Melanie R Nicol1, Prosperity Eneh1, Rita Nakalega2, Thomas Kaiser3, Samuel Kabwigu2, Esther Isingel2, Mags Beksinska4, Craig Sykes5, Mary Glenn Fowler6, Todd T Brown7, Christopher Staley3, Flavia Kiweewa Matovu2,8. 1. Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis. 2. Makerere University-John Hopkins University Research Collaboration, Kampala, Uganda. 3. Department of Surgery, University of Minnesota, Minneapolis. 4. School of Clinical Sciences, University of the Witwatersrand, Durban, South Africa. 5. Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill. 6. Department of Pathology, John Hopkins University, Baltimore, Maryland. 7. Department of Medicine, John Hopkins University, Baltimore, Maryland. 8. Department of College of Health Sciences, Makerere University, Kampala, Uganda.
Abstract
BACKGROUND: Effective concentrations of antiretrovirals in the female genital tract (FGT) are critical for suppression of viral shedding or effective preexposure prophylaxis. The disposition of tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) in the FGT have been previously described. Despite widespread use, however, lamivudine triphosphate (3TC-TP) exposure in the FGT is unknown. Depot medroxyprogesterone acetate (DMPA) and vaginal dysbiosis have been implicated in increased risk of human immunodeficiency virus (HIV) acquisition, but whether they alter TFV-DP or 3TC-TP exposure, and therefore compromise prevention efficacy, is unknown. METHODS: Fifty premenopausal women living with HIV in Kampala, Uganda, and receiving daily tenofovir disoproxil fumarate/lamivudine were recruited. Ectocervical biopsies were obtained for quantification of TFV-DP and 3TC-TP using liquid chromatography-mass spectrometry. 16S ribosomal RNA gene sequencing was performed on DNA extracted from vaginal swabs. Wilcoxon rank-sum was used to test for differences between contraceptive groups. RESULTS: 3TC-TP concentrations were on average 17-fold greater than TFV-DP concentrations in cervical tissues. TFV-DP concentrations in cervical biopsies were 76% greater in DMPA users compared with women using nonhormonal contraception (n = 23 per group). Abundance of Lactobacillus in vaginal swabs was correlated with 3TC-TP concentrations in cervical tissues. CONCLUSIONS: We found that TFV-DP concentrations were significantly greater in DMPA users compared with women using nonhormonal contraception, suggesting that prevention efficacy is unlikely to be compromised by DMPA use. Similar to reports of FTC-TP, 3TC-TP exposure was significantly greater than TFV-DP in cervical tissue and was correlated with abundance of Lactobacillus. These data support lamivudine as an option for preexposure prophylaxis. CLINICAL TRIALS REGISTRATION: NCT03377608.
BACKGROUND: Effective concentrations of antiretrovirals in the female genital tract (FGT) are critical for suppression of viral shedding or effective preexposure prophylaxis. The disposition of tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) in the FGT have been previously described. Despite widespread use, however, lamivudine triphosphate (3TC-TP) exposure in the FGT is unknown. Depot medroxyprogesterone acetate (DMPA) and vaginal dysbiosis have been implicated in increased risk of human immunodeficiency virus (HIV) acquisition, but whether they alter TFV-DP or 3TC-TP exposure, and therefore compromise prevention efficacy, is unknown. METHODS: Fifty premenopausal women living with HIV in Kampala, Uganda, and receiving daily tenofovir disoproxil fumarate/lamivudine were recruited. Ectocervical biopsies were obtained for quantification of TFV-DP and 3TC-TP using liquid chromatography-mass spectrometry. 16S ribosomal RNA gene sequencing was performed on DNA extracted from vaginal swabs. Wilcoxon rank-sum was used to test for differences between contraceptive groups. RESULTS: 3TC-TP concentrations were on average 17-fold greater than TFV-DP concentrations in cervical tissues. TFV-DP concentrations in cervical biopsies were 76% greater in DMPA users compared with women using nonhormonal contraception (n = 23 per group). Abundance of Lactobacillus in vaginal swabs was correlated with 3TC-TP concentrations in cervical tissues. CONCLUSIONS: We found that TFV-DP concentrations were significantly greater in DMPA users compared with women using nonhormonal contraception, suggesting that prevention efficacy is unlikely to be compromised by DMPA use. Similar to reports of FTC-TP, 3TC-TP exposure was significantly greater than TFV-DP in cervical tissue and was correlated with abundance of Lactobacillus. These data support lamivudine as an option for preexposure prophylaxis. CLINICAL TRIALS REGISTRATION: NCT03377608.
Authors: Mackenzie L Cottrell; Kuo H Yang; Heather M A Prince; Craig Sykes; Nicole White; Stephanie Malone; Evan S Dellon; Ryan D Madanick; Nicholas J Shaheen; Michael G Hudgens; Jacob Wulff; Kristine B Patterson; Julie A E Nelson; Angela D M Kashuba Journal: J Infect Dis Date: 2016-02-24 Impact factor: 5.226
Authors: Sharon M Seifert; Xinhui Chen; Amie L Meditz; Jose R Castillo-Mancilla; Edward M Gardner; Julie A Predhomme; Carolyn Clayton; Gregory Austin; Brent E Palmer; Jia-Hua Zheng; Brandon Klein; Becky J Kerr; L Anthony Guida; Caitlin Rower; Joseph E Rower; Jennifer J Kiser; Lane R Bushman; Samantha MaWhinney; Peter L Anderson Journal: AIDS Res Hum Retroviruses Date: 2016-09-19 Impact factor: 2.205
Authors: Renee Heffron; R Scott McClelland; Jennifer E Balkus; Connie Celum; Craig R Cohen; Nelly Mugo; Elizabeth Bukusi; Deborah Donnell; Jairam Lingappa; James Kiarie; Tina Fiedler; Matthew Munch; David N Fredricks; Jared M Baeten Journal: Lancet HIV Date: 2017-07-18 Impact factor: 12.767
Authors: J Gregory Caporaso; Christian L Lauber; William A Walters; Donna Berg-Lyons; James Huntley; Noah Fierer; Sarah M Owens; Jason Betley; Louise Fraser; Markus Bauer; Niall Gormley; Jack A Gilbert; Geoff Smith; Rob Knight Journal: ISME J Date: 2012-03-08 Impact factor: 10.302
Authors: Sharon L Achilles; Michele N Austin; Leslie A Meyn; Felix Mhlanga; Zvavahera M Chirenje; Sharon L Hillier Journal: Am J Obstet Gynecol Date: 2018-03-02 Impact factor: 8.661
Authors: Chelsea B Polis; Kathryn M Curtis; Philip C Hannaford; Sharon J Phillips; Tsungai Chipato; James N Kiarie; Daniel J Westreich; Petrus S Steyn Journal: AIDS Date: 2016-11-13 Impact factor: 4.177
Authors: Rogers Sekabira; Ian McGowan; Krista Yuhas; Rhonda M Brand; Mark A Marzinke; Yukari C Manabe; Ian Frank; Joseph Eron; Raphael J Landovitz; Peter Anton; Ross D Cranston; Peter Anderson; Kenneth H Mayer; K Rivet Amico; Timothy J Wilkin; Wairimu Chege; Adeodata R Kekitiinwa; Marybeth McCauley; Roy M Gulick; Craig W Hendrix Journal: AIDS Date: 2021-08-01 Impact factor: 4.632
Authors: Minlu Hu; Guru R Valicherla; Tian Zhou; Sharon L Hillier; Lisa C Rohan Journal: AIDS Res Hum Retroviruses Date: 2021-03-09 Impact factor: 2.205