Author: *Sara Hockney1
1. Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
*Correspondence to [email protected]
Disclosure: The author has declared no conflicts of interest.
Keywords: Cabotegravir (CAB), global health, HIV, HIV prevention, implementation science, lenacapavir (LEN), long-acting (LA) injectables, pre-exposure prophylaxis (PrEP).
Citation: Microbiol Infect Dis AMJ. 2025;3[1]:27-31. https://doi.org/10.33590/microbiolinfectdisam/JCTG4390
CABOTEGRAVIR FOR PRE-EXPOSURE PROPHYLAXIS: FROM TRIALS TO IMPLEMENTATION
Long-acting injectable CAB (CAB-LA), administered every 2 months, continues to demonstrate robust efficacy. In the US PrEPFACTS study, only three participants (0.2%) had evidence of seroconversion over a median follow-up of 325 days, although HIV testing only occurred in about 60% of injections, highlighting ongoing gaps in monitoring.1
Safety data for CAB-LA during pregnancy are increasingly reassuring, addressing a critical knowledge gap. The open-label extension of HPTN 084 monitored cisgender women who became pregnant while receiving CAB-LA and found pregnancy and infant outcomes comparable to population-level expectations.2,3 Maternal adverse effects, specifically gestational hypertension, were more frequent in those receiving CAB-LA, although serious complications were rare.3 Pharmacokinetic analyses demonstrated that CAB concentrations remain above protective thresholds across all trimesters, suggesting that no dose adjustments are necessary.3 While ongoing surveillance remains essential, these data provide clinicians and patients with evidence to support informed decision-making during pregnancy, a population historically underrepresented in clinical trials.
LENACAPAVIR FOR PRE-EXPOSURE PROPHYLAXIS: TOWARD TWICE-YEARLY DOSING
Carina Marquez, University of California, San Francisco, USA, reviewed the landmark PURPOSE 1 and PURPOSE 2 trials. PURPOSE 1, conducted among young women in sub-Saharan Africa, reported no HIV infections in the LEN arm, demonstrating 100% efficacy, although two seroconversions occurred in extended follow-up.4 PURPOSE 2, which included a broader, gender-diverse population, demonstrated a 96% reduction in HIV incidence. 4 These results led to FDA approval of LEN for PrEP in June 2025, offering the first twice-yearly injectable option and a potential solution to adherence-related challenges.
Practical considerations for LEN include injection-site reactions and the need for an oral loading dose to achieve immediate protection. Additionally, LEN is both a substrate for and moderate inhibitor of CYP3A4, creating potential drug–drug interactions. Strong inducers, such as rifampin, require dose adjustments, but dose adjustments are not needed for oral contraceptives or gender-affirming hormone therapy.4 Encouraging data on reproductive safety were also presented. In a nested pregnancy substudy within PURPOSE 1, over 480 participants became pregnant while receiving LEN. Rates of miscarriage, stillbirth, and preterm delivery were comparable to background population rates.2,4 LEN concentrations remained consistent during pregnancy, and minimal transfer was observed through breast milk.4
EXPANDING ACCESS: COST AND EQUITY CONSIDERATIONS
While new LA agents drew considerable attention, IDWeek 2025 also highlighted the broader systems-level factors shaping HIV prevention success. Centers for Disease Control and Prevention (CDC) data demonstrated that, between 2012–2022, mean state-level PrEP coverage increased from 0.6% to 26.3%, accompanied by a decline in HIV diagnosis rates from 13.0 to 10.6 per 100,000 people.3 States in the highest quintile of PrEP coverage experienced the steepest declines, confirming an inverse dose–response relationship between PrEP uptake and new infections.
Despite overall progress, wide regional and demographic disparities persist. Ofole Mgbako, NYC Health + Hospitals, New York, USA, reviewed the PrEP-to-need ratio, the number of PrEP prescriptions relative to HIV incidence, as a marker of equitable access.5 He noted substantial racial and ethnic inequalities across the USA. Josh Havens, University of Nebraska, Lincoln, USA, reported that only about 36% of individuals eligible for PrEP currently receive it.6 Coverage remains highest among White individuals at 94%, dropping to 24% for Hispanic/Latino persons, and only 13% for Black individuals.6
There is also inequitable access among women, who make up 19% of new HIV diagnoses but only 8% of PrEP users.5 Data from the STAR cohort, a longitudinal study of reproductive-age women without HIV in the Southern USA, showed that among 362 eligible women, only 9.9% had ever used PrEP.7 Barriers included cost, provider access, and inconsistent use, highlighting that clinical efficacy alone is insufficient without attention to access, equity, and patient-centered delivery.
Economic barriers remain a major deterrent to PrEP initiation and further compound existing inequities in access. Manufacturing analyses estimate that LEN could be produced for as little as 25 USD per person per year, yet USA list prices currently exceed 28,000 USD annually.⁸ Even for older oral PrEP regimens, financial and insurance-related barriers impede access. A 2024 national Walgreens survey found that 19% of individuals did not fill their first PrEP prescription within 14 days, primarily due to cost and coverage considerations.9 These findings underscore that affordability and streamlined insurance authorization remain central to achieving equitable HIV prevention outcomes.
INTEGRATING LONG-ACTING PRE-EXPOSURE PROPHYLAXIS INTO CLINICAL PRACTICE
While equitable access and affordability remain central to PrEP uptake, data presented at IDWeek 2025 emphasized that the real-world success of LA prevention depends on effective clinical integration. Implementation studies demonstrated that embedding PrEP within existing healthcare systems, through primary care, sexual health, pharmacy, and community-based settings, reduces burden on patients and providers while improving retention.5,6 Engaging non-physician healthcare workers, including nurses, pharmacists, and peer navigators, as well as leveraging mobile health clinics and telehealth platforms, further enhances engagement, particularly among marginalized populations.6
Real-world examples illustrate these dynamics: telehealth-based initiation of emtricitabine/tenofovir alafenamide fumarate PrEP at Vivent Health clinics achieved high satisfaction and 3-month follow-up, while the EquiPrEP study at Bellevue Hospital in New York, USA, found that over 83% of participants, including Black/Latine cisgender men who have sex with men, Black/Latine cisgender women, and transgender/nonbinary persons, were fully adherent to LA injectable PrEP, continued on LA injectable PrEP, or switched to oral PrEP over 6 months.5,10,11 These findings highlight the value of community-based partnerships, flexible delivery models, and strategies that address structural and patient-level barriers to sustain adherence and engagement.
Monitoring strategies remain a topic of active discussion. The 2021 CDC guidelines recommend both HIV antigen/antibody and RNA testing at PrEP initiation and follow-up to minimize the risk of starting or continuing PrEP during acute infection. Updated data presented by Collen Kelley, Emory University, Atlanta, Georgia, USA, using the HealthVerity database (2018–2023), challenge the incremental value of this dual approach. Following the 2021 guideline update, RNA testing among oral PrEP users increased more than sevenfold, yet positivity rates fell from 1.39% to 0.22%, and the positive predictive value dropped from 100% to 67%, translating to roughly 9,000 RNA tests required to identify one additional early infection compared with antigen/antibody testing alone.3 Reflecting these findings, International Antiviral Society-USA (IAS-USA) guidelines now omit follow-up HIV RNA monitoring for CAB-LA based on HPTN 083 data, and LEN protocols similarly do not require HIV RNA monitoring.3 While CDC guidance remains unchanged, the research suggests that routine RNA testing for asymptomatic individuals on LA PrEP may offer limited clinical benefit relative to cost and resource use.
THE BROADER PREVENTION LANDSCAPE
Building on these clinical integration and monitoring strategies, emerging LA and next-generation PrEP modalities offer additional opportunities to expand coverage and simplify HIV prevention. Results of the Phase I clinical trial of once-yearly intramuscular LEN demonstrated higher trough levels than were seen in PURPOSE 1 and PURPOSE 2, and an additional Phase III trial is underway looking at a once-a-year lower dose with concomitant oral load.3 Ultra CAB-LA is also under investigation as an intramuscular or subcutaneous injection every 4 months.4
Beyond injectables, IDWeek 2025 also spotlighted novel modalities poised to expand PrEP’s reach. The investigational oral agent MK-8527, a next-generation nucleoside reverse transcriptase translocation inhibitor, showed promise as a once-monthly oral PrEP option in early-phase trials.3,4 If validated in later studies, it may offer a valuable alternative for those who prefer pills to injections while easing adherence demands compared with daily regimens.
Researchers also presented encouraging data on broadly neutralizing antibodies as prevention tools. In a Phase I study, newborns exposed to HIV received VRC07-523LS, a long-acting monoclonal antibody, in addition to standard antiretroviral prophylaxis. The intervention was safe, well tolerated, and achieved sustained serum concentrations.3 Combinations of broadly neutralizing antibodies are also under investigation as an intravenous infusion given every 6 months.
GLOBAL SYSTEMIC CHALLENGES
Despite advancements in LA HIV prevention, barriers continue to limit global impact. In many low- and middle-income countries, HIV prevention remains highly dependent on external funding streams, including PEPFAR and the Global Fund to Fight AIDS, TB, and Malaria, leaving programs vulnerable to USA policy changes. In Malawi, abrupt reduction in USA support in early 2025 led to the suspension of community-based testing and prevention services, while treatment programs continued, demonstrating the vulnerability of prevention infrastructure and the risk of reversing epidemic control gains.5 If such cuts continue, modeling data predict a 50% increase in new HIV infections in Africa over the next 5 years, equating to 4.4–10.8 million additional new infections.5
Looking ahead, the introduction of LEN at a projected cost of 40 USD per patient per year in 120 high-incidence, resource-limited countries starting in 2027 represents a potential step forward.5 PEPFAR and Global Fund are likely to prioritize LEN implantation for an estimated two million people by 2028.5 However, this focused investment may inadvertently limit patient choice, as other PrEP formulations may become less accessible in these regions.
TAKE-HOME MESSAGE
LA HIV prevention, including CAB and LEN, is reshaping PrEP delivery by improving adherence and offering flexible options for diverse populations. Success depends not only on clinical efficacy, but also on equitable access, real-world integration, and sustainable implementation in the USA and globally. Bridging scientific innovation with structural and social considerations is essential to closing prevention gaps and reducing new infections worldwide.
