Mitochondrial Genotoxicity of Hepatitis C Treatment among People Who Inject Drugs

Abstract

Antiviral nucleoside analogues (ANA) are newly used therapeutics acting against the hepatitis C virus (HCV). This class of drug is well known to exhibit toxicity on mitochondrial DNA (mtDNA). People who inject drugs (PWID) are particularly affected by HCV infection and cumulated mitotoxic drug exposure from HIV treatments (antiretrovirals, ARV) and other illicit drugs. This study aims to explore the impact of direct-acting antiviral (DAA) treatments on mtDNA among PWID. A total of 470 actively injecting heroin users were included. We used quantitative PCR on whole blood to determine the mitochondrial copy number per cell (MCN) and the proportion of mitochondrial DNA deletion (MDD). These parameters were assessed before and after DAA treatment. MDD was significantly increased after HCV treatment, while MCN did not differ. MDD was even greater when subjects were cotreated with ARV. In multivariate analysis, we identified that poly-exposure to DAA and daily heroin injection or regular consumption of methamphetamines were positively associated with high MCN loss while DAA and ARV treatments or methadone use were identified as risk factors for having mtDNA deletion. These observations deserve attention since they were previously associated with premature cell ageing or cell transformation and therefore call for a long-term follow-up.

Oxidative Stress Induces Mitochondrial Compromise in CD4 T Cells From Chronically HCV-Infected Individuals

“…Several variables may contribute to mitochondrial dysfunction during HCV infection. For instance, DAA therapies target HCV via inhibiting the viral protease or polymerases; however, evidence has suggested that they also inhibit the function of cellular DNA polymerases, including DNA polymerase gamma (Polg), which is critical for replication of the mitochondrial genome (63)(64)(65). In this study, our HCV patients were all DAA-treatment naïve, suggesting that our observations of reduced mtDNA content in our cohort was primarily due to the HCV infection.…”

Long-Term Persistence of Mitochondrial DNA Instability among HCV-Cured People Who Inject Drugs

“…A detailed description of the assays has previously been published [ 8 ]. Succinctly, blood samples were collected on dried blood spot cards (DBS, WhatmanTM 903, GE Healthcare Bio-Sciences Corp.) and DNA was extracted using QIAamp DNA Mini kit (Qiagen, Courtaboeuf, France).…”

“…The percentage of MDD was obtained by relative quantification of two qPCRs (2 -ΔΔCt method), one targeting the region which encompasses more than 85% of the known mtDNA deletions and one targeting a very constant region, using DNA extracted from plasma-rich platelets as a calibrator. The MDD rate is the ratio of mutated mtDNA to total mtDNA and is expressed as a percentage [ 8 ].…”

“…This population is well known for its characteristically high prevalence of HCV infection and constitutes one of the key target populations to achieve HCV elimination, as stipulated by the World Health Assembly in the first Global Health Sector Strategy on Viral Hepatitis 2016–2021 [ 7 ]. Moreover, this population is continuously exposed to several other genotoxicants that might increase the risk of genetic instability [ 8 ]. Overall, we found that the variation in mtDNA copy per cell (MCN) did not differ significantly before and after treatment, while the proportion of detectable mtDNA deletions (MDD) increased after treatment.…”

“…Overall, we found that the variation in mtDNA copy per cell (MCN) did not differ significantly before and after treatment, while the proportion of detectable mtDNA deletions (MDD) increased after treatment. Combined exposition of DAA with other illicit drugs may explain some of these variations [ 8 ].…”