Future PrEP and new results from PURPOSE 1 and 2: does HIV exposure explain incident cases?
21 November 2024. Related: Early access, Conference reports, HIV prevention and transmission, HIV 17 Glasgow 2024.
L-R: Onyema Ogbuagu, Haoyi Wang and Linda-Gail Bekker with conference co-chairs Chloe Orkin and Alexandra Calmy at Glasgow 2024.
Simon Collins, HIV i-Base
The final session at Glasgow 2024 was titled PrEPing for the Future and included a keynote lecture, three oral abstracts and a panel discussion. [1]
The Lock Lecture, given by Linda-Gail Bekker from The Desmond Tutu HIV Centre at the University of Cape Town, comprehensively covered future PrEP, rightly presenting this as being inseparable from issues of PrEP access. [2]
Current access to oral PrEP is still far too low to be able to reach global goals of reducing new HIV transmissions in high incidence settings by 2030. It is shocking, for example, that pricing of oral PrEP in many middle-income countries effectively blocked access for the last decade. Peru was included in the iPrEX study that led to US approval in 2012, and yet oral PrEP has been accessed by less than 3000 people over the last ten years, despite the country having an increasing incidence of HIV.
In all settings, effective future access includes designing PrEP programmes that have a choice of different formulations (daily or monthly pills, 2–6 monthly injections, patches, rings, films and a potential rectal douche etc.) as well as choices of how to access these (fixed or mobile clinics, schools and other venues, by post, courier etc).
This also involves understanding the different reasons and motivations for using PrEP and that new dosing options are also becoming available, such as recent the UK recommendation of 2:7 dosing for women.
Multi-use products in development include combining HIV prevention with contraception in pills, implants and rings. Injectable formulations include longer-acting hydrogel depots using smaller volumes, resorbable annual pellet implants and 6-monthly infusible bNAb combinations – although some of these are only in early or preclinical stages of development.
And for all the excitement about the scientific advances of PrEP, access to generics which will be essential for global use are still several years away. For example, generic CAB-LA and generic lenacapavir are not currently expected until 2027, and then only in limited volumes.
This needs to be remembered when the headline news from Glasgow 2024 features updates on the PURPOSE 1 and 2 registrational studies for lenacapavir PrEP.
PURPOSE 1 was presented at the IAS 2024 conference in July, reported 100% efficacy, with superiority to oral PrEP and is already reported and published in NEJM. [3]
The update in Glasgow, presented by Linda-Gail Bekker, included new data on annual persistence to PrEP in a subset of 10% of study participants, defined as on-time injections and clinic visits for lenacapavir and by drug levels of oral PrEP (at weeks 13, 29, 36 and 52). [4]
Adherence to injections was high, with 91% injections (1832/2012) at week 26 and 94% (836/894) at week 52 being on time.
This was significantly higher than for oral PrEP where less than 20% of participants at week 26 and less than 10% at week 52 had drug levels associated with taking four or more daily doses a week. In a matched case-control analysis, medium or high adherence was significantly associated with reduced odds ratio of acquiring HIV: OR 0.11 (95%CI: 0.012 to 0.485), p=0.006. Adherence significantly declined over time in all women who became HIV positive, even when this started at high levels.
Overall, high adherence was reported by 79% participants compared to only 5% of participants on oral PrEP, p=0.0001.
The conference also included an oral abstract presentation from PURPOSE 2 using lenacapavir PrEP in cisgender gay and bisexual men, transgender men and non-binary people. The main study results were only reported at the R4P conference a month ago. [5]
In Glasgow, Onyema Ogbuagu from Yale School of Medicine, included a little more detail on the two cases of incident HIV infections in the study. Both were diagnosed with HIV-1 without evidence of delayed antibody results, and with good drugs levels at the likely time of exposure, and who at diagnosis both showed the N74D mutation in capsid. [6]
Patterns of adherence in PURPOSE 2 were also similar to PURPOSE 1, with 90% and 93% of injections administered on time at weeks 26 and 52. Although adherence to oral PrEP was higher, with 82% vs 62% having drug levels associated with 4 or more weekly doses at weeks 26 and 52 respectively, this was also declining over time.
PK data were also presented for lenacapavir for a preselected 10% of participants. This showed median drug levels remaining above the 4 x protein adjusted EC95 (15.5 ng/nL) and that all participants remained above the 1 x paEC95 (3.8 ng/mL) out to week 52 (n=52).
Although the difference between finding zero vs two cases of incident infections is numerically very close, and both studies reported very high efficacy, understanding the lower protection reported in PURPOSE 2 is scientifically very important. However, only limited information was available, partly due to reasons of confidentiality for the two study participants involved.
Participant A was diagnosed at week 13 using regular rapid and laboratory HIV Ag/Ab testing, with viral load of 934,000 copies/mL. Retrospective viral load testing at week 8 was undetectable (<20 c/mL) and 4.5 copies/mL using a 1 copy/mL test. Lenacapavir exposure was also high with drug levels at weeks 4, 8 and 13 of 26, 25 and 23 ng/mL, respectively, all significantly above the 4 x paEC95 of 15.5 ng/nL. This participant was a transgender woman who had transactional sex and tested positive for latent syphilis at baseline.
Participant B was diagnosed at week 26 with a negative rapid test but positive laboratory test, with a viral load of 14,500 copies/mL and negative viral load at week 13. Although lenacapavir levels low at weeks 4 and 8 they remained above the 1x paIC95 and were above the 4x pa IC95 from weeks 13 to 26. This was a cisgender gay man who had tested positive for chlamydia at baseline.
The two similarly designed PURPOSE studies, both with high efficacy results that included superiority compared to oral PrEP, were however in different populations that might impact on HIV risk. The differences including older age participants (range 17 to 74 vs 16 to 25 years), higher PrEP experience (23% vs 7%) and with >22% vs 0% reporting chemsex, all PURPOSE 2 vs 1, respectively.
Another difference, was that enrolment criteria for PURPOSE 2 included having receptive anal sex (rather than just condomless sex) which might make the overall cohort at a higher risk of HIV compared to PURPOSE 1, although this difference wasn’t seen in higher transmissions in the control arms, and might show differences compared to oral PrEP.
comment
Incident infections using long-acting PrEP, notably with cabotegravir-LA have largely been explained by very early prestudy infections which were missed by baseline screening. This is not the case with lenacapavir, as baseline screening included rapid point of care, laboratory 4th generation antibody and antigen tests and qualitative and quantitative RNA viral load, with the same tests at 3-monthly monitoring visits.
Low drug exposure also appears to be ruled out in these two cases.
Other incident cases on PrEP are often explained by low adherence, especially with oral PrEP, and it was assumed injectable formulations would overcome this.
Instead, the discussion at the conference focussed on a new concern related to levels of HIV exposure, focussing on the behaviour-related risks in terms of the number of times someone might have had sex, but notably should also have included that transmissions might have been linked to very high levels of HIV viraemia in the source partner, perhaps if they were in early stages of seroconversion themselves.
It would be useful to know whether the PK studies used to calculate target levels for the pa IC95 were based on very high levels of HIV exposure equivalent to 5–10 million copies/mL which can be reported in very early infection.
Despite the superiority of lenacapavir, these results should not be used to undermine the efficacy of oral PrEP which was also highly effective with good adherence.
Oral PrEP is also likely to be the only formulation available for many years and for most people.
The remarkable efficacy shown with lenacapavir comes with the responsibility of making this drug option widely available globally, and funders also need to plan ambitious coverage to ensure that when generic formulations become available after 2027, they achieve optimal price reductions due to economies of scale. So the responsibility for access is dependent on global health targets and not just the price set by manufacturers. [7]
References
Unless mentioned otherwise, references are to the programme and abstracts of HIV Glasgow 2024.
- PrEPing for the Future. Wednesday 13 November, 11.45 – 12.45
https://virtual.hivglasgow.org/programme/prep-ing-future (webcast currently for registered delegates) - Bekker L-G. PrEP Therapeutic Agents – What’s on the Horizon and Access? Keynote Lecture. HIV Glasgow 2024.
Bekker L-G et al. Annual persistence in use of twice-yearly lenacapavir versus daily oral PrEP in the PURPOSE 1 phase 3 trial. Glasgow 2024, Oral abstract O48. - AIDS 2024: Lenacapavir as PrEP is “beyond wonderful” but PURPOSE 1 study tells us so much more. HTB (29 July 2024).
https://i-base.info/htb/48260 - Lenacapavir PrEP in cisgender gay men, trans and gender-diverse people: results of the PURPOSE 2 study. (HTB (9 October 2024).
https://i-base.info/htb/49027 - Ogbuagu O et al. O49: Twice-yearly lenacapavir PrEP in cisgender gay men, transgender women and men, and gender-diverse people (PURPOSE 2). HIV Glasgow 2024. Oral abstract 49.
- The urgency of planning broad vaccine-like access to lenacapavir PrEP globally. HTB (13 October 2024).
https://i-base.info/htb/49073