Intravaginal ring delivery of tenofovir disoproxil fumarate for prevention of HIV and herpes simplex virus infection

Pedro M M Mesquita, Rachna Rastogi, Theodore J. Segarra, Ryan S. Teller, N. Merna Torres, Ashley M. Huber, Patrick F. Kiser, Betsy Herold

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Objectives: A safe and effective topical prevention strategy will likely require sustained delivery of potent antiviral drugs and a delivery system that simultaneously maximizes drug distribution and overcomes the behavioural challenges related to adherence. Activity against HIV and herpes simplex virus (HSV) would be advantageous, given the epidemiological link between the two pathogens. We hypothesize that tenofovir disoproxil fumarate (tenofovir DF), a prodrug of tenofovir, may be more potent than tenofovir and ideal for sustained intravaginal ring (IVR) delivery. Methods: The anti-HIV and anti-HSV activity of tenofovir and tenofovir DF were assessed in cell and explant models. Cumulative tenofovir DF release and stability from polyether urethane (PEU), ethylene-co-vinyl acetate (EVA) and silicone IVRs were compared, and the activity and safety of drug released were evaluated in cervical explants and in a polarized dual-chamber model. Results: Tenofovir DF inhibited HIV and HSV at ~100-fold lower concentrations than tenofovir and retained activity in the presence of semen. PEU rings delivered >1 mg/day of tenofovir DF for 30 days. Pre-treatment of cervical explants with 10 μg/mL tenofovir DF or eluants from PEU minirings resulted in >90% inhibition of HIV and reduced HSV-2 yields by 2.5 log. Tenofovir DF and eluants did not prevent cell growth or polarization, or have any deleterious effects on an epithelial barrier. Conclusions: The findings support the development of a PEU tenofovir DF ring, which may provide potent and sustained protection against HIV and HSV.

Original languageEnglish (US)
Article numberdks097
Pages (from-to)1730-1738
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume67
Issue number7
DOIs
StatePublished - Jul 2012

Fingerprint

Tenofovir
Virus Diseases
Simplexvirus
HIV

Keywords

  • Microbicides
  • NRTIs
  • PrEP

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Intravaginal ring delivery of tenofovir disoproxil fumarate for prevention of HIV and herpes simplex virus infection. / Mesquita, Pedro M M; Rastogi, Rachna; Segarra, Theodore J.; Teller, Ryan S.; Merna Torres, N.; Huber, Ashley M.; Kiser, Patrick F.; Herold, Betsy.

In: Journal of Antimicrobial Chemotherapy, Vol. 67, No. 7, dks097, 07.2012, p. 1730-1738.

Research output: Contribution to journalArticle

Mesquita, PMM, Rastogi, R, Segarra, TJ, Teller, RS, Merna Torres, N, Huber, AM, Kiser, PF & Herold, B 2012, 'Intravaginal ring delivery of tenofovir disoproxil fumarate for prevention of HIV and herpes simplex virus infection', Journal of Antimicrobial Chemotherapy, vol. 67, no. 7, dks097, pp. 1730-1738. https://doi.org/10.1093/jac/dks097
Mesquita, Pedro M M ; Rastogi, Rachna ; Segarra, Theodore J. ; Teller, Ryan S. ; Merna Torres, N. ; Huber, Ashley M. ; Kiser, Patrick F. ; Herold, Betsy. / Intravaginal ring delivery of tenofovir disoproxil fumarate for prevention of HIV and herpes simplex virus infection. In: Journal of Antimicrobial Chemotherapy. 2012 ; Vol. 67, No. 7. pp. 1730-1738.
@article{0911cb39f34d45ecb7f5d9f5cdc27a0a,
title = "Intravaginal ring delivery of tenofovir disoproxil fumarate for prevention of HIV and herpes simplex virus infection",
abstract = "Objectives: A safe and effective topical prevention strategy will likely require sustained delivery of potent antiviral drugs and a delivery system that simultaneously maximizes drug distribution and overcomes the behavioural challenges related to adherence. Activity against HIV and herpes simplex virus (HSV) would be advantageous, given the epidemiological link between the two pathogens. We hypothesize that tenofovir disoproxil fumarate (tenofovir DF), a prodrug of tenofovir, may be more potent than tenofovir and ideal for sustained intravaginal ring (IVR) delivery. Methods: The anti-HIV and anti-HSV activity of tenofovir and tenofovir DF were assessed in cell and explant models. Cumulative tenofovir DF release and stability from polyether urethane (PEU), ethylene-co-vinyl acetate (EVA) and silicone IVRs were compared, and the activity and safety of drug released were evaluated in cervical explants and in a polarized dual-chamber model. Results: Tenofovir DF inhibited HIV and HSV at ~100-fold lower concentrations than tenofovir and retained activity in the presence of semen. PEU rings delivered >1 mg/day of tenofovir DF for 30 days. Pre-treatment of cervical explants with 10 μg/mL tenofovir DF or eluants from PEU minirings resulted in >90{\%} inhibition of HIV and reduced HSV-2 yields by 2.5 log. Tenofovir DF and eluants did not prevent cell growth or polarization, or have any deleterious effects on an epithelial barrier. Conclusions: The findings support the development of a PEU tenofovir DF ring, which may provide potent and sustained protection against HIV and HSV.",
keywords = "Microbicides, NRTIs, PrEP",
author = "Mesquita, {Pedro M M} and Rachna Rastogi and Segarra, {Theodore J.} and Teller, {Ryan S.} and {Merna Torres}, N. and Huber, {Ashley M.} and Kiser, {Patrick F.} and Betsy Herold",
year = "2012",
month = "7",
doi = "10.1093/jac/dks097",
language = "English (US)",
volume = "67",
pages = "1730--1738",
journal = "Journal of Antimicrobial Chemotherapy",
issn = "0305-7453",
publisher = "Oxford University Press",
number = "7",

}

TY - JOUR

T1 - Intravaginal ring delivery of tenofovir disoproxil fumarate for prevention of HIV and herpes simplex virus infection

AU - Mesquita, Pedro M M

AU - Rastogi, Rachna

AU - Segarra, Theodore J.

AU - Teller, Ryan S.

AU - Merna Torres, N.

AU - Huber, Ashley M.

AU - Kiser, Patrick F.

AU - Herold, Betsy

PY - 2012/7

Y1 - 2012/7

N2 - Objectives: A safe and effective topical prevention strategy will likely require sustained delivery of potent antiviral drugs and a delivery system that simultaneously maximizes drug distribution and overcomes the behavioural challenges related to adherence. Activity against HIV and herpes simplex virus (HSV) would be advantageous, given the epidemiological link between the two pathogens. We hypothesize that tenofovir disoproxil fumarate (tenofovir DF), a prodrug of tenofovir, may be more potent than tenofovir and ideal for sustained intravaginal ring (IVR) delivery. Methods: The anti-HIV and anti-HSV activity of tenofovir and tenofovir DF were assessed in cell and explant models. Cumulative tenofovir DF release and stability from polyether urethane (PEU), ethylene-co-vinyl acetate (EVA) and silicone IVRs were compared, and the activity and safety of drug released were evaluated in cervical explants and in a polarized dual-chamber model. Results: Tenofovir DF inhibited HIV and HSV at ~100-fold lower concentrations than tenofovir and retained activity in the presence of semen. PEU rings delivered >1 mg/day of tenofovir DF for 30 days. Pre-treatment of cervical explants with 10 μg/mL tenofovir DF or eluants from PEU minirings resulted in >90% inhibition of HIV and reduced HSV-2 yields by 2.5 log. Tenofovir DF and eluants did not prevent cell growth or polarization, or have any deleterious effects on an epithelial barrier. Conclusions: The findings support the development of a PEU tenofovir DF ring, which may provide potent and sustained protection against HIV and HSV.

AB - Objectives: A safe and effective topical prevention strategy will likely require sustained delivery of potent antiviral drugs and a delivery system that simultaneously maximizes drug distribution and overcomes the behavioural challenges related to adherence. Activity against HIV and herpes simplex virus (HSV) would be advantageous, given the epidemiological link between the two pathogens. We hypothesize that tenofovir disoproxil fumarate (tenofovir DF), a prodrug of tenofovir, may be more potent than tenofovir and ideal for sustained intravaginal ring (IVR) delivery. Methods: The anti-HIV and anti-HSV activity of tenofovir and tenofovir DF were assessed in cell and explant models. Cumulative tenofovir DF release and stability from polyether urethane (PEU), ethylene-co-vinyl acetate (EVA) and silicone IVRs were compared, and the activity and safety of drug released were evaluated in cervical explants and in a polarized dual-chamber model. Results: Tenofovir DF inhibited HIV and HSV at ~100-fold lower concentrations than tenofovir and retained activity in the presence of semen. PEU rings delivered >1 mg/day of tenofovir DF for 30 days. Pre-treatment of cervical explants with 10 μg/mL tenofovir DF or eluants from PEU minirings resulted in >90% inhibition of HIV and reduced HSV-2 yields by 2.5 log. Tenofovir DF and eluants did not prevent cell growth or polarization, or have any deleterious effects on an epithelial barrier. Conclusions: The findings support the development of a PEU tenofovir DF ring, which may provide potent and sustained protection against HIV and HSV.

KW - Microbicides

KW - NRTIs

KW - PrEP

UR - http://www.scopus.com/inward/record.url?scp=84862678558&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862678558&partnerID=8YFLogxK

U2 - 10.1093/jac/dks097

DO - 10.1093/jac/dks097

M3 - Article

C2 - 22467632

AN - SCOPUS:84862678558

VL - 67

SP - 1730

EP - 1738

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

SN - 0305-7453

IS - 7

M1 - dks097

ER -