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NRTI Exposure Tied to Age-Linked Mitochondrial DNA Deletions
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Tenth International Congress on Drug Therapy in HIV Infection, November 7-11, 2010, Glasgow
Mark Mascolini
Cumulative exposure to certain nucleosides (NRTIs) speeds accumulation of a common age-associated mitochondrial DNA (mtDNA) deletion mutation, according to results of a study calculating proportional levels of these deletions with a real-time PCR assay [1]. The UK and US investigators suggested that their findings "plausibly provide a novel biological mechanism for the phenomenon of accelerated ageing recently described in long-term treated HIV-infected patients." HIV itself did not appear to play a role in this aging mechanism.
Soon after clinical recognition of lipoatrophy in NRTI-treated people, researchers linked use of certain NRTIs to mtDNA depletion that was reversible upon withdrawal of the culprit drugs. Because progressive pile-up of molecular defects, including mtDNA mutations, drives normal aging, researchers from the Institute of Human Genetics at Newcastle University and other centers planned these experiments.
The study involved 34 HIV-positive people--22 who had taken nucleosides and 12 who had not--all of whom had a leg skeletal muscle biopsy. Everyone was 50 or younger because age-associated mitochondrial dysfunction is not expected in people this young. The investigators excluded anyone with HBV or HCV infection, diabetes mellitus, and non-HIV-related neuromuscular disorders. They stratified study participants by lifetime exposure to four NRTIs implicated in mitochondrial dysfunction--didanosine (ddI), stavudine (d4T), zalcitabine (ddC), and zidovudine (AZT).
The investigators used a real-time PCR assay to calculate the proportional level of the most frequent age-associated mtDNA common deletion, and they used an ultradeep sequencing-by-synthesis assay to gauge levels of age-associated and random mtDNA point mutations in biopsy samples. The researchers used age-matched people with inherited defects of POLG1 (which encodes mtDNA polymerase-gamma) as positive controls for increased mtDNA point mutations.
mtDNA common deletion levels were significantly higher in the 22 people exposed to NRTIs than in the 12 antiretroviral-naive people with HIV (P = 0.027). The researchers saw an increasing trend to accumulation of the mtDNA common deletion in step with increasing exposure to multiple NRTIs: AZT only versus any NRTI plus more than one of the four implicated NRTIs (P = 0.012). Duration of NRTI exposure had borderline significance in correlating with mtDNA common deletion levels (r = 0.4, P = 0.07).
Multivariate regression analysis determined that age and NRTI exposure are independently associated with accumulation of the mtDNA common deletion (r = 0.63, P < 0.01). Common deletion levels did not correlate with current CD4 count, lowest-ever CD4 count, or viral load. Levels of age-associated and random mtDNA point mutations measured by ultradeep sequencing did not differ significantly between NRTI-exposed and unexposed people.
Because levels of the most common age-associated mtDNA common deletion rose with age and NRTI exposure, the investigators suggested that "these drugs may accelerate age-associated damage in mitochondria." The lack of correlation between common deletion levels and CD4 count or viral load suggested to the researchers that higher common deletion levels "are predominantly an effect of antiretroviral drugs rather than the virus itself."
The mtDNA common deletion levels measured in these young NRTI-treated people were equivalent to those seen only in "very elderly" people without HIV, the investigators noted. They cautioned, though, that the role of this mtDNA mutation in normal aging remains unclear. Since use of the four implicated NRTIs has stopped completely or waned sharply, the implications of these results for people taking current regimens also remains uncertain.
Reference
1. Payne BAJ, Hateley CA, Samuels DC, et al. Mitochondrial ageing and antiretroviral therapy exposure. Tenth International Congress on Drug Therapy in HIV Infection. November 7-11, 2010. Glasgow. Abstract O234.
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