Research Article: Hepatitis C virus genetic diversity by geographic region within genotype 1-6 subtypes among patients treated with glecaprevir and pibrentasvir

Date Published: October 4, 2018

Publisher: Public Library of Science

Author(s): Gretja Schnell, Preethi Krishnan, Rakesh Tripathi, Jill Beyer, Thomas Reisch, Michelle Irvin, Tatyana Dekhtyar, Liangjun Lu, Teresa I. Ng, Wangang Xie, Tami Pilot-Matias, Christine Collins, Jason Blackard.

http://doi.org/10.1371/journal.pone.0205186

Abstract

Hepatitis C virus (HCV) is genetically diverse and includes 7 genotypes and 67 confirmed subtypes, and the global distribution of each HCV genotype (GT) varies by geographic region. In this report, we utilized a large dataset of NS3/4A and NS5A sequences isolated from 2348 HCV GT1-6-infected patients treated with the regimen containing glecaprevir/pibrentasvir (GLE/PIB) to assess genetic diversity within HCV subtypes by geographic region using phylogenetic analyses, and evaluated the prevalence of baseline amino acid polymorphisms in NS3 and NS5A by region/country and phylogenetic cluster. Among 2348 NS3/4A and NS5A sequences, phylogenetic analysis identified 6 genotypes and 44 subtypes, including 3 GT1, 8 GT2, 3 GT3, 13 GT4, 1 GT5, and 16 GT6 subtypes. Phylogenetic analysis of HCV subtype 1a confirmed the presence of two clades, which differed by geographic region distribution and NS3 Q80K prevalence. We detected phylogenetic clustering by country in HCV subtypes 1a, 1b, 2a, 2b, and 5a, suggesting that genetically distinct virus lineages are circulating in different countries. In addition, two clades were detected in HCV GT4a and GT6e, and NS5A amino acid polymorphisms were differentially distributed between the 2 clades in each subtype. The prevalence of NS3 and NS5A baseline polymorphisms varied substantially by genotype and subtype; therefore, we also determined the activity of GLE or PIB against replicons containing NS3/4A or NS5A from HCV GT1-6 clinical samples representing 6 genotypes and 21 subtypes overall. GLE and PIB retained activity against the majority of HCV replicons containing NS3/4A or NS5A from HCV GT1-6 clinical samples, with a median EC50 of 0.29 nM for GLE and 1.1 pM for PIB in a transient replicon assay. The data presented in this report expands the available data on HCV epidemiology, subtype diversity by geographic region, and NS3 and NS5A baseline polymorphism prevalence.

Partial Text

Hepatitis C virus (HCV) infection affects 71 million people worldwide and is associated with liver disease and hepatocellular carcinoma [1–4]. HCV is genetically diverse and is classified into 7 genotypes, 67 confirmed subtypes, and 20 provisionally assigned subtypes [5]. The global distribution and prevalence of each HCV genotype (GT) varies by geographic region. HCV GT1 is the most prevalent worldwide and has a widespread geographic distribution, representing 46% of all HCV infections [1]. HCV GT3 is the second most prevalent genotype and accounts for 30% of global infections, and is more common in South Asia, Australasia, and some countries in Europe [1, 6]. HCV genotypes 2 and 4 are the next most common, each representing 9–13% of HCV infections with more limited geographic distribution. GT2 prevalence is higher in Asia and West Africa, while a high incidence of GT4 infection occurs in Central and Eastern sub-Saharan Africa, North Africa, and the Middle East [1, 6]. HCV genotypes 5, 6, and 7 are the most restricted in geographical distribution, with GT5 common in South Africa and GT6 prevalent in East and Southeast Asia [1], while GT7 infection has been reported in a small number of individuals from the Democratic Republic of Congo [7].

In this report, a large dataset of HCV GT1-6 NS3/4A and NS5A sequences was utilized to assess genetic diversity within HCV subtypes by geographic region. Among NS3/4A and NS5A sequences isolated from 2348 patient samples, phylogenetic analysis identified 6 genotypes and 44 subtypes, including 3 GT1, 8 GT2, 3 GT3, 13 GT4, 1 GT5, and 16 GT6 subtypes (Fig 1). In addition, we analyzed 20 GT2 samples where the subtype could not be determined by phylogenetic analysis due to lack of homology with the 11 confirmed GT2 subtypes, potentially representing novel GT2 subtypes. Subtype diversity was highest in GT2, GT4, and GT6, which are reported to be the most diverse genotypes and encompass 52 confirmed subtypes [5]. We detected phylogenetic clustering by country in HCV subtypes 1a, 1b, 2a, 2b, and 5a, suggesting that genetically distinct virus lineages are circulating in different countries. Since the prevalence of NS3 and NS5A baseline polymorphisms varied substantially by genotype and subtype among patients treated with a regimen of GLE/PIB, we also determined the activity of GLE or PIB against replicons containing NS3/4A or NS5A from HCV GT1-6 clinical samples representing 6 genotypes and 21 subtypes overall. In the transient HCV replicon assay, GLE and PIB retained activity against the majority of HCV replicons containing NS3/4A or NS5A from HCV GT1-6 clinical samples, confirming previous reports describing the pangenotypic activity of GLE and PIB [34, 35]. A separate publication [39] recently presented the pooled resistance analysis of HCV GT1-6 infected patients treated with GLE/PIB in 8 registrational clinical studies, and revealed a lack of impact of genotype, subtype, or baseline polymorphism prevalence on treatment outcome with the recommended treatment duration [39, 48, 49].

 

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http://doi.org/10.1371/journal.pone.0205186

 

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