Linking To And Excerpt From COREIM’s A Revolution in HIV Prevention & the PURPOSE Trials: Beyond Journal Club Segment with NEJM Group”

Posted on April 21, 2025 by Tom Wade MD

Please review Clinical Testing Guidance for HIV from U.S. Centers For Disease Control And Prevention (CDC).

Today, I review, link to, and excerpt from COREIM‘s A Revolution in HIV Prevention & the PURPOSE Trials: Beyond Journal Club Segment with NEJM Group.

All that follows is from the above resource.

Posted: April 16, 2025
By: Dr. Abarna Pearl, Dr. Clem Lee, Dr. Shreya P. Trivedi and Dr. Greg Katz
Graphic: Dr. Jimin Hwang
Audio: Dr. Shreya Trivedi
Peer Review: Dr. Lindsey Baden

Podcast: Play in new window | Download

Time Stamps

  • 02:25 HIV PReP Daily Truvada and Descovy
  • 07:48 On-Demand Prep
  • 13:25 Purpose Trials
  • 20:56 Discussion of Effectiveness to Efficacy
Sponsor: The New England Journal of Medicine Fellowship Program. Learn more about the one-year, full-time paid opportunity here and the application process.

Show Notes

Background

Guidelines 

See HIV.gov for more details: https://www.hiv.gov/hiv-basics/hiv-prevention/using-hiv-medication-to-reduce-risk/pre-exposure-prophylaxis

PrEP trials

DAILY PREP

iPrEx, NEJM, 2020

DISCOVER, Lancet, 2019

  • In 2019 the DISCOVER trial showed that  tenofovir alafenamide-emtricitabine (TAF-FTC), Descovy, was non inferior to TDF-FTC (Truvada) for use as PrEP in transgender men who have sex with men and cisgender MSM
  • Thus TAF-FTC (known as Descovy) is approved in transgender women and cisgender MSM
  • Has not been well studied for PrEP in women or others who have vaginal or neovaginal sex, or in those who inject drugs.
  • TAF is thought to have less bone and renal toxicity compared with TDF; but increased hyperlipidemia and weight gain
    • TAF is a pro-drug and is converted to the active agent in CD4 cells, therefore there is less plasma exposure to tenofovir, which is what causes renal and bone toxicity.

ON DEMAND PREP

ANRS-IPERGAY, NEJM, 2015

  • On demand Truvada (taken before and after sex) was compared to placebo in MSM and transgender women who have anal sex
  • Dosing is 2-1-1 (2 pills 2-24 hours before sex, 1 pill 24 hours after the first dose, and 1 pill 24 hours after the second dose)
  • There was a relative reduction in the TDF-FTC group of 86% (95% confidence interval, 40 to 98; P=0.002) compared to placebo
  • Reasonable for cisgender MSM who are taking TDF-FTC and can reliably predict when they will have condomless sex or certain transgender men, having anal intercourse
  • NB cannot use on-demand PrEP for those with concurrent hepatitis B, as TDF treats hepatitis B and stopping the drug can lead to a hepatitis flare

PREVENIR, Lancet, 2022

  • A prospective observational cohort study in France comparing daily Truvada with on-demand Truvada in MSM and transgender women
  • Participants were tested for HIV every 3 months
  • The median age was 36 years, 99% were MSM. About 1500 opted for daily PrEP and 1500  opted for on-demand PrEP. At a median follow-up of 22·1 months and there were three HIV infections in the daily PrEP group and three in the on-demand PrEP group.
  • Thus there was no difference in effectiveness in daily versus on-demand PrEP

LONG ACTING INJECTABLE PREP

HPTN 083, NEJM, 2021

  • In 2021, HPTN 083 showed that receiving long-acting intramuscular injectable, cabotegravir (an integrase strand transfer inhibitor), every eight weeks was superior to Truvada (TDF-FTC) at preventing HIV acquisition among cisgender men who have sex with men and transgender women who have sex with men (hazard ratio, 0.34; 95% confidence interval, 0.18 – 0.62).
  • This is likely due to improved adherence with the long-acting medication, comparing to oral PrEP, which needs to be taken every day
  • Long-acting cabotegravir was later shown to be superior to Truvada ( TDF-FTC) in cisgender women- hazard ratio 0·12 (95% CI 0·05–0·31) (HPTN 084, Lancet, 2022)
  • During these trials an altered presentation of HIV infection in patients who were on long acting cabotegravir, called “long-acting early viral inhibition,” was observed in 17/41 (41.5%) patients with new HIV infection across both of these trials.. Features of this include low HIV RNA levels and delayed diagnosis due to negative HIV 4th generation (antibody/antigen) screening test. This presents a caveat that

LONG ACTING VAGINAL RING PREP

MTN-020-ASPIRE, NEJM 2016

  • In 2016 the Ring and ASPIRE studies showed that a silicone vaginal ring releasing dapivirine, a non-nucleoside reverse transcriptase inhibitor, and replaced monthly, reduced HIV infection in cisgender women ages 18 and older.
  • The dapivirine ring reduced the incidence of HIV infection by 27% (95% confidence interval [CI], 1 to 46; P=0.046) compared to placebo
  • This has been approved in several African countries but is not approved used in the United States

NEW LONG ACTING PREP DRUG IN PURPOSE 1 and PURPOSE 2 – LENACAPAVIR

Lenacapavir

  • Lenacapavir (Sunlenca) is a novel, first-in-class, multistage HIV-1 capsid inhibitor with high potency and a long half-life, which has so far been approved for treatment of multi-drug resistant HIV in heavily treatment experienced individuals
  • Lenacapavir binds to protein subunits in the HIV capsid, which is within the HIV lipid membrane and surrounds HIV RNA.
  • This prevents capsid disassembly, transport of HIV RNA into the host cell nucleus, and, the other end of the HIV life cycle, capsid reassembly.
  • It can effectively inhibit HIV at concentrations as low as 50 picomolar, while most antiretrovirals work at nanomolar concentrations.
  • It also has a half life of 38 days
  • No homologues in body (unlike NRTI targets) so less toxicity
  • The downside is that it has a low barrier to resistance: HIV requires only one point mutation to become resistant.  By contrast, integrase strand transfer inhibitors (like cabotegravir)  have a high barrier to resistance.  This is less of an issue if used for PrEP since acquiring HIV while on PrEP would be rare.

PURPOSE 1 trial 

  • PURPOSE 1 was a double-blind, active-controlled RCT involving cisgender women in South Africa and Uganda, which compared subcutaneous lenacapavir every 26 weeks, to daily TDF/FTC (Truvada) and TAF/FTC (Descovy)
  • Since TAF/FTC (Descovy)  had not been extensively studied in cisgender women, the trial also aimed to assess its the efficacy of the agent in this population
  • Trial was performed in South Africa and Uganda where background incidence of HIV in cisgender women not on PrEP is high- 3.5 per 100 person-years
    • Remember, incidence (rate of new infections) is not the same as prevalence (proportion of total infections)
  • South Africa updated its PrEP guidelines in 2021, recommendingendorsing PrEP use for persons at greatest risk for HIV infection, including adolescent girls and young women as well as MSM, among others.
  • Participants were randomized 2:1:1 to lenacapvir, TAF/FTC and TDF/FTC groups
  • Since oral Truvada is known to be so effective in reducing HIV infection when taken consistently, a placebo group was considered unethical.
    • Background HIV incidence was instead estimated from patients screened at the start of the trial who were newly HIV positive at the outset.
    • An antibody based assay allowing estimation of the time since HIV infection was then used to infer the HIV incidence in a population not on any PrEP
  • Primary endpoint was incident HIV infection in the lenacapavir group, and in the TAF/FTC group, compared to the background HIV incidence
  • Safety endpoints- adverse events, clinical/lab abnormalities
  • In 5338 initially HIV negative participants there were 0 infections among 2134 participants in the lenacapavir group, 39 infections among 2136 participants in the TAF/FTC group, and 16 infections among 1068 participants in the TDF/FTC group.
  • 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 compared to HIV incidence with TDF/FTC (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.10; P<0.001).
  • HIV incidence with TAF/FTC did not differ significantly from background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55 to 1.28; P=0.21), and there was no significant difference in HIV incidence between TAF/FTC and TDF/FTC (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14).
    • Interpreted as no real impact on daily oral PrEP in reducing new HIV infections in this population
  • Injection-site reactions were the most common adverse event and they were more common in the lenacapavir group (70%) than in the Truvada and Descovy group combined (35 %)
  • Adherence to oral PrEP was low and decreased over time
    • This was , quantified by measuring levels of tenofovoir diphosphate, the active agent in oral PrEP, in red cells in a random 10% sample of participants

PURPOSE 2 trial

  • PURPOSE 2 was a double-blind, active-controlled RCT which assessed the efficacy of  subcutaneous lenacapavir every 26 weeks, compared to daily oral TDF/FTC  (Truvada) in cisgender men, transgender women, transgender men, and gender-nonbinary people.
  • Patients were randomized 2:1 to subcutaneous lenacapavir every 26 weeks and daily oral TDF/FTC
  • The primary outcome was incident HIV infection in the lenacapavir arm compared to the background HIV incidence
  • Adherence to lenacapavir and to oral Truvada was measured by measuring concentrations of these in a random 10% sample of participants
  • The median age was 29 years, with a third of participants younger than 25. 98 % were assigned male at birth, and 22 % identified as gender diverse. Two thirds identified as non-White, which broke down to 38 % who identified as Black, 13% as Asian and 63% as Hispanic or Latine
  • There were HIV infections in 2 participants in the lenacapavir group (0.10 per 100 person-years; 95% confidence interval [CI], 0.01 to 0.37) and in 9 participants in the F/TDF group (0.93 per 100 person-years; 95% CI, 0.43 to 1.77)
  • The incidence of HIV infection in the lenacapavir group was significantly lower than the the background incidence (incidence rate ratio, 0.04; 95% CI, 0.01 to 0.18; P<0.001) and the incidence in the F/TDF group (incidence rate ratio, 0.11; 95% CI, 0.02 to 0.51; P=0.002).
  • Adherence to oral PrEP was good in this population

Discussion/takeaways

  • The results of PURPOSE 1 and PURPOSE 2 are striking and could be revolutionary in the effort to end the HIV epidemic.
  •  In PURPOSE 1, amongst cisgender women in Subsaharan Africa, there were no HIV infections in the lenacapavir group – a substantial reduction compared to the background HIV incidence and compared to oral Truvada, currently the most common form of PrEP.
  • By contrast Descovy (TAF/FTC), which had not been extensively studied in women, appeared to be no different to TDF/FTC  in reducing HIV infections in women.
  • Interestingly TAF/FTC did not reduce HIV infections compared to the background HIV incidence – tests to measure drug concentrations in a sample of participants showed that this could largely be explained by non-adherence
  • PURPOSE 2, in MSM and gender diverse people, showed a similar striking result – a substantial reduction in HIV infection compared to both background HIV incidence and to the Truvada arm.
  • However adherence to oral Truvada was higher in this population compared to PURPOSE 1, which aligns with prior data regarding poor adherence to oral PrEP in cigender women
  • As a long acting medication which requires only two injections per year, lenacapavir is an option for patients who find adherence to a daily medication difficult, or who experience stigma associated with taking a daily medication
  • There is a caveat: efficacy (the ability of an intervention to work under ideal conditions like in an RCT) is different to effectiveness (the ability of an intervention to improve the health of patients in a real world setting).
  • Effectiveness is often much lower than efficacy due to hurdles in  implementation of an intervention after it is approved
  • The long-acting injectable PrEP medication, cabotegravir, is a case in point: despite the excitement following approval in 2021, it still only accounts for 1-3% of PrEP prescriptions in the US, due to poor insurance coverage and logistical challenges related to setting up clinics to administer the medication
  • In order to end the HIV epidemic globally, there needs to be an effort to make lenacapavir affordable in low and middle income countries, which bear the greatest burden of HIV.
  • Thus ending the HIV epidemic requires efforts on the part of individual clinicians, but also momentum from public health agencies and, more broadly, political will.
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