Over 185 million people are chronically

Hepatitis C Genotype 1 Virus With Low Viral Load and Rapid Virologic Response to Peginterferon/Ribavirin Obviates a Protease Inhibitor Brian L. Pearlman 1,2,3,4 and Carole Ehleben 2 The new standard of care for treatment-na ıve patients with hepatitis C virus (HCV) genotype 1 includes triple therapy with peginterferon, ribavirin, and a protease inhibitor. However, patients who achieve a rapid virologic response after 4 weeks of peginterferon and ribavirin therapy are likely to achieve a sustained virologic response (SVR), and we hypothesized that protease inhibitor therapy may be unnecessary in these patients. Treatment-na ıve, noncirrhosis patients infected with genotype-1 HCV and a low viral load at baseline were considered for inclusion (n 5 233). After 4 weeks of lead-in therapy with peginterferon a-2b and ribavirin, 101 patients (48%) had a rapid virologic response (defined as undetectable levels of hepatitis C virus RNA at 4 weeks) and were eligible to participate. Patients were randomized 1:1 to 20 weeks of additional therapy with peginterferon a-2b and ribavirin (double therapy) or to 24 weeks of peginterferon a-2b, ribavirin, and boceprevir (triple therapy). There was no significant difference in rates of SVR-12 in patients treated with double versus triple therapy. This similarity persisted regardless of viral subtype (genotype 1a or 1b), interleukin (IL)228b genotype (CC or non-cc), or ethnicity (African American versus non-hispanic white). Conclusion: Protease inhibitor therapy could be obviated in genotype 1-infected treatment-na ıve patients with low viral load at baseline who achieve undetectable viremia after 4 weeks of peginterferon/ribavirin.(hepatology 2014;59:71-77) Over 185 million people are chronically infected with the hepatitis C virus (HCV), 1 and more than 350,000 people die each year from hepatitis C-related liver diseases. 2 The therapy for chronic hepatitis C infection has historically been pegylated-interferon (PEG) plus ribavirin (RBV). This treatment can effect a sustained virologic response (SVR), 3,4 which is associated with long-term clearance of HCV infection, a virologic cure. 5-8 Viral load is a major determining factor in responsiveness to PEG/RBV, and a viral load of <800,000 IU/mL is considered low. More recent data suggest that the optimized threshold for serum HCV RNA to predict therapy outcome is 400,000 IU/mL. 9 Up to half of patients with genotype 1 HCV with low viral load (LVL) achieve a rapid virologic response (RVR), 10 defined as undetectable levels of HCV RNA after 4 weeks of treatment with PEG/RBV. RVR is used as a tool to predict outcomes and individualize therapy according to treatment-related viral kinetics, 11 and patients who achieve RVR are more likely to have an SVR. 12 Not only is LVL associated with achievement of RVR and better response to treatment, but in one study it was associated with better long-term outcomes. 13 Approximately 15%-20% of all genotype 1 HCV-infected patients have LVL. 14 A multitude of studies have demonstrated that genotype 1-infected treatment-na ıve patients with LVL at baseline who achieve RVR can be treated with 24 weeks of PEG/RBV therapy without compromising SVR rates. 10,15-21 Based on one of these trials, the European Medicines Agency (EMA) has approved the use of 24 weeks of PEG/RBV in genotype 1-infected patients with low baseline viral loads (<600,000 IU/mL) who achieve RVR. 10 Abbreviations: EMA, European Medicines Agency; ETR, end of treatment response; HCV, hepatitis C virus; LVL, low viral load; PEG, pegylated-interferon; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response. From the 1 Center for Hepatitis C, Atlanta Medical Center, Atlanta, GA; 2 Department of Graduate Medical Education, Atlanta Medical Center, Atlanta, GA; 3 Medical College of Georgia, Department of Medicine, Augusta, GA; 4 Emory University School of Medicine, Department of Medicine, Atlanta, GA. Received May 6, 2013; accepted July 3, 2013. 71

72 PEARLMAN AND EHLEBEN HEPATOLOGY, January 2014 However, a new era of hepatitis C therapy began in 2011, when protease inhibitors to the viral NS3-NS4a protease enzyme improved the SVR rate for genotype 1 HCV infection (specifically, boceprevir 22,23 and telaprevir 24,25 ). The new standard of care for HCV genotype 1-infected patients is triple therapy: PEG/ RBV plus a protease inhibitor. 26 Currently, treatmentna ıve, noncirrhosis patients who, after a 4-week lead-in with PEG/RBV, achieve undetectable serum virus at 8 and 24 weeks with triple therapy that includes boceprevir, are treated for a total of 28 weeks. 27 Yet these therapies come with a cost. Protease inhibitors for HCV infection have incremental side effects above those of PEG/RBV alone: high costs, substantial pill burden, the potential for resistance, and many drug-drug interactions. 27-29 Given these drawbacks, should a protease inhibitor, such as boceprevir, be given to all patients with genotype 1 infection? We hypothesized that protease inhibitor therapy could be obviated in patients who responded well to PEG/RBV treatment. Specifically, we considered therapy-na ıve patients with HCV genotype-1, LVL (<600,000 IU/mL), who achieved RVR. Patients and Methods Patients. Patients were considered for inclusion in the study if they were treatment-na ıve, infected with genotype-1 HCV, and had LVL at baseline (<600,000 IU/mL). Patients were 18 years of age or older and had a liver biopsy in the past 2 years consistent with chronic hepatitis. Cirrhosis patients were excluded. Before randomization, patients had been rapid virologic responders to 4 weeks of peginterferon a-2b (1.5 lg/kg/wk; PegIntron; Merck Whitehouse Station, NJ) and ribavirin (1-1.2 g/day based on weight: 1,000 mg/day for <75 kg or 1,200 mg/day for 75 kg). A rapid virologic responder was defined as undetectable HCV RNA using polymerase chain reaction (Taqman, Roche; detection limit 10 IU/mL). All testing was performed at a single reference laboratory. Pretreatment exclusion criteria included the following: HCV/human immunodeficiency virus coinfection; HCV genotype other than 1; biopsy-proven or strongly suspected clinical cirrhosis; other causes of liver disease, including coinfection with hepatitis B; creatinine clearance <50 ml/min (modification of diet in renal disease equation); platelet count <80 3 10 9 / L; neutrophil count <1.5 3 10 9 /L; hemoglobin concentration <13 g/dl and 12 g/dl in men and women, respectively; coexisting uncontrolled psychiatric or cardiopulmonary disorders; hemoglobinopathy; sarcoidosis; malignant neoplasm; receipt of immunosuppressive or immunomodulatory therapy in the previous 6 months; pregnancy; and men whose partners were pregnant or unwilling to use contraception during the study period. Female patients of childbearing age also agreed to avoid systemic contraception if ultimately randomized into the protease inhibitor-containing arm. Patients were also excluded if they imbibed significant amounts of alcohol (>30 g/day), or if they were active substance abusers in the past 6 months. Patient characteristics recorded at baseline included age, sex, body mass index, fasting glucose, 25-hydroxy vitamin D levels, ethnicity, histological results of pretreatment liver biopsy (Metavir scoring: F0, no fibrosis; F1, portal fibrosis; F2, few septa; F3, many septa without cirrhosis; F4, cirrhosis which were excluded), and quantitative HCV viral load (recorded as IU/mL at baseline, week 4 [randomization], weeks 8, 12, 24, endof-therapy and at 12 weeks posttreatment). Patients were stratified by genotype subtype (1a versus 1b) and by interleukin (IL)228B genotype (rs12979860). Patients were genotyped using the Illumina Human610- quad BeadChip (San Diego, CA) as described. 30 The study was investigator-initiated. The protocol was approved by Atlanta Medical Center s Institutional Review Board. The trial adhered to the ethical principles outlined in the World Medical Association Declaration of Helsinki. Patients were recruited from Atlanta Medical Center s Center for Hepatitis C and Sheffield Health Center, both ambulatory clinics, in downtown Atlanta, Georgia. Merck, the manufacturer of peginterferon-a2b, had no direct or indirect involvement in the study design, data collection, or preparation of the article. Treatment and Monitoring. Rapid virologic responders to PEG/RBV were randomly assigned in Address reprint requests to: Brian L. Pearlman, M.D., FACP, Center for Hepatitis C, Atlanta Medical Center, 285 Boulevard NE, Suite 525, Atlanta, GA 30312. E-mail: brianpearlman@hotmail.com; fax: 404-872-4061. Copyright VC 2013 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26624 Potential conflict of interest: Dr. Pearlman consults, advises, and is on the speakers bureau for Merck; C.E. has no conflicts of interest.

HEPATOLOGY, Vol. 59, No. 1, 2014 PEARLMAN AND EHLEBEN 73 Fig. 1. Study Participant Flow. G-1, genotype 1; LVL, low viral load; RVR, rapid virologic response; SVR, sustained virologic response; PEG, pegylated-interferon; RBV, ribavirin; BOC, boceprevir. open-label fashion to a 1:1 ratio to continue for an additional 24 weeks of PEG/RBV/BOC (boceprevir 800mgtid)(GroupA)ortocontinuewithanadditional 20 weeks of PEG/RBV only (Group B). Therapy dosing was not changed prerandomization and postrandomization; patients received full dose of medication unless the dose had been reduced for cytopenias during therapy. Boceprevir was never dose reduced, however. Growth factors of any variety were prohibited. All patients who were randomized and those who received at least one dose of study medication were included in the intention-to-treat population. All patients who received at least one dose of study medication and had at least one postbaseline safety assessment were included in the safety analysis. Patients were monitored at baseline and at monthly intervals by way of physical examination, patient weight, Beck s Depression Inventory, complete blood count and differential, hepatic profile, thyroidstimulating hormone, electrolytes, serum creatinine, serum uric acid, and serum beta-human chorionic gonadotropin testing, if applicable. Dose reductions for anemia were at investigators discretion using 200-400 mg ribavirin decrements in dose. For interferon-related neutropenia, dose reductions and treatment discontinuations were made only for absolute neutrophil counts under 0.5 3 10 9 and 0.25 3 10 9, respectively, and only at the investigators discretion. An end-of-treatment response was checked by way of serum RNA analysis at week 28 (Group A) and at week 24 (Group B), and again to assess SVR- 12 after therapy cessation. SVR-12 was the primary endpoint; the relapse rate was the secondary endpoint. Statistical Analysis. Only randomized patients were included in the treatment analysis. Physicians enrolled participants and obtained informed consent to participate. Randomizations were concealed until after patients consented to participate and interventions were assigned. Data were collected by a research nurse not involved in the patient s treatment. Patient baseline characteristics were compared using chi-squared tests and all outcome and subgroup analysis were performed using the same chi-squared tests and applying the Yates correction factor for cell size <10. Because population power estimates and expected frequencies were not specified beforehand, only nonparametric statistics were possible. The study was designed to randomize 100 patients to triple or double therapy; thus, after 100 patients were assigned to treatment, enrollment ceased. Except for an abstract submission in July 2012, at which time data were analyzed from patients who had finished treatment to date, outcome data were reviewed after the entire group of randomized patients had completed therapy. We chose to enroll 100 patients, believing that this number would be an adequate and representative sample of differences in triple versus double therapy in patients with LVL who achieve RVR; the number was not generated from a formal sample size calculation. Results Patient Profiles. Patients were recruited between July 2011 and May 2012 from two separate ambulatory clinics at Atlanta Medical Center: the Center for Hepatitis C and the Sheffield Health Center.

74 PEARLMAN AND EHLEBEN HEPATOLOGY, January 2014 Table 1. Baseline Characteristics Group A (Triple Therapy) n 5 49 Group B (Double Therapy) n 5 52 Mean age (yrs) 54 52 Male subjects (%) 61 63 BMI (mean) 28 29 Impaired fasting glucose (%) 12 15 African American subjects (%) 37 37 F3 fibrosis (%) 20 18 Genotype 1a (%) 39 38 Genotype 1b (%) 61 62 IL-28 CC (%) 65 66 IL-28 non-cc (%) 34 34 There were no significant differences between the groups. The trial participant flow is shown in Fig. 1. Of the 233 patients treated with the 4-week lead-in therapy, 112 had RVR (48%). Eleven subjects were ineligible or declined to participate, leaving 101 patients who were randomized to either triple (n 5 49) or to double therapy (n 5 52). Baseline characteristics were statistically similar in both treatment groups and are shown in Table 1. The mean age was 54 for the triple therapy group and 52 for the double therapy group. The baseline 25-hydroxy D levels were not statistically different between data arms (data not shown). Patients were then randomized 1:1 to 20 weeks of additional therapy with PEG/RBV or 24 weeks of PEG/RBV plus boceprevir (800 mg tid). All patients received follow-up at 12 weeks to determine SVR rates. In both groups, 46 patients completed follow-up. Side Effects. Side effects were not statistically different between treatment arms. In addition, there were no significant differences between groups treated with triple or double therapy with respect to medication dose reductions (triple 5 33%, double 5 33%; P 5 ns). Nor were there differences between the groups with respect to medication discontinuations (triple 5 6%, double 5 8%; P 5 ns) (Fig. 1). Viral Response. There were no significant differences in the primary endpoint, SVR-12 rates (44/49 [90%] patients in Group A versus 46/52 [88%] patients in Group B). Likewise, end-of-treatment response rates (46/49 [94%] patients versus 49/52 [94%] patients) and relapse rates (4% patients versus 6% of patients), were not statistically different between Groups A or B (Fig. 2). SVR-24 rates were identical with SVR-12 rates (90% for Group A and 88% for Group B). In subgroup analysis, the P value was not significantly different for SVR-12 rates between Groups A Fig. 2. Overall virologic response rates. ETR, relapse, and SVR-12 rates in patients treated with triple (PEG/RBV/BOC, n 5 49) or double (PEG/RBV, n 5 52) therapy were not significantly different. ETR, endof-treatment response rate; SVR, sustained virologic response; PEG, pegylated-interferon; RBV, ribavirin; BOC, boceprevir. and B with respect to the following comparisons: IL- 28 B subtype (CC versus non-cc) (Fig. 3), HCV subtype (genotype 1a versus 1b) (Fig. 4), and among African Americans (Fig. 5). Furthermore, there was no statistical difference among pretreatment HCV RNA values when analyzed for <400,000 IU/mL or <600,000 IU/mL, although the numbers in each subgroup were small, and there was no difference between F3 patients SVR rates, regardless of assigned therapy arm (data not shown). Also not shown was that IL-28B CC was a predictor of patients achieving RVR in the original group (n 5 233). Discussion In treatment-na ıve patients with HCV genotype-1 infection with LVL at baseline who achieved RVR with 4 weeks of PEG/RBV therapy, there was no significant difference in rates of end-of-treatment response (ETR), relapse or in SVR in patients treated with double versus triple therapy (double included 24 weeks of therapy total PEG/RBV, and triple included Fig. 3. IL-28B genotype analysis (rs12979860). SVR-12 rates were similar in patients treated with triple (PEG/RBV/BOC) or double (PEG/ RBV) therapy regardless of IL-28B genotype status. SVR, sustained virologic response; PEG, pegylated-interferon; RBV, ribavirin; BOC, boceprevir.

HEPATOLOGY, Vol. 59, No. 1, 2014 PEARLMAN AND EHLEBEN 75 Fig. 4. HCV genotype 1 subtype analysis. SVR-12 rates were similar between patients treated with triple (PEG/RBV/BOC) or double (PEG/ RBV) therapy regardless of HCV subtype (genotype 1a versus 1b). SVR, sustained virologic response; PEG, pegylated-interferon; RBV, ribavirin; BOC, boceprevir; HCV, hepatitis C virus. the addition of boceprevir at week 5, for 28 weeks of therapy total). This similarity persisted regardless of viral subtype (genotype 1a or 1b), IL-28b genotype status (CC or non-cc), or ethnicity (African American versus non-hispanic white). Safety and tolerability were similar in protease inhibitor-containing and protease inhibitor-sparing regimens. We chose to compare 24 to 28 weeks of therapy, since the former is the EMA-approved duration for peginterferon a-2b/ribavirin treatment in genotype 1- infected patients with baseline LVL who achieve RVR, and the latter is the standard duration for boceprevircontaining regimens in treatment-na ıve, noncirrhosis patients who are early virologic responders. We excluded patients with cirrhosis, since these patients cannot qualify for response-guided therapy because of increased rates of relapse with shorter therapy regimens. Ninety percent of patients in the triple therapy arm (Group A) achieved SVR-12 (and SVR-24), which corresponds to the SVR-24 rates in boceprevir-treated patients who achieved undetectable viremia at week 8 in the SPRINT-2 trial. 23 Likewise, 88% of patients who received double therapy (Group B) achieved SVR-12 (and SVR-24), which is comparable to 81%- 89% SVR-24 rates in genotype 1-infected patients who had achieved RVR with 24 weeks of PEG/RBV in previously published studies. 15,17 Because genotype 1b virus needs two nucleotide substitutions in its protease enzyme to confer resistance to a first-generation protease inhibitor like boceprevir (i.e., higher barrier to resistance than genotype 1a virus that needs merely one substitution), SVR rates are higher against the former viral subtype with triple therapy. 31,32 Yet dual therapy (PEG/RBV) has been shown to be more effective against HCV subtype 1a than 1b. 33 Thus, HCV subtyping may play a role in selecting future treatment options and predicting the development of resistance. 26,34 However, in our study in patients with LVL who achieved RVR, we found no difference in SVR rates between genotype 1a and 1b in groups treated with double or triple therapy. Polymorphisms in the region of the IL-28B gene on chromosome 19 have been associated with SVR and viral clearance. Patients with the CC genotype (rs12979860) are more likely to achieve SVR than are patients with the non-cc (CT or TT) genotype. 30,35 In fact, in interferon-based therapy without direct acting antiviral agents, the IL-28B polymorphism is the strongest pretreatment predictor of SVR in genotype 1 infection. 36 Even with triple therapy containing a protease inhibitor, IL-28B polymorphisms can affect SVR rates. 37 However, among our therapy-na ıve HCV genotype 1-infected patients with LVL and RVR, we did not see a difference in SVR rates between CC and non-cc for patients treated with double or triple therapy. African American patients have traditionally responded less well to PEG/RBV therapy, and this difference has been attributed, in part, to a decreased prevalence of the IL-28B gene in this population. 30 African Americans also respond less well to triple therapy relative to non-african Americans. 23 The SVR in African Americans in this trial (37% of total randomized subjects) were statistically equal regardless of the use of a protease inhibitor. The SVR rates (82%-84%) in this subgroup appear very high, but this can be attributed to the fact that all of these patients had a low baseline viral load and achieved RVR. Baseline patient ethnicity, viral subtype, and IL-28B genotype did not seem to impact SVR rates ultimately, regardless of therapy used. This amplifies the point that on-treatment predictors of therapy success trump pretreatment predictors. However, this analysis was limited to patients with baseline LVL. It is unclear if a protease inhibitor could Fig. 5. SVR rates for African-Americans treated with triple or double therapy. Among African-Americans, SVR-12 rates were similar in patients treated with triple (PEG/RBV/BOC) or double (PEG/ RBV) therapy. SVR, sustained virologic response; PEG, pegylated-interferon; RBV, ribavirin; BOC, boceprevir.

76 PEARLMAN AND EHLEBEN HEPATOLOGY, January 2014 be obviated in patients with high baseline viral load who likewise achieve RVR without a randomized trial; however, patients achieving RVR have similar rates of SVR in those treated with a regimen containing a protease inhibitor compared to dual therapy with PEG/ RBV alone. 23,24,31 This was a single-center, dual-clinic analysis with relatively small numbers. No formal statistical hypothesis testing was performed; thus, sample size per treatment group was not derived to control the probability of type 1 error or to provide sufficient statistical power. Treatment randomizations were revealed after patients consented to participate and interventions were assigned, so the study was not placebo-controlled. Finally, these results may not be generalizable to the other therapies commonly used to treat HCV. For example, we did not use peginterferon a-2a or the protease inhibitor telaprevir. Protease inhibitors are costly, 29 and are not yet available in many countries that lack the monetary resources to cover them. If this protease inhibitorsparing strategy were implemented in countries that can currently afford them, a significant cost-savings could potentially be achieved even if this strategy were limited to those genotype 1-infected patients with baseline LVL who achieve RVR. The issue of costeffectiveness of individualizing therapy according to RVR has already been demonstrated. Compared to the universal treatment of all genotype 1-infected patients with a protease inhibitor, the protease inhibitorsparing regimens in those patients achieving RVR were among the most cost-effective strategies studied. 38 The results of this current analysis confirm that there is no virologic advantage of adding a protease inhibitor to PEG/RBV therapy in patients with RVR, at least in those with LVL at baseline. In conclusion, in treatment-na ıve, noncirrhosis, chronically infected HCV genotype 1-infected patients who have low baseline viral load and achieve RVR, adding a protease inhibitor may offer no benefit in terms of therapy duration or efficacy. These results hold true irrespective of patient s viral subtype, IL-28B genotype, or ethnicity (African American versus non- Hispanic white). Acknowledgment: We thank Nomi Traub, Louis Lovett, Daniel Frilingos, and Tanna Lim for their invaluable help with the trial. We also thank the residents and staff of Atlanta Medical Center s Center for Hepatitis C and those of Sheffield Health Center. We thank Karen Staman for assistance in drafting and editing the article. References 1. 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;57:1333-1342. 2. WHO j Hepatitis C [Internet]. WHO. [cited 2013 Mar 27]. Available from: http://www.who.int/mediacentre/factsheets/fs164/en/ 3. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958-965. 4. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-982. 5. Koh C, Heller T, Haynes-Williams V, Hara K, Zhao X, Feld JJ, et al. Long-term outcome of chronic hepatitis C after sustained virological response to interferon-based therapy. Aliment Pharmacol Ther 2013; 37:887-894. 6. Swain MG, Lai M-Y, Shiffman ML, Cooksley WGE, Zeuzem S, Dieterich DT, et al. A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology 2010;139:1593-1601. 7. Giannini EG, Basso M, Savarino V, Picciotto A. Sustained virological response to pegylated interferon and ribavirin is maintained during long-term follow-up of chronic hepatitis C patients. Aliment Pharmacol Ther 2010;31:502-508. 8. Desmond CP, Roberts SK, Dudley F, Mitchell J, Day C, Nguyen S, et al. Sustained virological response rates and durability of the response to interferon-based therapies in hepatitis C patients treated in the clinical setting. J Viral Hepat 2006;13:311-315. 9. Zeuzem S, Rodrıguez-Torres M, Rajender Reddy K, Marcellin P, Diago M, Craxi A, et al. Optimized threshold for serum HCV RNA to predict treatment outcomes in hepatitis C patients receiving peginterferon alfa-2a/ribavirin. J Viral Hepat 2012;19:766-774. 10. Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006;44:97-103. 11. Poordad F, Reddy KR, Martin P. Rapid virologic response: a new milestone in the management of chronic hepatitis C. Clin Infect Dis 2008; 46:78-84. 12. Aziz H, Raza A, Waheed Y, Gill U, Gill ML. Analysis of variables and interactions among variables associated with a sustained virological response to pegylated interferon alfa-2a plus ribavirin in hepatitis C virus genotype 3-infected patients. Int J Infect Dis 2012;16:e597-e602. 13. Shindoh J, Hasegawa K, Matsuyama Y, Inoue Y, Ishizawa T, Aoki T, et al. Low hepatitis C viral load predicts better long-term outcomes in patients undergoing resection of hepatocellular carcinoma irrespective of serologic eradication of hepatitis C virus. J Clin Oncol 2013;31: 766-773. 14. Craxı A, Camma C. Treating patients with HCV genotype 1 and low viraemia: more than meets the eye. J Hepatol 2006;44:4-7. 15. Jensen DM, Morgan TR, Marcellin P, Pockros PJ, Reddy KR, Hadziyannis SJ, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. HEPATOLOGY 2006;43:954-960. 16. Mangia A, Minerva N, Bacca D, Cozzolongo R, Ricci GL, Carretta V, et al. Individualized treatment duration for hepatitis C genotype 1 patients: a randomized controlled trial. HEPATOLOGY 2008;47:43-50. 17. Ferenci P, Laferl H, Scherzer T-M, Gschwantler M, Maieron A, Brunner H, et al. Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology 2008;135:451-458. 18. Sarrazin C, Shiffman ML, Hadziyannis SJ, Lin A, Colucci G, Ishida H, et al. Definition of rapid virologic response with a highly sensitive real-time PCR-based HCV RNA assay in peginterferon alfa-2a plus ribavirin response-guided therapy. J Hepatol 2010;52:832-838.

HEPATOLOGY, Vol. 59, No. 1, 2014 PEARLMAN AND EHLEBEN 77 19. Arase Y, Suzuki F, Akuta N, Sezaki H, Suzuki Y, Kawamura Y, et al. Combination therapy of peginterferon and ribavirin for chronic hepatitis C patients with genotype 1b and low-virus load. Intern Med 2009; 48:253-258. 20. Craxi A, Koutsounas S, Ogurtsov P, Chemello L, Maticic M, Torras J, et al. Peginterferon alfa-2b plus weight-based ribavirin for 24 weeks in patients with chronic hepatitis C virus genotype 1 with low viral load who achieve rapid viral response. J Viral Hepat 2012;19:e120-e125. 21. Yu M-L, Dai C-Y, Huang J-F, Chiu C-F, Yang Y-HC, Hou N-J, et al. Rapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: a randomized trial. HEPATOLOGY 2008;47:1884-1893. 22. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1207-1217. 23. Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1195-1206. 24. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405-2416. 25. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011;364: 2417-2428. 26. Pearlman BL. Protease inhibitors for the treatment of chronic hepatitis C genotype-1 infection: the new standard of care. Lancet Infect Dis 2012;12:717-728. 27. Victrelis [package insert] [Internet]. Merck: Whitehouse Station, NJ; 2011. Available from: http://www.merck.com/product/usa/pi_circulars/ v/victrelis/victrelis_pi.pdf. 28. Incivek [package insert] [Internet]. Vertex Pharmaceuticals: Cambridge, MA; 2012. Available from: http://pi.vrtx.com/files/uspi_telaprevir.pdf. 29. Gellad ZF, Reed SD, Muir AJ. Economic evaluation of direct-acting antiviral therapy in chronic hepatitis C. Antivir Ther (Lond) 2012;17(6 Pt B):1189-1199. 30. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in IL28B predicts hepatitis C treatmentinduced viral clearance. Nature 2009;461:399-401. 31. Marcellin P, Cheinquer H, Curescu M, Dusheiko GM, Ferenci P, Horban A, et al. High sustained virologic response rates in rapid virologic response patients in the large real-world PROPHESYS cohort confirm results from randomized clinical trials. HEPATOLOGY 2012;56: 2039-2050. 32. Beinhardt S, Rutter K, St attermayer AF, Ferenci P. Revisiting the predictors of a sustained virologic response in the era of direct-acting antiviral therapy for hepatitis C virus. Clin Infect Dis 2013;56:118-122. 33. Pellicelli AM, Romano M, Stroffolini T, Mazzoni E, Mecenate F, Monarca R, et al. HCV genotype 1a shows a better virological response to antiviral therapy than HCV genotype 1b. BMC Gastroenterol 2012; 12:162. 34. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. HEPATOLOGY 2011;54:1433-1444. 35. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O Huigin C, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009;461:798-801. 36. Thompson AJ, Muir AJ, Sulkowski MS, Ge D, Fellay J, Shianna KV, et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology 2010;139:120-129 e18. 37. Jacobson IM, Catlett I, Marcellin P, Bzowej NH, Muir AJ, Adda N, et al. Telaprevir substantially improved SVR rates across all IL28B genotypes in the ADVANCE trial. EASL, International Liver Congress, Amsterdam, The Netherlands; 2013 (cited 2013 May 1). Available from: http://www1.easl.eu/easl2011/program/posters/abstract7.htm. 38. Camma C, Petta S, Enea M, Bruno R, Bronte F, Capursi V, et al. Cost-effectiveness of boceprevir or telaprevir for untreated patients with genotype 1 chronic hepatitis C. HEPATOLOGY 2012;56:850-860.