Six-monthly injectable PrEP is 89% more effective than oral PrEP in gay and bisexual men and trans people.

Gus Cairns, reporting from HIV Glasgow, 19 November 2024.

More details were presented last week at HIV Drug Therapy Glasgow 2024 of the PURPOSE 2 study, which compared the efficacy of six-monthly injections of the long-lasting drug lenacapavir with daily pills of tenofovir disoproxil/emtricitabine (TDF/FTC, also known as Truvada). Results were also been presented at the HIVR4P conference in Lima, Peru on 8 October, and more details on safety, demographics and efficacy were reported in Glasgow on 11 November. These follow on from the 100% effectiveness reported this summer by PURPOSE 1, a parallel study conducted with young cisgender women in South Africa and Uganda.

Dr Onyema Ogbuagu of Yale School of Medicine told HIV Glasgow that 3271 gay and bisexual men, trans women and men and non-binary people were randomised, on a 2:1 basis, to receive either lenacapavir injections plus placebo pills, or TDF/FTC pills and placebo injections.

There were nine HIV diagnoses in 1088 people receiving TDF/FTC and only two in 2183 people receiving lenacapavir. This equates to an annual HIV incidence of 0.93% in TDF/FTC recipients (one infection in every 107 people per year) versus 0.10% in lenacapavir recipients (one infection in every 969 people per year) meaning that lenacapavir was 89% more effective than TDF/FTC at preventing HIV acquisition. The efficacy of both lenacapavir and TDF/FTC were also compared with so-called ‘background HIV incidence’. This was determined by counting the proportion of people coming forward for the study who turned out to already have HIV, and using a recency assay to determine the proportion who had acquired the virus in the last year. Annual HIV incidence in this group was 2.37%, or one infection in 42 people per year. This meant that lenacapavir prevented 95.8% of infections that would likely have occurred without PrEP, while TDF/FTC prevented 60.8%.

PURPOSE 2 was conducted at 88 sites in seven countries – Argentina, Brazil, Mexico and Peru in Latin America, and in South Africa, the US and Thailand. The researchers recruited a more diverse group of participants than many other studies. Two-thirds were non-White (38% Black) and nearly a quarter (22%) were trans or non-binary: 15% trans women, 1% trans men, and 6% non-binary people. Their median age was 29 and one-third of them were under 25. Twenty-seven per cent had never taken an HIV test, only 23% had prior experience with PrEP, and just under a quarter had used chemsex drugs in the last three months. Participants were tested for HIV four, eight and 13 weeks after entering the study, and then every 13 weeks after that until week 52. They were also tested for STIs and those receiving TDF/FTC were tested for drug levels. Levels of lenacapavir were measured in a subgroup of 10% of recipients.

Adherence to lenacapavir was defined as the proportion of participants who were no more than two weeks late for their injections, and this was 90% and 93% for the second and third injections respectively. Adherence to TDF/FTC was defined as drug levels indicating at least four pills a week, two to three a week or less than two a week. The proportion taking four or more pills a week was 82% at week one, but fell to 62% by week 52, while the proportion taking less than two pills rose from 12% to 27%.

Seventy-four per cent of participants reported adverse events, but these were mainly injection site reactions. Sixty-three per cent receiving lenacapavir injections and 39% receiving placebo injections experienced nodules (lumps under the skin) at baseline, which is an expected effect of lenacapavir. The proportion experiencing injection site pain was similar in the lenacapavir and placebo injection arms (56% and 53%). The incidence of injection site reactions decreased over the course of the study, in both arms. Three to four per cent of adverse events were classed as serious – mostly not related to the study drug – and only seven people in each arm (less than 1%) discontinued the study owing to adverse events. STIs were counted as adverse events. At baseline 18-20% were diagnosed with chlamydia or gonorrhoea and 4% with syphilis. During the study 12-13% were diagnosed with rectal chlamydia, 9-10% with rectal gonorrhoea, and 4-5% with syphilis.

Unsurprisingly, there was interest in the two people who acquired HIV on lenacapavir, especially as that had been no such cases in PURPOSE 1. The first thing to say is that neither of them showed any evidence of LEVI (Long-acting Early Viral Inhibition) syndrome, in which a few people receiving cabotegravir injections as PrEP have developed HIV infections with very low viral loads, which make them hard to detect. Both participants had typical early HIV infections. One was diagnosed at week 13, having been negative at week 8, and the other at week 26, having been negative at week 13. They had viral loads of 934,000 and 14,100 respectively. The first had had effective drug levels of lenacapavir throughout; the second had a rather low level at week four, but effective levels thereafter. The nine people who acquired HIV on TDF/FTC all had evidence of low or zero adherence: two had very low drug levels, indicative of less than two doses a week, while the others had no detectable drug. Dr Ogbuagu said that because only two people had acquired HIV, he did not want to give too many identifying details. But the first person was a trans woman who was a sex worker and the second a gay man, both of whom had a high number of sex partners. He speculated that occasionally, very high amounts of HIV, perhaps alongside STIs (the first person had syphilis at baseline), might overwhelm the preventative action of lenacapavir PrEP. The two infections had some features in common with the only documented case of HIV infection in someone taking oral PrEP with near-perfect adherence and without drug resistance, though this person also showed some signs of LEVI syndrome.

Lenacapavir manufacturer Gilead Sciences said in a press release from HIV Glasgow that they would start filing to the approval of lenacapavir as a prevention drug by the end of this year (it is already approved for HIV treatment under the brand name Sunlenca). Last month they announced that they had signed royalty-free voluntary licensing agreements with six generic manufacturers to increase access to lenacapavir for HIV prevention in 120 resource-limited countries.
In the meantime, the PURPOSE 3, 4 and 5 studies, respectively in 250 cisgender women in the US, 180 people who inject drugs in the US, and 262 people in France and the UK are ongoing.
 
Reference
Ogbuagu Oet al. Twice-Yearly Lenacapavir PrEP in Cisgender Gay, Bisexual, and Other Men, Transgender Women and Men, and Gender‑Diverse People (PURPOSE 2). HIV Glasgow 2024, abstract O49.
Congress delegates can view the presentation here.
All abstracts from the congress are available here (open access).
 
Reporting from HIV Glasgow 2024 by Keith Alcorn, Gus Cairns and Roger Pebody has been financially supported by the Congress. The writers are editorially independent of the Congress and the presenting speakers.

Photo credit: Alan Donaldson Photography