Weekly Oral Matches Daily Control but Lymphocyte History and PrEP Gap Cloud Outlook

Merck Highlights Oral HIV Treatment and Prevention Pipeline at HIV Glasgow 2026

Merck announced it will present new data from its extensive oral HIV portfolio and pipeline at HIV Drug Therapy Glasgow 2026. The presentations will cover both HIV treatment and prevention, including updates on the once-daily IDVYNSO® (doravirine/islatravir), investigational once-weekly oral treatments islatravir/lenacapavir (ISL/LEN) and islatravir/ulonivirine (ISL/ULO), and the investigational once-monthly oral pre-exposure prophylaxis (PrEP) alimatravir (AMI). Key data include Phase 3 subgroup analyses and patient-reported outcomes for ISL/LEN, as well as resistance and weight analyses for IDVYNSO. The U.S. FDA has also accepted two supplemental New Drug Applications for IDVYNSO, setting a PDUFA date of April 22, 2027. This reflects Merck's commitment to expanding oral options to address diverse patient needs in HIV care.

• Merck will present Week 48 resistance and weight analyses from Phase 3 Trial 53 comparing once-daily IDVYNSO to BIC/FTC/TAF in treatment-naïve adults, alongside Week 96 patient-reported outcomes in virologically suppressed adults. Concurrently, the FDA has accepted two supplemental New Drug Applications (sNDAs) for IDVYNSO, based on Trial 053 and Trials 051/052 data, with a Prescription Drug User Fee Act (PDUFA) target action date of April 22, 2027, for both applications.
• New Phase 3 data from the ISLEND-1 and ISLEND-2 trials will be presented, detailing Week 48 safety and efficacy subgroup analyses for the investigational once-weekly oral regimen of islatravir/lenacapavir. These presentations will also include Week 48 patient-reported outcomes and a qualitative substudy from ISLEND-2, offering deeper insights into patient and provider experiences with this novel once-weekly dosing option for virologically suppressed adults.
• Merck is advancing alimatravir (AMI, MK-8527) as a potential once-monthly oral HIV pre-exposure prophylaxis. Adult enrollment is complete in two ongoing Phase 3 trials, EXPrESSIVE-10 and EXPrESSIVE-11, which are evaluating its safety and efficacy in diverse populations at higher risk of HIV exposure, including cisgender women, men who have sex with men, transgender individuals, and adolescent girls and young women.
• Week 24 data from the Phase 2b MK-8591B-060 study will be presented, which informed an updated population pharmacokinetic model of ulonivirine. This model characterizes exposure and activity over time to support dosing recommendations for the investigational once-weekly combination of ulonivirine 200 mg and islatravir 2 mg in adults living with virologically suppressed HIV-1, alongside Phase 1 clinical pharmacology data for ulonivirine.

IDVYNSO's Expanded Role: New Data Supporting sNDAs

Recent phase 2-3 trials in HIV-1 infection have evaluated capsid inhibitors, maturation inhibitors, and mosaic vaccine regimens. These studies enrolled heavily treatment-experienced, treatment-naive, and at-risk populations with virologic and safety follow-up through 24 to 52 weeks.

• CAPELLA phase 2/3 trial (NCT04150068) – lenacapavir with optimised background regimen in multidrug-resistant HIV-1: In cohort 1, 30 of 36 participants (83%, 95% CI 67-94) had less than 50 HIV-1 RNA copies per mL and 31 of 36 participants (86%, 71-95) had less than 200 HIV RNA copies per mL at week 52; nine participants (four in cohort 1, five in cohort 2) had emergent lenacapavir resistance, four resuppressed (HIV-1 RNA <50 copies per mL) while maintaining lenacapavir use, and one participant discontinued study drug owing to injection site reaction.

• CAPELLA phase 3 analysis – oral then subcutaneous lenacapavir once every 6 months versus placebo for 14 days followed by optimised background therapy: A decrease of at least 0.5 log copies per milliliter in viral load by day 15 was observed in 21 of 24 patients (88%) in the lenacapavir group and in 2 of 12 patients (17%) in the placebo group (absolute difference, 71 percentage points; 95% confidence interval, 35 to 90); at week 26, viral load of less than 50 copies per milliliter was reported in 81% of patients in cohort 1 and in 83% in cohort 2, with least-squares mean increase in CD4+ count of 75 and 104 cells per cubic millimeter, respectively; no serious adverse events related to lenacapavir were identified and lenacapavir-related capsid substitutions associated with decreased susceptibility developed in 8 patients during maintenance (6 with M66I substitutions).

• DOMINO phase 2b trial (NCT04493216) – once-daily oral GSK3640254 100, 150, or 200 mg plus two nucleoside reverse transcriptase inhibitors versus dolutegravir 50 mg plus two nucleoside reverse transcriptase inhibitors in adults naive to antiretroviral therapy: At Week 24, proportions with HIV-1 RNA <50 copies/mL were 83% (33/40), 91% (39/43), and 76% (32/42) in the GSK'254 100-mg, 150-mg, and 200-mg groups, respectively, vs 92% (33/36) in the DTG group, with protocol-defined virologic failure in one participant receiving DTG and eight participants receiving GSK'254 and no resistance detected; few participants reported drug-related serious adverse events (GSK'254: 150 mg, 2% [1/43]; 200 mg, 2% [1/42]).

• Mosaico phase 3 trial (HVTN 706/HPX3002, NCT03964415) – tetravalent mosaic adenovirus serotype 26-based vaccine (Ad26.Mos4.HIV) with bivalent clade C glycoprotein 140-mosaic gp140 versus saline placebo in cisgender men and transgender individuals: From month 7 to month 24 in the per-protocol population, HIV-1 incidence per 100 person-years was 3·63 (95% CI 2·77 to 4·67) in the vaccine group and 3·35 (2·53 to 4·36) in the placebo group, with estimated vaccine efficacy (months 7-24) of -0·7% (95% CI -50·9 to 32·8; p=0·97); medically attended adverse events occurred in 999 (51·4%) of 1942 participants given vaccine and 1002 (51·5%) of 1945 participants given placebo, and serious adverse events occurred in 82 (4·2%) of 1942 participants given vaccine and 77 (4·0%) of 1945 participants given placebo.

Merck's Pipeline: Advancing Oral Options for HIV Treatment and PrEP

Across published studies, investigational HIV-1 therapies showed variable efficacy relative to standard-of-care, with maturation inhibitors and lenacapavir achieving high rates of viral suppression, while valaciclovir lowered viral load without slowing CD4 decline and point-of-care viral load monitoring improved retention and result turnaround with similar suppression rates.
Investigational approaches were generally well tolerated, with injection-site reactions, gastrointestinal events, and HIV-specific virologic failure signals reported in specific studies.

Addressing Diverse Needs in the Evolving HIV Landscape

Recent HIV-1 research targets persistent gaps left by lifelong daily antiretroviral therapy, focusing on populations with limited options, adherence challenges, and disproportionate acquisition risk. Development has centered on novel mechanisms, long-acting dosing, and equitable prevention scale-up to achieve durable control.

• Heavily treatment-experienced adults with multidrug-resistant HIV-1 and ≤2 fully active antiretrovirals remaining, including those failing current regimens, evaluated with fostemsavir plus optimized background therapy, twice-daily dolutegravir-based regimens, lenacapavir plus optimized background regimen, and ibalizumab plus optimized background regimen through week 96, week 104, and week 240 for virologic response, CD4+ T-cell count and CD4+/CD8+ ratio improvement, and inflammatory biomarker reduction

• Virologically suppressed adults seeking alternatives to daily oral standard of care, including adults suppressed for at least 6 months with no previous virological failure switching to once-weekly oral islatravir (2 mg)-lenacapavir (300 mg), and people receiving long-acting injectables such as cabotegravir/rilpivirine and subcutaneous lenacapavir every 26 weeks to improve virological outcomes and treatment satisfaction

• Persons at substantial risk for acquiring HIV requiring pre-exposure prophylaxis with improved adherence and persistence, including female sex workers, men who have sex with men, persons who inject drugs, transgender persons, and persons in prisons and other enclosed settings, with 856,816 PrEP initiations supported by CDC in 2023 and 2,278,743 initiations during 2017-2023, 96.0% in sub-Saharan Africa, 64.0% female and 44.9% aged 15-24 years, and twice-yearly lenacapavir reducing HIV incidence to 0.00-0.10 per 100 person-years versus 0.93-2.37 in controls

• Women, Black and Hispanic/Latino populations, adolescents, and individuals in the US South and other settings with disparities in PrEP uptake, including cisgender women, men, and gender-diverse individuals in lenacapavir PrEP trials, women vulnerable to HIV post-trial in Harare, Zimbabwe with 20% ever using PrEP and 15% on PrEP at questionnaire administration, and adults and adolescents with newly diagnosed HIV-1 or initiated with PrEP in a US commercially insured population

• Populations in co-endemic settings where HIV-1 intersects hyperendemic arboviruses and regionally isolated pathogens, including South America with dengue, Zika, chikungunya, yellow fever, and mammarenaviruses causing episodic immune activation and organ dysfunction that alter drug pharmacokinetics, disrupt healthcare access and adherence, compromise ART efficacy, promote resistance, and influence latent reservoir dynamics, driving need for co-infection-aware capsid inhibitors, maturation inhibitors such as GSK3640254, and broadly neutralizing antibodies