Effect of Antibiotics on Penile Microbiome and HIV Susceptibility Study in Ugandan Men
- Conditions
- Foreskin HIV Susceptibility
- Interventions
- Registration Number
- NCT03412071
- Lead Sponsor
- University of Toronto
- Brief Summary
This pilot study will assess the impact of four antimicrobial products (3 topical, one systemic) on the foreskin microbiome and HIV susceptibility of foreskin-derived CD4+ T cells. Participants will include HIV-uninfected Ugandan men presenting for elective male circumcision to reduce their HIV risk.
- Detailed Description
RATIONALE: The foreskin is the site of most HIV acquisition in uncircumcised heterosexual men, and male circumcision (MC) reduces HIV risk by almost 60%. However, cultural and practical barriers have led to suboptimal uptake. Foreskin inflammation, defined by elevated levels of pro-inflammatory cytokines in the prepuce, is a key determinant of HIV acquisition risk in uncircumcised men, and anaerobic bacteria within the foreskin microbiome may be an important cause of this inflammation.
OBJECTIVES: A pilot in vivo - in vitro clinical study of four potential interventions to reduce HIV susceptibility in the foreskin by altering the microbiome. The study is a collaboration between the University of Toronto, IAVI-UVRI, and the Entebbe General Hospital. We will recruit 125 men presenting for elective MC, along with regular female sexual partners (if applicable). Participants will be randomized (n=25 per group) to immediate MC, or to one of four intervention arms: twice-daily application of topical metronidazole 0.75%; twice-daily application of topical clindamycin 2%; twice daily application of hydrogen peroxide 1%; or oral tinidazole 2g once a day for two days. Swabs for immune and microbiome studies will be collected before and after product. After 4 weeks the MC procedure will be performed; foreskin CD4+ T cell susceptibility to HIV will be quantified using a flow cytometry-based pseudovirus assay, and tissue immunohistochemistry performed. The primary and secondary endpoints are outlined below. A secondary study will assess the impact of penile topical antibiotic application on immunology and the microbiome in the genital tract of female sexual partners.
OUTCOMES: This in vivo - in vitro clinical trial will define the causal role of the penile microbiome in HIV susceptibility, and will assess potential strategies to take forward into HIV efficacy trials in uncircumcised heterosexual men.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 125
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Oral tinidazole group Oral Tinidazole 25 HIV-uninfected, uncircumcised men will be randomized to receive oral tinidazole 2g once a day for two days. Topical metronidazole (0.75%) group Topical metronidazole 25 HIV-uninfected, uncircumcised men will be randomized to apply topical 0.75% metronidazole cream to the foreskin twice a day for one week, and then twice a week for three weeks. Topical clindamycin (2%) group Topical Clindamycin 25 HIV-uninfected, uncircumcised men will be randomized to apply topical 2% clindamycin cream to the foreskin twice a day for one week, and then twice a week for three weeks. Topical hydrogen peroxide (1%) group Topical Hydrogen Peroxide 25 HIV-uninfected, uncircumcised men will be randomized to apply 1% hydrogen peroxide cream to the foreskin twice a day for one week, and then twice a week for three weeks.
- Primary Outcome Measures
Name Time Method % HIV entry into foreskin derived CD4+ T cells 4 weeks This measure will utilize a validated pseudovirus entry assay.
- Secondary Outcome Measures
Name Time Method Density of Langerhans cells in foreskin tissue 4 weeks Immunofluorescence microscopy (IF) will be used to quantify Langerhans cells in foreskin tissue after circumcision.
Tissue density of HIV-susceptible CD4+ T cells 4 weeks The density of CD4+ T cells in foreskin tissues will be assayed using immunohistochemistry, and the % pseudovirus entry (see primary endpoint, above) will be used to calculate the tissue density of HIV-susceptible CD4+ T cells.
CD4+ T cell subsets in foreskin tissue 4 weeks Immunofluorescence microscopy (IF) will be used to quantify CD4+ T cell subsets foreskin tissue after circumcision.
Presence of foreskin inflammation 4 weeks Cytokine/chemokines will be assayed by ELISA, and foreskin inflammation defined as the presence of ≥3/7 inflammatory cytokines within the top quartile for that cytokine.
Foreskin microbiome composition 4 weeks The foreskin (prepuce) microbiome will be characterized based on 16S rRNA sequencing.
Foreskin tissue explant HIV susceptibility 4 weeks Foreskin tissue susecptibility to HIV infection will be quantified, based on p24 ELISA after ex vivo incubation with a primary HIV isolate.
Trial Locations
- Locations (1)
UVRI-IAVI HIV Vaccine Program
🇺🇬Entebbe, Wakiso, Uganda