uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Prevalence of polymorphisms with significant resistance to NS5A inhibitors in treatment-naive patients with hepatitis C virus genotypes 1a and 3a in Sweden
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
Show others and affiliations
2015 (English)In: INFECTIOUS DISEASES, ISSN 2374-4235, Vol. 47, no 8, p. 555-562Article in journal (Refereed) Published
Abstract [en]

Background: The future treatment of hepatitis C virus (HCV) infection will be combinations of direct-acting antivirals (DAAs) that not only target multiple viral targets, but are also effective against different HCV genotypes. Of the many drug targets in HCV, one promising target is the non-structural 5A protein (NS5A), against which inhibitors, namely daclatasvir, ledipasvir and ombitasvir, have shown potent efficacy. However, since HCV is known to have very high sequence diversity, development of resistance is a problem against but not limited to NS5A inhibitors (i.e. resistance also found against NS3-protease and NS5B non-nucleoside inhibitors), when used in suboptimal combinations. Furthermore, it has been shown that natural resistance against DAAs is present in treatment-naive patients and such baseline resistance will potentially complicate future treatment strategies. Methods: A pan-genotypic population-sequencing method with degenerated primers targeting the NS5A region was developed. We have investigated the prevalence of baseline resistant variants in 127 treatment-naive patients of HCV genotypes 1a, 1b, 2b and 3a. Results: The method could successfully sequence more than 95% of genotype 1a, 1b and 3a samples. Interpretation of fold resistance data against the NS5A inhibitors was done with the help of earlier published phenotypic data. Baseline resistance variants associated with high resistance (1000-50000-fold) was found in three patients: Q30H or Y93N in genotype 1a patients and further Y93H in a genotype 3a patient. Conclusion: Using this method, baseline resistance can be examined and the data could have a potential role in selecting the optimal and cost-efficient treatment for the patient.

Place, publisher, year, edition, pages
2015. Vol. 47, no 8, p. 555-562
Keywords [en]
Hepatitis C virus, NS5A, prevalence, polymorphism, baseline resistance
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:uu:diva-259636DOI: 10.3109/23744235.2015.1028097ISI: 000357738200007PubMedID: 25851241OAI: oai:DiVA.org:uu-259636DiVA, id: diva2:847747
Note

Funding: Uppsala-Orebro Regional Research Council, Selander Foundation

Available from: 2015-08-21 Created: 2015-08-10 Last updated: 2020-03-26Bibliographically approved
In thesis
1. Study of Resistance in Hepatitis C Virus Prior to Treatment with Direct Acting Antivirals
Open this publication in new window or tab >>Study of Resistance in Hepatitis C Virus Prior to Treatment with Direct Acting Antivirals
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The rapid advancement of Hepatitis C (HCV) treatment presents a great challenge to clinicians in optimising therapy for their patients. Genotype (GT), efficacy, side-effects, drug combinations and treatment durations must be tailored to individual patients, considering comorbidities, degree of fibrosis, adherence and antiviral resistance.

Resistance associated substitutions (RASs) may impair treatment response to direct-acting antiviral agents (DAA). Almost all patients who fail treatment acquire RASs that may persist for years. Even treatment-naïve patients can harbour naturally occurring RASs against currently approved DAAs, i.e. resistance at baseline. Prevalence of key NS3 and NS5A-RASs is relatively high (3-9%) at baseline for DAA-treatment-naïve GT1a and 3a patients with population sequencing at 20% cut-off in Sweden and Norway.

The studies in this thesis comprise investigations on the prevalence and the effects of baseline RASs on treatment outcome in patients with HCV GT1 and GT3 receiving personalised treatment based on results from NS3 and NS5A resistance testing. We developed a pan-genotypic population sequencing method for detecting NS5A RASs (Paper I), which is certified and used in routine diagnostics at our laboratory together with our previously developed NS3 RAS sequencing method.  We acquired data on RAS prevalence and treatment outcome from the early DAA management and carried out a non-randomised, prospective real-life study seeking to examine the impact on treatment outcome in patients receiving treatment tailored to baseline resistance testing.

The studies were carried out between 2011 and 2017, one retrospective study comprising patients in the Uppsala region (Paper II) and two prospective studies with patients in a multicentre study involving sites in both in Sweden and Norway (Paper III and IV).

RAS prevalence data from the prospective studies was obtained from a total of 401 patients and was shown to be slightly lower than reported from previous studies. Still, although not statistically significant due to the low prevalence of RASs in the cohort, we could show that there was a trend toward tailoring treatment to baseline RAS testing has a favourable impact on treatment outcome over treatment according to standard recommendations, especially in patients with cirrhosis. The economical and best practise objectives were important factors to consider when treatment costs were high and adverse effects were challenging at the initiation of the studies.

In summary, this doctoral thesis presents results from real-life studies that indicate that tailoring treatment based on baseline RAS-testing have beneficial impact on patients that are treatment experienced and/or patients with cirrhosis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. p. 62
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1658
Keywords
Hepatitis C, HCV, DAA, RAS, resistance-associated substitution, baseline resistance, NS5A, NS3, SVR
National Category
Infectious Medicine
Research subject
Medical Virology; Microbiology; Infectious Diseases
Identifiers
urn:nbn:se:uu:diva-407561 (URN)978-91-513-0920-0 (ISBN)
Public defence
2020-05-19, Jupiter, Hubben, Plan 3, Dag Hammarskjölds Väg 38, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2020-04-27 Created: 2020-03-26 Last updated: 2020-05-19

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

Kjellin, MidoriLannergard, Anders

Search in DiVA

By author/editor
Kjellin, MidoriLannergard, Anders
By organisation
Infection medicineClinical Microbiology and Infectious MedicineInfectious Diseases
Infectious Medicine

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 370 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf