People with low mitochondrial DNA content in their blood after 48 weeks of treatment with either AZT (zidovudine, Retrovir) / 3TC (lamivudine, Epivir) or d4T (stavudine, Zerit) / ddI (didanosine, Videx / VidexEC) were significantly more likely to develop lipodystrophy 18 months later, according to the results of an analysis of blood samples presented findings at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington. The researchers suggest that testing mitochondrial DNA levels may provide a useful indicator of patients at higher risk of developing lipodystrophy.
Mitochondrial function and quantity can become impaired if nucleoside analogues inhibit the activity of mitochondrial DNA polymerase gamma, a vital repair kit that removes mutations in mitochondrial DNA which might otherwise cause cells to malfunction or die. Most lipodystrophy researchers now believe that mitochondrial toxicity caused by nucleoside analogues, especially d4T and ddI when used together, is a key contributor to fat wasting, or lipoatrophy, the most distincitive form of lipodystrophy.
Measurement of mitochondrial DNA content in cells in both fat tissue and plasma (peripheral blood mononuclear cells) has been carried out by a number of research groups, but no previous analysis has looked at such a large sample of patients, nor have other research groups been able to demonstrate a predictive value to measuring mitochondrial DNA in plasma as opposed to adipose tissue.
The analysis was carried out by French researchers using stored blood samples from the ALBI study, which randomised treatment-naive patients to receive either AZT/3TC, AZT/3TC alternating with d4T/ddI, or d4T/ddI for 48 weeks. Stored samples containing peripheral blood mononuclear cells were available for 37 of 51 patients in the AZT/3TC arm and 40 of 51 patients in the d4T/ddI arm. Blood samples were drawn at baseline and when individuals had completed 48 weeks of treatment.
The researchers found that:
- The mean mitochondrial DNA content fell from 5130 copies/cell at baseline to 2450 copies/cell at week 48 (p < 0.001).
- Although mitochondrial DNA levels were not significantly different at weeks 0 and 24, by week 48 they were significantly lower in the d4T/ddI group (1950 vs. 3020 copies/cell, p < 0.03).
- Thirty-nine per cent of patients had at least one symptom of lipodystrophy 30 months after starting treatment. Forty-four per cent of these patients had mitochondrial DNA levels below 1410 copies/cell, compared to 7% of those without lipodystrophy (p = 0.03). The odds ratio (OR) of lipodystrophy at month 30 in patients with mitochondrial DNA below 1410 copies/cell was 9.8 (p = 0.02). Thirty-five per cent of those originally randomised to AZT were still taking the drug at month 30, compared to 63% of the d4T group (p = 0.001).
- Although d4T/ddI treatment was significantly associated with lipodystrophy (OR 2.3, p < 0.001), after adjustment for mitochondrial DNA at week 48, there was no significant difference in the risk of lipodystrophy in d4T/ddI-treated patients when compared to AZT/3TC-treated patients.
Evaluating mitochondrial DNA levels in this population as a predictor of lipodystrophy excludes any complicating effect of a third drug that might also influence the way in which lipodystrophy manifests itself, but does not reflect clinical practice today, nor the effect of protease inhibitors on mitcohondrial function.