Abstract
Compared with healthy controls, HIV patients already have abnormal lipoprotein concentrations before the initiation of highly active antiretroviral therapy (HAART), which worsen with the therapy. HAART-associated dyslipidaemia features fundamental proatherogenic changes such as increased plasma triglycerides (TGs), increased total cholesterol and low-density lipoprotein cholesterol as well as decreased high-density lipoprotein cholesterol (HDL-C). The current guidelines for managing HIV-associated dyslipidaemia recommend diet and exercise counselling, alteration of HAART regimen or addition of lipid-lowering medications such as statins, fibrates and omega-3 (OM-3) fatty acids. Given that cardiovascular risk significantly increases with elevated lipid levels, selecting a drug to manage dyslipidaemia is particularly important. A case is described of an HIV patient who had severe hypertriglyceridaemia and bad metabolic parameters treated with rosuvastatin and OM-3 fatty acids. So we obtained a more marked reduction of TG levels than has never been described before in the literature, associated with a significant increase in HDL-C levels.
INTRODUCTION
Metabolic disorders, frequently seen in highly active antiretroviral therapy (HAART)-treated patients, include dyslipidaemia, hyperinsulinaemia and lypodistrophy. 1 HAART-associated dyslipidaemia features increased plasma triglycerides (TGs), increased total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), as well as decreased high-density lipoprotein cholesterol (HDL-C). 1–3 These fundamental proatherogenic changes can be further accompanied by increases in small dense LDL particles, lipoprotein A and apolipoproteins B, C-III, E and H. 1,4
The pathogenesis of HAART-related dyslipidaemia is complex and involves various drug-induced effects, in association with hormonal and immunological influences superimposed upon genetic predisposition. 5,6
HIV patients already have abnormal lipoprotein concentrations before initiation of HAART, which worsen after the initiation of therapy. Regimens containing protease inhibitors (PIs) are associated with increased risk of developing hyperlipidaemia. 3 Combination HAART was found to be associated with a 26% increase in relative risk of cardiovascular disease with a relative rate of myocardial infarction of 1–2-fold per year of PIs exposure. 7,8 Hypertriglyceridaemia itself has been recognized as an independent cardiovascular risk factor and should be considered in the management of HIV infection. 7,9 So selecting a drug to manage dyslipidaemia is particularly important.
We describe a case of an HIV patient who had severe hypertriglyceridaemia treated with a combination therapy of statin plus omega-3 (OM-3) fatty acids.
CASE REPORT
A 40-year-old HIV-infected Caucasian male (CDC C2, HIV-related encephalitis) patient came to our examination centre to continue follow-up because he had moved to this area. The patient had been treated with atazanavir (ATV)/r+ azidothymidine (AZT) and 3TC since 2002, and on admission he had 460 CD4/mm3; 589 CD8/mm3, ratio CD4/CD8 0.81; HIV-RNA <50 copies/mL; TGs 236 mg/dL; TC 204 mg/dL; non-HDL cholesterol (non-HDL-C) 180 mg/dL; HDL-C 24 mg/dL; fasting glucose 80 mg/dl; fasting insulin 20.1 µU/mL and HOMA-IR 3.9; aspartate aminotransferase 44 U/L; alanine transaminase 84 U/L.
He showed a progressive impairment of metabolic parameters and was treated with a low lipidic content diet and increased physical activity, with good adherence. In spite of this, metabolic parameters worsened and reached TGs 740 mg/dL; TC 220 mg/dL; non-HDL-C 193 U/L; HDL-C 27 mg/dL; fasting glucose 82 mg/dL, fasting insulin 116.9 µU/mL; HOMA-IR: 23.38.
We thus decided to start rosuvastatin 10 mg daily and OM-3 fatty acids 3 g three times a day. HAART was not changed because of the good viral and immunological response and the use of ATV which has negligible effects on serum lipids. 10 One week after the introduction of rosuvastatin plus OM-3 fatty acids, TGs were 615 mg/dL (percentage change from baseline −16.9%). After one month of therapy, the patient showed TGs 193 mg/dL (−73.9%), TC 188 mg/dL (−14.5%), non-HDL-C 145 mg/dL (−24.9%), HDL-C 43 mg/dL (plus 59.2%), AST 44 U/L, ALT 90 U/L and creatin phosphokinase (CPK) normal. Metabolic parameters were also stable at a further control after three months and no adverse events, such as increased CPK and transaminases, were observed.
DISCUSSION
Moderate hypertriglyceridaemia is an independent risk factor for cardiovascular disease. In persons with high TG levels, levels of LDL-C alone are not a sufficient indicator of the risk associated with atherogenic lipoproteins. 11 Thus, in addition to the primary goal of LDL-C reduction, the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III guidelines have identified non-HDL-C as a secondary target of therapy in persons with serum TG levels ≥200 mg/dL. Non-HDL-C is calculated as the difference between TC and HDL-C. 11 It is a good predictor of cardiovascular risk and includes the cholesterol contained in all the potentially atherogenic apolipoprotein. 1,11 This suggests a clinical need for effective treatment options to lower high levels of TG and non-HDL-C. The most recent NCEP guidelines suggest that a more aggressive approach to therapy is warranted. 11
The current published guidelines for managing HIV-associated dyslipidaemia recommend diet and exercise counselling, alteration of HAART regimen or adding lipid-lowering medications. 12
Statins, or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are used extensively in the general population and significantly improve lipid profiles, reducing plasma TGs and increasing HDL-C. Among statins recommended for the treatment of HIV-associated dyslipidaemia, rosuvastatin has shown reductions in LDL levels and a rate of LDL goal attainment significantly greater than others. 13
Fibrates, which are agonists of peroxisome proliferator-activated receptor alpha (PPARα), reduce plasma TGs but appear less effective than statins in preventing cardiovascular events. 14
A statin is recommended as an initial pharmacotherapy for LDL-C elevation and a fibrate is suggested for hypertriglyceridaemia. 1,3 However, treatment goals may not be reached with either statin or fibrates monotherapy alone and combining statins with fibrates has been criticized because of the potential adverse effects. An alternative treatment for hypertriglyceridaemia is OM-3 fatty acid supplementation, which may lower plasma TGs and increase HDL-C. However, few data are available on the effect of fatty acids on metabolic abnormalities in HIV patients. 15,16 Some data have shown benefits of OM-3 alone or plus fibrates in HAART-treated HIV patients. 16 In addition, a recent study showed a reduction of TG levels by 65.5% with combination OM-3 plus fibrates versus the modest effect of both monotherapies in HIV subjects on HAART. 17 This suggests that dual therapy may be preferable for HIV patients with extremely raised TGs.
CONCLUSION
In our patient, we opted for a combination therapy with rosuvastatin and fatty acids to exploit the drug potency and cardiovascular benefit provided, respectively. 18
Recent data show an increase in rosuvastatin plasma concentrations with ATV/r in HIV-seronegative subjects. 19 Thus, dose limitations of rosuvastatin with ATV/r may be needed.
Therefore, we obtained a marked reduction of TG levels to an extent that has never been described before in the literature, associated with a significant increase in HDL-C levels. These favourable results suggest that this association may be a valid therapeutic option in managing severe hypertrigliceridaemia in HIV patients.