Since the 1990s, clinicians have observed changes in body morphology and metabolic parameters that appeared to be related to the combination antiretroviral treatment regimens that were prolonging and improving quality of life for people with HIV infection. Numerous factors contribute to body morphological changes, including antiretroviral therapy, HIV infection itself, and perhaps immune reconstitution occurring in the context of ongoing disease (96–100).

People with HIV present with body changes, including what is now called lipoatrophy and/or lipohypertrophy (also known together as the lipodystrophy syndrome). The associated profound metabolic abnormalities, such as hyperglycemia, hyperinsulinemia, hyperlipidemia, and hypertension, are now commonly referred to as the metabolic syndrome.

One of the reasons for the wide range of prevalence rates of metabolic syndrome reported in patients on protease inhibitor regimens (2%–84%) (96, 101–103) has been the lack of uniformity of definitions, criteria, and assessment methodology.

Risk factors for lipodystrophy include exposure to protease and nucleoside reverse transcriptase inhibitors, duration of use of a protease inhibitor or a nucleoside reverse transcriptase inhibitor, duration and severity of HIV disease, viral load, time since reversal of clinical progression of HIV infection, increasing age, female gender, and extreme changes in body mass index (104). Fat accumulation is correlated with female gender, low viral load, and high body mass index. Fat depletion is associated with low body mass index and the use of the nucleoside reverse transcriptase inhibitor stavudine (105).

A retrospective cohort study showed that 13% of 221 patients treated with protease inhibitor therapy for 5 years developed lipodystrophy, suggesting that the effect of antiretroviral medication may be an important contributor to the development of the syndrome (106).

Males are reported to be at greater risk of developing metabolic abnormalities, including hypertriglyceridemia, hypercholesterolemia, and hyperglycemia. Another study has suggested that mixed fat redistribution (concurrent fat wasting and fat accumulation) may be related to effective HIV suppression by combination antiretroviral therapy (107). The greatest risk factor identified thus far has been protease inhibitor use. Data from one study (96) showed that 64% of patients (74 of 116) receiving protease inhibitor therapy suffered from lipodystrophy, as opposed to only 3% of patients (1 of 32) who had never received protease inhibitor therapy.

Lipoatrophic changes are characterized by subcutaneous fat depletion in the face, arms, legs, and gluteal region. Muscles of the extremities may appear more pronounced, and veins may appear more prominent in fat-depleted regions. (The fat wasting observed in this syndrome is distinguished from other wasting conditions associated with HIV infection, including the AIDS wasting syndrome, malnutrition, cachexia, adrenal insufficiency, and severe chronic infections.) Lipohypertrophy is characterized by truncal obesity, dorsocervical fat accumulation (buffalo hump), and breast enlargement (108–112).

The lipodystrophy syndrome appears to increase risk in HIV-positive patients for cardiovascular and cerebrovascular disease (113). The hypercholesterolemia may predispose individuals to accelerated atherosclerosis and premature coronary artery disease (114–117). One retrospective study (118) of more than 1,300 patients demonstrated an increased frequency of myocardial infarction in HIV-infected patients receiving protease inhibitor therapy (119, 120).

Many HIV-infected patients may exhibit more than one risk factor for the development of coronary artery and cerebrovascular disease: hypertriglyceridemia, low high-density lipoprotein cholesterol, increased low-density lipoprotein cholesterol, elevated diastolic blood pressure, decreased tissue plasminogen activator levels, and increased plasminogen activator inhibitor–1 levels. The median time to the development of hypercholesterolemia may precede that of lipodystrophy by 3–6 months (121, 122).

It is important to consider a diagnosis of metabolic syndrome in patients receiving antiretroviral therapy who manifest insulin resistance, particularly if fat redistribution, dyslipidemia, or hyperglycemia is present. Second-generation antipsychotic medications, often prescribed for late-stage HIV-associated dementia, delirium, and psychotic disorders, can increase the risk of metabolic syndrome. Second-generation antipsychotics less associated with metabolic syndrome are ziprasidone and aripiprazole (123). Clozapine and olanzapine have been implicated in a greater risk for development of metabolic syndrome (123–126).

Currently, there are no medications or treatments approved by the U.S. Food and Drug Administration for metabolic syndrome, although the statin drugs are being used and specifically tested. There are controlled studies to suggest effective interventions to reverse the development of lipodystrophy syndrome; rosiglitazone (127) and pioglitazone are being used and specifically tested. However, use of psychiatric medications least likely to affect the metabolic parameters described above may reduce patients' risk for developing a metabolic syndrome.

The changes in body morphology may have significant psychological effects on people with HIV who are already living with a stigmatized illness. Development of lipodystrophy may contribute to nonadherence to antiretroviral medications or exacerbate mood and anxiety disorders. Psychiatrists can help patients with HIV whose treatments may adversely affect quality of life balance the competing wishes to sustain health and well-being.