Twice-yearly HIV prevention shot succeeds in pivotal trial, but questions loom over future access

By Thabo Molelekwa and Marcus Low for Spotlight

1 Jul 2024

An HIV prevention injection that provides six months of protection per shot has been shown to be highly effective in a pivotal trial largely conducted in South Africa. But there are concerns about when the jab will become available and how widely.

An injection containing the antiretroviral drug lenacapavir is highly effective at preventing HIV infection for six months per shot. This is according to top-line study findings announced last week by the pharmaceutical company Gilead. Detailed study findings have not yet been presented at a major scientific conference or published in a reputable scientific journal.

The six months of protection provided per shot with lenacapavir is a substantial improvement on the two months of protection provided by another HIV prevention injection – long-acting cabotegravir (CAB-LA for short). CAB-LA has been registered by the South African Health Products Regulatory Authority (Sahpra), but as we recently explained in a Spotlight special briefing, access to that jab in South Africa is likely to remain very limited for at least a few years. Lenacapavir is not yet registered by Sahpra. It was registered in December 2022 by the US Food and Drug Administration for treating HIV in combination with other antiretrovirals, but it has not yet been approved for use as HIV prevention.

Lenacapavir is in a relatively new class of antiretroviral medicines called capsid inhibitors, which interfere with the protein shell that protects HIV’s genetic material and the enzymes it needs for viral replication. Lenacapavir is also available in pill form, but the new findings relate mainly to its formulation as a long-acting injection.

The new findings

The headline-making findings are from a study called PURPOSE 1 that was conducted in young women and girls in South Africa and Uganda (other PURPOSE studies are ongoing).

Study participants were split into three groups in a 2:1:2 ratio. The first group received the lenacapavir injection every six months and the second and third received daily antiretroviral HIV prevention pills – tenofovir disoproxil fumerate (TDF) and emtricitabine in group 2, and tenofovir alafenamide (TAF) and emtricitabine in group 3. There was no placebo arm in the study since assigning people to a placebo-only arm in an HIV prevention study is considered unethical since we already have proven HIV prevention methods. Participants who received the lenacapavir injection were, however, also given placebo pills and participants given the antiretroviral pills were also given placebo injections so that the study participants did not know which study arm they were on.

In addition to comparing HIV infections in the lenacapavir and TAF arms with the TDF arm, the researchers also compared it with the background rate of HIV incidence in the communities where the study was conducted.

Professor Linda-Gail Bekker, the chief executive at the Desmond Tutu Health Foundation and principal investigator for the South African part of the study, said participants were young people who were not living with HIV and were keen to use pre-exposure prophylaxis (PrEP – medicines to prevent HIV infection such as those used in the three study arms). Bekker said the participants were counselled for adherence to PrEP and advised to use, but not required to use, contraception. If they became pregnant, they were allowed to continue with PrEP with additional counselling. “Participants were seen frequently to check for any side-effects or abnormalities,” Bekker said.

Primary findings from the study were only expected in September 2024, but that changed when the study’s Data Safety Monitoring Board (DSMB) recently conducted a pre-planned interim analysis. Following this analysis, explained Bekker, the DSMB recommended halting the randomised phase of the study, “based on the fact that it appeared that the benefit in the lenacapavir arm far outweighed the oral PrEP arms”. The participants were to be told which study arm they were on and offered the opportunity to move onto lenacapavir injections if they had been on prevention pills.

Gilead told Spotlight that according to the DSMB the study had met its key efficacy endpoints of showing that twice-yearly lenacapavir injections were superior to prevention pills (the TDF combination) and superior to the background HIV incidence rate in the community.

According to Gilead, there were no new HIV infections among the 2,134 women in the lenacapavir group, compared with 16 among the 1,068 women in the TDF group and 39 among the 2,136 women in the TAF group. More technically, HIV incidence in the lenacapavir arm was 0 per 100 person-years, compared with 1.69 in the TDF arm and 2.02 in the TAF arm. While these numbers indicate that lenacapavir provided 100% protection in the study, it is possible that real-world efficacy might be lower.

“In the trial, lenacapavir was generally well tolerated and no significant or new safety concerns were identified,” Gilead said. The safety data will be particularly closely watched since the injection is meant for otherwise healthy people who may be less tolerant of side-effects than people who are ill.

Asked about the side-effects observed in the trial, Professor Francois Venter, executive director of Ezintsha at Wits University, said: “We need to see the full dataset, but it looks pretty good from what I see.” He underscored the importance of monitoring and addressing potential long-term side-effects: “As with all new drugs, we need to be cautious. This was a big study, and carefully conducted, but drug safety is always an ongoing project.”

‘Unprecedented and incredible’

The early responses from researchers and activists to the PURPOSE 1 findings have been overwhelmingly positive.

“To see no infections at all in over 2,000 young women (16-25 years) in Uganda and South Africa is just unprecedented and incredible,” said Bekker. “This really gives hope that this prevention modality, if widely available, could protect young women in this region.”

Similarly positive, Venter hailed the new findings as “one of the most significant results we have seen in HIV prevention history”. He said this milestone could reshape the landscape of HIV prevention both in South Africa and globally.

“Most importantly, with this 100%, it shows that if women use the methods, it works,” said Yvette Raphael, co-director of Advocacy for Prevention of HIV and Aids (APHA), “The number of new infections will definitely go down.” APHA serves as the secretariat of the African Women’s Prevention Community Accountability Board, which was involved in the study.

“When Gilead was designing the trials, they set up a meeting with us to start a partnership on how we, as African women, would be involved in this trial. One of the big things is that this study involves young women as well as pregnant and lactating people,” said Raphael. Studies of this nature often do not include pregnant women.

According to Venter, integrating lenacapavir into existing healthcare frameworks presents both challenges and opportunities. He points out that “PrEP uptake has been very low in the public and private sector”. Prevention pills have been available at public-sector clinics for several years – Spotlight has reported on possible reasons for the low uptake here.

But Venter is hopeful that the development of this new technology will “stimulate creative thinking” and potentially increase the adoption of HIV prevention methods. The twice-yearly dosing schedule of lenacapavir could significantly improve adherence compared with prevention pills that have to be taken every day. “Obviously, it takes away having to remember swallowing a tablet daily.”

But when will we get it?

Many will be hoping that things move more quickly with the lenacapavir injection than it has with CAB-LA (the two-monthly shot). As with lenacapavir, a pivotal CAB-LA study was stopped early when it became clear that the jab was highly effective. Those findings were announced in November 2020. CAB-LA was registered by Sahpra in November 2022, and as of mid-2024 access to CAB-LA in South Africa remains severely limited, with wide access expected only in 2027 or 2028 when generic versions are expected to hit the market. A similar timeline with the lenacapavir injection would mean wide access only after 2030 – though the fact that lenacapavir has already been registered as HIV treatment in Europe and the US might help shave off a few years.

A Gilead representative told Spotlight the company is “prioritising speed to enable the most efficient path” for the regulatory approval of the lenacapavir injection “in countries that account for most of the global disease burden”. He said they are exploring frameworks intended to facilitate faster access in target populations and countries, such as the European Medicines Agency’s EU Medicines for All, and the World Health Organization’s collaborative review and prequalification procedures. “We believe these frameworks could enable Gilead to secure approvals in key high-incidence, resource-limited countries as quickly as possible in relation to an EU approval,” he said.

Gilead has also indicated that it will license generic manufacturers to produce the injection. Having several companies manufacturing a drug typically leads to greater and more reliable supply. It also tends to result in significant price reductions once a sufficient number of generic manufacturers are in the market.

Lenacapavir injections are currently priced at about $40,000 (more than R700,000) per year in the US. They are not yet on the market in South Africa. According to Spotlight’s very rough back-of-the-envelope calculations the price would have to come down to under R1,000 per year (or under R500 per shot) to be considered cost-effective by the South African government (we based our calculation on what the Health Department has said about CAB-LA affordability).

“We are pursuing a direct voluntary licensing strategy for access to lenacapavir in high-incidence, resource-limited countries,” Gilead told Spotlight. “In view of the company’s ongoing commitment to communities affected by HIV, we have been developing a strategy to enable broad, sustainable access globally. A key component of this strategy is to deliver lenacapavir swiftly, sustainably, and in sufficient volumes, if approved, to high-incidence, resource-limited countries, which are primarily low- and lower-middle-income countries.”

Gilead told Spotlight they have a two-pronged access strategy “ensuring dedicated Gilead supply in the countries where the need is greatest until voluntary licensing partners are able to supply high-quality, low-cost versions of lenacapavir, and developing a robust direct voluntary licensing programme to expedite access to those versions of lenacapavir in high-incidence, resource-limited countries”.

Several community and activist groups, such as Afro CAB and HIV i-Base, have called on Gilead to move quickly in licensing generic manufacturers. A letter to Gilead from the People’s Medicines Alliance and a long list of signatories urged the company to license lenacapavir specifically to the Geneva-based Medicines Patent Pool (MPP). Gilead’s reference to their “direct voluntary licensing strategy” suggests the company has rejected this suggestion. Though MPP licences have in the past come in for criticism from some activists, the argument for MPP licences is that they are likely to result in more favourable terms from a public interest perspective than licences directly negotiated between companies. There is some precedent for MPP licences facilitating access to antiretrovirals. The pharmaceutical company ViiV’s decision to license the antiretroviral drug dolutegravir to the MPP is likely to have played an important role in that drug becoming widely available – more than 4.7 million people in South Africa are taking dolutegravir-based HIV treatment.

Providing all goes well with registration and licensing, there will also be questions about when governments and donors start buying the jabs and at what price and what volumes, and after that, questions about who will be eligible to get the injections and where.

Venter suggested that success hinges on two critical factors. “It totally depends on the willingness firstly of the drug company to give us access to the drug, and secondly on governments being creative about giving women who need it, access to the drug,” he said. This, he says, highlights the necessity of both pharmaceutical cooperation and governmental innovation in making the jab widely available. DM

This article was first published by Spotlight – health journalism in the public interest. Sign up to the Spotlight newsletter.

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South Africa

The new findings

‘Unprecedented and incredible’

But when will we get it?