Protocol for a randomized clinical trial exploring the effect of antimicrobial agents on the penile microbiota, immunology and HIV susceptibility of Ugandan men
Abstract Background The foreskin is the main site of HIV acquisition in a heterosexual uncircumcised man, but many men in endemic countries are reluctant to undergo penile circumcision (PC). Observational studies suggest that proinflammatory anaerobic bacteria are enriched on the uncircumcised penis...
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| Format: | Article |
| Language: | English |
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BMC
2019-07-01
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| Series: | Trials |
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| Online Access: | http://link.springer.com/article/10.1186/s13063-019-3545-7 |
| _version_ | 1819049418937073664 |
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| author | Ronald M. Galiwango Bernard Bagaya Juliet Mpendo Vineet Joag Brenda Okech Annet Nanvubya Ali Ssetaala Moses Muwanga Rupert Kaul |
| author_facet | Ronald M. Galiwango Bernard Bagaya Juliet Mpendo Vineet Joag Brenda Okech Annet Nanvubya Ali Ssetaala Moses Muwanga Rupert Kaul |
| author_sort | Ronald M. Galiwango |
| collection | DOAJ |
| description | Abstract Background The foreskin is the main site of HIV acquisition in a heterosexual uncircumcised man, but many men in endemic countries are reluctant to undergo penile circumcision (PC). Observational studies suggest that proinflammatory anaerobic bacteria are enriched on the uncircumcised penis, where they may enhance HIV susceptibility through increased foreskin inflammatory cytokines and the recruitment of HIV-susceptible CD4+ target cells. This trial will examine the impact of systemic and topical antimicrobials on ex vivo foreskin HIV susceptibility. Methods/design This randomized, open-label clinical trial will randomize 125 HIV-negative Ugandan men requesting voluntary PC to one of five arms (n = 25 each). The control group will receive immediate PC, while the four intervention groups will defer PC for 1 month and be provided in the interim with either oral tinidazole, penile topical metronidazole, topical clindamycin, or topical hydrogen peroxide. The impact of these interventions on HIV entry into foreskin-derived CD4+ T cells will be quantified ex vivo at the time of PC using a clade A, R5 tropic HIV pseudovirus assay (primary endpoint); secondary endpoints include the impact of antimicrobials on immune parameters and the microbiota of the participant’s penis and of the vagina of their female partner (if applicable), assessed by multiplex enzyme-linked immunosorbent assay and 16S rRNA sequencing. Discussion There is a critical need to develop acceptable, simple, and effective means of HIV prevention in men unwilling to undergo PC. This trial will provide insight into the causative role of the foreskin microbiota on HIV susceptibility, and the impact of simple microbiota-focused clinical interventions. This may pave the way for future clinical trials using low-cost, nonsurgical intervention(s) to reduce HIV risk in uncircumcised heterosexual men. Trial registration ClinicalTrials.gov, NCT03412071. Retrospectively registered on 26 January 2018. |
| first_indexed | 2024-12-21T11:31:51Z |
| format | Article |
| id | doaj.art-6f186e85fd2b49c58837ab17f02f6048 |
| institution | Directory Open Access Journal |
| issn | 1745-6215 |
| language | English |
| last_indexed | 2024-12-21T11:31:51Z |
| publishDate | 2019-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Trials |
| spelling | doaj.art-6f186e85fd2b49c58837ab17f02f60482022-12-21T19:05:32ZengBMCTrials1745-62152019-07-012011910.1186/s13063-019-3545-7Protocol for a randomized clinical trial exploring the effect of antimicrobial agents on the penile microbiota, immunology and HIV susceptibility of Ugandan menRonald M. Galiwango0Bernard Bagaya1Juliet Mpendo2Vineet Joag3Brenda Okech4Annet Nanvubya5Ali Ssetaala6Moses Muwanga7Rupert Kaul8Department of Immunology, University of TorontoHIV Vaccine Program, Uganda Virus Research Institute–International AIDS Vaccine InitiativeHIV Vaccine Program, Uganda Virus Research Institute–International AIDS Vaccine InitiativeDepartment of Immunology, University of TorontoHIV Vaccine Program, Uganda Virus Research Institute–International AIDS Vaccine InitiativeHIV Vaccine Program, Uganda Virus Research Institute–International AIDS Vaccine InitiativeHIV Vaccine Program, Uganda Virus Research Institute–International AIDS Vaccine InitiativeEntebbe General HospitalDepartment of Immunology, University of TorontoAbstract Background The foreskin is the main site of HIV acquisition in a heterosexual uncircumcised man, but many men in endemic countries are reluctant to undergo penile circumcision (PC). Observational studies suggest that proinflammatory anaerobic bacteria are enriched on the uncircumcised penis, where they may enhance HIV susceptibility through increased foreskin inflammatory cytokines and the recruitment of HIV-susceptible CD4+ target cells. This trial will examine the impact of systemic and topical antimicrobials on ex vivo foreskin HIV susceptibility. Methods/design This randomized, open-label clinical trial will randomize 125 HIV-negative Ugandan men requesting voluntary PC to one of five arms (n = 25 each). The control group will receive immediate PC, while the four intervention groups will defer PC for 1 month and be provided in the interim with either oral tinidazole, penile topical metronidazole, topical clindamycin, or topical hydrogen peroxide. The impact of these interventions on HIV entry into foreskin-derived CD4+ T cells will be quantified ex vivo at the time of PC using a clade A, R5 tropic HIV pseudovirus assay (primary endpoint); secondary endpoints include the impact of antimicrobials on immune parameters and the microbiota of the participant’s penis and of the vagina of their female partner (if applicable), assessed by multiplex enzyme-linked immunosorbent assay and 16S rRNA sequencing. Discussion There is a critical need to develop acceptable, simple, and effective means of HIV prevention in men unwilling to undergo PC. This trial will provide insight into the causative role of the foreskin microbiota on HIV susceptibility, and the impact of simple microbiota-focused clinical interventions. This may pave the way for future clinical trials using low-cost, nonsurgical intervention(s) to reduce HIV risk in uncircumcised heterosexual men. Trial registration ClinicalTrials.gov, NCT03412071. Retrospectively registered on 26 January 2018.http://link.springer.com/article/10.1186/s13063-019-3545-7HIV transmissionPenile microbiomeClinical trialAntimicrobialsUganda |
| spellingShingle | Ronald M. Galiwango Bernard Bagaya Juliet Mpendo Vineet Joag Brenda Okech Annet Nanvubya Ali Ssetaala Moses Muwanga Rupert Kaul Protocol for a randomized clinical trial exploring the effect of antimicrobial agents on the penile microbiota, immunology and HIV susceptibility of Ugandan men Trials HIV transmission Penile microbiome Clinical trial Antimicrobials Uganda |
| title | Protocol for a randomized clinical trial exploring the effect of antimicrobial agents on the penile microbiota, immunology and HIV susceptibility of Ugandan men |
| title_full | Protocol for a randomized clinical trial exploring the effect of antimicrobial agents on the penile microbiota, immunology and HIV susceptibility of Ugandan men |
| title_fullStr | Protocol for a randomized clinical trial exploring the effect of antimicrobial agents on the penile microbiota, immunology and HIV susceptibility of Ugandan men |
| title_full_unstemmed | Protocol for a randomized clinical trial exploring the effect of antimicrobial agents on the penile microbiota, immunology and HIV susceptibility of Ugandan men |
| title_short | Protocol for a randomized clinical trial exploring the effect of antimicrobial agents on the penile microbiota, immunology and HIV susceptibility of Ugandan men |
| title_sort | protocol for a randomized clinical trial exploring the effect of antimicrobial agents on the penile microbiota immunology and hiv susceptibility of ugandan men |
| topic | HIV transmission Penile microbiome Clinical trial Antimicrobials Uganda |
| url | http://link.springer.com/article/10.1186/s13063-019-3545-7 |
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