Vaginal microbiota and mucosal pharmacokinetics of tenofovir in healthy women using tenofovir and tenofovir/levonorgestrel vaginal rings

• Published in: PloS one 2019-05, Vol.14 (5), p.e0217229
• Main Authors: Thurman, Andrea Ries, Schwartz, Jill L, Ravel, Jacques, Gajer, Pawel, Marzinke, Mark A, Yousefieh, Nazita, Anderson, Sharon M, Doncel, Gustavo F
• Format: Article
• Language: English
• Subjects: Abundance; Adenine - analogs & derivatives; Adenine - pharmacokinetics; Adult; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - pharmacokinetics; Antiretroviral agents; Antiretroviral drugs; Antiviral Agents - administration & dosage; Antiviral Agents - pharmacokinetics; Bacterial vaginosis; Biology and Life Sciences; Contraceptive Agents, Hormonal - administration & dosage; Contraceptive Devices, Female; Contraceptive drug implants; Device Removal; Dosage and administration; Female; Gardnerella vaginalis; Gene sequencing; Genes; Genetic aspects; Genomes; Health aspects; Herpes Genitalis - prevention & control; Herpes viruses; HIV; HIV Infections - prevention & control; HIV patients; Human immunodeficiency virus; Humans; Infections; Lactobacillus; Levonorgestrel; Levonorgestrel - administration & dosage; Liquefied natural gas; Medical research; Medical schools; Medicine and Health Sciences; Microbicides; Microbiota; Microbiota (Symbiotic organisms); Microbiota - drug effects; Microbiota - genetics; Middle Aged; Mucosa; Mucous Membrane - drug effects; Mucous Membrane - metabolism; Organophosphates - pharmacokinetics; Pharmacokinetics; Pharmacology; Prevention; Q values; Randomization; RNA; rRNA 16S; Tenofovir; Tenofovir - administration & dosage; Tenofovir - pharmacokinetics; Tissues; Vagina; Vagina - drug effects; Vagina - metabolism; Vagina - microbiology; Women's health; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0217229

Recent data support that the vaginal microbiota may alter mucosal pharmacokinetics (PK) of topically delivered microbicides. Our team developed an intravaginal ring (IVR) that delivers tenofovir (TFV) (8-10 mg/day) alone or with levonorgestrel (LNG) (20 ug/day). We evaluated the effect of IVRs on the vaginal microbiota, and describe how the vaginal microbiota impacts mucosal PK of TFV. CONRAD A13-128 was a randomized, placebo controlled phase I study. We randomized 51 women to TFV, TFV/LNG or placebo IVR. We assessed the vaginal microbiota by sequencing the V3-V4 regions of 16S rRNA genes prior to IVR insertion and after approximately 15 days of use. We measured the concentration of TFV in the cervicovaginal (CV) aspirate, and TFV and TFV-diphosphate (TFV-DP) in vaginal tissue at the end of IVR use. The change in relative or absolute abundance of vaginal bacterial phylotypes was similar among active and placebo IVR users (all q values >0.13). TFV concentrations in CV aspirate and vaginal tissue, and TFV-DP concentrations in vaginal tissue were not significantly different among users with community state type (CST) 4 versus those with Lactobacillus dominated microbiota (all p values >0.07). The proportions of participants with CV aspirate concentrations of TFV >200,000 ng/mL and those with tissue TFV-DP concentrations >1,000 fmol/mg were similar among women with anaerobe versus Lactobacillus dominated microbiota (p = 0.43, 0.95 respectively). There were no significant correlations between the CV aspirate concentration of TFV and the relative abundances of Gardnerella vaginalis or Prevotella species. Tissue concentrations of TFV-DP did not correlate with any the relative abundances of any species, including Gardnerella vaginalis. In conclusion, active IVRs did not differ from the placebo IVR on the effect on the vaginal microbiota. Local TFV and TFV-DP concentrations were high and similar among IVR users with Lactobacillus dominated microbiota versus CST IV vaginal microbiota. Trial registration: ClinicalTrials.gov NCT02235662.