July 25, 2007
Switching between protease inhibitors (PIs) may lead to improved dosing frequency, better management of gastrointestinal and lipid toxicity and a reduction in ritonavir (RTV, Norvir) exposure levels. The SWAN study1 was the largest study to evaluate a switch to atazanavir (ATV, Reyataz) from another PI (either boosted or unboosted).
In this study, atazanavir was given without ritonavir, unless tenofovir (TDF, Viread) was present in the nucleoside reverse transcriptase inhibitor (NRTI) backbone. Switching to atazanavir was found to be non-inferior to continuing on another PI-based therapy from a virologic standpoint, and improvements in lipid and gastrointestinal tolerability were also noted with atazanavir. Despite these findings, questions remain about the efficacy of unboosted atazanavir. Indeed, most physicians prefer to prescribe boosted atazanavir when this agent is included in an antiretroviral regimen.
The ATAZIP study2 evaluated 248 individuals on stable lopinavir/ritonavir (LPV/r, Kaletra)-based therapy (HIV-1 RNA less than 200 copies/mL for 6 months or more) who were randomized to either continue the capsule formulation of lopinavir/ritonavir twice daily (n = 127) or switch to 300 mg atazanavir + 100 mg ritonavir once daily (n = 121). All individuals with more than four PI-associated mutations and/or who had failed more than two PI-containing regimens were excluded from the study. The primary endpoint assessed was the proportion of patients with treatment failure at 48 weeks; the need to switch therapy was regarded as failure. Also assessed was virologic failure, defined as two consecutive viral load measurements above 200 copies/mL.
Patients were well matched for baseline characteristics. Approximately 80% of all patients were male, and the median CD4+ cell count was about 450 cells/mm3. Twenty percent of participants had previously failed a PI-based regimen, and 20% had a baseline low-density lipoprotein (LDL) cholesterol level above 130 mg/dL. Similar numbers of patients in each group completed the study. In each arm, 14% of individuals discontinued study treatment, 4.7% and 5.0% due to adverse events in the lopinavir/ritonavir and atazanavir + ritonavir arms, respectively.
Protocol-defined treatment failure was observed in 17% of atazanavir + ritonavir recipients and 20% of lopinavir/ritonavir recipients (estimated difference -2.3%; 95% CI: -12% to 8%), thus meeting the predefined confidence intervals for non-inferiority. Virologic failure was uncommon and occurred in only 5% of atazanavir + ritonavir recipients and 6% of lopinavir/ritonavir recipients. Virologic failure was typically associated with a past history of treatment failure on a PI-based regimen or the presence of pre-existing primary PI resistance mutations. Changes in CD4+ cell count did not differ between the two treatment groups (increases of about 40 cells/mm3 in both arms).
Changes in lipid parameters from baseline to week 48 are summarized in the table below. Although high-density lipoprotein (HDL) cholesterol did not change in either group, significantly more favorable shifts in total cholesterol, LDL cholesterol and triglycerides were observed with the switch to atazanavir + ritonavir relative to continuing on lopinavir/ritonavir.
|Change in Fasting Lipid Parameters From Baseline to Week 48, mg/dL (%)||ATV/r|
(n = 121)
(n = 127)
|Total cholesterol||< .0001|
These data indicate that in individuals with a past treatment history and resistance profile consistent with atazanavir + ritonavir activity, switching from lopinavir/ritonavir to atazanavir + ritonavir maintains virologic efficacy and leads to sustained improvements in lipid levels.
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