Comparison of Virologic and Immunologic Responses to Raltegravir and Dolutegravir in the Gastrointestinal Tract of HIV-Positive Adults

Study Overview
=================
Brief Summary
-----------------
This is a Phase IV, open label, observational study to compare the gastrointestinal tissue concentrations, inflammatory response, and viral replication of two integrase-inhibitors, raltegravir and dolutegravir, in HIV-infected volunteers who are virologically suppressed in blood plasma. The study will be comprised of 20 HIV-infected volunteers who will be enrolled equally into two groups. Group A will consist of 10 subjects receiving an antiretroviral regimen of tenofovir, emtricitabine, and raltegravir, and Group B will consist of 10 subjects receiving an antiretroviral regimen of tenofovir, emtricitabine, and dolutegravir. Participants will provide small pieces of tissue, or biopsies, which will be taken from three distinct locations of the large intestine during a colonoscopy procedure. These biopsies will be used to measure the amount of raltegravir or dolutegravir, HIV virus, and inflammatory markers present in the gastrointestinal tract.

Detailed Description
-----------------
Purpose: To compare virologic and immunologic responses to raltegravir and dolutegravir in the gastrointestinal tract of HIV-positive men and women Participants: Twenty HIV-infected volunteers will be enrolled equally into two groups. Group A will consist of subjects receiving an antiretroviral regimen of raltegravir, tenofovir, and emtricitabine and Group B will consist of subjects receiving an antiretroviral regimen of dolutegravir, tenofovir, and emtricitabine. Procedures (methods): This is a Phase IV, open label study to compare the gastrointestinal tissue concentrations, cytokine response, and viral replication in gut-associated lymphoid tissue of two integrase-inhibitors in HIV-infected volunteers who are virologically suppressed in blood plasma. Subjects will undergo an observed bowel preparation, followed by a colonoscopy in which tissue will be obtained by a board-certified gastroenterologist from the terminal ileum/ascending colon, splenic flexture, and rectum/sigmoid colon. Blood plasma will be collected immediately prior to collection of tissue samples.

Official Title
-----------------
A Phase IV, Open-Label Study to Compare Virologic and Immunologic Responses to Raltegravir and Dolutegravir in the Gastrointestinal Tract of HIV-Positive Men and Women

Conditions
-----------------
Human Immunodeficiency Virus

Intervention / Treatment
-----------------
* Drug: Raltegravir
* Drug: Dolutegravir
* Procedure: Colonoscopy with biopsy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy HIV-positive adults aged 18-65, inclusive on the date of screening, with documentation of at least one positive HIV test. Healthy is defined as no clinically relevant abnormalities that would interfere with the interpretation of results, or pose unnecessary risk onto volunteers due to study procedures. Receiving an antiretroviral regimen containing tenofovir+emtricitabine with raltegravir (Group A) or dolutegravir (Group B) for > 3 months, with blood plasma HIV RNA < 50copies/mL for at least 4 weeks, or a 2 log decrease in baseline blood plasma HIV RNA. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the trial. Documentation of at least 80% adherence to antiretroviral regimen, through clinician or self-report, with no missed doses in the 3 days prior to the inpatient visit. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures. Women of childbearing potential must be utilizing at least one acceptable form of birth control. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, or neurologic disease that would pose unnecessary risk or interfere with study results. Subjects will be excluded for any condition that would increase risk from sedation, endoscopy, or biopsy. Subjects with a history of having a gastrectomy, colostomy, ileostomy, or any other clinically significant procedure altering the gastrointestinal tract, or any condition possibly affecting drug absorption. Subjects with inflammatory bowel diseases (ulcerative colitis or Crohn's disease). Female subjects who are currently pregnant or breastfeeding, or planning to become pregnant during the study period. Subjects who are unwilling to refrain from insertion of medical/recreation devices and products into the rectum, and from receptive anal intercourse, for 72 hours before inpatient study visit and through 7 days after the last biopsy unless instructed otherwise by the investigators. A positive urine drug screen. Untreated rectal sexually transmitted infection at screening. Treatment with an investigational drug within 2 months preceding study enrollment. Participated in a gastrointestinal biopsy study in the 3 months preceding study enrollment. Participants with a history of clotting or bleeding disorders. Participants with a history of abnormal reaction to, or complication from, conscious sedation or anesthesia Subjects who are unwilling or unable to comply with the following dietary restrictions in regard to study procedures, including a clear liquid diet during bowel preparation and a period of NPO (nil per os) prior to the colonoscopy. While confined, the total daily nutritional composition will be 50% carbohydrate, 15% protein, and 35% fat. The daily caloric intake should not exceed 3200kcal. Abnormalities of the colorectal mucosa, or significant colorectal symptom(s), which in the opinion of the clinician represents a contraindication to biopsy (including but not limited to presence of any unresolved injury, infectious or inflammatory condition of the local mucosa, and presence of symptomatic external hemorrhoids). Any other reason or condition that in the judgment of the investigators would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group A<br>Ten HIV-infected adults will be in Group A and take the HIV medication raltegravir in combination with tenofovir and emtricitabine as their provider-prescribed antiretroviral regimen. | Drug: Raltegravir<br> <br> * Other names: Isentress ®;Procedure: Colonoscopy with biopsy<br>* This procedure is not standard of care for patients receiving combination antiretroviral therapy (cART), but is necessary to obtain tissue samples.<br>|
| Group B<br>Ten HIV-infected adults will be in Group B and take the HIV medication dolutegravir in combination with tenofovir and emtricitabine as their provider-prescribed antiretroviral regimen. | Drug: Dolutegravir<br> <br> * Other names: Tivicay ®;Procedure: Colonoscopy with biopsy<br>* This procedure is not standard of care for patients receiving combination antiretroviral therapy (cART), but is necessary to obtain tissue samples.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rectal Tissue Concentrations of Ralegravir and Dolutegravir |  | 2 to 6 hours post dose | 
| RNA Concentrations From Gastrointestinal Tissues | We measured RNA concentrations in copies/1000cells for both drug groups | 2 to 6 hours post dose | 
| Percentage of Total CD8+ T-cells With CCR5 Expression | Local immunologic markers in gastrointestinal tract tissues | 2 to 6 hours post dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV, Gut-associated lymphoid tissue, raltegravir, Isentress, dolutegravir, Tivicay, pharmacodynamics