Addition of ribavirin to daclatasvir plus asunaprevir for chronic ...

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Journal of the Formosan Medical Association (2016) xx, 1e5

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.jfma-online.com

ORIGINAL ARTICLE

Addition of ribavirin to daclatasvir plus asunaprevir for chronic hepatitis C 1b patients with baseline NS5A resistance-associated variants improved response Chun-Ming Hong a, Chun-Jen Liu b, Shiou-Hwei Yeh c, Pei-Jer Chen a,* a

Department of Traumatology, National Taiwan University Hospital, Taipei, Taiwan Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan c Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan b

Received 11 September 2016; received in revised form 31 October 2016; accepted 30 November 2016

KEYWORDS direct-acting antivirals; hepatitis C; resistance-associated variant

Background/Purpose: Daclatasvir is a nonstructural protein 5A inhibitor with potent activity against hepatitis C virus genotypes 1e6 in vitro, and asunaprevir is a nonstructural protein 3 protease inhibitor with activity against genotypes 1, 4, 5, and 6. Despite a 90% sustained virologic response (SVR) rate, the SVR rate in patients with baseline NS5A-L31/Y93H polymorphisms decreased to around 40%. Therefore, an alternative regimen under the consideration of cost-effectiveness would be important. Whether the addition of ribavirin could improve the SVR rate among this group of patients remains unknown and hence our case series was reported. Methods: For six adult chronic hepatitis C 1b patients with a pre-existing NS5A-Y93H (>20%) polymorphism, we added ribavirin (800 mg/d) to daclatasvir/asunaprevir for 24 weeks and followed through 12-weeks post-treatment. Four of these patients received interferon/ribavirin treatment before but relapsed, while the other two were naı¨ve cases. Two of them had liver cirrhosis and one had hepatocellular carcinoma postcurative therapy. The primary efficacy end-point was undetectable hepatitis C virus RNA (hepatitis C virus RNA level of < 25 IU/mL) at 12 weeks after the end of the treatment (SVR12). Results: In total, five cases reached SVR12 eventually (SVR rate: 83%; 95% confidence interval: 18.6e99.1%). However, the viral load of one remaining patient rebounded from the 24th week

Conflicts of interest: The authors have no conflicts of interest relevant to this article. * Corresponding author. Department of Internal Medicine, National Taiwan University Hospital, Number 7, Chung-Shan South Road, Taipei 100, Taiwan. E-mail address: [email protected] (P.-J. Chen). http://dx.doi.org/10.1016/j.jfma.2016.11.014 0929-6646/Copyright ª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Hong C-M, et al., Addition of ribavirin to daclatasvir plus asunaprevir for chronic hepatitis C 1b patients with baseline NS5A resistance-associated variants improved response, Journal of the Formosan Medical Association (2016), http:// dx.doi.org/10.1016/j.jfma.2016.11.014

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C.-M. Hong et al. of treatment. No patients developed significant adverse effects during and after the treatment. Conclusion: In genotype 1b chronic hepatitis C patients with NS5A-Y93H polymorphism, the addition of ribavirin to daclatasvir/asunaprevir may increase the SVR12 rate with minimal side effects, and thus deserves more comprehensive trials in resource-limited areas. Copyright ª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

Introduction Chronic hepatitis C virus (HCV) infection is associated with progressive liver disease that can lead to cirrhosis and hepatocellular carcinoma. Current epidemiological studies estimate that 130e150 million people worldwide are chronically infected with HCV, resulting in up to 350,000 deaths annually.1,2 In Taiwan, about 578,000 people are chronically infected with HCV and the most prevalent genotype is genotype 1b, which accounts for more than 50% of all HCV infections.3e6 In the past few decades, combination therapy with pegylated-interferon and ribavirin (RBV) achieves sustained virologic response (SVR) rates of 40e50% in genotype 1 patients7; but is associated with significant adverse effects. In 2011, the first direct-acting antiviral agents (DAAs), boceprevir and telaprevir, were introduced. In Western countries, telaprevir and boceprevir were approved initially for the treatment of genotype 1 chronic HCV infection in combination with pegylated interferon and RBV. Nonetheless, severe drugedrug interactions can occur and the use of the first-generation protease inhibitors has therefore been significantly restricted. Later on, sofosbuvir/RBV and sofosbuvir/ledipasvir regimens were approved as oral antiHCV agents for genotype 2 and genotype 1/4, respectively. In late June 2016, the U.S. Food and Drug Administration just approved epclusa (sofosbuvir 400mg/velpatasvir 100mg) which is the first and only all-oral, pangenotypic single tablet regimen. Meanwhile, in northeast Asia, the first DAAs approved are daclatasvir (DCV) and asunaprevir (ASV) in Japan and Korea. DCV is a nonstructural protein 5A (NS5A) inhibitor with activity against HCV genotypes 1e6 in vitro,8 while ASV is a nonstructural protein 3 (NS3) protease inhibitor with activity against genotypes 1, 4, 5, and 6.9 The all-oral, interferon-free combination of DCV and ASV provided high rates (overall w90%) of SVR and was welltolerated in genotype 1b-infected patients in global and Asia studies.10,11 Among HCV genotype 1b-infected patients who experience virologic escape with DCV and ASV, the most common resistance-associated variants (RAVs) detected together occur at NS5A positions L31 and Y93, and NS3 position D168. The frequency of NS5A inhibitor-resistant variants in DAA-naı¨ve patients is about 4% worldwide but about 11e23% in Japan’s genotype 1b patient population.12 Since the SVR rates drop dramatically in both prior null responders and those who are intolerable/ineligible to pegylated-interferon/RBV with a pre-existing NS5A-Y93H polymorphism, the detection for RAVs before therapy would be beneficial for predicting the treatment response.

In addition, the genotype distribution of HCV in Taiwan is similar to that in Japan, with genotype 1b as the major one. For those with a baseline NS5A RAV, currently there are many new regimens [sofosbuvir/ledipasvir, or Viekira PAK (ombitasvir, paritaprevir, ritonavir/dasabuvir, etc.)]. However, these new DAAs are still very expensive. We therefore evaluated the possibility of the addition of RBV to investigate its cost-effectiveness. A recent study enrolling nine of the 10 patients with human immunodeficiency virus/HCV coinfection who experienced virologic failure after ledipasvir/sofosbuvir treatment provided evidence for the role of RBV.13 After relapse, seven had baseline or emerging NS5A-RAVs. Despite this, the nine relapsed patients were treated again for 24 weeks with ledipasvir/sofosbuvir plus RBV. Eight of the nine (89%) patients achieved SVR12. The results implied that the addition of RBV may be an effective salvage therapy for HCV patients with NS5A RAVs. In this case series, we report the efficacy and adverse effects of treating HCV patients with baseline NS5A RAVs using a combination of DCV and ASV with RBV.

Patients and methods Patients and data collection This open-label study was conducted at National Taiwan University Hospital after approval (Institutional Review Board/Research Ethics Committee Number is 201607052RINC). Exclusion criteria were patients with: (1) clinical or biochemical evidence of decompensated cirrhosis (Child-Pugh classification B or C); and (2) the presence of hepatocellular carcinoma. DCV was administered orally at a dose of 60 mg once daily, and ASV was administered orally at a dose of 100 mg twice daily. Of the six patients, four were men and two were women. Four patients were pegylated-interferoneRBV treatmentexperienced, while two were treatment-naı¨ve. Meanwhile, two patients had liver cirrhosis. Pre-existing NS5AY93H polymorphism was found among these six genotype 1b chronic HCV patients, but no NS5A L31 variants were detected. Ribavirin was added to these six patients for 24 weeks and followed through for 12-weeks post-treatment. The primary efficacy end-point was undetectable HCV RNA (an HCV RNA level of < 25 IU/mL) at 12 weeks after the end of the treatment (SVR12). All patients were assessed for safety by physical examination and by review of adverse events and clinical laboratory testing of blood samples on the 1st day of

Please cite this article in press as: Hong C-M, et al., Addition of ribavirin to daclatasvir plus asunaprevir for chronic hepatitis C 1b patients with baseline NS5A resistance-associated variants improved response, Journal of the Formosan Medical Association (2016), http:// dx.doi.org/10.1016/j.jfma.2016.11.014

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retreatment, Week 12, Week 16, and Week 20 during treatment, and at the end of treatment.

Determination of HCV NS5A N31 and Y95 polymorphisms The drug-associated variant at amino acid 31 and 75 in the HCV NS5A region was assessed with direct sequencing as shown in the Supplementary data.

Results Baseline characteristics All patients were Taiwanese. The median age of the patients (6 cases: 4 men and 2 women) was 68 years (Table 1). All patients had Y93H substitution at baseline, though no RAV was detected at L31.

Adverse events leading to discontinuation Overall, none of the patients discontinued the treatment because of adverse events. Among the patients with the addition of RBV, some minor adverse effects were noted such as skin itching, mild fever, decreased hematocrit, and face flushing. No major adverse effect or death was noted.

Clinical findings Five cases became HCV-RNA undetectable at the 12th week after the therapy (Figure 1). However, the viral load of one patient reached undetectable at Week 12 but then rebounded to 2,560,000 IU/mL at the 24th week of treatment. The patient with virologic breakthrough had liver cirrhosis and was treatment-experienced.

Discussion With the advent of direct-acting antiviral agents, the treatment for chronic HCV has reached another milestone and the treatment response is satisfactory in general. Table 1

Basic characteristics of the six patients.

Sex Age (y) Treatment Liver NS5A RAV cirrhosis naı¨ve/ experienced Cases no. 1a M 62 2b F 68 3 M 72 4 M 76 5 F 63 6 M 48

However, many obstacles remain to be overcome. The emergence of RAVs is one of the major issues. To date, treatment guidelines for patients with emergent RAVs have not been fully established. The most recent Japanese guideline recommends pretreatment analysis of NS5A L31/ Y93 RAVs before DSV plus ASV therapy, while the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases treatment guidelines do not recommend pretreatment resistance testing except in the case of NS3 Q80K variants in simeprevir-based therapy. Because DSV plus ASV has not been approved in Europe and America, it is therefore not recommended to check RAV before treatment. However, the American Association for the Study of Liver Diseases guidelines suggest that treatment resistance testing should be performed prior to retreatment in patients for whom prior NS5A therapy had failed, although no specific recommendations are provided.14e16 The best strategies to treat this population await more clinical studies. In resource-restricted areas or countries, the unmet need is even more significant because new DAAs are very costly. In our case series, we reported the experience of addition of RBV to ASV plus DSV dual therapy for patients with HCV genotype 1b infection and a baseline NS5A polymorphism. Although the exact mechanism and role of RBV is still unclear, several putative mechanisms have been proposed. The direct inhibition of the viral RNA polymerase is one of the proposed mechanisms. Another proposed mechanism is the antiviral activity that is related to a depletion of intracellular guanosine triphosphate pools caused by the inhibition of the inosine monophosphate dehydrogenase enzyme by RBV.17 Moreover, the mutagenic properties of RBV leading to “error catastrophe” have been studied. A recent study revealed that RBV exerts a mutagenic effect on HCV by inducing nucleotide transitions, suggesting that this effect could be a relevant factor explaining the antiviral activity of RBV.18 In summary, RBV may act through different mechanisms: (1) a direct antiviral activity partly explained by mutagenic properties; and (2) an indirect biochemical effect through an unknown mechanism. The preliminary results of our case series imply that further investigation is essential, especially in resource-limited areas.

TE TE TN TE TN TE

Y Y N N N N

Y93H/L31 Y93H(mixed)/L31 Y93H/L31 Y93H/L31 Y93H/L31 Y93H/L31

Ribavirin Baseline HCV ALT Cre Treatment VR24 RNA (IU/mL) (U/L) (mg/dL) start date

Y Y Y Y Y Y

1,980,000 321,000 1,250,000 4,960,000 1,470,000 1,279,989

30 121 23 18 80 48

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SVR12

2015/12/10 2,560,000 2015/12/17 UD 2015/10/27 UD 2015/03/10 UD 2015/03/10 UD 2014/12/02 UD

ALT Z alanine transaminase; Cre Z creatinine; F Z female; HCV Z hepatitis C virus; M Z male; RAV Z resistance-associated variants; SVR Z sustained virologic response; TE Z treatment experience; TN Z treat naive; UD Z undetectable; Y Z yes. a Relapsed case. b The patient had hepatocellular carcinoma status postcurative therapy.


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Figure 1 Dynamic change of hepatitis C virus (HCV) viral load of the six patients in our study. Five patients reached sustained virologic response (SVR)12, while the viral load of one patient rebounded from the 24th week of treatment.

As for adverse effects, some minor adverse effects were noted in our case series such as skin itching, mild fever, anemia, and face flushing. The adverse effects may be related to RBV. The patients could tolerate these minor adverse effects and no discontinuation of therapy was documented. No major adverse effect or death was noted. Our study has clinical implications especially for resource-limited areas or countries. The addition of RBV can be a cost-effective strategy for the patients with a preexisting NS5A RAVs. However, there are limitations in our case series. Firstly, the number of patients in our case series was small. Secondly, we may need more cases without the addition of RBV, whose renal functions are within the normal range, as another set of control. In summary, our preliminary data show that the addition of RBV could improve the SVR rates in genotype 1b chronic HCV patients with a baseline NS5A resistant-associated variant. However, due to several limitations of our current study, our results need to be validated by another well-designed large clinical trial.

Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jfma.2016.11.014.

References 1. World Health Organization. Hepatitis C key facts. Geneva, Swiss: WHO factsheet number 164; 2013. 2. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology 2013;57:1333e42. 3. Smith DB, Bukh J, Kuiken C, Muerhoff AS, Rice CM, Stapleton JT, et al. Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment Web resource. Hepatology 2014;59:318e27. 4. McEwan P, Ward T, Chen C-J, Lee M-H, Yang H-I, Kim R, et al. Estimating the incidence and prevalence of chronic hepatitis C infection in Taiwan using back projection. Value Health Reg Issues 2014;3:5e11. 5. Kao JH. Hepatitis C virus infection in Taiwan: past, present, and future. J Formos Med Assoc 2016;115:65e6. 6. Yu ML, Chuang WL, Chen SC, Dai CY, Hou C, Wang JH, et al. Changing prevalence of hepatitis C virus genotypes: molecular epidemiology and clinical implications in the hepatitis C virus hyperendemic areas and a tertiary referral center in Taiwan. J Med Virol 2001;65:58e65. 7. Bertino G, Ardiri A, Proiti M, Rigano G, Frazzetto E, Demma S, et al. Chronic hepatitis C: this and the new era of treatment. World J Hepatol 2016;8:92e106. 8. Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010;465:96e100.


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Ribavirin, daclatasvir, plus asunaprevir 9. McPhee F, Sheaffer AK, Friborg J, Hernandez D, Falk P, Zhai G, et al. Preclinical profile and characterization of the hepatitis C virus NS3 protease inhibitor asunaprevir (BMS-650032). Antimicrob Agents Chemother 2012;56:5387e96. 10. Manns M, Pol S, Jacobson IM, Ahn SH, Lim YS, Peng CY, et al. All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet 2014;384:414e29. 11. Kumada H, Suzuki Y, Ikeda K, Toyota J, Karino Y, Chayama K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology 2014;59:2083e91. 12. Kuiken C, Yusim K, Boykin L, Richardson R. The Los Alamos hepatitis C sequence database. Bioinformatics 2005;21: 379e84. 13. Cooper C, Naggie S, Saag M, Yang JC, Stamm LM, DvorySobol H, et al. Successful retreatment of HCV in patients coinfected with HIV who failed 12 weeks of ledipasvir/sofosbuvir. Clin Infect Dis 2016;63:528e31. 14. Chayama K, Hayes CN. HCV drug resistance challenges in Japan: the role of pre-existing variants and emerging resistant

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15.

16.

17.

18.

strains in direct acting antiviral therapy. Viruses 2015;7: 5328e42. Uchida Y, Kouyama J, Naiki K, Mochida S. A novel simple assay system to quantify the percent HCV-RNA levels of NS5A Y93H mutant strains and Y93 wild-type strains relative to the total HCV-RNA levels to determine the indication for antiviral therapy with NS5A inhibitors. PLoS One 2014;9:e112647. AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLDIDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology 2015;62: 932e54. He ´zode C, Bouvier-Alias M, Costentin C, Medkour F, FrancPoole E, Aalyson M, et al. Effect of an IMPDH inhibitor, merimepodib (MMPD), assessed alone or in combination with ribavirin, on HCV replication: implications regarding ribavirin’s mechanisms of action. Hepatology 2006;44:615A. Dietz J, Schelhorn SE, Fitting D, Mihm U, Susser S, Welker M-W, et al. Deep sequencing reveals mutagenic effects of ribavirin during monotherapy of hepatitis C virus genotype 1-infected patients. J Virol 2013;87:6172e81.
