Journal of Viral Hepatitis, 2015, 22, 992–1001
doi:10.1111/jvh.12427
Effectiveness of triple therapy with simeprevir for chronic hepatitis C genotype 1b patients with prior telaprevir failure E. Ogawa,1 N. Furusyo,1 K. Dohmen,2 E. Kajiwara,3 A. Kawano,4 H. Nomura,5 K. Takahashi,6 T. Satoh,7 K. Azuma,8 M. Nakamuta,9 T. Koyanagi,10 K. Kotoh,11 S. Shimoda,12 and J. Hayashi13 The Kyushu University Liver Disease Study (KULDS) Group 1
Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan; 2Department of Internal Medicine, Chihaya Hospital,
Fukuoka, Japan; 3Department of Hepatology, Steel Memorial Yawata Hospital, Kitakyushu, Japan; 4Department of Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan; 5The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan; 6Department of Medicine, Hamanomachi Hospital, Fukuoka, Japan; 7Center for Liver Disease, National Hospital Organization Kokura Medical Center, Kitakyushu, Japan; 8
Department of Medicine, Kyushu Central Hospital, Fukuoka, Japan; 9Department of Gastroenterology, Kyushu Medical Center, National Hospital
Organization, Fukuoka, Japan; 10Department of Medicine, Fukuoka City Hospital, Fukuoka, Japan; 11Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 12Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and
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Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan
Received January 2015; accepted for publication April 2015
SUMMARY. Favourable efficacy and safety profiles for sime-
previr in combination with pegylated interferon alpha (PEG-IFNa) and ribavirin (triple therapy) have been shown in clinical trials. This study was carried out to evaluate the effectiveness of simeprevir-based triple therapy for patients with prior telaprevir treatment failure. This multicentre, observational cohort consisted of 345 consecutive Japanese patients infected with HCV genotype 1b, including 20 who had experienced telaprevir-based triple therapy. Amino acid substitutions in the NS3/4A region were identified by direct sequencing at the time of relapse or breakthrough in treatment with telaprevir and at the initiation of treatment with simeprevir. Patients were stratified according to prior response to PEG-IFNa and ribavirin. Of the 20 patients with telaprevir treatment failure, 10 (50.0%) achieved sustained virological response at week 12 after the end of treatment (SVR12). For patients treatment na€ıve [3/4
INTRODUCTION Approximately 180 million people are chronically infected with hepatitis C virus (HCV) worldwide, and it is a major cause of cirrhosis and hepatocellular carcinoma (HCC) Abbreviations: DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IL-28B, interleukin-28B; ITPA, inosine triphosphatase pyrophosphatase; PEG-IFN, pegylated interferon; RVR, rapid virological response; SNP, single nucleoside polymorphism; SVR, sustained virological response. Correspondence: Jun Hayashi, MD, PhD, Kyushu General Internal Medicine Center, Haradoi Hospital, Higashi-Ku, Fukuoka 813-8588, Japan. E-mail:
[email protected]
(75.0%)] or with prior relapse [1/1 (100%)] or partial response [5/6 (83.3%)] to PEG-IFNa and ribavirin, almost all achieved SVR12, mainly because of the improvement of treatment adherence, especially to direct-acting antiviral agent and ribavirin. However, of the nine patients with prior null response to PEG-IFNa and ribavirin, only one (11.1%) achieved SVR12, despite all having received an adequate treatment dosage, and five (55.6%) achieved rapid virological response. The treatment outcome of simeprevir-based triple therapy for HCV genotype 1b patients with prior telaprevir failure depended on the prior response to PEG-IFNa and ribavirin. For patients with prior null response to PEG-IFNa and ribavirin, retreatment with simeprevir-based triple therapy is not a useful option. Keywords: hepatitis C virus, pegylated interferon, ribavirin, simeprevir, telaprevir.
[1,2]. Although eradicating HCV by antiviral treatment leads to a reduced risk of various liver-related complications [3,4], the only therapeutic option until recently was the combination of pegylated interferon alpha (PEG-IFNa) and ribavirin, both indirect antiviral agents. Antiviral treatment for chronic HCV infection has advanced considerably during the past half decade based on research that has increased our understanding of the molecular biology of the HCV. As a result, the direct-acting antiviral (DAA) agents, telaprevir and boceprevir, which target a viral nonstructural protein, the NS3/4A protease, have been available since 2011. Triple therapy with telaprevir in addition to PEG-IFNa and ribavirin significantly improved the efficacy of treatment, although it requires © 2015 John Wiley & Sons Ltd
Retreatment with simeprevir-based therapy frequent clinical monitoring to protect against severe adverse effects, such as impaired renal function, anaemia or eruptions [5–7]. Most patients with virological failure are in a high HCC risk group with advanced fibrosis [8]; thus, new antiviral treatments for these patients are most urgently required. An improved second-generation HCV NS3/4A protease inhibitor, simeprevir, became available for clinical use at the end of 2013. Clinical trials found favourable efficacy, safety and tolerability profiles for simeprevir-based triple therapy in comparison with a placebo group with PEGIFNa and ribavirin alone [9–14]. However, there are no clinical data available for the efficacy and safety of simeprevir-based triple therapy for patients with prior telaprevir failure. Almost all Japanese HCV patients are infected with genotype 1b, which has a higher genetic barrier for resistance than genotype 1a, and the profile of drug resistance mutation differs slightly between telaprevir and simeprevir; thus, these data will be of great future clinical utility by creating diversity in the treatment choices, especially in Asia. This multicentre cohort study of chronic hepatitis C genotype 1b patients with prior telaprevir treatment failure was carried out in a real-world clinical setting to evaluate the effectiveness and safety of simeprevir-based triple therapy.
PATIENTS AND METHODS Patients The Kyushu University Liver Disease Study (KULDS) Group consists of Kyushu University Hospital and its affiliated hospitals located in the northern Kyushu area of Japan. KULDS began researching the effectiveness and safety of simeprevir-based triple therapy in December 2013, in a real-world clinical setting. This observational cohort consisted of 345 consecutive Japanese patients who registered by December 2014. From all studied patients, we selected those who had previously experienced telaprevir-based triple therapy. Eligible patients were aged 20 years and older with confirmed chronic HCV genotype 1b infection. Exclusion criteria included positivity for antibody to human immunodeficiency virus or positivity for hepatitis B surface antigen, clinical or biochemical evidence of hepatic decompensation (Child-Pugh B or C), and any non-HCV-related liver disease, such as autoimmune hepatitis or primary biliary cirrhosis. After exclusions, the data of 20 patients were available for analysis. The study was conducted in accordance with the ethical principles of the 2008 Declaration of Helsinki and was approved by the Ethics Committee of Kyushu University hospital. Written informed consent was obtained from all patients before enrolment. This study is registered as a clinical study on the University Hospital Medical Information Network (ID 000016205). © 2015 John Wiley & Sons Ltd
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Clinical, laboratory and virological assessment Clinical parameters were measured by standard laboratory techniques at a commercial laboratory (SRL Laboratory, Tokyo, Japan). Body mass index was calculated as weight in kilograms/height in square metres. The estimated glomerular filtration rate was calculated based on the modification of diet in renal disease formula. Blood samples were obtained at baseline, every week from weeks 1 to 8, at 4week intervals thereafter until the end of treatment and then at 4-week intervals until 12 weeks after the end of treatment. HCV RNA was measured using real-time reverse transcriptase PCR assay (COBAS TaqMan HCV assay) (Roche Diagnostics, Tokyo, Japan), with a lower limit of quantitation of 15 IU/mL and an outer limit of quantitation of 6.9X107 IU/mL (1.2–7.8 log IU/mL refers to log10 IU/mL). Treatment outcome was categorized as follows: sustained virological response (SVR)12, undetectable HCV RNA at week 12 after the end of treatment: rapid virological response (RVR), undetectable HCV RNA at week 4. Prior treatment response to PEG-IFNa and ribavirin was categorized as follows: relapse, relapse of serum HCV RNA after treatment of patients whose HCV RNA level was undetectable at the end of treatment and the reappearance of HCV RNA at any time during treatment after virological response (breakthrough): partial response, a more than 2 log10 IU/mL decrease in the HCV RNA level from baseline until week 12 but detectable HCV RNA at last measurement on treatment but not earlier than week 20: null response, a decrease in the HCV RNA level of less than 2 log10 IU/mL at week 12.
Assessment of liver fibrosis Fibrosis status was assessed by biopsy or FIB-4 index. Liver biopsy was performed 1 month before the initiation of treatment with telaprevir. The minimum length of the liver biopsy was 15 mm, and at least 10 complete portal tracts were necessary for inclusion. For each specimen, the stage of fibrosis was established according to the METAVIR score [15]. FIB-4 index uses the following formula: age (years) 9 aspartate aminotransferase (U/L)/{platelet count (109/L) 9 [alanine aminotransferase (U/L)]1/2} [16]. A threshold value of >3.25 is the predictive value for the existence of advanced fibrosis that corresponds to METAVIR F3-4 stage [16,17].
Host DNA genotyping testing DNA genotyping was performed at baseline to explore possible associations between the host genetic polymorphism and the treatment outcome or severe anaemia. Human genomic DNA was extracted from peripheral blood. Genotyping of the interleukin-28B (IL-28B) (rs8099917) [18] and inosine
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triphosphatase pyrophosphatase (ITPA) (rs1127354) [19] genes was performed using the ABI TaqMan allelic discrimination kit (7500 Real-Time PCR System; Applied Biosystems, Carlsbad, CA, USA). The alleles of the IL-28B and ITPA single nucleoside polymorphisms (SNPs) were determined for all patients.
Assessment of NS3/4A protease inhibitor-resistant variants HCV RNA was extracted from blood serum and amplified by polymerase chain reaction with nested primers appropriate for the NS3 region. The genome sequences of N-terminal 609 nucleotides in the NS3 region were determined by direct sequencing [20]. All patients were examined for NS3/4A protease inhibitor-resistant variants at the time of relapse or breakthrough in treatment with telaprevir and at the initiation of treatment with simeprevir. These included V36A/G/L/M, T54A/S, Q80R/K, R155K/T/Q, A156S/V/T and D168A/V/T/H [21]. These variants have been identified as amino acid (aa) substitutions resistant to telaprevir (aa 36, aa 54, aa 155 and aa 156) and simeprevir (aa 80, aa 155, aa 156 and aa 168) [21,22].
Antiviral treatment Patients received a combination treatment of simeprevir (Sovriad; Janssen Pharmaceutical K.K., Tokyo, Japan) (100 mg once daily, orally), PEG-IFNa (2a or 2b) and ribavirin for 12 weeks, followed by an additional 12 weeks of PEG-IFNa and ribavirin alone. PEG-IFNa-2a (Pegasys; Chugai Co., Tokyo, Japan) (180 lg) or PEG-IFNa-2b (PegIntron; MSD K.K., Tokyo, Japan) (1.5 lg/kg) was administered as once-weekly subcutaneous injections. Ribavirin, CoPegas (Chugai) or Rebetol (MSD), was administered in combination with PEG-IFNa-2a or PEG-IFNa-2b, respectively. Ribavirin was given orally at a daily dose of 600–1000 mg based on bodyweight (600 mg for patients weighing 80 kg). All treatments were discontinued for patients with
