Foreskin HIV Susceptibility
Conditions
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.
Interventions
DRUGOral Tinidazole
Please see description under arms
Please see description under arms
DRUGTopical Clindamycin
Please see description under arms
DRUGTopical Hydrogen Peroxide
Please see description under arms
Sponsors
UVRI-IAVI HIV Vaccine Program
Entebbe General Hospital
University of Toronto
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
Randomized, open label with 5 arms
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Enrollment criteria include: 1. Aged 18 years or older 2. Biological male 3. Uncircumcised 4. HIV seronegative 5. Willing to comply with the requirements of the protocol 6. No current sexually transmitted infection (N. gonorrhoeae or C. trachomatis) 7. No clinically relevant genital symptoms / signs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| % HIV entry into foreskin derived CD4+ T cells | 4 weeks | This measure will utilize a validated pseudovirus entry assay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Uganda
Contacts
Primary ContactRupert Kaul, MD/PhD
Outcome results
None listed