{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:23:49Z","timestamp":1791591829175,"version":"4.3.4"},"reference-count":42,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T00:00:00Z","timestamp":1634688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["R01DA041978"],"award-info":[{"award-number":["R01DA041978"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003323","name":"Agence Nationale de Recherches sur le Sida et les H\u00e9patites Virales","doi-asserted-by":"publisher","award":["#12353, #12380"],"award-info":[{"award-number":["#12353, #12380"]}],"id":[{"id":"10.13039\/501100003323","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/jcm10214824","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T21:29:46Z","timestamp":1634765386000},"page":"4824","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mitochondrial Genotoxicity of Hepatitis C Treatment among People Who Inject Drugs"],"prefix":"10.3390","volume":"10","author":[{"given":"M\u00e9lusine","family":"Durand","sequence":"first","affiliation":[{"name":"Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, 34394 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Nagot","sequence":"additional","affiliation":[{"name":"Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, 34394 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quynh Bach Thi","family":"Nhu","sequence":"additional","affiliation":[{"name":"Faculty of Public Health, Hai Phong University of Medicine and Pharmacy, Haiphong 04212, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2447-6754","authenticated-orcid":false,"given":"Roselyne","family":"Vallo","sequence":"additional","affiliation":[{"name":"Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, 34394 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linh Le Thi","family":"Thuy","sequence":"additional","affiliation":[{"name":"Faculty of Public Health, Hai Phong University of Medicine and Pharmacy, Haiphong 04212, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huong Thi","family":"Duong","sequence":"additional","affiliation":[{"name":"Faculty of Public Health, Hai Phong University of Medicine and Pharmacy, Haiphong 04212, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binh Nguyen","family":"Thanh","sequence":"additional","affiliation":[{"name":"Faculty of Public Health, Hai Phong University of Medicine and Pharmacy, Haiphong 04212, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Rapoud","sequence":"additional","affiliation":[{"name":"Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, 34394 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Quillet","sequence":"additional","affiliation":[{"name":"Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, 34394 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong Thi","family":"Tran","sequence":"additional","affiliation":[{"name":"Faculty of Public Health, Hai Phong University of Medicine and Pharmacy, Haiphong 04212, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2000-7838","authenticated-orcid":false,"given":"Laurent","family":"Michel","sequence":"additional","affiliation":[{"name":"CESP UMR1018, Paris Saclay, Pierre Nicole Center, French Red Cross, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanh Nham Thi","family":"Tuyet","sequence":"additional","affiliation":[{"name":"Supporting Community Development Initiatives, Hanoi 11513, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oanh Khuat Thi","family":"Hai","sequence":"additional","affiliation":[{"name":"Supporting Community Development Initiatives, Hanoi 11513, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6130-7864","authenticated-orcid":false,"given":"Vinh Vu","family":"Hai","sequence":"additional","affiliation":[{"name":"Infectious & Tropical Diseases Department, Viet Tiep Hospital, Haiphong 04708, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Feelemyer","sequence":"additional","affiliation":[{"name":"School of Global Public Health, New York University, New York, NY 10003, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe Vande","family":"Perre","sequence":"additional","affiliation":[{"name":"Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, 34394 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don Des","family":"Jarlais","sequence":"additional","affiliation":[{"name":"School of Global Public Health, New York University, New York, NY 10003, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2974-3484","authenticated-orcid":false,"given":"Khue Pham","family":"Minh","sequence":"additional","affiliation":[{"name":"Faculty of Public Health, Hai Phong University of Medicine and Pharmacy, Haiphong 04212, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0104-9047","authenticated-orcid":false,"given":"Didier","family":"Laureillard","sequence":"additional","affiliation":[{"name":"Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, 34394 Montpellier, France"},{"name":"Infectious & Tropical Diseases Department, Caremeau University Hospital, 30029 N\u00eemes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6863-6350","authenticated-orcid":false,"given":"Jean-Pierre","family":"Mol\u00e8s","sequence":"additional","affiliation":[{"name":"Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, University of Antilles, 34394 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1002\/hep.31060","article-title":"Hepatitis C Guidance 2019 Update: American Association for the Study of Liver Dis-eases\u2013Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection","volume":"71","author":"Ghany","year":"2020","journal-title":"Hepatology"},{"key":"ref_2","unstructured":"World Health Organization (WHO) (2021, September 28). Viral Hepatitis 2016\u20132021: Towards Ending Viral Hepatitis. Available online: https:\/\/apps.who.int\/iris\/bitstream\/handle\/10665\/246177\/WHO-HIV-2016.06-eng.pdf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S1665-2681(19)31482-6","article-title":"Balapiravir plus peginterferon alfa-2a (40KD)\/ribavirin in a randomized trial of hepatitis C genotype 1 patients","volume":"11","author":"Nelson","year":"2012","journal-title":"Ann. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1517\/13543784.2015.982274","article-title":"Discontinued drugs in 2012\u20132013: Hepatitis C virus infection","volume":"24","author":"Gentile","year":"2015","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1128\/AAC.01922-15","article-title":"Role of mitochondrial RNA polymerase in the toxicity of nucleotide inhibitors of hepatitis C virus","volume":"60","author":"Feng","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Arnold, J.J., Sharma, S., Feng, J.Y., Ray, A.S., Smidansky, E.D., Kireeva, M., Cho, A., Perry, J., Vela, J.E., and Park, Y. (2012). Sensitivity of Mitochondrial Transcription and Resistance of RNA Polymerase II Dependent Nuclear Transcription to Antiviral Ribonucleosides. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1003030"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.antiviral.2017.04.005","article-title":"Structure-activity relationship analysis of mito-chondrial toxicity caused by antiviral ribonucleoside analogs","volume":"143","author":"Jin","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"40847","DOI":"10.1074\/jbc.M106743200","article-title":"Toxicity of Antiviral Nucleoside Analogs and the Human Mitochondrial DNA Polymerase","volume":"276","author":"Johnson","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.1172\/JCI120842","article-title":"The role of mitochondria in aging","volume":"128","author":"Jang","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.tox.2017.07.019","article-title":"Mitochondrial fusion, fission, and mitochondrial toxicity","volume":"391","author":"Meyer","year":"2017","journal-title":"Toxicology"},{"key":"ref_11","unstructured":"(2021, September 28). Sovaldi|European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/sovaldi#product-information-section."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1055\/a-1117-3004","article-title":"Contrasting Role of Dose Increase in Modulating Sofosbuvir-Induced Hepato-cyte Toxicity","volume":"70","author":"Yousefsani","year":"2020","journal-title":"Drug Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.1111\/1751-7915.13904","article-title":"Profiling the physiological pitfalls of anti-hepatitis C direct-acting agents in budding yeast","volume":"14","author":"Yahya","year":"2021","journal-title":"Microb. Biotechnol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1007\/s40262-015-0261-7","article-title":"Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir","volume":"54","author":"Kirby","year":"2015","journal-title":"Clin. Pharmacokinet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e02587-17","DOI":"10.1128\/AAC.02587-17","article-title":"Sofosbuvir and ribavirin liver pharmacokinetics in patients infected with hepatitis C virus","volume":"62","author":"Babusis","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_16","unstructured":"UNODC (2020, April 07). Drugs Data Base. Available online: https:\/\/dataunodc.un.org."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1007\/s00705-020-04716-1","article-title":"Global prevalence of HCV and\/or HBV coinfections among people who inject drugs and female sex workers who live with HIV\/AIDS: A systematic re-view and meta-analysis","volume":"165","author":"Rashti","year":"2020","journal-title":"Arch. Virol."},{"key":"ref_18","first-page":"38","article-title":"Towards HCV elimination among people who inject drugs in Hai Phong, Vietnam: Study protocol for an effectiveness-implementation trial evaluating an integrated model of HCV care (DRIVE-C: DRug use & Infections in ViEtnam-hepatitis C)","volume":"139","author":"Rapoud","year":"2020","journal-title":"BMJ Open"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"74","DOI":"10.3389\/fmolb.2017.00074","article-title":"Off-target effects of drugs that disrupt human mitochondrial DNA maintenance","volume":"4","author":"Young","year":"2017","journal-title":"Front. Mol. Biosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.4161\/auto.25468","article-title":"Decreased mitochondrial DNA copy number in the hippocampus and peripheral blood during opiate addiction is mediated by autophagy and can be salvaged by melatonin","volume":"9","author":"Feng","year":"2013","journal-title":"Autophagy"},{"key":"ref_21","first-page":"993","article-title":"Human Immunodeficiency Virus Type 1 gp120 and Tat Induce Mitochondrial Frag-mentation and Incomplete Mitophagy in Human Neurons","volume":"92","author":"Spector","year":"2018","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e90427","DOI":"10.1172\/jci.insight.90427","article-title":"Amphetamines promote mitochondrial dysfunc-tion and DNA damage in pulmonary hypertension","volume":"2","author":"Chen","year":"2017","journal-title":"JCI Insight"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.4049\/jimmunol.0903691","article-title":"Methamphetamine Causes Mitrochondrial Oxidative Damage in Human T Lymphocytes Leading to Functional Impairment","volume":"185","author":"Potula","year":"2010","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1097\/QAD.0000000000001027","article-title":"Mitochondrial injury and cogni-tive function in HIV infection and methamphetamine use","volume":"30","author":"Var","year":"2016","journal-title":"AIDS"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"25186","DOI":"10.1038\/srep25186","article-title":"Digital PCR methods improve detec-tion sensitivity and measurement precision of low abundance mtDNA deletions","volume":"6","author":"Belmonte","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_26","unstructured":"(2021, April 08). MITOMAP: A Human Mitochondrial Genome Database. Available online: http:\/\/www.mitomap.org."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"E45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT\u2013PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1001\/archinte.158.16.1789","article-title":"The AUDIT alcohol consumption questions (AUDIT-C): An effective brief screening test for problem drinking","volume":"158","author":"Bush","year":"1998","journal-title":"Arch. Intern. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1146\/annurev.genet.39.110304.095751","article-title":"A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine","volume":"39","author":"Wallace","year":"2005","journal-title":"Annu. Rev. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Schank, M., Zhao, J., Moorman, J.P., and Yao, Z.Q. (2021). The Impact of HIV- and ART-Induced Mitochondrial Dysfunction in Cellular Senescence and Aging. Cells, 10.","DOI":"10.3390\/cells10010174"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s40139-013-0024-9","article-title":"Interactions between Hepatitis C Virus and Mitochondria: Impact on Pathogenesis and Innate Immunity","volume":"1","author":"Wang","year":"2013","journal-title":"Curr. Pathobiol. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1089\/gtmb.2015.0132","article-title":"Mitochondrial DNA Copy Number in Egyptian Patients with Hepatitis C Vi-rus-Related Hepatocellular Carcinoma","volume":"19","author":"Hashad","year":"2015","journal-title":"Genet. Test. Mol. Biomark."},{"key":"ref_33","first-page":"2451","article-title":"Potential diagnostic and prognostic value of lymphocytic mitochondrial DNA deletion in relation to folic acid status in HCV-related hepatocellular carcinoma","volume":"18","author":"Zekri","year":"2017","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1093\/infdis\/jiy658","article-title":"Association between HIV infection and mitochondrial DNA copy number in peripheral blood: A population-based, prospective cohort study","volume":"219","author":"Sun","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1146\/annurev-med-042909-093756","article-title":"HIV infection, inflammation, immunosenescence, and aging","volume":"62","author":"Deeks","year":"2011","journal-title":"Annu. Rev. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.bbadis.2010.07.024","article-title":"Methadone induces necrotic-like cell death in SH-SY5Y cells by an impairment of mitochondrial ATP synthesis","volume":"1802","author":"Perez","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.brainresbull.2021.03.009","article-title":"The effects of morphine, methadone, and fentanyl on mi-tochondria: A live cell imaging study","volume":"171","author":"Nylander","year":"2021","journal-title":"Brain Res. Bull."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/liv.14283","article-title":"Direct-acting antiviral interactions with opioids, alcohol or illicit drugs of abuse in HCV-infected patients","volume":"40","author":"Lorenzini","year":"2020","journal-title":"Liver Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1159\/000491646","article-title":"Daclatasvir Plasma Levels in a Cohort of Patients with Hepatitis C Virus Infection Taking Methadone: A Prospective Analysis","volume":"24","author":"Boglione","year":"2018","journal-title":"Eur. Addict. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1016\/j.bbagrm.2012.04.002","article-title":"Human mitochondrial RNA polymerase: Structure-function, mechanism and inhibition","volume":"1819","author":"Arnold","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Monnin, A., Nagot, N., Eymard-Duvernay, S., Meda, N., Tumwine, J.K., Tyllesk\u00e4r, T., Van De Perre, P., and Mol\u00e8s, J.-P. (2020). Health Outcomes at School Age among Children Who Are HIV-Exposed but Uninfected with Detected Mitochondrial DNA Depletion at One Year. J. Clin. Med., 9.","DOI":"10.3390\/jcm9113680"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e1189","DOI":"10.1542\/peds.2008-2771","article-title":"Antiretroviral Exposure and Lymphocyte mtDNA Content among Uninfected Infants of HIV-1-Infected Women","volume":"124","author":"Aldrovandi","year":"2009","journal-title":"Pediatrics"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/21\/4824\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:19:40Z","timestamp":1760167180000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/21\/4824"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,20]]},"references-count":42,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["jcm10214824"],"URL":"https:\/\/doi.org\/10.3390\/jcm10214824","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,20]]}}}