Outcome and adverse events in patients with chronic hepatitis C treated with direct-acting antivirals: a clinical randomized study

Sølund, Christina; Andersen, Ellen Sloth; Mössner, Belinda Klemmensen; Laursen, Alex Lund; Røge, Birgit Thorup; Kjær, Mette; Gerstoft, Jan; Christensen, Peer Brehm; Pedersen, Martin Schou; Schønning, Kristian; Fahnøe, Ulrik; Bukh, Jens; Weis, Nina

doi:10.1097/meg.0000000000001192

Cited by 7 publications

(15 citation statements)

References 46 publications

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“…SVR was high (98.1%), with no significant differences between groups, in agreement with other Brazilian studies that found an SVR of 91.6‐95% . International studies also showed high rates of response to treatment, ranging from 78.6‐90%, depending on the treatment regimen used …”

Section: Discussionsupporting

confidence: 89%

“…2,7,20,21 The occurrence of at least one adverse reaction during treatment was reported by 83.2% of the patients, and the most frequently identified ADRs were fatigue, anemia, and headache. Solund et al (2018) found that 97% of patients had an ADR, a higher proportion than that found in our study. However, the most common adverse reactions were anemia (78%), fatigue (74%), and headache (46%).…”

Section: Discussioncontrasting

confidence: 83%

“…However, the most common adverse reactions were anemia (78%), fatigue (74%), and headache (46%). This difference may have occurred because all treatment regimens included ribavirin . Tong et al (2016) reported that 87.5% of study patients developed adverse reactions during treatment and the main ADRs were fatigue (71.1%), anemia (57%), and headache (35.9%) .…”

Section: Discussionmentioning

confidence: 99%

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Predictors of adverse drug reactions associated with ribavirin in direct‐acting antiviral therapies for chronic hepatitis C

Cursino

Monteiro

Duarte

et al. 2019

Pharmacoepidemiology and Drug

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Purpose To identify factors associated with the development of adverse drug reactions (ADR) in ribavirin therapeutic regimens. Methods A multicenter, prospective study was conducted in three public health hospitals in Rio de Janeiro between November 2015 and March 2018. Inclusion criteria were defined by patient follow‐up at pharmaceutical consultation at the time of drug dispensing as those who used sofosbuvir in combination with simeprevir, daclatasvir, and/or ribavirin. All patients were invited to participate in the study during the first interview. Adverse drug reactions were reported according to the treatment regimen and frequency of occurrence. Statistical analysis was used to compare adverse reactions between treatments and their associated factors. Results A total of 405 patients were included in the study (mean age 59.6 ± 9.6 years); 61.0% were female, 88.1% were infected with genotype 1, and 65.4% were cirrhotic. The most prescribed treatment was the combination of sofosbuvir, daclatasvir, and ribavirin (55.3%). The majority of patients reported at least one ADR during treatment (83.2%), of which fatigue, anemia, and headache were the most common. Being female (OR = 1.86, [1.08‐3.20]) and use of ribavirin (OR: 2.39; 95% CI [1.38‐4.13]) were predictors for the development of ADR, which was also associated with development of anemia (OR: 10.28; 95% CI: [5.78‐18.30]). Treatment efficacy was 98.1%. Conclusions Direct‐acting antiviral has been shown to be safe and effective. Therefore, use of ribavirin is questionable due to associated adverse reactions and similar efficacy to other treatments.

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Section: Discussionsupporting

confidence: 89%

Section: Discussioncontrasting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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Predictors of adverse drug reactions associated with ribavirin in direct‐acting antiviral therapies for chronic hepatitis C

Cursino

Monteiro

Duarte

et al. 2019

Pharmacoepidemiology and Drug

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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%

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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Antiviral drugs

Cani¹,

Kavanagh²

2019

Side Effects of Drugs Annual

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Outcome and adverse events in patients with chronic hepatitis C treated with direct-acting antivirals: a clinical randomized study

Cited by 7 publications

References 46 publications

Predictors of adverse drug reactions associated with ribavirin in direct‐acting antiviral therapies for chronic hepatitis C

Predictors of adverse drug reactions associated with ribavirin in direct‐acting antiviral therapies for chronic hepatitis C

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

Antiviral drugs

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