A study comparing fat loss in patients taking d4T or AZT has clearly demonstrated that treatment-naïve individuals who start treatment with a d4T-containing regimen lost approximately half their leg fat within two years of starting treatment, compared with a loss of approximately 10% in the AZT group over the same period.
The study, conducted by the Centre for Clinical Immunology and Biomedical Statistics at the Royal Perth Hospital in Western Australia, is possibly the most robust statistical analysis of differences in rates of lipoatrophy between the two nucleoside analogues, and taken together with the evidence from the ACTG 384 sub-study presented in the same session, convinced many at the Lipodystrophy Workshop that d4T carries a greater risk of fat wasting.
The study tracked 53 male treatment-naive patients who received DEXA scans at baseline and during their treatment course. This was not a randomised study; it prospectively tracked individuals who initiated treatment with regimens that contained AZT or d4T. The vast majority of patients also received 3TC. Patients were followed for at least 24 months, and the study only analysed patients who took the drug throughout the 24 months follow-up (an on–treatment analysis).
At baseline, participants had approximately 22% fat content in their legs. During the first year of treatment, individuals tended to gain weight. But as time went on, leg fat declined in both treatment groups. After 24 months, this had fallen to 13% in the d4T group and 19% in the AZT group (P
The study also evaluated the rate of fat loss in the legs compared to overall changes in body fat, and found that leg fat as a proportion of total body fat declined more steeply in the d4T group.
The researchers also analysed fat loss in 59 patients who had received prior treatment with AZT before commencing a triple HAART regimen. Those who switched to d4T after prior AZT treatment had greater fat loss and a greater decline in leg fat as a proportion of total fat than patients who continued on AZT for 30 months. This finding goes some way to refuting the view that fat loss associated with d4T in large cohort studies is attributable to prior AZT treatment or duration of nucleoside analogue exposure.
The researchers suggested that future studies should look in more detail at changes in fat over time rather than looking for the presence or absence of a diagnosis of lipoatrophy.
The same group also reported an association between a genetic mutation present in 11.4% of their patients and the risk of lipoatrophy. They looked at 220 patients, and found that presence of a mutation in the tumour necrosis factor alpha gene at position 238G/A was associated with an increased risk of lipoatrophy, and that it reinforced the effects of d4T and of age.
Nolan D et al. Effect of stavudine, zidovudine and HIV protease inhibitor therapy on subcutaneous leg fat wasting in HIV-infected males – a longitudinal study. Fourth International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, abstract 28, 2002.
Nolan D et al. Tumour necrosis factor alpha gene – 238G/A promoter polymorphism associated with more rapid onset of lipodystrophy. Fourth International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, abstract 26, 2002.