Wits RHI PURPOSE 1 Study: Lenacapavir PrEP Shows Near-Perfect Efficacy Amid Rare Breakthroughs

Groundbreaking Insights from Wits RHI's PURPOSE 1 Study on Lenacapavir PrEP

The latest full results from the PURPOSE 1 study, presented by researchers from the Wits Reproductive Health and HIV Institute (Wits RHI) at the Conference on Retroviruses and Opportunistic Infections (CROI) 2026, have reaffirmed the exceptional efficacy of twice-yearly injectable lenacapavir for HIV pre-exposure prophylaxis (PrEP). Conducted primarily among adolescent girls and young women (AGYW) in South Africa, this phase 3 trial highlights a near-perfect prevention rate, with only rare breakthrough infections observed despite high-risk settings. These findings, building on initial 2024 data showing zero infections, position lenacapavir as a transformative tool in South Africa's fight against HIV.

Wits RHI, affiliated with the University of the Witwatersrand, played a pivotal role as a lead site in Johannesburg's Hillbrow, enrolling over 200 young women and contributing critical data from one of South Africa's highest HIV incidence areas. This university-led research underscores higher education's vital contribution to public health innovations in the country.

Lenacapavir, a novel capsid inhibitor developed by Gilead Sciences, disrupts the HIV virus's protein shell, preventing replication. Administered subcutaneously just twice a year after an initial oral loading dose, it addresses key barriers to daily oral PrEP adherence, such as stigma, pill fatigue, and access issues prevalent among AGYW.

HIV Epidemic Context in South Africa Demands Innovative PrEP Solutions

South Africa bears the world's largest HIV burden, with approximately 7.5 million people living with HIV as of 2025, and AGYW aged 15-24 accounting for nearly a quarter of new infections despite representing just 10% of the population. In regions like Gauteng, where Wits RHI operates, HIV incidence among young women can exceed 4% annually, far outpacing global averages. Traditional daily oral PrEP options like emtricitabine/tenofovir disoproxil fumarate (F/TDF, Truvada) or emtricitabine/tenofovir alafenamide (F/TAF) have shown suboptimal real-world adherence, with continuation rates dropping below 30% after six months due to behavioral and social challenges.

The PURPOSE trials emerged from this urgent need, sponsored by Gilead and executed through global networks including South African universities. Wits RHI's involvement exemplifies how higher education institutions drive evidence-based interventions tailored to local epidemiology.

Design and Methodology of the PURPOSE 1 Trial

PURPOSE 1 was a multicenter, double-blind, randomized, active-controlled phase 3 trial enrolling 5,338 HIV-negative AGYW aged 16-25 across 54 sites in South Africa and Uganda. Participants were randomized 2:2:1 to subcutaneous lenacapavir (927 mg every 26 weeks), daily oral F/TAF (25 mg/200 mg), or daily oral F/TDF (200 mg/300 mg). The primary endpoint was HIV incidence, compared against background rates in the screened population (8,094 women).

• Lenacapavir arm: 2,134 participants
• F/TAF arm: 2,136 participants
• F/TDF arm: 1,068 participants

Follow-up extended up to 104 weeks, with quarterly HIV testing, adherence counseling, and risk reduction support. Wits RHI's Hillbrow site focused on urban AGYW facing compounded risks from transactional sex, violence, and limited healthcare access.

Impressive Efficacy Results: Near 100% Protection Demonstrated

Full CROI 2026 data revealed HIV incidence of 0.07 per 100 person-years (ppy) in the lenacapavir arm among over 2,000 participants, compared to 1.98 ppy for F/TAF and 1.94 ppy for F/TDF. This translates to just two seroconversions in lenacapavir versus 77 in oral PrEP arms. Incidence was significantly lower than background (2.41 ppy), with a rate ratio of nearly zero.

Dr. Nkosiphile Ndlovu from Wits RHI, who presented the findings, emphasized: "This positions twice-yearly lenacapavir as a powerful, low-burden option for populations urgently needing innovation." Initial interim results in 2024 reported zero infections, a historic first for PrEP trials.

Adherence challenges plagued oral arms, underscoring lenacapavir's advantage in discreet, infrequent dosing.

Analyzing the Rare Breakthrough Infections

Despite outstanding overall performance, two breakthrough infections occurred in PURPOSE 1's lenacapavir arm: one at week 52 post on-time injections, and another at week 95 after missing a dose and switching to oral PrEP (while still HIV-negative at switch). Four of five total seroconversions across PURPOSE 1 and 2 showed lenacapavir resistance mutations acquired during use, not transmitted. No clear cause identified for on-time breakthroughs with therapeutic levels, prompting ongoing genomic analysis.

• Breakthrough rate: Extremely low at 0.07 ppy
• Similar to other PrEP modalities
• Does not diminish enthusiasm; experts like Hyman Scott note "breakthroughs are rare and expected in large trials"

Wits RHI researchers stress these rarities highlight the need for real-world monitoring but affirm lenacapavir's superiority.

Photo by Vitaly Gariev on Unsplash

Safety Profile and Participant Experience

Lenacapavir was well-tolerated, with injection-site reactions in 68.8% (mostly mild) versus 34.9% placebo. Only 0.2% discontinued due to reactions. No new safety signals emerged, contrasting favorably with oral PrEP's adherence issues. Participants reported high satisfaction with biannual dosing, potentially boosting retention in South Africa's overburdened clinics.

Prof. Thesla Palanee-Phillips of Wits RHI hailed it as a "pivotal moment," crediting participant commitment.

PURPOSE 2 Complementary Findings in Men and Gender-Diverse Populations

PURPOSE 2 mirrored success in 2,179 MSM and gender-diverse individuals, with 0.11 ppy incidence (3 infections) versus 0.92 ppy on F/TDF. Two on-time breakthroughs occurred, aligning with PURPOSE 1 patterns. Combined, trials across 7,500+ participants confirm lenacapavir's broad-spectrum efficacy.

South African sites contributed significantly, enhancing generalizability.

Path to Rollout: Affordability and Access in South Africa

September 2025's landmark agreement between Unitaid, CHAI, Wits RHI, and Dr. Reddy’s Laboratories secures generic lenacapavir at US$40/year in 120 LMICs, including South Africa, from 2027. This matches oral PrEP costs, accelerating access post-FDA Yeztugo approval (2025). South Africa began rollout in late 2025, prioritizing high-burden groups.

Wits RHI leads real-world implementation studies, bridging trial to practice. For those exploring careers in such research, check higher ed research jobs or South Africa university opportunities.

Implications for South African Higher Education and Public Health

Wits RHI's leadership exemplifies how South African universities advance global health equity. The study trained dozens in clinical research, fostering talent amid SA's youth unemployment crisis. Policymakers now integrate lenacapavir into national programs, potentially averting 500,000+ infections by 2030 per models.

Challenges remain: scaling clinics, stigma reduction, and monitoring resistance. Future trials explore annual dosing.

Stakeholder Perspectives and Expert Opinions

Dr. Ndlovu: "Africans at the forefront of groundbreaking research." UNAIDS praises the rollout as a "new phase." Gilead's Stephanie Cox: "Extremely high efficacy despite rare breakthroughs." Community advocates urge education to counter misinformation.

Balanced views note oral PrEP's role for some, emphasizing choice.

Photo by ling ze on Unsplash

Future Outlook and Actionable Insights

Lenacapavir could reshape HIV elimination strategies, complementing vaccines and treatment. Wits RHI plans PURPOSE extensions, resistance surveillance. For educators and researchers, this highlights interdisciplinary impact. Explore research career advice or rate professors in public health.

In summary, Wits RHI's PURPOSE 1 study cements lenacapavir's role in HIV prevention. Visit higher-ed-jobs, university jobs, or career advice to join such transformative work. Share your thoughts below.