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Scientists had no antiretroviral drugs when the AIDS crisis began in 1981. Nearly 20,000 people died from AIDS during that first year, and the annual death toll rose to 1.6 million by 2004. After decades of research into therapies and preventive measures, though, global AIDS deaths have now fallen to about 600,000 annually.

For more than two decades, the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) has invested more than $100 billion to slow HIV’s spread worldwide. This initiative has prevented 26 million AIDS-related deaths and reduced the number of children born with HIV by about 7.8 million. Countries supported by PEPFAR saw HIV cases drop by 52 percent in 2023 compared to 2010, outpacing the 39 percent global decline.

Because of PEPFAR’s effectiveness, the United Nations (UN) set an ambitious goal in 2022 to end HIV transmission and eliminate AIDS-related deaths by 2030. However, PEPFAR’s future is now uncertain — and the UN’s plans are in jeopardy. In January 2025, the incoming Trump administration issued a 90-day freeze on PEPFAR while it conducts a “programmatic efficiencies” review. By February, the U.S. government issued a limited waiver that let PEPFAR resume HIV treatments abroad, pending further guidance.

If a permanent freeze goes into effect, researchers estimate there could be 8.7 million new HIV infections by 2029, undermining progress toward the UN’s goal. Despite these governmental setbacks, a recent breakthrough with an HIV preventative called lenacapavir offers hope.

In 2024, the pharmaceutical company Gilead announced that a single injection of lenacapavir protected 96 to 100 percent of recipients from HIV for up to six months. This success rate is better than any other prophylactic, including daily pre-exposure prophylaxis (PrEP) regimens such as Truvada, Descovy, or Apretude.¹ Lenacapavir is so effective, in fact, that the executive director of the United Nations Programme on HIV/AIDS called it a “miracle.”

Gilead is already offering the drug at reduced prices in 120 low-income countries with high HIV burdens, including South Africa. At a time when government HIV initiatives look uncertain, lenacapavir could prove a much-needed failsafe.

Turning Points

The first HIV medicine, zidovudine, originated in 1964, long before the AIDS crisis. Researcher Jerome Horwitz at the Michigan Cancer Foundation developed it as a potential cancer treatment by chemically-modifying thymine, a DNA building block. He hoped cancer cells would incorporate this “knockoff” nucleotide into their genomes and thus disrupt their replication. When tests showed that zidovudine did not work against cancer, though, Horwitz set it aside — but told his peers that this molecule, as well as similar DNA base mimics, were “a very interesting set of compounds that were waiting for the right disease.”

In 1974, Wolfram Ostertag, a German geneticist at the Max Planck Institute, explored whether zidovudine could block retroviruses, which carry RNA, and use a reverse transcriptase enzyme to convert it into DNA before integrating into the host genome. Since zidovudine failed to interfere with DNA-to-DNA replication, Ostertag wondered if it could block RNA-to-DNA replication instead. Experimenting with a retrovirus called murine leukemia virus, he found that zidovudine did, in fact, obstruct retrovirus replication by inhibiting reverse transcriptase.

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At that time, human retrovirus infections were rare, so researchers did not pursue zidovudine further until HIV/AIDS emerged in the 1980s. As cases mounted, however, researchers screened existing drugs against HIV in the hopes that some could treat infections. Zidovudine showed promise against multiple HIV strains in cultured cells, and the Food and Drug Administration (FDA) approved it for human studies within five months. By 1987, the FDA licensed zidovudine after trials showed it increased survival rates.

On its own, zidovudine extended patients’ lives by only one or two years because HIV mutated and evolved resistance over time. However, during the 1990s and early 2000s, researchers developed other antiretrovirals targeting various stages of HIV’s life cycle. Doctors began prescribing combinations of three or more antiretrovirals in 1995, making it unlikely that a mutant HIV strain resistant to one drug could evade the others.² Today, AIDS deaths are preventable where these medications are accessible, but people must take them daily. Pill fatigue and forgetfulness, coupled with costs, unfortunately, mean that many people, especially in low-income countries, often go un- or under-treated.

For that reason, long-term preventatives are probably a better strategy for controlling the disease.

A lifelong HIV vaccine would be ideal, but developing one has proved difficult. For instance, a Johnson & Johnson vaccine failed in late-stage trials in 2023, and Merck ended its Ad5 HIV vaccine trial after data suggested an increased risk of HIV infection among recipients.³ Scientists believe that, because HIV infects the same T helper cells that vaccines normally activate, these T cells become “targets” and inadvertently help spread the virus.

Researchers have instead focused on using antiretrovirals as preventives. Healthcare workers who became exposed to the virus while treating patients in the 1980s took zidovudine as a prophylactic. Once scientists developed additional antiretrovirals, Walid Heneine’s team at the Centers for Disease Control & Prevention (CDC) tested them in macaques. They found that combining tenofovir (also developed by Gilead) and emtricitabine blocked HIV’s reverse transcriptase and thus lowered infection rates if taken daily.

Starting in 2007, a human trial in Ecuador and Peru found that this drug duo reduced HIV incidence by 44 percent among men who have sex with men; adherence issues likely prevented full protection.

Later studies showed a 99 percent reduction in HIV infection when participants followed the daily regimen carefully. Health providers soon began prescribing this pill combination as a PrEP, which people in at-risk groups take daily,⁴ as well as a post-exposure prophylactic (PEP), which people take daily for 28 days after exposure to the virus.

Many patients avoid taking these medications, however, because of HIV-related stigma. In South Africa, 12.6 percent of adults said in a questionnaire that they would not buy groceries from a vendor known to have HIV. The same questionnaire revealed that 7.5 percent of adults believe children with HIV shouldn’t attend the same schools as HIV-negative children.

Additionally, about 40 percent of patients report unpleasant side effects from PrEP, such as diarrhea, dizziness, insomnia, or nausea.

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These challenges spurred researchers like Raphael Landovitz at UCLA to test a different drug, cabotegravir, as an intramuscular injection that could prevent HIV infections for long time periods. Cabotegravir inhibits HIV’s integrase enzyme, preventing the virus from embedding its DNA into human cells. ViiV Healthcare initially designed the drug, in 2013, by modifying the chemical structure of known integrase inhibitors to increase their potency. Human trials have shown that cabotegravir prevents HIV more reliably than daily PrEP pills and the FDA approved an injectable version in 2021; the only side effect is minor injection-site discomfort.

But cabotegravir has a weakness: the drug needs to be injected every other month; far more often than the appointments required to replenish PrEP pills, which only happen every six months. This greater frequency strains healthcare services in areas with limited resources, such as Sub-Saharan Africa.

This gap led researchers to explore drugs that could block HIV infections for even longer. A lenacapavir injection, given just twice a year, could offer a much-needed solution.

Multi-pronged Defense

Scientists at Gilead took an unconventional approach when they designed lenacapavir. Whereas early antiretrovirals targeted HIV’s reverse transcriptase or protease enzymes, Gilead went after a structural protein: the viral capsid.

The capsid carries the virus’ genome and enzymes into a host cell’s nucleus. Many developers erroneously assumed that the viral capsid couldn’t be targeted with drugs, because it interacts with numerous host proteins and so multiple drugs might be needed to block each interaction.

As researchers learned more about the capsid’s structure, though, Gilead’s team saw an opportunity. The capsid consists of repeating units of five and six copies of the p24 protein which, together, look a bit like a flower. Gilead chemists designed lenacapavir to wedge between these p24 units, forming seven hydrogen bonds that “lock” the capsid in place. This action blocks HIV from assembling new capsids and disassembling old ones.

The drug also, importantly, prevents HIV from squeezing through tiny pores in the nucleus. Specifically, it does so by binding to two host proteins, called CPSF6 and Nup153, which normally guide the virus into the nucleus. These proteins attach to the capsid via a phenylalanine amino acid, whose hexagonal carbon ring resembles lenacapavir’s difluorobenzyl ring. By occupying this same binding site, lenacapavir outcompetes CPSF6 and Nup153 and keeps the virus out of the nucleus.

Because lenacapavir disrupts so many capsid-related processes, the virus would need to acquire many simultaneous mutations to gain resistance. Even strains resistant to other antiretrovirals remain vulnerable to lenacapavir, simply because the drug targets such an unconventional part of HIV. This makes lenacapavir a good, stand-alone preventive option.

While Gilead has not revealed specifics about the development of lenacapavir, the compound stands out structurally from other drugs because it contains ten fluorine atoms. Pharmaceutical developers often avoid fluorine because the element can alter pharmacokinetics, making it hard to predict how a drug will be absorbed, metabolized, and excreted. However, the element also improves lenacapavir’s stability and slows down enzymatic oxidation, allowing the molecules to survive longer in the body.⁵

Lenacapavir also dissolves easily in fat and can be injected under the skin, where it slowly releases into the bloodstream from a “fat depot.” While most drugs enter the bloodstream faster than they are removed from the body, lenacapavir exhibits "flip flop kinetics" instead. By slowly entering the blood from fat depots, the drug does not build up to dangerous levels before it is cleared.

Lenacapavir is also extremely potent. Its half-life in the body is several weeks, and a concentration of just 105 picomoles per liter proves enough for the drug to work effectively in half of patients. This means that the initial lenacapavir injection doesn't have to be huge for the drug to retain efficacy for several months.

A related drug, cabotegravir, offers similar benefits but is slightly less potent. One would need twice as much of that drug to match lenacapavir’s effects. By contrast, the drugs used in oral PrEP are much less potent. Between 30 and 130 times as much tenofovir, or up to 6,000 times as much emtricitabine, would be required to achieve the same effect as lenacapavir, rendering those drugs unsuitable as long-acting injectables.

Near-Perfect Scores

Lenacapavir’s excellent features encouraged Gilead to run clinical trials in humans. The company has already completed a phase 3 trial, called PURPOSE 1, to study how well lenacapavir works at preventing HIV in cisgender women in South Africa and Uganda — a group that accounts for half of the 1.3 million new infections that occur globally each year.

Half of the participants received lenacapavir, and the other half an injectable placebo. All the participants in the study received PrEP because it would have been unethical to deprive them of an existing, licensed preventative.⁶ Most of the participants failed to take their PrEP during the trial, though; only 22 percent of women took more than four doses per week after two months, and PrEP adherence declined to just seven percent by the one-year mark.

Study results showed that 16 out of 1,068 participants in the placebo group contracted HIV, an infection rate similar to the background rate of 2.4 percent. By contrast, none of the 2,134 women who received lenacapavir twice a year caught the virus, suggesting near-complete protection in this study.⁷

In October 2024, an interim analysis from the phase 3 PURPOSE 2 trial showed similarly encouraging results in cisgender men and gender-diverse individuals who have condomless, receptive anal sex with multiple male partners. In that trial — which was conducted across 88 sites in Argentina, Brazil, Mexico, Peru, South Africa, Thailand, and the United States — only two people out of 2,179 who received lenacapavir caught HIV, translating to about 99.9 percent efficacy.

It’s not clear why the drug failed for these two participants. Perhaps they already had HIV at undetectable levels at the start of the study, or they metabolized the drug in atypical ways, or — less likely — the virus somehow evolved resistance. Regardless, the PURPOSE 2 trial results were so convincing that the Data Safety and Monitoring Board (an independent advisory group overseeing trials) recommended that Gilead provide lenacapavir to all participants. The company agreed.

Both trials suggest that the drug is safe. The main symptom reported by participants is minor injection-site pain. PrEP, by contrast, causes more serious side effects in up to two-fifths of recipients. But still, the PURPOSE 1 and 2 trials lasted only one year, so it’s possible that safety issues could manifest with more prolonged exposure. (This has happened before with other drugs. The painkiller rofecoxib, for example, was licensed before doctors discovered it increased the risk of cardiovascular disease.)

Lenacapavir could become the gold standard prophylactic against HIV, but only if it’s given to all vulnerable individuals. Scientists still don’t know if lenacapavir is safe for everyone, though, and none of the five PURPOSE trials are evaluating how safe the drug is in pregnant women — even though in 2022, 27.5 percent of pregnant women in South Africa had HIV.

A New Defense

Despite lenacapavir’s promise, there’s no guarantee it will reach everyone who needs it. One major barrier is cost: In the United States, the list price for the first year of lenacapavir treatment is $42,250, with subsequent years costing $39,000. By comparison, PrEP costs about $24,000 and cabotegravir costs $25,900 per year without insurance (though generic versions are available for about $60 per month.)

Pharmaceutical companies generally charge high rates for patented drugs to recoup their huge investments into research, development, trials, and marketing. For example, Gilead spends about $6 billion yearly on R&D for new drugs, several millions on clinical trials (with phase 3 clinical trials costing the most at roughly $20 million each), and around $985 million to cover marketing costs. As 90 percent of drugs that enter clinical trials don’t progress beyond them, pharmaceutical companies capitalize on their wins to continue funding research into new drugs.

Once companies recover their initial costs, they typically search for better ways to produce the drug cheaply, such as by adjusting their chemical synthesis steps, and at larger scales. By focusing on unit costs for ingredients, synthesis, syringes, packaging, shipping, and taxes, a group of independent researchers estimated that 10 million yearly doses could be sold for as little as $41 per person per year.⁸ This would be 1,000 times cheaper than the current price and still give Gilead a 30 percent profit margin.

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Gilead has already begun taking steps to lower the drug’s price, too. They’ve created voluntary licensing agreements with six other pharmaceutical manufacturers (Dr. Reddy’s Laboratories, Emcure, Eva Pharma, Ferozsons Laboratories, Hetero, and Mylan), permitting each of them to make and sell generic, cheap versions in 120 low-income countries.⁹

While these companies ramp up production, Gilead has also vowed to prioritize supplying affordable lenacapavir to the 18 countries that represent 70 percent of HIV burden, including South Africa and the Philippines. However, some nations outside this voluntary license agreement will still face high costs. Several middle- and high-income countries are excluded from these deals, even though they account for 20 percent of new HIV infections each year; that includes China, Colombia, and Russia. Countries such as Argentina, Brazil, Mexico, and Peru (all of which had test sites for the PURPOSE trials) are also excluded from the trade deal.¹⁰

Many Latin American countries would particularly benefit from lenacapavir because they lack access to cheap PrEP. Peru, for instance, does not provide the pill-form preventatives to citizens as a public health service, so only the wealthy can afford it through private means. (Out-of-pocket medical spending also tends to be higher in poorer countries.) While HIV rates in Peru have jumped by 52 percent in the past decade, only 0.9 percent of the 90,000 Peruvians who could benefit from PrEP are on the medication.¹¹

A Gilead spokesperson told The New York Times that the company will make efforts to lower lenacapavir’s price for excluded Latin American countries, but how far that price will drop — and whether public healthcare systems will be able to afford it — are unclear.

What explains Gilead’s decision to offer the drug cheaply to some countries while excluding others? The answer probably lies, as usual, in economies of scale.

In South Africa, there are about 150,000 new HIV infections each year. In Peru, that number is 6,300. If a market is too small to spread out costs, Gilead has less incentive to lower lenacapavir’s price enough that individuals or public health systems in that country can pay for them. In cases like this, a market-shaping tool called an advanced market commitment, or AMC, could help subsidize costs.

AMCs are agreements made by governments or charities to pay for a product at a future date, as Nan Ransohoff has explained in Works in Progress, and thus incentivize its manufacture. In 2009, a public-private partnership called the Gavi Alliance used an AMC to spur the development of pneumonia vaccines. They promised any company developing such an immunization that they would purchase $1.5 billion worth of doses — equivalent to 200,000 vaccines. The alliance was funded by the Bill and Melinda Gates Foundation as well as the governments of Canada, Italy, Norway, Russia, and the United Kingdom. Thanks to Gavi’s AMC, GlaxoSmithKline has provided over 1.2 billion doses of their vaccine since 2010, and last October Pfizer agreed to provide one billion units of their own injection.

A similar agreement could encourage Gilead to offer lenacapavir more widely to countries with fewer HIV cases, such as Peru, where the demand alone might not justify large-scale production. Just like with Gavi’s AMC for pneumococcal vaccines, the guarantee would specify a per-unit grant for a certain number of doses over a period of time until Gilead finds a way to produce and sell the drug cheaply enough in Peru and other excluded nations without subsidies.

Many experts have rightly hailed lenacapavir as an unprecedented achievement, and the journal Science featured the drug as its Breakthrough of the Year in 2024. While the U.S. government reviews PEPFAR and global HIV efforts remain in flux, lenacapavir may offer our best hope yet of slowing the virus’ spread. If Gilead and governments find ways to make it accessible to everyone at risk, the UN’s goal of ending HIV transmission by 2030 could actually come within reach.

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Thanks to Saloni Dattani and Ben Gordon for reading drafts of this.

Kamal Nahas is a researcher-turned-journalist based in Oxford, UK, who covers stories in biology, health, and technology.

Cite: Nahas, Kamal. “Making a ‘Miracle’ HIV Medicine.” Asimov Press (2025). DOI: https://doi.org/10.62211/84re-78gh

Lead image by Ella Watkins-Dulaney.

Ths article was published on February 23, 2025.

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Footnotes

1. Technically, “PrEP” can refer to any HIV preventative, including daily pills or injectable drugs like cabotegravir or lenacapavir. For the sake of this article, though, I use “PrEP” to refer only to the pills.
2. For example, HIV proteins are synthesized together as a polyprotein that the viral protease must split into individual proteins. Protease inhibitors obstruct that process. Other antiretrovirals prevent the virus from entering cells altogether by blocking fusion of the viral envelope with the cell membrane.
3. Importantly, this was a vaccine candidate that failed safety tests in clinical trials, which stopped it from ever being approved and rolled out to the public. This story demonstrates how clinical trials allow doctors to ensure vaccines are safe to take.
4. People can also take PrEP in an event-based fashion rather than daily, taking a double dose two to 24 hours before sex followed by a daily dose for two more days.
5. Flourine is the most electronegative element, meaning that when bonded with another atom, it exerts a stronger pull on their shared electrons. This increases the polarity of the two atoms, altering how easily they dissolve in water and how easily that bond breaks during metabolism.
6. Not all clinical trials conform to this ethical standard. A phase 3 clinical trial for a new tuberculosis vaccine is also taking place in South Africa, but they are comparing how well the vaccine candidate works against a placebo rather than an existing, licensed vaccine. Covered in-depth in another Asimov Press essay, this experimental design makes it difficult to tell how well the new vaccine stacks up against the existing one.
7. The clinical trial reports 2,134 cisgender women as the sample size, but only 1907 received the second injection. Some women didn’t receive the second injection for multiple reasons, such as becoming pregnant or withdrawing from the trial.
8. Note that this only considers marginal costs today; it excludes prior R&D and trial costs.
9. Gilead has launched other voluntary licenses in the past. In 2006, they issued one to Indian manufacturing companies, allowing them to make cheap versions of tenofovir, another HIV drug and one of the components of PrEP and PEP. This reduced the price of the drug by 89%, costing patients $1.80 per month.
10. Gilead has committed to providing lenacapavir to the study participants themselves.
11. Peru is not the only Latin American nation struggling to control HIV. While infections have plummeted by 39 percent globally, Latin America has experienced a nine percent increase between 2010 and 2023, making this a key region for curbing cases. Eight other countries have yet to introduce PrEP into their public health system. Only 204,000 people in the region take PrEP right now, falling well short of the UN’s target of 2.3 million people.