Mitochondrial Genotoxicity of Hepatitis C Treatment among People Who Inject Drugs.

Mélusine Durand,Didier Laureillard,Delphine Rapoud,Laurent Michel,Thanh Nham Thi Tuyet,Huong Thi Duong,Vinh Vu Hai,Jonathan Feelemyer,Nicolas Nagot,Catherine Quillet,Oanh Khuat Thi Hai,Roselyne Vallo,Philippe Vande Perre,Bình Nguyễn Thanh ,Hong Thi Tran,Pham Minh Khue ,Don Des Jarlais,Quynh Bach Thi Nhu,Linh Le Thi Thuy,Jean Pierre Molès

doi:10.3390/jcm10214824

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.

Highlights

For a decade, direct-acting antivirals (DAA) have been able to cure most hepatitis C virus (HCV)-infected patients with a strong efficacy against all HCV genotypes and a strong safety profile [1]
The mitochondrial copy number per cell (MCN) remained unchanged, whereas the proportion of detectable mitochondrial DNA (mtDNA) deletion was increased after treatment
We identified that poly-exposures to DAA and daily heroin injection or DAA and regular consumption of methamphetamine were positively associated with high MCN loss and that poly-exposure to DAA and ARV, or DAA and methadone were aggravating factors for the acquisition of mtDNA deletions

Summary

Introduction

Direct-acting antivirals (DAA) have been able to cure most HCV-infected patients with a strong efficacy against all HCV genotypes and a strong safety profile [1]. Numerous candidates have failed to complete the drug development process and have had to be stopped during phase II or III of clinical trials because of elevated toxicity, as is the case for balapiravir, for example, which caused serious adverse hematological, infectious, and ocular events, or INX-08189 (BMS-986094), which appeared cardiotoxic [3,4,5] These molecules, which acted as obligate or non-obligate chain terminators during viral replication, later appeared to be substrates of the mitochondrial RNA polymerase (PolRMT), responsible for the mitochondrial DNA (mtDNA) transcription and acting as primase to initiate mtDNA replication. The liver concentration of sofosbuvir during treatment (around 70 μM) is compatible with the concentration of the abovementioned experiments [14,15]

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