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

Ian McGowan, Timothy Wilkin, Raphael J. Landovitz, Chunyuan Wu, Ying Chen, Mark A Marzinke, Craig Hendrix, Paul Richardson, Susan Eshleman, Adriana Andrade, Wairimu Chege, Peter L. Anderson, Marybeth McCauley, Jason Farley, Kenneth H. Mayer, Peter Anton, Rhonda M. Brand, Ross D. Cranston, Roy Gulick

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)237-246
Number of pages10
JournalAIDS (London, England)
Volume33
Issue number2
DOIs
StatePublished - Feb 1 2019

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Tenofovir
Pharmacokinetics
Chemokine Receptors
Lymphoid Tissue
C Chemokines
HIV
Transgender Persons
T-Lymphocytes
Phenotype
CC Chemokines
maraviroc
Pre-Exposure Prophylaxis
HIV Infections
Mass Spectrometry
Flow Cytometry
Acquired Immunodeficiency Syndrome
Genotype
Clinical Trials
Biopsy
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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The pharmacokinetics, pharmacodynamics, and mucosal responses to maraviroc-containing pre-exposure prophylaxis regimens in MSM. / McGowan, Ian; Wilkin, Timothy; Landovitz, Raphael J.; Wu, Chunyuan; Chen, Ying; Marzinke, Mark A; Hendrix, Craig; Richardson, Paul; Eshleman, Susan; Andrade, Adriana; Chege, Wairimu; Anderson, Peter L.; McCauley, Marybeth; Farley, Jason; Mayer, Kenneth H.; Anton, Peter; Brand, Rhonda M.; Cranston, Ross D.; Gulick, Roy.

In: AIDS (London, England), Vol. 33, No. 2, 01.02.2019, p. 237-246.

Research output: Contribution to journalArticle

McGowan, I, Wilkin, T, Landovitz, RJ, Wu, C, Chen, Y, Marzinke, MA, Hendrix, C, Richardson, P, Eshleman, S, Andrade, A, Chege, W, Anderson, PL, McCauley, M, Farley, J, Mayer, KH, Anton, P, Brand, RM, Cranston, RD & Gulick, R 2019, 'The pharmacokinetics, pharmacodynamics, and mucosal responses to maraviroc-containing pre-exposure prophylaxis regimens in MSM', AIDS (London, England), vol. 33, no. 2, pp. 237-246. https://doi.org/10.1097/QAD.0000000000002038
McGowan, Ian ; Wilkin, Timothy ; Landovitz, Raphael J. ; Wu, Chunyuan ; Chen, Ying ; Marzinke, Mark A ; Hendrix, Craig ; Richardson, Paul ; Eshleman, Susan ; Andrade, Adriana ; Chege, Wairimu ; Anderson, Peter L. ; McCauley, Marybeth ; Farley, Jason ; Mayer, Kenneth H. ; Anton, Peter ; Brand, Rhonda M. ; Cranston, Ross D. ; Gulick, Roy. / The pharmacokinetics, pharmacodynamics, and mucosal responses to maraviroc-containing pre-exposure prophylaxis regimens in MSM. In: AIDS (London, England). 2019 ; Vol. 33, No. 2. pp. 237-246.
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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.",
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T1 - The pharmacokinetics, pharmacodynamics, and mucosal responses to maraviroc-containing pre-exposure prophylaxis regimens in MSM

AU - McGowan, Ian

AU - Wilkin, Timothy

AU - Landovitz, Raphael J.

AU - Wu, Chunyuan

AU - Chen, Ying

AU - Marzinke, Mark A

AU - Hendrix, Craig

AU - Richardson, Paul

AU - Eshleman, Susan

AU - Andrade, Adriana

AU - Chege, Wairimu

AU - Anderson, Peter L.

AU - McCauley, Marybeth

AU - Farley, Jason

AU - Mayer, Kenneth H.

AU - Anton, Peter

AU - Brand, Rhonda M.

AU - Cranston, Ross D.

AU - Gulick, Roy

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

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