Abstract
Sir; We read with great interest the paper by Falasca et al., 1 dealing with a very favourable efficacy of associated omega-3 fatty acids and rosuvastatin in a patient with extremely elevated serum triglyceride levels, during HIV infection, treated with antiretroviral therapy.
Hypertriglyceridaemia represents a frequent untoward event of potent combination antiretroviral therapy (cART), which is characterized in the majority of cases by elevated and persistent abnormalities that require pharmacological treatment with fibrates and/or omega-3 polyunsaturated fatty acids (PUFA), especially when dietary changes and increased physical exercise do not act significantly over time. 2–4 Unfortunately, the majority of HIV-infected patients are prone to suffer from a mixed dyslipidaemia, including both hypertriglyceridaemia and hypercholesterolaemia (with reduced serum HDL-cholesterol and increased serum LDL-cholesterol fractions). Hence present therapeutic strategies are still debated, since the more potent association of statins and fibrates puts patients at serious risk of serum creatinkinase rise, while the association of statins plus niacin and ezetimibe still lacks extensive data. 3,4 As a consequence, since in proportionally young persons elevated cholesterolaemia represents the main target, the association between a potent statin controlling hypercholesterolaemia, 3 plus the safe PUFA supplementation, allows one to contain concurrent hypertriglyceridaemia without adding toxicity. 3–5
The efficacy and safety of PUFA administered at different dosages have been evaluated in the management of HIV-infected patients with a predominant cART-associated hypertriglyceridaemia (characterized by plasma levels >300 mg/dL) compared with a standard continuative therapy performed with fibrates (fenofibrate, bezafibrate or gemfibrozil). Two hundred and twenty patients with HIV disease treated with nucleos(t)ide analogues and protease inhibitors (137 cases) or with a non-nucleoside reverse transcriptase inhibitor (83 subjects), who suffered from a mean hypertriglyceridaemia of 334.1 ± 48.7 mg/dL (range 289–2.121 mg/dL), received a open label treatment with PUFA (administered at three different daily dosages: 2, 3 or 4 g/day) (107 cases) or received fibrates at standard dosage (113 subjects), and were prospectically monitored at least quarterly for 24 subsequent months, without modifying the effective underlying cART. PUFA administration led to a mean reduction of triglyceridaemia of 7.5%, 15.3%, 15.7%, 15.2%, 16.4%, 15.8% and 15.6% after 3, 6, 9, 12, 15, 18 and 24 months, respectively (P < 0.0001 versus baseline levels), with statistically significant differences favouring the highest dosage (4 g/day) compared with the lower and the intermediate doses (2 and 3 g/day), which became apparent after the sixth month of study. Both PUFA and fibrate administration achieved a significant reduction (P < 0.0001) of serum triglyceride levels versus baseline values, although fibrates showed a systematically more potent activity during the entire 24-month duration of our investigation (P < 0.0001 versus PUFA in all quarterly determinations). Normal serum triglyceride levels were obtained at any time of treatment by 38 patients treated with PUFA (35.5%) (all of them receiving at least 3 g/day), as opposed to 56 subjects who received fibrates (49.6%, P = 0.049). These data were confirmed after controlling the figures for the concurrent cART and other concomitant conditions. Mild and transient gastrointestinal complaints (also attributable to underlying pharmacological regimens) were referred by 22 patients who received PUFA versus 43 subjects belonging to the fibrate group (P = 0.007). But drug interruption due to intolerance never occurred, except for two subjects showing persistently elevated serum creatinkinase levels (both treated with fibrates). The PUFA or fibrate add-on strategy contributed to prevent the modification of concomitant, effective cART, when an elevated and/or prolonged serum triglyceride rise represented the only or the main problem in the pharmacological management of HIV disease.
A pharmacological treatment of moderate–severe hypertriglyceridaemia is mandatory in HIV-infected patients receiving cART, since the benefits ensured by dietary–physical exercise programmes are somewhat limited, and also cART modifications (i.e. exclusion of protease inhibitors) have reduced efficacy 3,5,6 when compared with the adjunct of a hypolipidaemic therapy, and put our patients at risk to abandon an effective cART. Moreover, antiretroviral drugs other than protease inhibitors (like efavirenz) showed a non-negligible induction of metabolic abnormalities in both cART naïve and cART-experienced patients. 6 In a previous study of ours, PUFA given at 2 g/day only acted better than an isolated diet–exercise programme, but fibrates tested more effective. 7 An uncontrolled Italian study confirmed a significant effect of PUFA supplementation on hypertriglyceridaemia, but not on serum cholesterol fractions. 8 The first randomized, open-label study conducted by Wohl et al. 9 assessed a mixture of PUFA at 2 g/day versus a dietary–exercise programme, and demonstrated a mean 25% decline of tryglyceridaemia at week 4 in treated patients. 9 The most recent literature study compared PUFA at 3 g/day with fenofibrate, and the association of both strategies in 100 subjects with a very elevated median baseline triglyceridaemia (>650 mg/dL): after eight weeks, a 46% reduction of triglyceridaemia was attained in the PUFA group, compared with a 58% reduction in the fibrate-treated patients, compared with a 65.5% reduction in subjects receiving both medications; 10 this relevant study underlines the need to maintain a PUFA dosage of at least 3 g/day and shows an additive value of fibrates. Unfortunately, it does not address the most frequent question related to the often concomitant hypercholesterolaemia. Moreover, both HIV-mediated endothelial inflammation and antiretroviral-induced oxidant injuries may increase the risk of premature atherosclerosis, so that a primary prophylaxis also including PUFA has a robust pathogenetic rationale, 11 also recognized by the reimbursement of these drugs by national health care systems. 12
Our present data, which compare different daily dosages of PUFA versus standard fibrate administration, while confirming the greater activity of fibrates, also underline a favourable, safe and prolonged effectiveness of PUFA, if they are used at a daily dosage of at least 3 g/day. Since all main hypolipidaemic drugs (especially statins) are burdened by appreciable toxicity (especially skeletal muscle damage, potentially exacerbated by the concomitant use of fibrates and the cART itself), PUFA represent an effective and well-tolerated alternative to fibrate administration in these high-risk patients.