接受多替拉韦+拉米夫定双联疗法作为转换策略的患者血液和男性生殖器官隔室的药物病毒学分析（ANRS 167 LAMIDOL试验）

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

作者信息

Charpentier Charlotte, Peytavin Gilles, Raffi François, Burdet Charles, Landman Roland, Lê Minh P, Katlama Christine, Collin Gilles, Benalycherif Aida, Cabie André, Mentré France, Yazdanpanah Yazdan, Descamps Diane, Joly Véronique

机构信息

Université de Paris, INSERM UMR 1137 IAME, F-75018 Paris, France.

Laboratoire de Virologie, AP-HP, Hôpital Bichat-Claude Bernard, F-75018 Paris, France.

出版信息

J Antimicrob Chemother. 2020 Jun 1;75(6):1611-1617. doi: 10.1093/jac/dkaa035.

DOI:10.1093/jac/dkaa035

PMID:32091102

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.

摘要

目的

描述在多替拉韦+拉米夫定维持性双联治疗期间的血浆残留HIV病毒血症、细胞HIV储存库大小、血浆药物浓度及其在男性生殖道中的渗透情况。

患者与方法

ANRS167 LAMIDOL研究纳入了104例病毒学抑制的患者，将其转换为多替拉韦+拉米夫定治疗。在这项药物病毒学亚研究中，在多替拉韦+拉米夫定治疗的第0天（D0）、第24周（W24）和第48周测量超敏血浆病毒载量（USpVL）和血浆药物浓度，并在第-8周和第48周测量HIV-DNA。在D0和W24从18名参与者收集精液样本。使用超高效液相色谱-串联质谱法（UPLC-MS/MS）测量总血浆和未结合血浆及精液中的药物浓度。

结果

第-8周时HIV-DNA中位数为2.5 log10拷贝/106外周血单个核细胞（IQR = 2.2 - 3.0，n = 100），第48周时为2.4 log10拷贝/106外周血单个核细胞（IQR = 2.1 - 2.9，n = 100）（P = 0.17）。未检测到USpVL的患者比例在D0、W24和W48分别为38%（n = 98）、43%（n = 98）和49%（n = 97）（P = 0.08）。各时间点之间血浆多替拉韦的总浓度和未结合浓度稳定（P = 0.13），除一例之外所有血浆多替拉韦总浓度均充足。多替拉韦在血浆中的游离分数中位数为0.21%。24小时时血浆和精液中多替拉韦总浓度的中位数分别为1812 ng/mL和206 ng/mL。多替拉韦和拉米夫定的精液/血浆总浓度中位数比值分别为11.6%和2478%。在D0时，一名患者（5.9%）的精液中检测到HIV-RNA（365至475拷贝/mL），在W24时，两名患者（11.8%）的精液中检测到HIV-RNA。