Novel preclinical models of topical PrEP pharmacodynamics provide rationale for combination of drugs with complementary properties

Pedro M M Mesquita, Priya Srinivasan, Todd J. Johnson, Rachna Rastogi, Tammy Evans-Strickfaden, Michael S. Kay, Karen W. Buckheit, Robert W. Buckheit, James M. Smith, Patrick F. Kiser, Betsy Herold

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: The limited success of recent HIV topical pre-exposure prophylaxis clinical trials highlights the need for more predictive models of drug efficacy that better simulate what may happen during sexual exposure. To address this gap, we developed complementary in vitro models to evaluate the ability of drugs to retain anti-HIV activity if cells were washed with seminal plasma (simulating what may happen following exposure to ejaculate), and to protect drug-naive T cells (representing newly recruited immune cells) co-cultured with explants that had been pretreated with drug. We focused on tenofovir disoproxil fumarate (TDF), the non-nucleoside reverse transcriptase inhibitors dapivirine (DPV) and IQP-0528, and the entry inhibitors maraviroc (MVC) and the D-peptide chol-PIE-12 trimer (PIE12). Studies were extended to macaques and the ability of cervical biopsies obtained from animals treated with an intravaginal ring formulation of IQP-0528 to protect ex vivo co-cultured T cells was determined. The antiviral activity of cervicovaginal lavage samples against a primary Clade C isolate was also measured and correlated with drug levels.Results: Cells exposed to TDF were equally protected from HIV whether or not the drug-treated cells were washed with medium or seminal plasma prior to challenge. In contrast, several-fold higher concentrations of NNRTIs and entry inhibitors were needed to attain similar levels of HIV inhibition following a wash with seminal plasma. Conversely, the NNRTIs and PIE12, but not TDF or MVC, were effectively transferred from ex vivo treated explants and protected co-cultured T cells. Biopsies obtained from IQP-0528 ring-treated macaques also protected co-cultured T cells with viral inhibition ranging from 42-72%. Antiviral activity correlated with the concentration of drug recovered. Combinations of TDF with IQP-0528 protected in both in vitro models.Conclusions: Together, these models suggest that intracellularly retained drugs such as TDF may protect resident immune cells following coitus but sustained delivery may be required to protect immune cells subsequently recruited into the genital tract. Sustained delivery may also be critical for NNRTIs, which are rapidly transported out of cells and could be lost following sexual intercourse. An ideal approach may be a combination of drugs with complementary bioavailability profiles formulated for sustained delivery.

Original languageEnglish (US)
Article number113
JournalRetrovirology
Volume10
Issue number1
DOIs
StatePublished - Oct 24 2013

Fingerprint

Tenofovir
Drug Combinations
Pharmaceutical Preparations
Cultured Cells
Semen
HIV
T-Lymphocytes
Aptitude
Coitus
Macaca
Antiviral Agents
Biopsy
Reverse Transcriptase Inhibitors
Therapeutic Irrigation
Biological Availability
Clinical Trials
Peptides

Keywords

  • HIV
  • Intravaginal ring
  • Microbicide
  • Pre-Exposure Prophylaxis
  • Preclinical models

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

Cite this

Novel preclinical models of topical PrEP pharmacodynamics provide rationale for combination of drugs with complementary properties. / Mesquita, Pedro M M; Srinivasan, Priya; Johnson, Todd J.; Rastogi, Rachna; Evans-Strickfaden, Tammy; Kay, Michael S.; Buckheit, Karen W.; Buckheit, Robert W.; Smith, James M.; Kiser, Patrick F.; Herold, Betsy.

In: Retrovirology, Vol. 10, No. 1, 113, 24.10.2013.

Research output: Contribution to journalArticle

Mesquita, PMM, Srinivasan, P, Johnson, TJ, Rastogi, R, Evans-Strickfaden, T, Kay, MS, Buckheit, KW, Buckheit, RW, Smith, JM, Kiser, PF & Herold, B 2013, 'Novel preclinical models of topical PrEP pharmacodynamics provide rationale for combination of drugs with complementary properties', Retrovirology, vol. 10, no. 1, 113. https://doi.org/10.1186/1742-4690-10-113
Mesquita, Pedro M M ; Srinivasan, Priya ; Johnson, Todd J. ; Rastogi, Rachna ; Evans-Strickfaden, Tammy ; Kay, Michael S. ; Buckheit, Karen W. ; Buckheit, Robert W. ; Smith, James M. ; Kiser, Patrick F. ; Herold, Betsy. / Novel preclinical models of topical PrEP pharmacodynamics provide rationale for combination of drugs with complementary properties. In: Retrovirology. 2013 ; Vol. 10, No. 1.
@article{f3ebebe9f8d1434f946e3060a273b80e,
title = "Novel preclinical models of topical PrEP pharmacodynamics provide rationale for combination of drugs with complementary properties",
abstract = "Background: The limited success of recent HIV topical pre-exposure prophylaxis clinical trials highlights the need for more predictive models of drug efficacy that better simulate what may happen during sexual exposure. To address this gap, we developed complementary in vitro models to evaluate the ability of drugs to retain anti-HIV activity if cells were washed with seminal plasma (simulating what may happen following exposure to ejaculate), and to protect drug-naive T cells (representing newly recruited immune cells) co-cultured with explants that had been pretreated with drug. We focused on tenofovir disoproxil fumarate (TDF), the non-nucleoside reverse transcriptase inhibitors dapivirine (DPV) and IQP-0528, and the entry inhibitors maraviroc (MVC) and the D-peptide chol-PIE-12 trimer (PIE12). Studies were extended to macaques and the ability of cervical biopsies obtained from animals treated with an intravaginal ring formulation of IQP-0528 to protect ex vivo co-cultured T cells was determined. The antiviral activity of cervicovaginal lavage samples against a primary Clade C isolate was also measured and correlated with drug levels.Results: Cells exposed to TDF were equally protected from HIV whether or not the drug-treated cells were washed with medium or seminal plasma prior to challenge. In contrast, several-fold higher concentrations of NNRTIs and entry inhibitors were needed to attain similar levels of HIV inhibition following a wash with seminal plasma. Conversely, the NNRTIs and PIE12, but not TDF or MVC, were effectively transferred from ex vivo treated explants and protected co-cultured T cells. Biopsies obtained from IQP-0528 ring-treated macaques also protected co-cultured T cells with viral inhibition ranging from 42-72{\%}. Antiviral activity correlated with the concentration of drug recovered. Combinations of TDF with IQP-0528 protected in both in vitro models.Conclusions: Together, these models suggest that intracellularly retained drugs such as TDF may protect resident immune cells following coitus but sustained delivery may be required to protect immune cells subsequently recruited into the genital tract. Sustained delivery may also be critical for NNRTIs, which are rapidly transported out of cells and could be lost following sexual intercourse. An ideal approach may be a combination of drugs with complementary bioavailability profiles formulated for sustained delivery.",
keywords = "HIV, Intravaginal ring, Microbicide, Pre-Exposure Prophylaxis, Preclinical models",
author = "Mesquita, {Pedro M M} and Priya Srinivasan and Johnson, {Todd J.} and Rachna Rastogi and Tammy Evans-Strickfaden and Kay, {Michael S.} and Buckheit, {Karen W.} and Buckheit, {Robert W.} and Smith, {James M.} and Kiser, {Patrick F.} and Betsy Herold",
year = "2013",
month = "10",
day = "24",
doi = "10.1186/1742-4690-10-113",
language = "English (US)",
volume = "10",
journal = "Retrovirology",
issn = "1742-4690",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Novel preclinical models of topical PrEP pharmacodynamics provide rationale for combination of drugs with complementary properties

AU - Mesquita, Pedro M M

AU - Srinivasan, Priya

AU - Johnson, Todd J.

AU - Rastogi, Rachna

AU - Evans-Strickfaden, Tammy

AU - Kay, Michael S.

AU - Buckheit, Karen W.

AU - Buckheit, Robert W.

AU - Smith, James M.

AU - Kiser, Patrick F.

AU - Herold, Betsy

PY - 2013/10/24

Y1 - 2013/10/24

N2 - Background: The limited success of recent HIV topical pre-exposure prophylaxis clinical trials highlights the need for more predictive models of drug efficacy that better simulate what may happen during sexual exposure. To address this gap, we developed complementary in vitro models to evaluate the ability of drugs to retain anti-HIV activity if cells were washed with seminal plasma (simulating what may happen following exposure to ejaculate), and to protect drug-naive T cells (representing newly recruited immune cells) co-cultured with explants that had been pretreated with drug. We focused on tenofovir disoproxil fumarate (TDF), the non-nucleoside reverse transcriptase inhibitors dapivirine (DPV) and IQP-0528, and the entry inhibitors maraviroc (MVC) and the D-peptide chol-PIE-12 trimer (PIE12). Studies were extended to macaques and the ability of cervical biopsies obtained from animals treated with an intravaginal ring formulation of IQP-0528 to protect ex vivo co-cultured T cells was determined. The antiviral activity of cervicovaginal lavage samples against a primary Clade C isolate was also measured and correlated with drug levels.Results: Cells exposed to TDF were equally protected from HIV whether or not the drug-treated cells were washed with medium or seminal plasma prior to challenge. In contrast, several-fold higher concentrations of NNRTIs and entry inhibitors were needed to attain similar levels of HIV inhibition following a wash with seminal plasma. Conversely, the NNRTIs and PIE12, but not TDF or MVC, were effectively transferred from ex vivo treated explants and protected co-cultured T cells. Biopsies obtained from IQP-0528 ring-treated macaques also protected co-cultured T cells with viral inhibition ranging from 42-72%. Antiviral activity correlated with the concentration of drug recovered. Combinations of TDF with IQP-0528 protected in both in vitro models.Conclusions: Together, these models suggest that intracellularly retained drugs such as TDF may protect resident immune cells following coitus but sustained delivery may be required to protect immune cells subsequently recruited into the genital tract. Sustained delivery may also be critical for NNRTIs, which are rapidly transported out of cells and could be lost following sexual intercourse. An ideal approach may be a combination of drugs with complementary bioavailability profiles formulated for sustained delivery.

AB - Background: The limited success of recent HIV topical pre-exposure prophylaxis clinical trials highlights the need for more predictive models of drug efficacy that better simulate what may happen during sexual exposure. To address this gap, we developed complementary in vitro models to evaluate the ability of drugs to retain anti-HIV activity if cells were washed with seminal plasma (simulating what may happen following exposure to ejaculate), and to protect drug-naive T cells (representing newly recruited immune cells) co-cultured with explants that had been pretreated with drug. We focused on tenofovir disoproxil fumarate (TDF), the non-nucleoside reverse transcriptase inhibitors dapivirine (DPV) and IQP-0528, and the entry inhibitors maraviroc (MVC) and the D-peptide chol-PIE-12 trimer (PIE12). Studies were extended to macaques and the ability of cervical biopsies obtained from animals treated with an intravaginal ring formulation of IQP-0528 to protect ex vivo co-cultured T cells was determined. The antiviral activity of cervicovaginal lavage samples against a primary Clade C isolate was also measured and correlated with drug levels.Results: Cells exposed to TDF were equally protected from HIV whether or not the drug-treated cells were washed with medium or seminal plasma prior to challenge. In contrast, several-fold higher concentrations of NNRTIs and entry inhibitors were needed to attain similar levels of HIV inhibition following a wash with seminal plasma. Conversely, the NNRTIs and PIE12, but not TDF or MVC, were effectively transferred from ex vivo treated explants and protected co-cultured T cells. Biopsies obtained from IQP-0528 ring-treated macaques also protected co-cultured T cells with viral inhibition ranging from 42-72%. Antiviral activity correlated with the concentration of drug recovered. Combinations of TDF with IQP-0528 protected in both in vitro models.Conclusions: Together, these models suggest that intracellularly retained drugs such as TDF may protect resident immune cells following coitus but sustained delivery may be required to protect immune cells subsequently recruited into the genital tract. Sustained delivery may also be critical for NNRTIs, which are rapidly transported out of cells and could be lost following sexual intercourse. An ideal approach may be a combination of drugs with complementary bioavailability profiles formulated for sustained delivery.

KW - HIV

KW - Intravaginal ring

KW - Microbicide

KW - Pre-Exposure Prophylaxis

KW - Preclinical models

UR - http://www.scopus.com/inward/record.url?scp=84886051506&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84886051506&partnerID=8YFLogxK

U2 - 10.1186/1742-4690-10-113

DO - 10.1186/1742-4690-10-113

M3 - Article

VL - 10

JO - Retrovirology

JF - Retrovirology

SN - 1742-4690

IS - 1

M1 - 113

ER -