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A phase 1 randomized placebo-controlled safety and pharmacokinetic trial of a tenofovir disoproxil fumarate vaginal ring.

ABSTRACT: Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir (TFV), may be ideal for topical HIV preexposure prophylaxis because it has higher tissue and cell permeability than TFV; is not adversely impacted by seminal proteins; and its active metabolite, TFV-diphosphate (TFV-DP), has a long intracellular half-life. We engineered a TDF eluting polyurethane reservoir intravaginal ring (IVR) to provide near constant mucosal antiretroviral concentrations.A first-in-human randomized placebo-controlled trial was conducted to assess the safety and pharmacokinetics of the TDF IVR in healthy, sexually abstinent women (15 TDF and 15 placebo). Drug concentrations were measured in cervicovaginal fluid (CVF) obtained by swab, cervical tissue, plasma, and dried blood spots (DBS) over 14 days of continuous ring use.There were 43 total, 23 reproductive tract, and eight product-related grade 1 adverse events. Steady-state CVF TFV concentrations were achieved proximal (vagina, ectocervix) and distal (introitus) to the TDF IVR 1 day after ring insertion. Median tissue TFV-DP concentrations 14 days after TDF IVR placement were 120?fmol/mg (interquartile range 90, 550). CVF collected from the cervix 1 week and 2 weeks after TDF IVR insertion provided significant protection against ex-vivo HIV challenge. Eleven of 14 (78%) participants had detectable TFV-DP DBS concentrations 14 days after TDF IVR placement, suggesting that DBS may provide a surrogate marker of adherence in future clinical trials.A TDF IVR is safe, well tolerated, and results in mucosal TFV concentrations that exceed those associated with HIV protection. The findings support further clinical evaluation of this TDF IVR.

SUBMITTER: Keller MJ

PROVIDER: S-EPMC4767579 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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A phase 1 randomized placebo-controlled safety and pharmacokinetic trial of a tenofovir disoproxil fumarate vaginal ring.

Keller Marla J MJ Mesquita Pedro M PM Marzinke Mark A MA Teller Ryan R Espinoza Lilia L Atrio Jessica M JM Lo Yungtai Y Frank Bruce B Srinivasan Sujatha S Fredricks David N DN Rabe Lorna L Anderson Peter L PL Hendrix Craig W CW Kiser Patrick F PF Herold Betsy C BC

AIDS (London, England) 20160301 5

<h4>Background</h4>Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir (TFV), may be ideal for topical HIV preexposure prophylaxis because it has higher tissue and cell permeability than TFV; is not adversely impacted by seminal proteins; and its active metabolite, TFV-diphosphate (TFV-DP), has a long intracellular half-life. We engineered a TDF eluting polyurethane reservoir intravaginal ring (IVR) to provide near constant mucosal antiretroviral concentrations.<h4>Methods</h4>A first-in ...[more]

PMID: 26605514

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Project description:ObjectivesThe objective of this trial was to investigate the safety and preliminary effectiveness of a daily dose of 300 mg of tenofovir disoproxil fumarate (TDF) versus placebo in preventing HIV infection in women.DesignThis was a phase 2, randomized, double-blind, placebo-controlled trial.SettingThe study was conducted between June 2004 and March 2006 in Tema, Ghana; Douala, Cameroon; and Ibadan, Nigeria.ParticipantsWe enrolled 936 HIV-negative women at high risk of HIV infection into this study.InterventionParticipants were randomized 1:1 to once daily use of 300 mg of TDF or placebo.Outcome measuresThe primary safety endpoints were grade 2 or higher serum creatinine elevations (>2.0 mg/dl) for renal function, grade 3 or 4 aspartate aminotransferase or alanine aminotransferase elevations (>170 U/l) for hepatic function, and grade 3 or 4 phosphorus abnormalities (<1.5 mg/dl). The effectiveness endpoint was infection with HIV-1 or HIV-2.ResultsStudy participants contributed 428 person-years of laboratory testing to the primary safety analysis. No significant differences emerged between treatment groups in clinical or laboratory safety outcomes. Study participants contributed 476 person-years of HIV testing to the primary effectiveness analysis, during which time eight seroconversions occurred. Two were diagnosed in participants randomized to TDF (0.86 per 100 person-years) and six in participants receiving placebo (2.48 per 100 person-years), yielding a rate ratio of 0.35 (95% confidence interval = 0.03-1.93), which did not achieve statistical significance. Owing to premature closures of the Cameroon and Nigeria study sites, the planned person-years of follow-up and study power could not be achieved.ConclusionDaily oral use of TDF in HIV-uninfected women was not associated with increased clinical or laboratory adverse events. Effectiveness could not be conclusively evaluated because of the small number of HIV infections observed during the study.

Project description:BackgroundAn intravaginal ring that releases the tenofovir prodrug, tenofovir disoproxil fumarate, provided 100% protection in macaques against simian HIV and was safe in a 14-day clinical trial in sexually abstinent women. We aimed to assess the safety and pharmacokinetics of this intravaginal ring over 90 days in sexually active women.MethodsWe did a phase 1, single-blind, randomised, placebo-controlled trial to assess safety, pharmacokinetics, and acceptability of a tenofovir disoproxil fumarate intravaginal ring used continuously with monthly ring changes for 3 months. Sexually active women who were HIV negative were randomly assigned (3:1) to a tenofovir disoproxil fumarate ring or placebo ring. Primary safety endpoint was the proportion of women who had grade 2 or higher genitourinary adverse events judged related to study product and any grade 2 or higher adverse event as defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. We quantified tenofovir disoproxil fumarate and tenofovir concentrations in cervicovaginal fluid, tenofovir in plasma, and tenofovir diphosphate, the active metabolite, in cervical tissue and dried blood spots 1 month after each ring insertion. We compared changes over time in cervicovaginal fluid cytokine and chemokine concentrations and vaginal microbiota. The study was electively stopped early and is registered with ClinicalTrials.gov, number NCT02762617.FindingsBetween Feb 24 and July 20, 2017, 17 women were enrolled before study termination. 12 were assigned to receive the tenofovir disoproxil fumarate ring and five were assigned to receive the placebo ring. Two participants in the tenofovir disoproxil fumarate ring group completed 3 months of continuous ring use; eight were asked to discontinue ring use early because of ulcerations (grade 1) near the ring; in the remaining two women, rings were electively removed by study staff on day 20 and day 23. Ulcers were detected a mean of 32 days after ring use (range 23-56). Four of eight participants with ulcers were symptomatic with vaginal discharge; four had ulcers identified when examined; three had two ulcers; all ulcers resolved after ring removal. No participants in the placebo group developed ulcers. No grade 2 product-related adverse events were reported in either group and four non-product-related grade 2 adverse events were reported in the tenofovir disoproxil fumarate ring group. Cervicovaginal fluid tenofovir concentrations did not differ at day 14 (p=0·14) comparing the eight patients who did (median 1·0 × 105 ng/mL [IQR 9·1 × 104-1·1 × 105]) with the four who did not (6·0 × 104 ng/mL [5·6 × 104-1·1 × 105]) develop ulcers. No significant changes in vaginal microbiota were detected in either group. Concentrations of multiple inflammatory cytokines and chemokines were significantly higher at days 14 and 28 compared with baseline in the tenofovir disoproxil fumarate ring group but not the placebo group.InterpretationFuture studies are needed to establish whether the unanticipated finding of ulcerations is specific to this tenofovir disoproxil fumarate ring or generalisable to other sustained topical release formulations of tenofovir or its prodrugs.FundingNational Institutes of Health.

Dataset Information

A phase 1 randomized placebo-controlled safety and pharmacokinetic trial of a tenofovir disoproxil fumarate vaginal ring.

Publications

A phase 1 randomized placebo-controlled safety and pharmacokinetic trial of a tenofovir disoproxil fumarate vaginal ring.

Similar Datasets

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