An extremely different dysmetabolic profile between the two available nonnucleoside reverse transcriptase inhibitors: efavirenz and nevirapine.

To the Editor: Efavirenz and nevirapine play a key role in highly active antiretroviral therapy (HAART). Although potency and resistance of these compounds have been adequately investigated, less information exists about their toxicity, and particularly dysmetabolism, which represents an emerging problem for long-term patients treated with different regimens, although alterations could also depend on prior-concurrent protease inhibitor administration. Several experiences suggested to start with nonnucleoside reverse transcriptase inhibitors (NNRTI) or to switch antiretroviral therapy containing protease inhibitors towards NNRTI, in order to ameliorate or prevent dysmetabolism. To assess the metabolic safety profile of the 2 available NNRTIs, a cross-sectional evaluation performed in July 2003 allowed us to identify 1018 HIV-infected patients treated with HAART during $12 months. The metabolic pattern of study drugs was assessed in 3 different scenarios. The first included patients naive to antiretrovirals, who started an NNRTI-based regimen associated with 2 nucleoside/nucleotide analogues. The 2nd group included a broad spectrum of pretreated but still NNRTI-naive subjects, who switched their HAART due to therapeutic failure or toxicity: all patients at their secondtenth therapeutic change were part of this second group, except subjects resorting to a protease inhibitor–NNRTI association. Finally, patients who added for the first time an NNRTI while undergoing salvage regimens including $4 drugs (belonging to all available classes of antiHIVagents) represented the 3rd group; in these last subjects, NNRTIs were associated with protease inhibitors. When excluding antiretroviral-naive subjects, serum lipid-glucose levels were considered only after the first 3 months from the introduction of an NNRTI, in order to exclude as far as possible the shortand mid-term effects of previous anti-HIV combinations. Since July 2001, 686 overall patients, after giving their written consent, underwent treatment with either efavirenz or nevirapine, and 324 evaluable patients treated with efavirenz were compared with 299 individuals taking nevirapine in our open-label prospective observational survey. After excluding 63 patients (due to treatment duration <6 months, familial dyslipidemia or glucose intolerance, alcohol abuse, or adherence estimated <90%, on the ground of patients’ self-reports, questionnaires, and direct drug distribution and accountability performed every month), all individualswho received efavirenz were compared with those given nevirapine during 6 to $24 consecutive months, by a multivariate analysis focusing on serum lipid glucose levels and other metabolic anomalies (Table 1). Altered fasting triglyceridemia, cholesterolemia, and glycemia were defined by serum levels >172, 230, and 110 mg/dL, respectively. The 2 study groups proved comparable as to demographic-epidemiologic features, HIV disease stage, mean baseline HIV viremia and CD4 lymphocyte count, hepatitis coinfection, eventual antiretroviral therapy background, and eventual preexisting metabolic disturbances (frequency and severity) (data not shown). The eventual lipodystrophy was assessed by a targeted physical examination, patient’s perception, specific questionnaires, and evaluation of waist-hip ratio, plus abdominal ultrasonography study and dualenergy x-ray absorptiometry in selected cases: an amelioration of lipodystrophy was considered when both patient’s and physician’s assessments were concurrently favorable and the waist-hip ratio was modified by $10%. Gynecomastia was confirmed by ultrasonography. Among the 183 naive patients, an isolated altered triglyceridemia proved more common (P = 0.0027) in the efavirenz vs. the nevirapine group, and tendency to both hypertriglyceridemia and hypercholesterolemia appeared earlier than in nevirapine-receiving patients (P < 0.0001). When considering the 295 antiretroviral-experienced patients introducing an NNRTI for the first time, the frequency of elevated triglyceride levels appeared higher in the efavirenz group (P < 0.0001), with earlier development in patients under efavirenz vs. nevirapine (P < 0.0001). Also in the 145 subjects on a salvage HAART including an NNRTI plus a protease inhibitor–containing regimen, the rates of hypertriglyceridemia, hypercholesterolemia, and hyperglycemia proved greater among patients given efavirenz vs. nevirapine (P = 0.039, 0.013, and 0.0053, respectively), and the time to peak metabolic alterations tested more rapid in the whole efavirenz group compared with overall patients taking nevirapine, as to hypercholesterolemia and hyperglycemia (P = 0.0001), but not hypertriglyceridemia (Table 1). Comparing all the 324 patients receiving efavirenz with the 299 subjects on nevirapine, the frequency of elevated triglyceride, cholesterol, and glucose levels was much higher in those given efavirenz vs. nevirapine (P < 0.0001, <0.0001, and = 0.0003, respectively). The times to peak hyperglycemia (P < 0.0001) and to hypertriglyceridemia (P < 0.003) were significantly more rapid among efavirenztreated patients, while no significance was reached as to cholesterolemia. Some grade of lipodystrophy was present in 207 pretreated patients, but an appreciable improvement of these features occurred after NNRT