Involvement of Efavirenz in Lipodystrophy

Characteristic body-shape changes and seriousmetabolic complications such as insulin resistanceand dyslipidemia have been largely associated tothe use of protease inhibitors. On the other hand,peripheral lipoatrophy has been mainly linked tosome nucleoside analogues, particularly stavudine.So far, no data have definitively associated the developmentof lipodystrophy syndrome with the useof non-nucleoside reverse transcriptase inhibitors(NNRTI). However, two recent reports presentedduring the 13th International Symposium on HIV &Emerging Infectious Diseases, held in Toulon (France)in June 2004, have postulated for the first timean involvement of efavirenz in the lipodystrophysyndrome.In the first study, a group from Paris demonstrated,in vitro, that adipocyte differentiation may beinhibited in the presence of efavirenz (El Hadri, etal. [abstract OP 5.3]). Pre-adipocytes failed to accumulatecytoplasmic triacylglycerol droplets, and thiseffect reverted after removing efavirenz. The authorsfound that efavirenz induced a dose- and time-dependentreduction in gene and protein expressionof the lipogenic transcription factor SREBP-1c (sterolregulatory element-binding protein 1c). The resultwas a sharp reduction in the adipocyte lipogenicactivity in efavirenz-treated cells. These observationsmay be on the basis of the adipose tissue atrophyseen in patients exposed to efavirenz for long periodsof time.In the second study (Manfredi, et al. [abstractPP 4.35]), a large cross-sectional survey was conductedin Bologna (Italy). The lipid profile wasassessed in patients treated for at least 12 monthswith either nevirapine (n = 236) or efavirenz (n = 256).The groups were matched for concomitant antiretroviralmedications, age, gender, hepatitis coinfection,CD4 counts and plasma HIV-RNA. In subjectswho replaced with a NNRTI a prior PI-basedregimen due to dyslipidemia, a drop in triglyceridesand/or cholesterol greater than 30% was seenin 67% of patients on nevirapine, but only in 29%of those who switched to efavirenz (p < 0.01).Furthermore, in 141 drug-naive individuals, dyslipidemiaappeared in 19% of subjects receiving efavirenz, but only in 2% of patients on nevirapine(p < 0.001).These new data should alert physicians to thepotential risk of efavirenz for causing lipid abnormalitiesand lipodystrophy in HIV-infected individuals,and may favor the use of nevirapine, particularly inpatients with other cardiovascular risk factors.