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A nucleoside- and ritonavir-sparing regimen containing atazanavir plus raltegravir in antiretroviral treatment-naïve HIV-infected patients: SPARTAN study results.
Kozal, MJ, Lupo, S, DeJesus, E, Molina, JM, McDonald, C, Raffi, F, Benetucci, J, Mancini, M, Yang, R, Wirtz, V, et al
HIV clinical trials. 2012;(3):119-30
Abstract
BACKGROUND Nucleoside and ritonavir (RTV) toxicities have led to increased interest in nucleoside reverse transcriptase inhibitors (NRTIs) and RTV-sparing antiretroviral regimens. SPARTAN was a multicenter, randomized, open-label, noncomparative pilot study evaluating the efficacy, safety, and resistance profile of an investigational NRTI- and RTV-sparing regimen (experimental atazanavir [ATV] dose 300 mg bid + raltegravir [RAL] 400 mg bid [ATV+RAL]). The reference regimen consisted of ATV 300 mg/RTV 100 mg qd + tenofovir (TDF) 300 mg/emtricitabine (FTC) 200 mg qd (ATV/r+TDF/FTC). METHODS Treatment-naïve HIV-infected patients with HIV-RNA ≥5,000 copies/mL were randomized 2:1 to receive twice-daily ATV+RAL (n=63) or once-daily ATV/r+TDF/FTC (n=31). Efficacy at 24 weeks was determined by confirmed virologic response (CVR; HIV-RNA <50 copies/mL) with noncom-pleters counted as failures based on all treated subjects. RESULTS The proportion of patients with CVR HIV RNA <50 copies/mL at week 24 was 74.6% (47/63) in the ATV+RAL arm and 63.3% (19/30) in the ATV/r+TDF/FTC arm. Systemic exposure to ATV in the ATV+RAL regimen was higher than historically observed with ATV/r+TDF/ FTC. Incidence of Grade 4 hyperbilirubinemia was higher on ATV+RAL (20.6%; 13/63) than on ATV/r+TDF/FTC (0%). The criteria for resistance testing (virologic failure [VF]: HIV-RNA ≥400 copies/mL) was met in 6/63 patients on ATV+RAL, and 1/30 on ATV/r+TDF/FTC; 4 VFs on ATV+RAL developed RAL resistance. CONCLUSIONS ATV+RAL, an experimental NRTI- and RTV-sparing regimen, achieved virologic suppression rates comparable to current standards of care for treatment-naïve patients. The overall profile did not appear optimal for further clinical development given its development of resistance to RAL and higher rates of hyperbilirubinemia with twice-daily ATV compared with ATV/RTV.
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GBV-C viremia is associated with reduced CD4 expansion in HIV-infected people receiving HAART and interleukin-2 therapy.
Stapleton, JT, Chaloner, K, Zhang, J, Klinzman, D, Souza, IE, Xiang, J, Landay, A, Fahey, J, Pollard, R, Mitsuyasu, R
AIDS (London, England). 2009;(5):605-10
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Abstract
OBJECTIVE Interleukin-2 (IL-2) is a cytokine with multiple effects on lymphocytes including induction of CD4 T-cell proliferation. IL-2 administration has been shown to increase CD4 cell counts in HIV-infected people receiving antiretroviral therapy. GB virus C (GBV-C) is an apparently nonpathogenic flavivirus that replicates in CD4 T cells and inhibits HIV replication in vitro by mechanisms including downregulation of HIV entry coreceptors (CCR5 and CXCR4) and induction of chemokines (RANTES, MIP-1alpha, MIP-1 beta, and SDF-1). GBV-C replication is significantly inhibited in vitro by activation of primary CD4 cell cultures with IL-2 and phytohemagglutinin. We sought to determine if there is an interaction between GBV-C and IL-2 in vivo. METHODS GBV-C viremia status was characterized in 92 HIV-infected individuals participating in a randomized trial of IL-2 and antiretroviral therapy [AIDS Clinical Trials Group Study (ACTG) 328]. Changes in CD4 cell counts and HIV RNA levels in individuals assigned IL-2 were compared with those in individuals assigned antiretroviral therapy alone. RESULTS Individuals lacking GBV-C viremia had a significantly greater rise in CD4 cell count with IL-2, compared with GBV-C viremic individuals (by 511 cells/microl at week 84; interaction P = 0.02): GBV-C viremic individuals assigned IL-2 did not demonstrate a significant increase in CD4 cell count compared with individuals not assigned to receive IL-2 (95% CI for difference -255 to 397 cells/microl). CONCLUSION GBV-C viremia was associated with a block in CD4 cell expansion following IL-2 therapy in the ACTG 328 study, and GBV-C status may be an important factor in IL-2 treatment response.