HIV treatment evolving beyond 'once-daily'

Clinical outcomes for once-weekly oral agent·twice-yearly preventive injections have been unveiled

Studies on extending dosing interval in the field of prevention and treatment

Competition in human immunodeficiency virus (HIV) treatment development is shifting from viral suppression efficacy toward enhancing patient dosing convenience.

​As once-daily oral therapy has become the standard of care, clinical outcomes for once-weekly oral treatments and twice-yearly preventive injections are being disclosed, demonstrating shifts in both therapeutic and preventive strategies.

According to industry sources on July 23, major global pharmaceutical companies are scheduled to present research results on long-acting treatment strategies, including once-weekly HIV therapies and twice-yearly pre-exposure prophylaxis (PrEP), at the 26th International AIDS Conference (AIDS 2026) starting on July 26 in Rio de Janeiro, Brazil.

​First Phase 3 success for a once-weekly oral treatment

​The most highlighted result is the Phase 3 clinical trial results of an oral combination therapy combining Gilead's lenacapavir and MSD's islatravir.

​Lenacapavir is a long-acting agent that inhibits viral replication by targeting the HIV capsid. Islatravir is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) with a mechanism distinct from conventional reverse transcriptase inhibitors, acting to block viral replication.

​Gilead is expanding its long-acting strategy in both treatment and prevention based on lenacapavir. Following the launch of 'Sunlenca' as a therapeutic agent, the company applied a separate product name, 'Yeztugo,' for its preventive indication.

Until now, long-acting HIV treatment has centered on injectable agents administered up to once every two months or once-daily oral regimens. To achieve injectable-level dosing convenience with an oral formulation, both companies have been developing a once-weekly oral therapy combining the long-acting agent lenacapavir with the novel-mechanism islatravir.

​The global Phase 3 trials, designated ISLEND-1 and ISLEND-2, evaluated the efficacy and safety of switching from conventional daily oral therapy to once-weekly treatment (lenacapavir + islatravir) in virologically suppressed people living with HIV. Both studies demonstrated non-inferiority in viral suppression efficacy at 48 weeks compared to existing daily oral regimens.

ISLEND-1 is a study comparing maintenance therapy with Gilead's 'Biktarvy' (bictegravir + emtricitabine + tenofovir alafenamide) against switching to lenacapavir + islatravir following Biktarvy administration.

​Among 607 patients evaluated, none in the lenacapavir + islatravir arm failed to maintain viral suppression at week 48, compared with 1 patient (0.3%) in the Biktarvy maintenance arm.

​Similar results were confirmed in ISLEND-2, which enrolled patients maintaining various daily oral regimens. At week 48, the proportion of patients with HIV RNA at or above 50 copies/mL (the threshold for viral suppression) was 1 patient (0.3%) in the lenacapavir + islatravir group and 4 patients (1.3%) in the baseline regimen group.

Safety profiles were also comparable to existing therapies. Concerns regarding decreases in lymphocyte and CD4+ T-cell counts, previously raised during high-dose development, were not observed in these trials.

​If approved by regulatory authorities, lenacapavir + islatravir will become the world's first once-weekly oral HIV treatment.

Twice-yearly era for prevention… Expanding long-acting strategies

​Gilead 'Yeztugo'

In addition to HIV treatment, long-acting strategies are expanding into pre-exposure prophylaxis (PrEP) to prevent infection.

​Gilead will also present long-term follow-up data for its twice-yearly HIV prevention injection, Yeztugo. This study evaluated post-approval long-term preventive efficacy and real-world persistence, focusing on confirming the clinical value of long-acting PrEP.

n the PURPOSE 1 trial, 95% of eligible participants chose to continue with Yeztugo in the open-label extension, with zero incident HIV cases reported during the 52-week follow-up period.

​In PURPOSE 2 as well, 95% of participants selected Yeztugo administration, maintaining adherence rates above 90%.

​The twice-yearly administration regimen is recognized as a strategy that reduces pill burden and improves persistence compared to daily oral PrEP.

Beyond efficacy into a 'dosing interval' competition

​GSK 'Cabenuva'

​In addition to Gilead, GSK's injectable 'Cabenuva' (cabotegravir + rilpivirine), administered once monthly or once every two months, holds an established position in the long-acting HIV treatment market.

Gilead is also pursuing the development of next-generation long-acting therapeutics, including once-weekly oral treatments, twice-yearly preventive injections, and combinations of lenacapavir with broadly neutralizing antibodies (bNAbs).

​MSD also recently secured FDA approval for its once-daily islatravir-based combination tablet, 'Idvynso,' while concurrently advancing the development of a once-monthly oral PrEP candidate (MK-8527) and a once-weekly oral treatment.

​Currently, daily oral medication is the standard of care in HIV treatment. As development progresses from long-acting injectables to once-weekly oral therapeutics, options personalized to patients' lifestyles and treatment preferences are expected to become increasingly diverse.