February 28, 2002
The final session of the meeting was probably the best. There were several interesting and important presentations. I will discuss the late breaker from Jose Maria Gatell who presented data on the NEA (Nevirapine, Efavirenz and Abacavir) study done in Spain.
In this study, 460 patients were randomized to switch from a successful protease inhibitor-containing regimen to one of three different arms: nevirapine (155 patients), efavirenz (156 patients) and abacavir (149 patients). All of the patients maintained the nucleoside regimen they were taking before enrolling in the study. All of them had undetectable viral loads (less than 200 HIV RNA copies/mm3) and approximately 50 percent had previous experience with NRTIs before starting their first potent antiretroviral regimen (this becomes important later on).
After one year of follow up, approximately 77 percent of the patients have stayed on the original regimen they switched to. The reasons to discontinue that regimen were different depending on the arm to which the subject was randomized. Individuals randomized to the abacavir arm were more likely to have virologic failure. Individuals randomized to efavirenz or nevirapine were more likely to switch regimens because of toxicity. You guessed right if you predicted that patients on efavirenz were more likely to switch due to neurologic side effects and patients on nevirapine were more likely to switch due to rashes or liver toxicity. Patients who failed virologically in the abacavir arm were more likely to have previous nucleoside experience.
From a metabolic perspective, patients who switched to abacavir had decreases in total triglycerides and total cholesterol. Patients who switched to NNRTIs had decreases in LDL cholesterol and increases in HDL cholesterol, creating a better LDL to HDL cholesterol ratio (and presumably decreasing the cardiovascular risk).
This study is the largest randomized switch trial to switch from protease inhibitors to three more common current alternatives. The results are clear: Switches to NNRTIs are safe from a virologic perspective; they are associated with metabolic improvements, decreases in LDL levels and improvements in HDL cholesterol. Switches to abacavir are less safe from a virologic point of view (especially for patients with prior nucleoside experience), but are very well tolerated in regards to quality of life and lipid profile.
Studies such as this one do allow some insights into the potential role of protease inhibitors in the pathogenesis of the metabolic abnormalities associated with antiretroviral therapy. Abnormalities in glucose metabolism have been reported in HIV-negative subjects who received indinavir, and suggest a primary role for this protease inhibitor in the development of insulin resistance and hyperglycemia.
Other protease inhibitors, like ritonavir, have been associated more with hyperlipidemia. The reversal of abnormalities in glucose and lipid metabolism when protease inhibitors are replaced with NNRTIs or abacavir (and viremia remains undetectable), supports the conclusion that protease inhibitors are responsible for these problems. The lack of improvement in body fat redistribution after the switch suggests that the pathogenesis of this problem is more complex. The improvement in HDL cholesterol with NNRTIs (especially nevirapine) is interesting and consistent with recent findings from studies of naive subjects. It definitely requires further studies, because there are not very many drugs out there that do that. Maybe in the future some related compound will be used in cardiology.
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