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. 2022 Nov 30;75(11):1873-1882.
doi: 10.1093/cid/ciac313.

Characterizing HIV-Preventive, Plasma Tenofovir Concentrations-A Pooled Participant-level Data Analysis From Human Immunodeficiency Virus Preexposure Prophylaxis Clinical Trials

Maria Garcia-Cremades  1 , Katarina Vučićević  1   2 , Craig W Hendrix  3 , Priya Jayachandran  1 , Leah Jarlsberg  1 , Robert Grant  4 , Connie L Celum  5 , Michael Martin  6   7 , Jared M Baeten  5 , Jeanne Marrazzo  8 , Peter Anderson  9 , Kachit Choopanya  10 , Suphak Vanichseni  10 , David V Glidden  11 , Radojka M Savic  1
Affiliations

Characterizing HIV-Preventive, Plasma Tenofovir Concentrations-A Pooled Participant-level Data Analysis From Human Immunodeficiency Virus Preexposure Prophylaxis Clinical Trials

Maria Garcia-Cremades et al. Clin Infect Dis. .

Abstract

Background: Daily dosing of tenofovir disoproxil fumarate, with or without emtricitabine, has high efficacy in preventing human immunodeficiency virus (HIV) infection when individuals are adherent. The target protective plasma concentration of tenofovir (TFV), however, is not fully understood. The aim of this study is to estimate the protective TFV plasma concentration.

Methods: Participant data from TFV-based daily oral and topical active arms of phase 3 trials (iPrEx, VOICE, and Partners PrEP) were pooled (n = 2950). Individual specific risk scores (low and high risk) of acquiring HIV, based on an earlier placebo analysis, were created. Longitudinal TFV pharmacokinetics (PK), HIV outcome, individual risk scores and the effect of sex at birth data were integrated and analyzed using non-linear mixed effects models.

Results: Around 50% of the individuals were estimated to be adherent, which differed from self-reported adherence (∼90%) and large variation between longitudinal adherence patterns were identified. Following oral administration, the estimated protective TFV trough concentration was substantially higher in high-risk females (45.8 ng/mL) compared with high-risk males (16.1 ng/mL) and to low-risk individuals (∼7.5 ng/mL). Dosing simulations indicated that high-risk women require full adherence to maintain protective levels.

Conclusions: Using the largest PK-HIV outcome database to date, we developed a population adherence-PK-risk-outcome model. Our results indicate that high-risk females need higher levels of plasma TFV to achieve HIV protection compared with males. HIV protection exceeds 90% in all populations if daily adherence is achieved.

Keywords: HIV; HIV outcome; drug protective plasma concentration; preexposure prophylaxis.

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Conflict of interest statement

Potential conflicts of interest. D. V. G. has served on an Advisory Board for Merck and has personal fees from Gilead. C. W. H. contracts for clinical research, paid to Hopkins and unrelated to this work, from Gilead, Merck, and ViiV Healthcare; consulting fees from Gilead (scientific Advisory Board, travel support, paid to author), Merck (scientific Advisory Board, travel support and honoraria, paid to author), and ViiV Healthcare (scientific Advisory Board, travel support and honoraria, paid to author); US patents (2 issued patents related to HIV prevention technology); and a leadership role as founder of Prionde Biopharma, LLC (company to develop human immunodeficiency virus (HIV) prevention product). P. J. reports grants or contracts unrelated to this work: T32 GM007546 from the National Institute of General Medical Sciences (NIGMS). R. G. reports grants or contracts unrelated to this work from Gilead Sciences: employer, UCSF, has received funding to support work as a site investigator for clinical trials related to preexposure prophylaxis using agents other than FTC/TDF; and payment for expert testimony from the US Department of Justice (related to a patent held by the US Government related to preexposure prophylaxis using tenofovir esters and emtricitabine). C. L. C. reports consulting fees as a scientific advisor to Merck and Gilead Sciences. J. M. B. reports grants to institution, unrelated to this work, from NIH and BMGF and is an employee of Gilead Sciences (salary, stock, options). J. M. reports consulting fees and participation on Scientific Advisory Board from Merck and Gilead Sciences and is treasurer and board member for the Infectious Disease Society of America. P. A. reports contracts or grants unrelated to this work from Gilead Sciences (paid to institution); and consulting fees paid to author from Gilead Sciences, Merck, and ViiV. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Schematic representation of the PKPD model. The full PKPD model links the adherence-PK model for both routes of administration to the probability of acquiring HIV infection over time. The population-specific risk factors refer to the predictors of HIV risk for each study that were identified in the companion submitted paper. p(HIV) represents the probability of HIV. PK parameter definition: ka, absorption rate constant. CL, clearance; F, drug bioavailability; HIV, human immunodeficiency virus; Q, intercompartmental clearance; Vc and Vp, volume of central and peripheral compartment, respectively.
Figure 2.
Figure 2.
Enrollment, follow-up, and pharmacokinetics (PK) inclusion criteria for study participants. FTC, emtricitabine; HIV, human immunodeficiency virus; PrEP, preexposure prophylaxis; TDF, tenofovir disoproxil fumarate; TFV, tenofovir.
Figure 3.
Figure 3.
Summary of HIV-positive and HIV-*negative individuals and their Cavg levels distribution, for the different risk and sex at birth stratification groups for those in the oral administration arm (with or without FTC). Numbers indicate number of HIV seroconversions/total number of individuals in that subgroup. Proportion of HIV seroconversion by strata is shown in red. FTC, emtricitabine; HIV, human immunodeficiency virus; MSM, males who have sex with males; PrEP, preexposure prophylaxis; TDF, tenofovir disoproxil fumarate; TFV, tenofovir.
Figure 4.
Figure 4.
Final PKPD exploration and evaluation. (A) Predicted baseline HIV probability distribution of the pooled data using the risk predictor algorithm developed in the placebo arm analysis. (B) Kaplan-Meier VPC plot stratified by risk levels. (C) Kaplan-Meier VPC plot stratified by target concentration for moderate- to high-risk individuals. Continuous lines in the VPC plots represent real data; shaded areas represent 95% confidence intervals for simulated data. Moderate- to high-risk EC50 and EC90 values (Cavg) are 3.53 and 31.7 ng/mL for men and 11.2 and 100.8 ng/mL for women, respectively. HIV, human immunodeficiency virus; PKPD, pharmacokinetics/pharmacodynamic.
Figure 5.
Figure 5.
PK model simulations in men and women following oral administration of TDF (300 mg) for sample adherence patterns. Dark blue line represents the typical PK population profile, whereas gray shadows represent individual PK profiles (200) including interindividual variability variability. Dashed lines indicate the target Ctrough levels associated with a 90% decrease in the probability of HIV for men and women at high-moderate subgroups and for those in a low-risk subgroup. Arrows indicate the time the dose is administered. Sample adherence patters are daily (orange arrows), every 2 days (blue arrows), and every 3 days (purple arrows). HIV, human immunodeficiency virus; PK, pharmacokinetics; TDF, tenofovir disoproxil fumarate.
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References

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