Recent clinical data demonstrates unprecedented efficacy, with studies showing ≥99.9% protection against HIV infection across diverse populations.
For decades, the fight against HIV has relied on daily pills as the primary method of prevention for those at risk. While effective, these regimens have presented significant challenges—stigma, adherence difficulties, and barriers to access—that have limited their impact.
Now, a transformative advancement has emerged: lenacapavir, the first HIV prevention option requiring just two injections per year. Recent clinical data demonstrates unprecedented efficacy, with studies showing ≥99.9% protection against HIV infection across diverse populations 1 2 . This breakthrough offers more than just medical innovation; it represents a fundamental shift in HIV prevention strategy, providing a discreet, long-acting option that could potentially overcome the barriers that have hindered daily PrEP approaches.
"We have the tools and the knowledge to end AIDS as a public health problem. What we need now is bold implementation of these recommendations, grounded in equity and powered by communities." - Dr. Meg Doherty, WHO 4
As the World Health Organization officially recommends this twice-yearly injectable, we explore the science, data, and potential behind what many are calling the closest thing to an HIV vaccine we've ever had.
HIV prevention has undergone a remarkable evolution since the epidemic's early days. The concept of pre-exposure prophylaxis (PrEP)—using antiretroviral drugs to prevent HIV acquisition—revolutionized the field when the first daily oral pill was approved in 2012.
Today, multiple PrEP options exist, including daily oral medications and a two-monthly injectable. However, persistent challenges remain. Despite known effectiveness, only about 36% of people in the U.S. who could benefit from PrEP were prescribed it in 2022, with particularly low uptake among women, Black/African American, and Hispanic/Latino populations, and those in the U.S. South 2 .
Barriers include adherence challenges to daily medication, stigma associated with HIV prevention, and limited awareness among both providers and consumers 2 .
Lenacapavir (brand name Yeztugo) belongs to a novel class of drugs called HIV-1 capsid inhibitors. Unlike other antivirals that typically target just one stage of viral replication, lenacapavir is designed to disrupt the HIV lifecycle at multiple strategic points 1 2 .
It interferes with the virus's protective protein shell (the capsid), potentially disrupting:
This multi-stage mechanism—coupled with no known cross-resistance to other drug classes—makes lenacapavir a unique and powerful addition to the HIV arsenal 1 . The journal Science recognized its significance by naming lenacapavir the 2024 "Breakthrough of the Year" 1 2 .
Source: CDC PrEP Surveillance Data 2
The evidence supporting lenacapavir comes from Gilead's landmark PURPOSE program, hailed as "the most intentionally inclusive HIV prevention trial program ever conducted" 1 . Two Phase 3 trials—PURPOSE 1 and PURPOSE 2—generated the data that led to regulatory approvals:
These remarkable results led to the trials being stopped early after pre-planned interim analyses met pre-specified efficacy criteria, allowing all participants to be offered the superior prevention option 7 .
What sets the PURPOSE program apart is its deliberate inclusion of populations typically underrepresented in HIV clinical trials but disproportionately affected by HIV globally 1 . The trials generated robust data on:
This intentional design ensures the resulting data reflects the real-world populations who will benefit from the prevention method, addressing long-standing equity gaps in HIV research.
| Trial | Population | Participants | HIV Infections | Efficacy |
|---|---|---|---|---|
| PURPOSE 1 | Cisgender women and adolescent girls in sub-Saharan Africa | 2,134 | 0 | 100% |
| PURPOSE 2 | Cisgender men and gender-diverse people across multiple countries | 2,179 | 2 | 99.9% |
The PURPOSE 1 trial (NCT04994509) was a Phase 3, multisite, double-blinded, randomized controlled clinical efficacy trial conducted in South Africa and Uganda 7 . Its innovative design directly compared three prevention approaches:
The trial enrolled 8,094 females aged 16-25 who were screened to establish background HIV incidence rates, with 5,338 ultimately enrolled in the modified intention-to-treat analysis 7 .
The PURPOSE 1 results were striking. In the interim analysis, no HIV infections occurred among the 2,134 participants receiving lenacapavir over 52 weeks of follow-up 7 . This represented:
Even in post-primary analysis, only two incident HIV infections were identified in the lenacapavir group, maintaining exceptional protection levels 7 .
| Study Group | Number of Participants | HIV Infections | Efficacy vs. No PrEP | Efficacy vs. TDF/FTC |
|---|---|---|---|---|
| Lenacapavir | 2,134 | 0 | 100% | 100% |
| TAF/FTC | 2,136 | Data not provided | Data not provided | Data not provided |
| TDF/FTC | 1,068 | Data not provided | Data not provided | - |
Perhaps as important as the efficacy data were the participant preference findings from the PURPOSE trials. Both quantitative and qualitative data revealed strong predilection for the twice-yearly injection over daily oral options 1 . Surveys showed:
Key reasons included feeling more protected from HIV (69%) and greater confidence about not missing doses (77%) 1 . Qualitative data among 108 participants, particularly adolescents aged 16-17 years, noted that twice-yearly injections better suited their lifestyles compared with once-daily pills 6 . This preference data is crucial because real-world effectiveness depends not just on pharmacological efficacy but on user acceptance and adherence.
The development and testing of lenacapavir required sophisticated research tools and methodologies. The table below outlines essential components used in the PURPOSE trials and related research.
| Research Tool | Function in Lenacapavir Development |
|---|---|
| HIV-1 capsid protein assays | In vitro assessment of compound binding and disruption of capsid function |
| Cell-based antiviral assays | Evaluation of lenacapavir's inhibition of HIV replication in multiple cell types |
| HIV rapid diagnostic tests (RDTs) | Essential safety component: confirmed HIV-negative status prior to each injection |
| Central laboratory antigen/antibody tests | Confirmed HIV testing at scheduled visits |
| HIV RNA testing | Specialized testing for participants acquiring HIV during trials to characterize infection |
| CYP3A enzyme assays | Investigation of drug-drug interactions, particularly with TB medications |
| Pharmacokinetic modeling software | Projected and confirmed therapeutic drug concentrations over extended periods |
U.S. FDA approval for adults and adolescents weighing ≥35kg 2
WHO recommendation as an additional PrEP option 4
Even as twice-yearly lenacapavir reaches patients, research continues to push boundaries. Phase 1 data presented in March 2025 showed that two novel once-yearly formulations maintained plasma concentrations above effective levels for at least 56 weeks 6 8 .
Median trough concentrations at Week 52 were actually higher than those observed with the twice-yearly formulation at Week 26 6 . Gilead plans to launch a Phase 3 trial for once-yearly lenacapavir in the second half of 2025 6 , potentially further transforming HIV prevention paradigms.
Despite the excitement, important challenges remain. The U.S. list price of $28,218 per year has raised concerns about accessibility .
In response, Gilead has signed agreements with six generic manufacturers to produce and distribute the drug in 120 low- and middle-income countries and partnered with The Global Fund to supply enough doses for up to two million people over three years in eligible countries 1 .
How effectively these access strategies are implemented will significantly influence lenacapavir's public health impact.
Lenacapavir represents far more than just another pharmaceutical option—it embodies a fundamental shift in HIV prevention. By combining unprecedented efficacy with a twice-yearly dosing schedule that aligns with human behavior and preferences, it addresses core challenges that have limited the impact of previous PrEP methods.
The robust clinical data spanning diverse populations—including those traditionally excluded from research but disproportionately affected by HIV—provides confidence that this breakthrough can make a real difference where it's needed most.
As Dr. Meg Doherty of WHO stated, "We have the tools and the knowledge to end AIDS as a public health problem. What we need now is bold implementation of these recommendations, grounded in equity and powered by communities" 4 . Lenacapavir, particularly as even longer-acting formulations advance through research, offers perhaps our most powerful tool yet to finally change the trajectory of the HIV epidemic. The science has delivered; now the challenge lies in ensuring this revolutionary prevention option reaches all who could benefit.
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