Recombination is an important driver of genetic diversity, though it is relatively uncommon in hepatitis C virus (HCV). Recent investigation of sequence data acquired from HCV clinical trials produced twenty-one full-genome recombinant viruses belonging to three putative inter-subtype forms 2b/1a, 2b/1b, and 2k/1b. The 2k/1b chimera is the only known HCV circulating recombinant form (CRF), provoking interest in its genetic structure and origin. Discovered in Russia in 1999, 2k/1b cases have since been detected throughout the former Soviet Union, Western Europe, and North America. Although 2k/1b prevalence is highest in the Caucasus mountain region (i.e., Armenia, Azerbaijan, and Georgia), the origin and migration patterns of CRF 2k/1b have remained obscure due to a paucity of available sequences. We assembled an alignment which spans the entire coding region of the HCV genome containing all available 2k/1b sequences (>500 nucleotides; n = 109) sampled in ninteen countries from public databases (102 individuals), additional newly sequenced genomic regions (from 48 of these 102 individuals), unpublished isolates with newly sequenced regions (5 additional individuals), and novel complete genomes (2 additional individuals) generated in this study. Analysis of this expanded dataset reconfirmed the monophyletic origin of 2k/1b with a recombination breakpoint at position 3,187 (95% confidence interval: 3,172-3,202; HCV GT1a reference strain H77). Phylogeography is a valuable tool used to reveal viral migration dynamics. Inference of the timed history of spread in a Bayesian framework identified Russia as the ancestral source of the CRF 2k/1b clade. Further, we found evidence for migration routes leading out of Russia to other former Soviet Republics or countries under the Soviet sphere of influence. These findings suggest an interplay between geopolitics and the historical spread of CRF 2k/1b.

Besides seven major hepatitis C virus (HCV) genotypes (GT), a number of intergenotypic recombinant strains have been described. These so-called chimeras combine genetic characteristics of different HCV genotypes.

Aim of the study: Combination of ombitasvir/paritaprevir/ritonavir + dasabuvir +/- ribavirin (3DDA +/- RBV) therapy is shown to be effective in HCV genotype 1 (GT1) infected patients. However, sparse data exist in patients who failed previous boceprevir or telaprevir based therapies. Real life efficacy and safety of this combination were evaluated in HCV GT1b infected patients (mostly cirrhotics) with compensated liver disease who failed previous boceprevir or telaprevir based therapies more than a year before.Material and methods: Data of previous protease inhibitor failure patients, treated with 3DAA+ RBV for 12 weeks (GT1b and/or non-cirrhotics) or 24 weeks (non-GT1b cirrhotics), were retrospectively collected.Results: Population characteristics: boceprevir/telaprevir-failure: 82/45, GT1b: 117, cirrhotic: 111 (87.4%). SVR12/24 was observed in 103/105 patients (98.1%) of those who reached either time point. Four SAEs reported: one death due to myocardial infarction, another due to recurrent hepatocellular carcinoma after achieving SVR12, two hospitalizations (elevation of transaminases, pneumonia). Grade >= 3 AEs or laboratory abnormalities were reported in < 10% of patients; they were transient in all patients. No early discontinuation of drugs due to SAE has been reported.Conclusions: One year after previous failure of boceprevir or telaprevir based therapy, 12 weeks of 3DAA+ RBV combination in HCV GT1b infected patients is similarly effective and safe as in those with no previous HCV therapy, even in the presence of cirrhosis. These findings might be of particular interest in settings where alternative therapies for such patients are not available or not affordable.

Background:Hepatitis B virus (HBV) surface proteins (HBsAg) coat the viral particle and form subviral particles (SVPs). Loss of HBsAg represents a functional cure and is an important treatment goal.Methods:We analyzed the impact of the HBV genotypes A-E and pre-S mutations on SVP expression in hepatitis B virus e antigen (HBeAg)-negative chronic HBV-infected patients. A HBV genome harboring a preS1-deletion was analyzed in hepatoma cells.Results:We observed a genotype-specific ratio of the 3 surface proteins (SHBs/MHBs/LHBs), reflecting differences in the morphology and composition of SVPs. Deletions/mutations in the preS1/preS2 domain, detected in released viral genomes, did not affect the molecular weight of MHBs and LHBs in these patients. In contrast, LHB molecular weight was altered in vitro using an HBV genome harboring a preS1-deletion derived from one of these patients.Conclusion:Differences in composition of SVPs may result in genotype-specific immunogenicity and pathogenesis. In the patients with preS-mutations, secreted HBsAg and released viral genomes cannot be derived from the same genetic source. As viral genomes are derived from covalently closed circular DNA (cccDNA), HBsAg is presumably derived from integrated DNA. This important HBsAg source should be considered for novel antiviral strategies in HBeAg-negative chronic HBV-infected patients.

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Hunyady B, Abonyi M, Gerlei Z, et al. Ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin in HCV genotype 1 infected patients who failed previous protease inhibitor therapy. Clinical and Experimental Hepatology. 2018;4(2):83-90. doi:10.5114/ceh.2018.75957. APA Hunyady, B., Abonyi, M., Gerlei, Z., Gervain, J., Horváth, G., & Jancsik, V. et al. (2018). Ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin in HCV genotype 1 infected patients who failed previous protease inhibitor therapy. Clinical and Experimental Hepatology, 4(2), 83-90. https://doi.org/10.5114/ceh.2018.75957 Chicago Hunyady, Béla, Margit Abonyi, Zsuzsanna Gerlei, Judit Gervain, Gábor Horváth, Viktor Jancsik, and Gabriella Lengyel et al. 2018. "Ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin in HCV genotype 1 infected patients who failed previous protease inhibitor therapy". Clinical and Experimental Hepatology 4 (2): 83-90. doi:10.5114/ceh.2018.75957. Harvard Hunyady, B., Abonyi, M., Gerlei, Z., Gervain, J., Horváth, G., Jancsik, V., Lengyel, G., Makkai, E., Pár, A., Péter, Z., Pusztay, M., Ribiczey, P., Rókusz, L., Sarrazin, C., Schneider, F., Susser, S., Szalay, F., Tornai, I., Tusnádi, A., Újhelyi, E., Werling, K., and Makara, M. (2018). Ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin in HCV genotype 1 infected patients who failed previous protease inhibitor therapy. Clinical and Experimental Hepatology, 4(2), pp.83-90. https://doi.org/10.5114/ceh.2018.75957 MLA Hunyady, Béla et al. "Ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin in HCV genotype 1 infected patients who failed previous protease inhibitor therapy." Clinical and Experimental Hepatology, vol. 4, no. 2, 2018, pp. 83-90. doi:10.5114/ceh.2018.75957. Vancouver Hunyady B, Abonyi M, Gerlei Z, Gervain J, Horváth G, Jancsik V et al. Ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin in HCV genotype 1 infected patients who failed previous protease inhibitor therapy. Clinical and Experimental Hepatology. 2018;4(2):83-90. doi:10.5114/ceh.2018.75957.

HBV DNA and quantitative (q)HBsAg levels as prognostic markers for HBV‐related disease are mostly validated in Asia and their significance in Western populations is uncertain.

Aim Different combinations of direct antiviral agents (DAA) lead to high SVR rates in HCV genotype 1 infected patients. However, presence of baseline resistance-associated substitutions (RASs) represents a major risk factor for treatment failure. It is unknown whether choice of treatment based on RASs has the potential to decrease virologic failure rates. Methods Population-based sequencing of NS3 and NS5A genes was performed in HCV genotype 1 infected patients at a German university hospital. Treatment was individually selected based on resistance analyses. Results In total, 319 patients (50% treatment-experienced and 30% with cirrhosis) were included. With the treatment choice based on the baseline NS3 and NS5A resistance profile SVR rates between 96 and 100% were observed in all subgroups, including treatment-experienced patients with cirrhosis and HCV genotype 1a infected cirrhotic patients. Conclusions The choice of treatment based on the RASs status at baseline may be beneficial for optimizing treatment efficacy in patients with HCV genotype 1 infection and risk factors for treatment failure.

Seitdem Sodium Taurocholate cotransporting Polypeptide (NTCP) als essentieller Eintrittsfaktor für Hepatitis B und D Viren identifiziert werden konnte, sind mehrere Polymorphismen in NTCP beschrieben worden. Ziel unserer Studie war es zu untersuchen, ob drei in Menschen vorkommende NTCP Polymorphismen (I159 M, I223T, S267F) den Eintritt des Hepatitis D Virus (HDV) in Hepatozyten und die antivirale Effektivität von Myrcludex B beeinflussen.

HBV-DNA > 2000 IU/ml und qHBsAg > 1000 IU/ml sind basierend auf asiatischen Daten als prognostische Marker für einen ungünstigen HBV-Krankheitsverlauf etabliert.

Background & Aims: Little is known about the epidemiology and frequency of recombinant HCV genotype 2/1 strains, which may represent a challenge for direct antiviral therapy (DAA). This study aims to identify the epidemiology and phylogeny of HCV genotype 2/1 strains and encourages genotype screening, to select the DAA-regimen that achieves the optimal sustained virologic response.Methods: Consecutive samples from HCV genotype 2 infected patients, according to commercial genotyping, from Germany, Italy and Israel were re-genotyped by Sanger-based sequencing. Virologic, epidemiological, and phylogenetic analyses including other published chimeras were performed.Results: Sequence analysis of 442 supposed HCV genotype 2 isolates revealed 61 (genotype 2k/1b (n = 59), 2a/1b (n = 1) or 2b/1a (n = 1)) chimeras. No chimeras were observed in Italy, but the frequency was 14% and 25% in Germany and Israel. Treatment of viral chimera with sofosbuvir/ribavirin led to virologic relapse in 25/27 patients (93%). Nearly all patients treated with genotype 1-based DAA-regimens initially (n = 8/9), or after relapse (n = 13/13), achieved a sustained virologic response. Most patients with 2k/1b chimeras (88%) were originally from eight different areas of the former Soviet Union. All known 2k/1b chimeras harbour the same recombination breakpoint and build one phylogenetic cluster, while all other chimeras have different phylogenies.Conclusions: The HCV genotype 2k/1b variant derives from one single recombination event most likely in the former Soviet Union, while other chimeras are unique and develop independently. A relatively high frequency has been observed along the migration flows, in Germany and Israel. In countries with little migration from the former Soviet Union the prevalence of 2k/1b chimeras is expected to be low. Treatment with sofosbuvir plus ribavirin is insufficient, but genotype 1-based regimens seem to be effective.Lay summary: The frequency of recombinant HCV is higher than expected. A novel recombinant variant (HCV genotype 2a/1b) was identified. Screening for recombinant viruses would contribute to increased response rates to direct antiviral therapy. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

BACKGROUND & AIMS Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments. METHODS We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naïve patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis. RESULTS RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed. CONCLUSIONS We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.

Aktuell steigt die Zahl der Patienten mit einer Hepatitis C Virus (HCV) Genotyp (GT) 4 Infektion in Europa. Zur Behandlung stehen verschiedene direkt antiviral wirksame Substanzen (DAAs) zur Verfügung, welche aus Kombinationen eines NS5A-Inhibitors mit einem nukleotidischen NS5B-Inhibitor oder mit einem NS3 Protease-Inhibitor bestehen. Die Anzahl an Studien mit Resistenzdaten zum GT4 ist bisher gering. In dieser Arbeit wurden Resistenz-assoziierte Substitutionen (RASs) bei DAA-naiven und -erfahren Patienten in Verbindung mit dem Therapieansprechen analysiert.