British HIV Association adult antiretroviral treatment guidelines: Lipodystrophy

Introduction

It is now over 2 years since the widespread recognition of the metabolic and morphologic changes observed during antiretroviral therapy. The characteristic morphological changes observed are highly stigmatising to individuals and may lead to consideration of delaying commencement of therapy, modification of established therapy to alternative regimens or decisions to stop therapy to prevent or attempt to manage the problems. Similarly concerns and evidence are growing regarding the likely future morbidity associated with both lipid elevations and glucose intolerance, particularly in regards to vascular disease.

Arguments continue as to the linkage of the main components of the syndrome and indeed as to whether several different syndromes may exist. The main components, which may be observed individually or in combination in persons on antiretroviral therapy include:

• Dyslipidaemia with raised total cholesterol, low HDL cholesterol and raised triglycerides with increased lipid cycling or turnover
• Insulin resistance with hyperglycaemia, particularly in susceptible individuals
• Visceral, breast and/or local fat accumulation
• Generalized diminution of subcutaneous fat mass possibly with fat cell loss

In addition, other metabolic and physical changes may also be present in patients on long term antiretroviral therapy including raised serum lactate, low bone mineral density, avascular necrosis of the hip, hypogonadism, hypertension and accelerated cardiovascular disease. The linkage of these problems to other metabolic and morphologic changes remains to be elucidated.

Studies are now underway attempting to provide a clinical case definition, based on physician and patient agreement regarding significant and characteristic morphological changes, potentially enabling more homogeneous populations to be studied and comparisons made across intervention studies.

Only through understanding the ætiology can optimal management of these problems be established. The ætiology of peripheral lipoatrophy and other clinical and metabolic consequences of antiretroviral therapy remains largely enigmatic. Evidence from cross sectional surveys have pointed to an interaction between HIV disease and/or immune recovery and antiretroviral medication. Both PI and nucleoside analogues have been associated with the changes and theories published hypothesising how they may play a role. Evidence to date suggests these hypotheses to be, at best, incomplete. Patients with the syndrome who have never received PIs or have never received nucleoside analogues have been reported, suggesting that whilst it is possible that these drug classes or specific members of these classes may accelerate the onset of clinical manifestations they are not sufficient alone to cause the problems.

It is, therefore, not surprising that switching therapy away from whichever drug or drug class is the current fashion to blame has not led to resolution of the syndrome. Indeed, personal experience suggests that whilst metabolic problems may largely resolve during interruptions of therapy, improvement or resolution of significant facial or peripheral limb lipoatrophy does not occur over periods greater than 6 months off therapy.

As the onset of the morphological changes appears infrequent during the first year of therapy, prospective data comparing risk of these changes between regimens are not available although some data on lipid profiles on different regimens have been reported. Most data are, therefore, derived from cross-sectional studies hence have considerable methodological biases. In considering information from surveys or ‘cross-sectional studies’ it is reasonable to remember that statistical associations found in these studies may reflect patterns of drug use or relative statistical power in different subsets analyses and do not necessarily point to causation of the problem. Additionally, the absence of a consistent case definition may increase the risk of observer bias where blinding to treatment is not included.

A range of in vitro, animal and healthy volunteer studies have provided some pieces of information that may be relevant to the whole syndrome or specifically individual manifestations. The applicability, in particular of in vitro and animal models to the human situation is not established hence must be viewed with caution.

Management of Lipodystrophy

Broadly, management approaches to lipodystrophy depend on the current assumptions of ætiology. The approaches tend to be dictated at present by ‘fashion’ and perhaps ‘marketing’ rather than fact and science.

The risk versus benefit of these approaches have not been well tested so individuals switching must consider that they may risk their long-term HIV management in exchange for an uncertain outcome with regard to their lipodystrophy. Switching is therefore best evaluated within clinical trials.

Current approaches include:

• Assume PI ætiology ®

  Switch to NNRTI/Triple NA regimen

• Assume Thymidine analogue ætiology ®

  Switch to ddI, ABC based regimen

• Assume NA ætiology ®

  switch to PI + NNRTI regimen

• Assume Cytokine ætiology ®

  Use SIT/pulse therapy, consider loose viral control

• Assume Multifactorial ®

  Treat individual manifestations

• Assume Adipocyte Apoptosis ®

  consider Rosiglitazone.

The majority of switch studies maturing now are focussed on switching away from PIs although studies evaluating nucleoside switches are also underway. Details of comparative switch studies are available in The AIDS Reader 10(8):479-485, 2000. Similarly, adding new agents in to the regimen risks interactions with the antiretrovirals, side effects and toxicities from the new drugs and often only addresses one aspect of the syndrome, for example cholesterol elevation, rather than addressing why the problem has arisen.

However, in the absence of ætiology it may at present be best to use manifestation specific interventions until more definitive therapy is available.

The include:

• Dietary advice from a dietitian
• Exercise of >30mins 2-3 times/week
• Diabetic management with specialist advice (Table 1)
• Lipid management with specialist advice (Table 2)
• Plastic surgery with specialist advice. No clinical trial data are available to support the use of this approach.
• Consideration for participation in clinical trials if available.

Agents that do not appear suitable in the management of lipoatrophy include:

• Anabolic steroids due to concerns regarding worsening lipid profiles, fat loss and potential for liver function disturbances. Testosterone replacement for repeatedly hypogonadal and symptomatic men who are not hypogonadal due to previous anabolic steroid use may be considered.

Management of Lipids with specialist advice

* Caution with ritonavir or possibly other PIs levels of may elevate greater than four-fold.

Interactions with NNRTI agents have not been established.

Management of Glucose Intolerance with specialist advice

Routine for Evaluation of Persons on HAART for Metabolic and Morphologic Parameters

Research Based Tests Not Routine in Practice

*BIA measurement is not currently of established value