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Ribavirin induces hepatitis C virus genome mutations in chronic hepatitis patients who failed to respond to prior daclatasvir plus asunaprevir therapy
Author(s) -
Saito Yuhei,
Imamura Michio,
Uchida Takuro,
Osawa Mitsutaka,
Teraoka Yuji,
Fujino Hatsue,
Nakahara Takashi,
Ono Atsushi,
Murakami Eisuke,
Kawaoka Tomokazu,
Miki Daiki,
Tsuge Masataka,
Serikawa Masahiro,
Aikata Hiroshi,
AbeChayama Hiromi,
Hayes C. Nelson,
Chayama Kazuaki
Publication year - 2020
Publication title -
journal of medical virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.782
H-Index - 121
eISSN - 1096-9071
pISSN - 0146-6615
DOI - 10.1002/jmv.25602
Subject(s) - daclatasvir , sofosbuvir , ribavirin , hepatitis c virus , virology , replicon , medicine , ns3 , hepatitis c , ledipasvir , subgenomic mrna , virus , gastroenterology , biology , genome , genetics , gene
Ribavirin (RBV) induces nucleotide (nt) substitutions in hepatitis C virus (HCV) genome nonstructural (NS) regions. Although emergence of drug resistance‐associated variants is associated with direct‐acting antiviral treatment failure, the effect of RBV on genome substitutions in such patients is unknown. Genotype 1b HCV subgenomic replicon cells were treated with RBV for 120 hours. Six patients with chronic genotype 1b with HCV‐infected patients who failed to respond to prior daclatasvir plus asunaprevir (DCV/ASV) therapy were treated with 12 weeks of sofosbuvir and ledipasvir plus RBV after 4 weeks of RBV monotherapy. RBV‐induced genome mutations in the HCV NS region (nt3493‐9301) in replicon cells and in patients during 4 weeks of RBV monotherapy were analyzed by deep sequencing. RBV‐associated G‐to‐A and C‐to‐U transitions increased in a dose‐dependent manner in HCV replicon cells after the RBV treatment. In patients with prior DCV/ASV treatment failures, the median serum HCV RNA level was 6.25 ± 0.31 log IU/mL at the start of RBV therapy and decreased significantly to 5.95 ± 0.4 log IU/mL ( P = .03) after 4 weeks of RBV monotherapy. Although predominant HCV genome substitutions rates were similar between nontreatment and RBV‐treatment periods (0.042 and 0.031 per base pair, respectively; P = .248), the frequencies of G‐to‐A and C‐to‐U transitions significantly increased after RBV monotherapy. These transitions were enriched, particularly within the HCV NS3 region in all patients. RBV treatment induces G‐to‐A and C‐to‐U transitions in the HCV genome even in chronic patients with hepatitis C with prior DCV/ASV treatment failures.