A single shot of a new formulation of the antiretroviral drug lenacapavir could potentially protect against HIV infection for as long as a year. Spotlight reports on this and some of the other exciting research on long-acting anti-HIV medicines presented at the Conference on Retroviruses and Opportunistic Infections.
Several new developments in long-acting therapies for HIV treatment and prevention were presented to delegates at last week’s Conference on Retroviruses and Opportunistic Infections (Croi) in San Francisco. Among these was a study that looked at whether the drug lenacapavir could protect against acquiring HIV for a whole year.
Last year, results from the pivotal Phase 3 studies Purpose 1 and Purpose 2 showed that an injection of lenacapavir given every six months was highly effective at preventing HIV infection in diverse populations. It has not yet been approved by regulators for use in HIV prevention but a decision by the European Medicines Agency is expected this year.
Yearly formulation for HIV prevention might be possible
The new formulation of lenacapavir is expected to move to a Phase 3 study this year. It follows a Phase 1 study that found that if given once a year, it could achieve and maintain drug levels even higher than what was seen in the Purpose studies.
The drug’s manufacturer, Gilead Sciences, might be able to get some results to regulators by 2027, Mitchell Warren, chief executive officer of advocacy group Avac, told Spotlight.
The study was published in The Lancet medical journal last week. It tested two new formulations of lenacapavir. These formulations were given as two intramuscular injections to 40 adults. This is different from the subcutaneous injection used in the Purpose studies. The goal was to see if this method would achieve similar drug concentrations to the twice-a-year dose, Gilead’s Dr Renu Singh, who presented the latest findings at Croi, told delegates.
The novel formulations contained 5,000 milligrams of lenacapavir, combined with either 5% or 10% ethanol. Twenty people were given the first formulation and the remaining 20 were given the second formulation. The drug was administered using two 5ml intramuscular injections.
When the researchers measured the levels of lenacapavir in the blood, they found the drug levels were maintained for at least 12 months and were much higher than the levels seen in the twice-a-year dose of the subcutaneous injection.
The study was ongoing, Singh said, but based on the preliminary results, it was thought that a lower dose could maintain the target drug levels for once-a-year dosing. Modelling is being done to decide what dose will be optimal. She said the data support Gilead’s plan to move to a Phase 3 study later this year for a once-yearly intramuscular injection of lenacapavir for prevention.
According to Singh, both of the novel formulations were safe and well-tolerated. The side effects were mostly mild or moderate, with injection site pain being the most common and usually resolved within a week. The injection site reactions can be reduced by treating the area with ice before the injection is given. The intramuscular injection did not seem to cause nodules, like those associated with the subcutaneous injections in Purpose 1 and 2.
Two people experienced side effects classified as Grade 3 events. One had pain and fainting, which were linked to the study drug. The other had an ectopic pregnancy, which was not related to the study drug.
Warren explained that once the twice-a-year formulation of lenacapavir was approved by regulators, other versions of the drug would only need to show they work the same way in the body.
This type of study doesn’t need to be as large or time-consuming as the Purpose studies to provide results that can help regulators decide whether to approve the formulation for licensing.
Six-monthly lenacapavir is safe for adolescents
Back with twice-yearly injectable lenacapavir for prevention, we now know that adolescents aged 16 and 17 can safely use this product to prevent HIV. This is according to new data presented at Croi by Dr Katherine Gill, a researcher at the Desmond Tutu HIV Centre.
In a group of 124 adolescents who were included in the Purpose 1 trial, which was conducted in South Africa and Uganda, 56 got the lenacapavir HIV prevention injection, 45 were given an HIV prevention pill containing tenofovir alafenamide and emtricitabine (F/TAF), while 23 received another HIV prevention pill containing emtricitabine and tenofovir disoproxil fumarate (F/TDF). No HIV infections were seen in any of the study arms.
Gill said Purpose 1 was the first “pivotal Phase 3 prevention study” to include adolescents aged 16 and 17.
The injection was safe and well tolerated in these adolescents, with a safety profile and injection site reactions similar to what was seen in adults. There was one serious side effect reported in the study, but it was thought not to be related to lenacapavir. There were no side effects that were bad enough to lead to study discontinuation.
The levels of lenacapavir in the blood of adolescents and how their bodies responded to the drug were generally similar to adults. According to the researchers, this supports “the extrapolation of efficacy data from adults to adolescents”.
Important beyond the results
These results are crucial, not just because of the study findings, but because of the intentional early inclusion of adolescents in a Phase 3 study.
Normally, Gill explained, adolescents — despite accounting for a significant proportion of global HIV infections and often struggling with adherence to daily oral prevention pills — are excluded from clinical trials because of “stringent ethical and regulatory guidelines intended to protect them”. These restrictions, while intended to be protective, can significantly delay access to new interventions.
“A more progressive approach recognises that ethical inclusion and research is itself a form of protection, allowing adolescents to benefit from essential advancements while upholding appropriate safeguards. Conducting ethically sound, inclusive research that balances safety with timely access is essential,” she said.
Including adolescents in Purpose 1 was an intentional part of the study design from the beginning. Starting in 2019 before the study was conducted, Gill said, the researchers used good participatory practice principles by engaging civil society in the process and establishing global community accountability groups to assist in the study design.
“This early and continuous engagement allowed us to challenge the traditional approach of prioritising adults before involving adolescents,” said Gill. “By collaborating with regulators, rapidly reviewing adult safety data and working with local ethics committees in South Africa and Uganda, we were able to accelerate adolescent enrolment while ensuring the study was ethically sound and aligned with community needs.”
Including adolescents in research from the beginning could become “the new normal” thanks to the Purpose 1 design, said Warren. This study, he said, demonstrated a proof-of-principle that “you can design [a trial] with and for adolescents and see no delays”. This means that when lenacapavir is approved by regulators and recommendations are made by the World Health Organization (WHO), “the strength of the evidence presented … at Croi make it easy for regulators, WHO, and governments to provide it to a wide range of ages”.
Multipurpose technology for HIV prevention and contraception
Also at Croi, a small advance was reported in multipurpose technology that showed good results in monkeys. A new implant for women was tested that could serve as a long-acting method for both contraception and HIV prevention. The implant is a first-of-its-kind ultra-long-acting formulation that combines two drugs: cabotegravir and medroxyprogesterone acetate — which is used in the injectable contraceptive Depo-Provera. It is designed as a specialised implant called an In Situ Forming Implant.
The research was done in collaboration with a group of researchers at the Centers for Disease Control and Prevention (CDC) who were unable to attend Croi this year due to severe disruptions to CDC operations under the Trump administration.
The implant was given to six pigtail macaques, Professor Rahima Benhabbour from the University of North Carolina told delegates. The implants were removed from three after three months and kept in the other three for six months. The researchers found that the implants released sustained levels of both drugs — which suppress ovulation and protect against HIV infection.
When the implants were removed, the drug levels dropped within two to three weeks, allowing for the resumption of ovulation, meaning the effects of the drugs were reversed after the implant was taken out, said Benhabbour.
The data support the continued development of this implant, which could be a game-changer “in terms of one product that would protect against HIV and contraception as a long-acting injectable with single administration”, she said.
It would probably be many years before this product or a similar one came on the market, said Warren, since it involves combining a hormonal and antiviral product.
“But what’s so important is that science is moving forward,” he added. “It may be five or seven or eight years before we see that product, but only if we invest in that today and this is why the current funding issues are so excruciatingly painful.”
Long-acting HIV treatment in sub-Saharan Africa
In addition to prevention, there were some important advances reported in long-acting HIV treatment. Spotlight reported in-depth last year on why such long-acting HIV treatments are not available in South Africa.
The long-acting injection of the drugs cabotegravir and rilpivirine for HIV treatment has been approved for use in some people living with HIV and is available in high-income countries like the US. This injection could now also be considered for use in sub-Saharan Africa, according to results from the Cares study. This study was a Phase 3 open-label study conducted in South Africa, Kenya and Uganda.
The researchers enrolled 512 participants who were stable on treatment, had a viral load below 50 copies and had no history of treatment failure or hepatitis B infection. Of these, 255 were randomly assigned to receive the long-acting injectable every two months, while 257 continued with the daily oral standard of care. By week 96, 98% of the original participants remained in the study.
Dr Cissy Kityo from the Joint Clinical Research Centre in Uganda presented the study at the conference. She told delegates that the long-acting injectable treatment had high efficacy, with 97% of participants in the long-acting arm achieving viral suppression. It was non-inferior to (as good as) the oral standard of care.
Four participants in the long-acting group experienced virologic failure — meaning the HIV in their bodies increased to the point where the virus was no longer under control. One participant died from a surgical complication. The remaining three of them had mutations that made them resistant to either rilpivirine or cabotegravir. All were able to achieve viral suppression again when switched back to the standard daily antiretroviral tablets.
Kityo said when the study started, 74% of its participants had already been exposed to non-nucleoside reverse transcriptase inhibitors — the drug class that rilpirivirine belongs to.
The data from Cares provided “essential information for discussing a potential role for long-acting [therapies] in treatment programmes in sub-Saharan Africa, using the public health approach”, she said.
What this study was able to show, said Warren, was that this long-acting treatment was not only for wealthy countries but could also be delivered in resource-constrained settings. This raises the question of whether governments in these areas will consider adopting these products, especially given the recent cuts to Pepfar funding.
“We now have answered the scientific question and the baton, so to speak, gets passed to the next part of the relay race. Are policymakers willing to take it [long-acting cabotegravir and rilpivirine] up; do they see the value?” he asked.
Potential long-acting treatment with six-monthly shots
Another combination of two agents has shown promise as a potential long-acting treatment for HIV. This Phase 2 study looked at how lenacapavir together with the broadly neutralising antibodies (bNAbs) teropavimab and zinlirvimab compared to standard antiretroviral tablets.
Eighty adults living with HIV, with a stable viral load for at least a year, and susceptible to both the bNAbs were enrolled. Fifty-three received a combination of an infusion of 2,550mg of both the antibodies and 927mg of a subcutaneous injection of lenacapavir, while a control group of 27 people stayed on daily antiretroviral tablets. One participant in each arm discontinued the study.
The majority of participants (96%) in both arms remained virologically suppressed at week 26. One person in the lenacapavir arm experienced virological failure and developed resistance to lenacapavir and reduced susceptibility to one of the antibodies. Once resuming the daily tablets that the individual had been on before the switching, the person was able to re-suppress.
The most common side effect, affecting about 33 participants (62%), was injection site reactions. Around half of them reported having nodules, but these were considered mild. There were no side effects above Grade 3, and no one stopped treatment because of side effects. Additionally, there were no infusion reactions caused by the bNAbs.
The study is still ongoing, Dr Onyema Ogbuagu, an associate professor at Yale School of Medicine and director of the Yale HIV/AIDS Program clinical trials unit, told delegates when he presented the week 26 results. He said they would continue to evaluate the longer-term efficacy and safety, but the current results supported continuing the study as well as the future clinical development of a six-monthly dose for HIV treatment.
Cabotegravir and a broadly neutralising antibody
Results relating to another broadly neutralising antibody were presented by Dr Babafemi Taiwo from ViiV Healthcare — the company that manufactures the antiretroviral cabotegravir. The Phase 2b open-label trial looked at the safety and efficacy of using a combination of cabotegravir and the broadly neutralising antibody N6LS as a long-acting treatment for HIV, given every four months.
About 120 people were randomly assigned to one of three groups: one group received an intravenous (IV) infusion of the antibody every four months along with a monthly injection of cabotegravir; another group received the antibody as an injection every four months along with the same monthly injection of cabotegravir; and the third group received the standard daily antiretroviral tablets.
Fifty people got the IV infusion, 49 received the injection and 26 were given the daily tablets. Four participants, two in each of the N6LS arms, experienced virologic failure but were able to re-suppress HIV when switched back to antiretroviral tablets.
The IV infusions were tolerated better than the antibody injection in terms of side effects, with only four participants (8%) reporting injection site reactions — all of which were Grade 1 and resolved after three days. There were no serious side effects in the IV arm and no participants withdrew because of them. In comparison, the injection arm had 25 participants (50%) who experienced side effects, which for some lasted longer than three days.
The IV infusion will be evaluated in a phase 2 study, called Embrace 2 in combination with cabotegravir given intramuscularly every six months.
There are still some questions about the ability to use an antibody together with a long-acting antiretroviral. One of the challenges, Warren explained, is that long-acting formulations for antiretrovirals are getting longer and longer, while antibodies are not necessarily able to keep up at this point.
“This is one of the issues whether you’re pairing two injectable antiretrovirals together or whether you’re pairing an ARV with antibodies. One of the things you ideally want is a synchronous dosing schedule,” he said. There are also still unanswered questions about how best to deliver the antibodies. DM
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