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

A Double-Blind, Randomized, Pilot Study to Measure the Effect of Treatment Intensification With a Potent Integrase Inhibitor, Raltegravir (MK-0518), on the Level of Persistent Plasma Viremia Below 50 Copies/ml in Subjects on Protease Inhibitor- or Non-Nucleoside Reverse Transcriptase Inhibitor-Containing Regimens

Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in vitro activity against HIV-1 strains including those resistant to currently available antiretroviral drugs. The purpose of this study is to assess the effectiveness of raltegravir in further reducing viral load in HIV infected patients that have already achieved viral suppression below the level of detection of standard viral load assays when added to antiretroviral therapy (ART).

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