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Genital Inflammation is Not Associated with Decreased Vaginal Tenofovir Concentrations in Women Taking Oral PrEP
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Morris, Sheldon MD MPH1; Cottrell, Mackenzie Pharm. D2; Rawlings, Stephen A MD PhD1; Peterson, Scott PhD3; Karris, Maile MD1; Pacheco, Deedee CLT1; Chaillon, Antoine MD PhD1; Kay, Alexis BSc1; Chow, Karen BSc1; Anderson, Peter L. Pharm. D4; Gianella, Sara MD1; Blumenthal, Jill MD MAS1
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Abstract
Background:
We evaluated the association of inflammation and dysbosis on cervicovaginal fluid (CVF) tenofovir (TFV) concentrations in women taking oral tenofovir disoproxil fumarate/emtricitable (TDF/FTC) for HIV pre-exposure prophylaxis in the United States.
Setting:
Thirty-five women in a HIV PrEP implementation study attended their week 24 visit at a San Diego research clinic and provided CVF specimens.
Methods:
Women in the Adherence Enhancement Guided by Individualized Texting and Drug Levels (AEGiS) study had their CVF specimens evaluated for (i) sexually transmitted bacterial (Neisseria gonorrhoeae, Chlamydia trachomatis, Gardnerella and Trichomonas vaginalis), viral (HPV, CMV and HSV-1/2) and fungal (Candida) infections; (ii) microbiome composition by 16S sequencing (V3-V4 region); and (iii) cytokine profiles by ELISA (IL-8, MIP-1a, MIP-1b and IP-10). Univariate statistical analysis was used to determine factors associated with CVF TFV concentrations. CVF TFV of 100-1000 ng/mL benchmarked typical genital concentrations and tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) of 700 fmol/punch was considered adequate adherence.
Results:
Thirty-five women had CVF specimens collected. No factor was associated with CVF TFV concentrations or discordance of blood and vaginal concentrations. Among 27 participants assessed for vaginosis (Candida, Gardnerella or Trichomonas), women with Gardnerella (n=11) were more likely to have high (>1000 ng/mL) CVF TFV concentrations (82% versus 33%, p=0.02).
Conclusions:
Presence of genital viruses, cytokines or vaginal community state types were not associated with low CVF TFV concentrations in cisgender women taking oral TDF/FTC for pre-exposure prophylaxis. The surprising association observed between presence of Gardnerella and higher vaginal TFV concentrations needs further evaluation.
There were a number of limitations to our observational study. The sample size of only 35 women participating was small, and was likely due to the cost, complexity of the study and limited number of women taking oral PrEP to recruit from. In addition, not all factors were assessed in the 35 women, limiting the sample size further. We also could not assess the presence of Chlamydia, Gonorrhea or Trichomonas with TFV concentrations because none of the women
in this study tested positive for these organisms. The influence of genital tract STIs warrants further research.
DISCUSSION
In this study of cisgender women taking oral TDF/FTC for HIV prevention, we found high concentrations of TFV in the CVF in nearly all participants. Our study did not find differences in CVF TFV levels with presence of HSV, CMV, HPV, inflammatory cytokines (MIP-1a, MIP-1b, IP10 and IL-8) or vaginal community group. Non-Lactobacillus-dominated vaginal community types and the presence of Gardnerella were not associated with lower TFV concentrations with oral TDF/FTC.
Interestingly, presence of Gardnerella by DNA probe was associated with being 2.5 times more likely of having TFV in CVF of ≥1000 ng/mL, compared to those without Gardnerella. Higher concentrations of TFV could be produced through a unique vaginal environment created by Gardnerella. This is in contrast to the lower concentrations of TFV found in the CVF of women with Gardnerella who were using topical TFV gel.12 The local cytokine and cellular milieu with Gardnerella is surprisingly not well defined.20 Bacterial vaginosis does not usually appear to be related to extensive inflammation, and may actually have fewer granulocytes but greater numbers of CD4+ lymphocytes.21 Thus, CD4+ lymphocytes recruited to the vagina in bacterial vaginosis could be a source of TFV elevations through dephosphorylation of TFV-DP.22 Further investigation is needed to determine the influential sources of TFV in cervicovaginal fluid.
After two PrEP clinical trials did not show adequate HIV protection in cisgender women4,5, there were concerns that, in addition to low adherence and pharmacokinetic data favoring near perfect dosing23, biological mechanisms such as STIs, BV and inflammation could be diminishing PrEP efficacy. However, studies have demonstrated that these biological effects depend on product delivery, with vaginal dysbiosis influencing topical12,13 but not oral14 PrEP efficacy. We found high concentrations of TFV in the CVF, consistent with modeling studies showing protection against HIV acquisition with oral TDF/FTC23, despite the presence of various biological phenomena. These data serve to support the effect of oral PrEP with TDF/FTC is not undermined by abnormal vaginal microbiota or inflammatory changes.
There were a number of limitations to our observational study. The sample size of only 35 women participating was small, and was likely due to the cost, complexity of the study and and limited number of women taking oral PrEP to recruit from. In addition, not all factors were assessed in the 35 women, limiting the sample size further. We also could not assess the presence of Chlamydia, Gonorrhea or Trichomonas with TFV concentrations because none of the women in this study tested positive for these organisms. The influence of genital tract STIs warrants further research.
Overall, our findings should be reassuring to providers that prescribe PrEP to women in the form of oral TDF/FTC. There does not appear to be changes in TFV penetration from common bacterial and viral flora. Women who take tenofovir alfenamide fumarate (TAF) were not part of this study as it has not yet been approved for PrEP through receptive vaginal intercourse. As the prevention efforts moves increasingly towards TAF/FTC, further studies are needed in women to determine the penetration of TAF/FTC into cervicovaginal fluid.
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