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

NCT02218320 | Completed Results FDA Drug

• 1 other identifier: 14-1647
• Study Type: observational
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Human Immunodeficiency Virus

Keywords

HIV; Gut-associated lymphoid tissue; raltegravir; Isentress; dolutegravir; Tivicay; pharmacodynamics

Outcome Measures

Primary Outcomes (3)

• 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

Study Arms (2)

Group A

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; Procedure: Colonoscopy with biopsy

Group B

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; Procedure: Colonoscopy with biopsy

Interventions

Raltegravir DRUG

Also known as: Isentress ®

Group A

Dolutegravir DRUG

Also known as: Tivicay ®

Group B

Colonoscopy with biopsy PROCEDURE

This procedure is not standard of care for patients receiving combination antiretroviral therapy (cART), but is necessary to obtain tissue samples.

Group A; Group B

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Subjects will be recruited from University of North Carolina Infectious Diseases Clinic.

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

Clinical and Translational Research Center, UNC Hospitals

Chapel Hill, North Carolina, 27599, United States

Location

Related Publications (1)

• Weber MD, Andrews E, Prince HA, Sykes C, Rosen EP, Bay C, Shaheen NJ, Madanick RD, Dellon ES, De Paris K, Nelson JA, Gay CL, Kashuba AD. Virological and immunological responses to raltegravir and dolutegravir in the gut-associated lymphoid tissue of HIV-infected men and women. Antivir Ther. 2018;23(6):495-504. doi: 10.3851/IMP3236.

  PMID: 29714167 DERIVED

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome

Interventions

Raltegravir Potassium; dolutegravir; Colonoscopy; Biopsy

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Endoscopy, Gastrointestinal; Endoscopy, Digestive System; Diagnostic Techniques, Digestive System; Diagnostic Techniques and Procedures; Diagnosis; Endoscopy; Diagnostic Techniques, Surgical; Digestive System Surgical Procedures; Surgical Procedures, Operative; Minimally Invasive Surgical Procedures; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Specimen Handling; Investigative Techniques

Results Point of Contact

• Title: Dr. Angela Kashuba
• Organization: University of North Carolina at Chapel Hill

akashuba@unc.edu

919 966-9998

Study Officials

• Angela DM Kashuba, PharmD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 13, 2014
• First Posted: August 18, 2014
• Study Start: October 1, 2014
• Primary Completion: October 1, 2015
• Study Completion: October 1, 2015
• Last Updated: December 26, 2018
• Results First Posted: October 29, 2018

Record last verified: 2017-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)