Single-tablet regimens (STRs) have transformed the management of HIV, offering simplified dosing, improved adherence and durable virological suppression. However, as the population of people living with HIV continues to age and diversify, there is an increased need for alternative first-line options.
Presented at Conference on Retroviruses and Opportunistic Infections (CROI) 2026, Prof. Jürgen Rockstroh (Universitätsklinikum Bonn, Bonn, Germany) discusses week 48 results from the Phase III MK-8591A-053 study comparing doravirine/islatravir (DOR/ISL 100/0.25 mg) with bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) in treatment-naïve adults with HIV-1 (Abstract #177).
Q. What was the clinical rationale for comparing DOR/ISL with BIC/FTC/TAF as initial therapy, and what key unmet needs in first-line HIV treatment does this study aim to address?
BIC/FTC/TAF is the current standard of care in HIV. It works well for many people living with HIV, but more options are needed. As people age, their health needs often change and they may need to relook at their HIV treatment regimen. Some people may develop intolerance to INSTIs or need to modify their treatment regimen due to drug–drug interactions or a desire for fewer medications. In summary, having more treatment options helps to deliver individualised care..
Q. What were the findings from the study, and how should clinicians interpret these findings when initiating therapy in patients with high baseline HIV-1 RNA levels?
MK-8591A-053 (NCT05705349) met its primary efficacy endpoint of the percentage of adults living with HIV-1 who had not previously received antiretroviral treatment (treatment-naïve) achieving viral suppression (HIV-1 RNA <50 copies/mL), demonstrating non-inferiority for DOR/ISL compared to BIC/FTC/TAF at Week 48, 91.8% and 90.6%, respectively.
The safety profile was similar between both treatment groups and consistent with that observed in previous studies:
- Drug-related AEs were reported in 14.1% of participants on DOR/ISL and 18.0% on BIC/FTC/TAF, and discontinuations due to AEs were similar in both groups (1.1% vs. 2.2%).
- Immune reconstitution was similar in DOR/ISL versus comparator, with no between-group differences in mean increases in CD4/lymphocyte counts.
- There were few treatment failures in both groups, and <1% of DOR/ISL participants (2 of 269) developed resistance.
DOR/ISL demonstrated high efficacy in a global population, including those with high viral load, low CD4+ T-cell counts, and non-exclusionary pre-existing reverse transcriptase mutations.
Q. How should the treatment-emergent resistance findings inform clinical decision-making, particularly in patients with very high viral loads or baseline RT mutations?
At Week 48, treatment-emergent resistance was observed in <1% of DOR/ISL participants; 2 of 269 individuals developed resistance, and both individuals had >1,000,000 copies/mL pre-treatment HIV-1.
Across the three Phase 3 clinical trials, DOR/ISL demonstrated a high barrier to resistance, with less than 1% treatment-emergent resistance observed. Based on its potency and high barrier to resistance, we believe that DOR/ISL may represent a meaningful new option for people living with HIV and providers.
Beyond virological efficacy, tolerability and metabolic effects are increasingly important in regimen selection. What do the safety, weight and immunologic outcomes from this study suggest about the potential role of DOR/ISL in routine clinical practice?
People living with HIV may experience weight gain after initiating ART and face an increased risk of developing metabolic disorders, such as diabetes, due to a combination of factors, including chronic inflammation from the virus itself, age-related comorbidities, changes in body fat (lipodystrophy), and potential metabolic impacts of ART. The available data from the Phase 3 studies demonstrate that DOR/ISL has a neutral impact on weight and lipids.
Weight:
- MK-8591A-053 (treatment-naïve): Weight gain in the DOR/ISL and BIC/FTC/TAF groups at Week 48 was similar and showed an average increase of 3.6 kg (95% CI: 2.8, 4.4) for DOR/ISL and 3.9 kg (95% CI: 3.2, 4.7) for BIC/FTC/TAF.
- MK-8591A-052 (virologically suppressed): At Week 96, the mean weight change for DOR/ISL was minimal, 0.34 kg (95% CI: -0.28, 1.06). The BIC/FTC/TAF group showed a mean weight change of 0.43 kg (95% CI: -0.37, 1.24), also reflecting no significant change.
- MK-8591A-051 (virologically suppressed): Weight gain from Week 48 to Week 96 for participants who were on DOR/ISL for 96 weeks was -0.01 kg. The mean weight change during the first 48 weeks after switching to DOR/ISL (Week 48–96) was 0.89 kg, which was similar to the mean weight change observed in Group 1 from Week 0 to Week 48 (0.94 kg). Weight change was more pronounced in participants who switched from a weight-suppressive bART regimen containing efavirenz (EFV) and/or tenofovir disoproxil fumarate (TDF).
Lipids:
- MK-8591A-052 and MK-8591A-051 data demonstrated that lipids remained stable at Week 96.
Q. Looking ahead, where do you see DOR/ISL fitting within evolving HIV treatment strategies, and what additional data is needed to adopt this regimen more widely?
Over time, people may need to adjust their HIV treatment regimens because of comorbidities, concerns about toxicities, tolerability challenges, or a desire for regimens with fewer medications. The positive data presented at CROI are encouraging, showing that a non-INSTI option like investigational DOR/ISL could offer an important alternative.
Q. Beyond your presentation, what were the most important therapeutic and treatment updates presented at CROI 2026?
Like it or not, we are all ageing, and one of the most powerful themes at CROI this year was how HIV research is rising to meet the needs that come with that reality.
We are seeing real progress in both treatment and prevention options, with regimens that are more effective, more tolerable, and better tailored to people’s diverse needs. This evolution reflects the power of science when it is relentlessly focused on people and on meaningful, measurable progress. Looking ahead to next year, I hope to see even more young clinical scientists stepping forward to drive the next wave of innovation.
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Cite: Jurgen Rockstroh. Expanding first-line HIV options: MK-8591A-053 week 48 data on DOR/ISL in treatment-naïve adults. 26 Febraury 2026.
Editor: Katey Gabrysch, Editorial Director.
Disclosures: Jurgen Rockstroh has been a consultant for Gilead, has received grant/research support from
Boehringer, Provirex, on the advisory Board for Gilead and MSD, has received honoraria/honorarium from Abbvie, Gilead, Janssen, and ViiV healthcare.
The content was developed and edited by human editors. No fees or funding were associated with its publication. touchINFECTIOUS DISEASES utilize AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat).
This content has been developed independently by Touch Medical Media for touchINFECTIOUS DISEASES in collaboration with Prof. Jurgen Rockstroh. Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.
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