Africa: Aids 2024 – Exciting Developments With the Jabs Promising to Revolutionise HIV Prevention

Taking antiretrovirals to prevent HIV infection mostly still involves swallowing one or more pills a day. Some long-acting products that work for a month or two at a time have been approved but are not yet in wide use in South Africa. As delegates gathered for the 25th International AIDS Conference (AIDS 2024) last week, Elri Voigt takes stock of the latest developments in this fast-moving field.

When taken as prescribed, certain antiretroviral tablets are highly effective at preventing HIV infection. The snag is that not everyone at risk of HIV infection is always able to swallow a tablet every day for a variety of reasons.

This is why there is so much excitement in HIV circles about antiretroviral formulations that do not require people to take something every day. Two such long acting formulations have already been approved by the South African Health Products Regulatory Authority (SAHPRA), but access to these products remain very limited. One is an injection called long-acting cabotegravir (CAB-LA for short) that provides two months of protection per shot and the other is a vaginal HIV prevention ring, called the dapivirine ring, that must be replaced monthly.

The good news is that there are several even longer-acting products on the way that hold the promise of four or even six months of protection.

A shot every six months

Arguably, the biggest HIV news of the year so far broke at the end of June when it was reported that an injection containing the antiretroviral drug lenacapavir provides young women and adolescents with six months of highly effective protection against HIV infection per jab. At the time, Professor Linda-Gail Bekker, Chief Executive Officer at the Desmond Tutu Health Foundation, described the findings to Spotlight as “unprecedented and incredible”. Bekker led the South African part of the study.

While initial reporting on the study findings was largely based on a media release from Gilead Sciences, more detailed findings have now been presented at AIDS 2024 and published in the New England Journal of Medicine (NEJM).

The headline-making finding is that among 2 134 people in the lenacapavir injection arm of the study, there were zero HIV infections. This was much better than in the two other study arms where people were given HIV prevention tablets – in one group 39 out of 2 136 people acquired HIV and in the other 16 out of 1 068. (People in these latter two study arms received emtricitabine/tenofovir alafenamide and emtricitabine-tenofovir disoproxil fumarate, respectively). The study was stopped early given the strength of these findings.

The initial Gilead media release contained relatively little information on side effects and safety. Therefore, the more detailed safety data presented at AIDS 2024 and published in the NEJM were keenly anticipated. Healthy people taking preventative medicines tend to be less tolerant to side effects and safety risk than people taking treatments for diseases they already have.

All the products used in the study, according to Bekker, were safe and well tolerated and most adverse events were mild.

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Rates of most adverse events, like headache and urinary tract infections, were similar in the three study arms. One interesting difference is that people in the lenacapavir injection arm of the study were less likely to experience nausea and vomiting than people in the two prevention pill study arms.

The most common adverse event reported in the study was injection site reactions (people in the two prevention pill study arms were given placebo injections). In the lenacapavir arm, injection site reactions occurred in 69% of participants compared to 35% in the other study arms. Reports of injection site reactions decreased with subsequent doses.

our people (0.2%) in the lenacapavir arm of the study stopped taking the jabs because of injection-site reactions compared to none in the other two study arms. Over 60% of participants in the lenacapavir arm developed subcutaneous nodules – these are harmless, usually invisible, small lumps under the skin. The lenacapavir injection is administered under the skin in the stomach area.

Six people died during the study, but none of them were in the lenacapavir arm and none of the deaths are thought to be related to study drugs. There were 510 pregnancies in the study and based on the current data, there are no pregnancy-related red flags.

What happens next with lenacapavir?

Dr Nkosiphile Ndlovu, a Senior Research Clinician at the Clinical Trials Division at the Wits Reproductive Health and HIV Institute (Wits RHI) Research Centre, pointed out that there are two registrational trials looking at the lenacapavir injection for HIV prevention. The one in young women and adolescents that was just reported is called PURPOSE 1. PURPOSE 2, a similar study conducted in men, transgender people and gender non-binary individuals who have sex with men, is ongoing. Ndlovu was involved in PURPOSE 1.

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Mitchell Warren, executive director of US-based HIV advocacy group AIDS Vaccine Advocacy Coalition (AVAC), told Spotlight results from PURPOSE 2 are expected late this year or early next year. If these results show that lenacapavir as injectable HIV prevention given every six months is safe and effective, Gilead will then go to regulators and the World Health Organization (WHO) to have the product approved for use. In South Africa, Gilead will have to apply for registration with SAHPRA.

“We think that they may have data to go to the regulators by the middle of next year…and hopefully they would get approval from any number of regulators and then hopefully at the same time WHO recommendations [will come out], so that could all happen in 2025,” Warren said. “Ministries of Health, PEPFAR [President’s Emergency Plan For AIDS Relief], and Global Fund could begin to procure this product by late next year. So, you could see its introduction late 2025, early 2026,” he speculated.

Access concerns

While doctors and activists have welcomed the new lenacapavir findings, many have also expressed concern over when people will be able to get the jabs. “Recent use of lenacapavir for HIV prevention with 100% efficacy is a gamechanger but we need to look at timelines for access”, Dr Elizabeth Spooner and Neetha Morar, both of the South African Medical Research Council, told Spotlight.

One bit of good news in this regard is that it appears the jabs could potentially be made quite cheaply.

Research presented at AIDS 2024 by Dr Andrew Hill, of Liverpool University, suggests it is possible to produce generic versions of long acting lenacapavir at a fraction of the current price. Currently, Gilead is charging around $40 000 per person per year in wealthy countries. There is no price yet for South Africa.

By exactly how much the cost could potentially fall depends on scale. Hill estimates that at volumes sufficient for one million people the cost could drop to around $100 per person per year. At volumes sufficient for 10 million people it could go as low as $40 (under R800) per person per year. Judging by cost-effectiveness analysis conducted for other products, it is very likely South Africa’s Department of Health will be willing to procure at this latter price.

Hill’s estimates are based on the cost of ingredients and production and allows for 30% profit.

But when and on what terms generic manufacturers will be allowed to produce the lenacapavir jab remains uncertain.

Gilead previously told Spotlight that they will follow a “direct voluntary licensing strategy for access to lenacapavir in high-incidence, resource-limited countries”. We understand this to mean they will make licensing deals directly with generic companies, rather than through an intermediary like the UN-backed Medicines Patent Pool (MPP). But Gilead is under substantial pressure to change course. Most recently, in a strongly-worded statement, UNAIDS urged Gilead to work through the MPP.

Even if licenses are granted very quickly, be it directly or via the MPP, it will likely take several years before generic companies can produce lenacapavir jabs.

A cabotegravir jab every four months?

Before the release of the new lenacapavir findings, the long-acting therapy drawing the most attention was CAB-LA. As explained in a recent Spotlight special briefing, CAB-LA has been registered by SAHPRA, but access in South Africa will remain very limited for several years. Last week, Bhekisisa reported that PEPFAR is donating some CAB-LA jabs to South Africa, but, as expected, the numbers are very small.

One obvious disadvantage of CAB-LA compared to lenacapavir, is that the current CAB-LA formulation provides only two months of protection per shot compared to the six months with lenacapavir. In a context where getting a jab might require queueing at a clinic, requiring fewer jabs is a big deal.

Work is under way on a new formulation of cabotegravir that it is hoped will provide four months of protection per shot. The product is called cabotegravir ultra-long acting (CAB-ULA). Results from a phase 1 study on CAB-ULA presented at the Conference on Retroviruses and Opportunistic Infections (CROI) earlier this year suggested the formulation will work for four-monthly dosing.

It is still early days with this formulation, however. Dr Kimberley Brown, ViiV Healthcare’s Global Medical Affairs Leader for Cabotegravir, told Spotlight that ViiV cannot report on any timelines for when exactly the new formulation will move forward towards further development “because there’s many, many moving parts and interdependencies”.

She said that additional studies are needed with larger study populations to assess the best dose of Cabotegravir ultra-long acting that is both safe and achieves the best levels of the drug to ensure protection against HIV infection. She said ViiV is moving into a registrational study for four-month dosing later in the year, and the results for that study will be used for their regulatory filings.

A monthly pill

Another promising development is a long-acting antiretroviral pill called MK 8527. It is being developed as a weekly pill for HIV treatment and a monthly pill for HIV prevention.

Findings from two phase 1 studies presented at CROI earlier this year suggest that MK-8527 is safe and well-tolerated. Any drug related adverse events in the two studies were considered mild. The pharmacokinetic (what the body does to the drug) data from the studies was also promising.

Warren told Spotlight MK-8527 is now in a phase two study, with results expected at the end of the year, and if it is effective, the pharmaceutical company Merk will likely start a phase three study next year. With few exceptions, medicines are only registered for use by the public once safety and efficacy has been confirmed in large phase 3 trials.

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