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Real-World Implementation Outcomes of Lenacapavir for HIV Preexposure Prophylaxis:
Early Findings From a Multicenter United States Cohort
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Clinical Infectious Diseases, Published: 15 May 2026
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Despite these limitations, these data provide early insight into the practical considerations of delivering LEN PrEP in routine care. Our findings demonstrate that payer processes and early injection-related experiences may meaningfully influence implementation of LEN PrEP in routine practice (Supplementary Figure 1). Injection-site selection may represent a modifiable strategy to improve tolerability and early persistence, particularly given the observed associations with abdominal administration. Standardized approaches to ISR mitigation, including anticipatory counseling and supportive care protocols, may further reduce symptom burden and downstream clinical contact. As long-acting PrEP expands, implementation will require streamlined insurance and medication administration pathways (eg, direct-to-inject protocols) [9, 10], staff support for scheduling and follow-up, and proactive management of ISRs to improve timely initiation and persistence. Ensuring equitable access will be critical to scaling up LEN PrEP in our concerted efforts to end the HIV epidemic.
Abstract
Lenacapavir preexposure prophylaxis (PrEP) implementation across 17 US sites ( ampa#thinsp;= 501) was characterized by delays in initiation driven by payer processes. Early nonpersistence was uncommon (3.6%) but exceeded clinical trial discontinuation rates and was strongly associated with abdominal injections and injection-site reactions requiring clinical contact, underscoring modifiable barriers to early persistence.
Study Design and Setting
We conducted a retrospective cohort study of individuals initiating LEN PrEP between 18 June and 31 December 2025 across 17 US clinical programs. These included a mix of large academic medical centers and community-based PrEP programs, all with established infrastructure for HIV prevention services. However, sites varied in staffing models, pharmacy integration, and administrative support, reflecting heterogeneous real-world implementation environments.
RESULTS
Time to Initiation
Median time from prescription to first LEN injection was 27 days (IQR 14-51). Insurance type was significantly associated with time to initiation, with privately insured individuals experiencing a 7.5-day delay compared with self-pay or uninsured individuals (95% CI .2-14.9; P = .043); no significant differences were observed for Medicare or Medicaid recipients. Requiring a prior authorization was associated with an 11.6-day delay in initiation (95% CI 6.2-17.0; P < .001).
Injection Practices and Early Experience
The abdomen was the most common injection site (337/501, 67.3%). Pre- or postinjection supportive care was not consistently documented across sites: 198/501 (39.5%) received ice application and 18/501 (3.6%) received analgesics, while 301/501 (60.1%) had no documented supportive care. Confirmation of the day 2 oral loading dose was documented in 313/501 (62.5%). Injection-site reactions requiring clinical contact occurred in 72/501 (14.4%), most commonly due to pain (31/72, 43.1%) and nodules (26/72, 36.1%). Abdominal injection was associated with increased odds of ISR-related clinical contact compared with thigh injection (odds ratio [OR] 1.84; 95% CI 1.02-3.33; P = .042).
Early Nonpersistence
Over 93.6 person-years of observation (median follow-up 69 days [IQR, 41-106]), early nonpersistence occurred in 18/501 (3.6%), corresponding to 19.2 per 100 person-years (95% CI 11.4-30.5). All 18 events occurred among individuals receiving abdominal injections (18/337, 5.3% vs 0/164, 0%). Abdominal injection site was strongly associated with early nonpersistence (OR 19.05; 95% CI 1.14-318.12; P = .001). Injection-site reactions requiring clinical contact were also strongly associated with early nonpersistence (OR 18.68; 95% CI 5.92-68.66; P < .001; Table 2).
DISCUSSION
This study represents one of the first evaluations of real-world clinical outcomes of LEN PrEP in the United States where early implementation was shaped by both structural barriers and early patient experience. Our cohort largely reflected the demographics of current US PrEP users [6], with most having prior PrEP experience. Median time to initiation exceeded 3 weeks, varying by insurance type and prior authorization requirements, underscoring the influence of payer policies during early implementation [7]. These findings highlight structural barriers limiting LEN PrEP access that, if unmitigated, may exacerbate existing PrEP-to-need ratios among marginalized communities who stand to benefit the most from long-acting prevention options [8].
Although early nonpersistence was uncommon, rates were at least 3-fold higher than discontinuations reported in registrational trials; the relatively short duration of follow-up may also underestimate longer-term nonpersistence/definitive discontinuation outcomes. Injection-related factors emerged as the most strongly associated correlates of early nonpersistence. Abdominal injections were associated with both increased odds of ISR-related clinical contact and early nonpersistence, with no events observed among individuals receiving thigh injections.
Injection-site reactions requiring clinical contact occurred in approximately 1 in 7 participants, indicating a meaningful burden on both patients and clinical systems. In clinical trials, ISR severity also decreased with subsequent injections, suggesting that tolerability may improve over time [2, 3]. Notably, documentation of pre- or postinjection supportive care was absent in a majority of participants, which may reflect either underdocumentation or inconsistent use of mitigation strategies. Confirmation of the day 2 oral LEN dose was documented in approximately two-thirds of participants, highlighting potential gaps in adherence and/or documentation and the importance of structured workflows to support consistent initiation practices.
This study has several limitations. The short duration of follow-up precludes a comprehensive assessment of persistence, tolerability, and adherence; longer-term follow-up data will be essential to evaluate retention on LEN PrEP as patients reach subsequent injection timepoints. The observational design limits causal interpretation of associations, particularly with respect to injection site and early nonpersistence. In addition, incomplete documentation of supportive care and medication access pathways may have led to misclassification or underestimation of these variables. Finally, participating sites included large academic and community-based PrEP programs, all with established infrastructure for HIV prevention. As early adopters, these programs may have greater clinical, pharmacy, and administrative resources than other settings, which may limit generalizability. Implementation challenges, including staffing, workflow integration, and medication access, may be more pronounced in differently resourced environments.
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