Cross-country migration linked to people who inject drugs challenges the long-term impact of national HCV elimination programmes
2019; Elsevier BV; Volume: 71; Issue: 6 Linguagem: Inglês
10.1016/j.jhep.2019.08.010
ISSN1600-0641
AutoresBram Vrancken, Lize Cuypers, Ana Belén Pérez, Natalia Chueca, Joaquin Anton-Basantas, Alberto de la Iglesia, Javier Fuentes, Juan A. Pineda, Francisco Téllez, Enrique Bernal, Pilar Rincón, Miguel Angel Von Wichman, Ana Fuentes, Francisco Jesús Vera, Antonio Rivero‐Juárez, Miguel Jiménez, Anne–Mieke Vandamme, Féderico García,
Tópico(s)HIV, Drug Use, Sexual Risk
ResumoResponse to direct-acting antiviral therapy among ongoing drug users and people receiving opioid substitution therapyJournal of HepatologyVol. 71Issue 1PreviewThe epidemic of hepatitis C virus (HCV) infection has been driven in many countries by parenteral transmission through shared needles among people who inject drugs (PWID).1,2 Some reports have found that many PWID have a high willingness to receive HCV treatment.3,4 However, treatment uptake in the interferon era among PWID was very low, with about 1–2% of all HCV-infected PWID treated yearly.5,6 Most probably, this low incorporation of PWID to HCV treatment was due to barriers at different levels, including the poor tolerability of interferon. Full-Text PDF Reply to: “Cross-country migration linked to people who inject drugs challenges the long-term impact of national HCV elimination programmes”Journal of HepatologyVol. 71Issue 6PreviewWe appreciate the interest and comments by Vrancken et al. They had previously found that the most prevalent HCV genotype in Spain, genotype 1a, was linked to transmission networks outside the country.1 Specifically, the origin of those strains could be traced to a number of European countries, including France, Germany and Italy among others.1 In their letter, Vrancken et al. expand their data to HCV genotype 3a, most frequently found among people who inject drugs (PWID) in Spain. This is very relevant information. Full-Text PDF As of 2018, the majority of Western European countries – including Spain – have lifted restrictions to therapy based on disease severity in the context of HCV infections.[1]Marshall A.D. Pawlotsky J.M. Lazarus J.V. Aghemo A. Dore G.J. Grebely J. The removal of DAA restrictions in Europe – One step closer to eliminating HCV as a major public health threat.J Hepatol. 2018; 69: 1188-1196Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Long overdue, most national elimination programmes now also include access to care for people who inject drugs (PWID),[2]Lazarus J.V. Safreed-Harmon K. Stumo S.R. Jauffret-Roustide M. Maticic M. Reic T. et al.Restrictions on access to direct-acting antivirals for people who inject drugs: the European Hep-CORE study and the role of patient groups in monitoring national HCV responses.Int J Drug Policy. 2017; 47: 47-50Crossref PubMed Scopus (19) Google Scholar who are at the core of ongoing HCV transmission.[3]Robaeys G. Bielen R. Azar D.G. Razavi H. Nevens F. Global genotype distribution of hepatitis C viral infection among people who inject drugs.J Hepatol. 2016; 65: 1094-1103Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Macías et al.[4]Macías J. Morano L.E. Téllez F. Granados R. Rivero-Juárez A. Palacios R. et al.Response to direct-acting antiviral therapy among ongoing drug users and people receiving opioid substitution therapy.J Hepatol. 2019; 71: 45-51Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar have recently shown in this Journal that high viral cure rates can be achieved in this group, hereby providing evidence that targeting PWID in treatment programmes is worthwhile. However, the extent to which such national efforts can reduce the HCV burden not only depends on the uptake into care and treatment success rates, it is also determined by the relative importance of within-country transmission and virus importation from elsewhere. As the chronic nature of most HCV infections hampers reliably reconstructing contact networks from patient interviews, virus genetic data can be a valuable alternative source of information for elucidating the geographic history of virus lineages (e.g. 5Cuypers L. Vrancken B. Fabeni L. Marascio N. Cento V. Di Maio V.C. et al.Implications of hepatitis C virus subtype 1a migration patterns for virus genetic sequencing policies in Italy.BMC Evol Biol. 2017; 17: 70Crossref PubMed Scopus (18) Google Scholar, 6Al-Qahtani A.A. Baele G. Khalaf N. Suchard M.A. Al-Anazi M.R. Abdo A.A. et al.The epidemic dynamics of hepatitis C virus subtypes 4a and 4d in Saudi Arabia.Sci Rep. 2017; 7: 44947Crossref PubMed Scopus (20) Google Scholar). Using such data, we have recently shown that for the most prevalent subtype among PWID in Spain (40%,[7]Aguilera A. Navarro D. Rodríguez-Frias F. Viciana I. Martínez-Sapiña A.M. Rodríguez M.J. et al.Prevalence and distribution of hepatitis C virus genotypes in Spain during the 2000–2015 period (the GEHEP 005 study).J Viral Hepat. 2017; 24: 725-732Crossref PubMed Scopus (21) Google Scholar), HCV1a, infections often link to infections abroad – in recent years >50% link to Western European countries, mostly European Union (EU) member states – as opposed to other infections within Spain.[8]Pérez A.B. Vrancken B. Chueca N. Aguilera A. Reina G. García-del Toro M. et al.Increasing importance of European lineages in seeding the hepatitis C virus subtype 1a epidemic in Spain.Eurosurveill. 2019; 24Crossref Scopus (13) Google Scholar Hence, reducing HCV1a prevalence and spread across Europe will help to consolidate the impact of Spanish efforts to reduce the HCV burden. To investigate whether this is a general pattern that also holds for the second most prevalent subtype among PWID in Spain (26.5%,[7]Aguilera A. Navarro D. Rodríguez-Frias F. Viciana I. Martínez-Sapiña A.M. Rodríguez M.J. et al.Prevalence and distribution of hepatitis C virus genotypes in Spain during the 2000–2015 period (the GEHEP 005 study).J Viral Hepat. 2017; 24: 725-732Crossref PubMed Scopus (21) Google Scholar), HCV3a, we analysed newly generated HCV3a genome data covering parts of the NS5A and/or NS5B genes from 196 HCV3a-infected patients sampled between April 2014 and April 2017 across Spain (GenBank: accession numbers MN227780 - MN228016). Of the 60% for whom information on the probable route of transmission was available, 81.8% reported injecting drug use. These sequences were complemented with a background dataset of publicly available data from GenBank (totalling 2752 taxa), and analysed as previously described.5Cuypers L. Vrancken B. Fabeni L. Marascio N. Cento V. Di Maio V.C. et al.Implications of hepatitis C virus subtype 1a migration patterns for virus genetic sequencing policies in Italy.BMC Evol Biol. 2017; 17: 70Crossref PubMed Scopus (18) Google Scholar, 8Pérez A.B. Vrancken B. Chueca N. Aguilera A. Reina G. García-del Toro M. et al.Increasing importance of European lineages in seeding the hepatitis C virus subtype 1a epidemic in Spain.Eurosurveill. 2019; 24Crossref Scopus (13) Google Scholar The Ethics Committee of the San Cecilio Hospital, Granada, approved the study, and no informed consent was required as patient information was anonymised and de-identified prior to analysis. As for HCV1a,[8]Pérez A.B. Vrancken B. Chueca N. Aguilera A. Reina G. García-del Toro M. et al.Increasing importance of European lineages in seeding the hepatitis C virus subtype 1a epidemic in Spain.Eurosurveill. 2019; 24Crossref Scopus (13) Google Scholar we found that the transmission network size structure is not dominated by a few large exclusively Spanish transmission networks, meaning that HCV3a transmission hot spots in Spain more often bridge to networks abroad rather than being connected domestically. Whereas we previously found an increasing importance of European lineages in seeding the HCV1a epidemic in Spain,[8]Pérez A.B. Vrancken B. Chueca N. Aguilera A. Reina G. García-del Toro M. et al.Increasing importance of European lineages in seeding the hepatitis C virus subtype 1a epidemic in Spain.Eurosurveill. 2019; 24Crossref Scopus (13) Google Scholar our current reconstructions showed that HCV3a virus movements from within the EU account for ~85% of all migrations towards Spain, with little fluctuation over time. The number of imported HCV3a infections per year from other EU member states – which is a lower bound estimate – has increased on average by 1 to 4 per year, totalling 125 (95% credible interval: 92–158) introductions (Fig. 1). The trend and magnitude are similar to those for HCV1a, for which the number of lineage introductions totals 114 (95% credible interval: 72–156) (Fig. 1). The Spanish national strategy against HCV is based on a combination of factors, including a focus on increased screening and diagnosis, enhancing the treatment infrastructure, the availability of improved therapeutic regimens and targeting the groups at highest risk of transmitting HCV, including PWID.9European Liver Patients’ Association. The 2016 Hep-CORE report: Monitoring the implementation of hepatitis B and C policy recommendations in Europe. 2017. Available from: http://elpa-info.org/index.php/project/hep-core-study.Google Scholar, 10Grebely J. Matthews G.V. Lloyd A.R. Dore G.J. Elimination of hepatitis C virus infection among people who inject drugs through treatment as prevention: feasibility and future requirements.Clin Infect Dis. 2013; 57: 1014-1020Crossref PubMed Scopus (88) Google Scholar, 11Ministry of Health, Social Services and Equality: Office of the secretary for Health and Consumer Affairs. Strategic plan for tackling Hepatitis C in the Spanish national health system. 2015, May 21.Google Scholar Despite existing challenges and policy differences between regions, this multifactorial approach has led to Spain being one of the few countries in Europe that are reported to be on track to meet the World Health Organization HCV elimination targets by 2030.[12]Polaris Observatory. Center for Disease Analysis. Available from: http://cdafound.org/polaris/.Google Scholar As more recent subtype 1a and 3a infections are associated with illicit (injecting) drug use (e.g. [3]Robaeys G. Bielen R. Azar D.G. Razavi H. Nevens F. Global genotype distribution of hepatitis C viral infection among people who inject drugs.J Hepatol. 2016; 65: 1094-1103Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar), targeting this group that drives onwards spread, and for which Macías et al.[4]Macías J. Morano L.E. Téllez F. Granados R. Rivero-Juárez A. Palacios R. et al.Response to direct-acting antiviral therapy among ongoing drug users and people receiving opioid substitution therapy.J Hepatol. 2019; 71: 45-51Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar have demonstrated that treatment can be highly effective, is most desirable in many countries. However, across Europe, most countries have yet to embrace the universal treatment paradigm, and even more are yet to develop and implement a national strategy towards the elimination of HCV.[1]Marshall A.D. Pawlotsky J.M. Lazarus J.V. Aghemo A. Dore G.J. Grebely J. The removal of DAA restrictions in Europe – One step closer to eliminating HCV as a major public health threat.J Hepatol. 2018; 69: 1188-1196Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Our current and previous results[8]Pérez A.B. Vrancken B. Chueca N. Aguilera A. Reina G. García-del Toro M. et al.Increasing importance of European lineages in seeding the hepatitis C virus subtype 1a epidemic in Spain.Eurosurveill. 2019; 24Crossref Scopus (13) Google Scholar illustrate that in the absence of the latter, HCV will rapidly be re-seeded in the Spanish PWID population, challenging the long-term impact of the current Spanish intervention efforts. This demonstrates that there are beneficial scale-effects to implementing concurrent national efforts in the EU and elsewhere, without which the ultimate goal, namely eliminating HCV, will likely remain elusive. This work was supported by the Bijzonder Onderzoeksfonds KU Leuven (BOF) No. OT/14/115, the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO) (projects G066215N and G0E2317N, and a postdoctoral mandate to Bram Vrancken), and by grants from Fondo de Investigacion Sanitaria (www.isciii.es) (PI15/00713), Plan Nacional de I + D + I, Fondo Europeo de Desarrollo Regional-FEDER (www.redes/redes/inicio) (RD16/0025/0040) and GEHEP-SEIMC (GEHEP-004). Part of the computational resources and services were provided by the Hercules Foundation and the Flemish Government – department EWI-FWO Krediet aan Navorsers (Theys, KAN2012 1.2.249.12). All authors have nothing to disclose, except for Federico Garcia, Joaquin Anton-Basantas and Miguel Angel Von Wichmann who report grants and personal fees from Viiv Healthcare, personal fees from Gilead, personal fees from Abbvie and/or personal fees from MSD and/or personal fees from Janssen, outside the submitted work; and Anne-Mieke Vandamme who reports grants from the Research Foundation Flanders (FWO), during the conduct of the study (as declared in the acknowledgments section). Please refer to the accompanying ICMJE disclosure forms for further details. Bram Vrancken and Lize Cuypers designed and developed the phylogenetic analysis pipeline, performed the phylogeographic analyses and wrote subsequent drafts of the manuscript. Natalia Chueca and Ana Belen Pérez were responsible for performing all HCV sequencing experiments, and both assisted in writing the manuscript. Joaquin Anton-Basantas, Alberto de la Iglesia, Javier Fuentes, Juan Antonio Pineda, Francisco Téllez, Enrique Bernal, Pilar Rincón, Miguel Angel Von Wichman, Ana Fuentes, Francisco Vera, Antonio Rivero-Juárez, Miguel Jiménez provided samples from their clinical centre to be analysed within this study, and assisted in writing the manuscript. Anne-Mieke Vandamme provided substantial support to the phylogenetic computations and assisted extensively in writing the manuscript. Federico Garcia supervised the design of the analyses, the sequencing experiments and assisted extensively in writing the manuscript. None of the funding agencies were involved in the design of the study, nor in the collection, analysis and interpretation of the data, the writing of the manuscript and the decision to submit the manuscript for publication. The authors wish to thank Aida Selfa, Jose de Juan Ramirez, Juan Carlos Alados, Mar Masiá, María José Rios, Antonio Collado, Jesús Santos, Miguel García del Toro, Juan Manuel Pascasio, Jose Miguel Rosales-Zabal, Magdalena Lara, Teresa Aldamiz and Silvia Garcia-B as they provided samples from their clinical centre to be analysed within this study. The Ethics Committee of the San Cecilio Hospital in Granada approved the study. The following are the Supplementary data to this article: Download .pdf (.42 MB) Help with pdf files Supplementary Data 1
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