Long-acting HIV medicine comes from decades of research and advocacy

Long-acting HIV medicine comes from decades of research and advocacy

In the hunt for a cure, the results for society can be particularly powerful when the baton is passed from dedicated academic scientists to an innovative company via trusted community advocates.

Thanks to this series of contributions, what we now claim is the first HIV drug to provide long-lasting protection against infection - eliminating people's need for the daily pill. For her role in ensuring the drug, lenacapavir, came to life and to market, the AAAS Mani L. Bhaumikik Breakthrough of the Year is awarded to Wesley Sundquist, chair of biochemistry at the University of Utah. Moupali DAS, vice president, clinical development, HIV prevention and pediatrics at Gilead Sciences; and Yvette Raphael, co-founder and executive director of HIV Prevention Advocacy in Africa.

“These individuals represent the three arms of what it takes to create new science and then translate it for the world in a way that is truly capable of making a difference.”ScienceThe magazine's editor-in-chief Holden Thorp - who selected the winners.

“I was excited about how these three tell the story of the journey required to bring a drug to life,” said committee author William Powderly, co-director of the Division of Infectious Diseases at Washington University School of Medicine. “It requires multiple people, skills and partners.”

As of 2023, 39.9 million people were living with HIV worldwide, infecting more than 1 million people per year.

Even after decades of research, there is no cure for the disease caused by HIV, AIDS. But lenacapavir, which emerged from research on HIV's cone-shaped capsid protein, comes close and almost completely prevents new HIV infections from occurring. The drug protects people for six months with each shot.

“This drug is extraordinary – the closest thing to a vaccine we have,” Ranney said. She explained that she and many of her colleagues entered the public health community at the height of the AIDS pandemic in the 1980s and 1990s. “This drug is beyond the wildest dreams of what many of us could have imagined.”

Recognizing the people behind such significant scientific developments is a core philosophy for Spender Mani L. Bhaumik, Ph.D. – A physicist with countless contributions to the development of high-level lasers as well as AAAs and theScienceFamily of magazines.

“Probing intractable parts of the physical world, like a viral capsid, is critical to scientific innovation,” Bhaumik said. "And to ensure that insights from basic research can be applied and trusted by those they serve - now more than ever. I am delighted that this year's recognition goes to people in sectors whose rigorous approach makes such a valuable contribution."

The Mani L. Bhaumik Breakthrough of the Year Award was established in 2022 with a pledge of $11.4 million from Bhaumik: the largest in the organization's history. The award supports a cash prize of $250,000 annually for up to three scientists or researchers whose work best supports the awardScienceBreakthrough of the Year, the journal's choice for the top research advance of the year. In 2024,ScienceLenacapavir named the latest breakthrough.

Mapping HIV's capsid

Sundquist, who moved to the University of Utah as an assistant professor in 1992, played a key role in the drug's development, although his work was not immediately recognized. “Sundquist spent countless hours in the lab, made a critical discovery, and then watched it sit on the shelf for a while, which is what can happen in basic science,” Ranney said.

His contribution, which he began with his Utah-based laboratory, demonstrated the structure and functions of the capsid protein of the HIV virus. Sundquist focused on the capsid because he was aware that HIV deaths were increasing worldwide and that most scientists studying HIV treatments were looking at the virus's enzymes. “We wanted to work on one aspect of the unique problem,” he said, “and we were drawn to the unusual cone shape of the capsid.”

Until Sundquist's work, scientists believed that the capsid, which encloses the virus's genetic material, was largely a structural element. They did not see it as a particularly “drugable” target, particularly compared to enzymes, in part because it was considered very stable.

Working with a team, Sundquist published a newspaper in 1996ScienceThis defined the architecture of the capsid. This laid the foundation for a study in 2003 in theJournal of Virologyin which he and colleagues showed that when the HIV capsid was disrupted, even in subtle ways, viral replication was also disrupted.

“That was unexpected,” Sundquist said.

Clinical trials intentionally designed

However, even if these critical discoveries were made, it was not obvious that the capsid would be easily turned into a drug target. For his part, however, Sundquist didn't feel that it took very long after he and his colleagues published their 2003 results that Gilead Sciences contacted them.

Tomas Cihlář, a virologist at the company, visited Sundquist’s Labs. Cihlář, impressed by his discoveries, brought them back to his colleagues. The Gilead team wanted to see if they could use Sundquist's insights into how to hinder viral replication to design longer-acting HIV drugs for people living with HIV. While the standard of care – combination antiretroviral therapy – worked well, it required daily medication.

A dedicated group of scientists at Gilead Sciences showed perseverance as it took more than a decade (starting in 2006) to develop a drug based on Sundquist's findings. At that point, John Link, then VICE president of medicinal chemistry at Gilead, and his colleagues screened thousands of molecules to identify a potent capsid inhibitor.

“We sometimes think of the industry as having no power,” Ranney said. “But it was here for about 15 years – fits and starts – and Gilead as an institution kept supporting capsid inhibitors.”

The molecule's properties meant its effects could be extended beyond six months, a promising option for patients struggling with daily medications.

Gilead conducted the first trial of an injectable version of lenacapavir for people with HIV in 2018. “I was a medical monitor for the first Phase 1 trial,” said DAS, a winner of this year's Bhaumikik Breakthrough of the Year award on behalf of the many Gilead Sciences teams working on lenacapavir. This meant that DAS, a trained doctor, provided expert guidance to confirm the safety of trial participants.

At the time, Gilead was focused on evaluating lenacapavir for the treatment of HIV. However, the reality was that effective treatments such as antiretrovirals already existed. Meanwhile, many people around the world were still at high risk of acquiring HIV.

“I remember seeing results from the first study of lenacapavir treatment and thinking that this drug – because of its molecular properties – could also be very good for prevention.” Das said, “I immediately thought, How could we use this for prevention?”

The next step forward was to figure out how best to evaluate this drug to prevent HIV.

"Gilead had already established the company as leaders in the use of oral antiretroviral agents as prerequisite prophylaxis," said Myron Cohen, director of the Institute for Global Health and Infectious Diseases at the University of North Carolina at Chapel Hill and was also on the committee that selected the winners. "But many people found it difficult to maintain the use of daily oral pills. The development of long-acting agents, particularly injectable agents, became an important goal."

DAS played a critical role when Gilead Sciences made this decision. “She was the central person who created studies to get the evidence that it also worked for prevention,” Powderly said.

Her leadership was important in shaping the clinical trials known as Purpor 1 and Purpose 2, which began in 2021 and are among the most comprehensive HIV prevention programs ever conducted. The trials were carefully shaped to include people most in need of preventive care — and the people most underserved by previous trials. This included setting up testing sites in places where infections were occurring most.

“There were many times when we had to change hearts and minds in designing this testing program because we did a lot of things differently,” she said. Much of this had to do with the novel design and lenacapavir itself, but also who was included. DAS recalled a story of a young African teenage woman who was pregnant and came to a stakeholder meeting in Kigali, Rwanda. This meeting, organized by Gilead, included community representatives, government officials, regulators, ethicists, representatives and prerequisites of prophylactic investigators who Gilead brought together to discuss how best to design and implement the Prep trials in cisgender women. “‘Make sure people like me have a chance in the exams,” this woman had told us. I'll never forget her. “

Das firmly believes that better science happens when everyone is included. “It’s not charity,” she said. “It’s good science.”

The Purpose 1 trial evaluated lenacapavir in cisgender women and in adolescent girls in sub-Saharan Africa and Uganda, where some women plan to use daily oral preparation products. Some of the women in the study became pregnant. Purpose 1 results published in July 2024 showed that lenacapavir twice a year resulted in 100% effectiveness in preventing infections, a huge result. “It was so exciting to see the first results for lenacapavir for HIV prevention in women,” said Das.

For Purpose 2, DAS and her team recruited participants from locations disproportionately affected and underrepresented by HIV in previous HIV clinical trials, including parts of the United States, Brazil, Thailand, South Africa, Peru, Argentina, and Mexico. The study evaluated lenacapavir for preventing HIV in a variety of cisgender men and gender diverse populations. Results published in November 2024 showed that the drug reduced new infections by 96%.

Powderly said years of work by researchers at Gilead Sciences leading to DAS' effort were critical.

“The human voice is important”

Most people need HIV drugs at the center of purposeful trials, as it did, made possible because of an important partner - another winner of this year's Bhaumik Breakthrough of the Year: Yvette Raphael.

Das and Raphael met in Kigali, Rwanda in 2019, two years before the purpose trials began, at the same stakeholder meeting where DAS and the group convened by Gilead heard from the young pregnant African woman about including people like her in the legal proceedings. “Yvette really wanted to know what we would do differently,” Das said.

Raphael, an HIV prevention advocate and community leader living with HIV, had previously been involved in HIV drug trials. “We knew that past audits had made mistakes,” she said.

“Raphael was recognized as a tireless and thoughtful advocate for developing HIV prevention strategies for women,” Cohen said. “Your involvement in the development of lenacapavir – in trusted communications with Gilead and trial participants and their communities – was critical to the success of these studies.”

Raphael fought to ensure that people affected by HIV had access to information about new treatment options, including long-acting treatments that could improve quality of life. In Africa, particularly among African women, problems with HIV prevention strategies – largely in the form of daily pills – have persisted. Drugs that worked for men didn't work for women in part because social reasons made it harder for women to take a pill every day.

“An injection would have been better for women,” Powderly said. “But community trust and engagement were critical.”

Raphael, who served as Chair of the Purpose 1 Advisory Board from 2019 to 2024, told Gilead about the biggest challenges facing the African community.

“For lenacapavir trials, we wanted young people to be part of it so that the drug could be approved for them from the start,” said Raphael. Because young people need parental consent, she helped advise parents whether their teenage children could participate.

“It was also very important that pregnant women were included,” said Raphael. “We wanted to be sure that once this drug was approved, pregnant women could get it.”

Their efforts paid off, and the procedures that 1 trial, including women, pregnant women and adolescents, came together.

“The clinical trials would never have been as successful as they were if it weren't for Raphael,” Thorp said.

“The human voice is just as important as science to translate in the real world,” Ranney said. “Yvette’s leadership is a beautiful example of great science being done.”

For her part, Raphael said her collaboration with Das, where they both learned and pushed each other, was critical.

“I want to recognize Moupali’s fearlessness in creating greater community participation,” Raphael said. "We called her 'The-Rupter'... I've been involved in HIV prevention trials for 25 years and every time, we would do better. I think with Moupali this is the best thing we've done."

Ensuring that the people most affected by a drug are part of trials offers another benefit that comes later. "We can discover drugs and see them succeed in trials," Raphael said, "but the next results won't be as good if there's no one who owns these innovations and works to make them affordable and accessible. We didn't want this drug sitting on a shelf."

For Raphael, the outcome of the trials was nothing short of a miracle. “It’s amazing that you only need injections twice a year.” She said the biggest surprise for her was the 100% effectiveness in Purpose 1. "It was also surprising that it was such a short trial." In 2024, the trial was stopped early because of the success it had already shown, meaning the drug could be available sooner. “When that news broke,” she said, “Africa stood still.”

“The Purpose 1 and 2 trials are examples of how to do a better job ensuring that people who want to one day use the drugs have a voice,” Ranney said. “This speeds up the implementation of the drug on the other side.”

Raphael knows the research into this life-changing drug began decades ago in Sundquist's lab with studies of a viral capsid.

“This work has changed how people think about viral capsids,” Sundquist said. “It meant other people could think about capsids as drug targets.”

The future of life-changing basic research

However, today, with funding cuts to basic research taking place in the United States, there is increasing concern. "If there's a weakness in the pipeline and people don't know what they're targeting," Sundquist said, "then drugs won't get developed."

“My concern as we see funding for science cut,” Ranney said, “is that we may not fully feel the ripple effects for 10 or 20 years because it can take that long for discoveries to be incorporated into the lives of families and individuals.”

Raphael is concerned that cuts will “put life-saving drugs out the window”. While lenacapavir is being compared to a vaccine against HIV, it is not one. "This is not the final breakthrough for HIV prevention. Without continued funding for prevention and advocacy, we will not have the breakthroughs of tomorrow," she said.

Programs like the President's Emergency Plan for AIDS Relief, or PEPFAR – which has been an essential part of global health since it was created by President George W. Bush in 2003, are critical to supporting HIV prevention. A study published inAnnals of Internal MedicineIn February this year, it reported that eliminating PEPFAR would lead to 601,000 HIV-related deaths and 565,000 new HIV infections in South Africa over 10 years.

As of April 30, 2025, PEPFAR's current short-term authorization expired. “The logical funding for distributing lenacapavir in the developing world would come from Pepfar, a program that has been very successful and saved so many lives, but is basically on life support,” Sundquist said. “This means that lenacapavir is really at risk of not being widely distributed in the places where it is most needed.”

Ranney said her hope is that the selection of winners for this year's prize will serve to remind scientists of the importance of all phases of scientific innovation and the freedom of science to pursue big ideas. “It is important to fund basic research because we never know what the next world-changing discovery will be.”

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