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

Foreskin HIV Susceptibility Clinical Trial

Official title:

Testing the Ability of a Microbiome - Focused Intervention to Reduce HIV Susceptibility in Ugandan Men

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03412071
• Other study ID #: Penile microbiome antibiotics
• Status: Recruiting
• Phase: N/A
• First received: January 19, 2018
• Last updated: January 19, 2018
• Start date: December 7, 2017
• Est. completion date: December 7, 2019

Study information

• Verified date: January 2018
• Source: University of Toronto
• Contact: Rupert Kaul, MD/PhD
• Phone: (416) 946-7054
• Email: rupert.kaul[@]utoronto.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 125
• Est. completion date: December 7, 2019
• Est. primary completion date: December 7, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Disease Susceptibility
• Foreskin HIV Susceptibility

Intervention

Drug:
• Oral Tinidazole
Please see description under arms
• Topical metronidazole
Please see description under arms
• Topical Clindamycin
Please see description under arms
• Topical Hydrogen Peroxide
Please see description under arms

Locations

Country	Name	City	State
Uganda	UVRI-IAVI HIV Vaccine Program	Entebbe	Wakiso

Sponsors (3)

Lead Sponsor	Collaborator
University of Toronto	Entebbe General Hospital, UVRI-IAVI HIV Vaccine Program

Country where clinical trial is conducted

Uganda, 

References & Publications (21)

Anahtar MN, Byrne EH, Doherty KE, Bowman BA, Yamamoto HS, Soumillon M, Padavattan N, Ismail N, Moodley A, Sabatini ME, Ghebremichael MS, Nusbaum C, Huttenhower C, Virgin HW, Ndung'u T, Dong KL, Walker BD, Fichorova RN, Kwon DS. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity. 2015 May 19;42(5):965-76. doi: 10.1016/j.immuni.2015.04.019. — View Citation

Armstrong NR, Wilson JD. Tinidazole in the treatment of bacterial vaginosis. Int J Womens Health. 2010 Aug 9;1:59-65. — View Citation

Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J, Sitta R, Puren A. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med. 2005 Nov;2(11):e298. Epub 2005 Oct 25. Erratum in: PLoS Med. 2006 May;3(5):e298. — View Citation

Baggaley R, Doherty M, Ball A, Ford N, Hirnschall G. The Strategic Use of Antiretrovirals to Prevent HIV Infection: A Converging Agenda. Clin Infect Dis. 2015 Jun 1;60 Suppl 3:S159-60. doi: 10.1093/cid/civ091. — View Citation

Bailey RC, Moses S, Parker CB, Agot K, Maclean I, Krieger JN, Williams CF, Campbell RT, Ndinya-Achola JO. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet. 2007 Feb 24;369(9562):643-56. — View Citation

Bolduc JF, Ouellet M, Hany L, Tremblay MJ. Toll-Like Receptor 2 Ligation Enhances HIV-1 Replication in Activated CCR6+ CD4+ T Cells by Increasing Virus Entry and Establishing a More Permissive Environment to Infection. J Virol. 2017 Jan 31;91(4). pii: e01402-16. doi: 10.1128/JVI.01402-16. Print 2017 Feb 15. — View Citation

Bukusi E, Thomas KK, Nguti R, Cohen CR, Weiss N, Coombs RW, Holmes KK. Topical penile microbicide use by men to prevent recurrent bacterial vaginosis in sex partners: a randomized clinical trial. Sex Transm Dis. 2011 Jun;38(6):483-9. — View Citation

Esra RT, Olivier AJ, Passmore JA, Jaspan HB, Harryparsad R, Gray CM. Does HIV Exploit the Inflammatory Milieu of the Male Genital Tract for Successful Infection? Front Immunol. 2016 Jun 24;7:245. doi: 10.3389/fimmu.2016.00245. eCollection 2016. Review. — View Citation

Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, Nalugoda F, Kiwanuka N, Moulton LH, Chaudhary MA, Chen MZ, Sewankambo NK, Wabwire-Mangen F, Bacon MC, Williams CF, Opendi P, Reynolds SJ, Laeyendecker O, Quinn TC, Wawer MJ. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet. 2007 Feb 24;369(9562):657-66. — View Citation

Gray RH, Wawer MJ, Kigozi G. Programme science research on medical male circumcision scale-up in sub-Saharan Africa. Sex Transm Infect. 2013 Aug;89(5):345-9. doi: 10.1136/sextrans-2012-050595. Epub 2013 May 22. — View Citation

Jhingta P, Bhardwaj A, Sharma D, Kumar N, Bhardwaj VK, Vaid S. Effect of hydrogen peroxide mouthwash as an adjunct to chlorhexidine on stains and plaque. J Indian Soc Periodontol. 2013 Jul;17(4):449-53. doi: 10.4103/0972-124X.118315. — View Citation

Kigozi G, Wawer M, Ssettuba A, Kagaayi J, Nalugoda F, Watya S, Mangen FW, Kiwanuka N, Bacon MC, Lutalo T, Serwadda D, Gray RH. Foreskin surface area and HIV acquisition in Rakai, Uganda (size matters). AIDS. 2009 Oct 23;23(16):2209-13. doi: 10.1097/QAD.0b013e328330eda8. — View Citation

Liu CM, Hungate BA, Tobian AA, Serwadda D, Ravel J, Lester R, Kigozi G, Aziz M, Galiwango RM, Nalugoda F, Contente-Cuomo TL, Wawer MJ, Keim P, Gray RH, Price LB. Male circumcision significantly reduces prevalence and load of genital anaerobic bacteria. MBio. 2013 Apr 16;4(2):e00076. doi: 10.1128/mBio.00076-13. — View Citation

Menard JP. Antibacterial treatment of bacterial vaginosis: current and emerging therapies. Int J Womens Health. 2011;3:295-305. doi: 10.2147/IJWH.S23814. Epub 2011 Aug 23. — View Citation

Prodger JL, Gray R, Kigozi G, Nalugoda F, Galiwango R, Hirbod T, Wawer M, Hofer SO, Sewankambo N, Serwadda D, Kaul R. Foreskin T-cell subsets differ substantially from blood with respect to HIV co-receptor expression, inflammatory profile, and memory status. Mucosal Immunol. 2012 Mar;5(2):121-8. doi: 10.1038/mi.2011.56. Epub 2011 Nov 16. — View Citation

Prodger JL, Gray RH, Shannon B, Shahabi K, Kong X, Grabowski K, Kigozi G, Nalugoda F, Serwadda D, Wawer MJ, Reynolds SJ, Liu CM, Tobian AA, Kaul R. Chemokine Levels in the Penile Coronal Sulcus Correlate with HIV-1 Acquisition and Are Reduced by Male Circumcision in Rakai, Uganda. PLoS Pathog. 2016 Nov 29;12(11):e1006025. doi: 10.1371/journal.ppat.1006025. eCollection 2016 Nov. — View Citation

Prodger JL, Hirbod T, Kigozi G, Nalugoda F, Reynolds SJ, Galiwango R, Shahabi K, Serwadda D, Wawer MJ, Gray RH, Kaul R; Rakai Genital Immunology Research Group. Immune correlates of HIV exposure without infection in foreskins of men from Rakai, Uganda. Mucosal Immunol. 2014 May;7(3):634-44. doi: 10.1038/mi.2013.83. Epub 2013 Oct 23. — View Citation

Rashed HT. Evaluation of the effect of hydrogen peroxide as a mouthwash in comparison with chlorhexidine in chronic periodontitis patients: A clinical study. J Int Soc Prev Community Dent. 2016 May-Jun;6(3):206-12. doi: 10.4103/2231-0762.183114. Epub 2016 May 30. — View Citation

Sgaier SK, Reed JB, Thomas A, Njeuhmeli E. Achieving the HIV prevention impact of voluntary medical male circumcision: lessons and challenges for managing programs. PLoS Med. 2014 May 6;11(5):e1001641. doi: 10.1371/journal.pmed.1001641. eCollection 2014 May. — View Citation

TenoRes Study Group. Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study. Lancet Infect Dis. 2016 May;16(5):565-575. doi: 10.1016/S1473-3099(15)00536-8. Epub 2016 Jan 29. — View Citation

V Sgibnev A, A Kremleva E. Vaginal Protection by H2O2-Producing Lactobacilli. Jundishapur J Microbiol. 2015 Oct 17;8(10):e22913. doi: 10.5812/jjm.22913. eCollection 2015 Oct. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	% HIV entry into foreskin derived CD4+ T cells	This measure will utilize a validated pseudovirus entry assay.	4 weeks
Secondary	Tissue density of HIV-susceptible CD4+ T cells	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.	4 weeks
Secondary	CD4+ T cell subsets in foreskin tissue	Immunofluorescence microscopy (IF) will be used to quantify CD4+ T cell subsets foreskin tissue after circumcision.	4 weeks
Secondary	Density of Langerhans cells in foreskin tissue	Immunofluorescence microscopy (IF) will be used to quantify Langerhans cells in foreskin tissue after circumcision.	4 weeks
Secondary	Presence of foreskin inflammation	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.	4 weeks
Secondary	Foreskin microbiome composition	The foreskin (prepuce) microbiome will be characterized based on 16S rRNA sequencing.	4 weeks
Secondary	Foreskin tissue explant HIV susceptibility	Foreskin tissue susecptibility to HIV infection will be quantified, based on p24 ELISA after ex vivo incubation with a primary HIV isolate.	4 weeks