Effect of Schistosomiasis Mansoni on HIV Susceptibility and Female Genital Immunology

HIV Clinical Trial

Official title:

Effect of Schistosomiasis Mansoni and Its Treatment on HIV Susceptibility and Female Genital Immunology

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02878564
• Other study ID #: UT-Schisto
• Status: Completed
• Phase: Phase 4
• First received: August 15, 2016
• Last updated: October 26, 2016
• Start date: March 2016
• Est. completion date: October 2016

Study information

• Verified date: October 2016
• Source: University of Toronto
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Canadian Institutes of Health ResearchUganda: National Council for Science and Technology
• Study type: Interventional

Clinical Trial Summary

The aim of this study is to assess the impact of Schistosoma mansoni infection and its treatment on genital immunology and HIV susceptibility in Ugandan women.

Description:

Schistosomiasis mansoni is a water-borne disease caused by helminth Schistosoma mansoni (S. mansoni), in which adult worms deposit eggs in mesenteric blood vessels. Schistomiasis prevalence in the fishing communities in East Africa, and particularly in the Lake Victoria region, exceeds 60% and there is overlap in this region with a high prevalence of HIV (29%).

A recent epidemiological study found an association between S. mansoni and HIV infection in adult women residing near Lake Victoria in Tanzania. Furthermore, in primate studies S. mansoni infection was shown to increase susceptibility to SIV infection after rectal (but not intravenous) challenge, implying that S. mansoni might increase HIV susceptibility by altering local mucosal (gut) immunology.

While S. mansoni does not directly infect the genital tract, we hypothesize that the inflammation it causes in the gut may be associated with mucosal inflammation at other sites through activation of common mucosal homing integrins such as a4b7. Therefore in this study we propose to explore whether S. mansoni increases inflammation and/or HIV susceptibility in the endocervix of adult women.

HIV-uninfected adult women from Entebbe, Uganda will be screened for schistosomiasis using a commercial CCA rapid test kit, and infected women who fulfill the study eligibility criteria will be recruited into the study. Kato-Katz microscopy analysis will be performed to assess egg shedding at baseline. Additionally, urine microscopy will be done to screen for Schistosoma hematobium (which can directly involve the genital mucosa). Schistosomiasis treatment will be provided to all participants according to Ugandan clinical guidelines.

Endocervical cytobrush, vaginal SoftCup and blood samples will be collected at three time points; at baseline and 4 and 8 weeks after schistosomiasis treatment, at the same stage of the menstrual cycle. Using an ex vivo HIV entry assay and mucosal cytokine and microbiome analyses we will quantify the effect of S. mansoni and its treatment on cervical HIV susceptibility and genital inflammation.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: October 2016
• Est. primary completion date: October 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

• Positive (score above "trace") on a urine CCA rapid test

• Willing to be treated with praziquantel

• Willing to give informed consent, and answer short questionnaires on economic status, and sexual risk behavior.

• Willing to comply with the requirements of the protocol

• HIV and classical STI (see below) negative

Exclusion Criteria:

• HIV infected

• Malaria infected

• Pregnant.

• Irregular menstrual cycle, or actively menstruating at the time of genital sampling.

• Tested positive for classical STIs (syphilis, gonorrhea, chlamydia, Trichomonas vaginalis) or having genital ulcers

• Prior hysterectomy

• Deemed by physician to be unlikely to complete study protocol.

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Disease Susceptibility
• HIV
• Schistosomiasis
• Schistosomiasis mansoni

Intervention

Drug:
• Praziquantel
40 mg/kg, PO (orally administered tablets)

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
University of Toronto	UVRI-IAVI HIV Vaccine Program, Uganda

Country where clinical trial is conducted

Uganda, 

References & Publications (4)

Arnold KB, Burgener A, Birse K, Romas L, Dunphy LJ, Shahabi K, Abou M, Westmacott GR, McCorrister S, Kwatampora J, Nyanga B, Kimani J, Masson L, Liebenberg LJ, Abdool Karim SS, Passmore JA, Lauffenburger DA, Kaul R, McKinnon LR. Increased levels of inflammatory cytokines in the female reproductive tract are associated with altered expression of proteases, mucosal barrier proteins, and an influx of HIV-susceptible target cells. Mucosal Immunol. 2016 Jan;9(1):194-205. doi: 10.1038/mi.2015.51. Epub 2015 Jun 24. — View Citation

Chenine AL, Shai-Kobiler E, Steele LN, Ong H, Augostini P, Song R, Lee SJ, Autissier P, Ruprecht RM, Secor WE. Acute Schistosoma mansoni infection increases susceptibility to systemic SHIV clade C infection in rhesus macaques after mucosal virus exposure. PLoS Negl Trop Dis. 2008 Jul 23;2(7):e265. doi: 10.1371/journal.pntd.0000265. — View Citation

Downs JA, van Dam GJ, Changalucha JM, Corstjens PL, Peck RN, de Dood CJ, Bang H, Andreasen A, Kalluvya SE, van Lieshout L, Johnson WD Jr, Fitzgerald DW. Association of Schistosomiasis and HIV infection in Tanzania. Am J Trop Med Hyg. 2012 Nov;87(5):868-73. doi: 10.4269/ajtmh.2012.12-0395. Epub 2012 Oct 1. — View Citation

Joag VR, McKinnon LR, Liu J, Kidane ST, Yudin MH, Nyanga B, Kimwaki S, Besel KE, Obila JO, Huibner S, Oyugi JO, Arthos J, Anzala O, Kimani J, Ostrowski MA; Toronto HIV Research Group, Kaul R. Identification of preferential CD4+ T-cell targets for HIV infection in the cervix. Mucosal Immunol. 2016 Jan;9(1):1-12. doi: 10.1038/mi.2015.28. Epub 2015 Apr 15. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in the percentage of endocervical CD4+ T cells susceptible to HIV pseudovirus entry after treatment of schistosomiasis.	The percentage of endocervical CD4+ T cells per cytobrush infected ex vivo by an HIV pseudovirus construct, as quantified by flow cytometry.	1 month.	No
Primary	Change in the number of endocervical CD4+ T cells susceptible to HIV pseudovirus entry after treatment of schistosomiasis.	The number of endocervical CD4+ T cells per cytobrush infected ex vivo by an HIV pseudovirus construct, as quantified by flow cytometry.	1 month.	No
Secondary	Change in the percentage of blood CD4+ T cells susceptible to HIV pseudovirus entry after treatment of schistosomiasis.	The percentage of blood CD4+ T cells infected ex vivo by an HIV pseudovirus construct, as quantified by flow cytometry.	1 and 2 months.	No
Secondary	Change in the phenotype of endocervical and blood CD4+ T cells after treatment of schistosomiasis.	Surface expression of CCR5, CD69, CD38, HLA-DR, a4b7, CCR7 and CD45RA by endocervical and blood CD4 T will be assessed using flow cytometry.	1 and 2 months.	No
Secondary	Change in genital proinflammatory cytokine levels after treatment of schistosomiasis.	A predefined genital inflammation score based on genital levels of pro-inflammatory cytokines and chemokines [as per Arnold K et al, Muc Immunol, 2015] will be assessed.	1 and 2 months.	No
Secondary	Change in the cervico-vaginal microbiome after treatment of schistosomiasis.	The cervico-vaginal microbiome will be assessed by 16s rRNA sequencing before and after schistosomiasis therapy.	1 and 2 months.	No
Secondary	Change in the cervico-vaginal proteome after treatment of schistosomiasis.	The genital proteome will be assessed by mass spectrometry before and after schistosomiasis therapy.	1 and 2 months.	No
Secondary	Change in the percentage of endocervical CD4+ T cells susceptible to HIV pseudovirus entry after treatment of schistosomiasis.	The percentage of endocervical CD4+ T cells per cytobrush infected ex vivo by an HIV pseudovirus construct, as quantified by flow cytometry.	2 months.	No
Secondary	Change in the number of endocervical CD4+ T cells susceptible to HIV pseudovirus entry after treatment of schistosomiasis.	The number of endocervical CD4+ T cells per cytobrush infected ex vivo by an HIV pseudovirus construct, as quantified by flow cytometry.	2 months.	No