Effect of Schistosomiasis Mansoni on HIV Susceptibility and Female Genital Immunology

• ClinicalTrials.gov Identifier: NCT02878564
• Recruitment Status: Completed
• First Posted: August 25, 2016
• Last Update Posted: October 27, 2016
• Sponsor: University of Toronto
• Collaborator: UVRI-IAVI HIV Vaccine Program, Uganda
• Information provided by (Responsible Party): Rupert Kaul, University of Toronto

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Schistosomiasis Mansoni; HIV	Drug: Praziquantel	Phase 4

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Effect of Schistosomiasis Mansoni and Its Treatment on HIV Susceptibility and Female Genital Immunology
• Study Start Date: March 2016
• Actual Primary Completion Date: October 2016
• Actual Study Completion Date: October 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Praziquantel treatment; Participants will be HIV-uninfected women with asymptomatic Schistosoma mansoni infection; the study will examine the impact of standard praziquantel therapy (40 mg/kg po single dose) on genital immunology and HIV susceptibility.	Drug: Praziquantel; 40 mg/kg, PO (orally administered tablets); Other Name: Agopraz, bromoxel, biltricide

Outcome Measures

Primary Outcome Measures :

1. Change in the percentage of endocervical CD4+ T cells susceptible to HIV pseudovirus entry after treatment of schistosomiasis. [ Time Frame: 1 month. ]
   The percentage of endocervical CD4+ T cells per cytobrush infected ex vivo by an HIV pseudovirus construct, as quantified by flow cytometry.
2. Change in the number of endocervical CD4+ T cells susceptible to HIV pseudovirus entry after treatment of schistosomiasis. [ Time Frame: 1 month. ]
   The number of endocervical CD4+ T cells per cytobrush infected ex vivo by an HIV pseudovirus construct, as quantified by flow cytometry.

Secondary Outcome Measures :

1. Change in the percentage of blood CD4+ T cells susceptible to HIV pseudovirus entry after treatment of schistosomiasis. [ Time Frame: 1 and 2 months. ]
   The percentage of blood CD4+ T cells infected ex vivo by an HIV pseudovirus construct, as quantified by flow cytometry.
2. Change in the phenotype of endocervical and blood CD4+ T cells after treatment of schistosomiasis. [ Time Frame: 1 and 2 months. ]
   Surface expression of CCR5, CD69, CD38, HLA-DR, a4b7, CCR7 and CD45RA by endocervical and blood CD4 T will be assessed using flow cytometry.
3. Change in genital proinflammatory cytokine levels after treatment of schistosomiasis. [ Time Frame: 1 and 2 months. ]
   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.
4. Change in the cervico-vaginal microbiome after treatment of schistosomiasis. [ Time Frame: 1 and 2 months. ]
   The cervico-vaginal microbiome will be assessed by 16s rRNA sequencing before and after schistosomiasis therapy.
5. Change in the cervico-vaginal proteome after treatment of schistosomiasis. [ Time Frame: 1 and 2 months. ]
   The genital proteome will be assessed by mass spectrometry before and after schistosomiasis therapy.
6. Change in the percentage of endocervical CD4+ T cells susceptible to HIV pseudovirus entry after treatment of schistosomiasis. [ Time Frame: 2 months. ]
   The percentage of endocervical CD4+ T cells per cytobrush infected ex vivo by an HIV pseudovirus construct, as quantified by flow cytometry.
7. Change in the number of endocervical CD4+ T cells susceptible to HIV pseudovirus entry after treatment of schistosomiasis. [ Time Frame: 2 months. ]
   The number of endocervical CD4+ T cells per cytobrush infected ex vivo by an HIV pseudovirus construct, as quantified by flow cytometry.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Uganda

UVRI-IAVI HIV Vaccine program

Entebbe, Wakiso, Uganda

Sponsors and Collaborators

University of Toronto

UVRI-IAVI HIV Vaccine Program, Uganda

Investigators

• Principal Investigator: Rupert Kaul, MD/PhD; University of Toronto

More Information

Publications:

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.

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.

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.

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.

• Responsible Party: Rupert Kaul, Professor, University of Toronto
• ClinicalTrials.gov Identifier: NCT02878564
• Other Study ID Numbers: UT-Schisto
• First Posted: August 25, 2016
• Last Update Posted: October 27, 2016
• Last Verified: October 2016

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Rupert Kaul, University of Toronto:

Schistosomiasis mansoni; HIV susceptibility; Genital immunology; Mucosal immunology; HIV entry assay; Adult women

Additional relevant MeSH terms:

Schistosomiasis; Schistosomiasis mansoni; Disease Susceptibility; Disease Attributes; Pathologic Processes; Trematode Infections; Helminthiasis; Parasitic Diseases; Praziquantel; Anthelmintics; Antiparasitic Agents; Anti-Infective Agents