Addition of Raltegravir to Established Antiretroviral Suppressive Therapy

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.

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