Older HIV Drugs Contribute to Accelerated Aging

SUMMARY HIV patients treated with early NRTI drugs show evidence of mitochondrial DNA damage similar to that usually seen in much older people.

As people with HIV live longer due to effective antiretroviral therapy (ART), aging has become a key concern. A growing body of evidence suggests that HIV positive people may experience faster than normal aging, characterized by premature progressive organ disease and frailty.

Early nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine (AZT; Retrovir), didanosine (ddI; Videx), and stavudine (d4T; Zerit) have been linked to mitochondrial toxicity, or damage to energy-producing structures within cells. While these drugs are no longer recommended in the U.S. and Europe, they are inexpensive and therefore still commonly used in resource-limited countries.

Study results reported recently in the advance online edition of Nature Genetics suggest that this mitochondrial DNA damage plays a role in accelerated aging. Below is an edited excerpt from a press release issued by the Wellcome Trust in the UK describing the findings.

Premature Aging Caused By Some HIV Drugs, Study Shows

June 26, 2011 -- A class of anti-retroviral drugs commonly used to treat HIV, particularly in Africa and low income countries, can cause premature ageing, according to research published today in the journal Nature Genetics. The study shows that the drugs damage DNA in the patient's mitochondria -- the "batteries" which power their cells.

The findings may explain why HIV-infected people treated with antiretroviral drugs sometimes show advanced signs of frailty and age-associated diseases such as cardiovascular disease and dementia at an early age.

Nucleoside analogue reverse-transcriptase inhibitors (NRTIs) -- of which the most well known is zidovudine, also known as AZT -- were the first class of drug developed to treat HIV. They were a major breakthrough in the treatment of the disease, greatly extending lifespan and leading the condition to be seen as a chronic, rather than terminal, condition.

In high-income countries, such as Europe and North America, the older NRTIs are used less commonly now due to concerns over toxicity and side effects when taken over a long period of time. However, as they are now off-license and hence relatively cheap, the drugs have proved to be an important lifeline for people infected with HIV in Africa and low income countries.

Professor Patrick Chinnery, a Wellcome Senior Fellow in Clinical Science from the Institute of Genetic Medicine at Newcastle University, says: "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."

Mitochondria are the "batteries" in our cells which provide them with the energy to carry out their functions. During natural human ageing, these mitochondria acquire mutations, though it is unclear whether these mutations are a cause of ageing or a consequence.

In an attempt to understand what was happening at a cellular level, Professor Chinnery and colleagues studied muscle cells from HIV-infected adults, some of whom had previously been given NRTIs.

The researchers found that patients who had been treated with NRTIs -- even as long ago as a decade previously -- had damaged mitochondria which resembled that of a healthy aged person.

"The DNA in our mitochondria gets copied throughout our lifetimes and, as we age, naturally accumulates errors," explains Professor Chinnery. "We believe that these HIV drugs accelerate the rate at which these errors build up. So over the space of, say, ten years, a person's mitochondrial DNA may have accumulated the same amount of errors as a person who has naturally aged twenty or thirty years. What is surprising, though, is that patients who came off the medication many years ago may still be vulnerable to these changes."

Co-author and HIV specialist, Dr Brendan Payne, a Medical Research Council fellow from the Department of Infection and Tropical Medicine at the Royal Victoria Infirmary, Newcastle, believes that despite the side effects caused by NRTIs, they are still important drugs and the risks are relative.

"These drugs may not be perfect, but we must remember that when they were introduced they gave people an extra ten or twenty years when they would otherwise have died," he says. "In Africa, where the HIV epidemic has hit hardest and where more expensive medications are not an option, they are an absolute necessity."

Professor Chinnery and colleagues are now looking at ways to repair or stall some of the damage caused by the medication and believe that focusing on exercise -- which appears to have a beneficial effect on patients with mitochondrial diseases -- may help.

The study was funded by the Medical Research Council, the British Infection Society, the Newcastle Healthcare Charity, the UK NIHR Biomedical Research Centre for Aging and Age-related Disease and the Wellcome Trust.

Investigator affiliations: Mitochondrial Research Group, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. Department of Infection and Tropical Medicine, Royal Victoria Infirmary, Newcastle upon Tyne, UK; Centre for Human Genetics Research, Vanderbilt University, Nashville, TN.

7/8/11

Reference
BA Payne, IJ Wilson, CA hateley, et al. Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nature Genetics (abstract). June 26, 2011 (Epub ahead of print).

Other Source
Wellcome Trust. Premature Aging Caused By Some HIV Drugs, Study Shows. Press release. June 26, 2011.