Tenofovir disoproxil fumarate intravaginal ring for HIV pre-exposure prophylaxis in sexually active women

a phase 1, single-blind, randomised, controlled trial

Marla J. Keller, Lianna Wood, James M. Billingsley, Laurie L. Ray, Jessica Goymer, S. Sinclair, Aileen P. McGinn, Mark A Marzinke, B. Frank, Sujatha Srinivasan, Congzhou Liu, Jessica M. Atrio, L. Espinoza, N. Mugo, Hans M.L. Spiegel, Peter L. Anderson, David N. Fredricks, Craig Hendrix, Jeanne Marrazzo, Steven E. Bosinger & 1 others Betsy C. Herold

Research output: Contribution to journalArticle

Abstract

Background: An 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. Methods: We 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. Findings: Between 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. Interpretation: Future 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. Funding: National Institutes of Health.

Original languageEnglish (US)
Pages (from-to)e498-e508
JournalThe Lancet HIV
Volume6
Issue number8
DOIs
StatePublished - Aug 1 2019

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Tenofovir
Randomized Controlled Trials
HIV
Ulcer
Placebos
Microbiota
Prodrugs
Pre-Exposure Prophylaxis
Safety
Chemokines

ASJC Scopus subject areas

  • Epidemiology
  • Immunology
  • Infectious Diseases
  • Virology

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Tenofovir disoproxil fumarate intravaginal ring for HIV pre-exposure prophylaxis in sexually active women : a phase 1, single-blind, randomised, controlled trial. / Keller, Marla J.; Wood, Lianna; Billingsley, James M.; Ray, Laurie L.; Goymer, Jessica; Sinclair, S.; McGinn, Aileen P.; Marzinke, Mark A; Frank, B.; Srinivasan, Sujatha; Liu, Congzhou; Atrio, Jessica M.; Espinoza, L.; Mugo, N.; Spiegel, Hans M.L.; Anderson, Peter L.; Fredricks, David N.; Hendrix, Craig; Marrazzo, Jeanne; Bosinger, Steven E.; Herold, Betsy C.

In: The Lancet HIV, Vol. 6, No. 8, 01.08.2019, p. e498-e508.

Research output: Contribution to journalArticle

Keller, MJ, Wood, L, Billingsley, JM, Ray, LL, Goymer, J, Sinclair, S, McGinn, AP, Marzinke, MA, Frank, B, Srinivasan, S, Liu, C, Atrio, JM, Espinoza, L, Mugo, N, Spiegel, HML, Anderson, PL, Fredricks, DN, Hendrix, C, Marrazzo, J, Bosinger, SE & Herold, BC 2019, 'Tenofovir disoproxil fumarate intravaginal ring for HIV pre-exposure prophylaxis in sexually active women: a phase 1, single-blind, randomised, controlled trial', The Lancet HIV, vol. 6, no. 8, pp. e498-e508. https://doi.org/10.1016/S2352-3018(19)30145-6
Keller, Marla J. ; Wood, Lianna ; Billingsley, James M. ; Ray, Laurie L. ; Goymer, Jessica ; Sinclair, S. ; McGinn, Aileen P. ; Marzinke, Mark A ; Frank, B. ; Srinivasan, Sujatha ; Liu, Congzhou ; Atrio, Jessica M. ; Espinoza, L. ; Mugo, N. ; Spiegel, Hans M.L. ; Anderson, Peter L. ; Fredricks, David N. ; Hendrix, Craig ; Marrazzo, Jeanne ; Bosinger, Steven E. ; Herold, Betsy C. / Tenofovir disoproxil fumarate intravaginal ring for HIV pre-exposure prophylaxis in sexually active women : a phase 1, single-blind, randomised, controlled trial. In: The Lancet HIV. 2019 ; Vol. 6, No. 8. pp. e498-e508.
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abstract = "Background: An 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. Methods: We 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. Findings: Between 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. Interpretation: Future 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. Funding: National Institutes of Health.",
author = "Keller, {Marla J.} and Lianna Wood and Billingsley, {James M.} and Ray, {Laurie L.} and Jessica Goymer and S. Sinclair and McGinn, {Aileen P.} and Marzinke, {Mark A} and B. Frank and Sujatha Srinivasan and Congzhou Liu and Atrio, {Jessica M.} and L. Espinoza and N. Mugo and Spiegel, {Hans M.L.} and Anderson, {Peter L.} and Fredricks, {David N.} and Craig Hendrix and Jeanne Marrazzo and Bosinger, {Steven E.} and Herold, {Betsy C.}",
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TY - JOUR

T1 - Tenofovir disoproxil fumarate intravaginal ring for HIV pre-exposure prophylaxis in sexually active women

T2 - a phase 1, single-blind, randomised, controlled trial

AU - Keller, Marla J.

AU - Wood, Lianna

AU - Billingsley, James M.

AU - Ray, Laurie L.

AU - Goymer, Jessica

AU - Sinclair, S.

AU - McGinn, Aileen P.

AU - Marzinke, Mark A

AU - Frank, B.

AU - Srinivasan, Sujatha

AU - Liu, Congzhou

AU - Atrio, Jessica M.

AU - Espinoza, L.

AU - Mugo, N.

AU - Spiegel, Hans M.L.

AU - Anderson, Peter L.

AU - Fredricks, David N.

AU - Hendrix, Craig

AU - Marrazzo, Jeanne

AU - Bosinger, Steven E.

AU - Herold, Betsy C.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Background: An 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. Methods: We 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. Findings: Between 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. Interpretation: Future 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. Funding: National Institutes of Health.

AB - Background: An 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. Methods: We 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. Findings: Between 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. Interpretation: Future 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. Funding: National Institutes of Health.

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