Global regulatory collaboration for the assessment of lenacapavir as a long-acting pre-exposure prophylaxis against HIV infection

Availability of long-acting pre-exposure prophylaxis (PrEP) to prevent HIV infection will be essential for disease control. Despite substantial progress in prevention strategies, the number of people with HIV grew by 1.3 million in 2024 globally, with almost half of new carriers living in Africa. 1 Although PrEP has been recommended since 2015 by the World Health Organisation (WHO) for people at an increased risk of infection, 2 uptake has been limited and adherence is frequently inadequate. Daily oral PrEP is safe and efficacious in preventing HIV, particularly among men who have sex with men (MSM), serodiscordant couples, and people who inject drugs (PWIDs). 3 In addition, event-driven (on-demand) oral PrEP has been demonstrated to be as effective as daily dosing among MSM in Europe. 4 Notably, the efficacy was strongly associated with the levels of adherence. It is estimated that less than 30% of people who start using daily oral PrEP receive the HIV protective benefit of PrEP within six months of initiation due to discontinuation or poor adherence. 5 Oral PrEP discontinuation rates are highest in Sub-Saharan Africa, the region with the greatest HIV-1 burden. 5 The first evidence of the benefits of long-acting PrEP came from the development program of cabotegravir. People taking an injection once every two months showed better adherence and a reduced risk of HIV infection compared with daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). 6 It is therefore expected that long-acting PrEPs with even lower dosing frequencies will further improve adherence and, hence, HIV prevention strategies.Lenacapavir is a long-acting inhibitor of HIV-1 capsid function that is injected subcutaneously every six months. In 2022, it was authorised in the EU for the treatment of multidrug resistant HIV-1 infection in combination with other antiretroviral therapies. 7 On 24 July 2025, the Committee for Medicinal Product for Human Use (CHMP) of the European Medicines Agency (EMA) finalised its evaluation of lenacapavir for PrEP and considered the benefit-risk balance to be positive, recommending the marketing authorisation of lenacapavir for PrEP, in combination with safer sex practices, to reduce the risk of sexually acquired HIV-1 infection in adults and adolescents with increased HIV-1 acquisition risk. 8,9 Lenacapavir PrEP is the first medicine that was evaluated by EMA under accelerated assessment for a parallel EU-wide authorisation (marketed as Yeytuo 8 ) and the use outside EU 9 via EU medicines for all (EU-M4all) procedure. EU-M4all aims to facilitate patient access to essential medicines that prevent or treat diseases of major public health interest in low-and middle-income countries (LMICs) based on an EU scientific opinion. 10 During the assessment of lenacapavir PrEP, experts from WHO and national regulatory authorities (NRAs) from Kenya, Nigeria, South Africa, Thailand, Uganda, Vietnam, Zambia, and Zimbabwe contributed to the scientific discussions by adding geographical considerations and perspectives on healthcare and pharmacovigilance systems of their countries. This inclusive approach supports regulatory harmonisation and strengthens global capacity to protect public health. The accelerated assessment for lenacapavir shortened the timeline for review to 120 days instead of the standard 210 days since EMA considered that this product was of major public health interest.Evidence of efficacy submitted in the application was demonstrated by the results of two phase three studies in people at an increased risk of infection: PURPOSE 1, involving 8094 adolescent and adult cisgender women, and PURPOSE 2, involving 4634 adolescent and adult men, and gender-diverse persons. 11,12 The primary analyses showed that HIV-1 incidence in lenacapavir group was lower compared with an estimate of background HIV-1 incidence. However, CHMP considered the comparison unreliable, as it assumes that participants who were HIV-1 negative at screening and, therefore, were eligible for the randomised phase of the studies would subsequently contract HIV-1 at the same rate as the entire screened population, including those who were HIV-1 positive at screening and consequently were not eligible for the randomised phase. Secondary analyses, however, showed a clinically and statistically significant reduction in the incidence of HIV-1 infections with lenacapavir compared with daily oral TDF/FTC (PURPOSE 1: rate ratio (RR): 0.000, 95% confidence interval (CI): 0.000, 0.101; p