Feasibility of Measuring Immune Resp, Activation in Foreskin/Mucosa in HIV-, Uncircumcised High-HIV-risk MSM, Lima Peru

Study Overview
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Brief Summary
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Rectal and genital sampling in HIV prevention trials permits assessments at the site of HIV entry. Yet the safety and acceptability of circumcision and sigmoidoscopy (and associated abstinence recommendations) are unknown in uncircumcised men who have sex with men (MSM) at high risk of HIV infection. The purpose of this study is to evaluate the feasibility of methods for assessing baseline characteristics of the mucosa of MSM at risk of HIV infection in Lima, Peru.

Detailed Description
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The worldwide HIV/AIDS epidemic may only be controlled through development and utilization of a safe and effective vaccine that will prevent HIV infection. To fill gaps in the understanding of HIV vaccines, studies of mucosal immunity aim to complement assessments of systemic immunity. Yet it is unclear, and important to understand, how mucosal collections and the kinetics of immune activation they might initiate may impact peripheral blood endpoints in HIV vaccine trials. The HIV Vaccine Trials Network (HVTN) and the National Institute of Allergy and Infectious Diseases (NIAID) are conducting a single-site, exploratory cohort study evaluating the feasibility of sampling mucosa and assessing cellular immune responses in sexually active men who have sex with men, a population in which later-phase HIV vaccine clinical trials are often conducted. The primary purpose of HVTN 914 is to assess the feasibility of performing safe and tolerable circumcision and rectosigmoid biopsy studies on a study population of 30 healthy, HIV-seronegative, uncircumcised men in Lima, Peru, aged 21 to 30 years, who have sex with men and who are at high risk for acquisition of HIV; to assess institutional capacities to process mucosal samples; and to identify methods of evaluating foreskin and rectosigmoid mucosal immune responses that provide minimal variability for analysis of small sample sizes. The study is designed to mimic an HIV vaccine study mucosal collection protocol. Participants agree to elective sigmoidoscopy biopsy collections and circumcision, and actively participate in this study for approximately 7 months. The primary analysis will focus on pre- and post-procedure retention, safety laboratory values, sexual satisfaction, HIV risk behaviors, and levels of activation markers associated with vulnerability to HIV infection in samples of peripheral blood mononuclear cells. A total of 11 study visits (including a screening visit) occur at Weeks 0-5, 10, and 26-28. Study procedures include physical exams, blood and urine collection, HIV testing, and questionnaire. Elective rectosigmoid bioscopy is performed at Weeks 2 and 27. Elective circumcision is performed at Week 4. Some blood collected from participants will be stored and used in future research. Risk-reduction counseling will be conducted at all study visits.

Official Title
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A Cohort Study in Lima, Peru to Evaluate Feasibility of Measuring Immune Responses & Activation Levels in the Foreskin & Rectosigmoid Mucosa in HIV-negative, Uncircumcised Men Who Have Sex With Men & Who Are at High Risk for HIV Acquisition

Conditions
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HIV Infections, Acquired Immunodeficiency Syndrome, Lentivirus Infections, Retroviridae Infections, RNA Virus Infections, Virus Diseases, Sexually Transmitted Diseases, Viral, Sexually Transmitted Diseases, Immunologic Deficiency Syndromes, Immune System Diseases, Slow Virus Diseases

Intervention / Treatment
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* Procedure: Circumcision
* Procedure: Flexible sigmoidoscopy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male, age 21 to 30 years, who, in the 6 months prior to screening, experienced 1 or both of the following HIV risk criteria: unprotected anal intercourse with 1 or more male or MTF transgender partner(s); or anal intercourse with 2 or more male or MTF transgender partners. Note: Volunteers who have been in a monogamous relationship with an HIV-seronegative partner for > 6 months are excluded. Ability and willingness to provide informed consent Assessment of understanding: volunteer demonstrates understanding of the procedures and purpose of this study. Participants will complete a questionnaire prior to enrollment with verbal demonstration of understanding of all questionnaire items answered incorrectly. Willingness to receive HIV test results Willingness to discuss HIV infection risks (including sexual behavior and drug use) and amenable to HIV risk reduction counseling Willingness to undergo phlebotomy, rectal swab, sigmoidoscopy, and circumcision Willingness to adhere to safety protocols before and after sigmoidoscopy and circumcision Agrees not to enroll in another study of an investigational research agent prior to completion of the last required protocol clinic visit Hemoglobin ≥ 13.0 g/dL White blood cell (WBC) count = 3300 to 12,000 cells/mm3 Total lymphocyte count ≥ 800 cells/mm3 Remaining differential either within institutional normal range or with site physician approval Platelets = 125,000 to 550,000/mm3 Prothrombin time (PT) or partial thromboplastin time (PTT) ≤ 1.25 institutional upper limit of normal; International Normalized Ratio (INR) ≤ 1.5 Negative HIV-1 and -2 blood test: May use locally available assays that have been approved by HVTN Laboratory Operations. Exclusion Criteria: Volunteers who, in the six months prior to screening, have had sexual partners known to be HIV-infected Volunteers who, for the 6 months prior to screening, have been in a monogamous relationship with an HIV-seronegative partner History of immunodeficiency Foreskin covering less than half the glans Absolute medical indication for circumcision (balanitis or phimosis) Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or platelet disorder requiring special precautions). [This exclusion also applies to therapeutic anticoagulation that results in a prolonged PT/INR or PTT.] HIV vaccine(s) received in a prior HIV vaccine trial. For potential participants who received control/placebo in an HIV vaccine trial, the HVTN 914 PSRT will determine eligibility on a case-by-case basis Untreated clinical signs or symptoms of genitourinary or colonic infection Any medical condition contraindicating circumcision or flexible sigmoidoscopy with biopsies History of transactional sex (ie, exchange of sex for money, shelter, food, or drugs) in the preceding 6 months Any medical, psychiatric, occupational, or other condition that, in the judgment of the investigator, would interfere with, or serve as a contraindication to, protocol adherence, assessment of safety, or a participant's ability to give informed consent History of keloid scarring

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Intervention<br>Circumcision and flexible sigmoidoscopy | Procedure: Circumcision<br> <br> Procedure: Flexible sigmoidoscopy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre- and post-procedure retention | Number of enrolled trial participants that underwent each procedure visit and attended each follow-up visit | 28 weeks | 
| White blood cell counts | White blood cells per mm^3 | 28 weeks | 
| Hematocrit | Hematocrit values measured as percentage | 28 weeks | 
| Hemoglobin | Hemoglobin g/dL | 28 weeks | 
| Sexual satisfaction | Sexual satisfaction during receptive, insertive sex, and abstinence periods using a CASI behavioral questionnaire (5 point Likert Scale) | 28 weeks | 
| HIV risk behaviors | Sex without a condom according to a CASI behavioral questionnaire (Yes, No) | 28 weeks | 
| Levels of activation markers associated with vulnerability to HIV infection | Levels of CCR5, ki67+ Bcl2low, and integrin alpha4beta7 expression on CD4+ CD3+ T cells collected in blood | 28 weeks | 
| Procedure-related events | Number of procedure related events such as adverse drug reactions, hermorrage/hematoma, infection, pain, perforation/anatomic injury, and edema assessed for severity (NIH/NIAID DIvision of AIDS table for Grading of Severity of Adult and Pediatric Adverse Experiences). | 28 weeks | 
| Number of operational protocol deviations per mucosal sample | Number of deviations per mucosal sample | through study completion, an average of 7 months | 
| Proportion of mucosal samples that are evaluable | Percent of total samples (%) | through study completion, an average of 7 months | 
| Inter-person variability in mucosal responses | Median and range of variables in peripheral blood mononuclear cells, foreskin, and rectosigmoid mucosa | 28 weeks | 
| Intra-person differences in mucosal responses obtained from the rectosigmoid colon | Median and range of variables in peripheral blood mononuclear cells, foreskin, and rectosigmoid mucosa | 28 weeks | 
| Number of clinical protocol deviations per mucosal sample | Number of deviations per mucosal sample | through study completion, an average of 7 months | 
| Number of laboratory protocol deviations per mucosal sample | Number of deviations per mucosal sample | through study completion, an average of 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV Preventive Vaccine, HIV Seronegativity, Immune Response, Mucosal