Effect of Addition of Raltegravir (MK-0518) to PI- or NNRTI-Based ART Regimens in HIV Infected Subjects With Undetectable Viral Load

Although ART has reduced the morbidity and mortality from HIV-1 infection, most individuals
who stop ART experience rapid viral rebound. Effective ART can suppress viral load to less
than 50 copies/ml; however, current treatment regimens cannot completely eliminate the
infection. The primary purpose of this study was to assess the ability of the HIV-1 integrase
inhibitor, raltegravir, to reduce viral load when added to ART regimens of HIV-1 infected
patients who have achieved viral suppression to less than 50 copies/ml.

The study lasted 24 weeks. Participants were randomly assigned to one of two arms.
Participants in Arm A were administered raltegravir in addition to their usual ART regimen
from study entry until Week 12. At Week 12, subjects halted raltegravir use and received a
placebo until Week 24. Participants in Arm B were administered the placebo in addition to
their usual ART regimen from study entry until Week 12. At Week 12, subjects halted the
placebo and received raltegravir until Week 24. A real-time polymerase chain reaction (PCR)
single copy assay (SCA) capable of detecting 1 copy of HIV RNA was used to assay viral load.
The cross-over design allowed assessment of the effect of intensification with raltegravir
between the two arms at Weeks 10/12 and every participant enrolled in the study receiving
raltegravir for 12 weeks. Primary analysis focused on weeks 10/12 measurement and with no
washout period, typical analysis of cross-over design was not intended.

All participants had scheduled visits at Weeks 0, 2, 4, 10, 12, 14, 16, 22, and 24. A
targeted physical exam occurred at all visits. Blood and urine collection occurred at
selected visits. A medical/medication assessment occurred at trial entry. Drug dispensing and
an adherence questionnaire occurred at some visits. A pregnancy test occurred at select
visits. Participants' background ART medications were not provided by the study.

Inclusion Criteria:

- HIV-1 Infection

- ART for at least 12 months prior to study entry that includes at least two NRTIs and
either an NNRTI or a ritonavir-boosted PI

- No change in ART regimen for at least 3 months prior to study entry

- CD4 count of 200 or more at screening

- Viral load below the limit of quantification of an ultrasensitive assay for at least 6
months prior to study entry

- Viral load less than 50 copies/ml using Roche Amplicor HIV-1 RNA Ultrasensitive assay
within 60 days of study entry

- All viral load assays obtained within 6 months prior to study entry lower than limits
of quantification on all tests

- Pre-ART viral load level greater than 100,000 copies/ml

- Detectable viral load of 1 copy or more on the screening SCA

- Available pre-study entry plasma sample for SCA viral load determination

- Absolute neutrophil count of 750/mm3 or more

- Hemoglobin of 9 g/dL or more for female subjects and 10 g/dL or more for male subjects

- Platelet count of 50,000/mm3 or more

- Calculated creatinine clearance of 30 ml/min or more

- AST, ALT, and alkaline phosphate less than or equal to 5 x ULN

- Total bilirubin less than or equal to 2.5 x ULN. If subject is taking indinavir or
atazanavir at screening, total bilirubin must be less than or equal to 5 x ULN.

- Negative serum or urine pregnancy test within 48 hours prior to study entry for
females with reproductive potential

- Willing to use acceptable means of contraception

Exclusion Criteria:

- Previous documented virologic failure on an antiretroviral regimen

- Unstable clinical condition that would preclude the subject from undergoing study
procedures

- Use of immunosuppressive medications within 60 days prior to study entry. Participants
using inhaled or nasal steroids are not excluded.

- Opportunistic infection within 60 days prior to study entry

- Allergy or sensitivity to components of study drug

- Active drug or alcohol abuse

- Serious illness requiring systemic treatment within 60 days prior to study entry

- Receipt of non-HIV vaccination within 30 days prior to study entry

- Receipt of any HIV vaccines

- Plan to change background ART within 24 weeks after study entry

- Pregnant or breastfeeding