Most researchers believe that protease inhibitors are implicated in HIV-associated lipodystrophy, but the precise mechanisms that cause the condition remain unknown. Lipodystrophy does not appear to vary with the use of different protease inhibitors. An increased risk of lipodystrophy is reported with the addition of nucleoside reverse transcriptase inhibitors (like stavudine) to protease inhibitor therapy compared to monotherapy with protease inhibitors (Agenerase®, Aptivus®, Crixivan®, Invirase®, Kaletra®, Lexiva®, Norvir®, Prezista®, Reyataz® and Viracept®). Two main theories exist, based on in vitro studies.
Some researchers suggest that protease inhibitors cause a decreased production of retinoic acid and triglyceride uptake. Protease inhibitors have a high affinity for HIV-1 protease, an HIV enzyme similar to two endogenous proteins involved in lipid metabolism -
cytoplasmic retinoic acid-binding protein type 1 and lipoprotein receptor-related protein. Inhibition of cytoplasmic retinoic acid-binding protein type 1 impairs the production of retinoic acid, which results in a decreased fat storage and causes adipocytes apoptosis (fat cell death), with subsequent release of lipids into the circulation. This ultimately causes lipohypertrophy (fat build up). When the lipoprotein receptor-related protein is inhibited, it causes hyperlipidemia (high cholesterol) secondary to the failure of hepatic and endothelial removal of chylomicrons (fat particles present in lymph) and fatty acids from the circulation. This ultimately causes lipoatrophy (loss of fat).
The second theory suggests that antiretroviral therapy prevents the development of adipocytes (fat cells). Antiretrovirals, such as saquinavir, ritonavir and nelfinavir, directly inhibit the development of adipocytes from stem cells and increase the metabolic destruction of fat in existing adipocytes.
HIV-associated lipodystrophy is a progressive disease. The severity of symptoms is directly proportional to the patient's age, duration of disease and length of protease inhibitor therapy. Common symptoms are limited to the skin, and the condition may be disfiguring.
Lipohypertrophy, or fat build up ("fat pad'") may develop. Common symptoms include dorsocervical fat buildup (buffalo hump on the upper back or neck), increased circumference of the neck by 5-10cm, breast hypertrophy (increase in size), and fat accumulation on the body trunk (also called a crix belly or protease paunch).
Lipoatrophy (loss of fat under the skin, especially in the limbs and cheeks) may develop. Common symptoms include loss of fat from the cheeks, arms, shoulders, thigh and buttocks (peripheral wasting). The superficial veins (close to the skin surface) at these locations become highly visible.
General: If a patient expresses clinical signs of lipodystrophy, metabolic tests may be conducted to confirm a diagnosis. Imaging studies may also be performed to obtain detailed information about the patient's fat distribution.
Cholesterol: A blood test may be conducted to determine the patient's cholesterol levels. Typically, a patient who has lipodystrophy will have a fasting cholesterol level that is greater than or equal to 5.5mmol/L, a fasting triglyceride level that is greater than or equal to 2mmol/L and increased apolipoprotein c-III and apolipoprotein E levels.
Hyperglycemia and/or hyperinsulinemia: Blood tests may be performed to determine if the patient has high levels of sugar in the blood. Patients with lipodystrophy typically have a C-peptide level that is greater than 2.5mmol/L, decreased fasting glucose (6.1-7.0mmol/L) level or diabetes mellitus with fasting blood glucose level that is greater than 7.0mmol/L. Patients may have increased levels of serum plasminogen activator inhibitor type 1, tissue-type plasminogen activator and soluble type 2 tumor necrosis factor-alpha receptor. Patients may have decreased levels of serum insulin-like growth factor binding protein type 1. Patients may have increased cortisol levels.
Imaging studies: A magnetic resonance imaging (MRI) or computerized tomography (CT) scan may detect the accumulation of visceral fat in the abdomen compared to subcutaneous fat. The organs in the abdomen are normal, and no ascites (fluid in the abdomen) is present. A dual-energy X-ray absorptiometry may detect lumbar (lower back) spine bone density reduction that is associated with increased visceral fat accumulation.
Dyslipidemia (disorders in the lipoprotein metabolism) may occur in patients who have lipodystrophy. In general, patients who develop dyslipidemia have an increased risk of developing heart disease. However, studies show that unless HIV-infected patients with dyslipidemia have other risk factors making them predisposed to heart disease (like obesity or high blood pressure) their chances of heart attack are no greater than HIV-negative people.
Lipoatrophy is associated with hyperlipidemia (high cholesterol), insulin resistance (the body does not respond properly to insulin), hyperinsulinemia (high levels of insulin in the blood) and hyperglycemia (high blood sugar, which may lead to diabetes).