Addition of Raltegravir to Established Antiretroviral Suppressive Therapy

Phase 4

Terminated

Conditions: HIV

Interventions: Drug: Raltegravir

Registration Number: NCT01245101

Lead Sponsor: University of Miami

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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 15

Inclusion Criteria

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

At least 18 years of age
Documented HIV-1 infection
CD4+ count <350 cells/mm3 at the time of enrollment or CD4+ count increase of <100 cells/mm3 within the past 2 years
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:

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Raltegravir and then Observation	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.
Observation and then Raltegravir	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.

Primary Outcome Measures

Name	Time	Method
Episomal HIV cDNA Formation	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

Name	Time	Method
Markers of Immune Activation	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.