Older HIV Drugs Like AZT Cause Premature Aging

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The first class of drugs developed to treat HIV, which includes zidovudine (AZT), stavudine, and lamivudine, can both extend patients’ lifespan and cause premature aging. New research appearing in Nature Genetics reports that the older HIV drugs damage the DNA in the energy sources of cells—the mitochondria.

The flipside of life-extending HIV drugs

In the new study, a scientific team from various institutions evaluated muscle cells from adults who had HIV, some of whom had been treated with the older antiretroviral drugs, known as nucleoside analogue reverse-transcriptase inhibitors (NRTIs). The researchers found that even in patients who had been treated with NRTIs up to ten years ago, there was mitochondrial damage similar to that of a healthy aged individual.

According to one of the authors, Patrick Chinnery, a Wellcome Senior Fellow in Clinical Science from the Institute of Genetic Medicine at Newcastle University, DNA in the mitochondria accumulate errors either as a cause or a consequence of aging. He and his colleagues “believe that these HIV drugs accelerate the rate at which errors build up.”

Over time, the researchers believe that use of these HIV drugs results in an accumulation of “the same amount of errors as a person who has naturally aged twenty or thirty years.” Chinnery also noted that he and his colleagues were surprised that even when patients had stopped taking the drugs years ago they “may still be vulnerable to these changes.”

The ability of NRTIs to affect the mitochondria has been studied for more than a decade. In 2000, for example, a study published in The Lancet entitled “Toxicity of Nucleoside-Analogue Reverse-Transcriptase Inhibitors” noted that “NRTIs do inhibit mitochondrial DNA synthesis but may also interfere with mitochondrial RNA formation.”

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In a subsequent study (Laboratory Investigation) in 2005, researchers conducted a mouse study and compared antiretroviral combinations that did and did not contain NRTIs. They found that mice treated with NRTIs showed cardiomyopathy and worse mitochondrial defects, compared with no cardiac changes in the mice not treated with NRTIs.

Researchers with the new study note that their findings may explain why people with HIV who take NRTIs sometimes develop age-related diseases at an early age.

Even though older NRTIs are much less costly than newer HIV drugs, they are used less often in developed countries because they are associated with side effects. In poor regions of the world, however, such as Africa, the older HIV drugs are used extensively.

HIV specialist Dr. Brendan Payne, of the Department of Infection and Tropical Medicine at the Royal Victoria Infirmary and a coauthor of the study, noted that “In Africa, where the HIV epidemic has hit hardest and where more expensive medications are not an option, they are an absolute necessity.”

Given the apparent premature aging effect of the older HIV drugs, the study’s authors are investigating how to stall or fix some of the adverse impact of these medications. One possibility is exercise, which has been shown to help people who have mitochondrial diseases.

SOURCES:
Lewis W et al. Laboratory Investigation 2005; 85(85): 972-81
Walker UA et al. The Lancet 2000 Mar 25; 355(9209): 1096
Wellcome Trust release

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