The long-acting injectable antiretroviral drug lenacapavir (Sunlenca) was highly effective in preventing HIV infection in cisgender women in high-risk countries, according to an interim analysis of the phase III PURPOSE 1 trial, but questions remain about its affordability and safety in pregnancy.
Among adolescent girls and young women in South Africa and Uganda, pre-exposure prophylaxis (PrEP) with lenacapavir every 26 weeks reduced HIV incidence by 100% compared with daily oral emtricitabine/tenofovir disoproxil fumarate (F/TDF; Truvada) and background HIV incidence (P<0.001 for both), reported Linda-Gail Bekker, MBChB, PhD, of the Desmond Tutu HIV Centre at the University of Cape Town, during the recent International AIDS Conference in Munich.
The study was simultaneously published in the New England Journal of Medicine (NEJM).
Because of these findings, the researchers discontinued the randomised phase of the trial this month and offered all participants open-label lenacapavir, reports Medpage Today.
“Zero women receiving twice-yearly (lenacapavir) acquired HIV in PURPOSE 1,” Bekker told attendees.
“The introduction of oral PrEP has changed the lives of more than 6m people globally who have accessed it,” she noted. “Despite PrEP’s promise, many young women have found uptake, daily adherence, and persistence to daily PrEP (to be) a social, emotional, and physical challenge. For them, we need new and diverse options."
Of the incident HIV infections that occurred in the trial, none occurred among the 2 134 participants receiving lenacapavir (zero events per 100 person-years), whereas 39 infections occurred among 2 136 participants receiving daily oral emtricitabine/tenofovir alafenamide (F/TAF, Descovy; 2.02 events per 100 person-years), and 16 infections occurred among 1 068 participants who received F/TDF (1.69 events per 100 person-years). Background incidence of HIV in the screened population of 8 094 participants was 2.41 cases per 100 person-years.
Of note, HIV incidence with F/TAF did not differ significantly from background HIV incidence (incidence rate ratio [IRR] 0.84, 95% CI 0.55-1.28, P=0.21), and there was no meaningful difference in HIV incidence between F/TAF and F/TDF (IRR 1.20, 95% CI 0.67-2.14).
“So now we have a PrEP product with high efficacy,” wrote Rochelle Walensky, MD, MPH, of the Harvard Kennedy School of Government and Harvard Business School in Cambridge, Massachusetts, and Lindsey Baden, MD, deputy editor of NEJM, in an accompanying editorial. "That is great news for science but not (yet) great for women.
“The most critical question is how – more than a decade after PrEP was first approved in the United States and several years after the promising DISCOVER results among (men who have sex with men) – we have failed women at high risk for HIV infection for so long,” they noted.
Lenacapavir received FDA approval in December 2022 for the treatment of HIV in combination with other antiretrovirals among heavily treatment-experienced adults with multidrug resistant HIV-1 infections.
Previous clinical trials among cisgender women have commonly found challenges with adherence to daily oral pills for PrEP.
Although retention in PURPOSE 1 was high across all three study groups, poor adherence in the oral F/TAF and F/TDF groups possibly led to the incident HIV infections in these groups.
Most participants who developed incident HIV infections had low or no detectable tenofovir diphosphate levels from dried blood spot samples collected at trial visits.
In the adherence analysis of the trial, participants in the F/TAF group who had medium or high adherence – defined as two to three doses per week – had lower odds of becoming infected than those with low adherence (OR 0.11, 95% CI 0.01-0.49).
Walensky and Baden noted that while F/TDF is available for less than $50 per year in South Africa, lenacapavir currently costs $43 000 per year in the US, severely limiting access in low- to middle-income countries.
“The results of the PURPOSE 1 trial have now created a moral imperative to make lenacapavir broadly accessible and affordable as PrEP,” they wrote.
“A key challenge to decreasing the incidence of HIV infection is identifying high-risk populations (especially women), engaging them, and providing them easy, low-barrier, and low-cost access to a PrEP regimen that works and to which they can adhere," they added.
"Because previous PrEP regimens have proven to be highly effective when taken as prescribed, the PURPOSE 1 trial uniquely addresses only the last among these hurdles."
In the study, there were 193 pregnancies in the lenacapavir group, 219 in the F/TAF group, and 98 in the F/TDF group. At the time of the interim analysis, 54.3% of pregnancies were completed, and 45.7% were ongoing. Four participants in the F/TAF group and one participant in the F/TDF group became infected with HIV while pregnant.
"Given the high pregnancy rate among participants in the PURPOSE 1 trial, assessment of the safety of lenacapavir in pregnancy is a priority," the editorialists wrote. Currently, guidelines indicate that there are insufficient data to make recommendations for its use during pregnancy or breastfeeding.
The trial enrolled 5 338 adolescent girls and young women who were HIV-negative at baseline. The median age of participants was 21 years, and 2.3% were younger than 18.
All were sexually active with male partners, were not using PrEP, and had no HIV testing within the previous three months. A majority had a secondary school education.
About 80% had previously been tested for HIV, with a median time since last HIV test of about seven months, but only 6.3% reported any previous use of PrEP.
Participants were randomised 2:2:1 to receive lenacapavir, F/TAF, or F/TDF. All participants also received either an alternate oral placebo or subcutaneous injection. Participants had follow-up visits at weeks 4, 8, and 13, and then every 13 weeks, and received laboratory, pregnancy, and HIV testing.
Incidences of chlamydia, gonorrhoea, and vaginal trichomoniasis infections were high – approximately 48 to 50 events per 100 person-years – and similar across the three groups. Participants who were diagnosed with HIV during the trial were referred for HIV care.
Adverse event rates in the trial were generally similar across the three treatment groups. The most common adverse events were injection-site reactions, occurring in 68.8% of the lenacapavir group and in 34.9% who received placebo injections.
Headache, urinary tract infection, and genito-urinary chlamydia infection were also common across the three groups. Grade 3 or 4 adverse events were uncommon and occurred similarly across the treatment groups.
There were six deaths, all of which occurred in the F/TAF group, but they were not linked to the treatment.
Welensky and Baden noted that demographic data for South Africa suggest there are 4.5m adolescent girls and young women between 16 and 25 (PURPOSE 1 enrolment criterion), and the Joint United Nations Programme on HIV/Aids estimates an additional 750 000 South Africans among PrEP-eligible key populations.
With more than 5.25m eligible South Africans, as of 2021 a mere 350 000 (<7%) had ever received a PrEP prescription; durable use is probably far lower, they noted.
Reported barriers to PrEP use among young persons in the African context include social stigma, fear of side effects, long travel or wait times for appointments, inconvenient clinical operating hours, and drug costs.
To bridge the current canyon between PrEP efficacy and effectiveness, future efforts must address these challenges, they suggested. To start, PrEP drugs proven to work should be financially accessible to the populations in the countries studied. F/TDF is available in South Africa for less than $50 per year.
Meanwhile, lenacapavir currently costs about $43 000 annually in the US, and access to the drug in South Africa is severely limited. But, the results of the PURPOSE 1 trial have now created a moral imperative to make lenacapavir broadly accessible and affordable as PrEP to persons who were enrolled, as well as all those who are similarly eligible and could benefit, they wrote.
Study details
Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women
Linda-Gail Bekker, Moupali Das, Quarraisha Abdool Karim et al.
Published in the New England Journal of Medicine on 24 July 2024
Abstract
Background
There are gaps in uptake of, adherence to, and persistence in the use of preexposure prophylaxis for human immunodeficiency virus (HIV) prevention among cisgender women.
Methods
We conducted a phase 3, double-blind, randomised, controlled trial involving adolescent girls and young women in South Africa and Uganda. Participants were assigned in a 2:2:1 ratio to receive subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine–tenofovir alafenamide (F/TAF), or daily oral emtricitabine–tenofovir disoproxil fumarate (F/TDF; active control); all participants also received the alternate subcutaneous or oral placebo. We assessed the efficacy of lenacapavir and F/TAF by comparing the incidence of HIV infection with the estimated background incidence in the screened population and evaluated relative efficacy as compared with F/TDF.
Results
Among 5338 participants who were initially HIV-negative, 55 incident HIV infections were observed: 0 infections among 2134 participants in the lenacapavir group (0 per 100 person-years; 95% confidence interval [CI], 0.00 to 0.19), 39 infections among 2136 participants in the F/TAF group (2.02 per 100 person-years; 95% CI, 1.44 to 2.76), and 16 infections among 1068 participants in the F/TDF group (1.69 per 100 person-years; 95% CI, 0.96 to 2.74). Background HIV incidence in the screened population (8094 participants) was 2.41 per 100 person-years (95% CI, 1.82 to 3.19). HIV incidence with lenacapavir was significantly lower than background HIV incidence (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.04; P<0.001) and than HIV incidence with F/TDF (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.10; P<0.001). HIV incidence with F/TAF did not differ significantly from background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55 to 1.28; P=0.21), and no evidence of a meaningful difference in HIV incidence was observed between F/TAF and F/TDF (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14). Adherence to F/TAF and F/TDF was low. No safety concerns were found. Injection-site reactions were more common in the lenacapavir group (68.8%) than in the placebo injection group (F/TAF and F/TDF combined) (34.9%); 4 participants in the lenacapavir group (0.2%) discontinued the trial regimen owing to injection-site reactions.
Conclusions
No participants receiving twice-yearly lenacapavir acquired HIV infection. HIV incidence with lenacapavir was significantly lower than background HIV incidence and HIV incidence with F/TDF.
NEJM commentary – The Real PURPOSE of PrEP — Effectiveness, Not Efficacy (Open access)
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