Reducing d4T dose improves mitochondrial toxicity, but not lipoatrophy

Halving the dose of d4T (stavudine, Zerit) leads to improvement in laboratory markers of lipoatrophy, but not to any real physical improvements, says a report in the April 15^th edition of Clinical Infectious Diseases.

However, given that the reduced dose maintains viral suppression, there may be hope that the tactic can improve safety for people in the developing world, who often have few other treatment options.

d4T is thought to be the worst culprit for lipoatrophy and other body composition changes associated with antiretroviral therapy. However, there is some evidence that reducing or stopping the drug can slow or halt the changes in body composition and metabolism. Lowering the dose of d4T has also been shown to help to alleviate peripheral neuropathy, another side effect of the drug.

In the current study, researchers in the eastern United States tested the hypothesis that halving the dose of d4T would impact body composition, and metabolic measures often associated with body composition changes, specifically lipid levels and markers of mitochondrial toxicity.

The open-label, randomised controlled study enrolled 24 HIV-positive participants, all of who had been taking d4T for at least 24 weeks, reported an undetectable viral load and had at least one sign of mitochondrial toxicity. Nine participants continued with their usual dose of d4T (40 or 30 mg twice daily; the full-dose arm), while 15 participants had their dose reduced by half (20 mg or 15 mg twice daily; the half-dose arm). Participants were followed for 48 weeks, with measures of CD4 count, viral load, metabolic parameters and body composition taken at the study's beginning and end.

At baseline, 21 participants had lipoatrophy, with 13 being in the half-dose arm. The groups had similar characteristics except that the half-dose arm had a higher median BMI (26.6 versus 23), total lean body mass (62 kg versus 52 kg) and triglyceride levels (175 mg/dl versus 113 mg/dl).

At week 48, viral load, which was undetectable in all participants at baseline, rose to detectable levels in four patients in the half-dose arm and two in the full-dose arm (median 972 copies/ml). These six individuals had adherence of less than 80%, compared with a more than 90% adherence level among participants who maintained an undetectable viral load. Median CD4 count (558 cells/mm³ overall) did not change significantly over the 48 weeks of treatment.

To assess mitochondrial function, researchers measured mitochondrial DNA (mtDNA) levels in fat tissue and peripheral blood mononuclear cells and blood lactate and pyruvate levels. mtDNA levels fall and blood acid levels rise as mitochondrial toxicity develops.

At week 48, the half-dose group reported significant improvements in median fat mtDNA (+40 copies/cell), fat mtDNA percentage change from baseline (+67%) and median lactate levels (-0.027 mmol/l). No changes in these parameters were seen in the full-dose arm, and there were no other significant differences in between or within groups for the duration of the study.

To evaluate body composition and metabolism, researchers measured body mass index (BMI), blood pressure and blood levels of total cholesterol, HDL cholesterol, triglycerides and glucose. Lipoatrophy and lipohypertrophy were appraised subjectively by the participant and the physician. Dual-energy x-ray absorptiometry (DEXA) was performed to measure trunk and limb fat, lean body mass and bone mineral density (BMD).

There were few significant differences in body composition markers between or within groups from the start to the end of the study. There were no significant differences between or within groups in changes in lipid levels. Notably, median BMD decreased significantly in the full-dose arm (-1.7%), while there was no change in the half-dose arm. This effect on BMD hints at a link that requires further investigation, the researchers write.

In conclusion, the authors note that halving the dose of d4T maintained viral suppression and “modestly but significantly improved mitochondrial indices without changes in body composition.” Studies of stopping d4T and replacing it with another drug have led to more pronounced gains in both mitochondrial function and body composition, and the authors suggest that dose reduction is suboptimal for countering the fat loss associated with the drug.

Nonetheless, reducing d4T dose might be an option for increasing safety of the drug, which is still widely used in the developing world due to its low cost and the lack of other options. The World Health Organization recommended in 2007 that d4T dosing should be reduced to 30mg twice a day in order to counter toxicity. However, the authors of the US study published this week remark: “caution should be exercised with regard to the extent to which it would be safe to lower the dose (15–30 mg), because this low-dose strategy may be less tolerant to breaches in treatment adherence.”