scholarly journals Translational Approach to Predicting the Efficacy of Maraviroc-Based Regimens as HIV Preexposure Prophylaxis

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Nithya Srinivas ◽  
Mackenzie Cottrell ◽  
Kaitlyn Maffuid ◽  
Heather A. Prince ◽  
Julie A. E. Nelson ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Female Genital Tract ◽  
Mucosal Tissue ◽  
Colorectal Tissue ◽  
Preexposure Prophylaxis ◽  
Pharmacodynamic Analysis ◽  
Immunodeficiency Virus ◽  
Dosing Strategies ◽  
Female Genital

ABSTRACT Maraviroc-based regimens have been explored as preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV). In this study, we utilized mucosal tissue drug exposure data, combined with target concentrations generated in vitro, in a pharmacokinetic-pharmacodynamic analysis to predict the effects of drug combinations and adherence on PrEP efficacy. Mucosal tissue concentrations of maraviroc were measured in 24 healthy women. The 90% effective concentrations (EC90) of maraviroc (alone and combined with tenofovir and emtricitabine) for protection against HIV were identified in CD4+ T cells. Monte Carlo simulations were performed to identify dosing strategies to protect colorectal and female genital tract (FGT) tissues from HIV infection. Colorectal maraviroc concentrations were 350-fold higher than in the FGT. Under steady-state conditions, our model predicted that one 300-mg dose/week was sufficient to protect colorectal tissue from HIV in 99% of the population, while 300 mg daily would protect the FGT in only 63% of the population. FGT protection increased to >90% when maraviroc was used in combination with tenofovir (5 doses/week) or emtricitabine (3 doses/week). Poor adherence resulted in a drastic decrease in efficacy in the FGT but not colorectal tissue. However, greater forgiveness was seen when maraviroc was combined with tenofovir or emtricitabine, suggesting that maraviroc should not be used alone as PrEP.

scholarly journals Antiretroviral drug exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis

AIDS ◽  
2007 ◽  
Vol 21 (14) ◽  
pp. 1899-1907 ◽  
Author(s):  
Julie B Dumond ◽  
Rosa F Yeh ◽  
Kristine B Patterson ◽  
Amanda H Corbett ◽  
Byung Hwa Jung ◽  
...  
Keyword(s):  
Genital Tract ◽  
Drug Exposure ◽  
Female Genital Tract ◽  
Post Exposure Prophylaxis ◽  
Post Exposure ◽  
Antiretroviral Drug ◽  
Exposure Prophylaxis ◽  
Female Genital

scholarly journals Electrospun fibers for vaginal administration of tenofovir disoproxil fumarate and emtricitabine in the context of topical pre-exposure prophylaxis

2021 ◽  
Author(s):  
Rute Nunes ◽  
Sarah Bogas ◽  
Maria João Faria ◽  
Hugo Gonçalves ◽  
Marlene Lúcio ◽  
...  
Keyword(s):  
Tenofovir Disoproxil Fumarate ◽  
Drug Exposure ◽  
Female Genital Tract ◽  
Poly Vinyl Alcohol ◽  
Electrospun Fibers ◽  
Strict Adherence ◽  
Vaginal Administration ◽  
Drug Concentrations ◽  
Exposure Prophylaxis

AbstractWomen are particularly vulnerable to sexual HIV-1 transmission. Oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) is highly effective in avoiding new infections in men, but protection has only been shown moderate in women. Such differences have been associated, at least partially, to poor drug penetration of the lower female genital tract and the need for strict adherence to continuous daily oral intake of TDF/FTC. On-demand topical microbicide products could help circumventing these limitations. We developed electrospun fibers based on polycaprolactone (PCL fibers) or liposomes associated to poly(vinyl alcohol) (liposomes-in-PVA fibers) for the vaginal co-delivery of TDF and FTC, and assessed their pharmacokinetics in mice. PCL fibers and liposomes-in-PVA fibers were tested for morphological and physicochemical properties using scanning electron microscopy, differential scanning calorimetry and X-ray diffractometry. Fibers featured organoleptic and mechanical properties compatible with their suitable handling and vaginal administration. Fluorescent quenching of mucin in vitro – used as a proxy for mucoadhesion – was intense for PCL fibers, but mild for liposomes-in-PVA fibers. Both fibers were shown safe in vitro and able to rapidly release drug content (15-30 min) under sink conditions. Liposomes-in-PVA fibers allowed increasing genital drug concentrations after a single intravaginal administration when compared to continuous daily treatment with 25-times higher oral doses. For instance, the levels of tenofovir and FTC in vaginal lavage were around 4- and 29-fold higher, respectively. PCL fibers were also superior to oral treatment, although to a minor extent (approximately 2-fold higher drug concentrations in lavage). Vaginal tissue drug levels were generally low for all treatments, while systemic drug exposure was negligible in the case of fibers. These data suggest that proposed fibers may provide an interesting alternative or an ancillary option to oral PrEP in women.

scholarly journals A Human Immunodeficiency Virus (HIV)–Inducing Factor from the Female Genital Tract Activates HIV‐1 Gene Expression through the κB Enhancer

1998 ◽  
Vol 178 (5) ◽  
pp. 1343-1351 ◽  
Author(s):  
Lena Al‐Harthi ◽  
Gregory T. Spear ◽  
Farhad B. Hashemi ◽  
Alan Landay ◽  
Beverly E. Sha ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Immunodeficiency Virus ◽  
Genital Tract ◽  
Female Genital Tract ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Female Genital

Development of an in vitro dual-chamber model of the female genital tract as a screening tool for epithelial toxicity

2010 ◽  
Vol 165 (2) ◽  
pp. 186-197 ◽  
Author(s):  
Youssef Gali ◽  
Kevin K. Ariën ◽  
Marleen Praet ◽  
Rafael Van den Bergh ◽  
Marleen Temmerman ◽  
...  
Keyword(s):  
Genital Tract ◽  
Screening Tool ◽  
Female Genital Tract ◽  
Dual Chamber ◽  
Chamber Model ◽  
Female Genital

Development of an in vitro organ culture model to study transmission of HIV-1 in the female genital tract

10.1038/74743 ◽  
2000 ◽  
Vol 6 (4) ◽  
pp. 475-479 ◽  
Author(s):  
Kelly B. Collins ◽  
Bruce K. Patterson ◽  
Gregory J. Naus ◽  
Daniel V. Landers ◽  
Phalguni Gupta
Keyword(s):  
Organ Culture ◽  
Genital Tract ◽  
Female Genital Tract ◽  
Culture Model ◽  
In Vitro Organ Culture ◽  
Hiv 1 ◽  
Female Genital

scholarly journals Comparison of Female Genital Tract Cytokine and Microbiota Signatures Induced by Initiation of Intramuscular DMPA and NET-EN Hormonal Contraceptives - a Prospective Cohort Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Smritee Dabee ◽  
Ramla F. Tanko ◽  
Bryan P. Brown ◽  
Rubina Bunjun ◽  
Christina Balle ◽  
...  
Keyword(s):  
High Risk ◽  
Genital Tract ◽  
Cohort Analysis ◽  
Female Genital Tract ◽  
Vaginal Microbiota ◽  
African Women ◽  
Hormonal Contraceptives ◽  
Rrna Gene ◽  
Female Genital

BackgroundCervicovaginal inflammation, bacterial microbiota and hormonal contraceptives all influence sexual and reproductive health. To date, the effects of intramuscular depo-medroxyprogesterone acetate (DMPA-IM) versus injectable norethisterone enanthate (NET-EN) on vaginal microbiota or cytokines have not been compared back-to-back, although in-vitro data suggest that DMPA-IM and NET-EN have different pharmacokinetic and biologic activities. This study aimed at comparing the effects of DMPA-IM versus NET-EN initiation on cervicovaginal cytokines and microbiota in women at high risk for sexually transmitted infections (STIs) assigned to the respective contraceptives.MethodsWe collected socio-demographic characteristics and vaginal samples from women initiating DMPA-IM (ECHO Trial; n = 53) and NET-EN (UChoose Trial; n = 44) at baseline and after two consecutive injections to assess cytokine concentrations by Luminex, vaginal microbiota by 16S rRNA gene sequencing, STIs, bacterial vaginosis (BV) and candidiasis.ResultsCytokine concentrations did not change significantly after initiating DMPA-IM or NET-EN, although NET-EN versus DMPA-IM-associated profiles were distinct. While the abundance of bacterial taxa associated with optimal and non-optimal microbiota fluctuated with DMPA-IM use, overall community composition did not significantly change with either contraceptive. HSV-2 serology, chlamydial infection, gonorrhoea and candidiasis did not influence the associations between contraceptive type and cervicovaginal cytokines or microbiota.ConclusionsBoth DMPA-IM and NET-EN use did not lead to broad inflammatory or microbiota changes in the female genital tract of sub-Saharan African women. This suggests that NET-EN is likely a viable option for contraception in African women at high risk of BV and STIs.

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