Nevirapine-based HAART Increases HDL ("Good") Cholesterol in Patients with Sustained HIV Suppression

Antiretroviral therapy, especially using protease inhibitors (PIs), can cause blood lipid abnormalities, including elevated levels of low-density lipoprotein (LDL or "bad") cholesterol, that are associated with increased risk of cardiovascular disease. But some studies have shown than non-nucleoside reverse transcriptase inhibitors (NNRTIs) raise levels of high-density lipoprotein (HDL or "good") cholesterol, which is protective against heart disease.

The Nevirapine Intensive Lipid Evaluation (NILE) study, presented at the recent 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention in Sydney, Australia (July 22-25, 2007), aimed to understand the mechanisms underlying the effect of the NNRTI nevirapine (Viramune) on HDL levels in people with HIV.

As background, the investigators noted that HIV infection itself affects lipid levels, typically lowering both HDL and LDL cholesterol, causing a shift towards small dense LDL particles (LDL-B phenotype), and raising triglycerides at later stages of disease.

Thus, they proposed, the early lipid changes -- including a rise in HDL -- observed with any antiretroviral therapy may in part represent a "return to health," rather than a direct toxic drug effect

The open-label, non-randomized NILE study included 13 HIV positive participants (all men, with a mean age of 44 years). Subjects had HIV RNA levels < 50 copies/ml while on a regimen of AZT/3TC/abacavir (Trizivir) for at least 6 months, then added nevirapine at the usual dose (200 mg once daily for 2 weeks, then twice daily). They had no prior NNRTI exposure and no history of diabetes, hypertension, cardiovascular disease, or use of lipid-modifying medications.

At study entry and at weeks 6 and 24, the patients received primed bolus infusions of stable isotope L-[1-13C]-valine for 12 hours, in order to study apolipoprotein A-I (apoA-I) kinetics. Absolute production (APR) and fractional catabolic rates (FCR) of apoA-I were calculated, and levels of HDL-modulating enzymes were assessed.

Results

• After 24 weeks of follow-up in patients with sustained HIV suppression, use of nevirapine led to levated HDL and apoA-I levels.

• The magnitude of the HDL increase was compatible with earlier reports of studied of treatment-experienced patients (20%-21%).

• Rises in HDL and apoA-I were lower than those seen in treatment-naive HIV positive individuals, which suggests that part of the HDL rise in naive patients may result from a "return-to-health" effect.

The investigators concluded that nevirapine increases apoA-I and HDL levels by promoting apoA-I production without affecting HDLc catabolism (i.e., involving no cholesteryl ester transfer protein [CETP] inhibition).

The researchers suggested that these findings may contribute to understanding why, in HIV positive patients, increased cardiovascular disease risk has been reported with PI-based but not NNRTI-based therapy (as in the D:A:D study), and with interruption of NNRTI-based therapy (as in the SMART study).

In view of recent findings that CETP inhibitors (such as torcetrapib) which target HDL degradation may actually promote atherogenesis (formation of arterial plaques) and cardiovascular events, they wrote, these findings may hold promise for the development of novel therapies aimed at increasing HDL in ways that hopefully would offer protection against cardiovascular disease.

Departments of Vascular Medicine, Endocrinology and Metabolism, and Infectious Diseases, Academic Medical Center, Amsterdam, Netherlands; IATEC BV Amsterdam, Netherlands; Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands; Royal Free and University College Medical School, London, UK; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT.

08/31/07

Reference
R Sankatsing, R Franssen, E Hassink, and others. Nevirapine Increases High Density Lipoprotein-cholesterol by Stimulation of Apolipoprotein A-I Synthesis. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Sydney, Australia, July 22-25, 2007. Abstract WEPEB120LB.