It’s rare in any branch of medicine that a trial of a new drug can report 100% efficacy, and a first in HIV science. But that’s what happened on Friday, when Gilead Sciences announced that no HIV infections had been seen among 2134 young women and adolescent girls in South Africa and Uganda given twice-yearly injections of its innovative anti-HIV drug, lenacapavir, as pre-exposure prophylaxis (PrEP), in its PURPOSE 1 study.
Zero infections, to underline the Gilead’s own headline, means 100% efficacy, at least in this study.
Because lenacapavir’s efficacy was so demonstrably superior to the daily oral PrEP medications used as comparisons in the PURPOSE 1 study, the study’s Data Monitoring Committee ordered PURPOSE 1’s early closure (its primary results were originally due to be determined this September). Data Monitoring Committees have privileged access to trial data and can order closure if a trial drug is clearly so much better, or worse, than its comparators that it would be unethical to continue – or if results are so finely balanced the trial will never reach a clear result.
We already have PrEP drugs proven to be highly efficacious in other trials, so it was not ethical to compare the efficacy of lenacapavir to no active drug at all. So lenacapavir was compared with tenofovir alafenamide / emtricitabine and tenofovir disoproxil / emtricitabine pills (branded by Gilead as Descovy and Truvada). In the study, 5338 women were given one of three regimens: either twice-yearly lenacapavir injections plus dummy Descovy pills, lenacapavir plus dummy Truvada, or dummy lenacapavir injections plus either Descovy or Truvada. The active drugs were allocated on a 2:2:1 basis, so 2134 women took lenacapavir, 2136 took Descovy and 1068 took Truvada. Real or dummy lenacapavir pills were also given on the first two days of the study in order to build up the concentration of the drug to preventative levels rapidly. See here for the study design.
Because there was no placebo-only arm, the number of infections seen in the three study arms were compared with what is called the ‘background HIV incidence’ (bHIV). This was determined by testing a selection of the local population, matched to the trial population, for HIV – using a so-called recency assay which can detect which infections have occurred in, say, the last six months.
The bHIV incidence was 2.4% (i.e. 2.4 infections in 100 women per year). Because there were no infections in the lenacapavir arm, incidence was zero. There were 39 infections in the Descovy arm, equivalent to an incidence rate of 2.0%, only 16% lower than no PrEP at all, and the 16 infections in the Truvada arm worked out as an incidence of 1.7%, or 30% lower than no PrEP.
This incidentally implies that Truvada was 85% more effective than Descovy but, although Gilead don’t say so, this difference is unlikely to be statistically significant because efficacy was so low with both drugs. Nonetheless, these findings from the only study to ever test Descovy PrEP with cisgender women are not going to provide the evidence that would allow drug regulators to approve its use by women.
That’s all we really know so far as Gilead has only given us the headline figures: we may hear more at the AIDS 2024 conference in Munich next month, though full analysis may take longer.
But PURPOSE 1 is just the first in a suite of five studies of lenacapavir as PrEP. The others include PURPOSE 2, a large study in gay and bisexual men and trans people who have sex with men in the Americas, South Africa and Thailand; this is due to report at the beginning of next year. PURPOSE 3 and 4 are smaller US-based studies enrolling, respectively, cisgender women and people who inject drugs – the latter is only the second randomised controlled study to look at PrEP in this population. PURPOSE 5, enrolling people at high risk of HIV in France and the UK, was added in later when European regulators said they needed European data.
In some of these, the difference in efficacy between lenacapavir and the PrEP pills may not be as dramatic as it was in PURPOSE 1, conducted in adolescent girls and young women in South Africa and Uganda. PrEP studies have repeatedly shown that, often for reasons to do with HIV and sexual stigma, women in lower-income countries find adhering to daily oral PrEP difficult. This showed to some extent in the HPTN 083 and HPTN 084 studies, where injectable cabotegravir in the study in women was nearly 90% more effective in stopping HIV infection whereas in the gay men’s study it was “only” 70% more effective. And oral PrEP is already popular and effective among gay and bisexual men as evidenced not only by its efficacy in clinical trials but by actual PrEP-related falls in HIV incidence.
Still, 100% is 100% and, as Dr Andrew Hill of the University of Liverpool commented to aidsmap, “This is the closest we have ever been to a vaccine against HIV.” Indeed, in a world where people have become used to yearly or twice-yearly vaccinations against COVID, a twice-yearly injection under the skin may feel functionally little different from a COVID booster – just even more effective.
Hill, however, having worked for several pharma companies in the past, is now one of their most trenchant critics, and points out that, as with cabotegravir, the biggest barrier to supplying this apparently game-changing preventative drug will be cost.
As he points out, the current list price for lenacapavir in the US (under its brand name when used as HIV treatment, Sunlenca) is $40,000 a year, whereas generic tenofovir disoproxil / emtricitabine pills can be obtained even online for less than 1% of that price, and for considerably less than that in PrEP programmes. Hill has pointed out before that cabotegravir is unaffordable even for upper-middle-income countries and the same is true for lenacapavir.
“We have a way to prevent HIV infection which is completely unaffordable” he says. He notes that Gilead have not, unlike cabotegravir’s manufacturers ViiV, yet negotiated even a limited voluntary licence agreement with generic manufacturers that would allow lenacapavir to be made at low cost.
Last month, the People’s Medicine’s Alliance wrote to Gilead with the support of over 300 signatories to demand that the company urgently license lenacapavir via the Medicines Patent Pool. This week, the AfroCAB network of HIV community advocates called on Gilead to move faster on equitable access to lenacapavir. ”After thousands of our community members have taken part in clinical trials for lenacapavir and other injectable PrEP products, it is time that pharmaceutical companies, governments and donors play their part in driving access among the communities that supported the science,” they said.
In return, Gilead have announced: “We have been developing a…strategy is to deliver lenacapavir swiftly, sustainably and in sufficient volumes, if approved, to high-incidence, resource-limited countries.
“[We will ensure] 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 will develop a robust direct voluntary licensing program to expedite access to those versions of lenacapavir in high-incidence, resource-limited countries. We are moving with urgency to negotiate these contracts.”
Given, however, that there are still 1.3 million new infections in the world every year, the need for such an effective and easily-administered prevention measure against HIV remains urgent. As generic versions of injectable cabotegravir are not expected to be fully available till 2027 how soon, in the case of lenacapavir, is now?
Maybe that “100% efficacy” headline finding of PURPOSE 1 will prove to be a mixed blessing to Gilead, in that it could add to the political and ethical imperative to make its drug available quickly and cheaply.
Update. This article was amended on 24 June 2024 to include more details of how background incidence was estimated.