Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals

Dietz, Julia; Susser, S.; Vermehren, Johannes; Peiffer, Kai‐Henrik; Grammatikos, Georgios; Berger, Annemarie; Ferenci, Péter; Buti, Marı́a; Müllhaupt, Beat; Hunyady, Béla; Hinrichsen, Holger; Mauss, Stefan; Petersen, Jörg; Buggisch, Peter; Felten, G; Hüppe, D; Knecht, Gaby; Lutz, Thomas; Schott, Eckart; Berg, Christoph P.; Spengler, Ulrich; Hahn, Thomas von; Berg, Thomas; Zeuzem, Stefan; Sarrazin, Christoph

doi:10.1053/j.gastro.2017.11.007

Cited by 135 publications

(149 citation statements)

References 54 publications

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“…Most previous studies focused on the characterization of RASs for genotype 1 . While this study used genotype 1‐6 infectious culture systems for resistance profiling of grazoprevir and paritaprevir, selected RASs were in general comparable to those previously selected in replicons and in patients …”

Section: Discussionmentioning

confidence: 95%

“…In vitro testing is required for characterization of RASs. In constrast to enzyme and replicon assays, infectious HCV culture systems allow investigation of the complete genome and viral life cycle, and results obtained in such systems reflect in vivo data …”

Section: Discussionmentioning

confidence: 99%

“…However, resistance to DAAs is emerging . Thus, a subset of DAA‐treated patients is experiencing treatment failure, associated with the selection of HCV resistance–associated substitutions (RASs) . Furthermore, in certain regions, specific RASs pre‐exist in up to 50% of individuals .…”

mentioning

confidence: 99%

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Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants

Jensen¹,

Fahnøe²,

Pham³

et al. 2019

Hepatology

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Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance–associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as a RAS hotspot for genotype 1‐4, but not 5 and 6, escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156‐RASs were not maintained. For genotypes 1 and 2, persistence of 156‐RASs depended on genome‐wide substitution networks, co‐selected under continued PI treatment and identified by next‐generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156‐RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir, and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre‐existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156‐RASs, we observed genome‐wide selection of substitutions under treatment. Conclusion: Comprehensive PI resistance profiling for HCV genotypes 1‐6 revealed 156‐RASs as key determinants of high‐level resistance across clinically relevant PIs. We obtained in vitro proof of concept for persistence of highly fit genotype 1‐3 156‐variants, which might pose a threat to clinically relevant combination treatments.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants

Jensen¹,

Fahnøe²,

Pham³

et al. 2019

Hepatology

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“…RAS relevant for the NS5B inhibitor sofosbuvir are usually rapidly suppressed after treatment cessation due to a significantly impaired viral fitness. Resistance testing and the adaptation of antiviral regimes according to RAS is one possible option for retreatment [15, 16]. Currently, the only approved drug combination for the retreatment of patients with prior DAA failure is the combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) [3].…”

Section: Special Groups Of Patientsmentioning

confidence: 99%

Treatment of Chronic Hepatitis C: Efficacy, Side Effects and Complications

et al. 2019

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Background: Chronic hepatitis C virus (HCV) infection can lead to liver cirrhosis and its complications. Viral eradication is essential to prevent disease progression and reduces liver-related mortality and morbidity. Since the availability of direct-acting antivirals (DAA), HCV treatment has changed significantly. Current treatment strategies for different groups of patients as well as potential risks and caveats will be discussed in this review. Summary: Interferon-free (IFN-free) treatment not only shortens treatment duration, but also achieves high rates of viral clearance and is overall well tolerated. Genotype-restricted but also pangenotypic combinations are available. Usually two DAA of different drug classes are combined. For the majority of the patients, treatment duration ranges from 8 to 12 weeks. Liver and kidney function as well as prior treatment experience and potential drug-drug interactions influence substance choices and treatment duration. However, modern IFN-free treatment is not only safer, but also overall far more simplified and effective. Global HCV eradication might be an ambitious but not completely unrealistic goal to pursue. Key Messages: IFN-free antiviral treatment is safe and well tolerated. Patients can be treated almost independently of liver function or concomitant disease. Viral eradication is associated with reduced morbidity and mortality and better quality of life.

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“…Since the advent of direct‐acting antiviral (DAA) therapies for the treatment of chronic hepatitis C virus (HCV) infection, sustained virological response (SVR) rates have steadily increased from initially 60% in interferon‐based DAA treatment regimens to >90% for currently used DAA regimens, even in patients with liver cirrhosis . However, several factors are associated with increased rates of treatment failure, including previous DAA treatment experience, advanced liver cirrhosis, the presence of resistance‐associated substitutions (RAS), and conditions that have an impact on the bioavailability of the drugs, such as prior gastric surgery …”

mentioning

confidence: 99%

Transjugular Intrahepatic Portosystemic Shunt: A Possible Risk Factor for Direct‐Acting Antiviral Treatment Failure in Patients With Hepatitis C?

et al. 2019

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Direct‐acting antiviral (DAA) therapies have revolutionized the treatment of chronic hepatitis C virus infection, achieving sustained virological response (SVR) rates of >90% even in patients with advanced liver cirrhosis. Having observed an unusual case of repeated DAA therapy failures in a patient with a transjugular intrahepatic portosystemic shunt (TIPS), we assessed a possible association between prior TIPS placement and DAA failure. A structured search of our clinical database revealed 10 patients who had received DAA therapy after TIPS placement. At the time of therapy, most patients (8; 80%) presented with a Child‐Pugh score B, and the following DAA regimens were used: sofosbuvir/ledipasvir ± ribavirin (5 patients), sofosbuvir/daclatasvir ± ribavirin (3), sofosbuvir/velpatasvir (2), and sofosbuvir/velpatasvir/voxilaprevir (1). In total, 5 patients (50%) achieved an SVR, whereas a virological relapse occurred in the other half of the cases, including 2 patients with multiple relapses. In this patient cohort, SVR rates were unusually low for all regimens: sofosbuvir/ledipasvir ± ribavirin, 3/5 (60%); sofosbuvir/daclatasvir ± ribavirin, 2/3 (66%); sofosbuvir/velpatasvir, 0/2 (0%); and sofosbuvir/velpatasvir/voxilaprevir, 0/1 (0%), and patients with a TIPS made up a relevant proportion of DAA failures in patients with cirrhosis at our center: sofosbuvir/ledipasvir, 2/18 (11%); sofosbuvir/daclatasvir, 1/4 (25%); sofosbuvir/velpatasvir, 2/3 (66%); and sofosbuvir/velpatasvir/voxilaprevir, 1/1 (100%). Conclusion: We observed a high rate of virological relapse in patients with a TIPS who received DAA treatment and therefore postulate that TIPS placement may be a possible risk factor for DAA failure due to the profound hemodynamic changes evoked by the intervention. Longer treatment duration or addition of ribavirin might be warranted in these patients.

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Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals

Cited by 135 publications

References 54 publications

Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants

Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants

Treatment of Chronic Hepatitis C: Efficacy, Side Effects and Complications

Transjugular Intrahepatic Portosystemic Shunt: A Possible Risk Factor for Direct‐Acting Antiviral Treatment Failure in Patients With Hepatitis C?

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