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Oral and Long Acting PrEP at CROI 2025
New Insights on Oral and Long-Acting PrEP From CROI 2025: Perspectives From Africa

Released: April 10, 2025

Expiration: April 09, 2026

Kenneth Ngure
Kenneth Ngure, MPH, MSc, PhD
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Key Takeaways
  • Innovative approaches for expanding PrEP to key populations were presented at CROI 2025.
  • The future potential of monthly oral PrEP, yearly injectable PrEP, and on-demand PrEP for women could be particularly important in sub-Saharan Africa.

Among all the data presented at CROI 2025, I found myself most excited by the abstracts discussing innovative approaches to HIV pre-exposure prophylaxis (PrEP). I find it very encouraging that PrEP uptake in Africa increased by 35% between 2022 and 2023, with 2.6 million of the 3.5 million people who received PrEP at least once in 2023 hailing from Africa. However, this is still far below the UNAIDS goal of 10 million PrEP users by 2025. Clearly, more must be done to reach key populations, including devising new service delivery models, PrEP options, and addressing common barriers to PrEP. To that end, these are the abstracts from CROI 2025 that were most impactful to me: 

A Novel Monthly Pill for HIV PrEP: MK-8527
First, a poster by Kapoor and colleagues detailed a novel oral antiretroviral drug (MK-8527) that is in early stages of development for monthly PrEP. MK-8527 is a nucleoside reverse transcriptase translocation inhibitor that is phosphorylated intracellularly to its active form, MK-8527-TP. Preclinical studies in a rhesus macaque model and phase Ib trials determined that a once-monthly oral dose of at least 6 mg of MK-8527 is expected to maintain MK-8527-TP levels above the threshold for protection in more than 90% of the population. Phase II trials will evaluate 3-mg, 6-mg, and 12-mg doses among adults with a low chance of HIV exposure.

Although the safety and efficacy of this drug remain to be seen, a monthly pill would provide much-needed additional choices for HIV prevention and could be especially valuable for those who experience challenges with adherence to daily pills. Furthermore, I think the simplicity of this PrEP modality means that it could be dispensed through differentiated service delivery models, such as the private-sector pharmacy delivery model presented by Ortblad and colleagues, thereby also facilitating access to PrEP.

Promising Results on Longer-Acting IM Lenacapavir
Another key highlight from CROI 2025 was a study presented by Jogiraju and colleagues on once-yearly intramuscular (IM) lenacapavir (LEN). Here, investigators reported that yearly IM LEN demonstrated plasma concentrations above the threshold associated with protective efficacy for twice-yearly subcutaneous LEN more than 12 months. Injection-site reactions were mostly mild to moderate, with pain resolving within 1 week, and pretreatment with an ice pack significantly reduced discomfort.

These findings suggest that once-yearly IM LEN could enhance PrEP adherence by offering a long-acting, low-maintenance alternative. Progress with long-acting PrEP is especially important now that funding for HIV programs in low-resource settings, such as sub-Saharan Africa, has been vastly reduced. 

On-Demand Oral PrEP for Cisgender Women
In Africa, adolescent girls and young women account for 26% of new HIV infections overall, making them a priority population for PrEP. A pharmacokinetic/pharmacodynamic modeling study presented by Dumond and colleagues evaluated several on-demand tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) regimens for HIV prevention in women. Simulations predicted that the standard 2-1-1 IPERGAY regimen provided more than 80% protection for 5 days post sex, whereas extending dosing to 4 days was predicted to achieve more than 80% protection for 7 days. With this model, investigators predicted that 2-2-2-2 dosing would provide 95% protection for 7 days, and 2-1-1-1 would provide 84% at 7 days. Investigators suggested that the 2-1-1-1 regimen would balance safety, efficacy, and tolerability while maintaining a level of effectiveness similar to what was reported with 4 weekly doses of oral PrEP in clinical trials.

Altogether, these findings support further evaluation of extended on-demand PrEP dosing strategies in cisgender women to enhance HIV prevention options, especially for those who find it challenging or stigmatizing to take a daily pill. 

Additional Substudies From PURPOSE 1

Safety of LEN Among Adolescents
On a similar note of expanding PrEP options for women in Africa, investigators of the landmark phase III PURPOSE 1 trial of twice-yearly LEN in cisgender women presented 2 additional substudies. The first assessed the pharmacokinetics, safety, and efficacy of twice-yearly LEN in adolescent girls (aged 16-17 years) compared with young women (aged 18-25 years). Results showed comparable LEN plasma concentrations, adverse events, and laboratory findings between adolescents and adults, with no HIV infections observed among LEN recipients.

In this study, innovative consent strategies facilitated adolescent inclusion, demonstrating the importance and feasibility of integrating younger populations into broader HIV prevention efforts, especially as adolescents and young adults account for a sizeable portion of new infections in Africa and globally.

Adherence to FTC/TAF
Another analysis of PURPOSE 1 highlighted that nearly all HIV infections in participants receiving daily oral emtricitabine (FTC)/tenofovir alafenamide (TAF) were linked to low adherence, with rare instances of transmitted drug resistance and minimal delays in HIV diagnosis.

Among 37 participants who acquired HIV, 35 exhibited suboptimal adherence or nonadherence, reinforcing the importance of adherence for oral PrEP effectiveness. However, a lower chance of HIV infection was associated with medium or high adherence. Thus, FTC/TAF remains an effective, viable option for women who prefer daily PrEP.

Preferences for Injectable PrEP vs Daily Pills
Two additional studies assessed preferences for PrEP delivery and further highlighted the importance of choice in empowering people to engage in PrEP.

A quantitative survey (N = 5218) conducted by Mansoor and colleagues found that approximately two thirds of respondents preferred twice-yearly injections over daily pills, with 61% feeling more protected and more confident about their adherence with injections.

A qualitative substudy by Montgomery and colleagues of 108 adolescent girls and young women echoed these findings, emphasizing the convenience, ease of adherence, and reduced stigma associated with injectable PrEP.

Altogether, these findings show that the majority preferred injectable PrEP, but with a notable proportion of participants still favoring oral PrEP. These data reinforce the need for expansion of injectable PrEP and for diverse options, including oral PrEP, to improve uptake and persistence.

Impact of Urine TFV Testing on PrEP Adherence
Finally, a randomized controlled trial in Cape Town, South Africa, by Davey and colleagues assessed the impact of urine tenofovir (TFV) testing on oral PrEP adherence among 750 pregnant and postpartum women. Participants were randomized to receive either biofeedback counseling based on urine TFV results or standard counseling.

At 6 months, 32% of the biofeedback group tested positive for TFV compared with 25% in the control group (relative risk: 1.29; 95% CI: 1.03-1.63), indicating a modest but significant improvement in adherence.

Given the high dropout rate in this study, to me, these findings highlight the need for long-acting PrEP options and suggest that biofeedback could enhance adherence in women receiving oral PrEP.

Similar results on the benefits of using urine kits to monitor adherence were reported by Velloza and colleagues, who concluded that a urine test could help facilitate honest conversations between patients and healthcare professionals regarding challenges with adherence.

Your Thoughts
How will the studies presented at CROI 2025 shape the way you approach PrEP for your patients? Leave a comment to join the discussion!