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Effect of Antibiotics on Penile Microbiome and HIV Susceptibility Study in Ugandan Men

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ClinicalTrials.gov Identifier: NCT03412071
Recruitment Status : Recruiting
First Posted : January 26, 2018
Last Update Posted : January 26, 2018
Sponsor:
Collaborators:
UVRI-IAVI HIV Vaccine Program
Entebbe General Hospital
Information provided by (Responsible Party):
Rupert Kaul, 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.

Condition or disease Intervention/treatment Phase
Foreskin HIV Susceptibility Drug: Oral Tinidazole Drug: Topical metronidazole Drug: Topical Clindamycin Drug: Topical Hydrogen Peroxide Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 125 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, open label with 5 arms
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Testing the Ability of a Microbiome - Focused Intervention to Reduce HIV Susceptibility in Ugandan Men
Actual Study Start Date : December 7, 2017
Estimated Primary Completion Date : December 7, 2019
Estimated Study Completion Date : December 7, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
No Intervention: Control group
25 HIV-uninfected, uncircumcised men will be immediately circumcised following enrollment. This group will serve as the comparison to the four intervention groups.
Active Comparator: Oral tinidazole group
25 HIV-uninfected, uncircumcised men will be randomized to receive oral tinidazole 2g once a day for two days.
Drug: Oral Tinidazole
Please see description under arms
Other Name: FASIGYN 500mgs

Active Comparator: Topical metronidazole (0.75%) group
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.
Drug: Topical metronidazole
Please see description under arms
Other Name: Rozex 0.75%

Active Comparator: Topical clindamycin (2%) group
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.
Drug: Topical Clindamycin
Please see description under arms
Other Name: Dalacin cream 2%

Active Comparator: Topical hydrogen peroxide (1%) group
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.
Drug: Topical Hydrogen Peroxide
Please see description under arms
Other Name: Crystacide 1%




Primary Outcome Measures :
  1. % HIV entry into foreskin derived CD4+ T cells [ Time Frame: 4 weeks ]
    This measure will utilize a validated pseudovirus entry assay.


Secondary Outcome Measures :
  1. Tissue density of HIV-susceptible CD4+ T cells [ Time Frame: 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.

  2. CD4+ T cell subsets in foreskin tissue [ Time Frame: 4 weeks ]
    Immunofluorescence microscopy (IF) will be used to quantify CD4+ T cell subsets foreskin tissue after circumcision.

  3. Density of Langerhans cells in foreskin tissue [ Time Frame: 4 weeks ]
    Immunofluorescence microscopy (IF) will be used to quantify Langerhans cells in foreskin tissue after circumcision.

  4. Presence of foreskin inflammation [ Time Frame: 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.

  5. Foreskin microbiome composition [ Time Frame: 4 weeks ]
    The foreskin (prepuce) microbiome will be characterized based on 16S rRNA sequencing.

  6. Foreskin tissue explant HIV susceptibility [ Time Frame: 4 weeks ]
    Foreskin tissue susecptibility to HIV infection will be quantified, based on p24 ELISA after ex vivo incubation with a primary HIV isolate.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Foreskin HIV susceptibility can only be assessed in biological males.
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03412071


Contacts
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Contact: Rupert Kaul, MD/PhD (416) 946-7054 rupert.kaul@utoronto.ca

Locations
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Uganda
UVRI-IAVI HIV Vaccine Program Recruiting
Entebbe, Wakiso, Uganda
Contact: Bernard S Bagaya, PhD    +256787082820    bbagaya@iavi.or.ug   
Sponsors and Collaborators
University of Toronto
UVRI-IAVI HIV Vaccine Program
Entebbe General Hospital
Investigators
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Principal Investigator: Rupert Kaul, MD/PhD University of Toronto
Study Director: Ronald M Galiwango, MBChB/MSc University of Toronto

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Rupert Kaul, Professor - Principal Investigator, University of Toronto
ClinicalTrials.gov Identifier: NCT03412071     History of Changes
Other Study ID Numbers: Penile microbiome antibiotics
First Posted: January 26, 2018    Key Record Dates
Last Update Posted: January 26, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Disease Susceptibility
Disease Attributes
Pathologic Processes
Metronidazole
Clindamycin
Clindamycin palmitate
Clindamycin phosphate
Hydrogen Peroxide
Tinidazole
Anti-Infective Agents
Anti-Bacterial Agents
Antiprotozoal Agents
Antiparasitic Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Infective Agents, Local
Alkylating Agents
Antitrichomonal Agents