999. Using the F/TDF Adherence-Efficacy Relationship to Calculate Background HIV incidence: Results from the DISCOVER trial
Authors: Glidden David V , Dunn David T , Das Moupali , Ebrahimi Ramin , Zhong Lijie , Stirrup Oliver T , Anderson Peter L 
Published: January 2021

Abstract

Background
RRandomized trials of new PrEP agents compare to oral emtricitabine+tenofovir disoproxil fumarate (F/TDF) and do not have a placebo arm. We used the well-characterized adherence-efficacy relationship for F/TDF from iPrEX OLE, to back-calculate the (non-PrEP) background HIV incidence (bHIV) in the F/TDF arm of DISCOVER and estimate comparative efficacy (to bHIV).

Methods
TDISCOVER is an ongoing randomized active-controlled trial in 5,387 men who have sex with men and transgender women that demonstrated non-inferiority of F+tenofovir alafenamide (F/TAF) to F/TDF (IRR 0.47 (95% CI 0.19, 1.15). TFV-DP levels in DBS were assessed for all diagnosed with HIV and in a randomized subset of 10%. We used a Bayesian model with a prior distribution, derived from iPrEx OLE, relating TFV-DP levels to HIV prevention efficacy: eg TFV-DP levels of &lt; 350 (low), 350 to &lt; 700 (medium) and ≥700 (high) fmol/punch were assumed to provide 0%, 86% and 98% HIV protection, respectively. This prior, combined with F/TDF seroconversion rate and TFV-DP levels, yields Bayesian inferences on the bHIV. In R, STAN was used to sample 10,000 realizations from the posterior distribution.

Results
There were 6 vs. 11 post-baseline HIV infections (0.14 v. 0.25 per 100 person-years [PY]) on F/TAF and F/TDF. Of the 11 on F/TDF, 10 had low, 0 had medium, and 1 had high TFV-DP levels; among HIV-negative controls, 5% of the person-time had low, 9% had medium, and 86% had high TFV-DP levels. A non-informative prior distribution for bHIV, combined with the prior for TFV-DP level-efficacy relationship, yielded a posterior bHIV incidence [0.80 Bayesian credible interval (CrI)] of 3.4/100 [1.9, 6.0/100] PY; which suggests a median F/TAF efficacy [0.95 CrI] of 96% [88%,99%] and 93% [87%,96%] for F/TDF compared to bHIV. If we chose a conservative prior distribution for bHIV of 1.0/100 PY, the model yields a median posterior bHIV [0.80 CrI] of 2.8/100 [1.7, 4.7/100] PY; which suggests a median efficacy [0.95 Cr] of 95% [86%, 99%] for F/TAF and 92% [86%, 67%] for F/TDF compared to bHIV with corresponding number of HIV infections averted of 117 and 114, respectively (Figure).
Figure.

Conclusion
The F/TDF adherence-efficacy relationship can be used to back-calculate bHIV incidence in MSM/TW PrEP trials and assess the efficacy of new PrEP agents compared to bHIV.

Disclosures
David V. Glidden, MD, Gilead Sciences Inc. (Other Financial or Material Support, Personal fees) David T. Dunn, MD, Gilead Sciences Inc. (Other Financial or Material Support, Personal fees)Viiv Healthcare (Other Financial or Material Support, Personal fees) Moupali Das, MD, Gilead Sciences Inc. (Employee, Shareholder) Ramin Ebrahimi, MSc, Gilead Sciences Inc. (Employee, Shareholder) Lijie Zhong, PhD, Gilead Sciences Inc. (Employee, Shareholder) Oliver T. Stirrup, MD, Gilead Sciences Inc. (Other Financial or Material Support, Personal fees) Peter L. Anderson, PharmD, Gilead Sciences Inc. (Other Financial or Material Support, Personal fees)