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Statins in HIV-associated lipodystrophy and metabolic syndrome: is there a missing link?
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AIDS: Volume 20(7) 24 April 2006 p 1061-1063
Gharakhanian, Shahina; Boccara, Franckb; Capeau, Jacquelinec
From the aAP-HP Department of Infectious Diseases, Tenon University Hospital, Paris, France, & Drug Evaluation & Approval, Vertex Pharmaceuticals, Cambridge, Massachusetts, USA
bAP-HP Department of Cardiology, Saint Antoine University Hospital, Paris, France
cINSERM U680; Pierre & Marie Curie School of Medicine; UPMC and AP-HP; and Department of Biochemistry, Tenon University Hospital, Paris, France.
Note: The opinions expressed in this editorial by S. Gharakhanian, F. Boccara and J. Capeau are solely personal and do not engage, in any way or under any circumstance, their non-academic or academic employees or the institutions to which they are affiliated.
HIV-related abnormal fat redistribution, associated or not with metabolic anomalies, was first reported in 1997. A lipoatrophic aspect was characterized at an early stage when the first large cohorts were described. Elevated levels of triglycerides and total cholesterol, associated with decreased high-density lipoprotein cholesterol (HDLc) and increased low-density lipoprotein cholesterol (LDLc) were subsequently described in HIV patients receiving the HAART combination of antiretroviral agents [1-3]. The etiology of fat redistribution, hyperlipidemia and insulin resistance among patients with HIV infection has not been fully elucidated, and the syndromic association of these manifestations is the subject of regular debate and research [4]. The first case of coronary artery disease (CAD), published in 1998, followed by several case reports and series, thus, raised concerns about an emerging cardiovascular risk for patients. The prevention of CAD and the treatment of metabolic disorders therefore constitute new challenges in HIV medicine [5].
In this issue of AIDS, Patrick W. Mallon and co-authors present, a randomized, placebo-controlled study on the use of statins in HIV-infected subjects and are among the first to concomitantly examine several clinical and laboratory markers of HIV-associated lipodystrophy and metabolic syndrome. This placebo-controlled, 16-week study aimed to determine the effects of pravastatin, on markers of cardiovascular risk and lipodystrophy in HIV-infected, protease inhibitor (PI)-treated men with hypercholesterolaemia. A limited number of HIV-infected, hypercholesterolaemic men receiving stable PI-containing therapy underwent dietary assessment and advice and were then randomized to 3-months of pravastatin or placebo. The primary endpoint, time-weighted changes (TWAUC) in total cholesterol levels from week 0, was not significantly modified in the course of pravastatin treatment. TWAUC cholesterol values as from week 4 (initiation of pravastatin), a secondary endpoint, decreased more in the pravastatin group than in patients receiving placebo. Triglycerides levels remained unchanged. Apart from homocysteine, which decreased in the pravastatin group, there were no significant differences in other cardiovascular, lipid or glucose parameters. A 'vanguard' and novel result during this study was the significantly increased subcutaneous fat observed with pravastatin. From the patient's perspective, it is noteworthy that the amount of recovered limb fat was 0.72 kg after 12 weeks of pravastatin which was significantly greater than in patients under the placebo (0.19 kg). This recovery was superior to that observed under various switch strategies (e.g., 0.39 kg after 24 weeks during the MITOX study performed by the same team) [6].
The study by Mallon and coworkers raises two significant questions with respect to their evaluation and treatment of an entity that can, probably be termed most comprehensively and accurately, as 'HIV-associated lipodystrophy and metabolic syndrome'.
Firstly, what is the most appropriate methodology to assess the effects of lipid lowering agents, particularly statins, to ensure the treatment of dyslipidemia and to reduce related cardiovascular complications in the specific setting of HIV, that is characterized by the impact of multiple factors affecting lipid homeostasis and a real, albeit limited, increase in cardiovascular risk? How should individual physicians act in view of the contradictory or negative results concerning statins therapy for HIV dyslipidemia?
Secondly, other than surgical or dermatological procedures designed to correct disfigurements that are so distressing to patients, using space modifying techniques, is there a possible pharmacological approach to treat the fat redistribution abnormalities observed in HIV infected patients receiving HAART so as to ensure long-term patient improvement?
Pravastatin and fluvastatin are not metabolized through CYP-3A4 and can be prescribed safely in HIV-infected patients receiving PI (low dose) atorvastatine has been studied [7]. Rosuvastatin, a new statin which also does not involve CYP-3A4 is under evaluation [8]. Statins are the agent of choice for primary and secondary cardiovascular prevention achieving a 20% reduction in morbidity and mortality by lowering of LDLc levels by 1 mmol/l, irrespective of baseline LDLc values, as demonstrated by a recent prospective meta-analysis involving 90 056 (non-HIV) patients [9]. However because of interactions between statins and PI, the effects of the former in the setting of HIV has remained a subject of debate, as has their effects on reducing LDLc and modifying vascular properties (endothelial function, carotid intima-media thickness [10-12].
The results of the pilot study by Mallon and co-workers highlights the need to define and validate a methodological approach to the study of lipid-lowering agents (especially statins) in HIV infection. A pre-requisite would be to standardize the reporting of metabolic adverse effects in academic, investigator-initiated and registrational trials involving antiretroviral agents. The rationale behind the choice of a 16-week period, made by these authors, could be discussed. It is possible that in this particular setting, a significantly longer duration of treatment would be necessary particularly since the factors contributing to dyslipidemia are still present. Also, it is unsure that the difference, i.e., a 20% reduction in cholesterol levels (similar to that seen in other studies), used to estimate the number of patients, is appropriate to this particular setting. Meanwhile, individual patient management will be driven by published guidelines in the US and EU. The Infectious Diseases Society of America/Adults AIDS Clinical Group Guidelines (IDSA/ACTG) recommends target lipid levels and treatment of dyslipidemia in HIV infection. Because these guidelines draw heavily on the US National Cholesterol Education Program (NCEP) ATP III recommendations, it is considered that they should also apply to HIV-infected patients [7,12,13]. Likewise, in the EU, national guidelines stress the need to monitor and manage individual cardiovascular risk factors also drawing from non-HIV recommendations [14]. Whether, HIV-infected patients should be monitored, for primary prevention purposes as high risk, similar to diabetic patients, needs to be assessed in large randomized trials. Also as chronic inflammation and insulin-resistance, related to adipocyte dysfunction are key features in HIV infection, the value of LDLc or other (novel) biomarkers also need to be evaluated.
The study by Mallon and co-workers whose primary aim was to evaluate the effects on cholesterol of a commonly used statin with little interaction potential, concluded as to changes in the subcutaneous fat profile of patients studied, opening the way towards a new therapeutic option that deserves further consideration. The two endpoints in this study appear to be distinct although certainly are not from a patient perspective!
Overall, HIV-associated metabolic syndrome may be related to a combination of factors identifiable in the general population as well as being specifically related to HIV infection and its treatment. It can be hypothesized that these factors favor a proinflammatory, procoagulant and proatherogenic state which thus incrementally adds to any pre-existing condition unrelated to HIV [15]. Older age, lower body weight prior to antiretroviral treatment, a prior diagnosis of AIDS and a lower nadir CD4 cell count have been associated with lipoatrophy [16]. However, the role of antiretroviral agents in inducing lipoatrophy is one of the most discussed and investigated areas. Some PI have been shown to have an impact on adipogenesis via the transcription factor Sterol Regulatory Element-Binding (SREBP) 1 resulting in a lower level of the protein as well as the decreased activation of downstream pathways. Furthermore, some PI impair the nuclear localization of SREBP-1, and, alter the structure and stability of nuclear lamina, impairing the maturation of lamina. LaminaA [17] interacts with the nuclear membrane and with chromatin, more specifically with DNA and SREBP-1 through it's c-terminal domain. It is noteworthy that mutations of this domain are responsible for a genetic form of partial lipodystrophy, Dunningan's syndrome, which comprises peripheral lipoatrophy, fat accumulation, and metabolic alterations. In addition, different groups have demonstrated the presence of low-grade inflammation in lipoatrophic adipose tissue from patients, together with macrophages and an increased expression of proinflammatory cytokines such as tumor necrosis factor-ƒ¿ or interleukin-6 [18,19]. This inflammation may impair adipose function and result in fat loss and could also contribute to adipose tissue insulin resistance and clinical metabolic alterations.
The beneficial effects of statins beyond their ability to lower cholesterol levels, known as pleiotropic effects, have been the focus of much attention and research. Adipocytes lie at the heart of metabolic regulation. Statins impact adipocyte physiology, particularly via their effects on SREBP. Thus, the key pleiotropic effects of statins could be based on specific improvements in adipocyte functions through the activation of SREBP-1. It has further been hypothesized that SREBP-1 activation in adipocytes due to cytosolic cholesterol deprivation as a results of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition may be responsible for the beneficial effects of statins at the adipose tissue level [20]. Current evidence shows that acute coronary syndrome is accompanied by adverse changes concerning inflammation, the immune system, endothelial function and coagulation, which may be epiphenomena or causative. Statins have favorable effects on inflammation, the endothelium, and the coagulation cascade, improving adverse biological profiles in a dose-dependent manner both in vitro and in animal studies. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy - Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, differences were seen with respect to the LDL targets achieved that could be further discriminated in terms of C-reactive protein levels. Studies of non-vascular disease such as multiple sclerosis have further confirmed that statins may reduce inflammation. They can inhibit activation of the monocyte/macrophage system and reduce the production of chemokines and proinflammatory cytokines [21]. If this also occurs in lipoatrophic tissue, then this anti-inflammatory action could markedly improve adipose tissue dysfunction and, possibly, reverse fat loss [15].
Lipoatrophy has been demonstrated to be, at least in part, reversible [6], while HIV-infection has been shown to be associated with cardiovascular disease [16]. A unified and comprehensive approach is needed to enhance the therapeutic outcome of patients through reduction of these specific complications, and, therefore, patient distress, which can lead to treatment disruption [22].
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