, as with most switch trials, the participants were already virologically suppressed and had no resistance, so these findings cannot be extrapolated to treatment-naive patients with high viral loads or those with multi-drug resistance.
Conclusion
The Phase 3 trial results published by Colson et al. establish the fixed-dose combination of doravirine (100 mg) and islatravir (0.25 mg) as a robust, non-inferior alternative to B/F/TAF for maintenance therapy in HIV-1. By offering a potent, once-daily, single-tablet, two-drug option, this regimen addresses the need for diverse therapeutic avenues in HIV care. For clinicians, it provides an evidence-based alternative for patients seeking to switch their ART regimen due to side effects, drug-drug interactions, or a preference for simplified therapy without compromising virological control.
Funding and Clinical Registry
This study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co. The trial is registered at ClinicalTrials.gov under the identifier NCT05630755.
References
Colson AE, Mills AM, Ramgopal MN, et al. Switch to fixed-dose doravirine (100 mg) and islatravir (0·25 mg) once daily in virologically suppressed adults with HIV-1 on bictegravir, emtricitabine, and tenofovir alafenamide: 48-week results of a phase 3, multicentre, randomised, controlled, double-blind, non-inferiority trial. Lancet. 2026 Feb 7;407(10528):611-621. doi: 10.1016/S0140-6736(25)01948-8.