1887

Abstract

Combination therapy with glecaprevir (GLE) and pibrentasvir (PIB) has high efficacy for pan-genotypic hepatitis C virus (HCV)-infected patients. However, the efficacy for patients who acquired potent NS5A inhibitor resistance-associated variants (RAVs) as a result of failure to respond to previous direct-acting antiviral (DAA) therapies is unclear. We investigated the efficacy of GLE/PIB treatment for genotype 1b HCV strains containing RAVs using subgenomic replicon systems and human hepatocyte transplanted mice. Mice were injected with serum samples obtained from a DAA-naïve patient or daclatasvir plus asunaprevir (DCV/ASV) treatment failures including NS5A-L31M/Y93H, -P58S/A92K or -P32 deletion (P32del) RAVs, then treated with GLE/PIB. HCV was eliminated by GLE/PIB treatment in mice with wild-type and NS5A-L31M/Y93H but relapsed in mice with NS5A-P58S/A92K, followed by emergence of additional NS5A mutations after cessation of the treatment. In NS5A-P32del-infected mice, serum HCV RNA remained positive during the GLE/PIB treatment. NS5A-P58S/A92K showed 1.5-fold resistance to PIB relative to wild-type based on analysis using HCV subgenomic replicon systems. When mice were administered various proportions of HCV wild-type and P32del strains and treated with GLE/PIB, serum HCV RNA remained positive in mice with high frequencies of P32del. In these mice, the P32del was undetectable by deep sequencing before GLE/PIB treatment, but P32del strains relapsed after cessation of the GLE/PIB treatment. GLE/PIB is effective for wild-type and NS5A-L31M/Y93H HCV strains, but the effect seems to be low for P58S/A92K and NS5A-P32del RAVs. Although NS5A-P32del was not detected, the mutation may be present at low frequency in DCV/ASV treatment failures.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001268
2019-06-14
2019-09-23
Loading full text...

Full text loading...

References

  1. Sarrazin C. The importance of resistance to direct antiviral drugs in HCV infection in clinical practice. J Hepatol 2016;64:486–504 [CrossRef]
    [Google Scholar]
  2. Pawlotsky JM. Hepatitis C virus resistance to direct-acting antiviral drugs in interferon-free regimens. Gastroenterology 2016;151:70–86 [CrossRef]
    [Google Scholar]
  3. Kumada H, Suzuki Y, Ikeda K, Toyota J, Karino Y et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology 2014;59:2083–2091 [CrossRef]
    [Google Scholar]
  4. Itakura J, Kurosaki M, Higuchi M, Takada H, Nakakuki N et al. Resistance-associated NS5A variants of hepatitis C virus are susceptible to interferon-based therapy. PLoS One 2015;10:e0138060 [CrossRef]
    [Google Scholar]
  5. Uchida Y, Kouyama JI, Naiki K, Sugawara K, Inao M et al. Development of rare resistance-associated variants that are extremely tolerant against NS5A inhibitors during daclatasvir/asunaprevir therapy by a two-hit mechanism. Hepatol Res 2016;46:1234–1246 [CrossRef]
    [Google Scholar]
  6. Ng TI, Tripathi R, Reisch T, Lu L, Middleton T 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;62:e01620–17 [CrossRef]
    [Google Scholar]
  7. Ng TI, Krishnan P, Pilot-Matias T, Kati W, Schnell G et al. In Vitro antiviral activity and resistance profile of the next-generation hepatitis C virus NS5A inhibitor pibrentasvir. Antimicrob Agents Chemother 2017;61:e02558–16 [CrossRef]
    [Google Scholar]
  8. Kwo PY, Poordad F, Asatryan A, Wang S, Wyles DL et al. Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis. J Hepatol 2017;67:263–271 [CrossRef]
    [Google Scholar]
  9. Asselah T, Kowdley KV, Zadeikis N, Wang S, Hassanein T et al. Efficacy of glecaprevir/pibrentasvir for 8 or 12 Weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis. Clin Gastroenterol Hepatol 2018;16:417–426 [CrossRef]
    [Google Scholar]
  10. Forns X, Lee SS, Valdes J, Lens S, Ghalib R et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial. Lancet Infect Dis 2017;17:1062–1068 [CrossRef]
    [Google Scholar]
  11. Gane E, Lawitz E, Pugatch D, Papatheodoridis G, Bräu N et al. Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment. N Engl J Med 2017;377:1448–1455 [CrossRef]
    [Google Scholar]
  12. Poordad F, Felizarta F, Asatryan A, Sulkowski MS, Reindollar RW et al. Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment. Hepatology 2017;66:389–397 [CrossRef]
    [Google Scholar]
  13. Krishnan P, Schnell G, Tripathi R, Beyer J, Reisch T et al. Integrated resistance analysis of CERTAIN-1 and CERTAIN-2 studies in hepatitis C virus-infected patients receiving glecaprevir and pibrentasvir in Japan. Antimicrob Agents Chemother 2018;62:e02217–17 [CrossRef]
    [Google Scholar]
  14. Tateno C, Kawase Y, Tobita Y, Hamamura S, Ohshita H et al. Generation of novel chimeric mice with humanized livers by using hemizygous cDNA-uPA/SCID mice. PLoS One 2015;10:e0142145 [CrossRef]
    [Google Scholar]
  15. Uchida T, Imamura M, Kan H, Hiraga N, Hayes CN et al. Usefulness of humanized cDNA-uPA/SCID mice for the study of hepatitis B virus and hepatitis C virus virology. J Gen Virol 2017;98:1040–1047 [CrossRef]
    [Google Scholar]
  16. Teraoka Y, Uchida T, Imamura M, Osawa M, Tsuge M et al. Prevalence of NS5A resistance associated variants in NS5A inhibitor treatment failures and an effective treatment for NS5A-P32 deleted hepatitis C virus in humanized mice. Biochem Biophys Res Commun 2018;500:152–157 [CrossRef]
    [Google Scholar]
  17. Yoshimi S, Imamura M, Murakami E, Hiraga N, Tsuge M et al. Long term persistence of NS5A inhibitor-resistant hepatitis C virus in patients who failed daclatasvir and asunaprevir therapy. J Med Virol 2015;87:1913–1920 [CrossRef]
    [Google Scholar]
  18. Cheng G, Tian Y, Doehle B, Peng B, Corsa A et al. In vitro antiviral activity and resistance profile characterization of the hepatitis C virus NS5A inhibitor ledipasvir. Antimicrob Agents Chemother 2016;60:1847–1853 [CrossRef]
    [Google Scholar]
  19. Akuta N, Sezaki H, Suzuki F, Fujiyama S, Kawamura Y et al. Retreatment efficacy and predictors of ledipasvir plus sofosbuvir to HCV genotype 1 in Japan. J Med Virol 2017;89:284–290 [CrossRef]
    [Google Scholar]
  20. Kumada H, Watanabe T, Suzuki F, Ikeda K, Sato K et al. Efficacy and safety of glecaprevir/pibrentasvir in HCV-infected Japanese patients with prior DAA experience, severe renal impairment, or genotype 3 infection. J Gastroenterol 2018;53:566–575 [CrossRef]
    [Google Scholar]
  21. Itakura J, Kurosaki M, Hasebe C, Osaki Y, Joko K et al. Complex pattern of resistance-associated substitutions of hepatitis C virus after daclatasvir/asunaprevir treatment failure. PLoS One 2016;11:e0165339 [CrossRef]
    [Google Scholar]
  22. Doi A, Hikita H, Sakamori R, Tahata Y, Kai Y et al. Nonstructural protein 5A/P32 deletion after failure of ledipasvir/sofosbuvir in hepatitis C virus genotype 1b infection. Hepatology 2018;68:380–383 [CrossRef]
    [Google Scholar]
  23. Gane EJ, Shiffman ML, Etzkorn K, Morelli G, Stedman CAM et al. Sofosbuvir-velpatasvir with ribavirin for 24 weeks in hepatitis C virus patients previously treated with a direct-acting antiviral regimen. Hepatology 2017;66:1083–1089 [CrossRef]
    [Google Scholar]
  24. Lawitz E, Poordad F, Wells J, Hyland RH, Yang Y et al. Sofosbuvir-velpatasvir-voxilaprevir with or without ribavirin in direct-acting antiviral-experienced patients with genotype 1 hepatitis C virus. Hepatology 2017;65:1803–1809 [CrossRef]
    [Google Scholar]
  25. Kimura T, Imamura M, Hiraga N, Hatakeyama T, Miki D et al. Establishment of an infectious genotype 1b hepatitis C virus clone in human hepatocyte chimeric mice. J Gen Virol 2008;89:2108–2113 [CrossRef]
    [Google Scholar]
  26. Hiraga N, Imamura M, Tsuge M, Noguchi C, Takahashi S et al. Infection of human hepatocyte chimeric mouse with genetically engineered hepatitis C virus and its susceptibility to interferon. FEBS Lett 2007;581:1983–1987 [CrossRef]
    [Google Scholar]
  27. Miyanari Y, Hijikata M, Yamaji M, Hosaka M, Takahashi H et al. Hepatitis C virus non-structural proteins in the probable membranous compartment function in viral genome replication. J Biol Chem 2003;278:50301–50308 [CrossRef]
    [Google Scholar]
  28. Krieger N, Lohmann V, Bartenschlager R. Enhancement of hepatitis C virus RNA replication by cell culture-adaptive mutations. J Virol 2001;75:4614–4624 [CrossRef]
    [Google Scholar]
  29. Date T, Morikawa K, Tanaka Y, Tanaka-Kaneko K, Sata T et al. Replication and infectivity of a novel genotype 1b hepatitis C virus clone. Microbiol Immunol 2012;56:308–317 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001268
Loading
/content/journal/jgv/10.1099/jgv.0.001268
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error