Two randomised studies reported in the May 1st edition of the Journal 0f Acquired Immune Deficiency Syndromes show that modest improvements in limb fat occur within 48 weeks of switching from d4T (stavudine) to abacavir. However, the rate of fat restoration is slow, leading Australian researchers to imply that studies of the switch strategy carried out to date are too short to judge the long-term success of the strategy, and that patients should not expect to see substantial improvement within the first year of switching.
The first study, carried out by Mina John and colleagues at the Royal Perth Hospital in Western Australia, was funded by GlaxoSmith Kline to test whether switching from a regimen containing d4T and /or a protease inhibitor to one containing AZT and/or abacavir resulted in reduced fat loss after 48 weeks follow-up.
Thirty seven individuals with undetectable viral load (< 400 copies/ml) were randomised to maintain their existing PI-containing regimen (n=15) or switch to AZT/3TC/abacavir (n=22). All patients were receiving 3TC at baseline, and eight in the switch group were also receiving AZT. These patients switched from indinavir to abacavir. Of the remainder, seven patients changed d4T and nelfinavir for AZT and abacavir, while seven changed d4T and indinavir for AZT and abacavir.
There were no significant differences in CD4 cell count, fat mass, lactate, triglycerides or total cholesterol at baseline, and all metabolic parameters with the exception of triglyceride levels were within normal ranges. Total duration of prior treatment exposure was not stated, except to note that those receiving AZT at baseline had significantly longer exposure to the drug than d4T recipients (43.5 months vs 36.2 months respectively, p=0.02).
Fat changes were measured by DEXA scan at baseline, 24 and 48 weeks, with a CT scan of a single abdominal slice to measure abdominal fat changes.
After 48 weeks on the new regimen, intent to treat analysis showed that leg fat in the control group had continued to decline by an average of 10g a month, whereas it increased by an average of 7g a month in the switch group (p=0.05). The change in leg fat percentage was not statistically significant. Arm fat increased in the switch group (+12g/per month), but did not change substantially in the control group. On-treatment analysis results were substantially similar.
The extreme modesty of the fat gains recorded in this study were underlined by the on-treatment analysis of percentage fat changes. Patients who switched to abacavir gained just 95g (0.23%) in fat mass per leg after 48 weeks; in comparison, a recent study of the natural history of lipodystrophy showed that limb fat loss averaging 13% per year was being experienced by patients receiving regimens containing protease inhibitors and nucleoside analogues.
The authors point out that two processes appeared to be at work after the switch, depending on the baseline regimen. In those whose baseline regimen did not include d4T, the effect of a switch to abacavir appeared to be the sparing of further fat loss. This may be a consequence of less pronounced fat loss at baseline, and consequently, less pronounced fat gain since individuals will need to gain less in order to reach their `natural` fat equilibrium.
However, in individuals receiving d4T and a protease inhibitor at baseline, fat restoration was the predominant effect of a switch, perhaps due to more substantial fat loss.
A second observation in this study concerned the timing of fat restoration: the larger fat gain occurred after week 24, leading the authors to suggest that the rate of fat restoration may pick up speed as time goes on. Fat restoration occurs more quickly in the arms, they say, than in the legs.
No significant differences in cholesterol, triglycerides, lactate or abdominal fat emerged during the study. One patient experienced virologic rebound and three patients were forced to discontinue abacavir due to hypersensitivity reactions.
The second study, carried out by Graeme Moyle and colleagues at the Chelsea and Westminster Hospital in London, randomised 30 patients with viral load below 50 copies/ml either to switch from d4T to abacavir (group 1), to switch from a PI or NNRTI to abacavir (group 2), or to switch from d4T and a PI to AZT and abacavir (group 3). The study recruited participants with cholesterol levels above 5.2mmol/l and/or lipoatrophy who were receiving a d4T-containing regimen. This study was also part sponsored by GlaxoSmithKline.
At baseline 20 patients were receiving protease inhibitors (11 nelfinavir, six indinavir and three ritonavir/saqinavir) and ten were receiving NNRTIs (seven efavirenz and three nevirapine). Participants had received a PI or NNRTI-containing regimen for a mean of 29.7 months, and had a mean cholesterol level of 6.39 mmol/l (LDL cholesterol 4.2, HDL cholesterol 0.88, triglycerides 3.6mmol/l).
Body fat changes were monitored by DEXA scan at baseline and weeks 12, 24, 36 and 48. Leg fat increased significantly in patients who switched from d4T to abacavir (+1.08kg, or +52%) after 48 weeks, but declined slightly in those who continued d4T treatment (group 2) or switched to AZT and abacavir (group 3). Central fat, measured by CT scan, did not change significantly in any group. Patients reported no significant change in fat levels in the face, buttocks, arms or legs over 48 weeks of follow-up.
In patients who stopped taking a PI or NNRTI, LDL cholesterol levels fell substantially (-1.6, -1.1 mmol/L), as did total cholesterol (-1.7, -1.6 mmol/L), but in patients who changed from d4T to abacavir (group 1), LDL cholesterol did not fall, and total cholesterol showed a trend towards increase (+0.74mmol/l). Although measures of statistical significance are reported only for the pooled values, the authors state that the reductions in total and LDL cholesterol were significant. Triglyceride reductions in patients who continued d4T but switched from PI or NNRTI to abacavir were statistically significant. Insulin levels fell substantially in patients who replaced a protease inhibitor or NNRTI with efavirenz. All other metabolic parameters remained substantially unchanged.
“Replacing d4T with abacavir leads to improvements in limb fat mass, but these improvements are not accompanied by improvements in fasting lipids, " the authors state. "Replacement of a PI or NNRTI with abacavir is associated with improved fasting cholesterol (with trends to better triglycerides and insulin levels) but without benefits to fat mass.”
The authors speculate that since improvement in fat mass was not seen in patients who substituted AZT for d4T, thymidine analogues in general may contribute to the syndrome.
References
John M, et al. Randomized, controlled, 48 week study of switching stavudine and/or protease inhibitors to Combivir/abacavir to prevent or reverse lipoatrophy in HIV-infected patients. JAIDS 33: 29-33, 2003.
Moyle G et al. A 48 week, randomized, open label comparison of three abacavir-based substitution approaches in the management of dyslipidemia and peripheral lipoatrophy. JAIDS 33: 22-28, 2003.