Direct acting antiviral treatment of chronic hepatitis C in Denmark: factors associated with and barriers to treatment initiation

Sølund, Christina; Hallager, Sofie; Pedersen, Martin Schou; Fahnøe, Ulrik; Ernst, Anja; Krarup, Henrik; Røge, Birgit Thorup; Christensen, Peer Brehm; Laursen, Alex Lund; Gerstoft, Jan; Belard, Erika; Madsen, Lone Galmstrup; Schønning, Kristian; Pedersen, Anders Gorm; Bukh, Jens; Weis, Nina

doi:10.1080/00365521.2018.1467963

Cited by 17 publications

(20 citation statements)

References 31 publications

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“…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%

“…Serum or plasma from genotype 1a–infected patients with DAA treatment failure and acquisition of 156‐RASs were obtained from the European Resistance Database at the Department of Internal Medicine 1, University Hospital Frankfurt/German Center for Infection Research, External Partner Site Frankfurt, Germany (patients A, B, D, and E), and the National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Henri Mondor Hospital, Créteil, France (patient C). Treatment‐naïve patients were followed at Copenhagen University Hospital, Hvidovre . The study was conducted in accordance with the Declaration of Helsinki, and approval for the use of patient blood samples and retrospective collection of data for research purposes was obtained from the local ethics committees.…”

Section: Methodsmentioning

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: 99%

Section: Methodsmentioning

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

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“…The Spanish National Strategy for HCV treatment does not restrict DAA uptake in patients with recent drug or alcohol dependence , which is also in accordance with international clinical guidelines . Substance abuse has been identified as a major barrier to HCV treatment uptake in other settings . In this context, in a study conducted in Canada which included 1699 HIV/HCV‐coinfected patients, abuse of substances such alcohol [hazard ratio (HR) 0.74; 95% CI 0.58, 0.94] and active PWID (HR 0.60; 95% CI 0.38, 0.94) were associated with a lower rate of HCV treatment uptake.…”

Section: Discussionmentioning

confidence: 99%

Parenteral drug use as the main barrier to hepatitis C treatment uptake in HIV‐infected patients

et al. 2019

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ObjectivesOur objective was to identify patient factors associated with being untreated for hepatitis C virus (HCV) infection in HIV-coinfected patients. MethodsA prospective longitudinal study was carried out. HIV-infected patients with active chronic HCV infection included in the HERACLES cohort (NCT02511496) constituted the study population. The main study outcome was receipt of HCV direct-acting antiviral (DAA) treatment from 1 May 2015 to 1 May 2017. The population was divided into patients who were receiving HCV treatment during follow-up and those who were not. ResultsOf the 15 556 HIV-infected patients in care, 3075 (19.7%) presented with chronic HCV infection and constituted the study population. At the end of the follow-up, 1957 patients initiated HCV therapy (63.6%). Age < 50 years, absence of or minimal liver fibrosis, being treatment-na€ ıve, HCV genotype 3 infection, being in the category of people who inject drugs using opioid substitutive therapy (OST-PWID), and being in the category of recent PWID were identified as significant independent risk factors associated with low odds of DAA implementation. When a multivariate analysis was performed including only the PWID population, both OST-PWID [odds ratio (OR) 0.552; 95% confidence interval (CI) 0.409-0.746) and recent PWID (OR 0.019; 95% CI 0.004-0.087) were identified as independent factors associated with low odds of treatment implementation.We identified factors, which did not include prioritization of a DAA uptake strategy, that limited access to HCV therapy. The low treatment uptake in several populations seriously jeopardizes the elimination of HCV infection in the coming years.

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“…Definition of Danish treatment criteria at the time was liver biopsy (Metavir score ≥ F2), 19 transient elastography ≥10 kPa, clinical cirrhosis or, regardless of fibrosis status, extra‐hepatic manifestations (see Methods and Material in Appendix ) 19–21 . We previously published the demographic data for 22 patients with SVR, 17 patients with treatment failure, 16 and 13 patients with GT3 22 …”

Section: Methodsmentioning

confidence: 99%

Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non‐target sites, for DAA‐based treatment and retreatment outcome

Fahnøe

Pedersen

Sølund

et al. 2020

Journal of Viral Hepatitis

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Direct-acting antivirals (DAAs) have proven highly effective against chronic hepatitis C virus (HCV) infection. However, some patients experience treatment failure, associated with resistance-associated substitutions (RASs). Our aim was to investigate the complete viral coding sequence in hepatitis C patients treated with DAAs to identify RASs and the effects of treatment on the viral population. We selected 22 HCV patients with sustained virologic response (SVR) to match 21 treatment-failure patients in relation to HCV genotype, DAA regimen, liver cirrhosis and previous treatment experience. Viral-titre data were compared between the two patient groups, and HCV | 303 FAHNØE Et Al.

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Direct acting antiviral treatment of chronic hepatitis C in Denmark: factors associated with and barriers to treatment initiation

Cited by 17 publications

References 31 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

Parenteral drug use as the main barrier to hepatitis C treatment uptake in HIV‐infected patients

Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non‐target sites, for DAA‐based treatment and retreatment outcome

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