Premature to say atazanavir not linked to fat loss, says lipodystrophy expert

Doctors and patients should not assume that the absence of fat loss in a short-term study of atazanavir (Reyataz) is a reliable long-term indicator of the `fat-friendliness` of the drug, according to Dr Michael Dubé of the University of Indiana, writing in an editorial to be published in the January 15^th edition of Clinical Infectious Diseases.

Dr Dubé was commenting on an analysis of the phase III study which compared atazanavir to efavirenz in treatment-naïve patients over 48 weeks. All participants received a nucleoside analogue backbone of AZT/3TC. The study showed modest increases in body fat on both drugs as measured by DEXA scan at baseline and week 48.

Although the loss of fat seen during HIV therapy is chiefly attributable to treatment with the nucleoside analogues d4T (stavudine, Zerit) and AZT (zidovudine, Retrovir), protease inhibitors are also thought to contribute to the development of lipoatrophy. In the ACTG 384 metabolic substudy patients who received nelfinavir (Viracept) lost more body fat than those who received efavirenz (Sustiva), regardless of nucleoside analogue backbone, over 64 weeks of follow-up.

Atazanavir has been touted as the most metabolically friendly of the protease inhibitors due to its lack of effect on cholesterol, triglycerides and insulin. However its effects on body fat distribution remain unclear.

The metabolic substudy of the BMS 034 study recruited 211 patients, three quarters male, almost one third of them Hispanic and with a median CD4 cell count around 325 cells/mm³. The study lasted 48 weeks.

Paired CT scans from baseline and week 48 were available for 62 of 111 patients in the atazanavir group and 47 of 100 patients in the efavirenz group. Paired DEXA scans were available for 77 of the atazanavir group and 63 of the efavirenz group. The investigators do not explain why follow-up data for such large numbers of participants are missing, despite the fact that participating centres in the metabolic substudy were selected on their ability to carry out CT and DEXA scans.

The researchers found very modest increases in visceral (+4% ATV, +2% EFV) and subcutaneous adipose tissue (+5, +7%) in both groups at week 48 consistent with an improvement in immune function due to treatment, and there were no significant changes in the ratio of visceral or subcutaneous adipose tissue to total adipose tissue.

However, commenting on the findings Dr Michael Dubé pointed out that in the ACTG 384 metabolic substudy, fat levels began to decline before week 48 but remained significantly above the baseline level until week 64 in the d4T/ddI group – the patients at greatest risk of fat loss in that study. In the AZT/3TC group a trend towards lower limb fat levels did not become apparent until week 80.

“Because no DEXA scans were included early in the [atazanavir] study, it is possible that the limb fat findings reported at week 48 represented values that were significantly decreasing from earlier peak values that were not captured,” Dr Dubé writes.

The atazanavir study also excluded patients with baseline CD4 cell counts below 100 cells/mm³, which may have led to a lower incidence of lipoatrophy than in a real world setting, since some studies (but not all) have shown people with lowest ever CD4 cell counts below 100 to be at higher risk of developing lipoatrophy.

Although Dr Dubé describes the results as encouraging, he notes: “Longer-term follow-up studies (i.e. those with a duration of >48 weeks) with a full range of entry CD4 cell counts are needed, as are studies of the body fat effects of ritonavir-boosted atazanavir therapy and direct comparisons with other protease inhibitors, before any unique peripheral fat-sparing effects of atazanavir can be confirmed.”