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,^1-3 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.⁴ 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.⁵

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 second-tenth 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 anti-HIV agents) 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 short- and 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 individuals who 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 dual-energy 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.

Table 1

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 efavirenz-treated 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 NNRTI introduction in 7 patients only in the efavirenz group, vs. 25 treated with nevirapine (P = 0.0005). An apparently emerging untoward event like gynecomastia was diagnosed in 13 patients who took efavirenz, vs. 2 subjects taking nevirapine (P = 0.0074).

Nine years since HAART availability, the role of dysmetabolism on long-term outcome of HIV infection needs to be carefully considered,⁴ due to the prolonged patients' life expectancy. Effects on lipid glucose abnormalities prompted by prior protease inhibitor-based HAART were improved after switching to nevirapine vs. efavirenz, as also suggested by us. Also naive patients seemed to benefit from nevirapine vs. efavirenz introduction. Preliminary data disclosed that nevirapine may prompt an elevation of high-density lipoprotein (HDL) cholesterol levels, a reduction of total/HDL cholesterol rate, preserve from atherogenic lesions, and act on lipodystrophy.^6,7 However, the role of prior-concurrent anti-HIV therapy plays a confounding role when evaluating toxicity,^4,5 so that NNRTI introduction cannot always be considered an independent variable, and also a multivariate analysis becomes questionable in pretreated patients. A recent experience suggests that lipid profile cannot remain affected for a long time by prior antiretroviral regimens.⁸ Although belonging to the same therapeutic class, and sharing common mechanism of action and resistance mechanisms, the type, frequency, and severity of untoward effects of the 2 available NNRTIs prove significantly different. NNRTI tolerability must be carefully considered, since short- and long-term toxicity has a broad spectrum and proves extremely variable between the 2 drugs, in terms of frequency, features, and timing.^1-3 A quite prolonged follow-up (>24 months in our study) shows that efavirenz may not resolve (or might prompt) metabolic alterations, particularly those involving lipid glucose levels, lipodystrophy, and gynecomastia. When examining the overall 623 NNRTI-naive patients, a long-term observation of patients pretreated with other regimens seems to show a partial-to-significant amelioration of dysmetabolism among nevirapine-treated subjects, but stable or even worsening abnormalities (and gynecomastia) when efavirenz was introduced, while also antiretroviral-naive subjects starting with efavirenz-based combinations experienced increased triglyceridemia. As shown by our experience, which included both antiretroviral-naive and -experienced patients, and different concurrent medications (with and without protease inhibitors), when compared with nevirapine, efavirenz shows a tendency to give more frequent, relevant, and early dysmetabolism. The potential pathogenetic pathways of the different toxicity and dysmetabolic patterns of these 2 NNRTI drugs warrant extensive investigation. Preliminary studies seem to suggest a specific suppression of the lipogenic pathways exerted by efavirenz only.⁹

Roberto Manfredi, MD

Leonardo Calza, MD

Francesco Chiodo, MD

Department of Clinical and Experimental Medicine, Division of Infectious Diseases, University of Bologna, Alma Mater Studiorum, S. Orsola Hospital, Bologna, Italy