This drug could help end the HIV epidemic. Its rollout has hit speed bumps

South Africa and Zambia—Crime runs so high in Cape Town, South Africa’s Philippi township that drivers often keep their windows rolled up and run stop signs to prevent “smash and grab” of their cellphones. But amid the township’s sprawl of scrap lumber-and-tin shacks sits an oasis: a defunct cement factory converted into a community center that features a library, workspaces for artists and musicians, a soccer field, and an amphitheater. There, the Desmond Tutu Health Foundation (DTHF) is studying how best to fight high rates of HIV infection—another bane of Philippi. The study, run out of two mobile clinics, provides HIV and pregnancy testing, counseling, contraception, and a whole menu of HIV prevention options. Axtole Mamtolo came to the trucks on a brisk June morning because she was interested in a new type of pre-exposure prophylaxis (PrEP), the strategy of preventing infection by taking drugs. Mamtolo, 28, had reason to worry about HIV. Her father passed away the year she was born, and she suspects he had AIDS because the disease took her mother’s life 6 years later. She has an aunt and a nephew living with HIV. “It’s not something easy for them, so I didn’t want that for myself,” Mamtolo says. In 2019, she decided to try PrEP pills, a highly effective way to keep HIV at bay if you take them every day. She used them for several years. “I was staying with my baby daddy at that time, and I didn’t know what he was doing outside,” Mamtolo says. But the pills made her nauseous and dizzy, and she wasn’t great at sticking to the daily regimen. “Especially for us youngsters, we forget,” Mamtolo says. She stopped when she became pregnant in 2022. Mamtolo, who split up with her partner, has started dating again, and there’s a new form of PrEP that could make the strategy far more appealing to people like her: an injection of a drug called lenacapavir, known widely as LEN. In 2024, one dose—given as two injections—was shown to give almost complete protection against HIV for an unprecedented 6 months, leading Science to crown it the Breakthrough of the Year. “I was always praying for the injection to come, because I thought that’s something that’s going to be easier for most of us,” says Mamtolo, who received her first dose of LEN PrEP in the Philippi study. Mamtolo’s spotty and temporary use of oral PrEP is common, which explains why it has only led to a modest dip in annual new HIV infections in South Africa, home to 8 million of the estimated 41million living with HIV in the world. Adding LEN PrEP to the arsenal presents a new opportunity to slow, or even stop, the spread of HIV. The stakes are enormous. In an “optimistic” introduction scenario—in which about half of South Africa’s adolescent girls and young women, men who have sex with men (MSM), and sex workers would be on LEN PrEP by 2030—the country could effectively end its epidemic by 2039, according to a model by biostatistician Lise Jamieson and health economist Gesine Meyer-Rath of the University of the Witwatersrand. The model, posted on medXriv on 7 January, suggests the effort would increase the county’s HIV/AIDS expenditures by only 9% (see graphic, below). A similar scenario could play out in other parts of Africa, though it would require a massive rollout of the drug. A model constructed by epidemiologist Nora Rosenberg from the University of North Carolina at Chapel Hill and colleagues found that if 25 million women in 15 countries in sub-Saharan Africa received some form of PrEP and adhered to it, new infections in that population would drop by two-thirds. Hopes are running high. “Future generations will look back on this very important day and period and say that this was the moment when humanity finally gained the upper hand against HIV,” South African President Cyril Ramaphosa said on 5 June at a ceremony launching LEN PrEP in his country, held in a stadium in Mpumalanga province. By 1 July, eight other countries in sub-Saharan Africa had introduced LEN PrEP as well, and several others hope to do so soon. But as Science saw during visits in June to South Africa and Zambia, a poorer country where the rollout started on 1 December 2025, there are major obstacles. One is that far too little LEN PrEP is available—a problem sure to take center stage at the international AIDS conference taking place next week in Rio de Janeiro. “We are not receiving the commodities according to the schedule, and I think it’s the same complaint across almost every country that has started LEN,” says Lloyd Mulenga, who heads the infectious disease division of Zambia’s University Teaching Hospitals (UTH). Gilead, the company that developed the drug, has allowed the production of low-cost generic versions for developing countries, but they will only start to become available in 2027 at the earliest. Activists are angry that the company has excluded Brazil and other Latin American countries from the deal because they’re considered too wealthy. Adding to the challenge, much of the infrastructure that could have helped distribute LEN PrEP has been destroyed since U.S. President Donald Trump took office in January 2025 and began to make dramatic cuts to foreign aid. “It has blown the whole program apart, and we are picking up the pieces just at the time that we have this extraordinary new innovation,” says Linda-Gail Bekker, who runs DTHF. Major questions remain as well, which “implementation studies” are now trying to address. One is how many people will want to use the powerful new tool. Both South Africa and Zambia—where 11% of adults are living with HIV—have launched campaigns to spread the word. But the highest HIV infection rates are in teenage girls and young women, who often don’t think about the risks of the virus, says Salim Abdool Karim, who runs the Centre for the AIDS Programme of Research in South Africa (CAPRISA). “They are thinking about what’s the latest on TikTok and Facebook, who’s got what, and who’s going with which boyfriend,” Karim says. “We’ve got to get them to go for PrEP, and that is very hard to do.” And although a biannual shot may be easier than taking 365 pills, factors such as fear of needles and the pain of injections inevitably will lead some people to reject LEN PrEP. Paradoxically, HIV treatment success can also undermine PrEP. Young Africans have grown up in an era when treatment is widely available and AIDS is rare, says Patrick Mdletshe, an HIV advocate who heads community programs for CAPRISA. “They have a totally different attitude towards HIV that, for me, is quite concerning,” he says. “They have never seen the brutality of HIV.” With HIV, treatment itself is one of the most powerful prevention tools. Antiretroviral drugs can suppress the virus so effectively that infected people don’t transmit it. That finding, published in a landmark 2011 paper—which Science also deemed a Breakthrough of the Year—fueled a global effort to expand testing and treatment. The effort helped slash global incidence—the number of new infections per year—from 2.1 million in 2011 to 1.2 million last year. Some of those same drugs turned out to protect uninfected people who take them. Studies found that oral PrEP, introduced in the United States by Gilead Sciences under the brand name Truvada in 2012, reduced new infections between 45% and 75% in MSM, transgender women, uninfected partners in “discordant couples”—in which one has HIV but the other does not—and people who inject drugs. Widespread use of oral PrEP has led incidence to plummet in some urban areas of wealthy countries, particularly in MSM communities. But in South Africa and Zambia—which both introduced it in 2016—it hasn’t done much to slow new infections, especially in teenage girls and young women, says Leila Mansoor, a pharmacist who conducts prevention studies with CAPRISA. “They’re well, the world is their oyster, they don’t feel like anything can go wrong,” Mansoor says. “What motivates them to take a tablet?” Both countries approved two other forms of PrEP between 2022 and ’24: a vaginal ring containing an anti-HIV drug that lasts for 1 month, and an intramuscular injection of long-acting cabotegravir (CAB-LA), which protects for 2 months. The ring, like pills, only works if used consistently and offers about 60% protection at best. CAB-LA, produced by ViiV Healthcare, promised higher efficacy than oral PrEP, but the South African government deemed it too expensive, even at the company’s not-for-profit price. Zambia received a limited CAB-LA supply from the U.S. government, and the Trump administration nixed U.S. promises to provide an additional 360,000 doses to African countries. With the arrival of LEN, PrEP seemed poised to live up to its promise. A study called Purpose 1 compared LEN PrEP shots with PrEP pills in girls and women between ages 16 and 25 in South Africa and Uganda. The results were announced in 2024: Zero infections occurred in the LEN PrEP group—amounting to 100% efficacy. For participants on oral PrEP, the efficacy was 0%, largely because fewer than half took their pills regularly. Bekker received a standing ovation when she presented those results at a meeting in July 2024. Two months later, Gilead revealed that LEN PrEP also had near-perfect efficacy in Purpose 2, a study that enrolled gay and bisexual men and trans women and men. In October 2024, Gilead announced it would license LEN PrEP to six generic companies that could sell it at steep discounts to 120 low- and middle-income countries. Until they were ready to deliver, Gilead promised to provide the drug itself at no profit—reportedly for $60 a dose instead of the $14,000 it charges in wealthy nations. And in December 2024, the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund to Fight AIDS, Tuberculosis and Malaria announced they would provide LEN PrEP to 2 million people in 3 years. “We were incredibly optimistic in 2024,” Bekker says. “It looked like everything was falling into place.” Then Trump took office, quickly dismantling the U.S. Agency for International Development (USAID), which managed about half of PEPFAR’s funding. The administration also halted all aid to South Africa because of what it called “egregious actions” by its government, including the supposed seizures of Afrikaner-owned farms. Last month, the U.S. Department of State said it would phase South Africa out of PEPFAR altogether by 2027. The country was PEPFAR’s single largest beneficiary, receiving $435 million in 2024. South Africa buys its own HIV drugs, but the aid helped it pay health care workers and pharmacists, provide counseling, reach marginalized communities, and evaluate progress. A different dispute has disrupted aid to Zambia, which received more than $4 billion in support from PEPFAR over the past decade. In return for health aid, the U.S. now requires countries to sign a memorandum of understanding in which they commit to support health programs themselves and wean off aid by 2030. Negotiations with Zambia have stalled, reportedly because the U.S. wants access to health data, pathogen sequences and samples, and Zambia’s vast mineral deposits. The country currently receives only a dribble of U.S. aid. “Our greatest scientific opportunity in my 35 years working in the field has been met by the most outrageous political and economic decision imaginable,” says Mitchell Warren, who leads AVAC, a prominent U.S.-based advocacy group for global PrEP use. (AVAC is a plaintiff in a lawsuit that seeks to reverse the cuts.) Recently the Trump administration has appeared to switch course, saying it wants to prioritize HIV prevention, and LEN PrEP in particular. In a joint announcement with the Global Fund in April, it even upped the ante, pledging to provide LEN PrEP to 3 million people in 3 years. South Africa should get some of that supply; the Children’s Investment Fund Foundation and the Hasso Plattner Foundation will provide the country with additional doses. But so far, the drugs have been slow to arrive. By mid-June, South Africa had received 38,000 doses of LEN PrEP, which it decided to distribute to 360 sites, about 10% of its government clinics. The Vuyani Clinic in Cape Town, about 6 kilometers from Philippi, received 33 doses and had to start turning people away after 3 days. Zambia, a country of 22 million, had received a mere 13,000 doses at that point. Other countries across Africa have seen just a trickle of LEN PrEP as well (see map, below). The shortage triggered concerns at a meeting this summer at Cape Town’s Isivivana Centre, a community hub in the township of Khayelitsha. More than 65 people packed into a room to hear youth “champions” from the Advocates for the Prevention of HIV in Africa, community leaders, and representatives from the health ministry discuss ways to prevent infection. In a show of hands, participants declared LEN PrEP their favorite option. But they lamented how hard it was to find a dose. Nomfundo Eland, who heads Emthonjeni Counseling and Training and led the meeting, called the shortage “a disaster” and “a joke” and blamed South African policymakers for lacking a plan B after the collapse of U.S. funding. “Governments need to plan for their own citizens when it comes to health,” Eland said. If young people seek LEN PrEP only to be turned down, they may not come back, warned Ashia Nkotsa, a meeting participant who works in marketing and social media campaigns. “Perhaps this was rushed,” Nkotsa says. “We are dangling a carrot to these people who are so vulnerable.” Zambian health officials see that risk as well. “The danger of overmobilizing is you create doubt, mistrust in the community,” says Gladys Muyembe, a Ministry of Health administrator who oversees seven facilities in Lusaka, Zambia’s capital. “Then they go and tell others, ‘It’s never there.’” The reasons for the slow delivery remain murky, says Mulenga, who until recently headed the HIV response for Zambia’s Health Ministry. “When you speak to either Gilead or to the Global Fund, or even to the U.S. government, we get different answers,” Mulenga says. “It’s very frustrating, and the community, they blame government.” Gilead won’t reveal production figures but tells Science it has not hit its manufacturing capacity. Representatives from the Global Fund say other than a “hiccup” or two—including the Iran war, which halted flights—orders have arrived on schedule. “Yeah, there is more demand than we’re able to supply,” says Martin Auton, who heads planning and procurement for the Global Fund. “But somebody would have to pay [to meet] that additional demand, and at the moment we don’t have money for more.” The shortages could ease if the six generic companies begin to sell LEN PrEP next year. The Clinton Health Access Initiative has already helped broker a deal with Dr. Reddy’s Laboratories, an Indian manufacturer, to drop the annual price to $40 a person. Once supply is unleashed, a different question will come to the fore: how to maximize the drug’s uptake. Or, as Mulenga puts it, “How do we get the drugs into people’s bodies?” On a sunbaked morning in June, a private bus arrived in Desai, a poor community in Lusaka. A dozen people poured out and started to unload boxes with drugs, syringes, test tubes, gloves, and disinfectants. The crew—from the Ascend Futures Foundation, which was started by a former AVAC fellow—pitched a large tent that would serve as a makeshift clinic. Screens cordoned off an HIV testing station and an examination table. A team of “prevention ambassadors” walked off into the community to advertise the clinic’s free services, including family planning, condoms, HIV testing, and various PrEP options, including limited doses of LEN. By the end of the day, they had served nearly 300 people. To find out whether this kind of outreach will work for LEN PrEP, Unitaid, a global health agency funded largely through a special tax on airline tickets, is sponsoring several implementation studies. One is assessing whether new HIV infections drop if PrEP services move from a government hospital to a modest health post in Kuku compound, another poor neighborhood in Lusaka. By mid-June, Kuku’s clinic had provided LEN PrEP to 88 people. Sex workers and discordant couples were especially eager to join. “They are really excited, because they know their risk is high,” says Mirriam Mweene, a clinical officer with Unitaid. Another study, in South Africa’s KwaZulu-Natal province, is dispatching trained “peer navigators” between ages 15 and 30 into rural communities. Armed with computer tablets, they talk to youth about HIV prevention options and create a personalized action plan that they forward to a mobile clinic, drop-in center, or pharmacy. The study, which also tracks new infection rates, is led by epidemiologist Maryam Shahmanesh of the Africa Health Research Institute, whose earlier work showed peer navigators can make a major difference. If people don't know about LEN PrEP, “We’ll just have a shiny new tool that sits in a clinic,” Shahmanesh says. She also hopes to demonstrate that South African pharmacies—which are currently not permitted to test for HIV and offer PrEP—can play an important role. Although LEN PrEP is a powerful new tool, researchers stress it may not be right for everyone, and they want to better understand how demand for it compares with oral PrEP, vaginal rings, and condoms. “We need different options for different people,” says Elmari Briedenhann, who heads communications for a University of the Witwatersrand study taking place at mobile clinics in townships near Pretoria, South Africa. Karim is urging a far more radical way to deploy LEN PrEP in South Africa: Make it a routine part of health care for high school girls, unless their parents refuse. Many countries use this “opt-out” system for HIV testing among pregnant people, and it’s common for childhood vaccinations, too. He proposed a study that would compare providing LEN PrEP at mobile clinics set up at schools with simply informing girls about it and telling them they can get the drug at a local clinic. Karim acknowledges that the approach raises ethical quandaries, but says CAPRISA “had everyone’s commitment to explore this” during extensive discussions with communities and health officials in a rural area of KwaZulu-Natal where his team has worked for 2 decades. He thinks it might also work in brothels and other HIV transmission hot spots. USAID appeared interested in funding his $40 million study, he says, but the Trump administration derailed the grant proposal even before it axed the agency. Lenacapavir’s ability to relegate HIV to the history books will also depend on whether people stick with it. Those who drop out will lose protection, and those who quit and then restart will add to the strain on health budgets: Because the injected drug doesn’t work immediately, the first dose comes with LEN pills for 2 days, which costs an additional $15. If people delay their next dose, they will need another round of pills. One morning at a wing for women and newborn babies at UTH, nurse Glenda Malyangu phoned patients who had received the injection 6 months earlier but had not made appointments for a new one. Several did not answer. “I’m sure most of them know it’s me, because I give them my number,” she says. Some are mothers who took LEN PrEP when they were pregnant, and Malyangu suspects they lost interest after giving birth: “They think, ‘Ah, it’s OK, I’ve protected my baby.’” One patient had another reason to abandon LEN PrEP. “Hey, I’m waiting for you. … You are due,” Malyangu told her on the phone. Twenty minutes later, the woman, Caroline Mwale, walked into her office. She was a nurse who worked at the hospital. “I was caught,” Mwale said. She had avoided Malyangu’s calls for 2 weeks, she confessed, “but I’ve been thinking about it, because at the end of the day I have to protect myself.” At first, Mwale said she didn’t need another shot because her husband was traveling for a few months. Then she admitted the real reason she was reluctant: The first injection, back in January, had hurt. Each LEN PrEP dose consists of two shots—given under the skin, not into muscle—in the thighs, arms, belly, or rump, where the viscous fluid forms a sometimes-painful lump that slowly dissipates. Injection at fatty sites tends to cause less pain, and some clinics offer ice packs to numb the body before giving the shots. “I didn’t like that pain at all,” Mwale said. “My thighs got tight and were on fire for a week or so.” It remains unclear how many people will avoid a second dose, but follow-ups to the Purpose 1 and 2 studies, which researchers will present at the Rio conference next week, suggest more than 90% of those who started LEN PrEP return for subsequent shots for at least 1 year. Whether that holds for people not enrolled in a trial remains to be seen. Another unknown is how many gay and trans people, two populations at high risk of HIV infection, will get access to LEN PrEP in sub-Saharan Africa. Zambia, like several other countries in the region, criminalizes gay sex and is not planning to target deliveries to these groups. South Africa has far more liberal policies toward sexual and gender diversity, but many clinics for these populations closed after PEPFAR support ended. The uncertainties have made manufacturers and donors reluctant to think big, Warren says, which in part explains the limited supply today. “In every meeting we’ve had with developers and donors over the last 3 or 4 years, the question has been, ‘What’s the market for PrEP?’” Warren says. “The honest answer is, we don’t know.” New research could increase acceptance by making PrEP even less burdensome. Gilead is testing whether doubling the dose of LEN PrEP and making it an intramuscular shot could double protection to a full year. The company also has asked whether the U.S. Food and Drug Administration will allow it to market LEN pills as PrEP, contending that the Purpose trial data show they protected for 1 week. And Merck has developed a pill containing a different antiviral that might cost far less to manufacture than injectable LEN PrEP and could provide protection for 1 month. Two efficacy trials are slated to yield results next year. For now, however, the biggest hurdle to realizing PrEP’s potential is lack of money, Bekker says. She hopes the world realizes there’s a tremendous opportunity to seize. “There are unintended consequences to not controlling epidemics,” she says. “If we can finish the investment now, we save lives and dollars in the future.”