IAS 2021: Proving efficacy of next generation PrEP: counterfactual controls in lenacapavir and islatravir studies
A satellite session before IAS 2021 focused on the new research challenge for the next generation of PrEP studies and was organised by the Forum for Collaborative HIV Research. 
This included the critical issue of how to prove activity of new compounds given the near 100% efficacy with good adherence of current PrEP. The first randomised studies used either placebo (now unethical due to PrEP being the new standard of care) or active controls (that would need to be too large as non-inferiority studies).
The workshop focused on the FDA decision to accept results using counterfactual placebo arms as options for estimating background HIV incidence in active control studies. This approach has been used to study contraceptive efficacy that used background pregnancy incidence.
For PrEP studies, this can include data on STIs, cross sectional data from HIV recency tests at baseline and historical incidence data. However, for HIV this needs to allow or adjust for temporal trends in testing, ART use and viral suppression etc. 
Recency tests give an approximate HIV incidence at baseline from a similar population. However, the tests themselves are not sufficiently sensitive for individual use. Not all recent infections remain recent and some long term infections can wrongly show as recent. Instead, the tests are largely for epidemiological research, use a 12-month sensitivity cut-off to broadly define a recent infection.
The phase 3 PrEP studies using monthly oral islatravir and 6-monthly lenacapavir injections.
Phase 3 studies for these long-acting compounds are already planned using counterfactual placebo controls. [3, 4, 5]
The workshop included presentations and a roundtable discussion from key researchers involved in these studies.
Recency testing has already been widely used in surveillance systems Previously referred to as RITA or STARHS testing), including in the UK for more than a decade.
Dozens of related satellite and symposium meetings looked at the importance of having a choice from different formulations and delivery methods as part of global roll out of current and pipeline PrEP. [6, 7, 8]
- Forum for Collaborative Research. Innovative clinical trial designs to accelerate increase in PrEP choices. IAS 2021. Satellite meeting. SA15.
- Parkin N et al. HIV recent infection test-based incidence as a counter-factual for new PrEP trials. IAS 2021. Poster abstract PEC307.
- ClinicalTrials.gov. Oral islatravir (MK-8591) once-monthly as preexposure prophylaxis (PrEP) in men and transgender women who have sex with men and are at high risk for HIV-1 infection (MK-8591-024)
- ClinicalTrials.gov. Oral ISL QM as PrEP in cisgender women at high risk for HIV-1 infection (MK-8591-022)
- ClinicalTrials.gov. Study to assess the effectiveness and safety of lenacapavir for HIV pre-exposure prophylaxis,
- PATH, AVAC, International AIDS Society. Paving the road for new PrEP products: The promise of differentiated, simplified, and decentralized delivery to maximize the potential of new PrEP products. IAS 2021 satellite meeting SY20.
- Build it: But will they come? Prevention efficacy versus population effectiveness. IAS 2021 satellite meeting SY24.
- Bringing the Dual Prevention Pill to market: Opportunities for HIV and pregnancy prevention and implications for future multipurpose prevention technologies (MPTs). IAS 2021 satellite meeting SY27.