Two shots a year. That is all it takes for near-complete protection against HIV, according to results from the PURPOSE 1 and PURPOSE 2 clinical trials, now published in the New England Journal of Medicine.
99.9% of participants who received the injection remained HIV-negative throughout the trials.
The drug is called lenacapavir, and the FDA approved it for HIV prevention in June 2025 under the brand name Yeztugo.
Science magazine named it its Breakthrough of the Year for 2024, and that designation was earned.
To understand why, consider the scale of what it is up against.
In 2024, 1.3 million people were newly infected with HIV.
That is more than 3,500 people every single day.
Someone dies of HIV-related causes every single minute.
Young women and girls aged 15 to 24 accounted for 570 new infections per day in sub-Saharan Africa alone.
Existing prevention tools have made progress, but they have not been enough.
Lenacapavir changes the terms of that problem in a way nothing before it has.
How the Study Was Conducted
The PURPOSE trials were large-scale, randomized, double-blind studies designed to test lenacapavir against the best oral prevention drugs currently available.
They were not testing against a placebo.
They were testing against Truvada and Descovy, the gold-standard daily pills that have been the primary HIV prevention tools since 2012.
PURPOSE 1 enrolled more than 5,000 cisgender adolescent girls and young women in Uganda and South Africa, one of the highest-risk populations on earth for HIV infection.
Participants were randomly assigned to receive twice-yearly lenacapavir injections, once-daily Descovy, or once-daily Truvada.
PURPOSE 2 expanded the population significantly, enrolling cisgender men, transgender women, transgender men, and gender-nonbinary individuals aged 16 and older across 88 sites in the US, Argentina, Brazil, Mexico, Peru, Thailand, and South Africa.
In PURPOSE 2, participants were randomly assigned in a 2:1 ratio to receive lenacapavir every 26 weeks or daily oral Truvada.
Both trials monitored for HIV infections over a follow-up period of 52 weeks.
Both trials were halted early because lenacapavir’s results were so clearly superior to the oral alternatives that continuing the comparison was considered ethically unjustifiable.
Findings From the Study
In PURPOSE 1, lenacapavir produced zero HIV infections across 2,134 participants.
Not one infection.
That is a 100% reduction compared to background HIV incidence in the screened population.
In PURPOSE 2, only two participants in the lenacapavir group acquired HIV, representing a 96% reduction in infection risk.
Across both trials combined, 99.9% of participants who received lenacapavir remained HIV-negative.
Adherence to the injection was high, with 91.5% of all PURPOSE 1 participants receiving their on-time injection at week 26, and 92.8% receiving on-time injections at one year.
By contrast, adherence to the daily oral pills in both trials was low.
That single contrast contains the most important finding of the entire research program.
The drug was not dramatically better than oral PrEP in its biological mechanism.
It was dramatically better at actually being used.
What Lenacapavir Actually Does Inside the Body
To understand why lenacapavir works so well, it helps to understand what it targets.
HIV relies on a protein shell called a capsid to execute nearly every stage of its lifecycle inside the human body.
When the virus enters a cell, the capsid must disassemble at precisely the right moment and location to release the viral genome.
When new virus particles are being assembled, the capsid must rebuild with exact geometric precision.
Disrupt either process, and the virus cannot complete its lifecycle.
Lenacapavir binds to a highly conserved site on the capsid protein, meaning a site that stays stable across different HIV strains because mutations at that site tend to destroy the virus itself.
By targeting this site, it disrupts multiple stages of the viral lifecycle simultaneously, with no cross-resistance to existing antiretroviral drugs.
The drug is also engineered for long-acting release.
A single subcutaneous injection into the abdomen, thigh, or upper arm releases the drug steadily over the following six months, maintaining protective concentrations in the body throughout that entire window.
Because the protective level is continuous rather than peaking and dropping as a daily pill does, there is no window of reduced protection that could be exploited during HIV exposure.
The Problem This Drug Is Actually Solving
Most conversations about lenacapavir focus on its efficacy numbers.
The 99.9% figure is remarkable.
But to understand why this drug matters, you need to understand what has been failing, and why.
Daily oral PrEP has been available in the United States since 2012.
When taken consistently, it reduces the risk of sexually acquired HIV by approximately 99%.
On paper, that is nearly identical to what lenacapavir achieves.
In practice, the real-world results have been far weaker, and the reason is simple: people do not take a daily pill every day, across years, without interruption.
Around 3.5 million people were accessing oral PrEP globally in 2023, up from just 200,000 in 2017.
But that figure remains far short of the 10 million target set for 2025.
And of those accessing oral PrEP, a significant proportion are not taking it consistently enough for it to work.
The barriers are real.
Some people cannot maintain a daily medication habit over months and years.
Some carry HIV-related stigma from being seen with a pill associated with HIV prevention.
Some face gaps in healthcare access, meaning they cannot reliably get prescriptions refilled or maintain continuity of care.
Two injections a year remove almost all of those barriers at once.
There is no daily pill to remember, carry, or explain.
There is no monthly pharmacy visit.
There is no visible evidence of HIV prevention behavior that could invite unwanted questions.
The protection is simply there, continuously, for six months at a time, regardless of whether a person can maintain a daily medication routine.
What the Headlines Are Getting Wrong
Most coverage has treated this story as a scientific triumph and stopped there.
The science is genuinely extraordinary.
But the drug that could, in theory, end new HIV infections carries a US list price of $28,218 per patient per year.
Its production cost, according to researchers and generic manufacturers, is estimated at around $25 to $40 per person annually.
The gap between what the drug costs to make and what it costs to buy in high-income settings is roughly a thousand-fold markup.
That is not unusual in pharmaceutical economics.
What makes it particularly sharp here is that the populations who need lenacapavir most, specifically the communities where HIV transmission remains highest, are not the ones who can absorb a $28,000 price tag.
The world has been at this exact crossroads before.
In the early years of the AIDS crisis, effective antiretroviral treatment existed in wealthy countries while millions died in places that could not afford it.
It took a decade of activist pressure, legal battles, and generic manufacturing agreements to close that gap.
With lenacapavir, that fight started earlier, but it is far from over.
The Access Battle Happening Right Now
Gilead Sciences has signed voluntary licensing agreements with six generic drug manufacturers, including Dr. Reddy’s Laboratories and Hetero Labs of India, to produce affordable versions of the drug for 120 low- and middle-income countries.
Under agreements brokered by Unitaid, the Clinton Health Access Initiative, and the Gates Foundation, generic lenacapavir will be available at $40 per person per year in those countries starting in 2027.
That price point is a genuine achievement in global health diplomacy.
But it leaves two significant problems unresolved.
First, the 120-country coverage has significant gaps.
According to Andrew Hill at the University of Liverpool, approximately 30% of HIV transmission happens in countries excluded from Gilead’s licensing agreement, including countries in South America, the Middle East, North Africa, and Central Asia, where the HIV epidemic has been growing fastest.
Second, the generic versions will not be available until 2027 at the earliest.
In the meantime, PEPFAR and the Global Fund have made commitments to procure lenacapavir for up to 3 million people in high-incidence countries before generics fully meet demand.
That is a meaningful bridge, but coverage remains incomplete.
Every month of delay between what science can do and what the global health system can actually deliver is measured in preventable infections.
HIV is not a disease of the past.
It infected 1.3 million people in 2024, almost unchanged from the year before.
For a young woman living in sub-Saharan Africa, where the epidemic is most concentrated, the risk of HIV infection is a daily reality, not a distant statistical threat.
For a gay man in any country, oral PrEP requires not just access to healthcare but the willingness to carry and take a daily pill that marks you, visibly, as someone navigating HIV risk.
Lenacapavir removes those equations.
Two clinic visits a year, two injections, and protection is continuous, regardless of whether a person remembers a daily pill, fills a monthly prescription, or feels safe explaining their prevention choices to anyone.
For healthcare systems in low-income countries, the simplicity also matters enormously.
A twice-yearly injection requires fewer clinic touchpoints than a daily pill regimen, and it eliminates the adherence monitoring, refill reminders, and pharmacy supply chains that make oral PrEP so difficult to sustain at scale.
The WHO recommended lenacapavir as a PrEP option in July 2025, recognizing that its convenience and efficacy represent a meaningful advance over existing options.
As of November 2025, however, only three of the eight early-adopter countries identified for rapid introduction, specifically the United States, South Africa, and Zambia, had approved lenacapavir for HIV prevention.
The rest remain in pending or preparatory stages.
What Comes After Yeztugo
The FDA approval is not the endpoint of this innovation story.
Researchers are already investigating whether lenacapavir could eventually be administered annually rather than twice a year, with early pharmacokinetic trials underway.
Gilead is also testing lenacapavir in combination with broadly neutralizing antibodies (bnAbs), proteins that can block multiple strains of HIV simultaneously.
If those combinations perform as hoped, a single annual injection providing comprehensive protection across multiple HIV strains becomes significantly more plausible.
ViiV Healthcare, Gilead’s primary competitor in the long-acting HIV space, is developing its own next-generation injectable agents, meaning the competitive landscape will likely continue accelerating.
A monthly tablet or annual injection for HIV prevention may be a reality within a few years.
The scientific pipeline is more active than at any point since the early days of antiretroviral therapy.
A Solved Scientific Problem Inside an Unsolved Political One
For most of the past four decades, conversations about HIV prevention have been structured by two linked failures: adherence and access.
Getting protection to the people who needed it, in a form they could consistently use, was the problem that went unsolved.
Lenacapavir resolves the adherence half of that equation more completely than anything before it.
Two injections a year cannot be forgotten, stigmatized, or interrupted by pharmacy closures or prescription lapses.
The protection either happened at the last appointment or it did not, and six months later there is another appointment.
What remains unresolved is the access half, and the stakes attached to it are not academic.
A drug that could end the HIV epidemic, sold at $28,000 per year in wealthy countries while reaching only 120 lower-income countries for $40 starting in 2027, while a third of transmission hotspots remain outside the licensing agreement entirely, is not a solved problem.
It is a solved scientific problem sitting inside an unsolved political and economic one.
Science has delivered what it was asked to deliver.
Whether this moment in the HIV story will be defined by its discovery or by what was done to put it in the hands of everyone who needed it is still being written.
That question is worth paying attention to.
Sources and Further Reading
PURPOSE 2 Trial: Twice-Yearly Lenacapavir for HIV Prevention. New England Journal of Medicine, 2025
FDA approves Yeztugo (lenacapavir) for twice-yearly HIV prevention. Gilead Sciences, June 2025
UNAIDS welcomes new deals to make HIV prevention medicines affordable. UNAIDS, September 2025
