Clinical trial NCT02079077: Inducing Immune Quiescence to Prevent HIV Infection in Women
Official title: Limiting HIV Target Cells by Inducing Immune Quiescence in the Female Genital Tract
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV
Keywords: HIV, Immune quiescence, ASA, Hydroxychloroquin
Lead sponsor: University of Manitoba
Sponsor class: OTHER
Collaborators: name: University of Nairobi
First posted: 2014-03-05
Enrollment: 91
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: In this project, the investigators want to analyse the capacity of Acetylsalicylic acid and hydoxychlroquin (HCQ) to induce an Immune Quiescence (IQ) phenotype, which has been previously associated with natural protection to HIV infection. This phenotype is characterized by lower expression of genes involved in cellular activation, lower resting levels of inflammatory cytokine production, lower level of systemic activated T cells, increased levels of systemic T regulatory, increased production of anti-viral anti-protease serpins at the female genital tract and reduced numbers of HIV target cells (mainly CD4+ CCR5+ T cells) in the FGT ( female genital tract).

The objective of this study is to determine if daily oral administration of Acetylsalicylic acid or hydroxychlroroquin can reduce systemic and mucosal immune activation in HIV negative women.

Detailed description: The investigators will enrol 80 non female sex work low-risk HIV negative women and 80 HIV negative female sex worker HIV negative form Nairobi, Kenya and followed for a 3 months period.

During the first month, samples will be taken on a monthly basis

* blood,
* vaginal samples: cytobrush/scarper and cervico vaginal lavage (CVL). This is done to determine the baseline levels of systemic and mucosal immune activation of each woman. In this way, every women is acting as her own control thereby reducing variation between control and participant.

Chemokine/cytokine level, as well as cellular immune activation and T regulatory cells will be assessed.

At month two: the women will be divided in two different arms (oral administration of hydroxychloroquine: 200mg/day or Acetylsalicylic acid 81mg/day) and followed, on a monthly basis, for an 8 additional weeks.

During this time, monthly blood and vaginal samples (cytobrush/scraper and CVL) the investigators will be taken. They will measure change in the systemic and mucosal immune activation.

Immune Quiescence phenotype (decrease of T cells immune activation, lower immune genes activation expression and pro-inflammatory cytokine/chemokine expression) will be evaluated by flow cytometry, microarray, and multiplex bead array technology.

Here is how samples will be taken:

1. A sample of cervical mucus will be collected by using a cotton swab rotated 360º in the cervical os, and a second swab used to collect secretions from the posterior vaginal fornix. Both swabs will be transferred into a single vial containing 5 mL of phosphate-buffered saline (PBS) which will be transported to the laboratory to be tested and cultured for sexually transmitted infections such as gonorrhea, chlamydia etc.
2. Cervical cells will be collected by using a small brush and a wooden spatula. Both specimen will be transferred into a 15ml conical tube containing 5 ml of PBS. This specimen will be used to characterize the cellular populations in the specimen.
3. Cervico vaginal lavage will be performed by washing the endocervix with 2 ml of sterile 1x PBS. The liquid will be collected form the posterior fornix. Samples will be placed into a conical tube, centrifuged to remove cellular debris and the supernatant will be stored at -70°C and will be shipped in liquid nitrogen dry shipper to Winnipeg, Manitoba. Those specimens will be used for innate soluble factor detection (chemokines, cytokines, antibodies, innate protein, etc
4. 30ml of venous blood will be taken. (Peripheral Blood Mononuclear Cells will be extracted for immune activation analysis, DNA will be used for immune genes expression, plasma will be used for protein and innate soluble factor detection.)

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Eligibility criteria: Inclusion criteria:

1. Age greater than 18 years old and less than 50 years old
2. Uterus and cervix present
3. Willing to take daily acetylsalicylic acid or HCQ
4. Willing to undergo pelvic exams
5. In general good health, no chronic infection and not taking any anti-inflammatory or immunosuppressors
6. Being HIV negative
7. Without any cardiovascular disease
8. Being active in sex work (for the Female commercial sex worker group)

Exclusion criteria:

1. Age less than 18 years or more than 50 years old
2. Pregnancy (if a women becomes pregnant during the 10 weeks of the project she will be excluded)
3. Breast feeding
4. Pregnant in the last 12 months
5. Being positive for Sexual transmissible disease or bacterial vaginosis at week 0
6. Menopausal
7. No longer involve in sex work (for the female sex worker group)
8. Having a chronic disease
9. Taking any of the medication listed in annex 1 for health conditions
10. Being allergic to acetylsalicylic acid, other medication for pain or fever, tartrazine dye or chloroquine, hydroxuchloroquine, primaquine or any other medication
11. Having heartburn, stomach pain, stomach ulcer, anemia, hemophilia, kidney or liver disease, psoriasis, porphyria or other blood disease, G-6-PD deficiency, dermatitis (skin inflammation), alcoholism
12. Having experienced previous vision changes while taking chloroquine, hydroxychloroquine (Aralen) or primaquine.
13. Having a history of a diagnosed cardiovascular event, heart failure, peripheral arterial disease, angina, stoke, transient ischemic attack
14. Having a current or recurrent condition with a high risk of major bleeding
15. Having anemia
16. Current participation in a clinical trial

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Primary outcomes:
measure: Changes in Systemic Immune Activation From Baseline Observed by the CD69 Expression on CD4 T Cells
timeFrame: Baseline and 8 weeks
Secondary outcomes:
measure: Change in Number of CCR5+CD4+ T Cell Population at the Female Genital Tract.
timeFrame: baseline and 8 weeks
Other outcomes:
Locations:
city: Nairobi,
country: Kenya
facility: Kenyan Aids Control Project/University of Nairobi
Study officials:
affiliation: University of Manitoba
name: Keith R. Fowke, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lajoie J, Kowatsch MM, Mwangi LW, Boily-Larouche G, Oyugi J, Chen Y, Kimani M, Ho EA, Kimani J, Fowke KR. Low-Dose Acetylsalicylic Acid Reduces T Cell Immune Activation: Potential Implications for HIV Prevention. Front Immunol. 2021 Nov 18;12:778455. doi: 10.3389/fimmu.2021.778455. eCollection 2021.
citation: Lajoie J, Mwangi L, Fowke KR. Preventing HIV infection without targeting the virus: how reducing HIV target cells at the genital tract is a new approach to HIV prevention. AIDS Res Ther. 2017 Sep 12;14(1):46. doi: 10.1186/s12981-017-0166-7.