Pharmacovirological analyses of blood and male genital compartment in patients receiving dolutegravir + lamivudine dual therapy as a switch strategy (ANRS 167 LAMIDOL trial)

Abstract Objectives To describe plasma residual HIV viraemia, cellular HIV reservoir size, blood plasma drug concentrations and their male genital tract penetration during the maintenance dual therapy dolutegravir + lamivudine. Patients and methods ANRS167 LAMIDOL enrolled 104 virologically suppressed patients to switch to dolutegravir + lamivudine. In this pharmacovirological substudy, ultrasensitive plasma viral load (USpVL) and plasma drug concentrations were measured at Day 0 (D0), Week 24 (W24) and W48 of dolutegravir + lamivudine, and HIV-DNA was measured at W−8 and W48. Semen samples were collected at D0 and W24 from 18 participants. Total and unbound blood and seminal plasma drug concentrations were measured using UPLC–MS/MS. Results Median HIV-DNA was 2.5 log10 copies/106 PBMC (IQR = 2.2–3.0, n = 100) at W−8 and 2.4 log10 copies/106 PBMC (IQR = 2.1–2.9, n = 100) at W48 (P = 0.17). The proportion of patients with undetected USpVL was 38% (n = 98), 43% (n = 98) and 49% (n = 97) at D0, W24 and W48, respectively (P = 0.08). Total and unbound plasma dolutegravir concentrations were stable between timepoints (P = 0.13) and all total plasma dolutegravir concentrations except one were adequate. Median free fraction of dolutegravir in plasma was 0.21%. Median blood plasma and seminal plasma concentrations of total dolutegravir at 24 h were 1812 ng/mL and 206 ng/mL, respectively. Median seminal plasma/blood plasma total concentration ratios were 11.6% and 2478% for dolutegravir and lamivudine, respectively. HIV-RNA (365 to 475 copies/mL) was detected in seminal plasma of one patient at D0 (5.9%) and of two patients at W24 (11.8%). Conclusions These findings add further important information regarding the effectiveness of dolutegravir + lamivudine maintenance dual therapy in terms of plasma residual viraemia, cellular reservoir size and drug penetration in the male genital tract.

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Emtricitabine Seminal Plasma and Blood Plasma Population Pharmacokinetics in HIV-Infected Men in the EVARIST ANRS-EP 49 Study

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01517-15 ◽

2015 ◽

Vol 59 (11) ◽

pp. 6800-6806 ◽

Cited By ~ 7

Author(s):

Elodie Valade ◽

Jean-Marc Tréluyer ◽

Silvia M. Illamola ◽

Naïm Bouazza ◽

Frantz Foissac ◽

...

Keyword(s):

Blood Plasma ◽

Seminal Plasma ◽

Genital Tract ◽

Compartment Model ◽

Effect Compartment ◽

Population Pharmacokinetic ◽

Male Genital Tract ◽

Time Curve ◽

The Impact ◽

Male Genital

ABSTRACTWe aimed to describe blood plasma (BP) and seminal plasma (SP) pharmacokinetics of emtricitabine (FTC) in HIV-1-infected men, assess its penetration in the male genital tract, and evaluate its impact on seminal plasma HIV load (spVL) detection. Men from the EVARIST ANRS EP49 study receiving combined antiretroviral therapy with FTC and with suppressed BP viral load were included in the study. A total of 236 and 209 FTC BP and SP concentrations, respectively, were available. A population pharmacokinetic model was developed with Monolix 4.1.4. The impact of FTC seminal exposure on spVL detection was explored by receiver operating characteristic (ROC) curves and mixed-effects logistic regressions. FTC BP pharmacokinetics was described by a two-compartment model. The addition of an effect compartment with different input and output constants best described FTC SP pharmacokinetics. No covariates were found to explain the variability in SP. FTC exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) were higher in SP than in BP (median AUC0–24, 38.04 and 12.95 mg · liter−1· h, respectively). The median (range) SP-to-BP AUC0–24ratio was 2.91 (0.84 to 10.08). Less than 1% of FTC AUC0–24ratios were lower than 1. The impact of FTC SP AUC0–24or FTC SP-to-BP AUC0–24ratio on spVL detection was not significant (P= 0.943 or 0.893, respectively). This is the first population model describing FTC pharmacokinetics simultaneously in both BP and SP. FTC distributes well in the male genital tract with higher FTC concentrations in SP than in BP. FTC seminal plasma exposures were considered efficient in the majority of men.

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