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Global genotype distribution of hepatitis C viral
infection among people who inject drugs
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Jnl of Hepatology Dec 2016
HCV infection after injection drug use is very prevalent [3]. We found that genotype 1 is globally present in PWID. Genotype 1a is most prevalent in the Western world, whereas genotype 1b is most prevalent in Eastern Europe. In central Europe, there is a frontline from north to south in which genotype 1a fades into 1b and the other way around. Comparing with the general population, there is a significant higher prevalence of genotype 1a and a lower prevalence of 1b. Subtyping genotype 1 is still valid since the subtype can influence whether ribavirin should be administrated or not, and it still affects the outcome [6]. Earlier, studies evaluating pegylated interferon alfa/ribavirin plus a single direct-acting antiviral agent or different combinations of direct-acting antivirals (DAA) have shown that patients with genotype 1a infection have a worse response than patients with genotype 1b infection [[15], [16], [17], [18]]. With the development of the second generation direct-acting antivirals (simeprevir, sofosbuvir, daclatasvir, ledipasvir), subtyping has become less important as it only influences treatment schedule with the use of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir [[19], [20], [21], [22], [23], [24], [25], [26]].
In Japan, there is a very high prevalence of genotype 2 in PWID. The data used for Japan in this review based on the grading system, are from a study with 11 patients, of whom 9 patients are genotyped [27]. As such, this could be a risk of bias. However, in the other two studies in PWID, there is also a higher prevalence of genotype 2 in Japan, just as in the general population, so these findings could be correct [[1], [28], [29], [30]]. At the moment, these are the best and only usable data in Japan as there are no large studies in PWID. Larger studies are necessary to confirm these findings.
The spread of genotype 3 from India over Afghanistan into Europe, and further across the oceans to North and South America and Australia due to the opiate drug trafficking routes could be suggested [[31], [32]]. This route of spreading of HCV was suggested earlier as the spread of HIV-1 [[33], [34], [35]]. Our study confirms a high prevalence of genotype 3 in South Asia, fading via Europe to the rest of the world. Moreover, the prevalence of genotype 3 is globally higher in the PWID group, supporting this hypothesis. The finding of a higher prevalence of genotype 3 in PWID has also been 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 clearly needed. Except the high prevalence of genotype 4 in Northern Africa, we noted also a higher prevalence in Southern Europe, fading into the North (Fig. 3). A possible explanation for the distribution of genotype 4 in Europe could be by immigration patterns. However, this is impossible to confirm without phylogenetic analysis or contact tracing. Further research is needed to confirm or deny this hypothesis. Previous studies have shown an association between drug use and genotype 4 [[37], [38]]. The very high prevalence in Poland is not related to immigration, but to the use of intravenous drugs [39]. However, this high prevalence is regional (North-Eastern Poland) and could be lower in other regions [40]. Further studies should be conducted to verify these data, especially because of the large difference in prevalence between the PWID and general population.
Genotype 6 is mostly prevalent in Vietnam and China. It has spread to surrounding countries via local drug trafficking routes [[33], [41]]. The migration to Canada and Australia could be explained by immigration [[42], [43]]. Compared with the general population, prevalence is indeed higher in PWID in China, India and Taiwan [[44], [45], [46]]. It is much lower in Thailand [47]. As the prevalence is high in most studies of genotyping in China and Taiwan, these results are realistic for PWID [[48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59]]. More bias could be expected in India and Thailand, as there are only few studies available at this time [[45], [47]]. SVR rates still vary between the genotypes with this second generation of DAAs and thus genotype still influences treatment outcome [60]. Furthermore, these second generation antivirals are expensive, and are not available globally [60]. This last problem could be overcome by the use of generics, as Freeman et al. demonstrated [61]. Nonetheless, the goal of elimination of hepatitis C set by the World Health Organization (WHO) is still difficult to reach and effective screening programs to identify largely asymptomatic HCV infections in at-risk populations will be necessary [62]. A vaccine to prevent HCV infection would not have the same limitations and would be useful in primary and secondary prevention [63]. This second use may be of critical importance in extending antiviral therapy to individuals with ongoing risk for exposure to the virus, such as PWID [63]. These rates of reinfection in PWID are still a matter of controversy, and further research is necessary.
In our methodology, we followed the rules of selection and grading according to Nelson et al. in 2011. The search was extended by using 3 different search machines, and literature was reviewed by three independent reviewers. We did not perform a statistical meta-analysis with different studies per country as we did not have the original research data of all the studies who are reported in this systematic review, nor the data of the papers used by Gower et al. [1]. However, as this method was used before by a landmark paper by Nelson et al., we think that our data are representative for each country. Because of limitation of data we included the reports based on test results of fewer than 40 PWID and also the data of patients with HIV/HCV co-infection. Finally, the data for this review came from the most recent studies with the broadest representation (involvement of multiple centers). However, there are a number of limitations for this review.
Firstly, we cannot precisely determine the global distribution, as we can only compare the genotype distribution in countries where data were available. Most of the studies on genotypes in HCV-infected PWID are performed in Europe. In the Middle East, Africa and Australasia, only a limited number of studies are available and these studies mostly contain only a limited number of patients. In Southern America, data were only available in Brazil. Therefore, the applicability of the review is lower in these regions, and more studies are needed.
In two countries, namely Iceland and Nepal, studies older than 2000 were used. These studies could have less accurate serological testing modalities.
Further details about characterization of patients (country of birth, ethnicity, socio-economic status, gender, age, disease characteristics) were not always available, but could offer important additional information. It was also not easy to delineate non-IV substance users from PWID specifically in the cohort studies. Also, some studies recruited ‘lifetime PWID’, whereas others recruited ‘current’ or ‘past year’ PWID. As recruitment of PWID varied between different locations (prison, drug treatment centers, outpatient clinics), there may be also a difference in risk behavior and exposure to viral hepatitis. Finally, as data were mostly sub-national, from a limited number of locations, they could be less representative of the epidemic nationally. This last topic is less important, as our data showed consistency between the different studies in single countries. There was little variation between the prevalence of genotypes in single countries.
This review shows differences in HCV genotypes in PWID and the general population. Since also for the new DAAs the genotype determines the choice of therapy, it remains important to genotype all patients. As genotype 1 is the most prevalent in PWID and subtypes affect the choice of treatment, subtyping of genotype 1 should always be performed.
Practical implications for clinicians and policy-makers
Clinicians and policy-makers will have to keep the difference in HCV genotypes in PWID vs. non-PWID in mind when organizing treatment policies for PWID.
Conclusions, implications, recommendations
The most important genotype causing HCV infection in PWID globally is genotype 1, as is the case in the general 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 most important difference comparing to the general population are generally lower prevalence of genotype 1b, and higher prevalence of genotype 3 in PWID. As the genotype nowadays still determines the treatment, and as there is a different genotype distribution than in the general population, it is important to identify the genotype also in PWID. Further and larger studies are necessary to confirm these findings.

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