Results from a recent small study indicate that certain nucleoside reverse transcriptase inhibitors, particularly zidovudine, stavudine, didanosine, and zalcitabine, may cause irreversible premature aging in people with HIV. Signs of premature aging were found even in people who were no longer taking the NRTIs.

“What is surprising…is that patients who came off the medication many years ago may still be vulnerable to these changes,” said Professor Patrick Chinnery, lead author of the study, in a press release.

The aging appears to be caused by damage to cells’ energy production units, called mitochondria.

“HIV clinics were seeing patients who had otherwise been successfully treated but who showed signs of being much older than their years. This was a real mystery. But colleagues recognized many similarities with patients affected by mitochondrial diseases – conditions that affect energy production in our cells – and referred them to our clinic,” said Prof. Chinnery.

The authors of the study are currently investigating how to repair or prevent the damage caused by the antiretrovirals. Prof. Chinnery noted that exercise has been beneficial to HIV-negative people with these mitochondrial diseases and may help people who have taken nucleoside reverse transcriptase inhibitors (NRTIs) as well.

NRTIs were the first class of drug developed to treat HIV. Today they still provide the backbone for many treatment regimens, with current U.S. guidelines recommending two NRTIs plus a third antiretroviral from a different class as the optimal treatment for HIV.

However, previous studies have shown that NRTIs, particularly older NRTIs, may cause damage to mitochondria, which are small structures within cells that supply cellular energy. According to the study authors, damage to mitochondria has been linked to premature aging.

Mitochondria damage has also been linked to heart disease, dementia, and problems such as neuropathy, a nerve condition that causes pain, numbness, or tingling in the extremities. This could be why some HIV-positive individuals taking antiretrovirals have symptoms of these diseases at an early age.

In this study, researchers investigated the effect of NRTIs on the mitochondria of HIV-positive individuals. In particular, they compared mitochondrial damage in HIV-positive people who had previously taken NRTIs to levels of damage in two groups: HIV-positive people who had not been treated and therefore were not exposed to NRTIs, and HIV-negative people.

The study included 33 HIV-positive adults 50 years of age or under and 10 HIV-negative adults who were similar in age. The researchers collected information on HIV-positive participants’ current and past antiretroviral regimens, including length of NRTI exposure. All participants with NRTI exposure had taken at least one of the following: zidovudine (Retrovir), stavudine (Zerit), didanosine (Videx), or zalcitabine (Hivid).

The researchers also collected small tissue samples from participants’ muscles to examine their mitochondria and the DNA inside the mitochondria. Mitochondria have their own DNA, which is separate from the cell’s normal DNA.

Results showed that participants who had been treated with NRTIs showed more signs of damaged mitochondria than participants who had not been exposed to NRTIs or who were HIV negative. In particular, participants who had been treated with NRTIs had levels of a mitochondrial DNA mutation tied to aging that were similar to those in very elderly healthy adults.

The mutation, called the ‘common deletion,’ occurs spontaneously in adults as they get older and builds up over time. The mutation is irreversible and is thought to lead to many of the symptoms of aging.

Further analysis showed that NRTI exposure did not appear to cause the mitochondrial DNA to mutate faster or more often. Instead, the researchers hypothesized that the drugs caused DNA that had already mutated naturally to copy itself more often, resulting in a greater overall amount of mutated DNA.

The researchers noted that this may be why complications of NRTI treatment that are related to the mitochondria, such as neuropathy, are more common in older HIV-positive adults, who already have a larger number of these mutations.

For more information, please see the study in Nature Genetics (abstract).