Human Immunodeficiency Virus (HIV)
Conditions
Brief summary
This research is being done to learn how seminal fluid affects the lining of the colon, and whether this might make it easier for HIV to get into the body and cause infection.
Detailed description
Design of effective rectal microbicides to prevent HIV infection requires an understanding of rectal HIV transmission and the location within the lower gastrointestinal (GI) tract (luminal and mucosal) of HIV (cell-free and cell-associated) following exposure to infected seminal fluid. These basic details of HIV transmission have yet to be determined in human subjects, yet they are essential to select microbicide candidates if they are to be rationally designed to achieve effective concentrations at sites of HIV transmission. Rational development of a rectal microbicide also requires an understanding of those factors that may contribute to colonic mucosal injury - potential confounders of microbicidal effect. Such factors include exposure to seminal fluid which has been shown in animal and in vitro studies to cause histologic and permeability changes that might facilitate HIV transmission.
Interventions
BIOLOGICALRadiolabeled autologous seminal fluid
Autologous lymphocytes labeled with 250 microcuries In-111 and 500 microcuries Tc-99m in seminal fluid vehicle.
BIOLOGICALRadiolabeled Normosol-R
Autologous lymphocytes labeled with 250 microcuries In-111 and 500 microcuries Tc-99m in Normosol-R fluid vehicle.
Sponsors
amfAR, The Foundation for AIDS Research
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
MALE
Age
21 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Able to provide signed informed consent * Men of 21 years or older. * Prior history of receptive anal intercourse. * Laboratory values within the last 28 days: * Negative for HIV antibodies * Lymphocyte count within normal limits * Neutrophil count \> 1,000 cells/ml * Cluster of Differentiation 4 (CD4) cell count \> 500 cells/ml * Platelet count ≥ 150,000 cells/mm3 * Prothrombin Time (PT) within normal limits * Partial thromboplastin time (PTT) within normal limits. * No childbearing intentions.
Exclusion criteria
* Active anorectal disease or recent (3 months) anorectal surgery; * Diarrhea, defined as three or more loose stools per day, for at least three days prior to admission. * History of sleep apnea, or airway problems with previous sedation procedures. * History of significant adverse reaction to sedation medications. * Other history, including significant occupational radiation exposure, history of inflammatory bowel disease or any other diseases and lab results, such that, in the judgment of the investigator, study procedures are not considered safe for the subject's participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Epithelial Disruption Graded by a Pathologist Blinded to Study Intervention. | One hour | Endoscopy will be performed to obtain biopsy specimens at baseline and following each inpatient enema exposure. Samples will be obtained at each flexible sigmoidoscopy and set aside for batch sectioning and H&E staining. Slides will be reviewed and scored by a qualified pathologist blinded to treatment assignment using a qualitative scoring system. This scoring system uses semi-quantitative scoring that focuses on acute toxicity to epithelial cell layer similar to that seen in animal studies. This is a categorical grading scale, where 0 = Epithelial surface intact;1 = \<1/3 of surface denuded; 2 = 1/3 - 2/3rds of surface denuded;3 = More than 2/3rds of surface denuded. Six separate biopsies for each subject and each treatment intervention were analyzed in a multi-level analysis. In comparison with the baseline condition (no intervention), the odds and 95% confidence interval (CI) of having a higher epithelial denudation score were calculated for each intervention. |
Countries
United States
Participant flow
Recruitment details
Recruitment initiated September 2008, completed October 2009. Study participants recruited from previous trial participation and advertisements posted in the medical institutions.
Participants by arm
| Arm | Count |
|---|---|
| Seminal Fluid Then Normosol 2.5 mL radiolabeled autologous seminal fluid administered rectally x1. Two week pause between interventions. Then 2.5 mL radiolabeled Normosol-R administered rectally X1.
Radiolabeled autologous seminal fluid: Autologous lymphocytes labeled with 250 microcuries In-111 and 500 microcuries Tc-99m in seminal fluid vehicle.
Radiolabeled Normosol-R: Autologous lymphocytes labeled with 250 microcuries In-111 and 500 microcuries Tc-99m in Normosol-R fluid vehicle. | 5 |
| Normosol-R Then Seminal Fluid 2.5 mL radiolabeled Normosol-R administered rectally x1. Two week pause between interventions. Then 2.5 mL radiolabeled autologous seminal fluid administered rectally X1.
Radiolabeled autologous seminal fluid: Autologous lymphocytes labeled with 250 microcuries In-111 and 500 microcuries Tc-99m in seminal fluid vehicle.
Radiolabeled Normosol-R: Autologous lymphocytes labeled with 250 microcuries In-111 and 500 microcuries Tc-99m in Normosol-R fluid vehicle. | 5 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 2nd Study Intervention | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Seminal Fluid Then Normosol | Normosol-R Then Seminal Fluid | Total |
|---|---|---|---|
| Age, Continuous | 44 years | 40 years | 41.5 years |
| Region of Enrollment United States | 5 participants | 5 participants | 10 participants |
| Sex/Gender, Customized Male gender | 5 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 10 | 3 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
Epithelial Disruption Graded by a Pathologist Blinded to Study Intervention.
Endoscopy will be performed to obtain biopsy specimens at baseline and following each inpatient enema exposure. Samples will be obtained at each flexible sigmoidoscopy and set aside for batch sectioning and H&E staining. Slides will be reviewed and scored by a qualified pathologist blinded to treatment assignment using a qualitative scoring system. This scoring system uses semi-quantitative scoring that focuses on acute toxicity to epithelial cell layer similar to that seen in animal studies. This is a categorical grading scale, where 0 = Epithelial surface intact;1 = \<1/3 of surface denuded; 2 = 1/3 - 2/3rds of surface denuded;3 = More than 2/3rds of surface denuded. Six separate biopsies for each subject and each treatment intervention were analyzed in a multi-level analysis. In comparison with the baseline condition (no intervention), the odds and 95% confidence interval (CI) of having a higher epithelial denudation score were calculated for each intervention.
Time frame: One hour
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Seminal Fluid | Epithelial Disruption Graded by a Pathologist Blinded to Study Intervention. | 1.0 units on a scale |
| Normosol-R | Epithelial Disruption Graded by a Pathologist Blinded to Study Intervention. | 1.17 units on a scale |
Comparison: Null hypothesis is that there is no difference in epithelial surface disruption when comparing the two interventions. Power calculation was based on identifying a median difference in histology grade of 0.83, using a two-sided alpha of 0.05 with 90% power in 10 subjects.p-value: <0.05Wilcoxon (Mann-Whitney)