Etravirine Concentrations in the Cervicovaginal Compartment in HIV-1-Infected Women Receiving Etravirine-Containing Antiretroviral Therapy: DIVA 02 Study

Purpose of review Current antiretroviral treatment regimens represent significant improvements in the management of HIV-1 infection; however, these regimens have not achieved a functional or sterilizing cure. One barrier to achieving a cure may be suboptimal antiretroviral concentrations in sanctuary sites throughout the body, including the central nervous system, gut-associated lymphoid tissue, lymph nodes, and tissue macrophages. This review will focus on the problems associated with achieving effective concentrations in these restricted sanctuary sites, and potential strategies to overcome these barriers. Recent findings Sufficient data exist to conclude that antiretroviral drug distribution is not uniform throughout the body. Low tissue/reservoir concentrations may be associated with viral replication. Multiple means to increase drug concentrations in sanctuary sites are being investigated, including modification of currently utilized drugs, blockade of transporters and enzymes that affect drug metabolism and pharmacokinetics, and local drug administration. Accumulating data suggest these methods increase antiretroviral concentrations in reservoirs of viral replication. No method has yet resulted in the complete clearance of HIV. Summary New strategies for increasing antiretroviral concentrations in predominant sites of viral replication may provide more effective means for elimination of viral sanctuaries. Additional research is necessary to optimize antiretroviral tissue distribution in order to inhibit virus replication fully, and avoid resistance and replenishment of viral reservoirs that may persist in the face of antiretroviral therapy.

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“…In general, drugs do not distribute evenly throughout the whole body [11 ▪ ,12,13]. The reasons for this are complex and multifactorial.…”

Section: Pharmacologic Sanctuariesmentioning

confidence: 99%

Overcoming pharmacologic sanctuaries

Cory

Schacker

Stevenson

et al. 2013

Current Opinion in HIV and AIDS

132

100

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“…Median etravirine exposure in the CVF is similar to that of the BP with a CVF:BP etravirine AUC 12h ratio of approximately 1.3 [33, 39]. Nevirapine trough concentration in the CVF is ~80% of BP [40].…”

Section: Female Genital Tractmentioning

confidence: 99%

Pharmacokinetics of Antiretrovirals in Genital Secretions and Anatomic Sites of HIV Transmission: Implications for HIV Prevention

Trezza

Kashuba

2014

Clin Pharmacokinet

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The incidence of HIV remains alarmingly high in many parts of the world. Prophylactic use of antiretrovirals, capable of concentrating in the anatomical sites of transmission, may reduce the risk of infection after an unprotected sexual exposure. To date, orally and topically administered antiretrovirals have exhibited variable success in preventing HIV transmission in large-scale clinical trials. Antiretroviral mucosal pharmacokinetics may help explain the outcomes of these investigations. Penetration and accumulation of antiretrovirals into sites of transmission can influence dosing strategies and pre-exposure prophylaxis clinical trial design. Antiretroviral tissue distribution varies widely within and between drug classes, attributed in part to their physicochemical properties and tissue-specific drug transporter expression. Nucleoside (-tide) reverse transcriptase inhibitors, the CCR5 antagonist maraviroc, and the integrase inhibitor raltegravir demonstrate the highest penetration into the male and female reproductive tracts and colorectal tissue relative to blood. This review will describe antiretroviral exposure in anatomic sites of transmission, and place these findings in context with the prevention of HIV and the efficacy of pre-exposure prophylactic strategies.

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“…A PK study of women using DPV vaginal rings for 7d reported mean vaginal fluid concentrations of DPV in the range of 0.7–7.1 μg/mL [54]. The DIVA-2 study evaluated ETR concentrations in cervicovaginal fluid (CVF) after oral daily dosing of ETR in HIV-1-infected women, and found good penetration of ETR into the CVF at concentrations of 0.857 μg/mL at 12h after the last dose [52]. In comparison, our PVA fiber composite provided ~10-fold higher ETR concentration in lavage at 7 d after a single dose.…”

Section: Resultsmentioning

confidence: 99%

“…The mean vaginal tissue concentrations detected for the PVA fiber group at 72 h was 293 ng/g, nearly 150-fold higher than the in vitro IC 50 for ETR of ~2 ng/mL [52]. DPV vaginal ring studies in humans reported vaginal tissue concentrations in the range of 0.3 to 3.5 μg/g [54], similar to the range of ETR detected between 1–72h for the PVA fiber group for our study (0.3–1.9 μg/g).…”

Section: Resultsmentioning

confidence: 99%

Nanoparticle-releasing nanofiber composites for enhanced in vivo vaginal retention

et al. 2017

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Current approaches for topical vaginal administration of nanoparticles result in poor retention and extensive leakage. To overcome these challenges, we developed a nanoparticle-releasing nanofiber delivery platform and evaluated its ability to improve nanoparticle retention in a murine model. We individually tailored two components of this drug delivery system for optimal interaction with mucus, designing (1) mucoadhesive fibers for better retention in the vaginal tract, and (2) PEGylated nanoparticles that diffuse quickly through mucus. We hypothesized that this novel dual-functioning (mucoadhesive/mucus–penetrating) composite material would provide enhanced retention of nanoparticles in the vaginal mucosa. Equivalent doses of fluorescent nanoparticles were vaginally administered to mice in either water (aqueous suspension) or fiber composites, and fluorescent content was quantified in cervicovaginal mucus and vaginal tissue at time points from 24h to 7d. We also fabricated composite fibers containing etravirine-loaded nanoparticles and evaluated the pharmacokinetics over 7d. We found that our composite materials provided approximately 30-fold greater retention of nanoparticles in the reproductive tract at 24h compared to aqueous suspensions. Compared to nanoparticles in aqueous suspension, the nanoparticles in fiber composites exhibited sustained and higher etravirine concentrations after 24h and up to 7d, demonstrating the capabilities of this new delivery platform to sustain nanoparticle release out to 3d and drug retention out to one week after a single administration. This is the first report of nanoparticle-releasing fibers for vaginal drug delivery, as well as the first study of a single delivery system that combines two components uniquely engineered for complementary interactions with mucus.

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Etravirine Concentrations in the Cervicovaginal Compartment in HIV-1-Infected Women Receiving Etravirine-Containing Antiretroviral Therapy: DIVA 02 Study

Cited by 11 publications

References 12 publications

Overcoming pharmacologic sanctuaries

Overcoming pharmacologic sanctuaries

Pharmacokinetics of Antiretrovirals in Genital Secretions and Anatomic Sites of HIV Transmission: Implications for HIV Prevention

Nanoparticle-releasing nanofiber composites for enhanced in vivo vaginal retention

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