Efficacy of NS5A Inhibitors Against Hepatitis C Virus Genotypes 1–7 and Escape Variants

Gottwein, Judith M.; Pham, Long V.; Mikkelsen, Lotte S.; Ghanem, Lubna; Ramírez, Santseharay; Scheel, Troels K. H.; Carlsen, Thomas H. R.; Bukh, Jens

doi:10.1053/j.gastro.2017.12.015

Cited by 91 publications

(122 citation statements)

References 49 publications

Supporting

Mentioning

108

Contrasting

Unclassified

Order By: Relevance

“…RASs in the NS5A position for genotypes 1a and 3 are of particular interest, especially as they may persist for years . Similar to other studies the most frequent NS5A RASs were found at amino acid positions 28, 30, 31 and 93, against which the efficacy of NS5A inhibitors varies . NS5B nucleotide RASs are detected only in about 1% of failures to nucleotide containing DAA therapies and thus can be re‐used for retreatments after DAA failure .…”

Section: Discussionsupporting

confidence: 74%

“…26 Similar to other studies the most frequent NS5A RASs were found at amino acid positions 28, 30, 31 and 93, against which the efficacy of NS5A inhibitors varies. 27,28 NS5B nucleotide RASs are detected only in about 1% of failures to nucleotide containing DAA therapies and thus can be re-used for retreatments after DAA failure. 29 However, no correlation between RAS and SVR could be found in our study.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Management of patients with chronic hepatitis C failing repeated courses of interferon‐free direct acting antiviral combination therapy

et al. 2019

View full text Add to dashboard Cite

Summary Background Only few chronic hepatitis C patients treated with interferon (IFN)‐free direct acting antiviral (DAA) combinations fail to clear the virus. Most patients can be cured by retreatment with another DAA combination; however, some still fail to eradicate the virus. So far, little is known about how to best retreat these patients. In this study we summarise our real world experience of re‐retreatments. Methods One hundred and two patients who completed a DAA‐retreatment after virological failure to an IFN‐free DAA therapy and reached at least follow‐up 12 were included in this study.Twenty‐one (20.6%) of them relapsed again after retreatment (mean age 50.0 ± 10.6, 18 male, three female, GT1a:8, GT1b:4, GT1c:1, GT3a:7; GT4:1; cirrhosis:15; resistance associated substitutions [RAS]: 17/19; relapse after:SOF/SMV:2; 3D ± RBV:4; SOF/DCV ± RBV:4; SOF/LDV ± RBV:6; SOF/VEL:3; SOF/VEL/VOX:1; EBV/GZV:1).Treatment duration and addition of RBV were at the discretion of the treating physician. These 21 patients were studied in detail. Results Seventeen of the 21 patients finished a third DAA therapy: 13 achieved SVR12, three relapsed again (cirrhosis:2; SOF/VEL/RBV:GT3a; SOF/LDV/RBV:GT1a; EBV/GZV/SOF/RBV:GT1b), one was lost to follow‐up. One (GT1a, cirrhosis) achieved SVR12 after the third retherapy with 24 weeks of 3D/SOF/RBV, and one (GT3a, cirrhosis) achieved SVR4 after 24 weeks of glecaprevir/pibrentasvir, but died shortly thereafter. Overall, 95 (93.1%) of 102 patients achieved SVR12 after one or more retreatments. Sex, cirrhosis, genotype, RAS or baseline viral load were not associated with retreatment failure. Conclusion Most patients with failure to a DAA therapy achieved SVR after retreatment with a different regimen; however, 13.7% of patients required multiple retreatments.

show abstract

Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Management of patients with chronic hepatitis C failing repeated courses of interferon‐free direct acting antiviral combination therapy

et al. 2019

View full text Add to dashboard Cite

show abstract

“…). Genotype 3a is difficult to treat with DAAs, due to its relatively low sensititivy to several PIs and NS5A inhibitors . Our work suggests that an additional reason might be its greater propensity to develop resistance to PIs and sofosbuvir (this study and Ramirez et al).…”

Section: Discussionmentioning

confidence: 51%

“…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%

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

Jensen¹,

Fahnøe²,

Pham³

et al. 2019

Hepatology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…In the g7 samples, polymorphisms associated with resistance to NS3 and NS5A inhibitors in other genotypes were present in the majority of samples . Of particular note, the Y93H mutation (associated with a lowered 50% effective concentration [EC 50 ] to ombitasvir, daclatasvir, and velpatasvir) is present in the majority of g7 genomes . The Y93H natural polymorphism is present in only 3% of all sequences submitted to NCBI and occurs at a low frequency in other genotypes (e.g., in HCV g1, it represents 3.16% of sequences submitted to NCBI, and in g3, it represents 4.09% of sequences submitted to NCBI).…”

Section: Resultsmentioning

confidence: 99%

Highly Diverse Hepatitis C Strains Detected in Sub‐Saharan Africa Have Unknown Susceptibility to Direct‐Acting Antiviral Treatments

et al. 2019

View full text Add to dashboard Cite

The global plan to eradicate hepatitis C virus (HCV) led by the World Health Organization outlines the use of highly effective direct‐acting antiviral drugs (DAAs) to achieve elimination by 2030. Identifying individuals with active disease and investigation of the breadth of diversity of the virus in sub‐Saharan Africa (SSA) is essential as genotypes in this region (where very few clinical trials have been carried out) are distinct from those found in other parts of the world. We undertook a population‐based, nested case‐control study in Uganda and obtained additional samples from the Democratic Republic of Congo (DRC) to estimate the prevalence of HCV, assess strategies for disease detection using serological and molecular techniques, and characterize genetic diversity of the virus. Using next‐generation and Sanger sequencing, we aimed to identify strains circulating in East and Central Africa. A total of 7,751 Ugandan patients were initially screened for HCV, and 20 PCR‐positive samples were obtained for sequencing. Serological assays were found to vary significantly in specificity for HCV. HCV strains detected in Uganda included genotype (g) 4k, g4p, g4q, and g4s and a newly identified unassigned g7 HCV strain. Two additional unassigned g7 strains were identified in patients originating from DRC (one partial and one full open reading frame sequence). These g4 and g7 strains contain nonstructural (ns) protein 3 and 5A polymorphisms associated with resistance to DAAs in other genotypes. Clinical studies are therefore indicated to investigate treatment response in infected patients. Conclusion : Although HCV prevalence and genotypes have been well characterized in patients in well‐resourced countries, clinical trials are urgently required in SSA, where highly diverse g4 and g7 strains circulate.

show abstract

Efficacy of NS5A Inhibitors Against Hepatitis C Virus Genotypes 1–7 and Escape Variants

Cited by 91 publications

References 49 publications

Management of patients with chronic hepatitis C failing repeated courses of interferon‐free direct acting antiviral combination therapy

Management of patients with chronic hepatitis C failing repeated courses of interferon‐free direct acting antiviral combination therapy

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

Highly Diverse Hepatitis C Strains Detected in Sub‐Saharan Africa Have Unknown Susceptibility to Direct‐Acting Antiviral Treatments

Contact Info

Product

Resources

About