Participants in the 2NN study who received either nevirapine (Viramune) or efavirenz (Sustiva) experienced increases in high density lipoprotein (HDL) cholesterol over and above the degree that would be expected from a protease inhibitor-containing regimen, according to findings published this week in the new online journal Public Library of Science Medicine.
In patients who received nevirapine, study investigators report, the degree of improvement outranked the effect of statins on HDL cholesterol in the HIV-negative population, suggesting that the drug may have particular benefits for HIV-positive people with multiple risk factors for heart disease that include low HDL cholesterol.
Higher levels of HDL cholesterol have been associated with a reduced risk of cardiovascular disease in the general population, and HDL cholesterol levels are reduced in people with HIV infection, so the effects of different drugs on HDL cholesterol may have long-term significance for cardiovascular risk in people with HIV.
The 2NN study compared the clinical performance of nevirapine twice-daily and once-daily with efavirenz and with efavirenz plus nevirapine in 1216 patients across five continents. Data from 940 patients who took their allocated treatment throughout the study were analysed.
Using data from the 2NN study and two large prospective studies of cardiovascular risk in Finland and the United States, the investigators estimate that, based on the study results, taking efavirenz could reduce the risk of cardiovascular disease by 3% compared with protease-inhibitor-based regimens, whilst taking nevirapine could reduce the risk by 15%. The PI-treated comparator group consisted of 50 PI-treated patients with well characterised lipid profiles before and during highly active antiretroviral therapy (HAART; Riddler 2003).
The authors suggest that the effect of efavirenz in the study was probably due to the antiretrovirals used compensating for the lipid-lowering effect of untreated HIV and restoring lipid levels to normal.
However the additional effect of nevirapine, which is similar to that of the most powerful lipid-lowering agents in the statin and fibrate classes of drugs, may be due to a specific HDL-raising property. They are “currently conducting studies to unravel” this possibility.
Headline findings from the lipid study include:
- HDL-cholesterol increased by 43% in patients on nevirapine and 34% on efavirenz (p = 0.036).
- The ratio of total cholesterol to HDL-cholesterol increased by 6% on efavirenz, but decreased by 4% on nevirapine (p < 0.001). This ratio is the best guide to the likelihood of future cardiovascular events.
- Patients starting with low or normal HDL cholesterol at baseline had increases, whereas those with high HDL cholesterol had slight decreases. Among patients with normal HDL cholesterol, the increase on nevirapine was nearly three times that on EFV (p < 0.001).
- Regional differences in HDL changes were also evident, say the investigators, although data are not reported. HDL increases tended to be greater in Asia, Australia and South Africa than in South America. European patients had the largest increase in HDL cholesterol.
- Women did slightly better than men. They had a significantly larger increase of HDL cholesterol and a resultant decrease in their cholesterol to HDL cholesterol ratio.
- The larger the decrease in viral load, the larger the increase in all types of cholesterol: total cholesterol, HDL cholesterol and low density lipoprotein (LDL) or ‘bad’ cholesterol. The reverse effect was seen with triglycerides, which did not increase beyond normal ranges. However the increase in HDL and total cholesterol was greater (p < 0.001) than in LDL-cholesterol (p = 0.018).
Although the investigators say that the majority of the cholesterol change could be explained by the effect of HIV treatment on viral load, they point out that the increase in HDL cholesterol in the comparator group of protease inhibitor-treated patients (Riddler 2003) was ten times smaller than seen in the 2NN study despite similar HDL levels in the two populations at the initiation of HAART.
The investigators comment: “The magnitude of the HDL-c increase observed in our study must have occurred through additional mechanisms.”
The increase in HDL cholesterol observed is three times larger for efavirenz (34%) and four times larger for nevirapine (43%) than those seen in studies of the best-performing statin and fibrate drugs in HIV-negative patients with coronary heart disease (11%).
Academic author, Andrew Carr of St. Vincent's Hospital in Darlinghurst, Australia, commented: “These data suggest that nevirapine may be preferable to efavirenz in HIV-infected adults with other cardiovascular risk factors. However, perceived cardiovascular risk is only one factor that would affect the choice between these two drugs.”
Van Leth et al. Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naïve patients infected with HIV-1. PLoS Med 1: e19, 2004.
Riddler SA et al. Impact of HIV infection and HAART on serum lipids in men. JAMA 289: 2978-2982, 2003.