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