An Assessment of Lipodystrophy in Patients Receiving AZT or D4T regimen After Receiving AZT, DDI and/or DDC
      Reported by Jules Levin

There have been a number of studies addressing the question if certain NRTIs are associated with greater risk for lipoatrophy. There have been a number of studies associating d4T with increased risk for lipoatrophy, and a lesser number of studies have found increased risks associated with other NRTIs. None of these studies of been well designed enough to yield reliable results. At Retrovirus, Joly and colleagues from Paris reported on an analysis of 96 patients in a 150 patient study looking at whether or not d4T or AZT may contribute more to lipodystrophy. The study findings would be more conclusive if all the patients were evaluated.

To assess the incidence of clinical lipodystrophy and metabolic abnormalities in patients randomized between the AZT & d4T regimens, this analysis was recommended by the Data Safety Monitoring Board during the trial and was performed at the end of the extended follow-up, i.e. 30 months after initiation of the indinavir containing regimen. I presume the 96 patients in this analysis reflected the loss to study drop-out, but they are lost to the analysis. Joly said that since the study started in 1997, indinavir was taken three times daily without ritonavir.

So, this analysis was a cross-sectional study (a one time look) at month 30 of the study. They looked at Body Mass Index, fasting lipids & glucose, skinfold thickness (for lipoatrophy), and body changes as assessed by standard questionnaire.

NOVAVIR was a randomized, open-label, multi-center trial (started in 1997) comparing the efficacy and safety of AZT vs d4T where all participants received 3TC and indinavir. Participants were previously treated with AZT, ddI and/or ddC, but were naïve for d4T, 3TC and protease inhibitors. The months of prior NRTI use were about the same in both arms (21-24 months), but Joly did not address whether the duration of prior experience with ddI and ddC was comparable between the two arms.

Baseline CD4s & viral load, age, sex, and % of AZT mutations were comparable between the two arms. After 80 weeks the d4T arm (n=72) and the AZT arm (n=81) had a comparable percent <500 copies/ml (80%).

Joly reported that a higher proportion of patients receiving d4T than those receiving AZT (42% vs 20%) had 3 or more symptoms of lipoatrophy (fat depletion in the arms, legs, face, etc). When looking for just 1 or 2 symptoms of lipoatrophy there wasn't as much difference (28% d4T vs 22% AZT). Joly also reported females had a significantly increased risk for lipoatrophy & central fat accumulation. Central fat accumulation is discussed below. There was no difference in metabolic abnormalities between the two arms. A few flaws or limitations in the study: only 96 of 150 patients analyzed, study was not blinded and Joly did not say if the d4T recipients had more or less exposure to prior ddI or ddC therapy than the AZT recipients. Because the study was not blinded doctors conducting the skinfold measures may have known who was taking AZT or d4T. This could influence outcome, that's why studies are blinded. In addition, DEXA appears to be considered a better way to evaluate lipoatrophy and it was not used in this study. It's been suggested that skinfold measuring can be subject to tester bias.

At month 30, absolute CD4 count (549 vs 507), the cd4 increase from baseline (260 vs 237), % <500 copies/ml (79% vs 84%) and Body Mass Index (22.3 vs 22.7) were about the same in d4T and AZT arms, respectively.
Glucose and cholesterol were elevated equally in both arms. As well, triglycerides levels were comparable in the 2 arms.

Lipoatrophy - Skinfold Thickness (mm)

The only statistically significant objective measure showing a difference was the thigh skinfold. One reason all these studies have failed to detect reliable answers in which drugs may be more likely to increase risk for lipodystrophy is that the well done studies are difficult to implement and interpret. When looking at fat accumulation Joly said there was no observed difference between the 2 arms.

Joly reported an increased incidence in fat depletion (lipoatrophy) in the d4T recipients compared the AZT recipients: facial atrophy (49% vs 23%), lower limb atrophy (50% vs 22%), upper limb atrophy (30% vs 20%), buttocks atrophy (49% vs 20%), and venomegaly (veins standing out) (49% vs 22%).

Interestingly, about 30% of study patients receiving d4T did not have any lipoatrophy, and 57% receiving AZT did not have lipoatrophy. 28% receiving d4T had 1 or 2 symptoms of lipoatrophy compared to 22% of those receiving AZT. When looking at the proportion of patients with 3 or more symptoms of peripheral fat depletion, 42% vs 20% was the difference in comparing d4T vs AZT, respectively (p=0.018). And when comparing for central fat accumulation (3 or more symptoms) there was no difference between d4T & AZT. But when looking at only 1 or 2 symptoms of central fat accumulation there was a difference (42% vs 25%). Overall, 44% of patients had at least 1 sign of fat accumulation. Overall, 70% of patients in the d4T arm compared to 43% in the AZT arm had at least 1 clinical symptom of lipoatrophy.

When looking at other factors that might increase risk for lipoatrophy, being a female (0.04) was associated with increased risk, but age, baseline cd4, and baseline viral load were not. Increased age (0.018), lower baseline cd4 (0.045) and female sex (0.014) were associated with increased risk for central fat accumulation. In multivariate analysis increased age & female sex remained significant.