Application of Oral Bacteriotherapy to Promote Anal HPV Clearance in HIV Positive Individuals

Study Overview
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Brief Summary
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Published studies suggest that oral probiotic intake can promote the clearance of HPV genital infection and HPV related genital dysplasia in HIV negative women. In the present randomized, double blind, placebo controlled study, investigators will evaluate the ability of oral bacterio-therapy to enhance the clearance of anal HPV infection and anal HPV related dysplasia in HIV infected subjects. Participants will be evaluated for anal HPV infection and anal dysplasia before and after a 6 months course of daily investigational product intake (Viviomixx® or placebo). HPV infection rate and presence of dysplasia at baseline and at the end of the study will be compared.

Detailed Description
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Squamous Cell Carcinoma (SCC) of the anus and the anal canal represents a major concern for the HIV infected population, with incidence rates in the different sub populations (women, men, MSM) that are grater than those observed for other common neoplasms in the same HIV negative sub-populations. Nowadays, screening for anal precancerous dysplasia has been included in most national and international HIV management guidelines; in particular, italian guidelines suggest to screen for the presence of HPV related dysplasia: HIV+ MSM All individuals with previous or current evidence of ant-genital condyloma Women with cytology abnormalities on cervical Pap-smear Since no direct anti-HPV drug is currently available and control or clearance of the infection is possible only trough the effect of immune response, interest is addressed to find strategies to promote spontaneous clearance of infection. In published studies, oral bacterio-therapy demonstrated the ability to promote HPV clearance and HPV related dysplasia regression in HIV negative women. In the present randomized, double blind, placebo controlled trial, 40 HIV infected individuals with HPV related anal dysplasia will be enrolled. At baseline participants will undergo: anal HPV research and identification anal cytology anal brushing for evaluation of local inflammatory milieu and microbiota Subjects with identified HPV anal infection and anal dysplasia will undergo High Resolution Anoscopy (HRA). During HRA, extra biopsies of identified abnormal areas and biopsies of normal mucosa will be obtained. Extra biopsies will be used to investigate the distribution of intra-epithelial immune cells populations. Participants will then undergo 6 months of oral supplementation with probiotics (Vivomixx®) or placebo. At the end of the supplementation period (Vivomixx or placebo), participants will undergo: anal HPV research and identification anal cytology anal brushing for evaluation of local inflammatory milieu and microbiota HRA During HRA, extra biopsies of identified abnormal areas and biopsies of normal mucosa will be obtained. Extra biopsies will be used to investigate the distribution of intra-epithelial immune cells populations.

Official Title
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HPVinHIV: Study of Anal HPV Infection in the Setting of HIV Infected Individuals

Conditions
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HIV, Anal Dysplasia

Intervention / Treatment
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* Dietary Supplement: Vivomixx
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV infected individuals >18 years old stable and effective antiretroviral therapy since at least 12 months HPV associated anal dysplasia patient willing to provide written informed consent Exclusion Criteria: impossibility to intake the investigational product any contraindication to blood sampling inflammatory bowel disease use of antibiotics during the 3 months prior to the enrollment in the study pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral Bacteriotherapy Arm<br>Individuals in this study arm will undergo 6 months of daily intake of an oral probiotic formulation (Vivomixx: 4 sachets/day, each sachet containing 450 billion live bacteria). Probiotic sachets are indistinguishable from placebo | Dietary Supplement: Vivomixx<br>* Individuals in the interventional arm will undergo daily oral intake of probiotic supplement<br>|
| Placebo Comparator: Placebo Arm<br>Individuals in this study arm will undergo 6 months of daily intake of placebo (4 sachets/day). Placebo sachets are indistinguishable from probiotic | Other: Placebo<br>* Individuals in the placebo arm will undergo daily oral intake of placebo supplement<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the number of HPV positive anal swabs | Clearance of anal HPV infection will be defined as: negative swab at the end of the study in participants with positive swab at baseline positive swab at the end of the study that shows a different genotype from baseline | Anal swabs for HPV detection and genotyping will be performed at baseline and after the 6 months duration of the intervention | 
| Change from baseline in the number of dysplastic lesions | Clearance of anal dysplasia will be defined as: - normal histology in biopsies repeated at the end of the study on areas that showed the presence of histologically defined dysplasia at baseline. | Areas of the anal canal that were biopsied at baseline and whom histology showed the presence of dysplasia will undergo a second biopsy after the 6 months duration of the intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of adverse events | The rate of adverse events occurred during the study period will be evaluated and compared between both groups | This measure will be assessed after the 6 months duration of the intervention | 
| Comparison between intra-epithelial NK lymphocytes subpopulation in normal mucosa and dysplastic mucosa | Biopsies from dysplastic lesions and from normal mucosa will be taken at baseline. Biopsies will also be taken at the end of the study from previously biopsied areas, from normal mucosa and eventually from dysplastic areas that were not present at baseline. Intra-epithelial lymphocytes will be extracted from the biopsy tissue and stained to differentiate and quantify CD56+NK lymphocytes by flowcytometry. Changes from baseline will be expressed as relative difference. | Biopsies and intra-epithelial lymphocytes extraction will be performed at baseline and after the 6 months duration of the intervention | 
| Comparison between intra-epithelial CD4+ T lymphocytes subpopulation in normal mucosa and dysplastic mucosa | Biopsies from dysplastic lesions and from normal mucosa will be taken at baseline. Biopsies will also be taken at the end of the study from previously biopsied areas, from normal mucosa and eventually from dysplastic areas that were not present at baseline. Intra-epithelial lymphocytes will be extracted from the biopsy tissue and stained to differentiate and quantify CD4+ T lymphocytes by flowcytometry. Changes from baseline will be expressed as relative difference. | Biopsies and intra-epithelial lymphocytes extraction will be performed at baseline and after the 6 months duration of the intervention | 
| Comparison between intra-epithelial CD8+ T lymphocytes subpopulation in normal mucosa and dysplastic mucosa | Biopsies from dysplastic lesions and from normal mucosa will be taken at baseline. Biopsies will also be taken at the end of the study from previously biopsied areas, from normal mucosa and eventually from dysplastic areas that were not present at baseline. Intra-epithelial lymphocytes will be extracted from the biopsy tissue and stained to differentiate and quantify CD8+ T lymphocytes by flowcytometry. Changes from baseline will be expressed as relative difference. | Biopsies and intra-epithelial lymphocytes extraction will be performed at baseline and after the 6 months duration of the intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, HPV, Probiotics, High Resolution Anoscopy, Anal dysplasia