Cross-country migration linked to people who inject drugs challenges the long-term impact of national HCV elimination programmes

Cross-country migration linked to people who inject drugs challenges the long-term impact of national HCV elimination programmes To the Editor: 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 Long overdue, most national elimination programmes now also include access to care for people who inject drugs (PWID), 2 who are at the core of ongoing HCV transmission. 3 Macías et al. 4 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. 5,6). Using such data, we have recently shown that for the most prevalent subtype among PWID in Spain (40%, 7 ), 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 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 ), 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. 5,8 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 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 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. 9–11 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 As more recent subtype 1a and 3a infections are associated with illicit (injecting) drug use (e.g. 3), targeting this group that drives onwards spread, and for which Macías et al. 4 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 Our current and previous results 8 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. Conflict of interest 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. Authors’ contributions 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 Journal of Hepatology 2019 vol. xxx jxxx–xxx Keywords: HCV; PWID; Elimination; National strategy; Spain; European Union. JOURNAL OF HEPATOLOGY Letter to the Editor 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. Acknowledgments 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. 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 G0E8416N, 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). 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. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jhep.2019.08.010. References Author names in bold designate shared co-first authorship [1] Marshall AD, Pawlotsky JM, Lazarus JV, Aghemo A, Dore GJ, Grebely J. The removal of DAA restrictions in Europe – One step closer to eliminating HCV as a major public health threat. J Hepatol 2018;69:1188–1196. [2] Lazarus JV, Safreed-Harmon K, Stumo SR, 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;47:47–50. [3] Robaeys G,Bielen R, Azar DG, Razavi H, Nevens F. Global genotype distribution of hepatitis C viral infection among people who inject drugs. J Hepatol 2016;65:1094–1103. [4] Macías J, Morano LE, 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. [5] Cuypers L,Vrancken B,Fabeni L, Marascio N, Cento V, Di Maio VC, et al. Implications of hepatitis C virus subtype 1a migration patterns for virus genetic sequencing policies in Italy. BMC Evol Biol 2017;17:70. [6] Al-Qahtani AA, Baele G, Khalaf N, Suchard MA, Al-Anazi MR, Abdo AA, et al. The epidemic dynamics of hepatitis C virus subtypes 4a and 4d in Saudi Arabia. Sci Rep 2017;7:44947. [7] Aguilera A, Navarro D, Rodríguez-Frias F, Viciana I, Martínez-Sapiña AM, Rodríguez MJ, 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;24:725–732. [8] Pérez AB,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;24. [9] European 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. [10] Grebely J, Matthews GV, Lloyd AR, Dore GJ. Elimination of hepatitis C virus infection among people who inject drugs through treatment as prevention: feasibility and future requirements. Clin Infect Dis 2013;57:1014–1020. [11] Ministry 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. [12] Polaris Observatory. Center for Disease Analysis. Available from: http:// cdafound.org/polaris/. 1950 1960 1970 1980 1990 2000 2010 2020 Time (year) 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 Cumulative # of introductions into Spain that originate from within Europe subtype 1a subtype 3a Fig. 1. Frequent importation of HCV subtype 1a and 3a lineages into Spain mostly from other countries within the European Union. The lines correspond to the average cumulative number of introduction events for these subtypes from other countries within the European Union into Spain, with the shaded areas indicating the uncertainty (95% credible interval). Grey colors pertain to subtype 1a, and blue colors to subtype 3a. Letter to the Editor 2Journal of Hepatology 2019 vol. xxx jxxx–xxx Bram Vrancken 1,#, ⇑ Lize Cuypers 1,#, ⇑ Ana Belen Pérez 2 Natalia Chueca 2 Joaquin Anton-Basantas 3 Alberto de la Iglesia 4 Javier Fuentes 5 Juan Antonio Pineda 6 Francisco Téllez 7 Enrique Bernal 8 Pilar Rincón 6 Miguel Angel Von Wichman 9 Ana Fuentes 2 Francisco Vera 10 Antonio Rivero-Juárez 11 Miguel Jiménez 12 Anne-Mieke Vandamme 1,13 Federico García 2 1 KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Leuven, Belgium 2 Clinical Microbiology, University Hospital San Cecilio, Research Institute Ibs, Granada, Spain 3 Centro Penitenciario, Albolote, Granada, Spain 4 Clinical Microbiology, Hospital Juan Ramón Jimenez, Huelva, Spain 5 Hepatology Unit, Hospital Miguel Servet, Zaragoza, Spain 6 Infectious Diseases Unit, University Hospital of Valme, Sevilla, Spain 7 Infectious Diseases Unit, University Hospital of Puerto Real, Cádiz, Spain 8 Infectious Diseases, University Hospital Reina Sofía, Murcia, Spain 9 Infectious Diseases Unit, University Hospital Donostia, San Sebastian, Spain 10 Infectious Disease Unit, University Hospital Santa Lucía, Cartagena, Murcia, Spain 11 Infectious Diseases Unit, University Hospital Reina Sofía, Córdoba, Spain 12 Hepatology Unit, Hospital Carlos Haya, Málaga, Spain 13 Center for Global Health and Tropical Medicine, Microbiology Unit, Institute of Hygiene and Tropical Medicine, University Nova Lisbon, Lisbon, Portugal ⇑ Corresponding authors. Address: KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Leuven, Belgium. LC: Tel.: +32 16 32 11 76 or BV: +32 16 37 44 00. E-mail addresses:[email protected] (B. Vrancken), [email protected] (L. Cuypers). # These first authors contributed equally to this article. JOURNAL OF HEPATOLOGY Journal of Hepatology 2019 vol. xxx jxxx–xxx 3