Addition of Raltegravir to Established Antiretroviral Suppressive Therapy

• ClinicalTrials.gov Identifier: NCT01245101
• Recruitment Status: Terminated
• First Posted: November 22, 2010
• Results First Posted: December 23, 2016
• Last Update Posted: December 23, 2016
• Sponsor: University of Miami
• Collaborator: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Rafael Campo, University of Miami

Study Description

Brief Summary:

This study will examine whether intensification with raltegravir of a suppressive antiretroviral regimen in HIV infected patients with poor immune restoration has a beneficial effect on cryptic viral replication and the immune system. Specifically, the investigators will examine the effect that raltegravir intensification of ART has on episomal cDNA frequencies, immune activation, CD4+ cell counts and apoptosis, and markers of microbial translocation.

Condition or disease	Intervention/treatment	Phase
HIV	Drug: Raltegravir	Phase 4

Detailed Description:

This is a single-center, open-label, double-arm, crossover study which will include approximately 40 HIV-infected subjects on an established suppressive HAART for at least 2 years with evidence of undetectable HIV-1 RNA levels (either <50 copies/ml by RT-PCR or <75 copies/ml by bDNA assay) and CD4+ count of <350 cells/mm3 or an increase in CD4+count <100 cells/mm3 in the last 2 years. Participants (~20 Group 1 and ~20 in Group 2) will be randomly assigned to 1 of the 2 treatment arms described below in Table 1:

Table 1. Study groups and treatment assignments

Group A Raltegravir 400 mg PO q12h in addition to established ART (Part 1) followed by a washout period only on ART (Part 2) followed by ART (Part 3)

Group B Established ART (Part 1) followed by a washout period only on ART (Part 2) followed by raltegravir 400 mg PO q12h in addition to ART (Part 3)

The participants' pre-study HAART will be monitored so as to ensure that the distribution of NNRTI to PI-based regimens is roughly 1:1 and no higher than 2 (NNRTI):1 (PI).

The total duration of the study will be 40 weeks. This will include Part 1 (16 weeks) followed by Part 2 (8 weeks) followed by the crossover to Part 2 (16 weeks) (Figure 1). During Part 1 participants in Group A will receive open-label raltegravir in addition to their established antiretroviral regimen while Group B participants will continue taking their established antiretroviral regimen for 16 weeks. After completion of Part 1, both groups will enter Part 2 that will consist of a washout period of 8 weeks during which both groups will only take their established antiretroviral regimen without raltegravir. This will be followed by Part 3 during which the two study groups will undergo a crossover with respect to the treatment assignment during Part 1 so that Group A will continue to receive their established antiretroviral regimen while Group B will receive open-label raltegravir in addition to their established antiretroviral regimen for 16 weeks.

After obtaining informed consent, patients will be enrolled into the study, a study number will be assigned, a complete history will be obtained, and a physical exam will be performed. Blood will be drawn for the following laboratory exams at Day 1 and at Weeks 1, 2, 4, 10, 16, 24, 25 26, and 40 for Group A and at Day 1 and at Weeks 1, 2, 16, 24, 25, 26, 28, 34, and 40 for Group B:

• T-cell subsets
• Plasma viral load
• Episomal viral cDNA PCR
• HLA-DR levels
• CD38 levels

Blood will also be drawn for the following laboratory exams at Day 1 and at Weeks 4, 12, 16, 24, 28, 36, and 40 for both Group A and Group B to determine

• Plasma levels of LPS, 16s ribosomal DNA, and sCD14
• T cell receptor excision circles
• CD4+ and CD8+ T-cell apoptosis

At all visits, a directed physical exam will be performed on an as-needed-basis.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective, Open-Label, Double-Arm, Crossover, Single-Center Pilot Study to Evaluate the Addition of Raltegravir to Established Suppressive Antiretroviral Therapy While Monitoring Changes in Markers of Immune Activation Among HIV-1 Infected Individuals Without Adequate Immune Restoration
• Study Start Date: November 2010
• Actual Primary Completion Date: October 2012
• Actual Study Completion Date: May 2013

Arms and Interventions

Arm	Intervention/treatment
Experimental: Raltegravir and then Observation; The total duration of the study will be 40 weeks. This will include Part 1 (16 weeks) followed by Part 2 (8 weeks) followed by the crossover to Part 2 (16 weeks). During Part 1 participants in Group A will receive open-label raltegravir in addition to their established antiretroviral regimen while Group B participants will continue taking their established antiretroviral regimen for 16 weeks. After completion of Part 1, both groups will enter Part 2 that will consist of a washout period of 8 weeks during which both groups will only take their established antiretroviral regimen without raltegravir. This will be followed by Part 3 during which the two study groups will undergo a crossover with respect to the treatment assignment during Part 1 so that Group A will continue to receive their established antiretroviral regimen while Group B will receive open-label raltegravir in addition to their established antiretroviral regimen for 16 weeks.	Drug: Raltegravir; Raltegravir 400 mg twice daily in addition to subject's antiretroviral therapy.
Active Comparator: Observation and then Raltegravir; The total duration of the study will be 40 weeks. This will include Part 1 (16 weeks) followed by Part 2 (8 weeks) followed by the crossover to Part 2 (16 weeks). During Part 1 participants in Group A will receive open-label raltegravir in addition to their established antiretroviral regimen while Group B participants will continue taking their established antiretroviral regimen for 16 weeks. After completion of Part 1, both groups will enter Part 2 that will consist of a washout period of 8 weeks during which both groups will only take their established antiretroviral regimen without raltegravir. This will be followed by Part 3 during which the two study groups will undergo a crossover with respect to the treatment assignment during Part 1 so that Group A will continue to receive their established antiretroviral regimen while Group B will receive open-label raltegravir in addition to their established antiretroviral regimen for 16 weeks.	Drug: Raltegravir; Raltegravir 400 mg twice daily in addition to subject's antiretroviral therapy.

Outcome Measures

Primary Outcome Measures :

1. Episomal HIV cDNA Formation [ Time Frame: 16 weeks ]
   These are linear viral cDNAs that are subsequently circularized by the DNA repair apparatus of the host cell to form episomes. They are markers of ongoing viral replication.

Secondary Outcome Measures :

1. Markers of Immune Activation [ Time Frame: 16 weeks ]
   Flow cytometry will be performed in whole blood for analysis of markers of immune activation by standard methodology using a LSR-II flow cytometer. Percentage and absolute counts of CD8+CD38+ cells will be determined as the main outcome measure.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

To qualify for this study, participants will need to have:

1. At least 18 years of age
2. Documented HIV-1 infection
3. CD4+ count <350 cells/mm3 at the time of enrollment or CD4+ count increase of <100 cells/mm3 within the past 2 years
4. Plasma viral load <400 copies/ml at all testing time points within the preceding 2 years AND <50 copies/ml by RT-PCR or <75 copies/ml by bDNA at the 2 testing time points immediately preceding enrollment into the study

Exclusion Criteria:

To qualify for this study, patients must not meet any of the following exclusion criteria:

1. Pregnancy or breast-feeding
2. Prior use of raltegravir at any time in the past
3. Use of any investigational, immunomodulatory, immunosuppressive agents within 90 days prior or during this study
4. Alcohol or substance abuse that in the opinion of the investigator might interfere with patient compliance or safety
5. Any condition or pre-study laboratory abnormality that in the opinion of the investigator might interfere with patient compliance or safety

Contacts and Locations

Locations

United States, Florida

Infectious Diseases Research Unit, University of Miami Miller School of Medicine

Miami, Florida, United States, 33136

Sponsors and Collaborators

University of Miami

Merck Sharp & Dohme Corp.

Investigators

• Principal Investigator: Rafael E Campo, MD; University of Miami

More Information

• Responsible Party: Rafael Campo, Professor of Clinical, University of Miami
• ClinicalTrials.gov Identifier: NCT01245101
• Other Study ID Numbers: 20100499
• First Posted: November 22, 2010
• Results First Posted: December 23, 2016
• Last Update Posted: December 23, 2016
• Last Verified: October 2016

Keywords provided by Rafael Campo, University of Miami:

HIV raltegravir intensification replication activation

Additional relevant MeSH terms:

Raltegravir Potassium; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action