Abstract
Hepatitis C virus (HCV) genotypes have became important epidemiological markers in the management of HCV-infected subjects and infection treatment. The dynamics of HCV genotypes are changing in Europe. During a five-year (2009-2013) hospital-based surveillance in the area of Parma, Northern Italy, serum/plasma samples from 1,265 HCV RNA-positive subjects were genotyped. Subtypes 1b, 3a, and 1a were predominant (32.6 %, 19.1 %, and 17.8 %, respectively), with a correlation between viral load and gender. Subtypes 1a and 3a were more frequent in adults and males with a significant difference with the over-50 age group and females (P > 0.0001). Subtype 1b, as well as 2a/2c and G2 not-subtypeable (15.7 % and 7.2 %, respectively), were more common in females and in the over-50 age group compared to males (P < 0.0001, P < 0.0001, and P < 0.05, respectively) and the under-50 age group (P < 0.0001). While subtype 1b showed a nearly constant trend, subtype 1a peaked in 2012, when a consistent decrease in G2 was observed. The increasing detection of G4, mainly in adults, and subtypes 1a and 3a suggests their epidemiological relevance in the population. The detection of more than one HCV genotype in the same sample (0.2 %) and different genotypes in distant samples (5.1 %) from the same subject reinforces the opinion that re-infection and super-infection with different genotypes are not negligible events, especially in HIV-infected subjects. The dynamics of HCV genotypes could have significant implications for infection control.
Similar content being viewed by others
Abbreviations
- DAA:
-
direct-acting antiviral
- G:
-
genotype
- HCV:
-
hepatitis C virus
- HIV-1:
-
human immunodeficiency virus type 1
- IDU:
-
intravenous drug user
- n-s:
-
not-subtypeable
References
Bostan N, Mahmood T (2010) An overview about hepatitis C: a devastating virus. Crit Rev Microbiol 36:91–133. doi:10.3109/10408410903357455
Stoll-Keller F, Barth H, Fafi-Kremer S, Zeisel MB, Baumert TF (2009) Development of hepatitis C virus vaccines: challenges and progress. Expert Rev Vaccines 8:333–345. doi:10.1586/14760584.8.3.333
Zingaretti C, De Francesco R, Abrignani S (2014) Why is it so difficult to develop a hepatitis C virus preventive vaccine? Clin Microbiol Infect 20:103–109
Hiroishi K, Eguchi J, Ishii S, Hiraide A, Sakaki M, Doi H, Omori R, Imawari M (2010) Immune response of cytotoxic T lymphocytes and possibility of vaccine development for hepatitis C virus infection. J Biomed Biotechnol 2010:263810. doi:10.1155/2010/263810
Park SJ, Hahn YS (2010) Regulation of host innate immunity by hepatitis C virus: crosstalk between hepatocyte and NK/DC. Rev Infect 1:151–157
Imran M, Waheed Y, Manzoor S, Bilal M, Ashraf W, Ali M, Ashraf M (2012) Interaction of hepatitis C virus proteins with pattern recognition receptors. Virol J 9:126. doi:10.1186/1743-422X-9-126
Varchetta S, Mele D, Mantovani S, Oliviero B, Cremonesi E, Ludovisi S, Michelone G, Alessiani M, Rosati R, Montorsi M, Mondelli MU (2012) Impaired intrahepatic natural killer cell cytotoxic function in chronic hepatitis C virus infection. Hepatology 56:841–849. doi:10.1002/hep.25723
Hoofnagle JH (2002) Course and outcome of hepatitis C. Hepatology 36:S21–S29
Mühlberger N, Schwarzer R, Lettmeier B, Sroczynski G, Zeuzem S, Siebert U (2009) HCV-related burden of disease in Europe: a systematic assessment of incidence, prevalence, morbidity, and mortality. BMC Public Health 9:34. doi:10.1186/1471-2458-9-34
World Health Organization (WHO), Hepatitis C fact sheet no 164. http://www.who.int/mediacentre/factsheets/fs164/en/index.html. Accessed 10 Sept 2015
Ciccozzi M, Lo Presti A, Ciccaglione AR, Zehender G, Ciotti M (2012) Phylogeny and phylodinamic of hepatitis C in Italy. BMC Infect Dis 12:S5. doi:10.1186/1471-2334-12-S2-S5
Mariano A, Scalia Tomba G, Tosti ME, Spada E, Mele A (2009) Estimating the incidence, prevalence and clinical burden of hepatitis C over time in Italy. Scand J Infect Dis 41:689–699. doi:10.1080/00365540903095358
Cozzolongo R, Osella AR, Elba S, Petruzzi J, Buongiorno G, Giannuzzi V, Leone G, Bonfiglio C, Lanzilotta E, Manghisi OG, Leandro G, NUTRIHEP Collaborating Group, Donnaloia R, Fanelli V, Mirizzi F, Parziale L, Crupi G, Detomaso P, Labbate A, Zizzari S, Depalma M, Polignano A, Lopinto D, Daprile G (2009) Epidemiology of HCV infection in the general population: a survey in a southern Italian town. Am J Gastroenterol 104:2740–2746. doi:10.1038/ajg.2009.428
Guadagnino V, Stroffolini T, Caroleo B, Menniti Ippolito F, Rapicetta M, Ciccaglione AR, Chionne P, Madonna E, Costantino A, De Sarro G, Focà A, Lentini M, Staltari O, Sersale’s Study Group (2013) Hepatitis C virus infection in an endemic area of Southern Italy 14 years later: evidence for a vanishing infection. Dig Liver Dis 45:403–407. doi:10.1016/j.dld.2012.10.014
Medici MC, Valcavi P, Arcangeletti MC, Calderaro A, Martinelli M, De Conto F, Motta F, Pinardi F, Aloisi A, Ferraglia F, Casula F, Dettori G, Chezzi C (2003) Prevalenza di infezione da virus dell’epatite C in un gruppo di soggetti non selezionati per fattori di rischio in un’area geografica del Nord Italia. L’Igiene Mod 120:87–106
Valcavi PP, Natali A, Dieci E, Pilotti E, Chezzi C (1999) Prevalence of hepatitis C virus antibodies in a clinic-based group of Italians from one geographic area. Clin Microbiol Infect 5:125–129
Raffaele A, Valenti M, Iovenitti M, Matani A, Bruno ML, Altobelli E, D’Alessandro A, Barnabei R, Leonardis B, Taglieri G (2001) High prevalence of HCV infection among the general population in a rural area of central Italy. Eur J Epidemiol 17:41–46
Grebely J, Pham ST, Matthews GV, Petoumenos K, Bull RA, Yeung B, Rawlinson W, Kaldor J, Lloyd A, Hellard M, Dore GJ, White PA (2012) Hepatitis C virus reinfection and superinfection among treated and untreated participants with recent infection. Hepatology 55:1058–1069. doi:10.1002/hep.24754
Blackard JT, Sherman KE (2007) Hepatitis C virus coinfection and superinfection. J Infect Dis 195:519–524
Bukowska-Ośko I, Pawełczyk A, Perlejewski K, Kubisa N, Caraballo Cortés K, Rosińska M, Płoski R, Fic M, Kaźmierczak J, Popiel M, Zabek P, Horban A, Radkowski M, Laskus T (2015) Genetic variability of hepatitis C virus (HCV) 5’ untranslated region in HIV/HCV coinfected patients treated with pegylated interferon and ribavirin. PLoS One 10:e0125604. doi:10.1371/journal.pone.0125604
Eyster ME, Sherman KE, Goedert JJ, Katsoulidou A, Hatzakis A, The Multicenter Hemophilia Cohort Study (1999) Prevalence and changes in hepatitis C virus genotypes among multitransfused persons with hemophilia. J Infect Dis 179:1062–1069
Jarvis LM, Watson HG, McOmish F, Peutherer JF, Ludlam CA, Simmonds P (1994) Frequent reinfection and reactivation of hepatitis C virus genotypes in multitransfused hemophiliacs. J Infect Dis 170:1018–1022
Hayes CN, Chayama K (2015) Emerging treatments for chronic hepatitis C. J Formos Med Assoc 114:204–215. doi:10.1016/j.jfma.2014.09.001
Paterson JC, Miller MH, Dillon JF (2014) Update on the treatment of hepatitis C genotypes 2-6. Curr Opin Infect Dis 27:540–544. doi:10.1097/QCO.0000000000000114
Wendt A, Bourlière M (2013) An update on the treatment of genotype-1 chronic hepatitis C infection: lessons from recent clinical trials. Ther Adv Infect Dis 1:191–208. doi:10.1177/2049936113502647
Smith DB, Bukh J, Kuiken C, Muerhoff AS, Rice CM, Stapleton JT, Simmonds P (2014) Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource. Hepatology 59:318–327. doi:10.1002/hep.26744
Messina JP, Humphreys I, Flaxman A, Brown A, Cooke GS, Pybus OG, Barnes E (2015) Global distribution and prevalence of hepatitis C virus genotypes. Hepatology 61:77–87. doi:10.1002/hep.27259
Liberto MC, Marascio N, Zicca E, Matera G (2012) Epidemiological features and specificities of HCV infection: a hospital-based cohort study in a university medical center of Calabria region. BMC Infect Dis 12:S4. doi:10.1186/1471-2334-12-S2-S4
Marascio N, Matera G, Quirino A, Giancotti A, Barreca GS, Lamberti AG, Caroleo B, Liberto MC, Focà A (2012) Eleven-year distribution pattern of hepatitis C virus in southern Italy. J Pathogol 2012:631095. doi:10.1155/2012/631095
Marascio N, Ciccozzi M, Equestre M, Lo Presti A, Costantino A, Cella E, Bruni R, Liberto MC, Pisani G, Zicca E, Barreca GS, Torti C, Focà A, Ciccaglione AR (2014) Back to the origin of HCV 2c subtype and spreading to the Calabria region (Southern Italy) over the last two centuries: a phylogenetic study. Infect Genet Evol 26:352–358. doi:10.1016/j.meegid.2014.06.006
Marascio N, Liberto M, Barreca G, Zicca E, Quirino A, Lamberti A, Bianco G, Matera G, Surace L, Berardelli G (2014) Update on epidemiology of HCV in Italy: focus on the Calabria Region. BMC Infect Dis 14:S2. doi:10.1186/1471-2334-14-S5-S2
Petruzziello A, Coppola N, Diodato AM, Iervolino V, Azzaro R, Di Costanzo G, Di Macchia CA, Di Meo T, Loquercio G, Pasquale G, Cacciapuoti C (2013) Age and gender distribution of hepatitis C virus genotypes in the metropolitan area of Naples. Intervirology 56:206–212. doi:10.1159/000348506
Curcio F, Villano G, Masucci S, Plenzik M, Veneruso C, De Rosa G (2011) Epidemiological survey of hepatitis C virus infection in a cohort of patients from a ser.T in naples, Italy. J Addict Med 5:43–49. doi:10.1097/ADM.0b013e3181d131e0
Sereno S, Perinelli P, Laghi V (2009) Changes in the prevalence of hepatitis C virus genotype among Italian injection drug users-relation to period of injection started. J Clin Virol 45:354–357. doi:10.1016/j.jcv.2009.04.022
Stroffolini T, D’Egidio PF, Aceti A, Filippini P, Puoti M, Leopardi C, Almasio PL, DAVIS Drug Addicted, HCV Prevalence in Italy an Epidemiological, Observational, Cross-Sectional, Multicenter Study Participating Centers (2012) Hepatitis C virus infection among drug addicts in Italy. J Med Virol 84:1608–1612. doi:10.1002/jmv.23370
Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H (2014) Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol 61:S45–S57. doi:10.1016/j.jhep.2014.07.027
Hadinedoushan H, Salmanroghani H, Amirbaigy MK, Akhondi-Meybodi M (2014) Hepatitis C virus genotypes and association with viral load in Yazd, central province of Iran. Hepat Mon 14:e11705. doi:10.5812/hepatmon.11705
Petruzziello A, Coppola N, Loquercio G, Marigliano S, Giordano M, Azzaro R, Diodato AM, Iervolino V, Di Costanzo G, Di Macchia CA, Di Meo T, Paradiso L, Ferro R, Giuliano P, Russo F, Pasquale G, Cacciapuoti C (2014) Distribution pattern of hepatitis C virus genotypes and correlation with viral load and risk factors in chronic positive patients. Intervirology 57:311–318. doi:10.1159/000363386
Schijman A, Colina R, Mukomolov S, Kalinina O, García L, Broor S, Bhupatiraju AV, Karayiannis P, Khan B, Mogdasy C, Cristina J (2004) Comparison of hepatitis C viral loads in patients with or without coinfection with different genotypes. Clin Diagn Lab Immunol 11:433–435
Ansaldi F, Orsi A, Sticchi L, Buzzone B, Icardi G (2014) Hepatitis C virus in the new era: perspectives in epidemiology, prevention, diagnostics and predictors of response to therapy. World J Gastroenterol 20:9633–9652. doi:10.3748/wjg.v20.i29.9633
La Torre G, Gualano MR, Semyonov L, Nicolotti N, Ricciardi W, Boccia A (2011) Hepatitis C Virus infections trends in Italy, 1996-2006. Hepat Mon 11:895–900. doi:10.5812/kowsar.1735143X.767
Osella AR, Misciagna G, Guerra VM, Chiloiro M, Cuppone R, Cavallini A, Di Leo A, The Association for the Study of Liver Disease in Puglia (2000) Hepatitis C virus (HCV) infection and liver-related mortality: a population-based cohort study in southern Italy. Int J Epidemiol 29:922–927
Pizzillo P, Almasio PL, Ferraro D, Craxì A, Di Stefano R (2009) HCV genotypes in Sicily: is there any evidence of a shift? J Med Virol 81:1040–1046. doi:10.1002/jmv.21498
Balogun MA, Vyse AJ, Hesketh LM, Kafatos G, Parry JV, Ramsay ME (2009) Estimating hepatitis C infection acquired in England, 1986–2000. Epidemiol Infect 137:1249–1254. doi:10.1017/S0950268809002143
Vietri J, Prajapati G, El Khoury AC (2013) The burden of hepatitis C in Europe from the patients’ perspective: a survey in 5 countries. BMC Gastroenterol 13:16. doi:10.1186/1471-230X-13-16
Baden R, Rockstroh JK, Buti M (2014) Natural history and management of hepatitis C: does sex play a role? J Infect Dis 209:S81–S85. doi:10.1093/infdis/jiu057
Fabris P, Baldo V, Baldovin T, Bellotto E, Rassu M, Trivello R, Tramarin A, Tositti G, Floreali A (2008) Changing epidemiology of HCV and HBV infections in Northern Italy: a survey in the general population. J Clin Gastroenterol 42:527–532. doi:10.1097/MCG.0b013e318030e3ab
Ferraro D, Genovese D, Argentini C, Giordano V, Pizzillo P, Stroffolini T, Craxì A, Rapicetta M, Di Stefano R (2008) Phylogenetic reconstruction of HCV genotype 1b dissemination in a small city centre: the Camporeale model. J Med Virol 80:1723–1731. doi:10.1002/jmv.21276
Bruno S, Crosignani A, Maisonneuve P, Rossi S, Silini E, Mondelli MU (2007) Hepatitis C virus genotype 1b as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis: a 17-year prospective cohort study. Hepatology 46:1350–1356
Dal Molin G, Ansaldi F, Biagi C, D’Agaro P, Comar M, Crocè L, Tiribelli C, Campello C (2002) Changing molecular epidemiology of hepatitis C virus infection in Northeast Italy. J Med Virol 68:352–356
Vitale F, Villafrate MR, Viviano E, Perna AM, Bonura F, Di Benedetto MA, Mazzola G, Colletti P, Prestileo T, Romano N (1998) Distribution of hepatitis C virus genotypes among intravenous drug users. A ten-year study in Palermo, Sicily. New Microbiol 21:335–342
Ciccozzi M, Equestre M, Costantino A, Marascio N, Quirino A, Lo Presti A, Cella E, Bruni R, Liberto MC, Focà A, Pisani G, Zehender G, Ciccaglione AR (2012) Hepatitis C virus genotype 4d in Southern Italy: reconstruction of its origin and spread by a phylodynamic analysis. J Med Virol 84:1613–1619. doi:10.1002/jmv.23384
Njouom R, Caron M, Besson G, Ndong-Atome GR, Makuwa M, Pouillot R, Nkoghé D, Leroy E, Kazanji M (2012) Phylogeography, risk factors and genetic history of hepatitis C virus in Gabon, central Africa. PLoS One 7:e42002. doi:10.1371/journal.pone.0042002
Gededzha MP, Selabe SG, Blackard JT, Kyaw T, Mphahlele MJ (2014) Near full-length genome analysis of HCV genotype 5 strains from South Africa. Infect Genet Evol 21:118–123. doi:10.1016/j.meegid.2013.10.022
Henquell C, Guglielmini J, Verbeeck J, Mahul A, Thibault V, Lebray P, Laperche S, Trimoulet P, Foucher J, Le Guillou-Guillemette H (2011) Evolutionary history of hepatitis C virus genotype 5a in France, a multicenter ANRS study. Infect Genet Evol 11:496–503. doi:10.1016/j.meegid.2010.12.015
Verbeeck J, Kwanten L, D’Heygere F, Beguin A, Michiels S, Desombere I, Leroux-Roels G, Lemey P, Nevens F, Van Ranst M (2010) HCV genotype distribution in Flanders and Brussels (Belgium): unravelling the spread of an uncommon HCV genotype 5a cluster. Eur J Clin Microbiol Infect Dis 29:1427–1434. doi:10.1007/s10096-010-1021-0
Pang PS, Planet PJ, Glenn JS (2009) The evolution of the major hepatitis C genotypes correlates with clinical response to interferon therapy. PLoS One 4:e6579. doi:10.1371/journal.pone.0006579
Tuveri R, Rothschild C, Pol S, Reijasse D, Persico T, Gazengel C, Bréchot C, Thiers V (1997) Hepatitis C virus genotypes in French haemophiliacs: kinetics and reappraisal of mixed infections. J Med Virol 51:36–41
Ricchiuti A, Brunati A, Mirabella S, Pierini A, Franchello A, Salizzoni M (2005) Use of hepatitis C virus-positive grafts in liver transplantation: a single-centre experience. Transplant Proc 37:2569–2570
Sullivan DG, Wilson J, Carithers RL Jr, Perkins JD, Gretch DR (1998) Multigene tracking of hepatitis C virus quasispecies after liver transplantation: correlation of genetic diversification in the envelope region with asymptomatic or mild disease patterns. J Virol 72:10036–10043
Herring BL, Page-Shafer K, Tobler LH, Delwart EL (2004) Frequent hepatitis C virus superinfection in injection drug users. J Infect Dis 190:1396–1403
Schröter M, Feucht HH, Zöllner B, Schäfer P, Laufs R (2003) Multiple infections with different HCV genotypes: prevalence and clinical impact. J Clin Virol 27:200–204
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
This study was funded by grants from the University of Parma (Fondi di Ateneo FIL 2014-FIL2014_DECONTO_MCS).
Conflict of interest
Flora De Conto declares that she has no conflict of interest. Maria Cristina Medici declares that she has no conflict of interest. Francesca Ferraglia declares that she has no conflict of interest. Federica Pinardi declares that she has no conflict of interest. Alessandra Fazzi declares that she has no conflict of interest. Maria Cristina Arcangeletti declares that she has no conflict of interest. Carlo Chezzi declares that he has no conflict of interest. Adriana Calderaro declares that she has no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
HCV RNA detection and genotyping were performed according to a medical order; therefore, there was no need to obtain informed consent for the epidemiological analysis of related data.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
De Conto, F., Medici, M.C., Ferraglia, F. et al. Temporal dynamics of hepatitis C genotypes in a five-year hospital-based surveillance in Northern Italy. Arch Virol 161, 2727–2737 (2016). https://doi.org/10.1007/s00705-016-2975-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00705-016-2975-8