October 29, 2001
Concerns about the impact of lipids on the future health of persons with HIV continue to be a subject of considerable research interest. Previous work has suggested that there may be some differences in lipid elevation between protease inhibitors, with ritonavir being the biggest culprit and saquinavir and amprenavir less troublesome. However, in this era of boosted protease inhibitor regimens we have no data with which to differentiate these agents, as everyone gets some ritonavir. Among protease inhibitor-sparing regimens, there is also some speculation that differences may exist. In persons switching away from protease inhibitors, lipids seem to perform better with nevirapine and abacavir, and tend to stabilize with efavirenz. Efavirenz and nevirapine also tend to improve the ratio of "good" to "bad" cholesterols. Additionally, it is possible that lipid elevations may be linked with future development of at least some body shape changes. While some researchers suspect that this may be the case, no definitive evidence exists. If efficacy is similar among a range of treatment approaches, the effect a drug has on lipid levels will be important when choosing a treatment approach.
The Atlantic study was the first study to evaluate three treatment approaches: protease inhibitor (indinavir), NNRTI (nevirapine, given once daily) and a third NRTI (3TC) on the same NRTI backbone (d4T and ddI). Previously presented data on efficacy indicated that no differences were observed between combinations. However, the study may not have had a sufficient number of participants to have an adequate chance of demonstrating differences.
The study included the observation of lipid levels in an unfasted state. Food tends to affect triglycerides more than cholesterol levels. The sub-study on lipids is affectionately known as "Fatlantic" or, more formally, the Fat Redistribution and Metabolic Sub-study (FRAMS). Further data on morphologic change have not been reported.
One possible disadvantage of the FRAMS sub-study is that only 139 of the 298 patients were included in FRAMS. This may mean ascertainment biases exist. Differences between the sub-study patients and the overall study patients make them not fully representative of all patients. However, the baseline characteristics for CD4, viral load and HIV disease status were similar to the over all study. By 96 weeks, only 98 patients were available who had paired baseline and week 96 values and were on their original randomized therapy. Values at other timepoints were also available.
At week 24, the nevirapine (but not the IDV or 3TC) regimens were associated with an improvement in the "good" HDL to "bad" LDL cholesterol ratio. This was mainly driven by a 49% rise with nevirapine in the HDL cholesterol compared with around 9% with indinavir. The LDL cholesterol rose by a similar amount in each group. As HDL tends to be lower with HIV (as may total cholesterol), the small rise in HDL and LDL with the PI and 3NRTI approaches may be related to a simple correction of HIV-related lipid disturbances.
The cholesterol improvements persisted through to week 96. The numbers of patients available for assessment were 32, 28 and 38 in the NVP, IDV and 3TC arms, respectively. HDL cholesterol remained 40% higher than baseline with nevirapine but was significantly less improved with IDV (at just 6% higher) or 3TC (at 20% higher). The rise in LDL cholesterol remained non-significantly different among the arms: 3% with 3TC, 16% with IDV and 19% with NVP. This meant that the total cholesterol-to-HDL ratio, an established marker of future cardiac risk in general medicine, decreased (i.e., improved) by 6% with NVP and rose (i.e., worsened) by 25% with IDV and by 2% with 3TC. Triglycerides, also an independent risk factor for cardiac disease, rose in all arms: by 96% with IDV, 61% with 3TC and 46% for patients taking nevirapine.
The data suggest that regimens of similar efficacy may differ with regard to their effect on lipids and the potential for future cardiac risk. All other things being equal, nevirapine may be considered a good choice for individuals commencing therapy with multiple risk factors for future cardiac disease. Triple nucleoside regimens may be risk-neutral and PI regimens may tend to slightly increase risk. That being said, stopping smoking, eating a Mediterranean diet rich in fish oil and fruits/vegetables and exercising regularly may be more important than drug choice.
An on-going study comparing efavirenz and nevirapine for safety and efficacy, expected to report next year, will also investigate lipid changes to assess differences between these two NNRTIs.
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