July 14, 2004
F. Maggiolo's group from Italy presented a small, prospective, randomized switch study of the effects of differing NRTIs and NNRTIs on lipid metabolism. The study looked at 36 patients on effective HAART containing a TA, a second NRTI, and efavirenz (EFV, Sustiva, Stocrin), with undetectable viral loads (<50 copies/mL) for at least 8 months and either total cholesterol or triglyceride levels >300 mg/dL. The patients were randomized 1:1 to the switch group, which substituted nevirapine (NVP, Viramune) for efavirenz and a different non-TA NRTI for the TA, or to the control group, which continued the same treatment. The primary endpoint was the reduction of cholesterol and triglyceride levels. The authors presented intent-to-treat analysis of their results after 48 weeks.
Demographics were similar at baseline for the 18 patients enrolled in each arm (mostly male, mean age 43 years, similar risk factors for exposure and Centers for Disease Control classifications). Patients had received an average of 2.85 prior antiretroviral therapy regimens for 66 months, and had been undetectable for 30 of those months. CD4+ cell counts were similar between groups throughout the study, starting at 600 cells/mm3 and ending at 700 cells/mm3. Baseline mean cholesterol levels in the switch and control groups were 286 and 262 mg/dL, respectively; triglyceride levels were 535 and 392 mg/dL, respectively. All switch patients received nevirapine; 15 also received didanosine (ddI, Videx), 13 lamivudine (3TC, Epivir), and 8 abacavir (ABC, Ziagen). All control patients continued with efavirenz and lamivudine; 15 were also on stavudine (d4T, Zerit) and 3 on zidovudine (AZT, Retrovir).
After 48 weeks, the difference from baseline for cholesterol levels was -24 mg/dL (P = .008) and -7 mg/dL (P = NS) for the switch and control arms, respectively, with no significant difference between arms. Triglyceride levels were -144 mg/dL in the switch arm (P = .012) and 42 mg/dL in the control arm (P = NS), with the difference between arms being significant at P<.02. The mean variation in low-density lipoprotein (LDL) cholesterol was -30 mg/dL for the switch arm compared with -10 mg/dL for the control arm, with P<.02 between arms. High-density lipoprotein (HDL) cholesterol levels were significantly higher in the switch arm at 48 weeks (54 vs. 45 mg/dL; P = .02). The mean total cholesterol/HDL ratio was 5.8 in the switch group and 5.0 in the control group at 48 weeks, with P<.02 between groups.
One patient in the switch arm failed treatment, with resistance mutations including 65R/10N/181C/184V and 20R/36I/63P. One patient in the switch arm and four in the control arm stopped 8 months after randomization because of hypertriglyceridemia. Two other discontinuations occurred in the switch arm 8 months after randomization -- one for hepatotoxicity and one for virologic failure.
At 12 months of follow-up in this small cohort, changing to a non-TA/nevirapine-based regimen had resulted in a statistically significant (P<.02) decrease in triglyceride and LDL cholesterol, and an increase in total cholesterol/HDL ratio, while maintaining similar immunologic and virologic control. In patients with alterations of metabolic parameters, it may thus be possible to optimize HAART by selecting drugs with a lower atherogenic potential, nevirapine and non-TA NRTIs being possible candidates. Exact dosing schedules for the medications were missing from both the poster and abstract, but the conclusion described an "OD switch regimen," so all drugs may have been dosed once daily. The study suffered from small sample size and design difficulties, but it certainly whets our appetite for larger, randomized, controlled trials to discover more lipid-friendly regimens and to ascertain the differential lipid effects among medications between and within classes.
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