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Unmasking of a hepatitis c genotype 3a/1b dual infection in an individual treated with elbasvir/ grazoprevir

  • Rob W. van der Pluijm
    Correspondence
    Corresponding author. , Amsterdam University Medical Centers, University of Amsterdam, D3-209, Department of Internal Medicine, Division of Infectious Diseases, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
    Affiliations
    Division of Infectious Diseases, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, location University of Amsterdam, The Netherlands
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  • Loek P. Smits
    Affiliations
    Division of Infectious Diseases, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, location University of Amsterdam, The Netherlands
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  • Sjoerd P. Rebers
    Affiliations
    Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Centers, location University of Amsterdam, The Netherlands
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  • Janke Schinkel
    Affiliations
    Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Centers, location University of Amsterdam, The Netherlands
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  • Marc van der Valk
    Affiliations
    Division of Infectious Diseases, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, location University of Amsterdam, The Netherlands
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Published:November 22, 2022DOI:https://doi.org/10.1016/j.jhep.2022.11.016
      To the editor:
      Pan-genotypic direct-acting antivirals (DAA) for the treatment of hepatitis C viral (HCV) infections remain expensive. To reduce costs, genotype-specific regimes could be considered, according to the EASL guidelines.
      • Pawlotsky J.M.
      • Negro F.
      • Aghemo A.
      • Berenguer M.
      • Dalgard O.
      • Dusheiko G.
      • et al.
      EASL recommendations on treatment of hepatitis C: Final update of the series☆.
      The presence of mixed genotype HCV infections has been reported, and detection rates have been found to be method dependent.
      • Fernández-Caso B.
      • Fernández-Caballero J.Á.
      • Chueca N.
      • Rojo E.
      • de Salazar A.
      • García Buey L.
      • et al.
      Infection with multiple hepatitis C virus genotypes detected using commercial tests should be confirmed using next generation sequencing.
      The identification of a second infection with a different genotype could be of importance when considering genotype specific DAA.
      A 33-year-old male presented to our outpatient clinic with a newly diagnosed HIV-1/HCV co-infection with a CD4-count of 470/millilitres, CDC-classification B2. He had recently migrated from the Ukraine to the Netherlands and was not treated previously for HIV or HCV. As a potential source of infection, he reported the use of unsterilized needles during a hospital visit 10 years prior. He reported no intravenous drug use nor sex with men. HCV-RNA viral load was 1,500,000 IU/ml and a genotype 1b was reported
      • Murphy D.G.
      • Willems B.
      • Deschênes M.
      • Hilzenrat N.
      • Mousseau R.
      • Sabbah S.
      Use of sequence analysis of the NS5B region for routine genotyping of hepatitis C virus with reference to C/E1 and 5′ untranslated region sequences.
      . FibroScan showed no signs of fibrosis (6.5 kPa; Metavir F0-F1). Treatment with bictegravir/emtricitabine/tenofoviralafenamide was initiated for the HIV infection and 18 weeks thereafter the patient started a 12-week course of elbasvir/grazoprevir according to Dutch HCV treatment guidelines.
      Six weeks after HCV treatment initiation the HCV-RNA load was 1,100,000 IU/ml. He reported no issues with adherence and HIV-1 RNA was undetectable in the same sample. A reinfection or baseline mixed infection was suspected, and genotyping showed the presence of a genotype 3a infection at this time point. Sequence analysis using Sanger sequencing showed an A156G RAS (resistance associated mutation) in the NS3 gene, which is associated with a 1654 fold reduced susceptibility to glecaprevir.
      • Ng T.I.
      • Tripathi R.
      • Reisch T.
      • Lu L.
      • Middleton T.
      • Hopkins T.A.
      • et al.
      In vitro antiviral activity and resistance profile of the next-generation hepatitis C virus NS3/4A protease inhibitor glecaprevir.
      In addition, we detected a N244T as potential RAS in the NS5B gene, of which the clinical significance is unknown. No RAS in the NS5A gene were detected.
      Reanalysing the raw Sanger sequence data of the sample prior to initiation of DAA by specifically investigating the presence of minor or ambiguous peaks, suggested the presence of a minority genotype 3a co-infection, without mutations in NS3, but with the previously described N244T mutation in the NS5B gene. The elbasvir/grazoprevir was stopped and 6 weeks after cessation the genotype 1b infection was not detected anymore using the same technique. We started a 12-week course of the pan-genotypic treatment sofosbuvir/velpatasvir/voxilaprevir (Vosevi) resulting in a sustained virological response.
      This case demonstrates that in individuals treated with genotype specific DAA genotyping and resistance analysis at failure should be considered prior to retreatment. Alternatively, pan-genotypic regimens could be considered as a treatment option.

      Conflict of interest

      MvdV has received consultancy fees from Gilead, MSD, BMS, Johnson & Johnson, ViiV healthcare. The other authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

      Financial support

      None other than salaries provided for clinical work.

      Authors’ contributions

      Dr. Rob van der Pluijm and dr. Loek Smits (both MDs/Infectious disease fellows) treated this patient for HIV and hepatitis C under supervision of Prof. Marc van der Valk (MD/Infectious disease specialist). Sjoerd Rebers (Research technician) and Dr. Janke Schinkel (MD/clinical virologist) performed the genotyping and suggested the use of sofosbuvir/velpatasvir/voxilaprevir for the treatment of this combined (genotype 1b and 3a) hepatitis C infection. All authors were involved in writing this letter.

      References

        • Pawlotsky J.M.
        • Negro F.
        • Aghemo A.
        • Berenguer M.
        • Dalgard O.
        • Dusheiko G.
        • et al.
        EASL recommendations on treatment of hepatitis C: Final update of the series☆.
        J Hepatol. 2020;
        • Fernández-Caso B.
        • Fernández-Caballero J.Á.
        • Chueca N.
        • Rojo E.
        • de Salazar A.
        • García Buey L.
        • et al.
        Infection with multiple hepatitis C virus genotypes detected using commercial tests should be confirmed using next generation sequencing.
        Sci Rep. 2019;
        • Murphy D.G.
        • Willems B.
        • Deschênes M.
        • Hilzenrat N.
        • Mousseau R.
        • Sabbah S.
        Use of sequence analysis of the NS5B region for routine genotyping of hepatitis C virus with reference to C/E1 and 5′ untranslated region sequences.
        J Clin Microbiol. 2007;
        • Ng T.I.
        • Tripathi R.
        • Reisch T.
        • Lu L.
        • Middleton T.
        • Hopkins T.A.
        • et al.
        In vitro antiviral activity and resistance profile of the next-generation hepatitis C virus NS3/4A protease inhibitor glecaprevir.
        Antimicrob Agents Chemother. 2018;