HIV PrEP Revolution

Prior to PrEP, HIV prevention relied almost exclusively on behavioral interventions, condom use, and post-exposure prophylaxis. The concept of pre-exposure prophylaxis emerged from animal studies showing that tenofovir-based regimens could prevent simian immunodeficiency virus acquisition in macaques. These preclinical findings, combined with the success of antiretroviral therapy in preventing mother-to-child transmission and the biological plausibility of mucosal drug concentrations preventing viral establishment, provided the rationale for human efficacy trials. The stage was set for a paradigm shift from reactive to proactive HIV prevention.

The iPrEx trial was the landmark study that proved PrEP could work in humans. This multinational RCT randomized 2499 high-risk MSM and transgender women to daily oral TDF/FTC (tenofovir/emtricitabine) vs placebo, demonstrating a 44% overall reduction in HIV acquisition. Critically, among participants with detectable drug levels (indicating adherence), efficacy exceeded 90%. The Partners PrEP study in serodiscordant heterosexual couples in Kenya and Uganda showed 75% efficacy with TDF/FTC and 67% with TDF alone. These studies established that daily oral PrEP was highly effective when taken consistently, leading to FDA approval of Truvada for PrEP in 2012, the first biomedical HIV prevention intervention beyond barrier methods.

The evolution from daily pills to long-acting injectables represented the next breakthrough. The HPTN 083 trial demonstrated that injectable cabotegravir (CAB-LA) every 2 months was superior to daily oral TDF/FTC in MSM and transgender women, with 69% greater protection. HPTN 084 confirmed superiority in cisgender women in sub-Saharan Africa. The most dramatic advance came with lenacapavir, a novel capsid inhibitor requiring only twice-yearly subcutaneous injection. The PURPOSE 1 trial in women and adolescent girls in South Africa and Uganda showed zero HIV infections among 2134 participants receiving lenacapavir, compared to a background incidence of 2.41/100 person-years, achieving 100% efficacy. This result was unprecedented in HIV prevention research.

CDC PrEP guidelines have been updated multiple times to reflect the expanding evidence. The 2021 update recommended PrEP for all individuals at substantial risk of HIV, including MSM, heterosexual persons with HIV-positive partners, people who inject drugs, and those with recent STI diagnoses. Following CAB-LA approval in 2021, injectable PrEP was added as an option. WHO prequalification of CAB-LA in 2022 opened access in low- and middle-income countries. The integration of PrEP into routine primary care, rather than specialist HIV services, has become a key implementation goal.

The PrEP landscape is rapidly evolving toward long-acting options that address the Achilles heel of daily oral PrEP: adherence. Lenacapavir, requiring only twice-yearly injection, is pending regulatory approval for PrEP after the stunning PURPOSE 1 results. If approved, it could transform HIV prevention in high-burden settings where daily pill-taking and bimonthly clinic visits are barriers. Challenges remain around cost, access equity, and ensuring that long-acting PrEP reaches the populations at highest risk, particularly young women in sub-Saharan Africa. Research continues on PrEP implants, broadly neutralizing antibodies, and combination prevention strategies that could ultimately make HIV elimination achievable.