Gilead’s PURPOSE 5 trial reports 85.6% one-year PrEP persistence with twice-yearly lenacapavir versus 46.3% with daily oral F/TDF.
Written By: Faiza, PharmD
Reviewed By: Pharmacally Editorial Team
On November 6, 2026, Gilead Sciences announced primary results from its ongoing Phase 2 PURPOSE 5 trial (NCT06513312), demonstrating significantly higher one-year pre-exposure prophylaxis (PrEP) persistence with twice-yearly subcutaneous lenacapavir compared with daily oral emtricitabine/tenofovir disoproxil fumarate (F/TDF). The findings are scheduled for presentation at HIV Glasgow 2026 (November 8–11).
Maintaining consistent PrEP use remains a central challenge in HIV prevention. Although daily oral antiretroviral regimens substantially reduce the risk of HIV acquisition when taken as prescribed, long-term adherence can be affected by pill fatigue, privacy concerns and barriers to routine medication use. Long-acting prevention options aim to address some of these challenges by reducing dosing frequency.
Trial Design and Participant Characteristics
PURPOSE 5 is a randomized, open-label Phase 2 study specifically designed to compare persistence between long-acting injectable and daily oral PrEP among individuals with ongoing HIV prevention needs who were not taking PrEP at enrollment.
The trial enrolled 267 participants across the United Kingdom and France, randomized in a 2:1 ratio to receive either twice-yearly subcutaneous lenacapavir (n=180) or daily oral F/TDF (n=87). Of the F/TDF participants, 80 were evaluable for the primary persistence analysis.
The study population included cisgender men (72.3%), cisgender women (7.1%) and gender-diverse individuals (20.6%). Notably, 37.8% were PrEP-naive at baseline, indicating that the study included both new and previously experienced PrEP users.
Primary Endpoint Results: Higher Persistence with Lenacapavir
The primary endpoint assessed protocol-defined persistence through Week 52. Lenacapavir persistence required on-time injections at baseline and Week 26, within a permitted two-week window, followed by an on-time Week 52 visit. For F/TDF, persistence was assessed through dried blood spot (DBS) tenofovir diphosphate concentrations consistent with at least four doses per week (≥700 fmol/punch) at Weeks 13, 26, 39 and 52.
At Week 52, 85.6% (154/180) of lenacapavir recipients met the persistence criteria, compared with 46.3% (37/80) in the evaluable F/TDF group. The absolute difference was 39.3 percentage points (95% CI: 26.66–51.41; p<0.0001).
Although the findings demonstrate a statistically significant persistence advantage, the comparison involved different adherence assessment methods: injection and visit attendance for lenacapavir versus biomarker-based measurements for oral F/TDF. This distinction is important when interpreting the magnitude of the difference.
Additional Outcomes: HIV Acquisitions and Participant Retention
No HIV acquisitions occurred among participants receiving lenacapavir during the 52-week study period. One acquisition was reported in the F/TDF group, with drug-level analysis at diagnosis indicating adherence consistent with fewer than two doses per week.
Participant retention at Week 52 was also high in both groups, with 89.4% of lenacapavir recipients and 83.9% of F/TDF recipients attending their scheduled visits.
Although the absence of HIV acquisitions in the lenacapavir group is encouraging, the small number of events does not allow PURPOSE 5 to establish comparative antiviral efficacy between the two regimens.
Safety Findings
The safety profile of lenacapavir was generally consistent with previous studies in the PURPOSE programme. Serious adverse events occurred in 3.9% of lenacapavir recipients and 3.4% of F/TDF participants. Investigators considered none of these events treatment-related.
No participants discontinued lenacapavir because of adverse events. Injection-site reactions were common but generally mild to moderate, including nodules (67.8%), pain (60.0%), induration (20.6%) and erythema (17.8%). Despite the frequency of these local reactions, no adverse-event-related discontinuations were reported in the lenacapavir group.
Regulatory Status
Lenacapavir is a first-in-class HIV-1 capsid inhibitor that interferes with multiple stages of the viral lifecycle. In December 2022, the US Food and Drug Administration (FDA) approved it as Sunlenca, in combination with other antiretroviral medicines, for heavily treatment-experienced adults with multidrug-resistant HIV-1.
In June 2025, the FDA expanded its regulatory use by approving lenacapavir as Yeztugo for HIV-1 PrEP in adults and adolescents weighing at least 35 kg who are at risk of sexually acquired HIV.
Its preventive efficacy was established in the Phase 3 PURPOSE 1 (NCT04994509) and PURPOSE 2 (NCT04925752) trials. PURPOSE 5 complements this evidence by evaluating persistence rather than establishing new antiviral efficacy.
Clinical Interpretation and Health Systems Impact
The 39.3-percentage-point persistence advantage highlights the potential benefit of reducing dosing frequency from daily oral administration to two scheduled injections annually. This approach may help address adherence barriers among individuals who find continuous daily medication difficult to maintain.
However, broader implementation will depend on healthcare delivery capacity, reliable injection scheduling, equitable access and affordability, including appropriate insurance and reimbursement arrangements.
Several limitations require consideration. The open-label design may have influenced participant behaviour, recruitment was restricted to the UK and France, and the 52-week observation period does not establish multi-year persistence in routine clinical practice.
Ultimately, PURPOSE 5 demonstrates an advantage in protocol-defined persistence rather than intrinsic antiviral superiority over consistently taken daily F/TDF. Nevertheless, the findings reinforce the importance of treatment delivery, sustained engagement and individual preferences in supporting effective long-term HIV prevention.
References
Gilead Sciences. PURPOSE 5 one-year persistence and safety findings, November 6, 2026.
Study of Lenacapavir Taken Twice a Year for HIV Pre-Exposure Prophylaxis (PrEP) (PURPOSE 5), ClinicalTrials.gov ID NCT06513312
About the Writer
Faiza (Linkedin) is a Healthcare Writer at Pharmacally and a PharmD professional from St. Peter’s Institute of Pharmaceutical Sciences, Kakatiya University. she has academic and clinical interests in clinical pharmacy, pharmacovigilance and patient care. Her research focuses on serum biomarkers in acute pancreatitis and medication adherence. She is interested in clinical research, medical writing and evidence-based healthcare communication.