Exploring HIV Entry Blockade as a Pre-exposure Prophylaxis Strategy in Women
| Status: | Completed |
|---|---|
| Conditions: | HIV / AIDS |
| Therapuetic Areas: | Immunology / Infectious Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | December 2012 |
| End Date: | May 2015 |
Pre-exposure prophylaxis (PrEP) is an HIV prevention strategy in which HIV medicines are
used by a person before they are exposed to HIV in order to decrease his or her chance of
getting infected. In this study, we will investigate a new PrEP strategy in women using a
drug called maraviroc, a medicine used in the treatment of HIV infection called a CCR5
antagonist. We hypothesize that maraviroc could be a particularly good drug for PrEP because
it achieves high concentrations in the genital tract in women and decreases the number of
HIV-susceptible cells in the genital tract, and thus could potentially be dosed in more
favorable ways than the current PrEP drugs.
In order to further evaluate this PrEP strategy, we plan to measure the amount of maraviroc
in the blood and genital tract of HIV-negative healthy female volunteers before, during, and
after they are given maraviroc dosed either in the standard (twice a day) or reduced (once a
day) dose for 7 days compared with women who are not given maraviroc. We will also study
immune cells from the blood and genital tract from these women to see if maravoric has an
effect on these cells that would prevent them from becoming infected with HIV.
used by a person before they are exposed to HIV in order to decrease his or her chance of
getting infected. In this study, we will investigate a new PrEP strategy in women using a
drug called maraviroc, a medicine used in the treatment of HIV infection called a CCR5
antagonist. We hypothesize that maraviroc could be a particularly good drug for PrEP because
it achieves high concentrations in the genital tract in women and decreases the number of
HIV-susceptible cells in the genital tract, and thus could potentially be dosed in more
favorable ways than the current PrEP drugs.
In order to further evaluate this PrEP strategy, we plan to measure the amount of maraviroc
in the blood and genital tract of HIV-negative healthy female volunteers before, during, and
after they are given maraviroc dosed either in the standard (twice a day) or reduced (once a
day) dose for 7 days compared with women who are not given maraviroc. We will also study
immune cells from the blood and genital tract from these women to see if maravoric has an
effect on these cells that would prevent them from becoming infected with HIV.
RATIONALE Globally, over half of HIV-infected adults are women, and in the United States,
25% of all HIV/AIDS cases occur in women. Women often lack control over many available
prevention measures, underscoring a critical need to enhance HIV prevention options for
women. Pre-exposure prophylaxis (PrEP) is an HIV prevention strategy in which antiretroviral
(ARV) drugs are used prior to potential HIV exposure to reduce the likelihood of infection.
This strategy, which usually contains the drug tenofovir disoproxil fumarate (TDF), has
recently shown promise, but efficacy data suggest room for improvement, particularly for
women, in whom these data are conflicting. This study aims to prospectively examine ARV
pharmacology and mucosal immunology in order to evaluate a novel PrEP strategy in women -
blockade of HIV entry from its target cells at the mucosal surface using the CCR5 receptor
antagonist maraviroc (MVC). These actions of CCR5 receptor antagonism, if validated, could
lead to reduced HIV acquisition risk at more favorable dosing strategies than available for
current PrEP. Knowledge of pharmacological modulation of mucosal immunity and HIV
acquisition risk is fundamental to understanding, improving, and designing new PrEP
strategies.
DESIGN This is a prospective, observational cohort study with an intensive pharmacokinetic
component conducted in HIV-negative healthy women. Genital tract and whole blood samples
will be collected before, during, and after treatment with 7 days of oral MVC, dosed at
300mg twice daily (standard) or 300mg daily (reduced) compared with no treatment (control).
Genital tract and plasma MVC concentration will be measured using intensive pharmacokinetic
sampling to generate concentration-time profiles. Peripheral blood mononuclear cells (PBMC)
and endocervical cells harvested from whole blood and cervicovaginal lavage respectively
will be analyzed for CCR5 receptor occupancy, the number of CCR5-expressing HIV target
cells, and level of T cell activation.
DURATION 21 days after the first visit of the last participants. Enrollment is expected to
take 12 months.
SAMPLE SIZE 30 subjects (10 subjects per study group)
POPULATION HIV-negative healthy women, age 18 years or older, with normal menses.
25% of all HIV/AIDS cases occur in women. Women often lack control over many available
prevention measures, underscoring a critical need to enhance HIV prevention options for
women. Pre-exposure prophylaxis (PrEP) is an HIV prevention strategy in which antiretroviral
(ARV) drugs are used prior to potential HIV exposure to reduce the likelihood of infection.
This strategy, which usually contains the drug tenofovir disoproxil fumarate (TDF), has
recently shown promise, but efficacy data suggest room for improvement, particularly for
women, in whom these data are conflicting. This study aims to prospectively examine ARV
pharmacology and mucosal immunology in order to evaluate a novel PrEP strategy in women -
blockade of HIV entry from its target cells at the mucosal surface using the CCR5 receptor
antagonist maraviroc (MVC). These actions of CCR5 receptor antagonism, if validated, could
lead to reduced HIV acquisition risk at more favorable dosing strategies than available for
current PrEP. Knowledge of pharmacological modulation of mucosal immunity and HIV
acquisition risk is fundamental to understanding, improving, and designing new PrEP
strategies.
DESIGN This is a prospective, observational cohort study with an intensive pharmacokinetic
component conducted in HIV-negative healthy women. Genital tract and whole blood samples
will be collected before, during, and after treatment with 7 days of oral MVC, dosed at
300mg twice daily (standard) or 300mg daily (reduced) compared with no treatment (control).
Genital tract and plasma MVC concentration will be measured using intensive pharmacokinetic
sampling to generate concentration-time profiles. Peripheral blood mononuclear cells (PBMC)
and endocervical cells harvested from whole blood and cervicovaginal lavage respectively
will be analyzed for CCR5 receptor occupancy, the number of CCR5-expressing HIV target
cells, and level of T cell activation.
DURATION 21 days after the first visit of the last participants. Enrollment is expected to
take 12 months.
SAMPLE SIZE 30 subjects (10 subjects per study group)
POPULATION HIV-negative healthy women, age 18 years or older, with normal menses.
Inclusion Criteria:
- Female sex, defined by sex at birth
- Age greater than or equal to 18 years
- Negative HIV serology at screening
- Normal menses (within 22-35 day intervals) for at least 3 cycles
- Intact uterus and cervix
- Normal chemistry and CBC panels at screening, including
- Absolute neutrophil count (ANC) greater than 750/mm3
- Hemoglobin greater than 10.0 g/dL
- Platelet count greater than 100,000/mm3
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline
phosphatase less than 3 x upper limit of normal
- Total bilirubin less than 2.5 x upper limit of normal
- CrCl greater than or equal to 60 mL/min as estimated by the Cockcroft- Gault
equation
- Negative hepatitis B surface antigen
- Willing to use condoms for the duration of the study and abstain from sexual
intercourse for 48 hours before each genital tract sampling
- Able and willing to provide informed consent
Exclusion Criteria:
- Pregnancy (by clinical history or positive urine pregnancy test at screening)
- Breastfeeding
- Alcohol or substance use that, in the opinion of the study investigator, would
interfere with the conduct of the study
- History of loop electrosurgical excision procedure (LEEP), conization, or cryosurgery
- Use of systemic hormonal contraception
- Orthostasis at screening, defined as systolic blood pressure decrease of at least 20
mm Hg or a diastolic blood pressure decrease of at least 10 mm Hg within three
minutes of standing.
- Known history of heart or liver disease
- Known history of any medical condition that would interfere with conduct of the
study, in the opinion of the study investigator
- Symptoms of active vaginal infection at the time of screening, including new
ulcerative genital lesions or purulent and/or foul-smelling vaginal discharge
- Visible ulcerative genital lesions or purulent vaginal discharge during speculum
pelvic examination performed at the time of screening
- Concomitant use of medications that interact with maraviroc or known allergy to
maraviroc
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