Ian McGowan1, Timothy Wilkin2, Raphael J Landovitz3, Chunyuan Wu4, Ying Chen4, Mark A Marzinke5, Craig W Hendrix6, Paul Richardson5, Susan H Eshleman5, Adriana Andrade7, Wairimu Chege8, Peter L Anderson9, Marybeth McCauley10, Jason Farley7, Kenneth H Mayer11, Peter Anton3,12, Rhonda M Brand1, Ross D Cranston1, Roy Gulick2. 1. Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania. 2. Division of Infectious Diseases, Weill Cornell Medicine, New York, New York. 3. Division of Infectious Diseases, Department of Medicine, Center for AIDS Research and Education & Center for HIV Prevention, David Geffen School of Medicine at UCLA, Los Angeles, California. 4. Protocol Statistician, FHCRC-SCHARP, Seattle, Washington. 5. Division of Clinical Pharmacology, Department of Pathology. 6. Division of Clinical Pharmacology. 7. Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. 8. Division of AIDS, Clinical Prevention Research Branch, Prevention Sciences Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. 9. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado. 10. FHI 360, Washington, District of Columbia. 11. Department of Medicine, Fenway Health, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. 12. Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
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.
RCT Entities:
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 TFVdisoproxil 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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