US study confirms long-term use of AZT, d4T result in lipoatrophy

Long-term use of AZT or d4T results in subcutaneous fat loss in the triceps, abdomen and thigh, whereas long-term abacavir use results in significant subcutaneous fat gain in the abdomen, according to the results of CPCRA 061 – a non-randomised metabolic substudy of the FIRST (CPCRA 058) study, published in the May 1^st issue of the Journal of Acquired Immune Deficiency Syndromes.

CPCRA 058 was a large randomised controlled trial that compared dual class versus triple class therapy, and which first presented its results, reported here, at the Sixteenth International AIDS Conference in Toronto in 2006.

CPCRA 061 enrolled 422 participants (30% of the total in the FIRST study) between August 1999 and January 2002 and closed for follow-up in September 2005.

In this study, body composition measurements were performed by staff who had been extensively trained in the use of calipers to measure subcutaneous fat by assessing skinfold thickness. Five areas were measured: triceps (back of the arm), subscapular (front of the shoulder), suprascapular (rear of the shoulder/back of the neck), abdomen, and thigh.

A prior analysis of CPCRA 061, which found no major differences in the metabolic effects of some (now rarely used) protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) was published last year in the Journal of Acquired Immune Deficiency Syndromes, reported here.

In this study, the body composition effects of three nucleoside reverse transcriptase inhibitors (NRTIs) were compared: AZT (zidovudine, Retrovir, also in Combivir and Trizivir), d4T (stavudine, Zerit), and abacavir (Ziagen, also in Kivexa and Trizivir). All three arms also took the NRTI, 3TC (lamivudine, Epivir) and either a PI – most commonly nelfinavir (Viracept) or indinavir (Crixivan) – or one of the two NNRTIs, efavirenz (Sustiva) or nevirapine (Viramune).

A total of 192 participants took AZT, 63 took d4T and 53 took abacavir, and since this was not a randomised study, there were some differences in baseline demographics. Notably, individuals with a prior AIDS diagnosis and the lowest averages for weight, body mass index (BMI), and the five skinfold thicknesses were more likely to be taking d4T. Since prior AIDS was found to be associated with body composition changes, this was one of the variables adjusted for in multivariate analysis.

During the three years of follow-up, the median length of exposure to each NRTI was 2.8 years for AZT; 2.2 years for d4T; and 2.3 years for abacavir. However, the median time to a first change to the NRTI regimen was 2.2 years for AZT; 2.1 years for d4T; and 1.6 years for abavavir, suggesting that whereas the 55% of participants who switched from d4T remained off this drug, those who switched from the other two drugs (54% from AZT, number unreported from abacavir) may have subsequently restarted them.

After adjusting for age, gender, race, smoker status, prior injection drug use (IDU), prior AIDS, and viral load, the investigators found that at three areas - triceps, abdomen and thigh – subcutaneous fat losses over the study period were broadly similar for AZT and d4T, whereas abacavir resulted in subcutaneous fat gains. Subcutaneous fat loss was not seen at either the front (subscapular) or rear (suprascapular) of the shoulders on any of the three NRTIs.

For AZT, the greatest rate of subcutaneous fat loss was seen at the triceps (a rate of -9.73% per year; p<0.01), followed by the thigh (-7.53%; p<0.01) and abdomen (-5.77%; p<0.01).

For d4T, the greatest rate of subcutaneous fat loss was seen at the abdomen (-6.16%; p=0.09); followed by the thigh (-6.04%; p=0.03) and triceps (-3.14%; p=0.34), although this was not statistically significant.

The only statistically significant change seen on abacavir was subcutaneous fat gain at the abdomen (+11.91%; p<0.01).

However, even the participants on AZT and d4T gained subcutaneous fat at these three sites – triceps, abdomen and thigh – in the first twelve months, “suggesting,” write the investigators, “initial recovery after the initiation of ART followed by declines in the late period, representing the long-term treatment effect of d4T and [AZT] on body composition changes.”

“In conclusion,” they write, “this long-term nonrandomized evaluation of the effects of three different NRTI regimens in the presence of similar PI and/or NNRTI therapy identified significant subcutaneous tissue differences depending on the NRTI regimen used.”

At first, all three NRTIs were associated with improvements in body composition, they note, but with prolonged use of AZT or d4T “similar subcutaneous tissue losses were seen”, whereas with prolonged use of abacavir, “subcutaneous tissue gains were seen, reflecting differences in the long-term clinical effects of these medications.”

“The selection of an ART regimen,” they conclude, “should consider the associated toxicities (lipoatrophy with prolonged use of a thymidine analogue-based regimen), which can have a negative impact on the success of the regimen selected.”