Recent findings presented at the 26th International AIDS Conference have underscored a significant advancement in HIV treatment, with an investigational once-weekly oral regimen developed jointly by Gilead Sciences and Merck & Co. demonstrating sustained virologic suppression in two pivotal Phase 3 clinical trials, ISLEND-1 and ISLEND-2. This novel combination, comprising Merck’s islatravir and Gilead’s lenacapavir, represents a potential paradigm shift for adults living with virologically suppressed HIV, offering the prospect of reducing treatment frequency from daily to just once a week. The comprehensive results, unveiled six weeks after initial topline data were reported, have generated considerable optimism regarding improved patient adherence and quality of life.
Pivotal Phase 3 Trials Affirm Efficacy and Safety
The ISLEND program encompassed two distinct, large-scale Phase 3 studies, ISLEND-1 (NCT06630286) and ISLEND-2 (NCT06630299), which collectively enrolled 1,209 adults with HIV-1 who had already achieved virologic suppression on existing antiretroviral therapy (ART). The primary objective of these trials was to evaluate the efficacy and safety of switching to the once-weekly oral combination of 2 mg islatravir and 300 mg lenacapavir.
In the double-blind, active-controlled ISLEND-1 trial, participants were randomized 1:1 to either switch to the weekly ISL/LEN regimen or continue their once-daily single-tablet regimen of Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide), a current market leader. At Week 48, the results were highly favorable for the investigational regimen: none of the participants who switched to weekly ISL/LEN had HIV-1 RNA levels at or above 50 copies/mL, the standard threshold for virologic failure. This compared robustly with a mere 0.3% in the group that continued on daily Biktarvy, indicating non-inferiority and effective viral control. The safety profile also proved comparable, with treatment-related adverse event (AE) rates standing at 13.5% for ISL/LEN and 13.2% for Biktarvy. Common AEs in the ISL/LEN group included nausea and headache, each reported in 3% of participants. Serious adverse events (SAEs) were infrequent in both arms, occurring in 5.3% of ISL/LEN participants and 4.6% of those on Biktarvy.
ISLEND-2, an open-label study, further corroborated these findings under more varied conditions. Participants in this trial switched from a broader range of established two- and three-drug daily regimens. At Week 48, the efficacy endpoint showed that only 0.3% of ISL/LEN recipients experienced virologic rebound (HIV-1 RNA ≥ 50 copies/mL), significantly outperforming the 1.3% observed in participants who remained on their baseline daily therapies. The incidence of treatment-related adverse events was higher in the ISL/LEN arm (18%) compared to the standard of care group (<1%), a difference largely attributed to the open-label design and the fact that standard of care participants had been on their regimens for at least six months, beyond the typical onset period for new side effects. Headache (5%), nausea (3%), and diarrhea (3%) were the most frequently reported AEs in the ISL/LEN group. Importantly, discontinuations due to adverse events remained low in both arms, at 2% for ISL/LEN and 1.7% for baseline therapy. Across both trials, key markers of immune health, such as CD4+ T-cell counts, and body weight remained stable, reinforcing the regimen’s overall tolerability.
The Science Behind Once-Weekly Dosing
The ability to deliver effective HIV suppression with a once-weekly oral dose is a testament to the distinct pharmacological properties of islatravir and lenacapavir. Islatravir, developed by Merck, is a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI). This next-generation nucleoside analog works by blocking HIV-1 replication through multiple mechanisms, critically by inhibiting the translocation of reverse transcriptase. Its long intracellular half-life is a key factor enabling less frequent dosing. In April of the current year, the U.S. FDA approved islatravir in combination with doravirine (marketed as Idvynso) for certain adult patients with HIV-1 infection, demonstrating its established efficacy profile.
Lenacapavir, a first-in-class capsid inhibitor from Gilead Sciences, offers a completely different mechanism of action. It interferes with multiple essential steps of the HIV-1 lifecycle, including capsid assembly and disassembly, and nuclear import/export. Lenacapavir is already commercially available as Sunlenca for treatment-experienced individuals and as the twice-yearly injectable Yeztugo for HIV pre-exposure prophylaxis (PrEP). The sustained antiviral activity and unique pharmacokinetic profiles of both islatravir and lenacapavir, when combined, synergistically create a regimen suitable for weekly oral administration, marking a significant step forward from the daily pill burden that has long characterized HIV management.
Evolution of HIV Treatment and the Quest for Simplicity
The landscape of HIV treatment has undergone a remarkable transformation since the advent of the first antiretroviral drugs in the late 1980s. Early regimens often involved multiple pills taken several times a day, accompanied by significant side effects and complex dietary restrictions. This demanding regimen frequently led to challenges with adherence, which is crucial for preventing viral rebound and the development of drug resistance.
The subsequent decades witnessed continuous innovation, leading to highly active antiretroviral therapy (HAART) and eventually to single-tablet regimens (STRs) that consolidated multiple drugs into one daily pill. STRs like Gilead’s Biktarvy have revolutionized adherence and patient convenience, becoming the cornerstone of modern HIV management. However, even a daily pill can pose a burden for some individuals, particularly those with complex medication schedules for other comorbidities, those who travel frequently, or those who struggle with remembering daily doses.
The development of once-weekly oral therapy represents the next logical step in this evolution, building on the success of STRs and long-acting injectable options. It aims to further reduce the psychological and practical burden of daily medication, potentially enhancing long-term adherence and improving overall quality of life for people living with HIV. The patient satisfaction data from ISLEND-2, where a majority of participants reported greater satisfaction and perceived the weekly regimen as less burdensome, strongly supports this hypothesis. This feedback, gathered using the HIV Patient Perspective of Regimen Change instrument, provides crucial real-world insights into the potential benefits of the ISL/LEN combination beyond clinical endpoints.
A Chronology of Development and Prior Insights
The journey of the ISL/LEN combination is rooted in earlier research and development efforts. Prior to these Phase 3 trials, Gilead and Merck conducted a Phase 2 study of the same combination. In October 2024, they announced positive Week 48 results from this earlier study, which involved 104 virologically suppressed adults previously on Biktarvy. Participants were randomized 1:1 to either switch to weekly ISL/LEN or continue daily Biktarvy. At Week 48, 94.2% of ISL/LEN recipients and 92.3% of Biktarvy recipients maintained viral suppression, with no participant in either arm having HIV-1 RNA at or above 50 copies/mL. Encouragingly, at Week 96, all participants remaining in the extension phase maintained RNA levels at or below 50 copies/mL, with mean adherence exceeding 98%, and crucially, no emergent drug resistance was detected.
A notable observation from the Phase 2 study highlighted an important consideration for future implementation: one participant acquired hepatitis B and discontinued treatment. This led to discussions, including a panel at HIV Glasgow in November 2024, emphasizing the need to address hepatitis B immunization in trials and clinical use of regimens that do not contain tenofovir. Biktarvy, for instance, includes tenofovir alafenamide, which is active against hepatitis B, and switching to ISL/LEN would remove this co-coverage. This underscores the comprehensive patient management considerations that accompany advancements in HIV therapy.
Competitive Landscape and Market Implications
The financial stakes in the global HIV market are immense, making the potential entry of a once-weekly oral regimen a significant event. Gilead’s Biktarvy currently dominates the U.S. HIV treatment market, capturing over 52% share in the first quarter of 2026. In 2025, Biktarvy alone generated $14.3 billion, contributing nearly 70% of Gilead’s $20.8 billion HIV franchise revenue. This momentum continued into 2026, with first-quarter Biktarvy sales rising 7% to $3.4 billion and total HIV sales increasing 10% to $5.0 billion. Despite patent agreements protecting full-dose Biktarvy from U.S. generic competition until April 2036, Gilead appears strategically willing to introduce new, potentially more convenient options.
The introduction of ISL/LEN reflects a broader industry trend towards long-acting therapies. While ISL/LEN offers reduced frequency via an oral tablet, the competitive pressure also comes from injectable formulations. GSK’s ViiV Healthcare, through its product Cabenuva (cabotegravir and rilpivirine), has established the long-acting injectable category for HIV treatment, offering monthly or every-two-months dosing. Cabenuva generated £1.4 billion (approximately $1.85 billion) in 2025, a 42% increase, and its injectable PrEP drug Apretude brought in £439 million (approximately $578 million), up 62%. Cabenuva, based on results from ATLAS-2M, has demonstrated high suppression rates (94.3% for every-two-months and 93.5% for monthly dosing), reducing clinic visits to as few as six per year. The ISL/LEN regimen, by contrast, offers similar reduced-frequency dosing in the convenience of a home-taken tablet.
Gilead is also pursuing other Biktarvy successors. At CROI 2026, the company presented late-breaking Phase 3 results from the ARTISTRY-1 and ARTISTRY-2 trials for a daily oral bictegravir/lenacapavir single-tablet regimen. These trials showed virologic suppression comparable to Biktarvy at Week 48, supporting global regulatory filings for yet another simplified daily option. Merck, too, is active with its daily Idvynso (doravirine and islatravir), which received FDA approval in April 2026. In its Biktarvy-controlled Phase 3 trial, Idvynso achieved suppression rates of 92% compared to 94% for Biktarvy, with 1% of participants in each arm experiencing virologic rebound. A broader switch trial for Idvynso showed a rebound rate of 1% versus 5% for participants remaining on baseline therapy, with suppression rates of 96% and 92% respectively.
Broader Impact and Future Outlook
The potential approval of the Gilead and Merck once-weekly oral ISL/LEN regimen holds profound implications for individuals living with HIV, healthcare providers, and the pharmaceutical industry. For patients, it promises an unprecedented level of convenience, potentially improving medication adherence, reducing treatment fatigue, and enhancing overall quality of life. This could be particularly impactful for individuals who find daily pill-taking challenging or stigmatizing. From a public health perspective, improved adherence can lead to better long-term health outcomes, reduced viral transmission, and a lower incidence of drug resistance.
For healthcare systems, a weekly oral option could streamline patient management, potentially reducing the frequency of clinic visits associated with daily monitoring or injectable administration. While long-acting injectables offer reduced visit frequency, the oral nature of ISL/LEN provides an alternative for those who prefer pills over injections or for whom injectables may not be suitable.
The collaboration between Gilead and Merck on this regimen also highlights a strategic imperative for leading pharmaceutical companies to continue innovating in the HIV space. As patents on blockbuster drugs eventually expire, the development of next-generation therapies with enhanced convenience and efficacy is crucial for maintaining market leadership and addressing evolving patient needs. The robust clinical trial data presented for ISL/LEN position it as a formidable contender in the future of HIV care, with regulatory filings and potential approvals anticipated in the near future. The ongoing evolution of ART underscores a collective commitment to not only control the HIV epidemic but also to significantly improve the lives of those affected by it.
