The pharmacokinetics, pharmacodynamics, and mucosal responses to maraviroc-containing pre-exposure prophylaxis regimens in MSM. (1st February 2019)

• Record Type: Journal Article
• Authors: McGowan, Ian; Wilkin, Timothy; Landovitz, Raphael J.; Wu, Chunyuan; Chen, Ying; Marzinke, Mark A.; Hendrix, Craig W.; Richardson, Paul; Eshleman, Susan H.; Andrade, Adriana; Chege, Wairimu; Anderson, Peter L.; McCauley, Marybeth; Farley, Jason; Mayer, Kenneth H.; Anton, Peter; Brand, Rhonda M.; Cranston, Ross D.; Gulick, Roy
• Is Part Of: AIDS. Volume 33:Number 2(2019)
• Publication Date: 2019-02-01
• Subjects: explant challenge -- HIV -- maraviroc -- MSM -- pharmacodynamic -- pharmacokinetic -- clinical trial -- pre-exposure prophylaxis; AIDS (Disease) -- Periodicals; Acquired Immunodeficiency Syndrome; AIDS (Disease); Periodicals; Periodicals; 616.9792005
• DOI: 10.1097/QAD.0000000000002038
• Languages: English
• ISSNs: 0269-9370

Abstract

Abstract : Objective: HIV Prevention Trials Network 069/AIDS Clinical Trials Group A5305 was a study of 48-week oral pre-exposure prophylaxis (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 PrEP regimens [maraviroc (MVC), MVC + emtricitabine (FTC), MVC + tenofovir (TFV) disoproxil fumarate, and TFV disoproxil fumarate + FTC], and to determine whether ARV exposure was associated with ex-vivo suppression of HIV infection in colorectal explants. Methods: C-C chemokine receptor type 5 (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-1BaL, 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 with baseline was seen at Weeks 24 and 48, ranging from 1.4 to 1.8 log10 for all study regimens except the MVC-alone arm which did not show statistically significant viral suppression at Week 48. Tissue concentrations of TFV, TFV-diphosphate, and FTC were correlated with viral suppression. Conclusion: 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 with combination regimens, suggesting MVC monotherapy might be less effective than combination antiretroviral PrEP regimens.