TY  - JOUR
AU  - Garcia-Cremades, Maria
AU  - Vučićević, Katarina
AU  - Hendrix, Craig W
AU  - Jayachandran, Priya
AU  - Jarlsberg, Leah
AU  - Grant, Robert
AU  - Celum, Connie L.
AU  - Martin, Michael
AU  - Baeten, Jared M.
AU  - Marrazzo, Jeanne
AU  - Anderson, Peter
AU  - Choopanya, Kachit
AU  - Vanichseni, Suphak
AU  - Glidden, David V.
AU  - Savić, Radojka M.
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4338
AB  - 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.
PB  - Oxford University Press
T2  - Clinical Infectious Diseases
T1  - Characterizing HIV-Preventive, Plasma Tenofovir Concentrations-A Pooled Participant-level Data Analysis From Human Immunodeficiency Virus Preexposure Prophylaxis (PrEP) Clinical Trials
VL  - 75
IS  - 11
SP  - 1873
EP  - 1882
DO  - 10.1093/cid/ciac313
ER  - 

@article{
author = "Garcia-Cremades, Maria and Vučićević, Katarina and Hendrix, Craig W and Jayachandran, Priya and Jarlsberg, Leah and Grant, Robert and Celum, Connie L. and Martin, Michael and Baeten, Jared M. and Marrazzo, Jeanne and Anderson, Peter and Choopanya, Kachit and Vanichseni, Suphak and Glidden, David V. and Savić, Radojka M.",
year = "2022",
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.",
publisher = "Oxford University Press",
journal = "Clinical Infectious Diseases",
title = "Characterizing HIV-Preventive, Plasma Tenofovir Concentrations-A Pooled Participant-level Data Analysis From Human Immunodeficiency Virus Preexposure Prophylaxis (PrEP) Clinical Trials",
volume = "75",
number = "11",
pages = "1873-1882",
doi = "10.1093/cid/ciac313"
}

Garcia-Cremades, M., Vučićević, K., Hendrix, C. W., Jayachandran, P., Jarlsberg, L., Grant, R., Celum, C. L., Martin, M., Baeten, J. M., Marrazzo, J., Anderson, P., Choopanya, K., Vanichseni, S., Glidden, D. V.,& Savić, R. M.. (2022). Characterizing HIV-Preventive, Plasma Tenofovir Concentrations-A Pooled Participant-level Data Analysis From Human Immunodeficiency Virus Preexposure Prophylaxis (PrEP) Clinical Trials. in Clinical Infectious Diseases
Oxford University Press., 75(11), 1873-1882.
https://doi.org/10.1093/cid/ciac313

Garcia-Cremades M, Vučićević K, Hendrix CW, Jayachandran P, Jarlsberg L, Grant R, Celum CL, Martin M, Baeten JM, Marrazzo J, Anderson P, Choopanya K, Vanichseni S, Glidden DV, Savić RM. Characterizing HIV-Preventive, Plasma Tenofovir Concentrations-A Pooled Participant-level Data Analysis From Human Immunodeficiency Virus Preexposure Prophylaxis (PrEP) Clinical Trials. in Clinical Infectious Diseases. 2022;75(11):1873-1882.
doi:10.1093/cid/ciac313 .

Garcia-Cremades, Maria, Vučićević, Katarina, Hendrix, Craig W, Jayachandran, Priya, Jarlsberg, Leah, Grant, Robert, Celum, Connie L., Martin, Michael, Baeten, Jared M., Marrazzo, Jeanne, Anderson, Peter, Choopanya, Kachit, Vanichseni, Suphak, Glidden, David V., Savić, Radojka M., "Characterizing HIV-Preventive, Plasma Tenofovir Concentrations-A Pooled Participant-level Data Analysis From Human Immunodeficiency Virus Preexposure Prophylaxis (PrEP) Clinical Trials" in Clinical Infectious Diseases, 75, no. 11 (2022):1873-1882,
https://doi.org/10.1093/cid/ciac313 . .