February 13, 2003
"Results of the 2NN study: A randomized comparative trial of first-line antiretroviral therapy (ART) with regimens containing either nevirapine (NVP) alone, efavirenz (EFV) alone or both drugs combined, together with stavudine and lamivudine" is one of the most, if not the most, important clinical trials to be presented in this meeting. The formal presentation will take place on the last day, forcing all of us to stay until the last session to hear the results first hand. The 2NN study is massive and includes 1,216 treatment naïve participants from many countries. It was sponsored by Boehringer Ingelheim, but conducted and analyzed independently by a group of investigators lead by Dr. Lange in the Netherlands.
The study compared four different regimens in an open label design:
in addition to d4T (stavudine, Zerit) and 3TC (lamivudine, Epivir).
The study is especially important because it compares the two most widely used NNRTIs as first-line regimens. The side effect profile of these two drugs is quite different, with central nervous system toxicity predominating in EFV-containing regimens and liver and rash toxicity with NVP-containing regimens. The prevailing wisdom in the field is that EFV might be slightly more potent than NVP, but these drugs have never been compared directly head to head to prove that. In fact, small, not enough powered studies suggest that potency is very similar among combination regimens that include either drug for use in naïve patients. The results of multiple "switch" studies in which patients taking protease inhibitors were switched to a regimen of EFV or NVP also showed that the potency of these two drugs was pretty much equivalent in the experienced patient.
NVP is cheaper than EFV, so the question of which NNRTI should be used first is an important one, not only in terms of potency and tolerability, but also in economic terms. This poster reports the change in lipid parameters that occurred during the 2NN study. Metabolic abnormalities and other toxicities have been the main Achilles heel of antiretroviral therapy.
The conclusions of the study were not unexpected: NVP and EFV are associated with slight increases in total cholesterol and triglycerides and marked increases in HDL cholesterol (the "good cholesterol"), and these changes are more significant in the NVP-containing arms (that were analyzed together) than in the EFV-containing arms. The ratio of total cholesterol to HDL cholesterol (a marker of cardiovascular risk) was better in the patients taking NVP.
The study confirms the prevailing idea that NVP is more "lipid friendly" than EFV. The main limitation of the study was that the specimens were not collected fasting, although this fact was difficult to find in the poster. The non-fasting status affects triglyceride values and less the cholesterol and HDL cholesterol determinations, where the conclusions are probably more robust. The investigators are planning a cross-sectional analysis of the cohort to confirm the current results using fasting specimens.
The next important, still unanswered question is why and how NNRTIs increase HDL cholesterol levels. Several ongoing studies will try to tackle that one.
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