ArticlesAn objective case definition of lipodystrophy in HIV-infected adults: a case-control study
Introduction
Lipodystrophy (sometimes referred to as fat redistribution, including peripheral peripheral lipoatrophy, central fat accumulation, or lipomatosis) is common in adults taking protease inhibitors, nucleoside analogue reverse transcriptase inhibitors, or both, for HIV-1 infection.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 Lipodystrophy is disfiguring and potentially stigmatising, and thus can hinder adherence to, and reduce effectiveness of, antiretroviral treatment.12, 13 Furthermore, some associated metabolic features (reduced HDL cholesterol, hypercholesterolaemia, hypertriglyceridaemia, insulin resistance, type 2 diabetes, and lactic acidaemia) might increase the risk of cardiovascular disease.1, 3, 4, 5, 6, 7, 9, 10, 14, 15, 16 Despite the identification of HIV lipodystrophy 5 years ago,1 an objective case definition does not exist; this has led to substantial variations in reports of prevalence (20–80%), incidence, severity, risk factors, and responses to interventions. Objective physical or metabolic features that reliably define lipodystrophy have not been identified, perhaps because of the high variability between individuals in metabolic indices and soft-tissue mass and distribution. Five definitions of lipodystrophy have been proposed, 4, 17, 18, 19, 20 but all were generated from studies done in few sites and with mostly male participants; few included objective body composition data, and none was validated. Development of a case definition has been hampered further by uncertainty about whether lipodystrophy in patients with HIV is more than one syndrome. Is the disease defined by peripheral lipoatrophy, central fat accumulation, or both? And is it caused by either nucleoside analogue HIV reverse transcriptase inhibitors or HIV protease inhibitors?21, 22, 23 In fact, the phenotype is most commonly mixed, almost all patients receive these classes of drugs at some time, and all the physical features have been described in patients receiving only one of the drug classes.
Case definitions of clinically-defined rheumatological syndromes of unknown cause, such as rheumatoid arthritis and systemic lupus erythematosis, have been in existence for more than 30 years.24, 25 Such definitions have allowed workers in industry, regulators, researchers, and clinicians to make improved assessments of disease variables such as: prevalence and incidence across and within populations of patients; potential risk factors; pathogenesis; prevention; and treatment. An objective and standardised case definition of lipodystrophy should yield similar benefits.
In response to the increasing awareness of lipodystrophy after the licensing of antiretroviral drugs, the European Medicines Evaluation Agency convened a working group representing regulatory agencies, academia, antiretroviral manufacturers, and patients with HIV. This study is one of the group's initiatives. The design and analytical approach of this case-control study is similar to that used to develop rheumatological syndrome case definitions.24, 25 Our main aim was to develop an objective, sensitive, specific, and broadly applicable case definition of HIV lipodystrophy.
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Participants
We included patients with documented HIV infection, who were older than 17 years, did not have clinical signs of active AIDS in the 4 weeks before trial entry, and were able to complete all investigations. Since we aimed to address diagnosis of lipodystrophy in HIV-infected adults, we did not include controls who did not have the virus.
We recruited patients from 32 sites in North America (n=13), Europe (n=11), Australia (n=4), Asia (n=2), and South America (n=2), which were chosen by
Results
Of 1371 patients approached between October, 2000, and June, 2001, 1081 (79%) gave consent to participate (figure 1): 417 were defined as cases, 371 as controls, 288 were non-assigned, and five were ineligible. Table 1 shows patients, baseline and HIV-disease characteristics. A mean of 13 (SD 1·1) cases and 11·6 (3·0) controls were recruited per site during a mean of 9 weeks (4) and 13 weeks (7), respectively. Four sites failed to recruit at least 12 controls, largely because of logistic
Discussion
We have objectively defined HIV lipodystrophy by locally-derived and readily available clinical, metabolic, and body-composition data. Our syndromic case definition is a substantial advance on the approach of subjective diagnoses made by doctors, patients, or both, because the definition contains only objective indices and so is unbiased. Our definition should lead to improvements in the study of lipodystrophy prevalence, incidence, risk factors, pathogenesis, prevention, and treatment.
The
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