Abstract
Rationale
Globally, there are 1.3 million new HIV infections annually, with a disproportionate burden on young women and girls, especially in sub‐Saharan Africa (63% of new infections). Despite the demonstrated effectiveness of pre‐exposure prophylaxis (PrEP), global uptake remains low, reaching only 16.5% of the UNAIDS 2025 target. PrEP adherence is suboptimal in vulnerable populations. There is an urgent need to develop and implement alternative, user‐friendly PrEP strategies like long‐acting formulations that minimise reliance on daily dosing or frequent injections. Lenacapavir is a first‐in‐class, long‐acting capsid inhibitor that disrupts HIV replication at multiple stages. Following an oral loading dose, lenacapavir administered by subcutaneous injection provides six months of protection against HIV.
Objectives
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.
Search methods
We searched CENTRAL, PubMed, and two trial registers and conducted reference checking to identify eligible studies. The search is current to May 2025.
Eligibility criteria
We included randomised controlled trials (RCTs) with no date or language restrictions in any HIV‐negative person at risk of acquiring HIV through sexual contact or exposure to blood, comparing long‐acting injectable lenacapavir with oral PrEP, long‐acting injectable cabotegravir, placebo or no prophylaxis.
Outcomes
Our critical outcomes were: new HIV infections or relative risk of HIV infection; serious adverse events (SAEs); adverse events (AEs); adverse drug reactions: injection site reactions; and all‐cause mortality. We included data at 26‐ and 52‐week time points.
Risk of bias
We used the Cochrane RoB 2 tool to assess risk of bias in the included studies.
Synthesis methods
We meta‐analysed data for each outcome where possible, using the inverse variance statistical method with a random‐effects model. We reported risk ratios (RR) with 95% confidence intervals (CIs) for dichotomous data. Where this was not possible, we synthesised results using the direction of effect, guided by the Synthesis Without Meta‐analysis (SWiM) reporting guidelines. We used GRADE to assess the certainty of evidence.
Included studies
We included two studies with 8660 participants. The first trial, conducted in South Africa and Uganda, included adolescent girls and young women (16 to 25 years) and compared injectable lenacapavir with daily oral PrEP consisting of F/TAF in one comparator arm and F/TDF in the other. The second trial, conducted in the USA, Brazil, Thailand, South Africa, Peru, Argentina, and Mexico, included cisgender gay, bisexual and other men, transgender women, transgender men, and gender‐nonbinary persons of any age who have condomless, receptive anal sex with partners assigned male at birth. It compared injectable lenacapavir with F/TDF. In both trials, participants in the lenacapavir group received placebo tablets that matched the oral PrEP, and participants in the oral PrEP group received placebo injections that matched lenacapavir.
Synthesis of results
New HIV infections
Lenacapavir results in a large reduction in new HIV infections at 52 weeks compared to oral PrEP (RR 0.07, 95% CI 0.02 to 0.22; 2 studies, 8660 participants; high‐certainty evidence). There were 14 fewer new HIV infections per 1000 (ranging from 15 fewer to 12 fewer), with a number needed to treat for an additional beneficial outcome (NNTB) of 70.
Serious adverse events
Lenacapavir results in a slight reduction in SAEs at 52 weeks compared to oral PrEP (RR 0.78, 95% CI 0.61 to 0.99; 2 studies, 8660 participants; high‐certainty evidence). There were 8 fewer SAEs per 1000 (ranging from 15 fewer to 0 fewer), NNTB of 128.
Adverse events
Lenacapavir results in little to no difference in AEs at 52 weeks compared to oral PrEP (RR 0.99, 95% CI 0.96 to 1.01; 2 studies, 8660 participants; high‐certainty evidence). There were 8 fewer AEs per 1000 (ranging from 31 fewer to 8 more), NNTB of 55.
Adverse drug reactions: injection site reactions
Lenacapavir likely increases adverse drug reactions: injection site reactions compared to oral PrEP at 52 weeks (RR 1.68, 95% CI 1.20 to 2.33; 2 studies, 8660 participants; moderate‐certainty evidence). There were 295 more adverse drug reactions per 1000 (ranging from 87 more to 577 more), number needed to treat for an additional harmful outcome of 4.
All‐cause mortality
Lenacapavir results in little to no difference in all‐cause mortality at 52 weeks compared to oral PrEP (RR 0.57, 95% CI 0.11 to 3.06; 2 studies, 8660 participants; high‐certainty evidence). There were 1 fewer deaths per 1000 (ranging from 2 fewer to 4 more), NNTB of 1073.
We rated all critical outcomes as low risk of bias in both studies. We found no difference on subgroup analysis between comparators F/TDF and F/TAF.
Authors' conclusions
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.
Plain language summary
What are the benefits and risks of using lenacapavir for pre‐exposure prophylaxis against HIV?
Key messages:
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.
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.
Summary of findings
Summary of findings 1. Summary of findings table ‐ Lenacapavir compared to oral PrEP for any HIV‐negative person at risk of HIV acquisition (any age or gender).
| Lenacapavir compared to oral PrEP for any HIV‐negative person at risk of HIV acquisition (any age or gender) | ||||||
| Patient or population: any HIV‐negative person at risk of HIV acquisition (any age or gender) Setting: global; outpatients Intervention: lenacapavir Comparison: oral PrEP | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with oral PrEP | Risk with lenacapavir | |||||
| New HIV infections at 52 weeks | 15 per 1000 | 1 per 1000 (0 to 3) | RR 0.07 (0.02 to 0.22) | 8660 (2 RCTs) | ⊕⊕⊕⊕ Higha | Lenacapavir compared to oral PrEP results in large reduction in new HIV infections. |
| Serious adverse events at 52 weeks | 38 per 1000 | 29 per 1000 (23 to 37) | RR 0.78 (0.61 to 0.99) | 8660 (2 RCTs) | ⊕⊕⊕⊕ High | Lenacapavir compared to oral PrEP results in a slight reduction in serious adverse events. |
| Adverse events at 52 weeks | 764 per 1000 | 756 per 1000 (733 to 772) | RR 0.99 (0.96 to 1.01) | 8660 (2 RCTs) | ⊕⊕⊕⊕ Highb | Lenacapavir compared to oral PrEP results in little to no difference in adverse events. |
| Adverse drug reactions: injection site reactions at 52 weeks | 434 per 1000 | 729 per 1000 (521 to 1000) | RR 1.68 (1.20 to 2.33) | 8660 (2 RCTs) | ⊕⊕⊕⊝ Moderatec,d | Lenacapavir compared to oral PrEP likely increases adverse drug reactions: injection site reactions. |
| All‐cause mortality at 52 weeks | 2 per 1000 | 1 per 1000 (0 to 6) | RR 0.57 (0.11 to 3.06) | 8660 (2 RCTs) | ⊕⊕⊕⊕ Highe | Lenacapavir compared to oral PrEP results in little to no difference in all‐cause mortality. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_462147007340105201. | ||||||
a Not downgraded for indirectness: the populations for both studies were included in our specified population: the population in Bekker 2024 was cisgender women and in Kelly 2025 was men and gender‐diverse people. b Not downgraded for imprecision: the absolute 95% confidence interval ranges from a small reduction to a trivial increase. c Not downgraded despite considerable inconsistency (I² = 99%) because the inconsistency is in the magnitude of the effect, rather than direction of the effect. d Downgraded one level for imprecision: the wide absolute 95% confidence interval ranges from a small to an important increase in adverse drug reactions. e Not downgraded for imprecision: despite the low event rate, this is a rare event with a narrow absolute 95% confidence interval. None of the reported deaths were related to the intervention or comparator. We are confident that there is no difference between the intervention and comparator.
Background
Description of the condition
Globally, an estimated 1.3 million new HIV infections occur annually, with women and girls accounting for approximately 45% of all new infections in 2024 [1]. In sub‐Saharan Africa, there is a disproportionate burden among women and girls, constituting 63% of all new annual HIV infections [1]. In contrast, data from the US Centers for Disease Control and Prevention (CDC) indicate that in 2022, 67% of new HIV diagnoses occurred among gay men and other men who have sex with men, with over 70% of these diagnoses reported among individuals identifying as Black, Hispanic, or Latino [2]. These findings were similar in the 2024 CDC surveillance update [3]. Despite the recognised benefits of pre‐exposure prophylaxis (PrEP), global uptake remains limited, reaching only 16.5% of the Joint United Nations Programme on HIV/AIDS (UNAIDS) target of 21.2 million users by 2025 [4]. Among populations disproportionately affected by HIV, both the uptake of and adherence to existing PrEP modalities remain suboptimal [4]. These gaps highlight the urgent need to develop and implement alternative PrEP strategies – particularly long‐acting formulations that minimise reliance on daily oral dosing or frequent injection visits [4].
Description of the intervention and how it might work
Lenacapavir is a first‐in‐class capsid inhibitor that disrupts viral replication by binding to proteins within the capsid, resulting in multiple inhibitory effects [5]. Lenacapavir’s slow release from the injection site allows for a six‐month subcutaneous dosing regimen, which is initiated with an oral loading dose of two 300 mg lenacapavir tablets on days one and two [5]. Interim findings from ongoing studies are being lauded as a significant breakthrough in the fight against HIV transmission [6]. Lenacapavir has to date received approval from the US Food and Drug Administration, the European Medicines Agency, the South African Health Products Regulatory Authority, and the Zambia Medicines Regulatory Authority for use as PrEP [7, 8].
Why it is important to do this review
The World Health Organization (WHO) has published guidance on lenacapavir for PrEP informed by an unpublished systematic review, but this review did not include a meta‐analysis of studies to date [9]. Through both meta‐analysis of critical outcomes and narrative reporting, our review aims to summarise the evidence on the benefits and harms of long‐acting injectable lenacapavir compared to oral PrEP (tenofovir disoproxil fumarate plus emtricitabine (F/TDF) or oral tenofovir alafenamide plus emtricitabine (F/TAF)), long‐acting injectable cabotegravir, placebo or no prophylaxis.
Objectives
To evaluate the benefits and harms of long‐acting injectable lenacapavir for HIV pre‐exposure prophylaxis (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.
Methods
We followed the Methodological Expectations for Cochrane Intervention Reviews (MECIR) when conducting the review [10], and PRISMA 2020 for the reporting [11]. We used a prespecified protocol (PROSPERO registration: 1080791) that followed Cochrane rapid review methodology [12, 13] and was registered on 25 June 2025.
Differences between protocol and review
In the PROSPERO record, the review is titled 'Protocol to review lenacapavir as an alternative to oral tenofovir disoproxil fumarate plus emtricitabine or oral tenofovir alafenamide plus emtricitabine or injectable cabotegravir or placebo/no prophylaxis for preventing HIV'. This review was originally registered and conducted in response to a request from the National Department of Health in South Africa to inform national PrEP policy deliberations. For this Cochrane review, we simplified the title to 'Lenacapavir for pre‐exposure prophylaxis' to adhere to Cochrane style guidelines. We revised the description of included participants for clarity. Laboratory abnormalities reported in the trials included haematologic and biochemical derangements, but we were concerned that reporting aggregated numbers as a separate outcome would not be meaningful. Therefore, we reported laboratory abnormalities narratively in Table 2. Within each trial, a nested cross‐sectional study compared study arms to a proxy for background HIV incidence in the screened population (described further in Outcome measures). We conducted a Risk Of Bias In Non‐randomized Studies – of Interventions (ROBINS‐I) appraisal for this nested non‐randomised comparison and a GRADE assessment, as shown in Supplementary material 9.
1. Summary of serious adverse events, adverse events, adverse drug reactions, and laboratory abnormalities*.
| Study ID | Serious adverse events | Adverse events | Adverse drug reactions: injection site reactions | Laboratory abnormalities |
| Bekker 2024 | The proportion of serious adverse events was 2.8% (59/2138 participants) in the lenacapavir group, 4.0% (85/2137) in the F/TAF group, and 3.3% (35/1070) in the F/TDF group (Table S11). | AEs: Excluding injection site reactions, the most frequently reported adverse event was headache, occurring in 13.3% (285/2138) of participants receiving lenacapavir, 16.5% (352/2137) of those receiving F/TAF, and 14.5% (155/1070) of those receiving F/TDF. | Injection administration: A total of 25,329 injections were administered during the study: 10,154 injections among 2138 participants in the lenacapavir group and 15,175 injections among 3206 participants who received placebo injections corresponding to the F/TAF and F/TDF groups. | Laboratory abnormalities: Laboratory abnormalities were observed in 90.5% of participants (4792 of 5293). |
| Injection site reactions: Injection site reactions attributed to lenacapavir, placebo, or trial‐related procedures were reported in 68.8% (1470/2138) of participants in the lenacapavir group, 35.3% (755/2136) in the F/TAF group, and 33.9% (363/1070) in the F/TDF group; both latter groups received placebo injections. | Severity profile: The majority of these abnormalities were of mild or moderate severity (Grade 1 or 2). Grade 3 or 4 laboratory abnormalities were uncommon, occurring in fewer than 5% of participants in all treatment groups (Table S13). | |||
| Severity and progression of injection site reactions: Most injection site reactions were mild to moderate in severity (grade 1 or 2). Severe reactions were uncommon, and occurred at similar frequencies in both lenacapavir and placebo recipients, and no reactions were classified as serious. The frequency of injection site reactions declined with successive injections (Figure S6). | ||||
| Subcutaneous nodules: Subcutaneous nodules were documented in 63.8% of participants receiving lenacapavir and in 16.6% of those receiving placebo injections (Figure S6). |
Distribution by treatment group:
|
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| AE profiles: The overall proportion of participants experiencing adverse events was broadly comparable across the 3 study groups. However, nausea and vomiting were reported less frequently in the lenacapavir group (6.7% and 5.8%, respectively) compared with the F/TAF group (10.9% and 11.0%) and the F/TDF group (13.3% and 10.0%). | Keloid formation: No cases of keloid formation were reported. | |||
| Severity of AEs: The incidence of Grade 3 or higher adverse events was similar among the treatment arms, occurring in 4.1% (88/2138) of participants in the lenacapavir group, 4.4% (95/2137) in the F/TAF group, and 4.7% (50/1070) in the F/TDF group (Table S10). | Discontinuations: 4 participants (0.2%) in the lenacapavir group discontinued the study regimen due to injection site reactions, whereas no discontinuations were reported among placebo recipients. | |||
| Discontinuations: AEs leading to discontinuation of the study regimen were infrequent, reported in 0.2% (5/2138) of participants in the lenacapavir group, 0.1% (2/2137) in the F/TAF group, and in none of the participants in the F/TDF group (Table S12). | ||||
Deaths:
|
Pregnancy outcomes: A total of 510 pregnancies were documented among 487 participants, distributed as follows: 193 in the lenacapavir group, 219 in the F/TAF group, and 98 in the F/TDF group. At the time of the interim analysis:
|
|||
| Kelley 2025 | Serious adverse events occurred in 3.3% (71/2183) in the lenacapavir group and 4.0% (43/1088) in the F/TDF group. | Common AEs reported: When injection site reactions were excluded, the 3 most frequently reported adverse events were rectal chlamydial infection in 13.2% (289/2183) of participants in the lenacapavir group and 11.8% (128/1088) in the F/TDF group, oropharyngeal gonococcal infection in 13.0% (283/2183) of participants in the lenacapavir group and 10.9% (119/1088) in the F/TDF group, while rectal gonococcal infection occurred in 10.7% (233/2183) of participants in the lenacapavir group and 9.1% (99/1088) in the F/TDF group. | Injection administration: Across the study, 10,094 lenacapavir injections and 5145 placebo injections (administered to participants in the F/TDF group) were given. |
Laboratory abnormalities:
|
| Injection site reactions: Injection site reactions were observed in 1816 participants (83.2%) in the lenacapavir group and 756 participants (69.5%) in the F/TDF group. | ||||
Severity and progression of injection site reactions:
|
Renal function measures: A key difference between the groups was noted in renal function, as reflected by the median change from baseline in eGFR calculated using the Cockcroft‐Gault equation. At week 26, there was a slight increase in eGFR in the lenacapavir group (+1.2 mL per minute (interquartile range, −8.0 to 10.9)) compared with a decline in the F/TDF group (−3.0 mL per minute (interquartile range, −12.4 to 6.5)) (P < 0.001). At week 52, a similar pattern was observed, with an increase in the lenacapavir group (+0.6 mL per minute (interquartile range, −10.3 to 10.8)) and a decline in the F/TDF group (−2.9 mL per minute (interquartile range, −13.8 to 7.4)) (P = 0.002). | |||
Overall proportion and severity:
|
Higher‐grade abnormalities: Grade 3 and 4 laboratory abnormalities were infrequent, occurring in 11.3% (243/2153) of participants in the lenacapavir group and 13.7% (147/1071) in the F/TDF group (Table S15). | |||
| Discontinuations: AEs leading to discontinuation of the study regimen were infrequent, occurring in 0.3% (7/2183) of participants in the lenacapavir group and 0.6% (7/1088) in the F/TDF group (Table S14). | Subcutaneous nodules: These occurred more frequently among participants receiving lenacapavir than those receiving F/TDF (63.4% vs 39.2%). | |||
Deaths:
|
Pregnancy: No pregnancies were reported among study participants. | Keloid formation: No cases of keloid formation at the injection site were reported. | ||
| Discontinuations: Injection site reactions led to discontinuation of the study regimen in 26 participants (1.2%) in the lenacapavir group and 3 participants (0.3%) in the F/TDF group. |
AEs: adverse events; F/TAF: tenofovir alafenamide plus emtricitabine; F/TDF: tenofovir disoproxil fumarate plus emtricitabine; eGFR: estimated glomerular filtration rate.
*In both trials, adverse events (including injection site reactions and laboratory abnormalities) were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, version 2.1 (US National Institute of Allergy and Infectious Diseases, Division of AIDS, 2017); AEs were coded according to the Medical Dictionary for Regulatory Activities, version 27.0 (Medical Dictionary for Regulatory Activities, 2024).
Criteria for considering studies for this review
Types of studies
We included randomised controlled trials (RCTs) without any date or language restrictions. We did not include quasi‐randomised trials.
Types of participants
HIV‐negative people at risk of HIV acquisition through sexual contact or exposure to blood. There were no restrictions with regard to age, sex, sexual identity, sexual orientation, or comorbidity.
Types of interventions
We included long‐acting injectable lenacapavir as the intervention.
Comparators included:
oral PrEP (oral 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.
More information about the interventions and comparators, including route of administration, frequency, and drug classification, is available in Table 3.
2. Types of interventions: additional detail (specific to pre‐exposure prophylaxis against HIV).
| Intervention/Comparator | Administered by | Dose and route of administration | Frequency | Drug classification | Other comments* |
| Lenacapavir [50] | Healthcare provider |
Initiation dose:
Maintenance dose: 927 mg (2 x 1.5 mL injections) by subcutaneous injection |
Maintenance dose: Twice per year (26 weekly) ± 2 weeks |
HIV‐1 capsid inhibitor |
Missed doses: During the maintenance period, if more than 28 weeks have passed since the last injection, the dosage should be restarted as if from initiation. |
Oral PrEP
|
Patient (self‐administered once dispensed) |
|
1 tablet daily | Nucleoside reverse transcriptase inhibitors (NRTIs) |
Missed doses: The missed dose should be taken as soon as it is remembered on the same day and then continued as per the usual dosing schedule. |
| Long‐acting injectable cabotegravir (CAB‐LA) [51, 52] | Healthcare provider | 600 mg cabotegravir in 3 mL via IM** **Initiation can also be through oral lead in if tolerance to cabotegravir needs to be assessed first: 30 mg cabotegravir tablet by mouth |
Initiation dose: 1 injection at month 1 and month 2*** ***If through oral lead in is needed, 1 tablet daily for 28 days, with the first injection planned for the final day of oral‐lead‐in and then again after 1 month (as per initiation dose above) Maintenance dose: 1 injection every 2 months |
HIV‐1 integrase strand transfer inhibitors (INSTIs) |
Missed doses: Second injection missed:
Third or subsequent injection missed:
|
CAB‐LA: long‐acting injectable cabotegravir; F/TAF: tenofovir alafenamide plus emtricitabine; F/TDF: tenofovir disoproxil fumarate plus emtricitabine; IMI: intramuscular injection; INSTIs: HIV‐1 integrase strand transfer inhibitors; PrEP: pre‐exposure prophylaxis.
*Missed doses: for individuals who miss a scheduled injection (more than 2 weeks for lenacapavir; more than 1 week for cabotegravir) or oral medication (multiple consecutive doses), clinical reassessment, including an HIV test, should be performed prior to resumption of doses.
Outcome measures
We included critical and important outcomes, which were selected prospectively. We presented the critical outcomes in a summary of findings table and assessed the certainty of the evidence using the GRADE approach [14, 15].
Timing of outcome measurement
We collected data on outcomes from the included RCTs at midpoint (26 weeks) and endpoint (52 weeks), where relevant, and presented this information in Table 1.
Lenacapavir versus no prophylaxis: new HIV infections
There was no placebo or no treatment comparator arm in PURPOSE 1 (Bekker 2024 [16, 17, 18]) and PURPOSE 2 (Kelley 2025 [19, 20, 21, 22]), as randomising participants to no active HIV prophylaxis would be unethical in settings where PrEP is available. Both studies quantified incidence in the screened population by testing for recent HIV infection in all those who tested HIV positive at screening to estimate background HIV incidence. Incidence in the study arms was compared to this estimate of background HIV incidence. This is a non‐randomised comparison nested within the RCTs.
Critical outcomes
New HIV infections (or relative risk of HIV infection) diagnosed on "rapid point‐of‐care and central‐laboratory fourth‐generation antigen‐antibody testing" (52 weeks) (Bekker 2024; Kelley 2025).
-
Serious adverse events (SAEs)*, defined as "an event that, at any dose, results in the following:
death;
a life‐threatening situation [Note: the term 'life‐threatening' in the definition of 'serious' refers to an event in which the participant was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe];
in‐patient hospitalisation or prolongation of existing hospitalisation;
persistent or significant disability/incapacity;
a congenital anomaly/birth defect;
a medically important event or reaction: such events may not be immediately life‐threatening or result in death or hospitalisation, but may jeopardise the participant or may require intervention to prevent one of the other outcomes constituting SAEs" (52 weeks) (Bekker 2024; Kelley 2025) [23].
Adverse events (AEs)*, defined as "any untoward medical occurrence in a clinical study participant administered a study drug, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavourable and/or unintended sign, symptom, or disease temporally associated with the use of a study drug, whether the AE is considered related to the study drug or not. AEs may also include pretreatment or post‐treatment complications that occur as a result of protocol‐specified procedures or special situations" (52 weeks) (Bekker 2024; Kelley 2025) [23].
Adverse drug reactions*, specifically injection site reactions, including pain, erythema, induration or swelling, bruising and nodule formation (52 weeks) (Bekker 2024; Kelley 2025).
All‐cause mortality (52 weeks).
*In both included trials (Bekker 2024; Kelley 2025), adverse events were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, version 2.1 (US National Institute of Allergy and Infectious Diseases, Division of AIDS, 2017) and were coded according to the Medical Dictionary for Regulatory Activities, version 27.0 (Medical Dictionary for Regulatory Activities, 2024).
Important outcomes
Retention on PrEP, defined as "the proportion of participants who continued the trial regimen in a blinded manner" (26 and 52 weeks) (Bekker 2024; Kelley 2025).
Adherence to injectable PrEP or placebo, defined as "an on‐time injection (within 28 weeks after the last injection)" (Bekker 2024; Kelley 2025). In both studies, adherence to oral F/TAF and F/TDF therapy was assessed on the "basis of tenofovir diphosphate levels in red cells in dried‐blood‐spot samples from all trial visits from a randomly preselected 10% of participants in each group. Adherence levels were defined as low (<2 tablets per week), medium (2 or 3 tablets per week), or high (≥4 tablets per week), on the basis of tenofovir diphosphate concentration thresholds" (26 and 52 weeks) (Bekker 2024; Kelley 2025).
Incidence of other sexually transmitted infections (STIs) including Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis infection, were measured as the incidence rate per 100 patient years (26 and 52 weeks) (Bekker 2024; Kelley 2025).
Viral mutations among those who contract HIV, such as the N74D capsid resistance mutation in participants who received lenacapavir and the emtricitabine resistance mutation (M184V) in those who received F/TDF (52 weeks) (Kelley 2025).
Acceptability.
Satisfaction.
Search methods for identification of studies
We developed and conducted the search strategy without language or publication status or date restrictions, using elements from the prespecified PICO question. We consulted an experienced Information Specialist for guidance on refinement of the PubMed search strategy [24], as well as the technical supplement to Chapter 4 of the Cochrane Handbook for Systematic Reviews of Interventions [25].
Electronic searches
We searched the following databases:
Cochrane Central Register of Controlled Trials (CENTRAL; 2025, Issue 5), in the Cochrane Library;
PubMed (1997 to 28 May 2025);
ClinicalTrials.gov (searched on 25 May 2025);
World Health Organization International Clinical Trials Registry Platform (ICTRP) (searched on 25 May 2025).
Search strategies are available in Supplementary material 1.
Searching other resources
We reviewed the reference lists of retrieved articles and reviews and consulted experts in the field to enquire about any relevant ongoing or unpublished trials. We searched the websites of the journals that published the included studies, as well as PubMed and Retraction Watch, for any post‐publication amendments, but none were identified. According to the updated guidance on methods for conducting rapid reviews of effectiveness [13], it is recommended that searches of grey literature and supplementary sources be limited. We were aware of completed and ongoing trials of lenacapavir as PrEP and had access to the data available in these publications. Given this, and the time‐sensitive nature of this review, we did not search the grey literature.
Data collection and analysis
We uploaded the search results into Covidence [26] and removed any duplicates. We planned to contact study authors to obtain any missing information and confirm study eligibility as needed, but this was not required. All the comparisons and outcomes are presented in the summary of findings tables.
Selection of studies
Three review authors (SE, NG, ZA) independently screened the titles and abstracts for potentially eligible studies. We also utilised the Covidence machine‐learning model to assist with screening; those automatically excluded by Covidence were manually reviewed by one review author (NG). We obtained the full‐text reports of studies deemed potentially eligible and screened these for inclusion in the review. Any disagreements were resolved through discussion. We included a PRISMA flowchart (Figure 1) and 'Characteristics of included studies' table (Supplementary material 2, Table 4) [11]. No full‐text studies were excluded; characteristics of ongoing studies are presented in Supplementary material 4.
1.
PRISMA flow diagram.
3. Overview of Synthesis and Included Studies table illustrating key study characteristics.
| Study name (year) country | Study design | Intervention and comparator details | Population sample size | Outcomes with available data | Outcome measures | Outcome time point | Method of synthesis |
| Bekker 2024 South Africa and Uganda |
RCT Funding Funded by Gilead Sciences; PURPOSE 1 (ClinicalTrials.gov number, NCT04994509) |
Intervention Subcutaneous lenacapavir (927 mg, in two 1.5‐millilitre injections) every 26 weeks (within a window of ±7 days) with loading doses of two 300‐mg tablets of lenacapavir on each of days 1 and 2. Comparator/s
|
Population Adolescent girls and young women (16 to 25 years of age) who were sexually active with male partners, were not using PrEP, and had an unknown HIV status and no HIV testing within the previous 3 months, were eligible. Sample size N = 5368 participants were randomly assigned (2148 to lenacapavir, 2147 to F/TAF, and 1073 to F/TDF). |
|
Number of participants and events per study arm | 52 weeks | Meta‐analysis |
|
26 and 52 weeks | Narrative synthesis | |||||
| Kelley 2025 USA, Brazil, Thailand, South Africa, Peru, Argentina, and Mexico |
RCT Funding Funded by Gilead Sciences; PURPOSE 2 (ClinicalTrials.gov number, NCT04925752) |
Intervention Subcutaneous lenacapavir (927 mg, in two 1.5‐millilitre injections) every 26 weeks (within a window of ±7 days) with oral loading doses of two 300‐milligram tablets of lenacapavir each on days 1 and 2. Comparator Daily oral F/TDF (200 mg emtricitabine and 300 mg TDF) |
Population Eligible participants were cisgender, gay, bisexual, and other men, transgender women, transgender men, and gender‐nonbinary people who have condomless, receptive anal sex with partners assigned male at birth, were at least 16 years of age, had unknown HIV status, and reported no HIV testing or PrEP use in the 3 months before screening Sample size N = 3292 participants were randomly assigned (2195 to lenacapavir and 1097 to F/TDF). |
|
Number of participants and events per study arm | 52 weeks | Meta‐analysis |
|
26 and 52 weeks | Narrative synthesis |
F/TAF: tenofovir alafenamide plus emtricitabine; F/TDF: tenofovir disoproxil fumarate plus emtricitabine; PrEP: pre‐exposure prophylaxis; RCT: randomised controlled trial; TDF: tenofovir disoproxil fumarate; STIs: sexually transmitted infections.
Data extraction and management
One review author (SE) extracted the characteristics of included studies and outcome data, and two review authors (NG, ZA) checked the data extraction. Data were extracted into a piloted, standard data extraction form. We extracted the following information.
Methods: study design, trial number, number of study centres and locations, study setting, withdrawals, study dates and length of follow‐up.
Participants: number, mean age (range), gender, country, participant category (e.g. men who have sex with men (MSM), people who inject drugs (PWID)), and other relevant data.
Intervention: dose, schedule, route of administration, clinical trial phase, loading dose.
Comparator: dose, schedule, route of administration.
Outcome measures: study outcomes and time points reported (number of participants and events per arm of the study), number of participants randomised in each arm, number of withdrawals, adverse events, lost‐to‐follow‐up, and exclusions.
Where the authors did not provide these data, we planned to proceed as mentioned in the Dealing with missing data section.
Risk of bias assessment in included studies
We used the Cochrane RoB 2 tool to assess risk of bias [27], and followed Cochrane guidance [10, 27, 28]. Two review authors (SE, NG) independently assessed risk of bias in duplicate for all critical outcomes. Any disagreements were resolved through discussion. We used the RoB 2 Excel tool for RCTs (www.riskofbias.info/welcome/rob‐2‐0‐tool), and assessed outcomes using the intention‐to‐treat (ITT) effect.
We assessed the risk of bias across the following domains.
Bias arising from the randomisation process: evaluates whether allocation concealment was appropriately implemented and maintained, and whether any baseline imbalances between groups indicate potential issues with the randomisation procedure.
Bias due to deviations from the intended interventions: assesses the effect of assignment to intervention, including the potential influence of participants', carers', or researchers' awareness of intervention allocation; deviations arising from the trial context that could impact outcomes; the balance of such deviations between groups; the appropriateness of the analytical approach for estimating the effect of assignment; and the potential impact of analysing participants outside their assigned groups.
Bias due to missing outcome data: considers the completeness of outcome data across all or nearly all randomised participants; the likelihood that missing data may have introduced bias; and whether missingness was related to participants' health status or to the outcome itself.
Bias in measurement of the outcome: examines the appropriateness and consistency of outcome measurement methods between intervention groups, and whether awareness of intervention assignment by outcome assessors could have influenced the outcome assessment.
Bias in selection of the reported result: evaluates whether analyses were conducted according to a prespecified statistical analysis plan, and whether reported numerical results were selectively chosen from multiple possible measurements or analyses.
We used the signalling questions and algorithms in the tool to ascertain whether an outcome was at high risk of bias, had some concerns of bias, or was at low risk of bias. We defined the bias as per the table below.
| Risk of bias level | Definition |
| Low risk of bias | All domains are judged as having a low risk of bias. |
| Some concerns | At least one domain is judged to have some concerns of bias. |
| High risk of bias | At minimum, one domain is judged as being at high risk of bias. |
We did not exclude studies due to a high risk of bias, but we planned to report the risk and consider any high risk of bias when interpreting the results for the outcomes (see Sensitivity analysis). We used the overall risk of bias judgement when assessing the certainty of the evidence, as per GRADE recommendations [14].
Measures of treatment effect
We reported risk ratios (RR) with 95% confidence intervals (CIs) for dichotomous data. We did not anticipate any continuous data for the specified outcomes; and we planned to present time‐to‐event outcomes as hazard ratios (HR) with 95% CIs.
Unit of analysis issues
We considered each pair‐wise comparison for trials with multiple arms, and included those relevant to the review objectives. The trials are described in Supplementary material 2. There were no studies where multiple intervention groups were included in a meta‐analysis more than once. When multi‐arm trials were identified and included, and where the intervention arm was compared to two control arms, we avoided double‐counting of participants by splitting the total number of participants and events in the intervention arm into similar numbers.
Dealing with missing data
We assessed all outcomes on an ITT basis. We conducted a sensitivity analysis, where those with baseline HIV infection per arm were excluded from the denominators in each of the study groups, modified ITT. The analysis did not substantially affect the overall relative effect sizes and their 95% CIs. Hence, we have reported the original forest plots, associated effect sizes, and 95% CIs.
Reporting bias assessment
We planned to assess publication bias using funnel plots if 10 or more studies were included in the meta‐analysis for a specific outcome. However, there were only two included studies, so this was not done.
Synthesis methods
We analysed the data using RevMan [29]. Data were synthesised for each outcome, where possible, using the inverse variance statistical method with a random‐effects analysis model. To assess between‐study variance, we used restricted maximum likelihood (REML) and calculated the CIs for summary effects using Wald‐type [30]. Where this was not possible, we planned to synthesise results using the direction of effect, guided by the Synthesis Without Meta‐analysis (SWiM) reporting guideline [31].
We assessed heterogeneity, where possible, by inspecting forest plots for overlapping 95% CIs, and evaluating the Chi² test, P value, and I² statistic [32]. For the I² statistic, we classified heterogeneity as:
0% to 40%: may not be important;
30% to 60%: possible moderate heterogeneity;
50% to 90%: possible substantial heterogeneity;
75% to 90%: considerable heterogeneity.
Studies reporting zero events in both the intervention and comparator groups were excluded from the heterogeneity assessment, as the effect measure is undefined.
We used GRADE methodology to assess the certainty of the evidence for each outcome [33], employing GRADEpro GDT software [34].
Investigation of heterogeneity and subgroup analysis
We planned an a priori subgroup analysis of the critical outcomes based on comparator type (i.e. F/TDF or F/TAF) to identify potential effect modifiers, irrespective of the presence or absence of heterogeneity [10, 33].
Equity‐related assessment
We did not specifically investigate health inequities in this review. However, identifying effective HIV prevention interventions is a global priority. The burden of HIV is disproportionately concentrated in low‐ and middle‐income countries and among socially disadvantaged populations [35]. Adolescents and young people – particularly women – face heightened vulnerability due to gender inequality, limited access to sexual and reproductive health services, and exposure to gender‐based violence [36]. Key populations such as MSM, transgender individuals, and other gender‐diverse persons experience elevated risk driven by stigma, discrimination, and criminalisation, which impede access to prevention and treatment services [36]. HIV‐related stigma further perpetuates social and economic marginalisation, reducing opportunities for education, employment, and healthcare engagement. These structural and social determinants of health exacerbate inequities, creating cycles of disadvantage. HIV prevention interventions like long‐acting PrEP (e.g. lenacapavir) offer potential for an additional choice for vulnerable and at‐risk populations. Equitable implementation requires addressing affordability, access barriers, and systemic discrimination to ensure that those most affected can benefit from it. Therefore, in addition to reviewing the effectiveness of lenacapavir, which this review addresses, it is critical that further evidence on intervention access, costs, affordability, and equity‐focused implementation strategies be considered; otherwise, HIV prevention innovations risk reinforcing existing disparities rather than closing gaps.
Sensitivity analysis
We conducted a post hoc sensitivity analysis, where those with baseline HIV infection per arm were excluded from the denominators in each of the study groups (modified ITT analysis). We did not exclude studies due to high risk of bias; however, we reported and planned to consider the risk when interpreting the results for the critical outcomes.
Certainty of the evidence assessment
Two review authors (SE, NG) conducted the GRADE assessment, with all review authors reviewing and providing input. We summarised the meta‐analysis results in a summary of findings tables, and presented summary effect estimates for all outcomes. We used the GRADE framework to assess the certainty of the evidence [15]. We downgraded the certainty of the evidence based on the five GRADE considerations: risk of bias, inconsistency, indirectness, imprecision, publication bias. We judged the certainty of evidence as high, moderate, low, or very low, as defined below [27].
| Certainty of evidence | Definition |
| High | We are very confident that the true effect lies close to that of the estimate of the effect. |
| Moderate | We are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. |
| Low | Our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. |
| Very low | We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect. |
We resolved any disagreements through discussion or by involving a third review author (TK), and justified our decisions to downgrade the certainty of the evidence in footnotes.
Consumer involvement
This review was conducted in response to a priority question from the South African National Essential Medicines List Committee (NEMLC) to inform their decision‐making processes. This is further summarised in Supplementary material 8. The Plain language summary was drafted by ZA and reviewed by a layperson for readability.
Results
Description of studies
See Supplementary material 2 for the characteristics of included studies and Table 4 for the Overview of Synthesis and Included Studies (OSIS) table, which lists key characteristics of included studies, outcomes, and analyses. All comparisons and analyses can be found in Supplementary material 6, and a full data package is available in Supplementary material 7.
Results of the search
A PRISMA flow diagram is presented in Figure 1. We conducted electronic searches on 28 May 2025, identifying 178 potentially relevant records, of which 90 were duplicates. From the remaining 88 records, we excluded an additional 83 records at the title and abstract screening stage. We assessed five full‐text studies for eligibility, three of which were ongoing studies, and two of which were included in the meta‐analysis. There were no studies awaiting classification or excluded at the full‐text stage. The ongoing studies are described in Supplementary material 4.
Included studies
We included two RCTs with a total of 8660 participants aged 16 years or older, randomised at the individual patient level. See the OSIS table for a summary of the included trials (Table 4); detailed characteristics of the included studies are provided in Supplementary material 2.
Both studies were multicentre trials (Bekker 2024; Kelley 2025), conducted in South Africa and Uganda (Bekker 2024) and the USA, Brazil, Thailand, South Africa, Peru, Argentina, and Mexico (Kelley 2025). In both included trials, follow‐up visits occurred at 4, 8, and 13 weeks, and every 13 weeks thereafter, for a total study duration of 52 weeks. We did not contact authors of the Kelley 2025 trial, as we did not require additional information. However, we contacted the authors of the Bekker 2024 trial for clarification regarding adherence to study interventions in participants who acquired HIV infection during the study.
Participants
Inclusion criteria common to both trials were: individuals who were sexually active with male partners, were not using PrEP, had an unknown HIV status, and had no HIV testing within the previous three months. In the PURPOSE 1 trial, the population included adolescent girls and young women, 16 to 25 years of age (Bekker 2024). In the PURPOSE 2 trial, the population included cisgender gay, bisexual and other men, transgender women, transgender men, and gender‐nonbinary persons who have condomless, receptive anal sex with partners assigned male at birth (Kelley 2025).
Interventions
The intervention of interest was lenacapavir administered subcutaneously every 26 weeks, with a window of approximately seven days. In the PURPOSE 1 trial, Bekker 2024 compared lenacapavir to daily oral F/TAF or daily oral F/TDF (Bekker 2024). In the PURPOSE 2 trial, lenacapavir was compared to daily oral F/TDF (Kelley 2025). On days 1 and 2, participants randomised to lenacapavir received loading doses of two 300 mg lenacapavir tablets, and participants randomised to oral PrEP received two matched placebo tablets. Participants in the lenacapavir arm received placebo tablets that matched oral F/TAF or F/TDF, and participants in the oral PrEP arms received placebo injections that matched lenacapavir.
Outcomes
Outcomes assessed in both included trials were as follows.
New HIV infections
SAEs
AEs
Adverse drug reactions: injection site reactions
All‐cause mortality
Retention
Adherence
Incidence of other STIs
Viral mutations among those who contracted HIV
Funding
Both trials were funded by Gilead Sciences; however, there is no indication that the sponsor influenced the conduct, analysis, or reporting of the trial findings [17, 22].
Excluded studies
We did not exclude any studies at the full‐text review stage (Figure 1). We excluded 83 records at the title and abstract phase; a sample of these is listed in Supplementary material 3 and Supplementary material 10. A list of all 83 records is available on author request.
Ongoing studies
We identified three ongoing trials (NCT06101329 [37]; NCT06101342 [38]; NCT06513312 [39]), which are summarised in Supplementary material 4. All three trials compare lenacapavir 927 mg administered subcutaneously every 26 weeks, plus oral lenacapavir 600 mg on days 1 and 2, with F/TDF 200/300 mg administered daily for 52 weeks. They are all part of the PURPOSE trial series and are sponsored by Gilead Sciences.
PURPOSE 3 is currently being conducted in the USA, and is a phase 2, open‐label, multicentre randomised study to evaluate the pharmacokinetics, harms, and acceptability of twice‐yearly long‐acting subcutaneous lenacapavir for pre‐exposure prophylaxis in cisgender women 18 years and older, at increased risk for HIV acquisition. The study commenced on 17 November 2023, with an estimated completion date of January 2028 (NCT06101329).
PURPOSE 4 is currently being conducted in the USA, and is a phase 2, open‐label, multicentre, randomised study to evaluate the pharmacokinetics and harms of twice‐yearly long‐acting subcutaneous lenacapavir for pre‐exposure prophylaxis in people who inject drugs. The study commenced on 13 December 2023, with an estimated completion date of December 2028 (NCT06101342).
PURPOSE 5 is currently being conducted in France and the UK, and is a phase 2, open‐label, multicentre, randomised study to evaluate the persistence, harms, acceptability, and pharmacokinetics of twice‐yearly long‐acting subcutaneous lenacapavir for HIV PrEP in individuals who would benefit from PrEP. The study commenced on 7 October 2024, with an estimated completion date of December 2028 (NCT06513312).
Risk of bias in included studies
We used the RoB 2 tool to assess the methodological risk of bias in each RCT for each meta‐analysed outcome; see Supplementary material 5 for detailed justifications for all risk of bias judgements [40]. Our assessment data, including consensus responses to the signalling questions, can be accessed via this shared document.
Overall risk of bias by outcome
For the outcomes of new HIV infections, SAEs, AEs, adverse drug reactions, and all‐cause mortality, we assessed both trials as having a low risk of bias in all domains (Bekker 2024; Kelley 2025).
Synthesis of results
We meta‐analysed results from the two included RCTs as a single pair‐wise comparison, using the data comparing lenacapavir to oral PrEP, combining both oral PrEP arms: F/TDF (Bekker 2024; Kelley 2025) and F/TAF (Bekker 2024). We then conducted sub‐analyses by splitting the 'shared' group (i.e. the lenacapavir arm in the Bekker 2024 study) into two smaller groups of similar size, and compared one of the split groups to the F/TDF arm and the other to the F/TAF arm [41]. We included only critical outcomes in the summary of findings tables. We reported other outcomes narratively. We did not find any studies comparing lenacapavir to CAB‐LA or placebo.
Lenacapavir compared to oral PrEP
The full analysis results are presented in Supplementary material 6; the GRADE ratings for the critical outcomes are shown in Table 1.
Critical outcomes
New HIV infections
Lenacapavir results in a large reduction in new HIV infections at 52 weeks when compared to oral PrEP (RR 0.07, 95% CI 0.02 to 0.22; I² = 0%; 2 studies, 8660 participants; high‐certainty evidence; Figure 2; Analysis 1.1). That is an absolute effect of 14 fewer cases per 1000 (ranging from 15 fewer to 12 fewer), with a number needed to treat for an additional beneficial outcome (NNTB) of 70. This was similar in both subgroups: lenacapavir versus F/TDF (RR 0.08, 95% CI 0.02 to 0.32; I² = 0%; 2 studies, 5439 participants; Figure 2) and lenacapavir versus F/TAF (RR 0.03, 95% CI 0.00 to 0.41; I² not applicable; 1 study, 3221 participants; Figure 2).
2.
New HIV infections: lenacapavir versus oral PrEP.
Among the 4313 participants included in this review who received lenacapavir and were initially HIV‐negative, two acquired HIV infection, diagnosed at weeks 13 and 26 visits, respectively (Kelley 2025). Retrospective analysis of stored specimens using standard HIV‐1 ribonucleic acid (RNA) viral load assays from prior study visits demonstrated no evidence of delayed diagnosis in either participant (Bekker 2024, Kelley 2025).
Serious adverse events
Lenacapavir results in a slight reduction in SAEs at 52 weeks when compared to oral PrEP (RR 0.78, 95% CI 0.61 to 0.99; I² = 0%; 2 studies, 8660 participants; high‐certainty evidence; Figure 3). That is an absolute effect of 8 fewer cases per 1000 (ranging from 15 fewer to 0 fewer), with an NNTB of 128. Subgroups, when reviewed separately, showed little to no difference between treatment groups: lenacapavir versus F/TDF (RR 0.84, 95% CI 0.62 to 1.12; I² = 0%; 2 studies, 5439 participants; Figure 3) and lenacapavir versus F/TAF (RR 0.68, 95% CI 0.45 to 1.03; I² not applicable; 1 study, 3221 participants; Figure 3). More details on SAEs are provided in Table 2. Reported deaths were due to traumatic events or accidental injury and not deemed to be related to either intervention or comparators.
3.
Serious adverse events: lenacapavir versus oral PrEP.
Adverse events
Lenacapavir results in little to no difference in AEs at 52 weeks compared to oral PrEP (RR 0.99, 95% CI 0.96 to 1.01; I² = 0%; 2 studies, 8660 participants; high‐certainty evidence; Figure 4). That is an absolute effect of 8 fewer cases per 1000 (ranging from 31 fewer to 8 more), with an NNTB of 55. Subgroups showed similar results: lenacapavir versus F/TDF (RR 0.99, 95% CI 0.96 to 1.02; I² = 0%; 2 studies, 5439 participants; Figure 4) and lenacapavir versus F/TAF (RR 0.98, 95% CI 0.94 to 1.02; I² not applicable; 1 study, 3221 participants; Figure 4). More details on specific AEs are provided in Table 2.
4.
Adverse events: lenacapavir versus oral PrEP.
Adverse drug reactions: injection site reactions
Lenacapavir likely increases adverse drug reactions (injection site reactions) at 52 weeks when compared to oral PrEP (RR 1.68, 95% CI 1.20 to 2.33; I² = 99%; 2 studies, 8660 participants; moderate‐certainty evidence; Figure 5). That is an absolute effect of 295 more cases per 1000 (ranging from 87 more to 577 more), with a number needed to treat for an additional harmful outcome of 4. Subgroups showed similar findings for both F/TDF (Analysis 1.4: RR 1.56, 95% CI 0.93 to 2.59; I² = 99%; 2 studies, 5439 participants; Figure 5) and F/TAF (Analysis 1.4: RR 1.95, 95% CI 1.81 to 2.09; I² not applicable; 1 study, 3221 participants; Figure 5). Adverse drug reactions are further described in Table 2.
5.
Adverse drug reactions: lenacapavir versus oral PrEP.
All‐cause mortality
Lenacapavir results in little to no difference in all‐cause mortality at 52 weeks compared to oral PrEP (RR 0.57, 95% CI 0.11 to 3.06; I² = 17%; 2 studies, 8660 participants; high‐certainty evidence; Figure 6). That is an absolute effect of 1 fewer case per 1000 (ranging from 2 fewer to 4 more), with an NNTB of 1073. There were no events from Bekker 2024 for this outcome for the subgroup lenacapavir versus F/TDF comparison (RR 1.00, 95% CI 0.18 to 5.45; I² not applicable; 2 studies, 5439 participants; Figure 6). None of the deaths in either study were attributed to the intervention or comparator drug(s) (Table 2).
6.
All‐cause mortality: lenacapavir versus oral PrEP.
Important outcomes
Overall, these trials were well conducted, and we have not done an individual risk of bias assessment for the following important outcomes.
Retention at 26 and 52 weeks
In the PURPOSE 1 trial, at 26 weeks, retention was 90.3% (1940/2148) in the lenacapavir group compared to 89.7% (963/1073) in the F/TDF group, and 90.9% (1952/2147) in the F/TAF group (Bekker 2024). Similarly, at 52 weeks, retention was similar across trial groups: 45.9% (985/2148) in the lenacapavir group, 44.8% (481/1073) in the F/TDF group, and 45.3% (973/2147) in the F/TAF group (Bekker 2024). In the PURPOSE 2 trial, retention was similar across trial groups at 26 weeks: 85.7% (1882/2195) in the lenacapavir group compared to 86.8% (952/1097) in the F/TDF group (Kelley 2025). At 52 weeks, retention decreased but remained similar across trial groups: 36.1% (793/2195) in the lenacapavir group compared to 36.3% (398/1097) in the F/TDF group (Kelley 2025).
Adherence to PrEP
In the PURPOSE 1 trial, injections of lenacapavir or placebo were administered on time in 91.5% (4545/4967) of participants at week 26 and in 92.8% (2025/2181) of participants at week 52 (Bekker 2024). In the PURPOSE 2 trial, injections were administered on time in 91% (2606/2864) of participants at week 26 and in 92.8% (1016/1095) of participants at week 52 (Kelley 2025). In both trials, denominators were the number of participants expected to receive subcutaneous injections at those time points, and the proportion with 'on‐time' injections were similar between intervention and comparator groups. Two participants receiving lenacapavir acquired HIV infection (both in PURPOSE 2) (Kelley 2025). Plasma concentrations of lenacapavir in both of these participants were within the range observed in the broader pharmacokinetic cohort (Kelley 2025). In PURPOSE 1, adherence was low in the F/TAF group: 34% at week 8, 70% at week 26, and 84% at week 52. Adherence was similarly low in the F/TDF group: 50% at week 8, 89% at week 26, and 93% at week 52 (Bekker 2024).
Among the 4290 participants who received oral PrEP (2136 receiving F/TAF and 2154 receiving F/TDF), 64 participants acquired HIV infection (Bekker 2024; Kelley 2025), of whom 55 had no or low TDF concentrations detected, suggesting poor adherence. One participant had discontinued oral PrEP more than 10 days prior; one had a TDF concentration suggesting medium adherence; three had TDF concentrations suggesting high adherence; and four were missing adherence data (Bekker 2024; Kelley 2025).
Incidence of other sexually transmitted infections
The incidence of laboratory‐confirmed C trachomatis, N gonorrhoeae, or T vaginalis infections detected during routine asymptomatic screening every 26 weeks was high and comparable across the three study groups: 48.7 per 100 person‐years in the lenacapavir group (930 events over 1908.8 person‐years), 50.8 per 100 person‐years in the F/TAF group (965 events over 1899.4 person‐years), and 48.4 per 100 person‐years in the F/TDF group (452 events over 933.4 person‐years) (Bekker 2024).
There were more incident STIs identified in the lenacapavir group than in the F/TDF group: 71.8% (1504/2096) of participants in the lenacapavir group and 64.5% (668/1036) of participants in the F/TDF group; denominators were as reported in the trial (Kelley 2025). The incidence of laboratory‐diagnosed C trachomatis and N gonorrhoeae reported was 77.9 per 100 person‐years (1504 events during 1931.0 person‐years) in the lenacapavir group and 69.4 per 100 person‐years (668 events during 962.1 person‐years) in the F/TDF group (Kelley 2025).
Viral mutations among those who contracted HIV
The PURPOSE 1 trial did not report viral mutations (Bekker 2024). In the PURPOSE 2 trial, both participants in the lenacapavir group who acquired HIV infection harboured the N74D capsid resistance mutation at the time of HIV diagnosis (Kelley 2025); the emtricitabine resistance mutation M184V was detected in one participant in the F/TDF group (Kelley 2025).
Acceptability
This outcome was not reported in either of the included studies.
Satisfaction
This outcome was not reported in either of the included studies.
Lenacapavir compared to no PrEP
Neither included study reported on our other critical outcomes (SAEs, AEs, adverse drug reactions, and all‐cause mortality) or our important outcomes (retention on PrEP, adherence to PrEP, incidence of other STIs, viral mutations among those who contract HIV, acceptability, and satisfaction) for this comparison.
Critical outcomes
New HIV infections
In the PURPOSE‐1 trial (Bekker 2024), the background HIV incidence among screened participants was 2.41 per 100 person‐years (95% CI 1.82 to 3.19) in a cohort of 8094 individuals. HIV incidence per 100 person‐years was 0 (95% CI 0.00 to 0.19) in the lenacapavir arm (2134 individuals), 2.02 (95% CI 1.44 to 2.76) in the F/TAF arm (2136 individuals), and 1.69 (95% CI 0.96 to 2.74) in the F/TDF group (1068 individuals). Lenacapavir was associated with a 100% reduction in HIV incidence relative to the background rate (incidence rate ratio (IRR) 0.00, 95% CI 0.00 to 0.04). HIV incidence in the F/TAF group did not differ significantly from the background incidence (IRR 0.84, 95% CI 0.55 to 1.28). There was little difference in HIV incidence between F/TAF and F/TDF (IRR 1.20, 95% CI 0.67 to 2.14).
In the PURPOSE‐2 trial (Kelley 2025), the background HIV incidence among screened participants was 2.37 per 100 person‐years (95% CI 1.65 to 3.42) in a cohort of 4634 individuals. HIV incidence per 100 person‐years was 0.10 (95% CI 0.01 to 0.37) in the lenacapavir arm (2179 individuals) and 0.93 (95% CI 0.43 to 1.77) in the F/TDF group (1086 individuals). Lenacapavir was associated with a 96% reduction in HIV incidence relative to the background rate (IRR 0.04, 95% CI 0.01 to 0.18). Compared with F/TDF, the incidence of HIV infection with lenacapavir was 89% lower (IRR 0.11, 95% CI 0.02 to 0.51).
The WHO, in its unpublished systematic review using the ROBINS‐I tool, rated the risk of bias for these comparisons as serious for both trials due to confounding, bias in the classification of the intervention, selection bias, and bias in the selection of the outcome [9]. Our appraisal and GRADE assessment are similar to the WHO review (see Supplementary material 9). We assessed the certainty of evidence for this outcome as moderate, despite a serious risk of bias and indirectness due to a large effect, and all plausible confounding would reduce the demonstrated effect.
Sensitivity analysis
We conducted a post hoc sensitivity analysis, where those with baseline HIV infection per arm were excluded from the denominators in each of the study groups (modified ITT analysis) (Analysis 2.1; Analysis 2.2; Analysis 2.3; Analysis 2.4; Analysis 2.5). The analysis did not substantially affect the overall relative effect sizes and their 95% CIs. We therefore have reported the original forest plots, associated effect sizes, and 95% CIs. For the critical outcomes of new HIV infections, SAEs, AEs, adverse drug reactions, and all‐cause mortality, we judged both trials as having a low risk of bias in all domains (Bekker 2024; Kelley 2025), and so did not conduct the pre‐planned sensitivity analysis for high risk of bias.
Discussion
Summary of main results
We evaluated the benefits and harms of lenacapavir compared to oral fixed‐dose combination PrEP consisting of F/TDF or F/TAF, as well as to CAB‐LA, placebo, or no PrEP. We included two studies with a total of 8660 participants. We did not find any trials comparing lenacapavir to CAB‐LA, placebo, or no PrEP. Within both included trials, there was a non‐randomised comparison of lenacapavir with HIV incidence in the screened population as a proxy for a no‐PrEP arm.
Compared to oral PrEP, lenacapavir results in a large reduction in new HIV infections at 52 weeks and a slight reduction in SAEs at 52 weeks. There is little to no difference between groups in AEs and all‐cause mortality at 52 weeks. Twelve deaths were reported across the two trials: four in the lenacapavir arm and eight in the oral PrEP arm. None of the deaths in the trials were considered to be related to the study intervention or comparator(s). Lenacapavir likely increases injection site reactions at 52 weeks (Table 1).
We conducted a post hoc sensitivity analysis, where those with baseline HIV infection per arm were excluded from the denominators in each of the study groups (modified ITT analysis). These analyses had no significant impact on the certainty of the evidence or the conclusions drawn from the results. For the critical outcomes of new HIV infections, SAEs, AEs, adverse drug reactions, and all‐cause mortality, we judged both trials as having a low risk of bias in all domains and therefore did not conduct a sensitivity analysis excluding studies with a high risk of bias (Bekker 2024; Kelley 2025).
A similar large reduction in HIV incidence was seen when comparing lenacapavir study arms to background HIV incidence in the screened population. We assessed this comparison as having a high risk of bias [9].
Limitations of the evidence included in the review
While the two included trials, PURPOSE 1 (Bekker 2024) (adolescent girls and young women in South Africa and Uganda) and PURPOSE 2 (Kelley 2025) (men and gender‐diverse persons in various global settings, including a mix of high‐income and upper‐middle‐income countries), provide important data on key at‐risk populations, notable gaps remain. People who inject drugs (PWID) were not represented in the included studies, but ongoing trials (e.g. PURPOSE 4 [38] for PWID) may address this gap in future updates. There are also no data on certain key populations within resource‐limited settings, or on heterosexual cisgender males. The study populations represent young women in Africa (Bekker 2024), where pregnancy is common, but the number of pregnancy events reported in the trial was too few to identify rare harms. Pharmacovigilance strategies and research to ensure the ongoing collection of data on lenacapavir exposure during pregnancy will therefore be important if lenacapavir is implemented in large HIV prevention programmes for women.
Both included trials compared HIV incidence in the study arms with background incidence in the screened population (Bekker 2024; Kelley 2025). Although the studies were randomised, this comparison is not randomised and is at high risk of bias [9]. As comparison to a placebo or no intervention is no longer regarded as ethical, randomised trial evidence versus a placebo or no intervention in future studies is unlikely. We did not identify any studies comparing lenacapavir to CAB‐LA. Both of the included studies were industry‐sponsored, which may introduce several sources of bias (Bekker 2024; Kelley 2025); however, there is no indication that the sponsor influenced the conduct, analysis, or reporting of the trial findings.
Data on viral mutations in people receiving lenacapavir were very limited in the included trials, as there were no HIV acquisitions in the lenacapavir arm of one study (Bekker 2024), and only two in the other study (Kelley 2025). Future monitoring and research to identify any emergent resistance will be important.
Limitations of the review processes
The important outcomes of adherence to PrEP, incidence of other STIs, and viral mutations among those who contract HIV were reported narratively and not appraised, meta‐analysed, or formally assessed for certainty of evidence. Due to the need for rapid evidence‐informed evidence for national decision‐making, we followed Cochrane's updated rapid review methodology during certain aspects of the review process – one of these was using one review author to extract the data, with two review authors checking [13]. While improving efficiency, this may have introduced residual data extraction errors, confirmation bias, selective error detection, potential for systematic bias and reduced transparency and reproducibility. However, we tried to minimise these errors by using a standardised, piloted data extraction form (see Data extraction and management), ensuring that both review authors checked the data in duplicate and all outcomes and denominators, and by resolving any discrepancies through discussion. We only included RCTs; while RCTs are appropriate for assessing comparative effectiveness, the inclusion of observational studies may have provided additional information about adverse events.
Agreements and disagreements with other studies or reviews
The findings of this systematic review are consistent with the WHO systematic review, which included the same two pivotal trials [9]. While the WHO review reported findings narratively and provided separate GRADE assessments for each outcome within each trial, their certainty of evidence ratings are well‐aligned with the assessments presented here [9].
We meta‐analysed data from both trials, combining the oral PrEP arms and presenting them as subgroups. This allowed us to generate a single, more precise pooled effect estimate for lenacapavir's benefits and harms across the diverse at‐risk populations. This approach provides a clear, overall picture of the benefits of lenacapavir compared to oral PrEP.
There are currently no other completed studies of lenacapavir as PrEP, and the current evidence base for lenacapavir PrEP is based on the two trials included in this review (Bekker 2024; Kelley 2025). Future findings from the ongoing trials (PURPOSE 3 [37], 4 [38], and 5 [39]) will inform benefit and harms estimates across a range of populations, providing vital data for populations not covered in this review, such as PWID (PURPOSE 4 [38]).
Authors' conclusions
Implications for practice
In the included trials (Bekker 2024; Kelley 2025), lenacapavir, compared to either tenofovir disoproxil fumarate plus emtricitabine (F/TDF) or tenofovir alafenamide plus emtricitabine (F/TAF), resulted in a large reduction in new HIV infections, with little to no difference in harms apart from injection site reactions. This supports the broader implementation of injectable pre‐exposure prophylaxis (PrEP) in public health HIV prevention programmes. The recently published World Health Organization pre‐exposure prophylaxis (PrEP) guidelines recommend that long‐acting injectable lenacapavir be offered as an additional prevention choice for people at risk of contracting HIV [9].
In addition to the benefits described, lenacapavir requires fewer healthcare visits than oral PrEP and poses fewer adherence challenges. Lenacapavir is therefore an important PrEP choice to implement programmatically for people at risk of HIV acquisition. Although injection site reactions were quite common, the majority were mild to moderate, and very few resulted in lenacapavir discontinuation. As injection reactions may affect the acceptability of injectable lenacapavir, healthcare workers will require training in injection technique and support in managing these adverse drug reactions.
Equity‐related implications for practice
We did not conduct a PROGRESS‐Plus framework evaluation [42]. The long‐acting, six‐monthly dosing schedule of lenacapavir is inherently an equity consideration, as its use for PrEP may reduce adherence barriers and the need for frequent clinic visits, potentially improving access to PrEP for individuals with competing responsibilities [43]. The long dosing interval can also facilitate the integration of lenacapavir for PrEP into other preventive services, such as contraception, antenatal care, and postnatal care, as lenacapavir injections will be required only every six months. Centralised delivery could inadvertently limit access if not paired with community‐based or decentralised services, underscoring the need for inclusive implementation strategies [43]. Lenacapavir is likely to be used extensively in adolescent girls and young women, who have otherwise been known to struggle with adherence to daily oral PrEP [44].
Cost is currently a barrier to accessing lenacapavir [45]. To date, initial supplies to low‐ and middle‐income countries have been dependent on donor funding or donations from manufacturers. Modelling studies for Eastern and Southern Africa, two areas with among the highest HIV burdens, suggest cost thresholds ranging from USD 7.50 to USD 106 per dose would be needed to achieve cost‐effectiveness, depending on the country studied, even when targeting high‐risk groups only [46, 47]. Cost‐effectiveness thresholds would be lower still if a broader rollout were targeted to non‐high‐risk groups. Achieving these thresholds would require a marked reduction from the currently available prices. Even if cost‐effectiveness thresholds are met, affordability will still pose a challenge in resource‐limited settings, especially if a broad rollout is envisaged.
Implications for research
Although women could become pregnant while on lenacapavir trials, the number of pregnancy exposures was not sufficient to adequately characterise harms in pregnancy as well as risk of rare harms. Research characterising the safety of lenacapavir use in pregnancy is needed.
We currently lack data on some important at‐risk groups. The three ongoing PURPOSE trials will provide additional data on lenacapavir benefits and harms in people who inject drugs [38], cisgender women in the USA [37], and men who have sex with men and gender‐diverse persons in high‐income settings [39]. Trials in men who have sex with men, gender‐diverse people, and adolescents under 16 years of age in resource‐limited settings are needed.
In addition to randomised trials to characterise benefits and harms, implementation studies that allow clients to choose a PrEP intervention, with long‐term follow‐up, will be important for characterising real‐world effectiveness, durability of HIV prevention with lenacapavir, and identifying barriers to adherence. The emergence of lenacapavir resistance is a concern, and HIV‐1 resistance surveillance is necessary to monitor for the emergence of lenacapavir‐associated resistance mutations.
Supporting Information
Supplementary materials are available with the online version of this article: 10.1002/14651858.CD016347.
Supplementary materials are published alongside the article and contain additional data and information that support or enhance the article. Supplementary materials may not be subject to the same editorial scrutiny as the content of the article and Cochrane has not copyedited, typeset or proofread these materials. The material in these sections has been supplied by the author(s) for publication under a Licence for Publication and the author(s) are solely responsible for the material. Cochrane accordingly gives no representations or warranties of any kind in relation to, and accepts no liability for any reliance on or use of, such material.
Supplementary material 1 Search strategies
Supplementary material 2 Characteristics of included studies
Supplementary material 3 Characteristics of excluded studies
Supplementary material 4 Characteristics of ongoing studies
Supplementary material 5 Risk of bias
Supplementary material 6 Analyses
Supplementary material 7 Data package
Supplementary material 8 Consumer involvement table
Supplementary material 9 Appraisal and GRADE for non‐randomised nested study
Supplementary material 10 Sample of studies excluded at Title and Abstract Screening stage
a.
These authors should be considered joint first author
New
Additional information
Acknowledgements
The authors acknowledge the members of the South African National Essential Medicines List Committee, its Expert Review Committee, Essential Drugs Programme Oversight Group, and the National Department of Health who provided insight and expertise that supported the review. We also thank Michael McCaul from the South African GRADE Network for initial input into the GRADE approach, Solange Durão from the South African Medical Research Council (SAMRC) for input into the PICO, and Joy Oliver from the SAMRC for input into the PubMed search strategy and reviewing the Plain language summary, as well as the National Department of Health for part‐funding the work through the Evidence to Decision (E2D) Collaboration.
Editorial and peer‐reviewer contributions
The following people conducted the editorial process for this article:
Sign‐off Editor (final editorial decision): Prof Geraint Rhys Davies, University of Liverpool;
Managing Editor (selected peer reviewers, provided editorial guidance to authors, edited the article): Hannah Payne, Cochrane Central Editorial Service;
Editorial Assistant (conducted editorial policy checks, collated peer‐reviewer comments, and supported the editorial team): Cynthia Stafford, Cochrane Central Editorial Service;
Copy Editor (copy editing and production): Lisa Winer, Cochrane Central Production Service;
Peer reviewers (provided comments and recommended an editorial decision): Nathan Ford, University of Cape Town (clinical/content review); Samson Grover Joseph, Nursing Officer, AIIMS Delhi (patient and public review); Nuala Livingstone, Cochrane Evidence Production and Methods Directorate (methods review); Jo Platt, Central Editorial Information Specialist (search review).
Disclosure of artificial intelligence use
During the preparation of this work, ChatGPT [48] was used to assist with paraphrasing text from the documents included. After using this tool/service, the content was reviewed and edited as needed. Additionally, the Grammarly software [49] was used to check spelling and grammar and edited as appropriate.
Contributions of authors
TK and KC: conception of the review. SE, NG, GT, TK, and KC: design of the review. NG with support from SE and GT: co‐ordination of the review. SE, NG, ZA, JN, HD, and KC: development of the protocol. SE, NG, and ZA: search and selection of studies for inclusion in the review. SE, NG, and ZA: data collection. SE and NG: risk of bias assessment. SE, NG, GT, and TK: data analysis. SE, NG, and TK: GRADE assessment. SE, NG, ZA, GT, PZS, JN, HD, TK, and KC: interpretation of data. SE, NG, ZA, GT, PZS, JN, HD, TK, and KC: writing of the review. The final submission was reviewed and approved by all authors.
Declarations of interest
SE: employee of the South African Medical Research Council, Health Systems Research Unit and of the School of Medicine, University of KwaZulu‐Natal (UKZN), member of the Evidence to Decision (E2D) Collaboration project; no commercial or non‐commercial conflicts of interest relevant to this review.
NG: employee of the South African Medical Research Council, Health Systems Research Unit; Member of the Expert Review Committee of the National Essential Medicines List Committee; member of the Evidence to Decision (E2D) Collaboration project; no commercial or non‐commercial conflicts of interest relevant to this review.
ZA: employed as an independent pharmacist contractor with the Clinton Health Access Initiative and fully seconded to the Affordable Medicines Directorate, National Department of Health, South Africa. Member of the Oversight Group that supports the National Essential Medicines List Committee and its supporting Committees. Locum pharmacist in the private sector for the Clicks Group, a South African retail pharmacy chain.
GT: I work at Groote Schuur Hospital and regularly consult in the emergency medicine department and various outpatient clinics through my work in the Division of Clinical Pharmacology at the University of Cape Town. I am also a current member of the National Essential Medicines List review committee in South Africa.
JN: work as an infectious diseases specialist in the public sector in South Africa. Co‐opted expert for the South African Department of Health's Expert Review Committee.
PZS: I am the collaborating University of Cape Town Principal Investigator for research investigating genetic predictors of weight gain in participants on antiretroviral therapy sponsored (subcontracted) by King's College London, which is funded by Gilead; Specialist clinical pharmacologist at Groote Schuur Hospital; I am a member of the South African National Department of Health's Expert Review Committee, which consists of experts who review evidence and make recommendations to the National Essential Medicines List Committee regarding the National Standard Treatment Guidelines and Essential Medicines List.
HD: HIV diagnostic committee for HPTN 084: cabotegravir for PrEP; Sanofi (SA) sponsorship: vaccinology conference; Infectious diseases physician – ongoing clinical advice on PrEP in public and private sector; Member of Expert Review Committee, National Department of Health, South Africa and past member of National Essential Medicines List Committee, National Department of Health, South Africa.
TK: Member of the National Essential Medicines List Committee in South Africa; also a member of the National Advisory Group on Immunisation in South Africa; Technical advisor for the World Health Organization on guidelines as a methodologist; Co‐investigator on National Ministry of Health‐funded grant to support methods development and evidence synthesis for national decision‐making in South Africa.
KC: Member of the South African National Essential Medicines List Committee (NEMLC), and chair of NEMLC Expert Review Committee until 2025. Currently, member of NEMLC Expert Review Committee. Completed evidence review of lenacapavir for NEMLC and participated in decision‐making regarding inclusion of lenacapavir in South African Essential Medicines List.
Sources of support
Internal sources
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National Department of Health, South Africa
This research was supported in part by the E2D Collaboration, which brings together the National Department of Health, the Health Systems Research Unit and Cochrane South Africa at the South African Medical Research Council, and the Centre for Evidence‐based Health Care at Stellenbosch University. The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the National Essential Medicines List Committee (NEMLC), the Expert Review Committee to the NEMLC, the South African Medical Research Council, Stellenbosch University, or the National Department of Health.
External sources
No sources of support provided
Registration and protocol
We used a prespecified protocol (PROSPERO registration: 1080791) that followed Cochrane methodology [12]. This protocol was registered on 25 June 2025.
Protocol to Review Lenacapavir as an Alternative to Oral Tenofovir Disoproxil Fumarate Plus Emtricitabine or Oral Tenofovir Alafenamide Plus Emtricitabine or Injectable Cabotegravir or Placebo/No Prophylaxis for Preventing HIV (2025) Available from: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251080791
Data, code and other materials
As part of the published Cochrane review, the following is made available for download for users of the Cochrane Library: full search strategies for each database (Supplementary material 1); study data, including study information, study arms, and study results or test data (Supplementary material 6; Supplementary material 7); consensus risk of bias assessments in a Google Drive link; and analysis data, including overall estimates and settings, subgroup estimates, and individual data rows (Supplementary material 6). Appropriate permissions have been obtained for such use. Analyses and data management were conducted within Cochrane’s authoring tool, RevMan, using the inbuilt computation methods. Template data extraction forms from Excel are available from the authors on reasonable request.
Notes
Published notes in RevMan are for editor use only. Authors should leave this section blank.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary material 1 Search strategies
Supplementary material 2 Characteristics of included studies
Supplementary material 3 Characteristics of excluded studies
Supplementary material 4 Characteristics of ongoing studies
Supplementary material 5 Risk of bias
Supplementary material 6 Analyses
Supplementary material 7 Data package
Supplementary material 8 Consumer involvement table
Supplementary material 9 Appraisal and GRADE for non‐randomised nested study
Supplementary material 10 Sample of studies excluded at Title and Abstract Screening stage
Data Availability Statement
As part of the published Cochrane review, the following is made available for download for users of the Cochrane Library: full search strategies for each database (Supplementary material 1); study data, including study information, study arms, and study results or test data (Supplementary material 6; Supplementary material 7); consensus risk of bias assessments in a Google Drive link; and analysis data, including overall estimates and settings, subgroup estimates, and individual data rows (Supplementary material 6). Appropriate permissions have been obtained for such use. Analyses and data management were conducted within Cochrane’s authoring tool, RevMan, using the inbuilt computation methods. Template data extraction forms from Excel are available from the authors on reasonable request.