How PrEP Works: From Daily Pills to Twice-Yearly Shots

What Is PrEP — and Why Does It Matter?

Pre-exposure prophylaxis, known as PrEP, is a medical strategy in which HIV-negative people take antiretroviral medication before any potential exposure to the virus. When taken correctly, PrEP dramatically reduces the chance of contracting HIV — a virus that, without treatment, progressively dismantles the immune system and remains incurable. According to HIV.gov, PrEP is recommended for anyone who is at substantial risk of HIV through sex or injection drug use.

Since its first FDA approval in 2012, PrEP has been a cornerstone of HIV prevention programs worldwide. But its biggest limitation has always been a simple one: people have to take a pill every single day.

How the Original PrEP Pills Work

The first approved oral PrEP regimen, sold as Truvada, combines two drugs — emtricitabine and tenofovir. Both are nucleoside reverse transcriptase inhibitors (NRTIs). To understand how they work, it helps to know how HIV replicates.

When HIV enters the body, it targets CD4 T-cells — the immune system's command cells. Inside the cell, HIV carries its genetic blueprint as RNA, not DNA. To reproduce, it must convert that RNA into DNA using an enzyme called reverse transcriptase. NRTIs block this step by mimicking the building blocks of DNA; when the virus incorporates them into its growing DNA chain, the chain terminates and replication halts.

Daily oral PrEP is roughly 99% effective against HIV from sex when taken consistently, according to the U.S. Department of Health and Human Services. The catch: "when taken consistently." Studies consistently show that real-world adherence falls well short of perfect — meaning many people at risk remain under-protected.

A New Target: The Viral Capsid

Lenacapavir, approved by the FDA in June 2025 and sold as Yeztugo, works through a completely different mechanism. Instead of blocking reverse transcriptase, it targets the HIV capsid — the conical protein shell that encloses and protects the virus's genetic cargo.

According to the NIH's clinical drug database, lenacapavir binds directly to the interface between HIV capsid protein (p24) subunits. This disrupts multiple essential stages of the virus's life cycle simultaneously:

• Nuclear import: After entering a cell, HIV's capsid must travel to the nucleus to deposit its DNA. Lenacapavir over-stabilizes the capsid, preventing it from releasing its contents at the right moment.
• Assembly and release: When new viruses are being built inside an infected cell, the capsid must assemble correctly. Lenacapavir interferes with this assembly process.
• Core formation: It disrupts the structural scaffolding needed to form new infectious viral particles.

Because lenacapavir targets a part of HIV that is highly conserved — meaning the virus struggles to mutate away from it without losing function — it is effective against strains resistant to other drug classes. It is classified as the world's first capsid inhibitor, a genuinely new class of antiretroviral.

What Clinical Trials Found

The evidence for lenacapavir as a prevention tool is striking. In the landmark PURPOSE 1 trial, published in the New England Journal of Medicine, 2,134 HIV-negative cisgender adolescent girls and women in South Africa and Uganda received two subcutaneous injections every six months. Not a single participant contracted HIV — representing 100% efficacy compared to the control arm, which recorded 16 infections.

A companion study, PURPOSE 2, enrolled men who have sex with men, transgender women, transgender men, and gender non-binary individuals. Published also in the New England Journal of Medicine, this trial found a 96% reduction in HIV infections compared to the standard daily oral PrEP regimen. The World Health Organization issued a formal recommendation for lenacapavir as a PrEP option in July 2025.

Why the Twice-Yearly Format Changes Everything

The most transformative aspect of lenacapavir is not its mechanism — it is its dosing. Two injections per year, administered under the skin of the abdomen, provide continuous protection. This eliminates the core weakness of oral PrEP: the daily adherence burden.

For people whose circumstances make daily pill-taking difficult — whether due to stigma, unstable housing, or complex daily routines — a twice-yearly injection removes the most common point of failure. Public health researchers have long argued that the best prevention tool is the one people will actually use.

Access and the Road Ahead

The main challenge now is cost and distribution. Lenacapavir was developed by Gilead Sciences and carries a high list price in wealthy countries. To address this, Gilead has licensed generic manufacturing rights to producers in low- and middle-income countries — a critical step given that sub-Saharan Africa bears the greatest HIV burden. The CDC formally recommended lenacapavir as a PrEP option for the United States in 2025, and access programs are expanding.

PrEP itself is not a vaccine and does not cure HIV. It does not protect against other sexually transmitted infections. But with near-perfect efficacy delivered twice a year, lenacapavir represents the most significant advance in HIV prevention since PrEP itself was introduced — and potentially one of the most important public health tools of the decade.