Global genotype distribution of hepatitis C viral ... · Global genotype distribution of hepatitis C viral infection among people who inject drugs Geert Robaeys1,2,3,y, Rob Bielen1,2,⇑,y,

Research Article

Global genotype distribution of hepatitis C viral infectionamong people who inject drugs

Geert Robaeys1,2,3,y, Rob Bielen1,2,⇑,y, Darush Ghezel Azar1,3, Homie Razavi4, Frederik Nevens3

1Ziekenhuis Oost-Limburg, Dept. of Gastro-enterology and Hepatology, Schiepse Bos 6, 3600 Genk, Belgium; 2Hasselt University, Faculty ofMedicine and Life Sciences, Martelarenlaan 42, 3500 Hasselt, Belgium; 3KULeuven, Dept. of Gastro-enterology and Hepatology, Herestraat 49,

3000 Leuven, Belgium; 4Center for Disease Analysis, 1120 W South Boulder Road, Suite 102, Louisville, CO 80026, USA

Background & Aims: Hepatitis C viral infection (HCV) after injec-tion drug use is very prevalent. The kind of genotype determinesthe response to treatment. However, no systematic reviewupdate on the global genotype distribution of HCV in peoplewho inject drugs (PWID) is currently available.Methods: A systematic review was performed by using the key-words: Genotype, Hepatitis C, Injection drug user/Intravenousdrug user/Substance user/ PWID, Name of countries in Pubmed,Embase and PsycINFO. The results were compared with thereview of Gower et al. in 2014, concerning the distribution ofHCV genotypes in the general HCV population.Results: Using these keywords, 132 studies in 48 countries (from1995 to 2015) were collected. After grading these results, thedata of 48 studies were used to determine the distribution ofgenotypes in PWID. Genotype 1 is the most prevalent genotypeall over the world in PWID. In Europe, genotypes 1, 3 and 4 arehighly prevalent. In North and South America and in Australiagenotype 1 and 3 are most prevalent. In Asia genotype 2 and 6,and Africa genotype 1a and 4 are mostly observed. Overall, themost important differences comparing with the general popula-tion are a lower prevalence of genotype 1b in the PWID popula-tion and higher prevalence of genotype 1a and 3.Conclusions: There is a different prevalence of genotype distri-bution in PWID than in the general population. Genotype 3 isespecially highly prevalent in the Western countries.Lay summary: Hepatitis C viral infection after injection drug useis very prevalent. The most important genotype causing HCVinfection in PWID globally is genotype 1, as is the case in the gen-eral population, but also genotype 3 is highly prevalent in PWID.Genotype 4 is most prevalent in Africa, spreading into Europe,whereas genotype 2 and 6 are more located in Asia. The mostimportant difference comparing to the general population aregenerally lower prevalence of genotype 1b, and higher prevalence

Journal of Hepatology 20

Keywords: Hepatitis C; Genotype; Systematic review; People who inject drugs;PWID.Received 7 March 2016; received in revised form 28 July 2016; accepted 30 July 2016;available online 9 August 2016⇑ Corresponding author. Address: Faculty of Medicine and Life Sciences, HasseltUniversity, Martelarenlaan 42, 3500 Hasselt, Belgium. Tel.: +32 89/321560; fax:+32 89/327916.E-mail address: [email protected] (R. Bielen).

y These authors contributed equally as joint first authors.

of genotype 1a and 3 in PWID. As the genotype nowadays stilldetermines the treatment, and as there is a different genotypedistribution than in the general population, it is important toidentify the genotype also in PWID.� 2016 European Association for the Study of the Liver. Publishedby Elsevier B.V. All rights reserved.

Introduction

The hepatitis C virus (HCV) infects approximately 70–85 millionpeople according to the latest data of the Polaris observatory,published by Gower et al. in 2014 [1]. Today, illegal drug usersare at the origin of the persistent HCV epidemic [2]. HCV infectionafter injection drug use is very prevalent as was shown in a globalsystematic review by Nelson et al. [3]. The largest populations ofHCV-positive persons who inject drugs (PWID) live in EasternEurope (2.3 million, range 1.2–3.9) and East and Southeast Asia(2.6 million, 1.8–3.6) [3]. The three countries with the largestpopulations of PWID with HCV are China (1.6 million, range1.1–2.2), Russia (1.3 million, range 0.7–2.3) and the USA (1.5 mil-lion, range 1.0–2.2) [3].

HCV genotypes/subtypes are clinically significant as theknowledge of the different genotypes are relevant to vaccinedevelopment and the management of chronic HCV infection[1,4–6]. The kind of genotype determines the response to antivi-ral treatment and fibrosis progression could differ between geno-types [7–10]. Thus, the HCV genotype, including genotype 1subtype, should be assessed prior to treatment initiation [10].HCV genotypes have also been shown to be a major tool for inves-tigating outbreaks and for understanding the epidemiology of theHCV infection [11,12]. In the general population overall, genotype1 accounts for 46% of all anti-HCV infections among adults, fol-lowed by genotype 3 (22%), genotype 2 (13%), genotype 4(13%), genotype 6 (2%), and genotype 5 (1%), as shown by the sys-tematic review of Gower et al. [1]. There are significant variationsin global regions. For instance, in North America, Latin Americaand Europe genotype 1 dominates infections with HCV. NorthAfrica and the Middle East have a large genotype 4 population.HCV infections in Asia are predominately caused by genotype 3followed by genotype 1. In Australasia genotype 1 dominates

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Table 2. Decision rules for data selection and extraction processes.

Selection, grading and clarification of reports of HCV testingReports of HCV testing were restricted to serological test results for anti-HCV, HCV RNA and HCV genotyping.If reports of HCV testing were available from the same sample(s) and same site(s) in multiple years, only the most recent report was select-ed.

JOURNAL OF HEPATOLOGY
followed by genotype 3 [1]. However, also genotype distributionscan also vary in different regions within countries [13,14]. SincePWID are today the major risk group for HCV and to our knowl-edge no global systematic reviews on the worldwide genotypedistribution of HCV genotypes in PWID have been published upto now, we conducted a systematic review on the global distribu-tion of genotypes in PWID.
Reports of HCV testing from one city were assumed to be from a single site unless otherwise stated.Reports of HCV testing were assumed to be single site and single sample type unless otherwise stated.If calculation or typographical errors were detected in source doc-uments, reports were recalculated and clarified with authors where possible.

Grade and date-based selection of reportsIf recent (2000 onwards) grade A (multi-sample multi-site) reports were available, we selected the range of these and did not select lower graded reports. If recent grade A reports were unavailable, we selected the range of recent reports of the next highest grade. Older reports were selected if no recent reports were available.Recent grade B (B1/multi-site single sample, or B2/single sample multi-site) reports were selected in preference to older grade B reports. Recent grade C reports were selected in preference to older grade B reports. Older grade C reports were selected if no grade B reports were available. Grade D reports were only used if no higher grade was available.Pre-2000 reports were selected only if later reports were unavailable.

Additional selection and exclusion criteriaReports from self-report studies (grade E) or unspecified methodolo-gies (ungraded) were excluded.Reports of genetic or saliva testing, or residue from syringes were excluded.Reports from studies restricted to ‘young’ PWID were excluded.Reports from studies excluding PWID of either gender were excluded if mixed gender reports were available.

Mathers et al. detail the selection of PWID prevalence reports and generation ofPWID estimates [64].

Materials and methods

We defined PWID as ‘someone who has used intravenous drugs at least once’.

Search strategy

The peer-reviewed literature databases Pubmed, Embase and PsychInfo wereused. We performed a systematic search using the following keywords: Geno-type, hepatitis C, injection drug user/intravenous drug user/substance user/PWID,name of countries. Searches were documented using myendnoteweb.com. Searchresults were systematically screened by three authors. Searches ended in January2015.

Quality assessment

Detailed methodological information was used to grade and select studies forinclusion. Data were graded according to the principles defined by Nelsonet al. in 2011 (Tables 1 and 2) [3]. These are described in detail in Table 1. Weexcluded reviews, case reports, grey literature and online databases. In compar-ison with the Nelson paper, we did include the reports based on test results offewer than 40 PWID since the data about genotype in PWID are limited. We alsoincluded the reports of PWID with HIV/HCV co-infection. Information wasextracted on: (1) study methods (eligibility criteria, recruitment and enrolmentdates, and recruitment methods and locations); (2) reports of HCV testing (num-ber of participants tested, number and proportion testing in whom genotype wasdefined).

Data synthesis

Since in most of the countries very few recent or only one study was found, thedescriptive synthesis method was chosen. The data were synthesized in tables.The data of the most recent studies with the highest numbers of patients wereused for the data in the figures. To describe differences between the genotypedistribution in PWID and the general population, an independent t test wasperformed. Differences between the distribution of genotypes in Eastern Europeand the Western world were investigated with a Mann-Whitney U test. Datawere normally divided. This was checked by the one-sample Kolmogorov-Smirnov test and a P-Plot. All statistical analyses were performed with SPSS�.

Table 1. Classification system used in the evaluation of study methodologies.

Grade Hepatitis prevalence dataA Multi-site seroprevalence study with >1 sample types (e.g.,

needle-syringe programmes, drug treatment centres, incarcer-ated PWID)

B B1 Seroprevalence study, single sample type and multiple sites B2 Seroprevalence study, multiple sample types and a single siteC Seroprevalence study, single sample type and single siteD Registration or notification of cases of hepatitis infectionE Prevalence study using self-reported hepatitis status, saliva or

RNA testing onlyU Ungraded: Report with methodology unknown

No hierarchical relationship was assumed between B1 and B2. ‘C’ and ‘D’ wereonly used if no other studies were available. ‘E’ and ‘U’ data were not used.


Results

We found 392 articles in Pubmed, and 11 extra articles in Embasecompared to Pubmed. No extra articles were found using Psy-chInfo. Fig. 1 shows the search process and flow chart. Searchresults from 403 sources were systematically screened. Datawere considered eligible if the number or prevalence of genotypeof HCV-infected PWID in a country or sub-national area wasmentioned. 207 articles were excluded on the basis of title orabstract. 196 peer-reviewed documents were reviewed in full,and 64 were excluded (Fig. 1). Thus, 132 retrospective studieson genotypes of HCV infection in PWID were found from 1995to 2015. Eighty-four sources were graded lower or were withinrange but older, or with a lower study population than sourcesused to generate estimates, and were not selected. As such, weused 48 sources to generate an estimation of the prevalence ofthe specific genotypes of hepatitis C among PWID, as listed inTable 3. This is visualised by the map in Figs. 2 and 3. Moreover,in Fig. 2 the distribution of genotypes in the general population isdisplayed, as is the prevalence of HCV worldwide. This simplifiesthe comparison of HCV genotypes between the general popula-tion and PWID.

vol. 65 j 1094–1103 1095

:txetlluffosisabnodedulxesecruos4oo6ss

:gnivomerretfttadetcelestonsecruos48

84 sources were graded lower or were within range but older, or with lower study population than sources used to generate estimates.

403 articles in electronic databases (PubMed, Embase, PsycINFO) after removal of duplicates

207 sources excluded on basis of title or abstract.

dessessasesruocertxetlluf691

24 No results of genotyping/no genotypingylnoDIWPgnomagnipytonegfostluseroN52

10 No specification between genotype subgroups 2 samples with age/gender restriction3 reports of regions, no data for countries only

48 sources used to generate an estimation of the prevalence of the specific genotypes of hepatitis C among PWID in 48 countries across

132 reports on genotyping of HCV among PWID*

64 sources excluded on basis of full text:

84 sources not selected after removing:

10 world regions

•••••

•

Fig. 1. Search process and flow chart. ⁄PWID, people who inject drugs.

Research Article

As shown in Table 3, Figs. 2 and 3, genotype 1 is prevalent allover the world. It is subdivided in genotype 1a and 1b. Genotype1a is more prevalent in Northern America and Western Europe,but a very high prevalence is also observed in Philippines, Nepal,Indonesia, Kenya and Morocco. Genotype 1b is more prevalent inEastern Europe, Cyprus, Germany, Saudi Arabia, and South Korea.In central Europe there is a frontline from north to south in whichgenotype 1a fades into 1b and the other way around. This differ-ence in genotype 1b is also significant between the Westernworld and Eastern Europe. This is demonstrated in Table 4. Geno-type 2 is almost exclusively present in Far East Asia, especiallyJapan, South Korea, Pakistan, Philippines and also Georgia. Thereis a lower but still important genotype 2 prevalence in PWID inNorthern America. Genotype 3 has spread globally. Genotype 4remains high in North Africa, but is spreading across Europe fromthe South. There is a notable high prevalence in Poland. Finally,genotype 6 has the highest prevalence in Vietnam and China, fad-ing into their neighbouring countries. Comparing these results tothe study of Gower et al., there are significant differences [1]. Themain observation is that globally genotype 1a and genotype 3 aremore prevalent in PWID, whereas genotype 1b is more prevalentin the general population. This is shown in Table 5.

Discussion

HCV infection after injection drug use is very prevalent [3]. Wefound that genotype 1 is globally present in PWID. Genotype 1a

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is most prevalent in the Western world, whereas genotype 1bis most prevalent in Eastern Europe. In central Europe, there isa frontline from north to south in which genotype 1a fades into1b and the other way around. Comparing with the general popu-lation, there is a significant higher prevalence of genotype 1a anda lower prevalence of 1b. Subtyping genotype 1 is still valid sincethe subtype can influence whether ribavirin should be adminis-trated or not, and it still affects the outcome [6]. Earlier, studiesevaluating pegylated interferon alfa/ribavirin plus a singledirect-acting antiviral agent or different combinations of direct-acting antivirals (DAA) have shown that patients with genotype1a infection have a worse response than patients with genotype1b infection [15–18]. With the development of the second gener-ation direct-acting antivirals (simeprevir, sofosbuvir, daclatasvir,ledipasvir), subtyping has become less important as it only influ-ences treatment schedule with the use of ritonavir-boosted pari-taprevir, ombitasvir and dasabuvir [19–26].

In Japan, there is a very high prevalence of genotype 2 inPWID. The data used for Japan in this review based on the gradingsystem, are from a study with 11 patients, of whom 9 patients aregenotyped [27]. As such, this could be a risk of bias. However, inthe other two studies in PWID, there is also a higher prevalence ofgenotype 2 in Japan, just as in the general population, so thesefindings could be correct [1,28–30]. At the moment, these arethe best and only usable data in Japan as there are no large stud-ies in PWID. Larger studies are necessary to confirm thesefindings.

The spread of genotype 3 from India over Afghanistan intoEurope, and further across the oceans to North and South Amer-ica and Australia due to the opiate drug trafficking routes couldbe suggested [31,32]. This route of spreading of HCV was sug-gested earlier as the spread of HIV-1 [33–35]. Our study confirmsa high prevalence of genotype 3 in South Asia, fading via Europeto the rest of the world. Moreover, the prevalence of genotype 3 isglobally higher in the PWID group, supporting this hypothesis.The finding of a higher prevalence of genotype 3 in PWID has alsobeen suggested in other studies [14,36].

Genotype 4 is also known as the African genotype. However,data for PWID in Africa are very scarce. Further research is clearlyneeded. Except the high prevalence of genotype 4 in NorthernAfrica, we noted also a higher prevalence in Southern Europe, fad-ing into the North (Fig. 3). A possible explanation for the distribu-tion of genotype 4 in Europe could be by immigration patterns.However, this is impossible to confirm without phylogeneticanalysis or contact tracing. Further research is needed to confirmor deny this hypothesis. Previous studies have shown an associa-tion between drug use and genotype 4 [37,38]. The very highprevalence in Poland is not related to immigration, but to theuse of intravenous drugs [39]. However, this high prevalence isregional (North-Eastern Poland) and could be lower in otherregions [40]. Further studies should be conducted to verify thesedata, especially because of the large difference in prevalencebetween the PWID and general population.

Genotype 6 is mostly prevalent in Vietnam and China. It hasspread to surrounding countries via local drug trafficking routes[33,41]. The migration to Canada and Australia could beexplained by immigration [42,43]. Compared with the generalpopulation, prevalence is indeed higher in PWID in China, Indiaand Taiwan [44–46]. It is much lower in Thailand [47]. As theprevalence is high in most studies of genotyping in China and Tai-wan, these results are realistic for PWID [48–59]. More bias could

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Table 3. Results of systematic review on HCV genotype distribution in PWID.

Countries Author Year Sample size Enrollment dates Genotypes (%)1a 1b 1 other/not

known2 3 4 5 6 Other

Eastern EuropeBulgaria Ciccozzi M et al. [65] 2011 20 Not shown 30.0 4.5 65.0Croatia Kurelac I et al. [66] 2011 106 2003-2010 24.6 18.9 12.2 1.9 38.7 3.8Czech Republic Krekulová L et al. [67] 2009 222 2005-2007 40.5 35.1 23.4 1.0Estonia Tallo T. et al. [68] 2007 33 1994-2004 63.0 37.0Georgia Bouscaillou et al. [69] 2014 199 2012 17.8 23.3 70.0 11.1Hungary Tresó B et al. [70] 2013 198 2006-2011 74.2 22.7 3.0Macedonia Kiprijanovska et al. [71] 2013 783 2008-2013 35.9 64.0 0.1Poland Chlabicz et al. [40] 2008 111 Not shown 8.1 30.6 37.8 23.4Russia Shustov AV et al. [72] 2005 97 2001-2002 53.8 3.6 42.1 0.5Slovenia Seme K et al. [73] 2009 516 1993-2007 38.6 1.6 58.1 1.7Western EuropeBelgium Matheï C et al. [74] 2005 152 1999-2000 48.7 1.4 41.2 8.8Denmark Krarup et al. [75] 2000 114 Not shown 43.0 3.5 50.0 3.5France Larsen C et al. [76] 2010 2063 2001-2007 16.4 10.3 9.6 2.8 25.4 7.7 0.1 28.0Germany Schröter M et al. [77] 2004 172 2000-2001 23.0 31.0 8.0 31.0 7.0Greece Elefsiniotis et al. [78] 2006 152 2000-2005 23.7 60.5 11.8 3.9Iceland Löve et al. [79] 1996 40 1991-1993 57.5 2.5 37.5 2.5Ireland Keating S et al. [80] 2005 299 1997-2003 48.8 2.0 48.5 0.7Italy Stroffolini et al. [81] 2012 237 2009 23.6 11.4 14.3 1.7 39.7 9.3Netherlands Grady et al. [82] 2015 54 1985-2012 54.0 11.0 30.0 5.0Portugal Calado RA et al. [83] 2011 67 2008-2009 49.2 6.0 22.4 22.4Spain Serra MA et al. [84] 2003 115 Not shown 40.0 17.4 0.9 27.0 14.8Sweden Lidman C et al. [85] 2009 172 2004-2006 43.0 9.9 39.5 1.2 6.4Switzerland Senn O et al. [86] 2009 86 2002-2008 50.0 39.5 10.4United Kingdom Hope VD et al. [87] 2011 114 2006 52.6 5.3 40.0 1.8East and Southeast AsiaChina Garten et al. [44] 2005 126 Not shown 19.0 0.8 38.1 42.1Indonesia Prasetyo et al. [88] 2013 30 2009 46.6 3.3 16.6 26.6 6.6Japan Satoh et al. [27] 2004 9 2001-2003 100Philippines Kageyama S et al. [89] 2009 387 2002-2007 72.6 27.4South Korea Yun H et al. [90] 2008 61 2005-2006 38.0 54.0 3.0 5.0Taiwan Liu JY et al. [46] 2008 243 1993-2006 29.2 13.2 8.2 21.4 28.0Thailand Hansurabhanon et al.

[47]2002 419 Not shown 1.0 17.9 74.9 3.5 2.7

Vietnam Tanimoto T et al. [91] 2010 194 2007 23.7 20.6 0.5 5.6 49.4South AsiaAfghanistan Sanders-Buell et al. [92] 2013 71 2006-2008 35.2 2.8 62.0India Saha K et al. [93] 2014 73 2007-2008 15.1 15.1 1.4 54.7 13.7Iran Jamalidoust et al. [94] 2014 550 2009-2012 51.5 34.9 13.7Nepal Shrestha et al. [95] 1997 44 1996 48.8 44.2 7.0Pakistan Ur Rehman L et al. [96] 2011 28 Not shown 7.1 35.7 28.6 14.3 14.3Central AsiaUzbekistan Kurbanov F et al. [97] 2008 55 2005-2006 27.3 3.6 67.3 1.8Latin AmericaBrazil Sawada L et al. [98] 2011 47 2004-2008 59.6 40.4


Journal of Hepatology 2016 vol. 65 j 1094–1103 1097

Table 3 (continued)

Countries Author Year Sample size Enrollment dates Genotypes (%)1a 1b 1 other/not

known2 3 4 5 6 Other

North AmericaCanada Jacka et al. [99] 2014 655 1996-2012 47.8 6.3 10.1 32.5 0.6 1.3 1.4United States of America

Uccellini L et al. [100] 2012 1524 1999-2001 69.0 10.0 9.3 10.6 1.1

AustralasiaAustralia Aitken CK et al. [101] 2004 134 2001-2002 29.0 9.4 13.8 2.2 36.2 5.1 7.2Middle East and North AfricaCyprus Demetriou VL et al.

[102]2010 14 2008 43.0 57.0

Lebanon Mahfoud Z et al. [103] 2010 28 Not shown 21.0 57.0 18.0 4.0Libya Alashek W et al. [104] 2008 134 2003-2008 26.2 60.4 13.4Morocco Trimbitas et al. [105] 2014 74 2011-2013 60.8 4.1 25.6 9.4Saudi Arabia Alzahrani AJ et al. [106] 2009 131 Not shown 16.0 58.0 0.7 11.3 10.0 3.8Sub Saharan AfricaKenya Muasya et al. [107] 2000 26 Not shown 73.0 27.0

48 countries 10 world regions

Fig. 2. Global distribution of HCV genotypes in the general population (inner circle) and PWID (outer rim). HCV prevalence in general population (central map)according to Gower et al. [1]. This figure was modified from the original figure of Gower et al. with permission from the authors.

Research Article

1098 Journal of Hepatology 2016 vol. 65 j 1094–1103

Fig. 3. Global distribution of HCV per genotype in PWID.


be expected in India and Thailand, as there are only few studiesavailable at this time [45,47].

SVR rates still vary between the genotypes with this secondgeneration of DAAs and thus genotype still influences treatmentoutcome [60]. Furthermore, these second generation antiviralsare expensive, and are not available globally [60]. This last prob-lem could be overcome by the use of generics, as Freeman et al.demonstrated [61]. Nonetheless, the goal of elimination of hep-atitis C set by the World Health Organization (WHO) is still diffi-cult to reach and effective screening programs to identify largelyasymptomatic HCV infections in at-risk populations will be nec-essary [62]. A vaccine to prevent HCV infection would not have


the same limitations and would be useful in primary and sec-ondary prevention [63]. This second use may be of critical impor-tance in extending antiviral therapy to individuals with ongoingrisk for exposure to the virus, such as PWID [63]. These rates ofreinfection in PWID are still a matter of controversy, and furtherresearch is necessary.

Limitations

In our methodology, we followed the rules of selection and grad-ing according to Nelson et al. in 2011. The search was extendedby using 3 different search machines, and literature was reviewed

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Table 4. Statistical analysis of genotype distribution between the Westernworld and Eastern Europe.

Western World Eastern Europe p valueGenotype 1 Mean

Std devStd. error mean

0.510.120.03

MeanStd devStd. error mean

0.520.160.05

0.77

Genotype 1a


0.420.190.06


0.260.140.07

0.13

Genotype 1b


0.120.090.03


0.340.220.09

0.02

Genotype 1 other


0.120.030.02


0.12n.a.n.a.

0.98

Genotype 2 MeanStd devStd. error mean

0.050.040.01


0.020.010.01

0.20


0.360.120.03


0.430.160.05

0.21


0.070.060.16


0.080.100.05

0.82

Genotype other


0.080.110.05


0.010.010.00

0.27

Genotype 5 is not present in these world regions, and is thus not displayed in thistable. Furthermore, genotype 6 is only present in one country (Canada), and thusno statistical analysis was performed.

Table 5. Statistical analysis of difference in global genotype distribution ofHCV between PWID and the general population according to Gower et al. [1].

PWID General population p valueGenotype 1 Mean

Std devStd. error mean

0.470.170.03


0.520.200.03

0.149

Genotype 1a


0.330.200.04


0.180.160.03

0.002

Genotype 1b


0.210.180.04


0.340.210.03

0.013

Genotype 1 other


0.110.050.02


0.180.210.04

0.461


0.130.220.04


0.110.110.02

0.629


0.390.170.03


0.260.170.03

0.002


0.080.070.01


0.090.140.02

0.876


0.020.030.02


0.020.040.01

0.905


0.200.200.07


0.060.140.04

0.052

Genotype other


0.070.070.02


0.050.050.01

0.452

This analysis was performed using the data of all countries which could providedata for the PWID and general population, so that the total population wascomparable in both groups.

Research Article

by three independent reviewers. We did not perform a statisticalmeta-analysis with different studies per country as we did nothave the original research data of all the studies who are reportedin this systematic review, nor the data of the papers used byGower et al. [1]. However, as this method was used before by alandmark paper by Nelson et al., we think that our data are rep-resentative for each country.

Because of limitation of data we included the reports based ontest results of fewer than 40 PWID and also the data of patientswith HIV/HCV co-infection. Finally, the data for this review camefrom the most recent studies with the broadest representation(involvement of multiple centers). However, there are a numberof limitations for this review.

Firstly, we cannot precisely determine the global distribution,as we can only compare the genotype distribution in countrieswhere data were available. Most of the studies on genotypes inHCV-infected PWID are performed in Europe. In the Middle East,Africa and Australasia, only a limited number of studies are avail-able and these studies mostly contain only a limited number ofpatients. In Southern America, data were only available in Brazil.Therefore, the applicability of the review is lower in theseregions, and more studies are needed.

In two countries, namely Iceland and Nepal, studies older than2000 were used. These studies could have less accurate serolog-ical testing modalities.

Further details about characterization of patients (country ofbirth, ethnicity, socio-economic status, gender, age, disease char-acteristics) were not always available, but could offer importantadditional information. It was also not easy to delineate non-IVsubstance users from PWID specifically in the cohort studies.


Also, some studies recruited ‘lifetime PWID’, whereas othersrecruited ‘current’ or ‘past year’ PWID. As recruitment of PWIDvaried between different locations (prison, drug treatment cen-ters, outpatient clinics), there may be also a difference in riskbehavior and exposure to viral hepatitis. Finally, as data weremostly sub-national, from a limited number of locations, theycould be less representative of the epidemic nationally. This lasttopic is less important, as our data showed consistency betweenthe different studies in single countries. There was little variationbetween the prevalence of genotypes in single countries.

Implications

This review shows differences in HCV genotypes in PWID and thegeneral population. Since also for the new DAAs the genotypedetermines the choice of therapy, it remains important to geno-type all patients. As genotype 1 is the most prevalent in PWIDand subtypes affect the choice of treatment, subtyping of geno-type 1 should always be performed.

Practical implications for clinicians and policy-makers

Clinicians and policy-makers will have to keep the difference inHCV genotypes in PWID vs. non-PWID in mind when organizingtreatment policies for PWID.

vol. 65 j 1094–1103

Conclusions, implications, recommendations
The most important genotype causing HCV infection in PWIDglobally is genotype 1, as is the case in the general population,but also genotype 3 is highly prevalent in PWID. Genotype 4 ismost prevalent in Africa, spreading into Europe, whereas geno-type 2 and 6 are more located in Asia. The most important differ-ence comparing to the general population are generally lowerprevalence of genotype 1b, and higher prevalence of genotype 3in PWID. As the genotype nowadays still determines the treat-ment, and as there is a different genotype distribution than inthe general population, it is important to identify the genotypealso in PWID. Further and larger studies are necessary to confirmthese findings.

Conflict of interest

The authors who have taken part in this study declared that theydo not have anything to disclose regarding funding or conflict ofinterest with respect to this manuscript.

Authors’ contributions

All the authors contributed significantly to this manuscript, andread the last draft before submitting the article.

Acknowledgements

We thank Dr. Katie Razavi-Shearer for her contribution in creat-ing Fig. 2. We thank Thomas Reyskens, Liesbeth Grondelaersand Carine Thaens for their contributions in creating Fig. 3. Thisstudy is part of the Limburg Clinical Research Program (LCRP)UHasselt-ZOL-Jessa, supported by the foundation Limburg SterkMerk, province of Limburg, Flemish government, Hasselt Univer-sity, Ziekenhuis Oost-Limburg and Jessa Hospital.

Supplementary data

Supplementary data associated with this article can be found, in theonline version, at http://dx.doi.org/10.1016/j.jhep.2016.07.042.

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Author names in bold designate shared co-first authorship

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Global genotype distribution of hepatitis C viral ... · Global genotype distribution of hepatitis C viral infection among people who inject drugs Geert Robaeys1,2,3,y, Rob Bielen1,2,⇑,y,