Regression of lipodystrophy in HIV-infected patients under therapy with the new protease inhibitor atazanavir

Antiretroviral therapy against HIV has resulted in various metabolic alterations and body fat redistributions. The lipodystrophy syndrome is most often seen in HIV-infected patients treated with protease inhibitors (PI). Atazanavir is a novel and potent PI without relevant lipid elevations. Here, we report on three patients with rapid regression of dorsocervical and abdominal fat accumulations, respectively, after switching antiretroviral therapy from established PI to atazanavir.

Highly active antiretroviral therapy (HAART) has dramatically reduced the morbidity and mortality of HIV-infected patients [¹]. However, several metabolic side-effects have been described to be associated with long-term HAART. These include hypertriglyceridemia, hypercholesterinemia, insulin resistance, impaired glucose tolerance, and lactic acidemia. In addition, heterogenous clinical features of body fat changes can be observed frequently in patients receiving HAART. Some patients demonstrate lipoatrophic features, such as the loss of subcutaneous adipose tissue from the face (sunken cheeks) and the extremities. Frequently, patients have concomitant deposits of adipose tissue over the dorsocervical spine, called 'buffalo hump', in the intra-abdominal region, and breast enlargement. These metabolic alterations and body fat changes have been summarized in the so-called lipodystrophy syndrome, reviewed by Carr [²]. Metabolic abnormalties, especially hypertriglyceridemia, hypercholesterinemia and diabetes mellitus, may lead to an increased risk of cardiovascular disease [^3,4]. The lipodystrophy syndrome has been associated mainly with the use of protease inhibitors (PI) [⁵], but may also occur in the absence of PI [^6,7]. Therapy-associated physiognomic alterations may lead to stigmatization and thus compromised adherence to antiretroviral therapy.

Lipodystrophy is diagnosed based on the presence of lipoatrophy or fat accumulations by physical examination, technical assessments such as dual-energy X-ray absorptiometry and cross-sectional computerized tomography, and patient's report. The exact role of PI in metabolic changes and the induction of fat redistribution remains unclear. Various definitions of the lipodystrophy syndrome exist and different diagnostic tools are used. An objective case definition has recently been published, and may help to standardize the diagnosis and evaluation of lipodystrophy [⁸].

Atazanavir is a new potent and safe azapetide PI, with no clinical effect on total cholesterol and fasting triglyceride levels in HAART-naive patients [^9-11]. In HAART-experienced patients significant decreases were observed in total cholesterol, fasting LDL-cholesterol and fasting triglyceride levels [^9,10,12,13].

We report here on three HIV-infected patients, who were switched to atazanavir from established PI- containing antiretroviral regimens as a result of hyperlipidemia, and reported to the physician a reduction of fat accumulations over the dorsocervical spine, or the abdominal region, respectively.

Case reports

The three patients were treated in an early access programme of atazanavir (Bristol-Myers Squibb, Germany; Protocol AI424-900) in two medical practices and a university hospital outpatient clinic, respectively. The clinical and laboratory characteristics are given in Table 1.

Table 1

All three patients were included in the early access programme because of elevated cholesterol and triglyceride levels. After switching to atazanavir from other PI, a reduction in fasting cholesterol, LDL-cholesterol and triglyceride levels was documented. Furthermore, atazanavir achieved sustained virological control and maintained CD4 cell counts. In all patients the total bilirubin value increased under therapy with atazanavir but without clinical significance (Table 1).

All three patients experienced a decrease in their fat deposits, denoted by a reduction in their collar sizes and a newly recognised 'dent' over the dorsocervical spine (patients 1 and 3), or by a reduction in waist size (American size 31 to 29) in patient 2, respectively.

Clinical and objective signs were a regression of the fat deposits, which remained during therapy of 3 months. The body weight in all patients was stable throughout therapy with the new antiretroviral regimen (see Table 1).

Lipodystrophy is a complex and heterogenous syndrome with various metabolic alterations and clinical features in HIV-infected patients treated with antiretroviral combination drug regimens. In our three patients, the regression of either the dorsocervical fat deposit (buffalo hump) or abdominal obesity was reported after switching antiretroviral therapy from another PI- containing regimen to a therapy containing atazanavir 400 mg once a day. Clinical changes of the buffalo hump, with a reduction and a central dent over the spine and a reduced waist size, respectively, were obvious. The possibility that these changes could also be influenced by a modification of their daily activities or their diet cannot be excluded. Nonetheless, in all three patients the body weight did not decrease, suggesting that diet or modified physical activities had not had a major influence on these body changes.

In concordance with earlier observations in our three patients, fasting triglyceride and cholesterol levels decreased during therapy with atazanavir. Most notably, switching antiretroviral therapy from established PI to atazanavir led to a regression of pre-existing fat accumulations. In all three patients atazanavir was given 'unboostered', i.e. without a concomitant dose of 100 mg ritonavir. Interim results at week 16 from one study have shown a superior lipid profile for atazanavir 300 mg/ritonavir 100 mg a day or atazanavir 400 mg/saquinavir 1200 mg a day, respectively, compared with the lopinavir/ritonavir regimen [^9,10]. Whether ritonavir 100 mg has an effect on body fat accumulation is unclear.

Objective assessments of the changes in fat distributions in patients receiving atazanavir are ongoing in two studies. Preliminary analysis of one study revealed only small increases of total body fat and appendicular fat, indicating little evidence of lipdodystrophy for both atazanavir-containing and efavirenz-containing regimens [⁹].

In summary, switching to atazanavir 400 mg once a day from other PI-containing antiretroviral regimens resulted in decreases in total cholesterol and fasting triglyceride levels and in a regression of body fat accumulations, whereas the CD4 cell count and viral response were preserved. We propose that in patients with lipodystrophy syndrome, switching to atazanavir from established PI could lead to a reversal of the metabolic alterations and most notably to a rapid regression of pre-existing body fat accumulations.