Pilot Study of Adding Raltegravir (MK-0518) to Antiretroviral Therapy in Patients With Low Level Viremia

Investigating the Source of HIV-1 Viremia in Patients on Antiretroviral Therapy Through Intensification With MK-0518

The medicines used to treat HIV can suppress but cannot kill all the virus in the body. A small amount of virus remains at low levels in the part of the blood called the plasma. It is of crucial importance to identify the source of the residual virus in patients receiving antiretroviral therapy. The purpose of this study is to investigate whether the source of low level plasma virus is from latent (old) infection or ongoing (new) infection. MK-0518 is a investigational drug, which means that is not yet FDA approved, that works in a different way to other anti-HIV medicines to help kill the virus. We hypothesize that addition of MK-0518 to a stable anti-HIV regimen will reduce the viral load further in patients with undetectable plasma virus.

This is a non-randomized, non-comparative, single center trial of antiretroviral therapy intensification using the investigational integrase inhibitor MK-0518 and an investigational viral load assay to measure response to additional antiviral therapy. Eighteen patients will receive open-label MK-0518 400 mg P.O. every 12 hours for 28 days in addition to their prescribed antiretroviral therapy. Patients will take their doses of MK-0518 without regard to food. The study will enroll patients on antiretroviral therapy regimens with Cluster of Differentiation 4 (CD4) counts greater than 200 cells/ul, HIV-1 RNA levels <50 copies RNA/ml plasma using a commercial assay(conventional Amplicor) and with detectable plasma virus (viral loads ≥ 1 copies RNA/ml plasma, Single copy assay, "SCA"). Acceptable antiretroviral regimens will include those on Nucleoside reverse transcriptase inhibitors ("NRTIs") + protease inhibitor (PI)I, NRTIs + non-nucleoside reverse transcriptase inhibitors (NNRTIs), + PI, or NRTIs + NNRTI-containing regimens. Patients cannot have prior evidence of resistance to antiretroviral drugs. Patients will be screened for intensification by history, physical exam, and laboratory evaluations (see below). Patients who are eligible and who agree to participate will intensify their antiretroviral therapy for 28 days with MK-0518 400 mg by mouth twice a day. During the 28- day drug addition, patients will have samples drawn for SCA assay at entry and on days 7, 14, 21, and 28 (+/- 1 d), with the last day of intensification as day 28. Patients will have additional phlebotomy after intensification on days 29, 30, 35, 42, 49 and 58 (+/- 1 day). The intensification period is followed by a post- intensification period to determine whether removal of the drug resulted in viral RNA changes.

Inclusion Criteria:

• HIV-1 infection documented by positive HIV-1 ELISA and positive
• Male or female at least 18 years of age, and able to provide written, informed consent
• Current antiretroviral therapy with Department of Health and Human Services (DHHS)-recommended regimen: NRTIs + PI, NRTIs + NNRTI + PI, or NRTIs + NNRTI
• Screening CD4 > 200 cells/ µl and CD4%> 14%; does not require prophylaxis for opportunistic infections
• Receiving a stable antiretroviral regimen for 4 months prior to screening
• HIV-1 RNA level below the limit of detection by commercial HIV-1 RNA determination assays for at least 12 months prior to screening.
• HIV RNA ≥ 0.6 copy RNA/ml plasma by SCA(single copy assay)
• Hgb ≥ 9.0 mg/dl, absolute neutrophil count > 1000/mm3, platelet count > 100,000/mm3
• Alkaline phosphatase, Aspartate transaminase (AST) and Alanine aminotransferase (ALT) < 2.0 x upper limit of normal
• Willing to take MK-0518 for 28 days in addition to ongoing antiretroviral therapy
• Be considered clinically stable, in the opinion of the investigator, at the time of entry into the study; i.e., clinical status and all chronic medications should be unchanged for at least two weeks prior to entry.

Exclusion Criteria:

• Prior participation in an MK-0518 or other integrase inhibitor trial
• Requires prohibited medications noted in the protocol
• Requires cytotoxic agents including hydroxyurea or vaccinations during the study period
• Received immunosuppressive therapy including steroids within one month prior to treatment in this study
• Used any investigational agents within a month prior to treatment in this study
• Documented resistance to any drug in each of the 4 classes of licensed antiretroviral agents by genotype or phenotype
• Any febrile illness (T>38oC) in the 3 weeks prior to enrollment
• Any vaccination in the 6 weeks prior to enrollment
• Diagnosis of acute hepatitis due to any cause
• Positive Hepatitis B surface antigen
• Severe renal insufficiency defined as a calculated creatinine clearance at time of screening as < 30 ml/min, based on the Cockcroft-Gault equation.
• Condition (including but not limited to alcohol or other substance use) which in the opinion of the investigator would interfere with patient compliance or safety