Lenacapavir Achieves Nearly Twice the One-Year Persistence of Daily Oral F/TDF for HIV Prevention
Gilead Sciences, has announced positive results from its PURPOSE 5 clinical trial, demonstrating significantly higher persistence with twice-yearly injectable lenacapavir for HIV prevention compared with once-daily oral emtricitabine/tenofovir disoproxil fumarate (F/TDF). The Phase 2 study evaluated people in the United Kingdom (UK) and France who could benefit from pre-exposure prophylaxis (PrEP) but were not taking PrEP when they entered the trial.
The findings showed that 85.6% of participants receiving twice-yearly lenacapavir remained persistent on PrEP through Week 52, compared with 46.3% of participants receiving daily oral F/TDF. The difference between the treatment groups was statistically significant, highlighting the potential advantages of a long-acting prevention option for people who may find it challenging to maintain a daily medication routine.
The results will be presented at HIV Glasgow 2026 and provide additional evidence about the importance of treatment persistence in HIV prevention. Although effective PrEP medications are available, maintaining consistent use remains a major challenge in real-world settings. Gilead’s PURPOSE 5 study was specifically designed to examine this issue by comparing persistence between a long-acting injectable prevention option and a daily oral PrEP regimen.
The trial also reported zero HIV acquisitions among participants receiving twice-yearly lenacapavir during the 52-week study period. One HIV acquisition occurred in the F/TDF group, with drug-level analysis at the time of diagnosis indicating medication exposure consistent with fewer than two doses per week.
PURPOSE 5 Highlights Higher Persistence With Twice-Yearly Lenacapavir
The primary findings from PURPOSE 5 showed a substantial difference in one-year PrEP persistence between participants receiving lenacapavir and those taking daily oral F/TDF.
At Week 52, 154 of 180 participants in the lenacapavir group, representing 85.6%, met the study’s definition of persistence. In comparison, 37 of 80 participants in the F/TDF group, or 46.3%, remained persistent on their assigned PrEP regimen.
The absolute difference between the groups was 39.3 percentage points, with a 95% confidence interval of 26.66% to 51.41%. The result was statistically significant, with a p-value of less than 0.0001.
These findings indicate that participants starting twice-yearly lenacapavir were considerably more likely to maintain consistent PrEP use over one year than participants starting a daily oral regimen.
PURPOSE 5 is particularly relevant because it is the first randomized study specifically designed to compare persistence between a long-acting HIV prevention option and daily oral PrEP among individuals who were not currently taking PrEP at enrollment.
The study’s focus on people not taking PrEP at baseline helps address an important gap in HIV prevention research. While clinical studies have established the effectiveness of PrEP medications, their real-world impact depends substantially on whether individuals start treatment, continue using it and maintain adequate medication exposure during periods when they may be vulnerable to HIV acquisition.
The higher persistence observed with lenacapavir suggests that reducing the frequency of medication administration may help address some of the practical barriers associated with daily oral prevention.
Study Population Included Diverse Participant Groups
PURPOSE 5 is an ongoing Phase 2, randomized, open-label clinical study evaluating PrEP persistence among people with HIV prevention needs in the UK and France.
The study enrolled individuals who were not taking PrEP at the time of enrollment. Participants were randomized in a 2:1 ratio to receive either twice-yearly subcutaneous lenacapavir or once-daily oral F/TDF and were followed for 52 weeks.
A total of 267 participants enrolled in the trial. The study population included cisgender men, who represented 72.3% of participants; cisgender women, who accounted for 7.1%; and gender-diverse individuals, who represented 20.6%.
Additionally, 37.8% of participants were PrEP-naïve at baseline, meaning they had not previously used PrEP. The inclusion of individuals with different gender identities and prior PrEP experiences provides information about persistence across a varied population with HIV prevention needs.
The trial’s design allowed investigators to assess how participants maintained their assigned prevention regimens over time. Rather than focusing exclusively on whether individuals initiated PrEP, the study examined whether they continued receiving or taking medication according to predefined treatment schedules and drug-exposure requirements.
This distinction is important because starting PrEP does not necessarily translate into sustained protection. Individuals may discontinue daily medication for a variety of practical or personal reasons, potentially creating periods when they are no longer adequately protected against HIV.
Strict Definitions Used to Measure PrEP Persistence
Gilead used specific protocol-defined criteria to determine whether participants remained persistent on their assigned treatment.
For participants receiving lenacapavir, persistence was defined by receiving the scheduled injections on time at Day 1 or baseline and at Week 26, within a permitted window of plus or minus two weeks. Participants also needed to attend the scheduled follow-up visit at Week 52.
For participants receiving daily oral F/TDF, persistence was assessed using dried blood spot (DBS) measurements of tenofovir diphosphate (TFV-DP), a biomarker indicating medication exposure.
Participants in the F/TDF group were considered persistent when their TFV-DP concentrations were consistent with taking at least four doses per week. The required concentration threshold was at least 700 femtomoles per punch, assessed at Weeks 13, 26, 39 and 52.
These definitions enabled investigators to compare persistence using measures appropriate to each treatment approach. For lenacapavir, the assessment focused on receiving scheduled injections and attending the follow-up visit. For oral F/TDF, the assessment relied on objective drug-level measurements rather than attendance or self-reported medication use alone.
The difference in persistence rates therefore reflects whether participants met the specific treatment-use requirements established by the study protocol.
No HIV Acquisitions Reported in the Lenacapavir Group
Another important finding from PURPOSE 5 was the absence of HIV acquisitions among participants receiving twice-yearly lenacapavir during the 52-week study period.
In the F/TDF group, one HIV acquisition was reported. Drug-level analysis conducted at the time of diagnosis indicated exposure consistent with fewer than two doses of F/TDF per week.
This finding is relevant to the relationship between medication persistence and HIV prevention. Daily oral F/TDF is an established prevention option when taken as prescribed, but protection depends on maintaining adequate medication exposure. Inconsistent use can reduce the effectiveness of a daily regimen.
The absence of HIV acquisitions in the lenacapavir group is an encouraging observation from the study. However, the trial was primarily designed to compare PrEP persistence, and the number of participants and duration of follow-up should be considered when interpreting HIV acquisition findings.
Participant retention remained high in both treatment groups throughout the study. At Week 52, 89.4% of participants in the lenacapavir group attended the study visit, compared with 83.9% of participants in the F/TDF group.
The retention results indicate that most participants in both groups remained engaged with the clinical study through the final reported assessment. Importantly, study visit attendance and treatment persistence were measured differently, meaning that attending a visit did not automatically establish that a participant met the protocol’s persistence criteria.
Persistence Remains a Major Challenge in HIV Prevention
Despite significant progress in HIV prevention, new infections continue to occur globally. According to UNAIDS, approximately 1.2 million people acquired HIV worldwide in 2025.
The continued number of new infections underscores the need for prevention strategies that are not only effective but also practical for sustained use.
Pre-exposure prophylaxis has become an important component of HIV prevention programs. Daily oral F/TDF is currently the most commonly used oral PrEP medication globally and can provide highly effective protection when taken as prescribed.
However, maintaining daily medication use can be difficult for some individuals. Real-world experience has shown that people may discontinue PrEP during the first year, even when they remain at risk of HIV acquisition.
Factors that can affect persistence may include the demands of taking medication every day, individual preferences, privacy considerations and challenges associated with maintaining regular treatment routines. As a result, the availability of an effective prevention medication does not necessarily guarantee consistent use.
Twice-yearly lenacapavir offers a different approach by reducing the frequency of administration to one injection every six months. Instead of remembering to take a tablet each day, individuals receiving the injectable option need to attend scheduled appointments for their injections.
This extended dosing schedule may be particularly relevant for people who prefer long-acting prevention approaches or experience challenges with daily oral medication. The PURPOSE 5 findings suggest that this approach may help more people remain on PrEP over time.
Clinical Experts Emphasize the Importance of Long-Term Persistence
Professor Chloe Orkin, MBE, Clinical Professor of Infection and Inequities at Queen Mary University of London, highlighted the importance of maintaining PrEP use after treatment initiation.
According to Professor Orkin, starting PrEP is an important first step, but continued use is essential for preventing HIV acquisition during periods of risk.
She noted that participants in the UK and France who received twice-yearly lenacapavir were substantially more likely to remain on PrEP than those receiving daily oral medication.
Professor Orkin said the findings suggest that long-acting injectable prevention options could help address an important barrier to sustained HIV prevention. She also highlighted the study’s ability to reach a high proportion of individuals who were new to PrEP, an important consideration for expanding prevention access among people who may benefit from these interventions.
Jared Baeten, M.D., Ph.D., senior vice president of Clinical Development and Virology Therapeutic Area Head at Gilead Sciences, said the study was designed to examine one of the most important challenges in HIV prevention: helping people remain on PrEP for as long as they need protection.
Dr. Baeten emphasized that the results demonstrate the potential of twice-yearly lenacapavir to narrow the gap between initiating PrEP and maintaining its use.
He also noted that improving persistence could have an important impact on broader efforts to end the HIV epidemic in Europe and globally.
Safety Findings Consistent With Previous Lenacapavir Studies
The safety profile observed in PURPOSE 5 was generally consistent with findings from previous studies evaluating lenacapavir for HIV prevention.
Serious adverse events were uncommon in both treatment groups. They occurred in 3.9% of participants receiving lenacapavir and 3.4% of participants receiving daily oral F/TDF.
Investigators determined that none of the serious adverse events were related to study treatment. In addition, no participants in the lenacapavir group discontinued treatment because of adverse events.
The most frequently reported treatment-related events associated with lenacapavir were mild or moderate injection-site reactions (ISRs), which occurred following subcutaneous administration.
Reported injection-site reactions included:
- Nodules in 67.8% of participants.
- Injection-site pain in 60.0%.
- Induration in 20.6%.
- Erythema in 17.8%.
These reactions reflect local effects associated with administering the injectable medication. Although injection-site reactions were common, the company reported that no participants discontinued lenacapavir treatment due to adverse events.
The overall safety findings provide additional information about the tolerability of twice-yearly lenacapavir in the PURPOSE 5 population. The low incidence of serious adverse events and absence of treatment-related serious adverse events are relevant to the continued evaluation of this long-acting prevention approach.
Potential to Expand HIV Prevention Choices
The PURPOSE 5 findings add to the growing body of clinical evidence supporting long-acting approaches to HIV prevention.
While daily oral PrEP remains an important and widely used option, not every individual finds a daily medication schedule suitable for long-term use. Offering different prevention approaches may help individuals select a regimen that better fits their preferences and circumstances.
By requiring administration only once every six months, lenacapavir could reduce the day-to-day demands associated with oral PrEP. The higher persistence rate observed in PURPOSE 5 suggests that this dosing schedule may help address one of the practical challenges limiting the sustained use of HIV prevention medication.
The study also highlights the importance of evaluating prevention options beyond their biological effectiveness. For HIV prevention to have a meaningful impact at the population level, individuals need to be able to access an appropriate option and maintain its use during periods when protection is needed.
Gilead’s results indicate that twice-yearly lenacapavir may offer an alternative for people who face difficulties with daily oral PrEP or prefer a long-acting injectable approach.
Overall, PURPOSE 5 demonstrated that 85.6% of participants receiving twice-yearly lenacapavir remained persistent through Week 52, compared with 46.3% of participants receiving daily oral F/TDF. The statistically significant difference, together with zero reported HIV acquisitions in the lenacapavir group and a generally consistent safety profile, supports further consideration of long-acting PrEP as part of broader HIV prevention strategies.
The findings will be presented at HIV Glasgow 2026 and provide additional insight into how less frequent dosing may help improve persistence among people who could benefit from PrEP. As global efforts continue to reduce new HIV infections, prevention options that support sustained use will remain an important part of addressing the epidemic.
About PURPOSE 5
PURPOSE 5 is the first randomized study designed specifically to compare persistence between a long-acting injectable HIV prevention option and daily oral PrEP among individuals who would benefit from PrEP and were not currently taking oral PrEP. The Phase 2 study conducted in the United Kingdom and France evaluates whether twice-yearly lenacapavir can improve persistence compared with daily oral F/TDF over 52 weeks.
PURPOSE 5 is part of Gilead’s broader PURPOSE clinical development program evaluating lenacapavir across diverse populations and settings with the goal of expanding HIV prevention choice through long-acting prevention options.
About the PURPOSE Program
Gilead’s landmark PURPOSE program is the most comprehensive and diverse HIV prevention trial program ever conducted. The program comprises five HIV prevention trials around the world that are focused on innovation in science, trial design, community engagement, and health equity.
The PURPOSE 1 and PURPOSE 2 trials evaluated the safety and efficacy of twice-yearly injectable lenacapavir to reduce the chance of getting HIV. The ongoing Phase 2 and 3 program, consisting of PURPOSE 1-5 studies, is assessing the potential of lenacapavir to help a diverse range of people around the world who could benefit from PrEP.
More information about the PURPOSE program, including individual trial descriptions, populations and locations, can be found at www.purposestudies.com.
About Lenacapavir
Twice-yearly lenacapavir is approved in multiple countries as pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV in adults and adolescents who are at risk of HIV acquisition. Lenacapavir is also approved in multiple countries for the treatment of multi-drug-resistant HIV in adults, in combination with other antiretrovirals.
The multi-stage mechanism of action of lenacapavir is distinguishable from other currently approved classes of antiviral agents. While most antivirals act on just one stage of viral replication, lenacapavir is designed to inhibit HIV at multiple stages of its lifecycle and has no known cross resistance exhibited in vitro to other existing drug classes.
Lenacapavir is being evaluated as a long-acting option in multiple ongoing and planned early and late-stage clinical studies in Gilead’s HIV prevention and treatment research program, including a once-yearly injection for HIV prevention. Lenacapavir is being developed as a foundation for potential future HIV therapies with the goal of offering both long-acting oral and injectable options with several dosing frequencies, in combination or as a mono agent, that help address individual needs and preferences of people and communities affected by HIV. The journal Science named lenacapavir its 2024 “Breakthrough of the Year.”