Mitochondrial damage and lactic acidosis

April 2001     View PDF     En español

How anti-HIV drugs affect mitochondria

Mitochondria need an enzyme called polymerase gamma to reproduce. Almost all nucleoside analogue drugs (NRTIs) such as Epivir (lamivudine, 3TC), HIVID (zalcitabine, ddC), Retrovir (zidovudine, AZT), Videx (didanosine, ddI), Zerit (stavudine, d4T), and Ziagen (abacavir) interfere with polymerase gamma to some degree. As a result, the NRTI class of drugs can block the production of new mitochondria, which then results in lower numbers of mitochondria and interference with their ability to function normally.

Among the nucleoside analogues, lab studies suggest HIVID and Videx interfere the most with polymerase gamma followed by Zerit. Lab studies also suggest that ddC and Zerit are the strongest blockers of making new mitochondria (Videx wasn’t studied). However, lab studies may not accurately predict what happens in the body. The other three nucleoside analogues are rather weak in this regard. It’s not known whether using nucleoside analogues together interferes with this enzyme synergistically (where 1+1 = more than 2). At least one group of researchers claims Zerit is most commonly related to mitochondrial damage in people, though others do not accept this finding.

Early results from a small study show that people on NRTIs have fewer mitochondria in cells compared to HIV-positive people not taking NRTIs or HIV-negative people. Fewer mitochondria were only seen among people taking Zerit and not among people on other NRTIs. The average number of mitochondria decreased by 44%. One interesting but unexplained observation was that people with fat loss in the face, arms or legs (lipoatrophy) had fewer mitochondria while people who developed a buffalo hump had an increased number.

Another recent study also looked at the number of mitochondria in cells. Forty people participated, ten with fat wasting (group A), ten without signs of fat redistribution (B), ten never on anti-HIV therapy (C) and ten HIV-negative people (D). The number of mitochondria was looked at from tissue samples from the back of the neck, abdomen and mid-thigh.

The study found that people in group A had fewer mitochondria than those in group B who, in turn, had fewer mitochondria than groups C or D. No differences in the number of mitochondria were found in cells between groups C or D. This study suggests that fewer mitochondria result from anti-HIV therapy and not HIV disease itself.