Hypertriglyceridemia has been recognized as an independent risk factor in the development of CHD.11
The most recent NCEP guidelines suggest that a more aggressive approach to therapy is warranted, although the exact goal concentration for this lipid is still unclear, because TGs, even in the range of 150 mg/dL, have been found to promote CHD in population-based studies.14,29
HIV-infected patients on HAART frequently have elevated TGs and low HDL-C, similar to those levels found among persons with type 2 diabetes, which places them in the high-risk category for CHD.30
In addition, HIV infection is associated with diminished vascular endothelial function31
and elevated hs-CRP; thus, aggressive and effective lipid-lowering therapy is likely to be beneficial in reducing the overall risk of CHD, because these patients live longer.32
Fish oil has been used to treat hypertriglyceridemia for 2 decades. The first description was in the early 1980s, and fish oil was found to reduce TG concentration by as much as 80% in subjects with familial hypertriglyceridemia.17
These subjects are phenotypically similar to subjects on HAART therapy in that they have extremely high very-low-density lipoprotein (VLDL) TG levels, normal to low LDL-C, and low HDL-C. In these subjects, an increase in LDL-C secondary to fish oil was described similar to what was observed in the present study. The increase in LDL-C was much less prominent in subjects with low baseline TGs. The effectiveness of fish oil in lowering TG levels has a clear dose response relation, as demonstrated by Harris et al.33
In addition, fish oil has been shown to have efficacy in lowering TGs in subjects with drug-induced (retinoids) hypertriglyceridemia.34
We demonstrated that fish oil and fenofibrate alone could produce significant decreases in TG levels; however, few patients on either therapy achieved TG levels lower than the NCEP target of ≤200 mg/dL. Of note, most of our subjects were male and these results may not be generalizable to a female population, although we are unaware of any data that suggest a difference based on gender. The combination of both agents was found to reduce TG levels further and to increase the proportion of subjects with a TG level ≤200 mg/dL among those not achieving this target during monotherapy. These results demonstrate the relative ability of each agent and their combination to treat hypertriglyceridemia in HIV-infected persons. The modest effect of monotherapy on absolute TG levels suggests that for HIV-infected patients with extremely elevated TGs, dual therapy may be preferable.
Administration of fish oil has been shown to have a beneficial effect in lowering TGs in HIV-infected subjects in 2 other trials. De Truchis et al20
used a dose of EPA plus DHA of 1.8 g/d and demonstrated a median decrease of 25.5% in TGs. The median baseline TG was 410 mg/dL in this group, which was lower than in our subjects. Wohl et al21
administered 2.9 g/d of EPA plus DHA in HIV-infected subjects on HAART and demonstrated a mean decrease in fasting TGs of 25% in subjects with a mean baseline TG of 461 mg/dL. In both studies and in our study, the tolerability of fish oil was excellent. Our study used a higher dose of fish oil (4.86 g/d of EPA plus DHA), our subjects started with higher baseline TGs (median of 662 mg/dL) than in the other studies, and we demonstrated a 46% decrease in TGs. Thus, it seems, as in non-HIV-infected subjects, that the dose of fish oil correlates with the extent of response.
The combination of fish oil and fenofibrate was well tolerated with minimal toxicity. Although we did not evaluate LDL particle size, data from other studies suggest that the expected increase in LDL-C is secondary to an increase in larger more buoyant LDL, which is not as atherogenic as the dense small LDL-C.19,27,35-38
In addition, initial LDL-C levels for subjects in our study were lower than those in the general population and only increased to levels that are considered normal for most subjects. It is unclear if the increase in LDL secondary to fenofibrate and fish oil is long term and what the clinical implications of this effect are. Standard of practice is to lower TGs first when TG levels exceed 500 mg/dL; after TGs are <400 mg/dL, the LDL can be calculated to determine if LDL-lowering therapy is indicated.13,24
The small increase in HDL-C was also expected and may partially counteract the effect on LDL-C.
Fish oil has been previously shown to be immunosuppressive by altering cytokine production in PBMCs, reducing the percentage of helper T cells, and decreasing the mitogenic response to concanavalin A.39
In contrast to what has been previously reported in healthy volunteers, we did not observe any change in CD4 cell percent or absolute CD4 cell count in subjects taking fish oil; in addition, the LPA responses to CMV and Candida
antigens were not altered by the fish oil supplement. Thus, this dose of fish oil seems to be immunologically safe.
Aside from evaluating the immunologic parameters, it was important to demonstrate that fish oil administration had no adverse pharmacokinetic effect on boosted lopinavir—a PI in the ARV class most closely associated with elevated TGs. Fish oil did not alter the trough concentration of lopinavir, suggesting that fish oil would not be expected to modulate the antiviral efficacy of ritonavir-boosted PIs.
In summary, we have demonstrated that fish oil at the EPA plus DHA dose of 4.86 g/d is effective in combination with fenofibrate in lowering TGs in HIV-infected subjects with hypertriglyceridemia on HAARTwho fail to respond to single-drug lipid-lowering therapy. Most subjects failed to achieve the goal TG concentration of ≤200 mg/dL when treated with fenofibrate or fish oil alone. When fish oil was combined with fenofibrate, however, a further reduction in TGs was obtained without any safety concerns. HIV-associated dyslipidemia remains a difficult condition to treat, and our trial further demonstrates the need for evaluation of combination therapies or strategies to manage this comorbidity. Whether higher doses of omega-3 fatty acids would result in a more effective antilipid effect should be studied; however, immunologic monitoring should also be assessed.