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

Date Published: May 20, 2019

Publisher: Public Library of Science

Author(s): Andrea Ries Thurman, Jill L. Schwartz, Jacques Ravel, Pawel Gajer, Mark A. Marzinke, Nazita Yousefieh, Sharon M. Anderson, Gustavo F. Doncel, Francesca Ceccherini-Silberstein.


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.

Partial Text

Over 35 million people worldwide are infected with human immunodeficiency virus type 1 (HIV-1) [1]. Herpes simplex virus type 2 (HSV-2) is one of the most prevalent sexually transmitted infection (STI) globally and is linked to an increased risk of HIV-1 acquisition and transmission [2, 3]. Almost half of all pregnancies worldwide, estimated to be over 100 million annually, are unintended [4–6]. Products that offer protection against multiple STIs (e.g. HSV-2 and HIV-1), or both STIs and unintended pregnancy, termed multi-purpose prevention technologies (MPTs), are urgently needed to reduce these global health burdens. Women have overwhelmingly indicated they prefer an MPT product over single-indication products [7]. CONRAD and our collaborators developed two MPT intravaginal rings (IVRs) which release tenofovir (TFV) alone (active against HIV-1 and HSV-2) and TFV in combination with levonorgestrel (LNG) (contraceptive) for at least 90 days [8, 9], and performed a phase I study in healthy women [10].

This is the first study to use 16S rRNA gene sequence analyses to examine the effect of TFV releasing IVRs on the vaginal microbiota composition and structure, and describe the impact of vaginal microbiota composition on topical vaginal TFV PK. These data are important given the current concerns regarding the potential negative impact of the vaginal microbiome on topical antiretroviral PK, with particular emphasis on TFV PK in two recent studies [16, 17] of single agent topical, peri-coitally dosed products.

This first-in-woman study of two IVRs releasing TFV and TFV/LNG showed that the IVRs were well-tolerated and safe [10]. These data support that the IVRs did not adversely change vaginal microbiota composition and structure during 2–3 weeks of use. Importantly, high local levels of TFV and TFV-DP were achieved with the IVRs among women with a diversity of vaginal microbiota, including BV associated bacteria. We propose that these IVRs will fill an important gap as MPTs that women, particularly those in less developed countries, can utilize to protect themselves from HIV-1, HSV-2 and unintended pregnancies.