TUAC0403LB
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Title
DISCOVER study for HIV pre-exposure prophylaxis (PrEP): F/TAF has a more rapid onset and longer sustained duration of HIV protection compared with F/TDF
Presenter
Christoph D. Spinner
Authors
C.D. Spinner1, J. Brunetta2, P. Shalit3, M. Prins4, M. Cespedes5, A. Mathias6, S. Majeed6, R. Ebrahimi6, D. Brainard6, M. Das6, S. McCallister6, F. Cruickshank7, J. Halperin8, J.E. Gladstein9, P.W.G. Mallon10
Institutions
1Technische Universität München, Department of Medicine II, Munich, Germany, 2Maple Leaf Medial Clinic, Toronto, Canada, 3UWSOM, University of Washington, Seattle, United States, 4Public Health Service of Amsterdam (GGD), Department of Infectious Diseases Research and Prevention, Amsterdam, Netherlands, 5Icahn School of Medicine at Mount Sinai, Division of Infectious Disease, New York, United States, 6Gilead Sciences, Foster City, United States, 7University of Miami, School of Medicine, Department of Infectious Diseases, Miami, United States, 8CrescentCare Health and Wellness Center, New Orleans, United States, 9Global Healthcare LA, Los Angeles, United States, 10School of Medicine, University College Dublin, Dublin, Ireland

Background: In DISCOVER, F/TAF was statistically noninferior to F/TDF. However, there were numerically 53% fewer HIV infections in the F/TAF arm vs. F/TDF . We explored HIV risk, STIs, adherence, and pharmacokinetic (PK) data to evaluate this imbalance.
Methods: In all participants (N=5,387), we compared HIV risk from computer-aided self-interview, lab-assessed STIs, and adherence by pill count and self-report. In a randomized subset, we measured adherence by intracellular TFV-DP concentrations in peripheral blood mononuclear cells (PBMCs) (Week 4; n=324) and in dried blood spots (DBS) (every 12 weeks; n=309). We assessed the relationship between adherence (TFV-DP in DBS) and efficacy using exact conditional logistic regression in a nested case-control-study; every incident HIV case paired with 5 controls matched by treatment arm, diagnosis date, rectal STI, and geography (cases=22, controls=109). We estimated duration of protection using PK data from historic Phase 1 studies to simulate TFV-DP concentrations for TAF and TDF.
Results: There were no differences in HIV risk, STIs, or adherence by pill count or self-report (N=5,387). Week 4 PBMC TFV-DP levels were 6.3 fold higher with F/TAF vs. F/TDF; 98% of F/TAF vs 65% of F/TDF participants had TFV-DP above the protective threshold (p< 0.001). The median duration of protection after last dose at steady state was 60% longer for F/TAF vs. F/TDF. Low DBS TFV-DP levels (adherence < 2 doses/week) were associated with increased risk of HIV for F/TAF: odds ratio [OR] 29.4 and F/TDF: OR 13.2 (p< 0.001 for both) with similar results from sensitivity analyses excluding suspected baseline infections.
Conclusions: Low TFV-DP concentrations were associated with an increased risk of HIV acquisition.There was no difference in HIV risk or adherence between arms, but there were significant differences in TFV-DP levels. TAF has advantageous PK parameters for HIV prevention compared to TDF including a more rapid, higher, and longer sustained duration of TFV-DP levels above the protective threshold in PBMCs, which may explain the lower number of HIV infections in the F/TAF vs. F/TDF in DISCOVER.


Drug (Active Moiety)TAF 25 mg (TFV-DP)TDF 300 mg (TFV-DP)
Median (IQR) PBMC Ctau fmol/106 cells (Ctau [trough] is the concentration at 24 hrs post dose)404 (226, 711)61 (34, 105)
Protective Threshold in PBMCs (EC90) fmol/106cells40 (Anderson, 2012)40 (Anderson, 2012)
Time to Protective Threshold1-2 hrs post single dose (historic Phase 1 data from GS-US-380-4017, Schwartz, 2018)3-4 days (Anderson, 2012)
Median Duration of Protection after Last Daily Dose (after steady state achieved)16 days10 days
[Table 1: Key HIV Prevention Clinical Pharmacology Parameters: TFV-DP with F/TAF and F/TDF]