The pharmacokinetics, pharmacodynamics, and mucosal responses to maraviroc-containing pre-exposure prophylaxis regimens in MSM

Abstract

HPTN 069/ACTG A5305 was a study of 48-week oral PrEP regimens in MSM and transgender women A rectal substudy was included to evaluate drug concentrations in rectal compartment vs. blood, gut-associated lymphoid tissue (GALT) responses to four antiretroviral (ARV) PrEP regimens (maraviroc (MVC), MVC + emtricitabine (FTC), MVC + tenofovir disoproxil fumarate (TDF), and TDF + FTC), and to determine whether ARV exposure was associated with ex vivo suppression of HIV infection in colorectal explants. Methods: CCR5 genotype was characterized using PCR. At baseline and at weeks 24, 48, and 49, GALT phenotype was characterized by flow cytometry, rectal biopsies were challenged with HIV-1 BaL , and tissue and plasma pharmacokinetics were measured via mass spectrometry. Results: Exposure to MVC was not associated with increased expression of CD4+/CCR5+ HIV target T-cells. Significant ex vivo viral suppression compared to baseline was seen at Weeks 24 and 48, ranging from 1.4 to 1.8 log 10 for all study regimens except the MVC-alone arm which did not show statistically significant viral suppression at Week 48. Tissue concentrations of tenofovir (TFV), TFV-diphosphate (DP), and FTC were correlated with viral suppression. Conclusions: MVC-containing HIV PrEP regimens did not increase GALT CD4+ T-cell activation or the CD4+/CCR5+ phenotype. No virologic suppression was seen with MVC-alone at Week 48 compared to combination regimens, suggesting MVC monotherapy might be less effective than combination ARV PrEP regimens.

Translational Approach to Predicting the Efficacy of Maraviroc-Based Regimens as HIV Preexposure Prophylaxis

“…These data suggest that MVC in combination with either TFV or FTC would show enhanced effectiveness as PrEP compared to that of the monotherapy regimen. Our conclusions agree with those of McGowan et al (25), who showed that MVC alone showed limited viral suppression in an ex vivo rectal biopsy system compared to MVC in combination with either TFV or FTC.…”

Higher colorectal tissue HIV infectivity in cisgender women compared with MSM before and during oral preexposure prophylaxis

“…We report the mucosal tissue pharmacokinetics, pharmacodynamic and flow cytometry results of CGW (first reported here) in comparison to previously reported MSM results [14]. This tissue substudy was nested within HPTN 069/ACTG 5305 study (NCT01505114), a Phase 2 prospective, randomized, controlled, double-blind trial of the safety and tolerability of three candidate PrEP regimens, MVC 300 mg, MVC 300 mg/FTC 200 mg (MVC/FTC) and MVC 300 mg/TDF 300 mg, compared with a control group who received TDF 300 mg/FTC 200 mg [15,16].…”

“…The isolation of colorectal biopsy mononuclear cells and flow cytometry analysis for CD3þ, CD4þ, CD8þ and CD45þ [surface (FCS) and intracellular markers (FCI)] and CD38þ, CD69þ, HLA-DRþ, CCR5þ, CXCR4þ, Ki67þ (FCS only) was described previously [14,22].…”

The Pre-clinical Toolbox of Pharmacokinetics and Pharmacodynamics: in vitro and ex vivo Models

“…These results reflect the heterogeneity in CCR5 conformation and/or expression in the different mucosal tissues, which cannot be assessed in TZM-bl cells, a model expressing high levels of CCR5 (Fletcher et al, 2016; Herrera et al, 2016). Interestingly, the limited activity of maraviroc observed in tissue explants predicted the lack of efficacy of this drug in oral PrEP NHP studies (Massud et al, 2013) and clinical trials (Fox et al, 2016; Gulick et al, 2017; McGowan et al, 2019) despite accumulation of the drug in the mucosal compartments.…”

“…Studies in NHPs delivered proof of principle that efficacy of topical dosing with tenofovir against rectal challenge could be replicated by ex vivo challenge of tissue resections obtained from NHPs topically dosed in vivo (Cranage et al, 2008). In fact, this approach of ex vivo challenge of mucosal biopsies is increasingly being used as an endpoint of ex vivo efficacy of PrEP (Anton et al, 2012; Harman et al, 2012; Richardson-Harman et al, 2012, 2014; McGowan et al, 2015, 2019; Fox et al, 2016) and vaccine trials (Herrera et al, 2014). This model can be used with cervicovaginal samples frozen at the trial sites and thawed at a centralized facility for ex vivo challenge (Gupta et al, 2006; Lackman-Smith et al, 2008); however, it requires the use of fresh tissue when assessing efficacy in the colorectal tract (McGowan et al, 2012).…”