PrEP4U: Assessing the Effectiveness of Integrated Same-Day Lenacapavir Initiation and Follow-up Choice on PrEP Persistence

PrEP4U is designed as a pragmatic, randomized implementation trial to test strategies that could directly inform real-world roll-out of lenacapavir. By integrating:

• Same-day initiation based on rapid HIV testing, and
• Choice of follow-up delivery location (home, community, or clinic) the study addresses two of the most pressing implementation questions for long-acting injectable PrEP.

The primary hypothesis is that giving participants choice in follow-up location will improve PrEP persistence compared to a clinic-only model. Secondary analyses will evaluate safety of rapid testing, acceptability, and participant costs. Exploratory analyses will assess HIV incidence and resistance.

Findings from PrEP4U will provide essential evidence to guide scalable, equitable, person-centered delivery models for lenacapavir PrEP in the U.S. and globally.

Study Overview

• Status: Not yet recruiting
• Conditions: HIV Pre-exposure Prophylaxis Use
• Intervention / Treatment: Other: Follow up via standard clinic; Other: Choice of follow up

Detailed Description

Since the introduction of oral PrEP over a decade ago, more than 1.3 million HIV infections occur globally each year, far exceeding the UNAIDS 2030 target of < 335,000 cases. UNAIDS estimated that only 2.3 million people used PrEP in 2023, far below the target of 10 million by 2025. Oral PrEP persistence remains low, with many individuals discontinuing within 6-12 months. Factors contributing to low uptake and persistence include pill fatigue, stigma, access barriers, and medical mistrust. The gap is especially stark in sub-Saharan Africa and Latin America, where PrEP coverage lags behind epidemic burden.

The United States mirrors this global picture; despite broad access to healthcare, disparities in uptake and continuation persist along racial, ethnic, and gender lines. According to the CDC, in 2022 only 36% of individuals eligible for PrEP were prescribed it. Marked disparities exist: Black and Hispanic/Latino individuals and women represent a disproportionate share of new HIV diagnoses but a much smaller fraction of PrEP users. In Massachusetts, for example, Black and Hispanic/Latino individuals accounted for 35% and 31% of new HIV cases in 2022, yet only 7% and 12% of PrEP users in 2023, respectively. These disparities highlight ongoing barriers to access, stigma, and persistence.

Lenacapavir is a first-in-class HIV-1 capsid inhibitor with a novel mechanism of action and an exceptionally long half-life, enabling subcutaneous administration every 26 weeks. PURPOSE 1 and PURPOSE 2, large multicenter randomized clinical trials, established lenacapavir's efficacy for HIV prevention. In PURPOSE 2, a Phase 3 randomized trial of over 3,000 participants at risk for HIV infection, HIV incidence with lenacapavir was 0.10 per 100 person-years, compared to 0.93 per 100 person-years in the oral F/TDF arm and 2.37 per 100 person-years in the background incidence cohort. Lenacapavir reduced HIV incidence by 96% compared with background incidence and by 89% compared with oral PrEP. No major safety concerns were identified, though 1.2% discontinued due to injection-site reactions. These findings, published in the New England Journal of Medicine in 2025, demonstrated that twice-yearly lenacapavir is a highly effective PrEP agent.

Lenacapavir addresses key limitations of oral PrEP:

• Persistence challenges with daily oral adherence.
• Barriers to clinic attendance for frequent refills or injections.
• Stigma associated with oral PrEP use, which may be mitigated by less frequent, more discreet dosing.

Thus, lenacapavir has the potential to transform HIV prevention - if delivery strategies are optimized.

While clinical trials demonstrate efficacy, implementation science questions remain:

1. Same-day initiation: Oral PrEP initiation has successfully shifted to same-day models. However, injectable PrEP initiation has been complicated by requirements for multiple laboratory tests, delaying access. PURPOSE 1 and 2 used a combination of rapid HIV Ag/Ab, laboratory Ag/Ab, and quantitative RNA tests prior to injection. In real-world settings, RNA testing may be impractical and introduce delays. Rapid HIV testing, with confirmatory laboratory Ag/Ab tests pending, is a feasible approach aligned with WHO guidance. This balance enables timely initiation without undue barriers.
2. Follow-up and persistence: Lenacapavir's twice-yearly dosing reduces pill burden but raises questions of where and how injections are delivered. Relying on centralized hospital clinics may perpetuate barriers (transportation, stigma, scheduling). In contrast, home-based and community-based PrEP delivery have shown promise for improving persistence and acceptability.

Suffolk County, Massachusetts - home to central Boston - is designated a high-burden HIV area in the U.S. "Ending the HIV Epidemic" initiative, reporting 118 new HIV diagnoses in 2022. Despite broad health insurance coverage and a state-sponsored PrEP assistance program, PrEP uptake and persistence remain insufficient among Black, Hispanic/Latino, and female populations. PrEP4U will specifically recruit participants from these priority populations through community partner organizations, mobile van services, and clinical sites. The trial is designed to address equity gaps by testing models of care that reduce stigma, bring services closer to people, and incorporate patient choice.

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Meighan Krows; Phone Number: 617-726-2000; Email: mkrows@mgb.org

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Sexual Health Clinic
      • Contact: Kevin Ard, MD; Phone Number: 617 726 2748; Email: kard@mgh.harvard.edu
      • Principal Investigator: Kevin Ard, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• HIV negative
• Eligible for HIV PrEP per CDC guidelines
• Able and willing to provide informed consent
• Willing to receive injectable lenacapavir and adhere to study procedures
• Residing inMassachusetts with expected availability for 6-month follow-up

Exclusion Criteria:

• Known HIV infection at baseline
• Contraindication to lenacapavir injection (e.g., hypersensitivity, significant drug interactions)
• Pregnancy at baseline (participants who become pregnant during the trial may remain enrolled if they choose)
• Participation in another interventional HIV prevention study
• Any condition judged by the investigator to compromise safety or study integrity

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: PrEP Clinic; The PrEP Clinic arm will be randomized to receive follow up at the clinic	Other: Follow up via standard clinic; Follow up will take place at the clinic where the first dose was administered.
Experimental: PrEP Choice; The PrEP Choice arm allows participants to choose where they receive their follow up	Other: Choice of follow up; Randomization to either standard clinic follow up or choice of where follow up takes place

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PrEP persistence at 6 months	Proportion of participants in the PrEP Choice arm versus the PrEP Clinic arm who successfully receive the second on-time injection	26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of same-day initiation based on rapid HIV testing	Proportion of individuals in whom rapid and laboratory Ag/Ab test results are consistent.	26 weeks
Acceptability of same-day initiation and follow-up models	Participant acceptability scores measured using structured surveys	26 weeks
Participant costs associated with PrEP delivery models	Average participant costs (financial and time) per injection visit in clinic versus community/home settings	26 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
HIV Incidence by Study Arm	HIV incidence rate (per 100 person-years) by arm	26 weeks
Lenacapavir Resistance in HIV Seroconverters	Proportion of HIV infections with confirmed resistance mutations	26 weeks
Subgroup Analyses of Persistence	Identification of populations for whom differentiated delivery has the greatest impact	26 weeks

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Brigham and Women's Hospital
• Investigators: Principal Investigator: Ruanne V Barnabas, MBChB, PhD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): February 2, 2026
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2026

Study Registration Dates

• First Submitted: January 5, 2026
• First Submitted That Met QC Criteria: January 5, 2026
• First Posted (Actual): January 13, 2026

Study Record Updates

• Last Update Posted (Actual): January 13, 2026
• Last Update Submitted That Met QC Criteria: January 5, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: HIV PrEP; Injectable PrEP; Lenacapavir
• Other Study ID Numbers: 2025P002691

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Interested parties may contact the central contact with requests for data. Data sets will be provided based on approval of request/concept by protocol team.
• IPD Sharing Time Frame: Once analysis of the study objectives is complete. Tentatively January 2027
• IPD Sharing Access Criteria: The protocol team will review all data requests. Upon approval of requests the data analyst will work with the requester to provide the data in an acceptable format, using a secure access link.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes