AIDS 2024: Lenacapavir as PrEP is “beyond wonderful” but PURPOSE 1 study tells us so much more 

29 July 2024. Related: Conference reports, HIV prevention and transmission, World AIDS 25 Munich 2024.

Simon Collins, HIV i-Base

Whatever your reason for attending or reading about the AIDS 2024 conference, lenacapavir as PrEP together with questions about access, will be your headline news.

After presenting the PURPOSE 1 study – in which lenacapavir was shown to be 100% effective in cisgender women – lead investigator Linda-Gail Bekker referred to the results as “beyond wonderful”, including for generating data in pregnant and lactating women. [1]

They were just as compelling for Winnie Byanyima, head of UNAIDS, who two days earlier in the opening ceremony, called for immediate plans for global access to lenacapavir PrEP, including in low- and middle-income countries (LMICs), especially countries that took part in the research. [2]

But the careful design of the PURPOSE 1 raised many more issues that were often missed in some of the rapid reports sent out as breaking news.

This includes:

• HIV testing before PrEP is perhaps one of the most effective ways to diagnose people who do not know they are living with HIV. Over 500 women who were screened to join PURPOSE 1 were diagnosed this way and were then able to access HIV care.
• Adherence to oral PrEP was alarmingly low – perhaps lower than any other PrEP study in women, even though oral PrEP should now be widely known to be highly effective. Low adherence to oral PrEP in young women in southern Africa however has been reported in many other studies. This is why long-acting injectable options are so exciting – including CAB-LA.
• The study produced new data on oral F/TAF as PrEP in cisgender women. Even though low adherence complicates the results, this might support use by cisgender women who are not able to use F/TDF, so long as adherence is good.
• Numerous challenges about future pricing and access and a high-profile announcement on how resolving access issues will be critical to the global HIV response.
• Exciting potential for very broad use on a population level to be the most important factor in reducing new HIV infections to zero.
• New issues about the implications for lenacapavir as treatment when planning health programmes.

Background

Lenacapavir was approved in 2022 to be used in combination with other HIV meds to treat people with multidrug resistance or limited ART options for other reasons. It is a new type of HIV drug called a capsid inhibitor and the very long-acting formulation enables it to be given as a subcutaneous injection every six months. [3, 4]

Like many other new and pipeline drugs, lenacapavir is also being studied as first- and second-line treatment in people living with HIV. And as PrEP to protect against HIV in people who are HIV negative. [5]

Other formulations of lenacapavir include daily and weekly oral tablets and oral tablets are already used as a loading dose (2 x 300 mg) on each of days 1 and 2 when first starting the long-acting injection. This is to help reach the target drug levels rapidly.

The injection forms a subcutaneous depot under the skin that then slowly releases lenacapavir over the next 6 months. Sometimes this causes a small bump or nodule that then steadily goes down as the drug is released.

PURPOSE 1 study

Most media reports focussed on the astonishing levels of 100% protection from the 6-monthly lenacapavir injections. This was the headline news in mainstream media and thousands of delegates in the conference hall acknowledged this as a milestone by spontaneously responding with a standing ovation.

But the second experimental PrEP arm in PURPOSE 1 – using daily oral F/TAF – produced results that are also important, although limited by low adherence.

Although F/TAF is already approved as PrEP in the US and used off-label as PrEP in other countries including the UK, this has so far only been an option for gay and bisexual men and transgender women, due to lack of data in cisgender women or transgender men.

The results in PURPOSE 1 using daily F/TAF are slightly more complicated to explain, but were similar to daily oral F/TDF. This is also an essential result. Even though F/TAF is still an expensive patented medicine compared to F/TDF in many countries, it has a different side effect profile and is a much smaller tablet. It is important that data now supports expanding the number of people who could have this option.

Study design

The double-blind, phase 3, PURPOSE study randomised 5338 young women aged 16 to 25 in a 2:2:1 ratio to 6-monthly lenacapavir injections, daily oral F/TAF or daily oral F/TDF as the active control. Placebo injections were given to participants in the two oral arms and a placebo tablet (matching either F/TAF or /TDF) was given to participants receiving lenacapavir.

The study also included a no-PrEP observational group to track background rates of HIV during the study, as including a placebo arm was decided to not be ethical.

Screening included both 4th generation rapid point-of-care HIV Ab/Ag and PCR viral load testing. People who tested positive were further tested with an HIV avidity test to estimate background HIV incidence in recent infections and they were linked to HIV clinical care.

Follow-up was at weeks 4, 8, 13 and then every subsequent 13 weeks. The study was run in 25 clinics in southern Africa and 3 clinics in Uganda, in regions where the annual incidence of HIV in young women was at least 3.5% a year.

Between August 2020 to August 2021, the study screened more than 8000 women, and 504 (6%) were found to be already HIV positive. Of these, 92/504 (18%) were recent transmissions. A further seven women were later diagnosed as being in acute infection that included very high baseline viral load (mean: 32 million c/mL). This shows the potential for PrEP programmes to enable early HIV diagnoses, and to link to support and HIV services.

The study also generated results much earlier than expected. The pre-specified interim analysis in May 2024, when half the cohort reached 52 weeks follow-up, found that lenacapavir was so effective that the study was unblinded in order to offer lenacapavir to all participants.

Efficacy results

During 4821 person-years of follow-up, there were 55 incident infections: none in the lenacapavir group, 39 in the F/TAF group, and 16 in the F/TDF group.

This was an incidence of 0.00, 2.02, and 1.69 per 100 person-years, respectively. The background HIV incidence in the no-PrEP group was 2.41 per 100 person-years. See Table 1.

Table 1: Planned interim results from PURPOSE 1 study

IRR = Incidence Rate Ratio. F/TAF = emtricitabine/tenofovir alafenamide. F/TDF = emtricitabine/tenofovir disoproxil. PrEP = Pre-exposure prophylaxis.

Participant retention was also high and similar across arms, with roughly 96%, 83% and 91% still engaged at weeks 26, 52 and 104, respectively.

In the two primary efficacy analyses comparing PrEP to the background incidence, lenacapavir was highly effective (incidence rate ratio, IRR: 0 [95%CI: 0 to 0.04], p =0.00014).

However, F/TAF did not show significant protection (IRR: 0.84 [95%CI: 0.55 to 1.28], p=0.21). This lack of benefit from F/TAF is linked to very low adherence and does not mean that oral F/TAF didn’t work. This interpretation is supported by the secondary analysis using the active control arm of oral F/TDF. Again, lenacapavir was highly protective (IRR 0 [95%CI: 0 to 0.1], p<0.001) but F/TAF was not numerically or significantly different (IRR 1.2 [95%CI: 0.67 to 2.14]).

These results were also supported by differences in adherence.

More than 90% of lenacapavir injections were on time, including at weeks 26 and 52. Missing an injection by more than a week required HIV testing and restarting with the oral loading doses.

However, very few participants in both F/TAF and F/TDF arms took even one or two pills a week, based on drug levels measured in dried blood spot samples in 10% participants. For example, only 20% of participants at week 26 and 10% at week 52 took four or more pills in the F/TAF arm compared to <5% participants in the F/TDF arm at both weeks 26 and 52.

Low drug levels of oral PrEP were highly significantly related to the risk of becoming HIV positive (OR 0.11 [95%CI: 0.01 to 0.49], p=0.0006).

Side effects and safety

The safety results were good for all three arms with headache being the most commonly reported side effect in 13 to 16% of participants, generally grade 1 or 2.

Excluding injection site reactions (ISRs), only about 3% of participants reported serious side effects, with less than 0.2% of discontinuations (only five people in the lenacapavir arm and two people on F/TAF). Nausea and vomiting were generally mild and were reported significantly less in the lenacapavir arm (roughly 6% vs 12% with oral PrEP).

Although six people died during the study, all in the F/TAF arm, none were reported as related to the study drugs. However, given the strong link between HIV status and intimate partner violence it would be important to know whether HIV was considered as a potential factor in the three cases that sounded like horrific assaults.

ISRs were also mainly grade 1 or 2 and reduced in number over time, reported in 68% vs 34% of active vs placebo arms, with 63% vs 16% reporting nodules. Four participants (0.2%) in the lenacapavir arms discontinued due to ISRs. Continued follow-up will be important as median number of injections is only five.

PURPOSE 1 was notable for deciding to not require women to use contraception, unlike many other studies with investigational drugs. The researchers responded to community demands to generate real-world data, including during and after pregnancy. Approximately 10% of women have so far become pregnant with roughly half still ongoing. No differences have been seen compared to rates in the general population and safety studies will continue.

Access and pricing

Results of PURPOSE 1 were simultaneously published in the NEJM and the accompanying editorial sets lenacapavir in the context of continued high incidence of HIV in young women in southern Africa (3000 diagnoses every week) and that it is 12 years since oral PrEP with F/TDF was approved by the FDA. [6, 7]

The editorial stresses a “moral imperative to make lenacapavir PrEP broadly accessible and affordable as to persons who were enrolled in the study, as well as to all those who are similarly eligible and could benefit.” This involves investing time, resources and political will to enable generic access and funding.

The issues of pricing and access, including the importance of licensing to enable generic formulations, is reported in detail by Polly Clayden in this linked HTB report. [8]

Outstanding issues and questions

The interim PURPOSE 1 results raise many other questions and need further follow-up data from the open-label stage of the study.

• Will breakthrough infections occur on lenacapavir, either if injections are missed, or if PrEP is discontinued? And will drug resistance be seen?
• Similar to other formulations of PrEP, accurate baseline screening outside a clinical trial will be a challenge as lenacapavir becomes more widely available. This is to identify people in very early infection who would quickly develop drug resistance to lenacapavir monotherapy that would not be identified for another six months.
• Long term follow-up is also needed on the resolution of nodules associated with increased numbers of injections, and whether these resolve completely for all participants.
• The need for oral dosing complicates starting lenacapavir PrEP and the current oral formulation is apparently a complex molecule to manufacture. New oral formulations are already in development including a weekly oral tablet with early data presented as a post at AIDS 2024. [9] Although a low priority at the moment, it would be good to know whether the weekly oral tablet would provide a single weekly pill as oral PrEP and possibly PEP.

All PrEP drugs in PURPOSE 1 were developed and marketed by Gilead Sciences although F/TDF is now off-patent and is widely available in generic formulations.

comments

These efficacy results raise urgent and exciting issues relating to drug pricing and access. Also, the demand for such effective PrEP globally could easily outstrip demand as treatment.

Applying for regulatory approval will apparently also need results from at least one other ongoing phase 3 study. PURPOSE 2, running just over six months behind PURPOSE 1, is being run in gay and bisexual cisgender men, transgender women and men and people who are non-binary, and has sites in Argentina, Brazil, Mexico, Peru, South Africa, Thailand and the US. [7]

Extensive access has the potential to effectively prevent further HIV infections on a population level, by diagnosing people who are already HIV positive and providing herd-like immunity.

Although the high rate of STIs was reported at baseline (25% chlamydia, 9% gonorrhoea, 7% trachomatis vaginalis, 3% syphilis) and with a high continued incidence at each 26-week visit (roughly 50/100 patient years for any STI), PrEP monitoring also has the potential to steadily reduce STI prevalence from earlier diagnosis and treatment.

Finally, at least one leading researcher has suggested that lenacapavir should be largely reserved for use as PrEP, other than in cases of MDR HIV. This challenging proposal, mainly linked with a concern for drug resistance, is a difficult argument to make, but can be included in future discussions. The lenacapavir pipeline includes a weekly oral combination with islatravir and use with long-acting bNAb infusions or long-acting injectable cabotegravir. 

As with each advance in PrEP, lenacapavir will further raise the bar for future research, especially if it becomes the standard of care. But each new PrEP formulation or extended dosing options could expand the number of people prepared to use PrEP based on mosaic effectiveness. [11]

Placebo-controlled studies could arguably have been ethical for lenacapavir to show a rapid signal of efficacy, by only enrolling people who wouldn’t take oral PrEP. Given the very low adherence to oral PrEP this is almost what happened. Efficacy could also be analysed by using the overall number of people at risk as the denominator.

So the results of PURPOSE 1 also expanded the pool of people willing to consider PrEP, as adherence results suggest 80% of participants had no interest in oral PrEP, even within an incredibly supportive and careful research study.

This approach could support approval of PrEP compounds that have lower efficacy in studies because the formulation itself dramatically expands the number of people willing to use it.

Links

• Press release of early results.
• Abstract at AIDS 2024
• Webcast at AIDS 2024
• Full paper in NEJM
• Editorial in NEJM
• Lenacapavir listed studies on clinicaltrials.gov

References

Unless stated otherwise, all references are to the programme and abstracts of the 25th International AIDS Conference, 22–26 July 2024, Munich, Germany. Links to some webcasts might initially be limited to registered delegates.

1. Bekker L-G et al for the PURPOSE 1 Study Team. Twice-yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women: Interim analysis results from the PURPOSE 1 study. AIDS 2024. Oral abstract OAB 2602.
   https://programme.aids2024.org/Abstract/Abstract/?abstractid=1 (abstract)
   https://aids2024.iasociety.org/cmVirtualPortal/_iasociety/aids2024/session/0000038550/2a84199e3516f7c8ca5e084c10ecc5e45263173a/00000000402 (webcast)
2. Winnie Byanyima, AIDS at a crossroads. Opening ceremony for AIDS 2024. 22 July 2024.
   https://programme.aids2024.org/Programme/Session/585 (programme)
   https://aids2024.iasociety.org/cmVirtualPortal/_iasociety/aids2024/session/0000042150/2dd92967d4f1da94ab261162fdaf580684f830c3/0000000040 (webcast)
3. Lenacapavir approved in the EU and UK to treat multidrug resistant HIV. (HTB September 2022).
   https://i-base.info/htb/43776
4. Lenacapavir approved in the US for multidrug resistant HIV. HTB (February 2023).
   https://i-base.info/htb/44720
5. Clinical trials.gov. Completed, ongoing and upcoming lenacapavir studies currently listed (July 2024).
   https://clinicaltrials.gov/search?intr=lenacapavir&viewType=Table&limit=25&page=1
6. Bekker L-G et al for the PURPOSE 1 Study Team. Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women. NEJM. DOI: 10.1056/NEJMoa2407001. (24 July 2024).
   https://www.nejm.org/doi/full/10.1056/NEJMoa2407001
7. Walensky EP and Baden LR.The Real PURPOSE of PrEP — Effectiveness Not Efficacy, NEJM Editorial (24 July 2024).
   https://www.nejm.org/doi/full/10.1056/NEJMe2408591
8. Clayden P. Lenacapavir could be produced for $40 a year: 1000-fold lower than current US price for treating MDR HIV. (HTB July 2024).
   https://i-base.info/htb/48224
9. Shaik NA et al. Safety and pharmacokinetic profile of single and multiple ascending doses of GS‑4182, an oral prodrug of lenacapavir, in participants without HIV-1. AIDS 2024. Poster abstract WEBEP117.
   https://programme.aids2024.org/Abstract/Abstract/?abstractid=10130
10. Clinicaltrials.gov. Study of Lenacapavir for HIV Pre-Exposure Prophylaxis in People Who Are at Risk for HIV Infection (PURPOSE 2).
    https://clinicaltrials.gov/study/NCT04925752
11. Glidden DV et al. Mosaic effectiveness: measuring the impact of novel PrEP methods. Lancet HIV. 2019 Nov;6(11):e800-e806. doi: 10.1016/S2352-3018(19)30227-9.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824959