Clinical Studies

ASHM, AZT and d4T are the baddies when it comes to lipoatrophy and mitochondrial toxicity

Lipoatrophy, mitochondrial toxicity and sensory neuropathy were the main topics of this paper session. Mitochondrial toxicity is caused by the inhibition of DNA polymerase gamma and this results in a reduction in mitochondrial DNA copy number. Using real-time PCR, mitochondrial DNA copy number can be a sensitive and accurate tool for diagnosing mitochondrial toxicity. With this assay, mitochondrial DNA copy number in sub-cutaneous fat is significantly correlated with the dideoxy-based NRTIs (DDx), AZT and d4T. Of these two drugs, d4T is much worse than AZT. Mitochondrial DNA copy number is significantly reduced in chronically infected patients compared to acutely infected patients, indicating that HIV itself contributes to mitochondrial toxicity. As well CD4 cell number plays a small but significant role in mitochondrial toxicity. The current studies are too small to be of clinical significance yet. Lipoatrophy is caused by the thymidine based NRTIs, which include AZT and d4T, as well as protease inhibitors. When patients withdraw from AZT/d4T therapy there is a significant improvement in limb and thigh fat. In a more detailed study where patients switches from AZT/d4T to Abacavir, there was a significant increase (0.4 kg, 10 percent) in body fat as measured by DEXA scan and CT but the rate of improvement means it would take 4 to 5 years for fat levels to normalise. Sensory neuropathy (SN) is the most common neurological complication of HIV infection. Rates are increasing as people get older and have been infected for longer, but most importantly, the DDx drugs are the greatest cause (RR=26). A pathological test is being developed based on skin biopsy. When this has been refined it could well replace the less sensitive and less specific clinical diagnosis.