Another inflection point in the HIV/AIDS response

This part of the story may sound all too familiar.

Just before the opening of the International AIDS Society’s (IAS) 25th International AIDS Conference in Munich, Germany, the Joint United Nations Programme on HIV/AIDS (UNAIDS) released their latest global HIV/AIDS statistics. The report shows that 1.3 million people worldwide were newly infected with HIV in 2023. This represents a 39% reduction over the number of new infections in 2010, but it is the exact same number of people who acquired the virus in 2022. Slightly more people, 1.5 million, acquired HIV in 2021.

“Despite massive progress, we still have a major challenge,” said Peter Piot, a former IAS president who is now a professor of global health at the London School of Hygiene and Tropical Medicine. Access to antiretroviral therapy, HIV testing, and multiple HIV prevention options is increasing in many parts of the world, while in others, progress has stalled.

Piot is a veteran of the field — this year’s gathering marked his 22nd International AIDS Conference — and he was one of many in Munich to conclude that the global HIV/AIDS response is at a critical inflection point. UNAIDS and the O’Neill Institute’s Center for HIV Infections and Disease Policy at Georgetown Law and Emory University reached the same conclusion in their recent reports. “The global AIDS response is at a crossroads: success or failure will be determined by which path leaders take today,” reads the latest update from UNAIDS.

This isn’t the first time the global response or at least different components of it — certainly, HIV prevention research — has been at a crossroads. But today, there are multiple threats to both sustaining and accelerating efforts to end AIDS as a public health threat.

As UNAIDS Executive Director Winnie Byanyima writes: “Progress is imperiled by the fraying of solidarity between and within countries,” as well as “the recent surge in the promotion of anti-rights, anti-gender, and anti-democracy policies.” In addition: “A widening funding gap is holding back the HIV response in low- and middle-income countries.” According to UNAIDS data, HIV funding today has fallen to the same level it was in 2013.

These challenges can’t be solved by innovation alone. This doesn’t mean, however, that innovation can’t and won’t play an important role in determining the HIV pandemic’s trajectory. “Advances in technology, in particular in the development of long-acting treatment and prevention options, can protect the health of everyone living with or at risk of HIV,” writes Byanyima.

One of the most newsworthy stories to emerge from AIDS 2024 was the recent data from a large, randomized Phase 3 clinical trial establishing the efficacy of the long-acting antiretroviral lenacapavir for HIV pre-exposure prophylaxis (PrEP). The trial, PURPOSE 1, compared two daily oral antiretroviral-based PrEP regimens with the subcutaneously administered lenacapavir among more than 5,300 cisgendered women in South Africa and Uganda. Results presented in Munich and published online in the New England Journal of Medicine (NEJM) show that over the course of the trial, 55 women acquired HIV, all of them in the two daily PrEP groups. None of the women receiving twice-yearly injections of lenacapavir acquired HIV during the study period, translating to 100% efficacy.

This trial “exemplifies not only that women can dependably adhere to this administration schedule but also that levels of an HIV-1 capsid inhibitor can remain high enough over a period of 6 months to reliably prevent infection,” write Rochelle Walensky and Lindsey Baden in an accompanying editorial in the NEJM.

Lenacapavir is not the first long-acting PrEP option. In 2021, the U.S. Food and Drug Administration approved a long-acting, injectable form of the antiretroviral cabotegravir for HIV PrEP in at-risk adults and adolescents. Long-acting cabotegravir is administered by intramuscular injection every two months following two injections at the start and has shown high efficacy in preventing HIV infection (see AVAC’s PrEPWatch for more on this and other options). But as with all PrEP regimens, even the long-acting versions, adherence is key to protection.

The results of the PURPOSE 1 trial clearly underscore the challenge of adherence to daily, oral PrEP regimens. Among women in the two groups receiving daily pills to prevent HIV infection, HIV incidence was the same as in the general population when documented adherence was low. Meanwhile, adherence was high in the lenacapavir group — 92% of women who received the twice-yearly injections adhered to their visits — establishing a clear advantage for this dosing regimen.

This set off what some, including Jeanne Marrazzo, director of the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health, coined as “lenacapavir fever.” Some even went so far as to tout this antiretroviral regimen as a “miracle” tool for HIV prevention.

Others, including Walensky and Baden, were more restrained in their optimism. “So now we have a PrEP product with high efficacy. That is great news for science but not (yet) great for women,” they wrote. “Now, the imperative is to spend time, resources, and political will on access, implementation, and delivery.”

Another imperative, according to experts at the conference, is continuing to pursue other non-antiretroviral based prevention options, including passive administration of HIV-specific broadly neutralizing antibodies (bnAbs) and vaccines. Although the lenacapavir results are impressive, “it’s not going to necessarily be for everyone,” says Susan Buchbinder, director of HIV prevention research in the San Francisco Department of Public Health. “We’re trying to get prevention to as many people as possible.” And that requires more options.

In recent articles, we’ve detailed the ongoing efforts to develop bnAbs for malaria and for infectious diseases more broadly and reviewed some of the advantages and challenges to this approach, some of which became apparent during the COVID-19 pandemic.

For HIV, results of the Antibody Mediation Prevention trials, which culminated in 2021, are setting a course for the future of bnAb-based prevention. These studies showed that a high concentration of bnAbs with different specificities is likely needed to fend off the exceedingly wide array of viral variants in circulation. As a result, researchers are now focusing on advancing a triple combination of engineered bnAbs for HIV prevention.

A combination of three antibodies, VRC07-523LS, PGT121LS, and PGDM1400LS, all of which are engineered to have extended half-lives, are now under study in a series of Phase 1 trials being conducted by the HIV Vaccine Trials Network, IAVI, the National Institute of Allergy and Infectious Diseases (NIAID), and others. This triple combination of bnAbs should provide coverage against more than 90% of the currently circulating viral variants, according to a presentation by Dan Barouch in a satellite session at AIDS 2024.

Barouch, who is affiliated with Harvard Medical School, the Beth Israel Deaconess Medical Center, and the Ragon Institute of MGH, MIT and Harvard, and his team are also evaluating the therapeutic efficacy of these three bnAbs. At the conference, Barouch said that a small study of 12 people living with HIV showed that this bnAb combination can provide substantial therapeutic efficacy, with 10 of the 12 volunteers (83%) maintaining viral suppression for at least 28 weeks after suspending antiretroviral therapy following their first infusion of the three bnAbs. Five of the 12 volunteers (42%) controlled viremia for more than a year. This research will be published soon in Nature Medicine, according to Barouch.

For prevention, researchers are increasingly considering how passive administration of bnAbs could be used to protect babies and infants from acquiring HIV either during labor and delivery or during the breastfeeding period. This was the subject of another satellite session at the IAS conference, which was sponsored by IAVI and was focused on their recently released action plan (Accelerating bnAbs for peri- and post-natal prophylaxis) or more colloquially dubbed “bnAbs for babies” by Linda-Gail Bekker, deputy director of the Desmond Tutu HIV Centre at the University of Cape Town in South Africa and a member of IAVI’s Board of Directors, who chaired the session.

Stopping pediatric HIV infections is still an urgent need. Lynda Stranix-Chibanda, a pediatrician from the University of Zimbabwe, notes that 120,000 children aged 0 to 14 acquired HIV last year. “We’re off track. For the last 10 years there is no remarkable change,” she says. “It’s time to leverage new technology to tip the balance and reduce the number of new infections, and bnAbs are one of the new technologies in progress.”

Stranix-Chibanda described several advantages of bnAb-based prevention, including their good safety and pharmacokinetic profiles in infants and their ability to be used for both pre- and post-exposure prophylaxis. She told the IAS audience that this short-term intervention could deliver life-long benefits. Additionally, infants require much smaller doses of bnAbs, which eliminates one of the biggest barriers to their use — the high cost to manufacture and deliver them.

Sebastien Morin, senior manager of policy, strategy, and market access at the Medicines Patent Pool, is confident that the field can overcome issues related to the cost of manufacturing monoclonal antibodies. “We can make it affordable; we can make it cost-effective,” he says. This may require innovative manufacturing platforms and technologies, but these are all challenges he thinks can be addressed, as detailed earlier this month in a review article in PLOS Global Public Health published by representatives from the Medicines Patent Pool, IAVI, Unitaid, and Wellcome.

Another non-antiretroviral based prevention strategy is of course an HIV vaccine. Devin Sok, formerly at IAVI and now head of science at the Global Health Investment Corporation, detailed the scientific progress in the vaccine field in a plenary session. And in another satellite session, researchers, advocates, and public health experts addressed the persistent need for a vaccine even in the era of highly efficacious, long-acting PrEP.

“How remarkable it is that we can ask the question of whether or not we need a vaccine,” says Marrazzo. “We need to take some time to celebrate that.”

But Marrazzo wasted little time in celebrating, quickly noting that NIAID is 100% committed to developing an HIV vaccine. She says any hope to eliminate HIV has to involve a vaccine. “We’re not going to get there with antiretroviral-based interventions alone.”

Buchbinder echoed this sentiment. In Mosaico, a recently completed HIV vaccine efficacy trial, Buchbinder says all potential volunteers were counseled about the efficacy and benefits of PrEP and connected with low-cost PrEP services in their community; however, many chose not to take it and those were the individuals who were ultimately eligible to enroll in the trial. We need to be working as hard we can to get these interventions to people but at the same time recognize that there are people who don’t want PrEP, she says.

Mitchell Warren, executive director of AVAC, warned against throwing antiretroviral-based prevention under the bus to justify the need for a vaccine when there is a strong business proposition for why a vaccine remains an important goal. “We need a vaccine because we need a vaccine,” he says.

And, if we eventually have a vaccine and highly effective HIV-specific bnAbs alongside long-acting antiretroviral-based PrEP, perhaps the story coming out of the UNAIDS reports will be different. “There is a path to end AIDS,” writes Byanyima. “It is not a mystery. It is a choice.”