The effect of the first-generation HCV-protease inhibitors boceprevir and telaprevir and the relation to baseline NS3 resistance mutations in genotype 1: experience from a small Swedish cohort

Abstract

Background: The clinical experience with protease-inhibitor (PI) triple regimen appears disappointing regarding effect, side effects, high work load, and costs. This real-world study evaluates baseline and emerging resistance-associated substitutions (RASs) and their significance for treatment outcome.

Method: Thirty-six genotype 1a/b patients treated according to Swedish recommendations during 2011–2013 with triple therapy including pegylated interferon and ribavirin in combination with a protease-inhibitor, either boceprevir (BOC) or telaprevir (TVR), were retrospectively evaluated. Frozen serum samples from the patients were tested for resistance with pan-genotypic population sequencing.

Results: Overall, 56% (20/36) of the patients achieved sustained viral response (SVR). The SVR was comparable between BOC (64%; 9/14) and TVR (50%; 11/22) (p = 0.07), and the IL28B type non-CC (48%; 12/25) and CC (46%; 6/13) (p = 0.77). The SVR was higher in patients without cirrhosis (89.5%; 17/19) (p < 0.0005), in treatment-naïve patients (70%; 14/20) (p = 0.02), and those with low viral load (<800,000 IU/mL) (66.7%; 8/12) (p < 0.0002), compared to those with cirrhosis (17.6%; 3/17), treatment-experienced (37.5%; 6/16), and high viral load (>800,000 IU/mL) (50%; 12/24).

Conclusion: PI triple regimes were highly effective in treatment-naïve patients without cirrhosis, but in this real-world cohort an inferior effect was evident in cirrhotic and treatment-experienced patients. Although tested on a limited sample, the baseline resistance testing seems to have no impact on prediction of therapy outcome. The reason could be that the baseline RASs T54S and V55A have relatively low resistance towards BOC and TVR. Emerging RASs, mainly R155K, with known high resistance to BOC and TVR were frequently found in non-responders.

Keywords:

• Boceprevir
• hepatitis C
• protease inhibitor
• RAS
• resistance association substitution
• telaprevir

Acknowledgements

The important contribution of the staff at the Department of Infectious Diseases, and Mia Wadelius and Hugo Khonke at the Department of Clinical Pharmacology, is gratefully acknowledged.

T.W. and E.L., during their doctor’s studentship in the Department of Infectious Diseases, collected data from the patients’ notes and filed them in a data base. M.K. did the search for stored blood samples and was responsible for the logistic measures and the laboratory work on HCV resistance; she also did parts of the revision of the manuscript, interpretation of resistance data, and revision of tables. A.L. put all the materials together into a final manuscript and did the statistics and tables. J.L. was the advisor in the interpretation of resistance data and also did the revision of the manuscript.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

Financial support was received from the Uppsala-Örebro Regional Research Council, Scandinavian Society for Antimicrobial Chemotherapy Foundation, and the Selander Foundation (J.L.). A.L. was supported by ALF funding from Uppsala County Council and Uppsala University.

Notes on contributors

Midori Kjellin

Midori Kjellin, MSc, PhD student at Clinical Microbiology, Department of Medical Sciences, Uppsala University.

Terése Wesslén

Terése Wesslén, MD student, at Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital.

Erik Löfblad

Erik Löfblad, MD student, at Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital.

Johan Lennerstrand

Johan Lennerstrand, PhD, Associate Professor at Clinical Microbiology, Department of Medical Sciences, Uppsala University.

Anders Lannergård

Anders Lannergård, MD, PhD, Chief Physician at Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital.