Key messages:
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Compared to daily oral pre-exposure prophylaxis (PrEP), lenacapavir reduces the number of new HIV infections by many more; causes slightly fewer serious unwanted effects; and results in little to no difference in overall unwanted effects or risk of death. Lenacapavir likely causes more mild to moderate injection site reactions than oral PrEP.
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Future studies should include other groups of people at risk of getting HIV, and should monitor for any emerging drug resistance (when the virus changes over time so that the medicine used to prevent it no longer works) developing against PrEP.
What is pre-exposure prophylaxis for HIV?
Pre-exposure prophylaxis (PrEP) is a medicine taken by HIV-negative people to reduce the risk of getting HIV. HIV is a virus spread through contact with infected body fluids, such as sexual fluids and blood from people living with the disease. Each year, about 1.3 million people become newly infected with HIV, so preventing HIV is an important global health priority. PrEP with some antiviral medicines is one of the key ways to avoid the spread of HIV.
Current PrEP options include daily oral (taken by mouth) medications, such as tenofovir disoproxil fumarate plus emtricitabine (F/TDF) or tenofovir alafenamide plus emtricitabine (F/TAF), and injections given every two months (cabotegravir). These preventative medicines are only effective if taken regularly (i.e. daily for the oral medication and every two months for cabotegravir, the longer-acting injection). Lenacapavir is a newer, long-acting medicine that only needs to be injected every six months.
What did we want to find out?
We wanted to find out if lenacapavir works better than oral antiviral medicines (F/TDF and F/TAF), cabotegravir, placebo (dummy treatment) or no PrEP in preventing HIV. We also wanted to know if lenacapavir causes any unwanted effects.
What did we do?
We searched for studies that compared lenacapavir with oral PrEP, cabotegravir, placebo or no PrEP in people who are HIV-negative but are at risk of contracting HIV.
We summarised the findings and rated our confidence in the evidence based on study methods and sizes.
What did we find?
We found two studies including 8660 people at risk of contracting HIV. Both studies compared lenacapavir with oral PrEP for 52 weeks. The studies included adolescent girls, young women, gender-diverse people, and men who have sex with men. We did not find any studies comparing lenacapavir with cabotegravir.
Lenacapavir prevented many more new HIV infections than oral PrEP. Overall, unwanted effects were similar between treatment groups, but lenacapavir caused more local injection site reactions. There was no difference between lenacapavir and oral PrEP in the number of deaths reported, and no deaths were found to be related to either treatment.
What are the limitations of the evidence?
We are confident in most of the available evidence. However, our findings are based on only two studies, both of which lasted just one year, which is not long enough to understand the long-term benefits and harms of lenacapavir. No studies compared lenacapavir with cabotegravir, another injectable PrEP medicine. Ongoing research may lead to changes in our understanding of the effects of lenacapavir in more diverse populations.
How up-to-date is the evidence?
The evidence is current to May 2025.
Pročitajte cijeli sažetak
Ciljevi
To evaluate the benefits and harms of long-acting injectable lenacapavir for HIV PrEP compared to oral fixed-dose combination PrEP (tenofovir disoproxil fumarate plus emtricitabine (F/TDF) and/or oral tenofovir alafenamide plus emtricitabine (F/TAF)), long-acting injectable cabotegravir (CAB-LA), or placebo or no prophylaxis.
Metode pretraživanja
We searched CENTRAL, PubMed, and two trial registers and conducted reference checking to identify eligible studies. The search is current to May 2025.
Zaključak autora
When compared to oral PrEP, lenacapavir results in a large reduction in new HIV infections at 52 weeks, with one HIV infection prevented for every 70 people receiving lenacapavir rather than oral PrEP, that is 14 fewer HIV infections per 1000 people treated with lenacapavir. Lenacapavir results in a slight reduction in SAEs and little to no difference in AEs compared to oral PrEP. Lenacapavir likely increases the risk of injection site reactions compared with oral PrEP, but discontinuation of lenacapavir in the included trials due to injection site reactions was rare. There is little to no difference in mortality between lenacapavir and oral PrEP. No studies compared lenacapavir to injectable long-acting cabotegravir, placebo or no prophylaxis. Within the included trials, there was a non-randomised comparison of lenacapavir with background HIV incidence in the screened population as a proxy for a no-PrEP arm. There was a large reduction in HIV incidence in the lenacapavir study arms compared to background HIV incidence in the screened populations.
Funding
This Cochrane review was part-funded by the South African National Department of Health (NDoH) through the Evidence to Decision (E2D) Collaboration project. The E2D Collaboration is a partnership between the NDoH, the South African Medical Research Council, and Stellenbosch University (2024 to 2028). The views expressed in this review do not necessarily represent the views of the funder.
Registration
PROSPERO (2025) CRD420251080791.
