Protease Inhibitors in Chronic Hepatitis C: An Update

Protease Inhibitors in Chronic Hepatitis C: An Update
COMPLETE SLIDE DECK (Chapters 1 – 6) Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine University of Toronto November 2012

Management of Hepatitis C: Updated Guidelines from the Canadian Association for the Study of the Liver (CASL) Robert P. Myers, MD, MSc Associate Professor, Liver Unit Division of Gastroenterology University of Calgary

Objectives: HCV Management
Review updated CASL recommendations for management of HCV genotype 1* Burden of HCV in Canada Pre-treatment assessment Triple therapy including boceprevir and telaprevir Adverse effects Drug-drug interactions Antiviral resistance * Recommendations for non-1 genotypes are unchanged from the 2007 CASL HCV guidelines.

Burden of HCV in Canada Significant medical and economic burden
Seroprevalence unknown Risk Group Population Prevalence Prevalent Cases Proportion of Cases IDU, total 268,200 52% 140,000 58% Current IDU 84,400 62% 52,500 22% Previous IDU 183,800 48% 87,500 36% Transfusion 3,325,700 0.8% 25,900 11% Hemophilia 2,200 40% 900 0.4% Other 27,624,300 0.27% 75,800 31% Total 31,220,500 243,000 100% Although hepatitis C has a significant medical and economic burden in Canada, its exact prevalence is unknown. Estimates based on decision modeling suggest that the seroprevalence in 2007 was 0.8%, or an estimated 243,000 infected individuals. The majority of cases (~60%) are among former or current injection drug users (IDUs), approximately 11% among recipients of blood products including patients with hemophilia, and the remainder of other causes (e.g. immigrants from endemic regions). Remis RS. PHAC 2007

Burden of HCV in Canada ~8,000 incident cases annually (80% IDUs)
Proportion diagnosed unclear (<80%) HCV-related complications rising Insufficient manpower to treat all cases 900 Cirrhosis 800 700 600 Decomp 500 Modelled incidence It is estimated that ~8,000 incident (new) cases are diagnosed annually in Canada, the majority among IDUs. In the absence of a large scale serosurvey, the proportion that have been already diagnosed is unclear. Data based on decision models and hospitalizations have confirmed that the complications of HCV (e.g. decompensated cirrhosis, hepatocellular carcinoma, and liver transplantation) are increasing due to aging of the affected cohort. These complications are not expected to decline for at least another decade. Currently in Canada, a relatively small number of physicians treat hepatitis C, leading in some cases to prolonged wait times for patients before being adequately evaluated and treated. It is clear that we currently have insufficient manpower to treat all affected cases. 400 HCC 300 Transplant 200 100 1967 1972 1977 1982 1987 1992 1997 2002 2007 2012 2017 2022 2027 Year Remis et al. PHAC 2007

Antiviral Therapy Must be Maximized to Make an Impact
 80% SVR rate 60% SVR rate 40% SVR rate 100 90 34% ↓ 80 70 68% ↓ Liver-related death vs. no treatment (%) 60 50 40 In order to reduce the burden of HCV-related complications, it is vital that the dissemination of therapy is maximized (i.e. more patients are treated). The data in this figure, which is based on modeling in the U.S., illustrates the importance of treating more patients even in the era of DAA therapy, which have SVR rates approaching 80%. If we increase the proportion of patients treated to 50% (current estimates suggest that fewer than 20% of patients are treated), we will only reduce the proportion of liver-related deaths in 2020 by 34%. Even with 100% treatment uptake and an 80% rate of SVR, only 68% of deaths will be prevented by 2020. 30 20 Current* 25% 50% 75% 100% Proportion of population treated * Assumes 30% Dx & up to 25% Rx’d in Outcomes at 2020. Davis GL et al. Gastroenterology 2010; 138(2):513-21

Burden of HCV in Canada: CASL Recommendations
A large population-based seroprevalence survey should be conducted to accurately define the prevalence of hepatitis C in Canada. The design of the study should include populations with an increased risk of hepatitis C, particularly IDUs and immigrants from endemic countries. Increased resources are necessary to improve hepatitis C treatment capacity in Canada, including the training of expert treaters and public funding for treatment nurses. Regarding the burden of HCV in Canada, CASL has made two major recommendations. First, to understand the burden of disease, a large, population-based, seroprevalence study should be conducted. This study should include high-risk groups, including IDUs and immigrants from endemic countries, so as to get an accurate assessment of HCV prevalence in Canada. Second, in order to maximize treatment uptake so as to reduce the burden of HCV-related complications, it is vital that increased resources be dedicated to improving treatment capacity in Canada. In addition to improving the diagnosis of infected patients, public funding should be provided for the training of expert treaters and treatment nurses. Myers RP et al. Can J Gastro 2012; 26(6):359-75

Who Should Be Treated? CASL Recommendations
In the opinion of CASL, the treatment of patients with chronic HCV should be made on a case-by-case basis following a discussion of the risks and benefits of therapy between the patient and provider. Strict criteria imposed by committees such as the Common Drug Review should not interfere with this decision-making process. Factors to consider regarding the initiation of treatment are illustrated on this slide. They include the probability of a sustained virologic response (SVR); the likelihood of progression to advanced disease and the prospect of novel therapies before this occurs; and a patient’s anticipated tolerability of therapy (e.g. considering comorbidiities). Other factors to consider include a patient’s concerns regarding infectivity (e.g. for health care workers and women contemplating pregnancy); the presence of extrahepatic manifestations of HCV that may respond to successful viral eradication; and the life expectancy of the patient (i.e. whether they will benefit from a cure). Myers RP et al. Can J Gastro 2012; 26(6):359-75

Who Should Be Treated? CASL Recommendations
All patients with chronic HCV, particularly those with liver fibrosis, should be considered candidates for antiviral therapy. Patients with extrahepatic manifestations of HCV should be considered for antiviral therapy. Persistently normal ALT does not exclude significant liver disease nor preclude the need for antiviral therapy. CASL recommends that all patients with chronic HCV, particularly those with evidence of liver fibrosis, should be considered candidates for antiviral therapy. Patients with extrahepatic manifestations of HCV (e.g. cryoglobulinemic vasculitis, porphyria cutanea tarda, etc.) are a special group as these complications typically respond to successful viral eradication. Finally, in some regions within Canada, public reimbursement for therapy requires documentation of an abnormal serum ALT concentration. Since persistently normal ALT does not exclude significant liver disease or influence the probability of successful treatment, CASL recommends that serum ALT not be considered in the decision to initiate therapy. Myers RP et al. Can J Gastro 2012; 26(6):359-75

Pre-Treatment Assessment: Is Liver Biopsy Really Necessary?
Some fibrosis assessment necessary Prognosis Necessity of treatment Surveillance for HCC & varices F2 threshold less important with improved therapies Biopsy is imperfect Sampling error; variability in pathologic interpretation Numerous noninvasive alternatives to biopsy The Common Drug Review has recommended that liver biopsy be performed prior to treatment to document at least moderate (stage 2) liver fibrosis. CASL agrees that some assessment of fibrosis is necessary in all patients with chronic HCV in order to estimate prognosis and determine the necessity of treatment, as well as to target surveillance for hepatocellular carcinoma (HCC) and varices in patients with underlying cirrhosis. However, in the era of therapies with SVR rates approaching 80% in genotype 1-infected patients, a threshold of stage 2 fibrosis – which was proposed when interferon and ribavirin dual therapy cured only ~40% of these patients - is likely no longer relevant. As an example, biopsies are not typically performed in patients with HCV genotypes 2 or 3, who are cured approximately 80% of the time with PEG-IFN and RBV dual therapy. It is also important to recognize that liver biopsy is an imperfect tool for assessing fibrosis due to sampling error and variability in pathologic interpretation. Finally, numerous alternatives to liver biopsy are now widely available for the noninvasive staging of fibrosis (see next slide). Bedossa P et al. Hepatology 2003; 38(6):

Pre-Treatment Assessment: Non-invasive Measures of Fibrosis
Test (Reference) Components Cut-off F2-F4 vs. F0-F1 Sensitivity/specificity FibroScan (Castera, 2005) Liver stiffness by transient elastography ≥7.1 kPa 67% / 89% APRI (Shaheen, 2007) AST/ULN x 100 Platelets ≥0.5 ≥0.7 ≥1.5 81% / 50% 84% / 70% 35% / 91% FibroTest (Poynard, 2004) α2M, haptoglobin, apo-A1, GGT, bilirubin ≥0.58 56% / 83% FibroSpect II (Patel, 2004) α2M, HA, TIMP-1 ≥0.36 77% / 73% Hepascore (Adams, 2005) α2M, HA, GGT, bilirubin ≥0.50 89% / 63% FibroMeter (Leroy, 2005) α2M, HA, AST, platelets, PT, urea 75% / 78% This slide includes various serum and imaging-based methods for the noninvasive assessment of HCV-related fibrosis. The sensitivity and specificity of these tools for the diagnosis of stage 2 to 4 fibrosis at specified cut-off values are also demonstrated. As you can see, no method is clearly superior to the others. Whereas some tools are proprietary (e.g. FibroTest, FibroSpect II, and FibroMeter), others are non-proprietary (e.g. APRI). The FibroScan is an ultrasound-based tool based on transient elastography that measures liver stiffness as a surrogate of liver fibrosis. This tool is available at a number of centers in Canada and has proven useful for the non-invasive staging of fibrosis in typical outpatient clinical settings.

Pre-Treatment Assessment: CASL Recommendations
Assessment of Disease Severity All patients with HCV should have an assessment for the severity of liver fibrosis. Acceptable methods include liver biopsy, TE (FibroScan), and serum biomarker panels (e.g. APRI, FibroTest, Fibrometer), either alone or in combination. Alternatively, cirrhosis can be confidently diagnosed in some patients with clear clinical or radiographic evidence. Regarding the assessment of disease severity prior to antiviral treatment, CASL recommends the following: All patients with HCV should have an assessment for the severity of liver fibrosis. Acceptable methods include liver biopsy, transient elastography (FibroScan), and serum biomarker panels (e.g. APRI, FibroTest, Fibrometer). These can be used either alone or in combination. Alternatively, in some patients with clear clinical or radiographic evidence of cirrhosis (e.g. a shrunken, nodular liver on ultrasound), these tools are not necessary to confirm the diagnosis. Myers RP et al. Can J Gastro 2012; 26(6):359-75

Virologic Testing HCV RNA and genotype testing are essential to the management of patients with chronic hepatitis C. HCV RNA testing should be performed using a sensitive quantitative assay (lower limit of detection ≤ IU/mL) with a broad dynamic range. Standardized results should be expressed in IU/mL and be available within a maximum of 7 days in order to facilitate management decisions. Although genotype 1b has higher response rates vs. genotype 1a, testing for HCV subtype is not indicated This may change with newer DAAs available in the future CASL has made several additional recommendations regarding pre-treatment patient assessment. Virologic testing is vital to the management of these patients. Specifically, all patients should have HCV RNA and genotype testing so as to confirm chronic infection, guide the selection of therapy, and determine the optimal course of treatment. HCV RNA testing should be performed using a sensitive quantitative assay with a broad dynamic range and a lower limit of detection (LLOD) of less than 10 to 15 IU/mL. Standardized results should be expressed in IU/mL and be available within a maximum of one week in order to facilitate management decisions. Determination of the HCV subtype (e.g. genotype 1a vs. 1b) is not clinically indicated. Myers RP et al. Can J Gastro 2012; 26(6):359-75

Numbers on bars represent n
Interleukin 28B (IL28B) Single-nucleotide polymorphisms (SNPs) on chromosome 19 Encodes IFN-λ3 Associated with viral clearance ~50% of ethnic variation in SVR rates Strongest pre-treatment predictor of SVR, but on-treatment response more important 100 P=1.06x10-25 P=2.06x10-3 P=4.39x10-3 P=1.37x10-28 80 Numbers on bars represent n 60 SVR (%) 40 20 102 433 336 70 91 30 14 35 26 186 559 392 T/T T/C C/C T/C C/C T/C C/C T/C C/C Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) - a DNA sequence variation occurring when a single nucleotide (A, T, C, or G) in the genome differs between individuals - near the interleukin 28B (IL28B) gene on chromosome 19 that are strongly associated with both spontaneous and PEG-IFN and RBV treatment-induced HCV clearance. Patients with the favourable CC genotype at rs and HCV genotype 1 have an approximately 80% chance of SVR compared to just 40% among those with non-CC genotypes. There is marked ethnic variation in the prevalence of the IL28B genotypes. The CC genotype is highly prevalent in Asians, but relatively uncommon in Africans; Caucasians and Hispanics have an intermediate prevalence. It is estimated that inter-racial differences in the prevalence of the IL28B genotypes account for approximately 50% of the ethnic variation in response rates to this therapy. In patients with HCV genotype 1, the IL28B genotype is the strongest pre-treatment predictor of response to PEG-IFN and RBV therapy. However, on-treatment responses (e.g. rapid virologic response [RVR]) - to either dual or triple therapy - are better predictors of outcome than the IL28B genotype. European-Americans African-Americans Hispanics Combined rs SVR (%) Non-SVR (%) Ge. Nature Suppiah. Nat Genet Tanaka. Nat Genet Thomas. Nature 2009.

IL28B Genotyping The IL28B genotype may provide valuable information regarding the likelihood of SVR and the probability of qualifying for shortened treatment duration in previously untreated patients with genotype 1. The role of IL28B genotyping is limited in treatment- experienced patients and those with genotypes other than 1 and 4. A non-favourable IL28B genotype does not preclude antiviral therapy. IL28B genotyping may provide information regarding the likelihood of treatment response and the probability of qualifying for shortened treatment duration in previously untreated patients with HCV genotype 1. However, the role of IL28B genotyping is limited in treatment-experienced patients and those with genotypes other than 1 and 4. Because many patients with non-favorable IL28B genotypes may respond to therapy, patients with these genotypes should not be excluded from treatment. Myers RP et al. Can J Gastro 2012; 26(6):359-75

Antiviral Therapy for HCV Genotype 1: CASL Recommendations
Triple therapy including peginterferon (PEG-IFN), ribavirin (RBV), and a protease inhibitor (telaprevir or boceprevir) is the new standard of care in treatment-naïve and previous treatment failures. Boceprevir (800 mg every 8 hours with food) is administered after a 4-week lead-in period of PEG-IFN and RBV. Duration of therapy depends on patient characteristics and treatment response. Telaprevir (750 mg every 8 hours with non-low fat food) should be started simultaneously with PEG-IFN and RBV and given for the initial 12 weeks of therapy. Two new protease inhibitors, boceprevir and telaprevir, have recently been approved by Health Canada for the treatment of patients with HCV genotype 1. When combined with PEG-IFN and RBV, these drugs lead to markedly improved SVR rates (in the 70% to 80% range) and permit shortened therapy in a significant proportion of patients. Additional presentations provide more specifics regarding clinical trial data and treatment algorithms for use with these agents. As a result of these encouraging results, CASL now recommends triple therapy including PEG-IFN, RBV, and telaprevir or boceprevir as the new standard of care in treatment-naïve and previous treatment failures with HCV genotype 1. Both medications must be taken every 8 hours with food (non-low fat for telaprevir), however, other administration details differ. Boceprevir is initiated after a 4-week lead-in period of PEG-IFN and RBV, and the duration of therapy depends on patient characteristics and the response to treatment. Telaprevir is started simultaneously with PEG-IFN and RBV and given for the initial 12 weeks of therapy only. Myers RP et al. Can J Gastro 2012; 26(6):359-75

Response-Guided Therapy (RGT): CASL Recommendations
RGT - the tailoring of treatment duration based on early viral kinetics - can be employed in selected patient subgroups. Boceprevir: HCV RNA negative at weeks 8 through 24 Telaprevir: HCV RNA negative at weeks 4 through 12 SVR rates of ~90% have been reported with 24 to 28 weeks of therapy in patients qualifying for RGT. Partial responders treated with telaprevir, patients with cirrhosis, and prior null responders should not receive RGT. Response-guided therapy (or RGT) refers to the tailoring of treatment duration based on early viral kinetics. Such a strategy can reduce the duration of exposure to these costly and potentially toxic therapies while providing similar SVR rates to a 48 week course of treatment. CASL recommends RGT in appropriately selected subgroups since SVR rates of ~90% have been reported with 24 to 28 weeks of therapy in patients qualifying for RGT. The RGT rules differ for boceprevir and telaprevir. For boceprevir, RGT is acceptable for patients who are HCV RNA negative at weeks 8 through 24 of therapy. This occurred in 44% of patients in the SPRINT-2 phase 3 trial. In these patients, a 28 week course of therapy resulted in a 96% rate of SVR. For telaprevir, patients who are HCV RNA negative from weeks 4 through 12 qualify for RGT. In the phase 3 ADVANCE trial, approximately 57% to 58% of telaprevir-treated patients achieved this outcome (termed an ‘eRVR’) and stopped therapy at 24 weeks. The SVR rate in these patients was 83% to 89% (depending on the study arm). RGT cannot be applied to all patient subgroups. Specifically, partial responders treated with telaprevir, patients with cirrhosis and prior null responders should not receive RGT. These patients should be treated for 48 weeks. Myers RP et al. Can J Gastro 2012; 26(6):359-75

Adherence to Antiviral Therapy: CASL Recommendations
Adherence to treatment and to futility rules, and close monitoring of concomitant drugs and side effects are particularly important with PI-based therapy. Optimal management of this population should be conducted by well-trained, experienced personnel. Adherence to PEG-IFN and RBV dual therapy and triple therapy including the PIs is associated with improved rates of SVR. Failure to adhere to the recommended treatment schedules and stopping rules when using the PIs may also increase the risk of resistance. Numerous characteristics of these regimens have a negative impact on adherence including the necessity to take multiple medications for prolonged periods, by different routes of administration, and with numerous adverse effects. Several features of boceprevir and telaprevir add further complexity including the increased pill burden (up to 12 extra pills per day), different dosing schedules (TID vs. BID dosing), additional adverse effects, specific dietary constraints, and potentially dangerous drug-drug interactions. Importantly, experts in multidisciplinary settings have treated the vast majority of individuals that have received these medications thus far. In light of these complexities, CASL has made the following recommendations regarding adherence: First, adherence to treatment and to futility rules, and close monitoring of concomitant drugs and side effects are particularly important with PI-based therapy. Second, optimal management of this population should be conducted by well-trained, experienced personnel. Myers RP et al. Can J Gastro 2012; 26(6):359-75

Futility Rules: CASL Recommendations
Strict adherence to futility rules is vital to limit exposure to potential side effects of these costly therapies that will not achieve SVR, and to reduce emergence of antiviral resistance. All therapy – including PEG-IFN and RBV – must be discontinued if futility rules are met: Boceprevir: HCV RNA ≥100 IU/mL at week 12 or detectable at week 24 Telaprevir: HCV RNA >1,000 IU/mL at week 4 or 12, or detectable at week 24 Identical futility rules apply to treatment-naïve and treatment-experienced patients. As mentioned on the previous slide, adherence to futility rules is particularly important to PI-based therapy. Strict adherence to futility rules will limit exposure to potential side effects of these costly therapies in patients that will not achieve SVR, and likely reduce the emergence of antiviral resistance. In patients who meet futility rules, all therapy (including PEG-IFN and RBV) must be discontinued. The futility rules differ between boceprevir and telaprevir although identical rules apply to treatment-naïve and treatment-experienced patients. Specifically, for boceprevir, all treatment should be stopped if HCV RNA is ≥100 IU/mL at week 12 or detectable at week 24. For telaprevir, treatment should be stopped if HCV RNA exceeds 1,000 IU/mL at weeks 4 or 12, or HCV RNA remains detectable at week 24. Myers RP et al. Can J Gastro 2012; 26(6):359-75

If futility rules met, RNA is rising!
Futility Rules Indicate Treatment Failure Even if the Viral Load Has Declined 107 1,800,000 106 99.9% reduction: Continue? 105 104 HCV RNA (IU/mL) 1,230 103 475 102 If futility rules met, RNA is rising! Stop therapy! Close adherence to futility rules is vital to avoid exposure of patients to treatment that will not succeed and reduce the development of antiviral resistance. In this hypothetical patient on telaprevir-based triple therapy, HCV RNA has fallen from 1.8 million IU/mL at baseline to 1,230 IU/mL at week 4. Although this represents a 99.9% reduction in HCV RNA, the futility rules for telaprevir dictate discontinuation of all therapy because HCV RNA at week 4 is greater than 1,000 IU/mL. Clinical trial data indicate that no patient with this type of response will have an SVR even if treatment is continued for 48 weeks. In actual fact, this patient’s HCV is rising at week 4 from a nadir level of 475 IU/mL at week 2, likely due to the emergence of antiviral resistance. 10 1 W0 W1 W2 W3 W4 Slide courtesy of Dr. J. Feld.

Adverse Effects of the Protease Inhibitors (PIs)
PI-based therapy associated with more adverse effects than PEG-IFN and RBV dual therapy No data to support switching from one PI to another to manage toxicity Major adverse effects differ by PI Boceprevir: anemia (~50%), dysgeusia (~40%) Telaprevir: anemia (~40%), rash (~40%), anorectal symptoms (~30%) Patients treated with PI-based combination therapy experience more adverse effects than those treated with PEG-IFN and RBV alone. There are no data to support switching from one PI to another as a strategy to manage toxicity. The major adverse effects differ by PI. For boceprevir, the most important adverse effects are anemia and dysgeusia (abnormal taste sensation) which occur in ~50% and 40% of patients, respectively. For telaprevir, anemia, rash, and anorectal symptoms including burning and pruritus, occur in ~40%, 40%, and 30% of patients, respectively. Myers RP et al. Can J Gastro 2012; 26(6):359-75

Adverse Effects of the Protease Inhibitors (PIs): CASL Recommendations
Treatment with PIs should be supervised by experienced personnel and adverse effects monitored closely. Close monitoring of hemoglobin levels is essential during antiviral treatment for HCV, particularly during the administration of PIs. Management of anemia may include any of the following strategies: RBV dose reduction (first line), transfusion of packed red blood cells, and/or erythropoietin administration. In light of the additional adverse effects of PI-based triple therapy over dual therapy with PEG-IFN and RBV, CASL has the following recommendations: First, treatment with PIs should be supervised by experienced personnel and adverse effects monitored closely. Second, due to the high frequency of anemia with these agents, close monitoring of hemoglobin levels is essential during antiviral treatment for HCV, particularly during the administration of PIs. Hemoglobin should be monitored weekly for at least the first 2 months of therapy. Third, management of anemia may include any of the following strategies: RBV dose reduction – which is the recommended first line approach - transfusion of packed red blood cells, and/or erythropoietin administration. Studies have demonstrated that with PI-based triple therapy, RBV dosage reductions are not associated with a reduced probability of SVR compared with alternative strategies (or SVR rates achieved in patients without anemia). Myers RP et al. Can J Gastro 2012; 26(6):359-75

Drug-Drug Interactions (DDIs)
Boceprevir and telaprevir are substrates and inhibitors of CYP3A4* CYP3A4 metabolizes many common drugs Potential increased drug concentrations with PI co-administration Drugs that induced CYP3A4 may reduce PI concentration (i.e. antiviral treatment efficacy) Numerous potential DDIs with PI-based therapy Antiarrhythmics, anticoagulants, anticonvulsants, antihistamines, antibacterials, antiretrovirals, statins, herbal products, immunosuppressants, OCPs, phosphodiesterase inhibitors, and some sedatives/hypnotics Boceprevir and telaprevir are substrates and inhibitors of CYP3A4. Other less relevant metabolic pathways include P-glycoprotein and aldoketoreductase. CYP3A4 metabolizes many common drugs; hence, there are numerous potential drug-drug interactions (DDIs) with the PIs. Many medications may have increased serum concentrations when administered with PIs. Conversely, drugs that induce CYP3A4 may reduce PI concentration. Therefore, boceprevir and telaprevir are contraindicated with medications that are potent inducers of CYP3A4 (which would reduce plasma concentrations and their antiviral efficacy) and those that are highly dependent on CYP3A4 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Medications with potential DDIs with boceprevir or telaprevir are numerous and include the following classes: antiarrhythmics, anticoagulants, anticonvulsants, antihistamines, antibacterials, antiretrovirals, statins, herbal products (e.g. St. John’s Wort), immunosuppressants, phosphodiesterase inhibitors, and some sedatives/hypnotics. Due to an interaction between the PIs and oral contraceptives that can reduce the efficacy of the latter, a second method of contraception should be used during treatment with these agents. * Minor elimination pathways include P-glycoprotein and aldoketoreductase.

Drug-Drug Interactions (DDIs): CASL Recommendations
Prior to the initiation of PIs, potential DDIs must be considered, including those attributable to prescription and over-the-counter pharmaceuticals and herbal preparations. Review product monographs and useful online resources for potential DDIs prior to initiating therapy. Regarding DDIs, CASL has made the following recommendations: First, prior to the initiation of PIs, potential DDIs must be considered, including those attributable to prescription and over-the-counter pharmaceuticals and herbal preparations. In order to identify such DDIs, it is recommended that health care providers review the relevant product monographs and useful online resources for potential DDIs prior to initiating therapy. Two helpful websites are included at the bottom of the slide. Myers RP et al. Can J Gastro 2012; 26(6):359-75

Antiviral Resistance All resistance variants pre-exist
Not caused by PIs, but unmasked by selective pressure Reflect inadequate response to PEG-IFN/RBV Predominant cause (80-90%) of incomplete viral suppression, breakthrough, or relapse Genotype 1a > 1b Modest or null IFNa-ribavirin effect 1 Emergence of antiviral-resistant variants during PI-based treatment has been reported in all trials. Indeed, pre-treatment testing in phase 3 trials of boceprevir and telaprevir has confirmed the presence of these variants in 5% to 7% of patients using poorly sensitive methods (i.e. population sequencing). Due to the high replication rate of HCV and the low fidelity of its RNA-dependent RNA polymerase, these variants are present at low frequencies before DAA exposure. Resistant variants are not caused by PIs; rather they are unmasked by selective pressure of these agents. As shown in the Figure, an inadequate PEG-IFN and RBV response leads to suppression of the wild-type sensitive virus, but cannot adequately suppress pre-existing resistant variants, thus leading to the expansion of the latter population. In the clinical trials, the majority of patients (80-90%) who experienced incomplete viral suppression, breakthrough, or relapse upon treatment cessation harboured resistant variants. HCV genotype 1a has a higher risk of resistance than genotype 1b due to the higher genetic barrier of the latter subtype. -1 HCV RNA change from baseline (Log10 IU/mL) -2 Resistant HCV -3 -4 Wild-type, sensitive HCV -5 Study time Pawlotsky JM. Hepatology May; 53(5):

Antiviral Resistance: CASL Recommendations
In order to reduce the development of antiviral resistance to the PIs, patients who meet futility rules indicating a high likelihood of treatment failure should discontinue therapy immediately. Dosage reductions of boceprevir and telaprevir should not be utilized to manage treatment-related side effects. To prevent resistance, PIs must be stopped if either PEG-IFN or RBV are discontinued. There is no role for pre-treatment resistance testing. Regarding antiviral resistance, CASL has made the following recommendations: First, in order to reduce the development of antiviral resistance to the PIs, patients who meet futility rules indicating a high likelihood of treatment failure should discontinue therapy immediately. Second, dosage reductions of boceprevir and telaprevir should not be utilized to manage treatment-related side effects. Third, to prevent resistance, PIs must be stopped if either PEG-IFN or RBV are discontinued. Finally, since pre-existing variants do not appear to impact the probability of SVR or treatment decisions with the first-generation PIs, routine pre-treatment resistance testing is not recommended. Myers RP et al. Can J Gastro 2012; 26(6):359-75

Summary: CASL Guidelines for the Management of HCV
Must maximize case-finding, referral, and antiviral Rx to reduce HCV burden in Canada. Barriers to treatment (e.g. need for biopsy) should be minimized. New therapies (boceprevir and telaprevir) markedly improve SVR rates in genotype 1 (treatment-naïve and experienced), but are complex and have additional side effects. In summary, in order to reduce the future burden of hepatitis C in Canada, we must maximize case-finding, referral of diagnosed cases, and the dissemination of antiviral therapy. Barriers to treatment, including the requirement for pre-treatment liver biopsy, should be removed. Finally, newly approved protease inhibitors – boceprevir and telaprevir – have markedly improved SVR rates in patients with HCV genotype 1, but treatment regimens are complex and additional side effects require consideration.

Important Hepatitis C Protease Inhibitor Drug Interactions in Mono and HIV Coinfection
Alice Tseng, Pharm.D., FCSHP, AAHIVP Toronto General Hospital University of Toronto

Outline Review principles of drug interactions
Understand how the pharmacology of DAAs contribute to drug interactions Highlight important HCV drug interactions Outline a strategy for identifying and managing drug interactions Identify pertinent HCV drug interaction resources

Drug Interactions Pharmacodynamic
Change in pharmacological effect of a drug Additive, synergistic, or antagonistic activity or toxicity e.g., ribavirin + AZT =  anemia Pharmacokinetic Change in the amount of drug(s) in body Absorption, distribution, metabolism, elimination may be affected Often involves CYP450 system or transporters Drug interactions may be classified as being either pharmacokinetic or pharmacodynamic in nature. With pharmacodynamic interactions, additive, synergistic, or antagonistic drug combinations may affect parameters of pharmacological response, including efficacy and toxicity. Pharmacodynamic drug–drug interactions may be beneficial, when agents with complementary mechanisms of action (eg, reverse transcriptase inhibitors plus PIs or NNRTIs) are administered to enhance clinical efficacy. In contrast, certain combinations may be undesirable if antagonism or additive toxicity occurs. For example, lamivudine and zalcitabine have been shown to negatively interact in vitro, likely via competition for intracellular phosphorylation, and thus should not be coadministered. Similar concern exists regarding the combination of zidovudine and stavudine. With pharmacokinetic interactions, absorption, distribution, metabolism, or elimination may be affected, resulting in an alteration of the amount and/or concentration of one or both agents in the body. Sometimes this is desirable if the pharmacokinetic profile of a drug is improved. On the other hand, certain interactions may be undesirable when the disposition of an agent with a narrow therapeutic index is affected. 30

Interactions Affecting Drug Metabolism
Majority of drugs transformed to inactive forms prior to elimination through Phase I (oxidation) or Phase II (conjugation) reactions Phase I primarily involves cytochrome P450 system Superfamily of microsomal heme-containing enzymes Primarily located in liver, small bowel; also kidney, lung, brain CYP3A is the most abundantly expressed isoenzyme, is involved in the metabolism of ~50% of clinically used drugs others: CYP2D6, 2C9, 2B6, 1A2, etc. P-glycoprotein Efflux membrane transporter which prevents drug accumulation in cells; has broad substrate specificity, and inhibiting or inducing the activity of this protein can lead to significant alterations in drug exposure Many drugs that are administered orally are fat-soluble. This is a desirable characteristic for oral absorption because lipophilic agents can passively diffuse through membranes of the gut, whereas drugs that are not lipophilic pass unaltered through body in the stool. However, once lipophilic drugs are absorbed, they circulate in blood bound to plasma proteins, or are sequestered in fat; thus, they are not readily excreted by the kidney into the urine. Therefore, to eliminate these agents, they are converted in the body to more water-soluble metabolites which can then be excreted by the kidney. The majority of these conversions occur in the liver, via phase I and phase II reactions. Phase I reactions are the most common, and involve the cytochrome P450 system. The cytochrome P450 system is a superfamily of microsomal heme-containing enzymes which chemically oxidize or reduce drugs and endogenous substances such as steroid hormones, fatty acids, and prostaglandins. CYP450 enzymes are present in high concentrations in the liver; they are also present in lower concentrations in other areas of the body, including the gastrointestinal tract, kidneys, lungs, and brain. The presence and amount of certain CYP isozymes may also vary between individuals (ie, genetic polymorphism). Classified into families, subfamilies, and individual enzymes – families: all members have >40% identity in amino acid sequences (indicated by a number) – subfamilies: amino acid sequences are >55% identical (indicated by letter) – individual enzymes within a subfamily (indicated by number). To date, at least 14 families, 22 subfamilies, and 36 CYP enzymes have been identified in human beings. Of these, only 3 families (CYP1, CYP2, CYP3) are currently thought to be responsible for the majority of hepatic drug metabolism. CYP3A is the most abundantly expressed isoenzyme and is involved in the metabolism of about 50% of clinically used drugs P-glycoprotein (P-gp) is an ATP-dependent, efflux membrane transporter. Originally detected in numerous tumour cell types, and implicated in the role of multidrug resistance (MDR). P-gp expels drug from cells, resulting in decreased intracellular drug concentrations, and consequently decreased antitumour activity. In addition, P-glycoprotein is present in tissues: – epithelial cells of the gastrointestinal tract, liver, and kidney – expressed at level of the blood-brain barrier – also noted in subsets of CD4+ T lymphocytes. P-gp has broad substrate specificity, and appears to play a role in the transport of many natural substances and xenobiotics, resulting in: – decreased drug absorption (gastrointestinal tract) – enhanced elimination into bile (liver) and urine (kidney) – prevention of drug entry into the central nervous system (blood-brain-barrier). P-Glycoprotein has broad substrate specificity, and inhibiting or inducing the activity of this protein can lead to significant alterations in drug exposure. – oral absorption: oral bioavailability may be limited by the presence of CYP3A4 in the GI tract and liver (first-pass effect), as well as P-gp, which may transport absorbed drug back into the intestinal lumen. – CNS exposure: in addition to other factors such as lipophilicity, plasma protein binding, molecular weight, and concentration, P-gp may play a significant role in limiting drug penetration into the brain. Examples of P-gp inducers: phenobarbital, phenytoin, rifampin, St John’s wort Examples of P-gp inhibitors: erythromycin, clarithromycin, diltiazem, felodipine, intraconazole, ketoconazole, nicardipine, grapefruit, HIV protease inhibitors, HCV protease inhibitors References: Kashuba ADM, Bertino JS Jr. Mechanisms of drug interactions I. In: Piscitelli S, Rodvold K, eds. Drug Interactions in Infectious Diseases, 2nd edition. New Jersey: Humana Press.  2005, pp Metheny CJ, Lamb MW, Brouwer KLR, Pollack GM. Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy 2001;21: 31

Terms Definition Interaction Impact Common Examples Substrate
Agent which is primarily cleared via a certain enzymatic pathway Rate of drug breakdown is affected by presence of enzyme inhibitors or enzyme inducers antidepressants, azoles, benzodiazepines, statins, corticosteroids, calcium channel blockers, macrolides, rifamycins, HIV PIs & NNRTIs Inhibitor Agent which competes with another drug for binding at enzymatic site Decreased clearance of substrate drug; quick onset & resolution of interaction effect macrolides, azoles, HIV protease inhibitors Inducer Drug that stimulates the production of additional metabolic enzymes Increased clearance of substrate drug; slower onset and resolution of interaction effect anticonvulsants, rifamycins, HIV NNRTIs, St. John’s wort A substrate is any drug that is metabolized by one or more of the P450 enzymes or other transporter systems. The majority of metabolized drugs are substrates for the CYP3A4 enzyme. Examples of CYP3A4 substrates include: anti-infectives (macrolides, azoles, rifamycins, many antiretrovirals), benzodiazepines, antidepressants, anticonvulsants, statins, calcium channel blockers, corticosteroids, etc. A P450 enzyme inhibitor is any drug that inhibits the metabolism of a P450 substrate. This inhibition process is generally competitive in nature (ie, the inhibitor competes with a substrate for binding at the enzyme’s binding site), and is reversible. Competitive inhibition depends upon: – the affinity of the substrate for the enzyme being inhibited – the concentration of substrate required for inhibition – the half-life of the inhibitor drug This competitive mechanism results in accumulation of the target drug (substrate). Inhibition interactions usually occur rapidly, ie, within a few doses, once sufficient concentrations of the inhibiting agent are present in the liver. These interactions also tend to resolve quickly once the offending agent (inhibitor) is removed. NB: a drug does not necessarily need to be a P450 substrate to be an enzyme inhibitor (eg, fluconazole is primarily excreted renally, but is a moderate to weak P450 inhibitor). Common classes of inhibitors include macrolide antibiotics, azole antifungals, HIV protease inhibitors. Another, less common mechanism of inhibition is noncompetitive; this can occur as a result of inactivation of the enzyme. The duration of this type of inhibition may be longer if new enzymes need to be synthesized after removal of the inhibitor drug. An enzyme inducer stimulates the production of more P450 enzymes. It does this by binding directly to promoter elements in the DNA region, resulting in an increase in P450 transcription (ie, increasing messenger RNA), and subsequently increasing the amount of enzymes present. The presence of these additional enzymes results in a net increase in metabolic activity; the body is able to eliminate substrates more quickly, which results in a net reduction in substrate concentrations. Unlike inhibition, induction persists for several days, even after the inducing drug is gone. This is because the enzymes persist for several days following induction. Enzyme induction is also influenced by age and liver disease. For instance, elderly patients, or those with cirrhosis or hepatitis may be less susceptible to enzyme induction. Inducers may also vary by specificity and potency: – Some inducers are able to influence several types of enzymes. – Inducers also affect enzyme activity to varying degrees. For example, rifampin is a more potent inducer than rifabutin and, as such, substrate levels are more likely to be reduced to a greater extent in the presence of rifampin vs. rifabutin. Common classes of inducers include anticonvulsants, rifamycins, and HIV non-nucleoside reverse transcriptase inhibitors. It should be noted that herbal/complementary agents can also be associated with pharmacokinetic interactions. St. John’s Wort is a popular remedy for treatment of mild-to-moderate depression. However, St. John’s wort is a potent inducer of CYP3A4, and can cause significant drug interactions. It is contraindicated in patients taking either boceprevir or telaprevir. In contrast to enzyme inhibition interactions, enzyme induction interactions generally have a slower onset and resolution of effect. Enzyme induction interactions do not usually become apparent for a week or more, since the enzyme inducer must first reach steady state, and new drug metabolizing enzymes need to be synthesized. Usually, maximum induction effect is attained after approximately 2 weeks. Similarly, once the inducing agent is removed, the interaction may take a few weeks to resolve (time for the inhibitor to be cleared, and for enzymes to degrade). References 1. Food and Drug Administration. Risk of drug interactions with St. John’s wort. JAMA 2000;283:1679. 32

Boceprevir and Telaprevir Pharmacology
Dosing 800 mg q8h with food 750 mg q8h with food (20 g fat) Substrate CYP3A4, P-gp, AKR CYP3A4, Pgp Inhibitor 3A4, P-gp 3A4, P-gp, renal transporters (?) Inducer No inducing effects in vitro (in vivo?) Boceprevir and telaprevir are substrates and inhibitors of CYP3A4. Boceprevir is also metabolized via aldoketoreductases, but this appears to be a minor pathway. Both agents also inhibit p-glycoprotein and telaprevir may inhibit renal transporters. Boceprevir and telaprevir have not demonstrated enzyme inducing activity in vitro. Maintaining adequate plasma concentrations is important for directly acting antiviral agents. These drugs have short half-lives, and thus must be taken at regular (every 8 hours) dosing, with the proper amount of food for in order to be adequately absorbed. Use of other agents which inhibit or induce CYP3A4 and/or p-glycoprotein can result in altered plasma concentrations of DAAs. Many phase 3 HCV agents are also substrates of CYP450, P-gp, and/or other transporters, and may also possess inhibiting or inducing properties. Therefore, there is a high potential for interactions between current and future directly acting antiviral agents and other drug classes. These interactions may be clinically significant, complex, and sometimes unpredictable. = +++ potential for interactions with other drugs can be clinically significant sometimes unpredictable 33

Potential Consequences of DAA Drug Interactions
Interactions may occur in a two-way manner: Concentrations of DAA may be altered by other drug(s) Concentrations of concomitant drug(s) may be altered by DAA Potential consequences include: Increased risk of toxicity Decreased efficacy Maintenance of adequate drug concentrations is necessary to achieve optimal virological benefit. The use of interacting drugs which inhibit or induce CYP3A4 and/or p-glycoprotein can result in altered plasma concentrations of DAAs. Potential consequences of drug interactions include: Increased risk of toxicity. Increased drug concentrations may increase the risk of dose-related side effects. This in turn may lead to decreased quality of life, risk of non-adherence, or dose reduction or even premature drug discontinuation. Decreased antiviral efficacy. Decreased drug concentrations may lead to suboptimal disease/symptom control, inadequate viral suppression, development of drug resistance, incomplete treatment response or disease progression. Given the fact that there may be cross-resistance between not only current but also future DAAs in development, current as well as future HCV treatment options may be compromised. It is important to note that interactions may occur in a two-way manner with DAAs, since they are both substrates and inhibitors of CYP3A4 and p-glycoprotein. In other words, DAAs can increase concentrations of other drugs, which may lead to increased risk of toxicity. In turn, other drugs can either increase or decrease concentrations of DAAs, which may lead to either increased risk of toxicity or decreased antiviral efficacy. The clinical significance of an interaction will depend upon several factors, including: – the magnitude of change in pharmacokinetic parameters – the efficacy and toxicity of the affected agent(s). the nature/severity of the disease(s) being treated 34

Statin Interactions Most statins are P450 substrates
DAAs can significantly increase statin levels: Atorvastatin: 130%  with boceprevir, 7.88-fold  with telaprevir Pravastatin: 60%  with boceprevir  risk of toxicity, including myopathy and rhabdomyolysis Boceprevir Telaprevir Lovastatin, Simvastatin CONTRAINDICATED Atorvastatin May need to  atorvastatin dose; do not exceed >20 mg/d CONTRA- INDICATED Pravastatin Start with recommended dose and monitor for toxicity. Possible  in statin; use with caution. Rosuvastatin, Fluvastatin Possible  in statin; use with caution. Atorvastatin – Lipitor; lovastatin – Mevacor; simvastatin – Zocor; rosuvastatin – Crestor; pravastatin – Pravachol; fluvastatin – Lescol pitavastatin – Livalo (N/A in Canada) – via UGT Most statins are substrates of the P450 system, primarily CYP3A4. However, there are some within-class differences: atorvastatin, lovastatin, simvastatin: CYP3A4 rosuvastatin: <10% metabolized; 2C9, 2C19, Pgp? pravastatin: % Clrenal; CYP3A(?), OATP1B1, OATP2B1 fluvastatin: CYP2C9 >>3A4 (minor) Boceprevir and telaprevir can significantly increase concentrations of statins, which can lead to increased risk of toxicity including myopathy and rhabdomyolysis. Atorvastatin 40 mg + boceprevir: atorvastatin AUC  130% and Cmax  170% vs atorvastatin alone Suggest  atorvastatin dose with concomitant BOC; monitor for symptoms of statin toxicity if using >40 mg/d atorvastatin Pravastatin 40 mg + boceprevir: pravastatin AUC  60% and Cmax  50% vs. pravastatin alone Can initiate pravastatin at the recommended dose when co-administered with BOC, with close clinical monitoring Atorvastatin 20 mg+ telaprevir: In healthy subjects, the kinetics of single dose amlodipine 5 mg/atorvastatin 20 mg (coformulated) were assessed alone and with steady-state telaprevir 750 mg q8h. In the presence of telaprevir, atorvastatin Cmax  10.6-fold and AUC  7.88-fold. Atorvastatin, lovastatin and simvastatin are contraindicated with telaprevir. In March 2012, the FDA issued a Drug Safety Communication regarding the risk of increased toxicity with statins when combined with either HIV or HCV protease inhibitors. The product monographs were subsequently updated to reflect these dosing recommendations. References: Lee JE, Van Heeswijk RPG, Alves K, et al. Effect of the hepatitis C virus protease inhibitor telaprevir on the pharmacokinetics of amlodipine and atorvastatin. Antimicrob Agents Chemother 2011;55(10): Hulskotte EGJ, Gupta S, Xuan F, et al. Pharmacokinetic evaluation of the interaction between the HCV protease inhibitor boceprevir and the HMG-CoA reductase inhibitors atorvastatin and pravastatin [abstract 122]. HEP DART, December 4-8, 2011, Koloa, Hawaii. U.S. Food and Drug Administration. HIV/AIDS Update - Important info about interactions between certain HIV drugs and cholesterol-lowering statin drugs. March 1, 2012. [Victrelis & Incivek Product Monographs, FDA HIV/AIDS Drug Safety Communication, March 1, 2012] 35

Atorvastatin Interactions with Boceprevir and Telaprevir
Atorvastatin 40 mg + boceprevir: Atorvastatin AUC  130% and Cmax  170% vs. atorvastatin alone Suggest  atorvastatin dose with concomitant BOC; monitor for symptoms of statin toxicity if using >40 mg/d atorvastatin Atorvastatin 20 mg + telaprevir: Atorvastatin AUC  7.88-fold Combination is contraindicated 30,000 100 25,000 Atorvastatin alone Atorvastatin + Boceprevir 10.0 20,000 With telaprevir Atorvastatin concentration (pg/mL) 15,000 Concentration (ng/mL) 1.00 10,000 Without telaprevir 0.10 5,000 0.01 Boceprevir and telaprevir can significantly increase concentrations of statins, which can lead to increased risk of toxicity including myopathy and rhabdomyolysis. Atorvastatin 40 mg + boceprevir: atorvastatin AUC  130% and Cmax  170% vs. atorvastatin alone Suggest  atorvastatin dose with concomitant BOC; monitor for symptoms of statin toxicity if using >40 mg/d atorvastatin Pravastatin 40 mg + boceprevir: pravastatin AUC  60% and Cmax  50% vs. pravastatin alone Can initiate pravastatin at the recommended dose when co-administered with BOC, with close clinical monitoring Atorvastatin 20 mg+ telaprevir: In healthy subjects, the kinetics of single dose amlodipine 5 mg/atorvastatin 20 mg (coformulated) were assessed alone and with steady-state telaprevir 750 mg q8h. In the presence of telaprevir, atorvastatin Cmax  10.6-fold and AUC  7.88-fold. Atorvastatin, lovastatin and simvastatin are contraindicated with telaprevir. In March 2012, the FDA issued a Drug Safety Communication regarding the risk of increased toxicity with statins when combined with either HIV or HCV protease inhibitors. The product monographs were subsequently updated to reflect these dosing recommendations. References: Lee JE, Van Heeswijk RPG, Alves K, et al. Effect of the hepatitis C virus protease inhibitor telaprevir on the pharmacokinetics of amlodipine and atorvastatin. Antimicrob Agents Chemother 2011;55(10): Hulskotte EGJ, Gupta S, Xuan F, et al. Pharmacokinetic evaluation of the interaction between the HCV protease inhibitor boceprevir and the HMG-CoA reductase inhibitors atorvastatin and pravastatin [abstract 122]. HEP DART, December 4-8, 2011, Koloa, Hawaii. U.S. Food and Drug Administration. HIV/AIDS Update - Important info about interactions between certain HIV drugs and cholesterol-lowering statin drugs. March 1, 2012. 8 16 24 32 40 48 10 20 30 40 50 Time (hrs) Nominal time (hrs) Hulskotte EGJ et al. HEP DART 2011, Koloa, Hawaii, poster 122 Lee JE et al. Antimicrob Agents Chemother 2011, 55(10): 36

Concentration (ng/mL)
Effect of Steady-State Telaprevir on the Pharmacokinetics of Amlodipine 5 mg 5.00 Calcium channel blockers (CCBs) Amlodipine, diltiazem, felodipine, nifedipine, nicardapine, verapamil are CYP3A4 substrates Concentrations may be  by boceprevir or telaprevir Use with caution, clinical monitoring Consider dose reduction With telaprevir 0.50 Concentration (ng/mL) Without telaprevir 0.05 In healthy subjects, the kinetics of single dose amlodipine 5 mg/atorvastatin 20 mg (coformulated) were assessed alone and with steady-state telaprevir 750 mg q8h. In the presence of telaprevir, amlodipine Cmax  27% and AUC  179%. Monitor for dose-related amlodipine toxicity when coadministering with telaprevir. Calcium channel blockers are CYP3A4 substrates, and drug concentrations may be increased in the presence of boceprevir or telaprevir. Caution is warranted and clinical monitoring of patients is recommended if concomitant therapy is required. References: Lee JE, Van Heeswijk RPG, Alves K, et al. Effect of the hepatitis C virus protease inhibitor telaprevir on the pharmacokinetics of amlodipine and atorvastatin. Antimicrob Agents Chemother 2011;55(10): Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC July 27, 2011. Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA, May, 2011. 0.01 50 100 150 200 250 Nominal time (hrs) Amlodipine AUC  179% Monitor for dose-related toxicity Lee JE et al. Antimicrob Agents Chemother 2011, 55(10): 37

Antihypertensive Medications
Class Examples Potential DAA Interactions ACEI Enalapril, lisinopril, ramipril (renal) Not expected ARBs Losartan (2C9>>3A4 to active metabolite) Candesartan, irbesartan (2C9) Eprosartan, olmesartan, telmisartan, valsartan (biliary) Possible  effect Low Beta- blockers Propranolol (2D6, 3A4, 2C19), carvedilol (2D6, 2C9> 1A2, 2E1, 3A4) Acebutolol, labetalol, metoprolol, pindolol (2D6) Atenolol, nadolol (renal) Possible  Calcium channel blockers Amlodipine, diltiazem, felodipine, nifedipine, verapamil (3A4) Risk of  CCB exposures; use with caution Diuretics Hydrochlorothiazide, furosemide, spironolactone (renal) Indapamide (2C9, 2D6, 3A4) Calcium channel blockers are CYP3A4 substrates, and drug concentrations may be increased in the presence of boceprevir or telaprevir. Caution is warranted and clinical monitoring of patients is recommended if concomitant therapy is required. Calcium channel blocker dose reduction may be necessary. Pharmacokinetic interactions are not expected with ACE inhibitors, most diuretics, and most beta-blockers which are excreted by the kidneys. Exceptions include the diuretic indapamide, and the beta-blockers propranolol and carvedilol, which are metabolized through a variety of CYP450 pathways including 3A4. These particular agents have not been studied with boceprevir or telaprevir, and the clinical significance of coadministration is unknown, since CYP3A4 is one of many isozymes involved in drug metabolism. Nevertheless, caution is warranted with these combinations. Clinicians may wish to consider initiating therapy with lower doses of these agents if patients are receiving DAAs. Most angiotensin II receptor blockers (ARBs) are not metabolized by CYP450 enzymes and undergo biliary excretion, and hence are not predicted to interact with DAAs. In contrast, losartan is primarily converted to its active metabolite, E-3174 by 2C9 and to a lesser extent by 3A4; as such, there is a potential risk of interaction with DAAs, where reduction in formation of the metabolite and hence decreased effect may occur. Candesartan and irbesartan are substrates of 2C9, and the potential for pharmacokinetic interactions with DAAs is low. References: Kiser JJ, Burton JR, Anderson PL, Everson GT. Review and management of drug interactions with boceprevir and telaprevir. Hepatology 2012;55: Peyriere H, Eiden C, Macia J-C, Reynes J. Antihypertensive drugs in patients treated with antiretrovirals. Ann Pharmacother 2012;46:703-9. 38

Treatment of Depression in HCV
Place in Therapy Examples (route of metabolism) Potential DAA Interactions First Line Escitalopram, citalopram (2C19, 3A4>>2D6) 35%  with TVR, no interaction with BOC Second Line Paroxetine, fluoxetine (2D6), bupropion (2B6) Sertraline (2B6>2C9/19, 3A4, 2D6), venlafaxine (2D6>3A4), desvenlafaxine (UGT>>3A4), mirtazapine (2D6, 1A3, 3A4) Low Possible  Third Line Nortriptyline (2D6) Imipramine (2D6, 1A2, 2C19, 3A>UGT) No Evidence Modafinil (3A4; induces 3A4) Amantadine (not metabolized) Possible ;  DAA Not expected Avoid Duloxetine (1A2, 2D6) - CONTRAINDICATED Additive risk of hepatotoxicity Patients with HCV may require antidepressant therapy. Escitalopram has been studied with both boceprevir and telaprevir. In healthy volunteers, the kinetics of single dose escitalopram 10 mg were not altered to a clinically significant manner in the presence of multiple dose boceprevir 800 mg TID. The pharmacokinetics of boceprevir were similar with and without coadministration of escitalopram. No dosage adjustment is expected to be required with coadministration of this combination.[Hulskotte et al. 2011] In healthy volunteers, coadministration of escitalopram 10 mg daily with telaprevir 750 mg q8h for 7 days resulted in 35%  escitalopram AUC, while telaprevir exposures were not affected. The dose of escitalopram may need to be titrated according to clinical response. [Van Heeswijk et al. 2010] Antidepressants that are primarily metabolized by CYP pathways such as 2D6 or 2B6 (e.g., bupropion, paroxetine, fluoxetine, nortriptyline) are considered to be at low risk for pharmacokinetic interactions with boceprevir or telaprevir. Drugs which are metabolized through a variety of CYP isozymes including 3A4 (e.g., desvenlafaxine, sertraline, venlafaxine, mirtazapine, imipramine) may theoretically be at risk of pharmacokinetic interactions with boceprevir or telaprevir, but the clinical significance is not known since these particular combinations have not been studied, and CYP3A4 may play a relatively minor role in metabolism of these agents. Close monitoring of patients who require concomitant therapy with antidepressants and HCV treatment is recommended. Duloxetine is contraindicated in patients with any liver disease resulting in hepatic impairment because of the risk of hepatotoxicity. References: de Knegt RJ, Bezemer G, Van Gool AR, et al. Randomised clinical trial: escitalopram for the prevention of psychiatric adverse events during treatment with peginterferon-alfa-2a and ribavirin for chronic hepatitis C. Aliment Pharmacol Ther 2011;34: Eli Lilly Canada Inc. Cymbalta (duloxetine) Product Monograph, Toronto, ON, November 6, 2011. Hulskotte EGJ, Gupta S, Xuan F, et al. Coadministration of the HCV protease inhibitor boceprevir has no clinically meaningful effect on the pharmacokinetics of the selective serotonin reuptake inhibitor escitalopram in healthy volunteers [abstract]. HEP DART, December 4-8, 2011, Koloa, Hawaii. McNutt MD, Liu S, Manatunga A, et al. Neurobehavioral effects of interferon-α in patients with hepatitis-C: symptom dimensions and responsiveness to paroxetine. Neuropsychopharmacology 2012;37: Ramasubbu R, Taylor VH, Samaan Z, et al. The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and select comorbid medical conditions. Annal Clin Psychiatry 2012;24: Van Heeswijk RPG, Boogaerts G, De Paepe E, et al. The pharmacokinetic interaction between escitalopram and the investigational HCV protease inhibitor telaprevir [abstract 12]. 5th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 23-24, 2010, Boston, MA. 39

Methadone Interactions
Methadone is metabolized by CYP2B6, CYP2C19 & CYP3A, 85% protein bound; R-isomer is biologically active enantiomer Boceprevir interaction: In the presence of steady-state boceprevir, R-methadone AUC  16%, Cmax  10%; no clinical effects noted including opioid withdrawal Boceprevir exposures not affected by methadone Telaprevir interaction: In the presence of steady-state telaprevir, R-methadone Cmin  31%, Cmax  21% and AUC  21%, but median unbound Cmin of R-methadone was similar before and during telaprevir coadministration and no withdrawal symptoms were noted A priori methadone dose adjustments are not required when initiating DAA therapy, but close monitoring is recommended, with methadone dose adjustments if necessary Methadone does not induce or inhibit CYP450 isoenzymes, so would not be expected to affect the pharmacokinetics of other agents including boceprevir and telaprevir. Methadone is available as a combination of R- and S-isomers, and undergoes N-demethylation primarily via CYP3A4, CYP2B6, and CYP2C19 to inactive metabolites.[1] As such, the pharmacokinetics of methadone may be affected by other drugs which are CYP inducers or inhibitors. Interaction Study with Boceprevir: In HCV-negative volunteers on stable, maintenance doses ( mg QD) of methadone, boceprevir 800 mg q8h was coadministered for 6 days. In the presence of boceprevir, exposures of R-methadone were decreased (AUC  16%, Cmax  10%) and S-methadone were decreased (AUC  22%, Cmax  17%). These changes did not result in clinically significant effects including withdrawal. Boceprevir exposures in the presence of methadone were similar to historical controls. Dose adjustment is likely not necessary when boceprevir is co-administered with methadone.[2] Clinical monitoring is recommended, with dose adjustments of methadone if necessary during concomitant treatment with boceprevir. Interaction Study with Telaprevir: In HCV-negative volunteers on stable methadone maintenance therapy (median methadone dose 85 mg, range mg/day), telaprevir 750 mg q8h was co-administered for 7 days. In the presence of telaprevir, R-methadone Cmin  31%, Cmax  21% and AUC  21%. The AUC ratio of S-/R-methadone was comparable before and during coadministration of telaprevir. The median unbound fraction of R-methadone  from 7.92% to 9.98% during coadministration with telaprevir, but the median unbound Cmin of R-methadone was similar before and during telaprevir coadministration. A priori methadone dose adjustments are not required when initiating telaprevir, but close monitoring is recommended, with dose adjustments if necessary.[3] References: 1. Gerber JG, Rhodes RJ, Gal J. Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19. Chirality 2004;16:36-44. 2. Hulskotte EGJ, Feng H-P, Bruce RD, et al. Pharmacokinetic interaction between HCV protease inhibitor boceprevir and methadone or buprenorphine in subjects on stable maintenance therapy [abstract PK_09]. 7th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 27-28, 2012, Cambridge, MA. 3. Van Heeswijk RPG, Vandevoorde A, Verboven P, et al. The pharmacokinetic interaction between methadone and the investigational HCV protease inhibitor telaprevir [abstract PK_18]. 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, 2011, Cambridge, MA. Hulskotte et al , Van Heeswijk et al 40

Hormonal Contraceptives with DAAs
Hormonal contraceptives may not be as effective in women taking boceprevir or telaprevir Boceprevir (Victrelis): 99%  AUC drospirenone, 24%  AUC EE Use 2 alternate effective methods of contraception during treatment with BOC and Peg IFN/RBV Drospirenone (Yaz®, Yasmin®, Angelique®) is contraindicated Telaprevir (Incivek): 28%  AUC, 33%  Cmin of EE Use 2 additional non-hormonal methods of effective birth control during TVR dosing and for 2 months after the last intake of TVR. Hormonal contraceptives may not be a reliable form of contraception during boceprevir or telaprevir treatment. Telaprevir: In the presence of steady-state telaprevir, ethinyl estradiol AUC was reduced 28% and Cmin was reduced 33%. Therefore, female patients of childbearing potential should use 2 additional non-hormonal methods of effective birth control during telaprevir dosing and for 2 months after the last intake of telaprevir. Boceprevir: The results of the drug interaction study between boceprevir 800 mg TID and oral drospirenone/ethinyl estradiol (3 mg/0.02 mg daily) at steady-state demonstrated an increased systemic exposure of drospirenone (AUC, 99 %; Cmax, 57 %) without notably affecting the exposures of ethinyl estradiol (AUC, 24 % ↓, no change in Cmax). Therefore, two alternative effective methods of contraception, including intrauterine devices and barrier methods, should be used in women during treatment with boceprevir and concomitant PegIFNα/ribavirin. Co-administration of boceprevir with drospirenone is contraindicated due to the potential for increased drospirenone concentrations and risk of hyperkalemia. References: Garg V, Van Heeswijk RPG, Yang Y, et al. The pharmacokinetic interaction between an oral contraceptive containing ethinyl estradiol and norethindrone and the HCV protease inhibitor telaprevir. J Clin Pharmacol 2011;Oct 30 [epub ahead of print]. Kasserra C, Hughes E, Treitel M, et al. Clinical pharmacology of boceprevir: metabolism, excretion, and drug-drug interactions [abstract 118]. 18th Conference on Retroviruses and Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA. Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC July 27, 2011. Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA, May, 2011. 41

Benzodiazepine Interactions
Majority are substrates of CYP3A4 Risk for prolonged/excessive sedation Oral midazolam & triazolam are contraindicated with boceprevir and telaprevir IV midazolam: consider  dose, close monitoring for respiratory depression or prolonged sedation Other benzodiazepines:  dose and monitor Consider using benzodiazepines that are glucuronidated: Lorazepam, oxazepam, temazepam The majority of benzodiazepines are substrates of CYP3A4, and hence are susceptible to interactions with CYP3A4 inhibitors. Significantly elevated benzodiazepine concentrations may result in prolonged or excessive sedative effects. Midazolam is a CYP3A4 substrate. 5 to 9-fold  AUC with boceprevir or telaprevir using oral midazolam. Therefore, oral midazolam is contraindicated with HCV protease inhibitors. IV midazolam: 3.4-fold  AUC with telaprevir; no data with boceprevir. Co-administration with telaprevir should be done in a setting which ensures clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Alternative options for short-term sedation: lorazepam (Ativan) or propofol (Diprivan) Triazolam is also contraindicated with boceprevir & telaprevir. For alprazolam, buspirone, diazepam, flurazepam, nitrazepam, zolpidem, zopiclone, eszopiclone: reduce benzodiazepine dose and titrate according to response. An alternative is to use a benzodiazepine which undergoes a different route of metabolism. Oxazepam, lorazepam, and temazepam undergo glucuronidation, and may be less susceptible to inhibition interactions with DAAs. References: Garg V, Chandorkar G, Farmer HF, et al. Effect of telaprevir on the pharmacokinetics of midazolam and digoxin. J Clin Pharmacol 2012;Jan 26 [Epub ahead of print]. Kasserra C, Hughes E, Treitel M, et al. Clinical pharmacology of boceprevir: metabolism, excretion, and drug-drug interactions [abstract 118]. 18th Conference on Retroviruses and Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA. Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC July 27, 2011. Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA May, 2011. 42

Inhaled Corticosteroids
Corticosteroids are CYP3A4 substrates Potential for  corticosteroid concentrations resulting in significantly reduced serum cortisol concentrations Inhaled/nasal fluticasone, budesonide: Avoid co-administration with HCV PIs if possible, particularly for extended durations. May wish to use corticosteroid associated with less adrenal suppression (e.g., beclomethasone, ciclesonide) Use lowest possible dose, consider non-steroidal options Corticosteroids are substrates of CYP3A4. Fluticasone has a longer receptor-binding half-life and a higher volume of distribution compared to other inhaled corticosteroids, and hence may be associated with higher rates of adrenal suppression, particularly at increased exposures. Product Monograph information on inhaled/nasal fluticasone and budesonide: Potential for  corticosteroid concentrations resulting in significantly reduced serum cortisol concentrations. Avoid co-administration if possible, particularly for extended durations.1 Inhaled beclomethasone or ciclesonide, or intranasal beclomethasone or triamcinolone may be safer alternatives, but caution is still warranted. Use lowest possible corticosteroid dose and monitor closely for systemic corticosteroid side effects.23 Of note: Systemic dexamethasone is a CYP3A4 inducer, and may potentially decrease DAA concentrations. The product monographs recommend avoiding combination if possible, use with caution if necessary. References: Foisy MM, Yakiwchuk EMK, Chiu I, et al. Adrenal suppression and Cushing’s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature. HIV Med 2008;9(6): Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC July 27, 2011. Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA May, 2011. Victrelis & Incivek. Product Monographs, 2011 43

PDE5 Inhibitors (sildenafil, tadalafil, vardenafil)
PDE5 inhibitors are substrates of CYP3A4 Potential for DAAs to  concentrations Dose-related side effects (headache, vasodilation, dyspepsia, visual disturbances) Contraindicated with DAAs if using for PAH For erectile dysfunction, use a lower dose with DAAs: Sildenafil: 25 mg q48h, tadalafil: 10 mg q72h Do not use vardenafil Sildenafil, tadalafil and vardenafil are oral phosphodiesterase inhibitors approved for the treatment of erectile dysfunction. Sildenafil and tadalafil are also approved for the treatment of pulmonary arterial hypertension. PDE5 inhibitors are substrates of CYP3A4. DAAs may potentially increase PDE5 inhibitor concentrations, which may increase the risk of dose-related side effects including headaches, vasodilation, dyspepsia and visual disturbances. Vardenafil should not be used with either boceprevir or telaprevir. Sildenafil and tadalafil are contraindicated with DAAs if used for management of pulmonary arterial hypertension; for management of erectile dysfunction, dosing should be reduced: sildenafil: 25 mg q48h (usual dose is mg daily) tadalafil: 10 mg q72h (usual dose is mg daily) References: Victrelis Product Monograph, July 2011. Incivek Product Monograph, August 2011. 44

Interactions Between HCV & HIV Medications
Challenges in treating HIV/HCV co-infected patients Additive toxicities: Anemia: ribavirin, zidovudine, DAAs CNS: interferon, efavirenz Potential for negative 2-way interactions  concentrations of HIV agents  concentrations of HCV DAAs Boceprevir and telaprevir are substrates and inhibitors of CYP3A4. Both agents also inhibit p-glycoprotein and telaprevir may inhibit renal transporters. Similarly, HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors are substrates and inhibitors or inducers of numerous CYP450 hepatic enzymes and transporters. The CCR5 inhibitor maraviroc is a CYP3A4 substrate but does not exert inhibiting or inducing effects on the P450 system. Therefore, there is a high potential for drug interactions in the co-infected population, particularly if simultaneous treatment of HCV and HIV is required. Both antiretrovirals and current HCV treatment have multiple adverse effects. For example, didanosine, stavudine, and zidovudine should be avoided with pegylated interferon and ribavirin because of increased risks of mitochondrial toxicity and anemia. Some controversy exists whether concomitant abacavir may be associated with a reduced response to pegylated interferon and ribavirin, but a recent in vitro study showed that the anti-HCV activity of ribavirin was not modified by abacavir. It is important to achieve adequate ribavirin trough levels via weight-based dosing, and there is insufficient evidence to recommend avoiding this combination. Ribavirin may cause a decrease in the total lymphocyte count, which can affect CD4 cell counts. Therefore, the CD4 percentage, rather than the absolute number, may be a more appropriate measure of immunologic efficacy during ribavirin treatment. Another example is the combination of pegylated interferon and efavirenz, where additive CNS effects including depression, mood changes, and suicidality, may occur. Pharmacokinetic interactions between directly acting agents and antiretrovirals can result in negative impact on concentrations of DAAs and/or antiretrovirals. As such, these interactions between DAAs and antiretrovirals may limit cART treatment choices, which may be particularly challenging in HIV-treatment experienced patients. If dose modifications are required, such changes may be associated with significant increases in cost. There is also the potential for underdosing of antiretrovirals and/or DAAs, which may lead to treatment failure and development of resistance. Whenever possible, non-essential medications should be discontinued for the duration of HCV treatment. References: Tseng A, Foisy M. Important drug-drug interactions in HIV-infected persons on antiretroviral therapy: an update on new interactions between HIV and non-HIV drugs. Curr Infect Dis Report 2012; 14(1):67-82. Kiser JJ, Burton JR, Anderson PL, Everson GT. Review and management of drug interactions with boceprevir and telaprevir. Hepatology 2012;55: 45

Antiretroviral Treatment Options for Patients on Boceprevir or Telaprevir
Protease Inhibitors (PIs) Avoid with ritonavir-boosted protease inhibitors Avoid ritonavir-boosted darunavir, fosamprenavir and lopinavir Atazanavir/ritonavir OK Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Avoid efavirenz Dose  with efavirenz Etravirine (?) Etravirine OK No data Rilpivirine OK Integrase Inhibitor Raltegravir OK Maraviroc potential / maraviroc; potential benefit on fibrosis? Nucleoside Reverse Transcriptase Inhibitors Tenofovir OK Avoid AZT (anemia) This table summarizes potential and demonstrated pharmacokinetic interactions between ARVs and DAAs. Negative two-way interactions have been observed between both boceprevir and telaprevir and ritonavir-boosted protease inhibitors, with significant reductions in exposures of HCV agents and HIV protease inhibitors. Therefore, telaprevir should not be coadministered with ritonavir-boosted darunavir, fosamprenavir, or lopinavir,15 and boceprevir is not recommended for use with boosted atazanavir, darunavir or lopinavir.16 With NNRTIs, telaprevir may be used at a higher dose with efavirenz,17 and without dosage adjustment with etravirine or rilpivirine.18 In contrast, boceprevir concentrations are significantly reduced in the presence of efavirenz, and this combination should be avoided.19 Recent data indicate etravirine concentrations are reduced in the presence of boceprevir; the clinical significance of this effect is unknown, and formal recommendations on coadministration are currently lacking.20 Raltegravir is not a P450 substrate, inducer or inhibitor, and may be used with both HCV agents without dosage adjustment.21, 22 Tenofovir is eliminated renally; in healthy volunteer studies, tenofovir Cmax was increased in the presence of boceprevir23 and tenofovir AUC was increased in the presence of telaprevir.24 These changes are not considered to be clinically relevant, and tenofovir may be coadministered with both boceprevir and telaprevir. References: 15. Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA May, 2011. 16. Hulskotte EGJ, Feng H-P, Xuan F, et al. Pharmacokinetic interaction between the HCV protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, lopinavir, and darunavir [abstract 771LB] 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle, WA. 17. Van Heeswijk RPG, Vandevoorde A, Boogaerts G, et al. Pharmacokinetic interactions between ARV agents and the investigational HCV protease inhibitor TVR in healthy volunteers [abstract 119]. 18th Conference on Retroviruses and Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA. 18. Kakuda TN, Leopold L, Nijs S, et al. Pharmacokinetic interaction between etravirine or rilpivirine and telaprevir: a randomised, two-way crossover trial [abstract O_18]. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona, Spain. 19. Schering Corporation a subsidiary of Merck & Co. Victrelis (boceprevir) Product Monograph. Whitehouse Station, NJ May, 2011. 20. Hammond K, Wolfe P, Burton J, et al. Pharmacokinetic interaction between boceprevir and etravirine in HIV/HCV seronegative volunteers [abstract O_15]. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona, Spain. 21. de Kanter C, Blonk M, Colbers A, et al. The influence of the HCV protease inhibitor boceprevir on the pharmacokinetics of the HIV integrase Inhibitor raltegravir [abstract 772LB]. 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, WA. 22. Van Heeswijk RPG, Garg V, Boogaerts G, et al. The pharmacokinetic interaction between telaprevir and raltegravir in healthy volunteers [abstract A1-1738a]. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy, September 17-20, 2011, Chicago, IL. 23. Kasserra C, Hughes E, Treitel M, et al. Clinical pharmacology of boceprevir: metabolism, excretion, and drug-drug interactions [abstract 118]. 18th Conference on Retroviruses and Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA. 24. Van Heeswijk R, Gysen V, Googaerts G, et al. The pharmacokinetic interaction between tenofovir disoproxil fumarate and the investigational HCV protease inhibitor telaprevir [abstract A-966]. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 25-28, 2008, Washington, DC. 46

Managing Drug Interactions: 1) Medication Reconciliation
Ensure medication records are up to date at each visit Prescription, OTC, vitamins/herbals, recreational drugs, inhalers, topical, prn agents Confirm doses, prn drugs Include all agents that have been started or stopped Patient education: Encourage patients to ask before taking any new prescription/non-prescription drug or supplement Communication with other HCP! Given the rapid pace of HCV drug development, keeping abreast of potential interactions is an ongoing challenge. It is impossible to analyze all possible drug combinations prior to the licensing of a drug. Consequently, patients may receive combinations of drugs for which pharmacokinetic interaction data are not available. Even when drug interaction data are available for a particular combination, individual patient factors must also be taken into consideration when determining the clinical significance. Therefore, it is critical to utilize a systematic approach to identifying and managing actual and potential drug interactions in clinical practice. Steps include: Medication Reconciliation. In addition to agents for HCV infection, many patients require treatment for concomitant conditions such as including HIV coinfection, psychiatric illness, illicit substance use, cardiovascular comorbidities, or solid-organ transplantation. Patients may also be taking vitamins, food supplements, complementary or alternative medicine (CAM) agents, or recreational agents, either regularly or occasionally. Obtaining an accurate (best possible) medication history through reviews of patient-related documents from GP care, specialist interventions, hospital reports, pharmacy refill records, and patient interview is essential. At each clinic visit, patients should be encouraged to inform staff of drugs that have been started or stopped, or dosages that have been altered. Patients should also be reminded that they should not be given any new drugs (except in an emergency) without checking for potential interactions with their hepatitis medications first. If the physician prescribing the new drug is unfamiliar with DAAs, they should be encouraged to check with the hepatology physician or team. Patients should be encouraged to inform all health care providers of all the medications they are taking to minimize the risk of inadvertent drug interactions. Communication with all health care providers involved in the care of the patient is critical. Patients are also encouraged to utilize one pharmacy for all their prescriptions in order to facilitate thorough drug reviews by the pharmacist. 47

Managing Drug Interactions: 2) Identify Potential Interactions
Use a systematic approach to identify combinations of potential concern Apply knowledge of known PK characteristics Overlapping CYP pathways, substrate, inducer, inhibitor High index of suspicion with key classes of drugs Utilize current drug information resources: Product monographs, CPS, literature Conference abstracts, specialized HCV drug interaction websites Step 2: Identifying interacting drug combinations. Familiarity with the basic pharmacokinetic and pharmacodynamic characteristics of the involved agents may help practitioners predict the likelihood of interactions. Boceprevir and telaprevir are substrates of the cytochrome P450 system, and also possess enzyme inhibiting and possibly inducing properties. If concomitant medications are also metabolized by or affect the CYP450 system, then the potential for a pharmacokinetic interaction should be considered. A high index of suspicion with key classes of drugs should be maintained; the following 2 slides summarize drug classes that are currently contraindicated with boceprevir or telaprevir. The field of HCV-related drug interactions is growing rapidly, making many of the standard drug information resources such as product monographs and the Compendium of Pharmaceutical Sciences (CPS) out of date. It may also take months for pharmacokinetic studies to be published in the medical literature. Therefore, pharmacists must utilize current sources of information to make an accurate assessment, including conference abstracts and specialized drug interaction websites which are updated on a regular basis. Drug interaction websites with a focus on HCV drug interactions include by the University of Liverpool Pharmacology Group, and by the Toronto General Hospital. 48

Drugs Contraindicated with Boceprevir and Telaprevir (1)
1-adrenoreceptor antagonist Alfuzosin Hypotension, cardiac arrhythmia Antiarrhythmics Quinidine, propafenone, amiodarone. Flecainide (TVR) serious/life-threatening cardiac arrhythmia Antimycobacterials Rifampin Loss of virologic response Ergot derivatives Acute ergot toxicity Herbal product St. John’s wort Statins Lovastatin, simvastatin. Atorvastatin (TVR) Myopathy including rhabdomyolysis Neuroleptic Pimozide Serious/life-threatening cardiac arrhythmia Many other drugs from several different classes are at risk of drug interactions with DAAs. The product monographs of boceprevir and telaprevir provide a list of drugs with known or potential CYP3A4 interactions. Examples of interacting drug classes include benzodiazepines (e.g., midazolam), HMG coenzyme A reductase inhibitors (statins), macrolides, antimycobacterials (e.g., rifampin), anticonvulsants, antiarrhythmics, psychotropics, antifungals, erectile dysfunction drugs, antipsychotics, inhaled corticosteroids, calcium channel blockers and more. References: Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC July 27, 2011. Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA, May, 2011. Victrelis & Incivek. Product Monographs, 2011 49

Drugs Contraindicated with Boceprevir and Telaprevir (2)
PDE-5 inhibitor Sildenafil. tadalafil (BOC); vardenafil (TVR) Visual abnormalities, hypotension, prolonged erection, syncope Sedatives/ hypnotics Oral midazolam, triazolam Increased sedation or respiratory depression Other Cisapride, astemizole, terfenadine Serious/life-threatening cardiac arrhythmia Anticonvulsants (BOC) Carbamazepine, phenytoin, phenobarbital Loss of virologic response OC (BOC) Drospirenone Hyperkalemia Aldosterone antagonist (TVR) Eplerenone Triptans (TVR) Eletriptan Coronary artery vasospasm, MI, vent. tachycardia, VF The non-sedating antihistamines astemizole (Hismanal) and terfenadine (Seldane) are substrates of CYP3A4. In the presence of CYP3A4 inhibitors, concentrations of these agents are significantly increased, and the risk of dose-related adverse events (including cardiotoxicity) is increased. Similar concern exists for cisapride. Therefore, use of these agents should be avoided in people currently taking medications that inhibit CYP450. The metabolism of many benzodiazepines may be signficantly reduced by the presence of CYP450 inhibitors. To minimize the risk of excessive sedation, practitioners may wish to consider reducing the benzodiazepine dose, or using an agent with a different metabolic pathway (eg, lorazepam, oxazepam, or temazepam). Calcium channel blockers are primarily metabolized by CYP3A. Therefore, these agents should be used cautiously with inhibiting agents, to avoid excessive drops in blood pressure. Many antidepressants are substrates of CYP3A4. They are at risk of interacting with agents that inhibit this isoenzyme; greatest precaution with ritonavir. References: Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC July 27, 2011. Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA, May, 2011. Victrelis & Incivek. Product Monographs, 2011 50

Managing Drug Interactions: Therapeutic Options
Determine clinical significance Evaluate therapeutic options: Alter drug dose/dosing frequency Substitute with alternate agent Can any drugs be permanently or temporarily discontinued while on DAA treatment? Consider patient convenience and cost factors Patient counselling & close monitoring is critical Determining clinical significance. The clinical significance of an interaction will depend upon several factors, including: – the magnitude of change in pharmacokinetic parameters – the efficacy and toxicity of the affected agent(s) - the nature and severity of the disease(s) being treated Evaluating therapeutic options. Management options may vary depending upon a number of factors, including the mechanism and clinical consequences of the interaction, availability of therapeutic alternatives, patient convenience, and cost. Space dosing times. e.g., to avoid absorption interactions. Can this be done in a practical and/or convenient way for the patient? Change drug dose or dosing frequency. The potential impact of dosage manipulation on patient adherence should be carefully considered. This in turn may depend upon the drug formulations available, existing pill burden and dosing schedule, and cost. For instance, to adequately adjust for the interaction between telaprevir and efavirenz, telaprevir should be increased to 1125 mg every 8 hours. This results in an increased pill burden and increased drug cost. In such situations, therapeutic alternatives to either efavirenz may need to be considered. On the other hand, the interaction between sildenafil and boceprevir or telaprevir is more straightforward to manage. The standard sildenafil dose is 50 mg taken as needed approximately minutes before sexual activity, maximum once per day. In the presence of boceprevir or telaprevir, sildenafil dose should be reduced to 25 mg once every 48 hours. A 25 mg tablet formulation of sildenafil is available. Change agent (eg, change simvastatin to low-dose atorvastatin or rosuvastatin for lipid management). What are the comparative efficacy, side effects, cost, availability, compliance issues, and drug interactions associated with the new agent? 3) Monitor the patient. In all situations, the patient should be counselled and monitored for potential changes in drug efficacy or toxicity. In certain situations (eg, low likelihood of an interaction occurring, minor or insignificant clinical impact of a potential interaction) the practitioner may wish to maintain the patient’s current regimen and monitor the patient’s condition. Remember the onset of interaction will depend upon the mechanism (inhibition = rapid; induction = gradual); understanding these time frames may be useful when counselling patients on when to expect potential effects. 51

Summary High potential for pharmacokinetic interactions between directly acting antivirals and other drug classes Consequences may include therapeutic failure and increased toxicity Often, interactions can be managed, but heightened level of awareness is needed Use a systematic approach to identify and manage individual drug regimens Importance of a specialized, inter-disciplinary team including pharmacy 52

Additional Resources General Hansten PD. Science Med 1998;16-25.
Kashuba ADM, Bertino JS Jr. Drug Interactions in Infectious Diseases, 2nd edition, c. 2005, pp:13-39. Metheny CJ et al. Pharmacotherapy 2001;21: Interactions in HCV and HIV: Kiser J et al. Hepatology 2012;55: Tseng & Foisy. Curr Infect Dis Rep 2012;14:67-82. Internet Toronto General Hospital Immunodeficiency Clinic; Liverpool Pharmacology Group; General Hansten PD. Understanding drug-drug interactions. Science Med 1998:16-25. Kashuba ADM, Bertino JS Jr. Mechanisms of drug interactions I. In: Piscitelli S, Rodvold K, eds. Drug Interactions in Infectious Diseases, 2nd edition. New Jersey: Humana Press.  2005, pp Metheny CJ, Lamb MW, Brouwer KLR, Pollack GM. Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy 2001;21: Interactions in HCV Tseng A, Foisy M. Important drug-drug interactions in HIV-infected persons on antiretroviral therapy: an update on new interactions between HIV and non-HIV drugs. Curr Infect Dis Report 2012; 14(1):67-82. Kiser JJ, Burton JR, Anderson PL, Everson GT. Review and management of drug interactions with boceprevir and telaprevir. Hepatology 2012; 55: Internet 1. Toronto General Hospital Immunodeficiency Clinic; < 2. Liverpool HIVPharmacology Group; < 53

Side Effects of Antiviral Therapy for Hepatitis C
Dr. Mark Levstik, FRCP(C) Associate Professor Medicine Division of Gastroenterology Multiorgan Transplant Unit London Health Sciences Centre 54

Side Effects with Boceprevir and Telaprevir
Hematological: (common to both PIs) Anemia, Neutropenia Effect is additive with INF and RBV Gastrointestinal Dysgeusia (BOC) Diarrhea (TVR & ? BOC) Anorectal irritation (TVR) Dermatological Telaprevir specific rash 55

Side Effect Comparison of Phase III studies
Adverse Effect Peg Interferon/ RBV Boceprevir/ P/R Telaprevir/ Anemia <100g/dl 30% 50% 17% 36% Rash 19% 34% 56% Fatigue 59% 58% Diarrhoea 15% 20% 26% Nausea 42% 46% 28% 39% Dysgeusia 16% 35% 3% 10% Anorectal 7% 29% Side effects across the groups are fairly uniform. Enhanced anemia is seen in both groups. Telaprevir has more anorectal irritation as well as increased rash and severe rash. Dysgeusia and anemia increased with boceprevir; Rash, anorectal irritation and anemia increased with telaprevir. Incivek Product Monograph, June 2012 Victrelis Product Monograph, August 2012 56

Safety of Protease Inhibitors in Real Life: CUPIC Study
Patients HCV genotype 1 infection Compensated cirrhosis (Child Pugh A) Treatment-experienced Relapsers Partial responders ( >2 log10 HCV RNA decline at Week 12 but never negative) Null responders theoretically excluded Treated in the French early access program (From February 2011) Registry – early access program evaluation of 16 week data of Boceprevir and Telaprevir. Both medications used in a cohort of patients as seen in liver practice, to document the safety and efficacy in more clinically advanced patients. Hezode C et al. EASL 2012, Abstract 8 57

CUPIC: Treatment Regimen
Interim analysis Peg-IFN + RBV BOC + Peg-IFN α-2b + RBV Follow-up BOC : 800 mg/8h; peg-IFNα-2b : 1,5 µg/kg/week; RBV : mg/d Peg-IFN α-2a + RBV TVR + Peg-IFN α-2a + RBV Follow-up Outline of treatment algorithms for both medications which followed product monographs. TVR : 750 mg/8h; peg-IFNα-2a : 180 µg/week; RBV : mg/d 4 8 12 16 36 48 72 Weeks SVR assessment Hezode C et al. EASL 2012, Abstract 8 58

CUPIC: Patients Characteristics
Baseline patient characteristics similar between BOC and TVR The CUPIC cohort had more advanced liver disease than in registration trials. In BOC arm 26% would not meet RESPOND-2 inclusion criteria In TVR arm 34% would not meet REALIZE inclusion criteria Previous treatment response (%) BOC TVR Partial responders 49 52 Relapsers 48 40 Null responders Patient demographics in this study outlines a harder to treat group due to cirrhosis which would not be seen in registry trials. Null responders were theoretically excluded. Hezode C et al. EASL 2012, Abstract 8 59

CUPIC: Preliminary Safety Findings (16-Week Interim Analysis)
Patients, n (% patients with ≥ 1 event) Boceprevir n=159 Telaprevir n=296 Serious adverse events (%) 38.4 48.6 Premature discontinuation Due to SAEs (%) 23.9 7.4 26.0 14.5 Death (%) 1.3 2.0 Infection (Grade 3/4) (%) 2.5 8.8 Rash Grade 3 (%) Grade 4 (SCAR) (%) 6.8 0.7 Pruritus (Grade 3/4) (%) 0.6 3.7 Hepatic decompensation (%) 4.4 In this group of patients the adverse effects are higher than what was seen in Phase III studies. This was expected due to their more advanced disease. This chart outlines more specific concerns such as infection, and other side effects between the treatment groups. Noteworthy are the rates of serious adverse events and particularly infection, which are not seen in non-cirrhotic patients. Hezode C et al. EASL 2012, Abstract 8 60

CUPIC: Preliminary Safety Findings (16-Week Interim Analysis)
Patients, n (% patients with ≥ 1 event) Boceprevir (n=159) Telaprevir (n=296) Anemia (%) Grade 2 (8.0 – <10.0 g/dL) Grade 3/4 (<8,0 g/dL) EPO use Blood transfusion 22.6 10.1 66.0 10.7 19.6 56.8 15.2 Neutropenia (%) Grade 3 (500 – <1000/mm3) Grade 4 (<500/mm3) G-CSF use 4.4 0.6 3.8 4.0 0.7 2.4 Thrombopenia (%) Grade 3 ( – <50 000) Grade 4 (<25 000) Thrombopoïetin use 6.3 1.9 11.8 1.3 1.7 As expected the rate of anemia is higher in sicker patients, requiring careful monitoring and more frequent interventions for adjuvant therapy such as transfusion and EPO use, compared to non-cirrhotic patients. Neutropenia and thrombocytopenia although present, are not a significant treatment altering occurance. Hezode C et al. EASL 2012, Abstract 8 61

Take Home Message from CUPIC
PI therapy in patients with cirrhosis is associated with more severe and more frequent AEs Anemia Increased EPO use, ribavirin dose reductions and transfusions Increased risk of severe infection Increased risk of hepatic decompensation Although significant adverse events are more frequent in this group, the patients as a whole do well with PI triple therapy. 62

Boceprevir Specific Side Effects
Dysgeusia and decreased appetite more prevalent than control Hematological side effects more prevalent than control in Phase 2/3 naïve studies: Neutropenia (<0.75 x 109 /L): 31% vs. 18% in controls Platelets (< 50 x 109 /L): 3% vs. 1 % in controls Anemia: 50% vs. 30% in controls Grade II (<100 g/L): 49% vs. 29% Grade III (<85 g/L) : 6% vs. 3% Erythropoietin use 47% vs. 24% and pRBC 3% vs. 1% Boceprevir has an enhanced effect on cell counts compared to standard of care Peg/RBV. Overall, retreatment patients report fewer or less severe side effects and have lower rates of anemia. Dose reduction and erythropoetin use are greater than in SOC. Dose reduction had no impact on SVR. Victrelis Product Monograph, August 2012 63

Telaprevir Specific Side Effects
Rash, anorectal disorders, diarrhea and anemia more common than control Rash seen > 50%, leads to 6% discontinuations Mild – 37% Moderate – 14% Severe – 5% Anorectal disorders seen with increase in diarrhea, itching and burning: 29% vs. 7% in controls Anemia: 32% vs. 15% in controls Grade II (< g/dL): 27% vs. 27% Grade III ( g/dL) : 51% vs. 24% Triple therapy with Telaprevir is similar to Boceprevir in that side effects mimic those with Pegylated Interferon and Ribavirin alone. Anorectal burning and itching as well as rash are more prevalent. However, discontinuation due to dermatological side effects < 6%, and management with OTC medications usually is sufficient. Rates from Pooled Placebo-Controlled Studies 108, C216, 104, 104EU, and 106 Incivek Product Monograph, June 2012 64

Anemia Management 65

Mechanism of RBV-Associated Anemia
RBV uptake into RBC  adenosine kinase  RBV-triphosphate Erythrocytes lack enzymes to hydrolyze RBV phosphates RBV-phosphates are “trapped” Erythrocyte T1/2 > 40 days RBV concentration in RBC 60-fold higher than serum (60:1) Marked depletion of RBC adenosine triphosphate (ATP) Impairs anti-oxidant defense mechanisms Induces RBC oxidative membrane damage Premature extravascular RBC removal by the reticuloendothelial system Recently, research has led to a better understanding of the mechanism of interferon alfa and ribavirin treatment associated with anemia, as well as insight into new management strategies. Ribavirin causes a dose-dependent, extravascular hemolytic anemia. The mechanism is incompletely understood but appears to involve the uptake of ribavirin into the red blood cell with subsequent phosphorylation to the triphosphate state. Unlike other cells, the erythrocytes lack the enzymes needed to remove the ribavirin metabolite, which leads to very high intra-erythrocyte concentration of ribavirin and depletion of ATP. These changes leave the red blood cell susceptible to oxidative stress and lead to removal of the RBC from the circulation and subsequent hemolysis within the RES cells. Reference: 17. De Franceschi L, Fattovich G, Turrin F et al. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology ;31(4): 997. De Franceschi L. Hepatology 2000; 31: 66

Ribavirin Dose Reduction vs. EPO ?
Retrospective analyses of Boceprevir phase III studies have suggested that reducing the dose of RBV did not alter the SVR rate. In patients treated with PEG+RBV (dual therapy), the effect of RBV dose reduction ON SVR was minimal if occurring when HCV-RNA was undetectable. Sulkowski MS et al. J Hepatol 2011; 54:S194-5. Reddy KR et al. Clin Gastroenterol Hepatol 2007; 5:124-9 67

Boceprevir Anemia Management: Erythropoietin vs
Boceprevir Anemia Management: Erythropoietin vs. Ribavirin Dose Reduction Study Genotype 1 patients, naive of treatment, Hb < 150 g/L at baseline 687 patients treated with boceprevir RGT After completion of 4 week PEG-IFN/RBV lead-in, all patients initiated boceprevir Hemoglobin ≤100 g/L Randomisation Patients were randomized once they developed anemia with a hemoglobin of <100 g/dl to either EPO use or Ribavirin reduction. If they experienced further anemia below 85g/L then a secondary anemia strategy was employed, either transfusion or EPO/RBV protocols (whichever was not used initially). Erythropoietin (40,000 IU/wk SC) n = 251 Ribavirin dose reduction (DR) n = 249 Hemoglobin ≤ 85 g/L: Secondary Strategy (EPO, RBV DR, transfusion) EPO: erythropoietin PEG-IFN: peginterferon RBV: ribavirin Poordad et al. EASL 2012, Abstract 1419 68

Results – Primary and Key Efficacy End Points
End-of-treatment response, relapse, and SVR were comparable between RBV DR and EPO arms 100  (95% CI) -0.7% (-8.6, 7.2)* 82 82 RBV DR 71 71 75 EPO Patients (%) 50 25 Type of anemia strategy did not have an effect on SVR. 10 10 203/249 205/251 178/249 178/251 19/196 19/197 EOT Response SVR Relapse DR, dose reduction; EOT, end of treatment; EPO, erythropoietin; RBV, ribavirin; SVR, sustained virologic response. *The stratum-adjusted difference (EPO vs. RBV DR) in SVR rates, adjusted for stratification factors and protocol cohort. Poordad et al. EASL 2012, Abstract 1419 69

Summary - Anemia Management
Ribavirin dose reduction does not decrease SVR No advantage to Erythropoietin use, but may be used Consider pRBC transfusion to maintain safe Hb DAA should not be reduced DAA should not be restarted or continued without Peg/RBV Ribavirin may be increased once Hb recovers Severe anemia is rare, but if present despite RBV initial dose reduction, further RBV reductions may be needed. CBC should be measured weekly, prior to PEG-INF dosing. Rapid anemia may require reducing the dose of PEG-IFN, but this may be increased to full dose once anemia is under control. If anemia clinically severe requiring transfusion, stopping of DAA may be necessary and should not be restarted. Erythropoetin has been used in concert with RBV reductions in severe cases, and improves patient well being prior to the increase in Hb. Hb augmentation peaks at 4 weeks after initiation of EPO. Note: Do not continue Erythropoetin to Hb> 120 g/L. 70

Protease Inhibitors: Management of Anemia
Hb < 100 g/L any time during treatment Boceprevir Telaprevir RBV dose reduction Up to 3 x 200 mg increments* Reduce RBV to 600 mg/day Hb < 85 g/L Hb > 85 g/L Graphic representation of the suggested anemia treatment algorithm. Note, all patients should be on MVI with confirmed adequate iron stores. For Hb <85 g/L: Decrease Ribavirin to 600mg per day if a precipitous drop in Hb If uncontrolled stop Peg/RBV and DAA. Do not restart DAA if Hb improves, but may restart Peg/RBV EPO: 40-60,000 IU/wk AND/OR Transfusion Maintain RBV dose reduction * Note: First dose reduction of 400mg if patient receiving 1400mg/day RBV dose reduction to 600 mg can be used with Boceprevir as wel 71

Rash Management - Telaprevir
72

Rash Rash more prevalent in DAA but >50% with Telaprevir
Rash can be categorized: Mild to moderate: < 30% of skin area Moderate: 30-50% of skin area Severe: generalized rash may progress with bullae, vesicles < 5% of patients Rash is common with PEG/RBV therapy, but especially more common with Telaprevir based triple therapy. Mild or moderate rash occurs, but severe rash with sequelae is rare. Incivek Product Monograph, 2012 73

Rash Management Recommendations
Mild: Watchful monitoring Oral antihistamines, moisturizers, topical steroids Moderate: < 50% body Monitor closely for progression/systemic symptoms Antihistamines, moisturizers, topical steroids Worsening/Severe: > 50% body ( < 4% of patients ) Stop telaprevir, observe closely for 7 days IF no better, stop Ribavirin, observe for 7 days. IF no better, stop Pegylated Interferon Moisturizers and antihistamines may be useful to control symptoms in most. Avoid hot baths and tight clothes. If rash worsening, dose reduction or discontinuation may be necessary. However, the rash often develops and worsens with ongoing therapy and patients may require intervention after weeks of telaprevir. Incivek Product Monograph, 2012 Hézode C. Liver International. 2012; 32 Suppl 1:32-8 Cacoub P et al. Journal of Hepatology. 2012; 56(2):455-63 74

Telaprevir Severe Rash < 1%
DRESS: Drug rash with eosinophilia and systemic symptoms Rash, fever, facial edema ± hepatitis/nephritis Eosinophils may not be present Stevenson-Johnson Syndrome Fever, target lesions and mucosal erosions/ulcers STOP ALL drugs Requires hospitalization May require systemic steroids Severe skin manifestations of DRESS and SJS are very rare, but require immediate medical care. All medications must be stopped and not restarted. May require specialized nephrology care and systemic steroids. DO NOT RESTART MEDICATIONS Incivek Product Monograph, 2012 Hézode C. Liver International. 2012; 32 Suppl 1:32-8 Cacoub P et al. Journal of Hepatology. 2012; 56(2):455-63 75

Other Side Effects of Boceprevir and Telaprevir
76

Gastroenterological Side Effects
Nausea, vomiting, diarrhea Small meals three times daily with PI dosing useful Fiber, loperamide aid with loose stool Dysgeusia noted in Boceprevir patients Metallic taste, rarely leads to dose reduction or discontinuation Improved with chocolate administration GI side effects common in all patients. Frequent small meals, fiber, and loperamide aid in decreasing GI upset. Dysgeusia is an unpleasant side effect of Boceprevir and fortunately improves with chocolate. 77

Gastroenterological Side Effects: Telaprevir
Nausea, vomiting and diarrhea common with TPV/PEG/RBV Anorectal irritation: Anorectal burning, itch and hemorrhoidal irritation common: > 29% Therapy: Frequent small meals, 21g fat per dose Fiber, loperamide and topical hydrocortisone therapy, help relieve symptoms Anorectal irritation is a common complaint of patients on telaprevir. An acute sense of burning is noted and quite debilitating. Topical therapy and a decrease in bowel flow is useful in relieving patient discomfort. Incivek Product Monograph, 2012 Hézode C. Liver International. 2012; 32 Suppl 1:32-8 Cacoub P et al. Journal of Hepatology. 2012; 56(2):455-63 78

Management of Depression
Occurs in up to 37% of patients Conduct pre-therapy and routine assessments with CES-D or other depression scale Adjust interferon dose or discontinue therapy according to depression severity May warrant use of antidepressants Recommended agents to use with BOC and TVR: Escitalopram, citalopram (see Dr. Tseng’s chapter on DDIs) Depression, the most common psychiatric adverse event associated with interferon-based combination therapy, occurs in up to 37% of patients,and is associated with the interferon component of therapy. As noted, interferon may cause depression by altering neuroendocrine or neurotransmitter functions or by modulating the expression of cytokines. There is also evidence that interferon may deplete serotonin levels, thereby inducing depression. Routine assessments for depression, such as with the Center for Epidemiologic Studies Depression (CES-D) Scale, should be conducted. The dose of interferon may need to be adjusted based on the severity of depression, and in severe cases, treatment may need to be discontinued. [See PEGETRON (peginterferon alfa-2b) Powder for Injection Prescribing Information for specific guidelines for depression.] Treatment should be discontinued permanently for patients who experience severe depression, and psychiatric consultation should be sought. Treatment-related depression may warrant use of antidepressants. 79

Direct-Acting Antiviral Therapy: Boceprevir and Telaprevir
Patient side-effect education is important to success Pre-therapy recommendations include: Multivitamin, hydration, acetaminophen analgesia Dietary recommendations to decrease GI toxicity effects ( small meals, fiber, loperamide ) Skin care through moisturizers and antihistamines Close patient and hepatitis team communication Monitor and pre-empt severe side effects Drug and duration specific Beginning therapy for HCV has evolved to a pre-emptive strategy to decrease side effects and increase compliance. To aid tolerability patients are educated as to side effects and how to manage them. Initial therapy includes hydration, multivitamins and analgesia to counter act interferon side effects and decrease anemia. Frequent small meals, loperamide and topical anorectal steroids decrease nausea, and anorectal complaints. Moisturizers, topical steroids and antihistamines decrease common minor skin irritation, while education warns patients as to the signs and symptoms of more serious reactions. 80

Case Study: Treatment Naive
Edward Tam MD FRCPC Medical Director LAIR Centre 81

Ms. MH 31 year old female Diagnosed in 2004 with genotype 1a HCV
Previous IVDU Otherwise healthy Meds: Milk thistle No Biopsy ALT 1-2 x ULN on serial monitoring This young woman was initially seen in 2004 and diagnosed with genotype 1a chronic hepatitis C after undergoing screening bloodwork completed by her family physician in the setting of prior IVDU. Following initial evaluation, she was found to have minimally elevated enzymes and no clinical manifestations of chronic liver disease. Liver biopsy was offered initially, but deferred by the patient due to the invasive nature of the procedure. 82

Ms. MH Followed periodically with monitoring of liver biochemistry
FibroScan December 9, 2010: 4.9 kPa What evidence supports the use of Milk Thistle? Is FibroScan a reliable and accurate tool for fibrosis assessment? Does it represent a viable alternative to liver biopsy? Given this patient’s reluctance to pursue liver biopsy, FibroScan was completed when available. Fortunately, findings were in keeping with the absence of significant underlying fibrosis. Increasingly, non-invasive tools for fibrosis assessment are being used, thus avoiding the need for biopsy in many cases. Fibrosis assessment remains an important aspect of treatment planning, in particular given the multiple anti-viral agents in development, which may improve both efficacy and side-effect profile for those individuals who are able to safely defer therapy at this time. Of the non-invasive tools used for fibrosis assessment, FibroScan is one of the more commonly used in Canada. Other alternatives include FibroTest and APRI (AST-to-platelet ratio index). Milk Thistle has now been shown in a randomized controlled trial to have no effect on viral load or ALT. 83

FibroScan versus Liver Biopsy
1.00 0.75 Sensitivity 0.50 AUROC (95% CI) ≥ F2: 0.74 ( ) ≥ F3: 0.89 ( ) F4: 0.94 ( ) 0.25 Many published studies have validated the use of FibroScan as an effective tool for fibrosis staging compared to liver biopsy. In this multicentre Canadian study, FibroScan was used to obtain liver stiffness measurements in 251 patients with a diagnosis of hepatitis B, hepatitis C, or non-alcoholic fatty liver disease. When compared to liver biopsy, FibroScan performed very well, with an AUROC for the diagnosis of cirrhosis of While FIbroScan is very effective at excluding bridging fibrosis and cirrhosis, it is less able to distinguish between earlier fibrosis stages. While FibroScan is a valuable tool that can provide clinically meaningful information for most patients, it does have its limitations. Unlike liver biopsy, FibroScan was designed as a fibrosis assessment tool only and thus is unable to determine the grade of inflammation in the liver, or to provide additional diagnostic information. Patient factors such has high BMI, elevated ALT, and vascular congestion may also affect results, or result in the inability to obtain a reliable measurement. 0.00 0.00 0.25 0.50 0.75 1.00 1-Specificity Myers RP et al. Can J Gastroenterol Nov;24(11):661-70 84

Ms. MH FibroScan December 9, 2010: 4.9 kPa (consistent with stage 0 – 1 fibrosis) Discussions with patient throughout 2011 regarding therapy Although no medical urgency, very keen to pursue therapy for personal reasons Despite the lack of medical urgency to pursue therapy, the patient had a strong preference to seek curative treatment. Certainly, there are many considerations in treatment planning, and fibrosis staging represents only one aspect that may inform the patient-physician discussion. 85

Ms. MH January 6, 2012, treatment initiated with pegylated interferon alpha-2b (120mcg) plus ribavirin (500mg BID), as planned lead-in to boceprevir-based treatment. Week 0 HCV RNA 5.29 logs ALT 106 Hb 144 Plts 295 Neutrophils 6.0 In this situation, the decision to initiate therapy was driven by the patient’s desire rather than medical urgency. Medication reimbursement issues may be obstacles in this situation, but fortunately in this case, the patient did have access to extended health benefits, allowing for access to therapy. Positive pre-treatment predictors of response in this situation (as defined in the SPRINT-2 study) included HCV RNA level < 400,000 IU/ml, age < 40, and absence of cirrhosis. 86

Ms. MH: Week 4 Results Week 0 Wk 2 Wk 4 HCV RNA 5.29 logs -- Undetectable ALT 106 53 33 Hb 144 120 108 Plts 295 236 214 Neutrophils 6.0 2.0 During the lead-in phase with pegylated interferon and ribavirin, this patient experienced anticipated side effects of nausea, fatigue, myalgias, impaired concentration, SOB on exertion, cough, and occasional headaches. Wk 4 bloodwork did confirm an undetectable viral load, which in the SPRINT-2 cohort was found to be the best predictor of SVR when considering both pre-treatment and on-treatment factors: OR for decrease in HCV RNA of 1 log or more versus < 1 log decrease at week 4: 9.0 (6.3 – 12.8). The question of whether the addition of Boceprevir is even necessary in this situation may in fact be reasonably posed, given this patient’s robust response to the dual therapy lead-in. Data available from the IDEAL study, as well as from SPRINT-2, suggest that individuals receiving dual therapy who achieve an undetectable viral load at the end of 4 weeks of therapy have exceedingly high chances of achieving SVR. This is demonstrated independent of the addition of Boceprevir. Given the undetectable HCV RNA at the end of WK4 lead-in (dual therapy), is adding Boceprevir necessary? 87

Significance of Lead-in Response
SPRINT-2: SVR based on degree of early interferon response (log decline in HCV RNA at week 4 of P/R in all patients (cohort 1 + cohort 2) PR48 BOC RGT BOC/PR48 100 97 89 89 89 89 90 90 79 80 80 74 70 72 65 58 60 60 % of patients with SVR 45 43 40 33 28 28 30 21 In an analysis of the data from SPRINT-2, undetectable HCV RNA at the end of the lead-in phase was a strong predictor of SVR, including for those individuals who were randomized to the control arm (pegylated interferon and ribavirin only). As SVR rates are exceedingly high independent of the addition of Boceprevir, whether withholding triple therapy in the setting of an RVR (undetectable HCV RNA at the end of WK4) represents a reasonable strategy is an interesting question. From a practical standpoint, given the lag-time before an HCV RNA result may become available, it almost always will not be possible to make a real time decision at the conclusion of WK4, and so the lead-in period would have to be extended while waiting for the WK4 RNA result if the intention was to persist with dual therapy in the setting of RVR. In addition, while SVR rates for individuals treated with dual therapy only who achieve RVR are very high, these results are achieved with a total treatment duration of 48 weeks. The addition of Boceprevir at the end of 4 weeks also achieves exceedingly high cure rates for those experience RVR, but also with the high likelihood of doing so with a 28 week total treatment course. Lastly, in the rare circumstance that a patient who achieves RVR is instructed to persist with dual-therapy, and subsequently goes on to experience virologic failure, the question may arise as to whether the outcome would have been different if Boceprevir had been added at the conclusion of WK4. 20 5 <0.5 ≥4.0 <0.5 ≥4.0 <0.5 ≥4.0 0.5-<1.0 1.0-<1.5 1.5-<2.0 2.0-<3.0 3.0-<4.0 0.5-<1.0 1.0-<1.5 1.5-<2.0 2.0-<3.0 3.0-<4.0 0.5-<1.0 1.0-<1.5 1.5-<2.0 2.0-<3.0 3.0-<4.0 Undetectable Undetectable Undetectable Log10 viral load decrease after weeks of P/R lead-in Vierling et al. EASL 2011. 88

Results Through Week 12 Boceprevir added with 5th interferon injection
Wk 4 Wk 6 Wk 8 Wk 10 Wk 12 HCV RNA Undetectable -- ALT 33 27 26 22 28 Hb 108 107 101 91 94 Plts 214 179 177 175 174 Neutrophils 2.0 1.3 1.6 1.2 Boceprevir added with 5th interferon injection HCV RNA remains undetectable Due to worsening anemia and fatigue, RBV dose reduced to 600mg total daily dose after wk 10 results The frequency and severity of anemia is known to be increased in the setting of protease inhibitor based therapy versus that seen with peg/rbv only. Data from a randomized controlled trial is now available demonstrating that the approach to anemia management – whether RBV dose reduction versus erythropoeitin use - does not appear to have an impact on SVR rates. In this situation, the strategy of a 400 mg decrease in RBV dosing was used, with stabilization of Hb by week 12. The additional side effect of dysgeusia was encountered with the addition of boceprevir. For this patient, it was effectively managed through dietary focus on ginger, citrus flavours, and bananas around the time of boceprevir administration. 89

Results Through Week 24 Wk 12 Wk 16 Wk 20 Wk 24 HCV RNA Undetectable -- ALT 28 32 25 24 Hb 94 105 101 103 Plts 174 171 164 169 Neutrophils 1.2 1.4 1.0 HCV RNA remained undetectable through week 24, and patient qualifies for shortened duration therapy (to D/C at week 28) Given that HCV RNA was undetectable at weeks 8 and 24, and no other futility rule was met, this patient qualifies for shortened duration therapy and will discontinue pegylated interferon ribavirin, and boceprevir at the end of WK28. From data obtained in SPRINT-2, SVR rates for individuals qualifying for shortened duration therapy are anticipated to be approximately 96%. 90

Case Study: Cirrhosis Nir Hilzenrat, MD
Gastrointestinal Division, Department of Medicine, SMBD- Jewish General Hospital, Associate Professor of Medicine, McGill University, Montreal, Quebec 91

Case History 58 year old woman, acquired hepatitis C from blood transfusion 30 years prior Symptoms – mild fatigue and depression ALT 2xULN Synthetic function normal Viral load 3x105 IU/mL Liver biopsy (2002) F 3/4, activity 2/4 92

Case History Previous treatment in 2000 with pegylated interferon and ribavirin < 1 log drop at week 12 Treatment discontinued Treatment-related side effects Severe fatigue Fall in Hb level (148 g/L to 108 g/L). 93

Comments Previous treatment failures classified into Null responder Viral load does not fall by 2 logs at week 12 Partial responder Viral load falls by > 2 logs, but never negative Relapser Viral load negative on therapy but positive after therapy Telaprevir (REALIZE study ) response in null responders was 29% (21/72) Boceprevir (PROVIDE study) response in null responders was 40% (19/47) The likelihood of response to triple therapy in prior treatment failures depends on many factors, including the nature of the prior response. Zeuzem, S. et al. N Engl J Med 2011; 364: Bronowicki, JP., International Liver Congress 2012, Abstract 204, EASL 2012 94

Comments Probability of response with F3 or F4 and prior treatment failure (48 weeks of therapy) Telaprevir Boceprevir % n Relapser 87 48/55 83 15/18 Partial responder 34 11/32 46 6/13 Null responder 14 7/50 - Vertex Pharmaceutical (Canada) Incorporated. Product Monograph: Incivek (Telaprevir tablets). (Accessed February 1, 2012) Bruno,S., Boceprevir in Addition to Standard of Care Enhanced SVR in Hepatitis C Virus Genotype-1 With Advanced Fibrosis/Cirrhosis: Subgroup Analysis of SPRINT-2 and RESPOND-2 Studies, Oral Presentation, EASL 2011 95

Case Continued Patient made aware of low probability of cure (15-40%)
However, she was willing to start treatment It was accepted that we will assess the continuity of the treatment based on the response rate, i.e., HCV-RNA level, and the severity of adverse effect during the treatment Fibroscan prior suggested cirrhosis ALT x 4 ULN Liver synthetic function normal Viral load 2.8x106 IU/ml 96

Case Continued Treatment was started with Peg INF/RIBA and boceprevir
At week 4 viral load decline was 0.8 logs Question How important is the magnitude of the decline in viral load following the lead-in phase (TW4) of the PR & BOC treatment? 97

Importance of 4-Week HCV RNA in Boceprevir Triple Therapy
In RESPOND-2 likelihood of SVR for relapsers and partial-responders was associated with response to interferon in the lead-in phase SVR in all patients SVR in F3/F4 < 1 log drop at wk 4 33% 14-25% > 1 log drop at wk 4 73% 55-87% Bruno,S., Boceprevir in Addition to Standard of Care Enhanced SVR in Hepatitis C Virus Genotype-1 With Advanced Fibrosis/Cirrhosis: Subgroup Analysis of SPRINT-2 and RESPOND-2 Studies, Oral Presentation, EASL 2011 Bacon BR et al. N Engl J Med 2011;364: 98

Comments In the PROVIDE study, the SVR for null responders was 40%
Week 4 HCV RNA < 1 log decline from baseline SVR 36% Week 4 HCV RNA >1 log decline from baseline SVR 55% Bronowicki, JP., Sustained Virologic Response (SVR) in Prior PegInterferon/Ribavirin (PR) Treatment Failures After Retreatment with Boceprevir (BOC) + PR: PROVIDE Study Interim Results, International Liver Congress 2012, Abstract 204, EASL 2012 99

Case Continued The result was discussed with the patient.
She was made aware that the likelihood of achieving SVR is poor. However, the patient asked to reassess the probability of her success rate after 4W of PR & BOC treatment, i.e., 8W of the whole treatment. 100

Question The HCV RNA at week 8 was undetectable
What is the likelihood of achieving SVR? According to RESPOND-2 study, 74 patients / 84 total number of patients (88%) with an undetectable HCV RNA level at week 8 were able to achieve SVR. This is for all patients, and may not apply to cirrhotics. In the F3/F4 patients, those who were HCV RNA negative at week 8 had an 80% (RGT) to 90% (48 wks Rx) likelihood of SVR. Reference: 1) Bacon BR. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364: 2) Bruno,S., Boceprevir in Addition to Standard of Care Enhanced SVR in Hepatitis C Virus Genotype-1 With Advanced Fibrosis/Cirrhosis: Subgroup Analysis of SPRINT-2 and RESPOND-2 Studies, Oral Presentation, EASL 2011 101

Question How long should she be treated for?
At week 12 and 24 the HCV RNA remained undetectable Usual side effects, anemia, fatigue and depression The SPRINT-2 study showed that naïve patients with high fibrosis stage should be treated with PR & BOC for 44W following the lead-in phase. The SVR rate was of 52% in BOC/PR48 vs. 41% in the response-guided therapy. In the RESPOND-2 study, i.e. treatment with BOC for experienced patients, the odds to achieve SVR was higher in patients who were treated with PR & BOC 44W following lead-in phase compared to the response-guided therapy group. In the F3/F4 category, those who received RGT achieved 44% SVR and those who received 48 weeks Rx achieved SVR in 68%. Reference: 1) Poordad F. et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364: 2) Bruno,S., Boceprevir in Addition to Standard of Care Enhanced SVR in Hepatitis C Virus Genotype-1 With Advanced Fibrosis/Cirrhosis: Subgroup Analysis of SPRINT-2 and RESPOND-2 Studies, Oral Presentation, EASL 2011 102

Question What are the recommended approaches for this patient (i.e. cirrhotic null responder to previous PR treatment) according to the American Association of the Study of Liver Diseases (AASLD) and Canadian Association of the Study of Liver Diseases (CASL) updated guidelines? The AASLD’s new update on the retreatment of HCV genotype 1 (1) state that the decision to re-treat a null responder should be individualized, particularly in patients with cirrhosis. The CASL’s new update (2) state that noncirrhotic patients with HCV genotype 1 who have demonstrated a null response to previous PR therapy should be considered for triple therapy. Treatment–experienced patients with HCV genotype 1 and cirrhosis should not be retreated with response-guided therapy. 1) Ghany MG. Et al. 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: 2) Myers RP et al. An update on the management of chronic hepatitis C: consensus guideline from the Canadian association for the Study of the Liver. Can J Gastroenterol 2012;26: 103

Investigational Anti-HCV Drugs Beyond Boceprevir and Telaprevir
Stephen D. Shafran MD, FRCPC, FACP Professor, Division of Infectious Diseases Department of Medicine University of Alberta 104 104

Investigational Drugs for HCV with Activity in Humans
Direct-acting antivirals (DAAs) Non-DAAs Peginterferon lambda (IFN-) Tarabivirin Pro drug of ribavirin Higher ratio of liver to RBC distribution than RBV Less anemia than with RBV Silibinin (milk thistle extract, IV formulation) Cyclophilin inhibitors (eg. Alisporivir*) Additional data regarding non-DAAs other than PegIFN lambda is not provided in this presentation. Nitazoxanide is omitted due to its dubious activity. * Development on hold due to cases of pancreatitis 105 105

Pegylated Interferon Lambda
IFN- (a type III interferon) receptors are expressed in hepatocytes but in fewer other cells than IFN-a (a type I interferon). In a phase-IIa trial in treatment-naïve patients, pegIFN- μg weekly + RBV resulted in similar or higher virologic responses at weeks 4 and 12 vs. pegIFNa-2a + RBV with less toxicity.1 Background about IFN-λ and comparison with IFN-α. 1. Muir A et al. AASLD Abstract 821 106 106

EMERGE: PegIFN-λ/RBV vs. PegIFNa-2a/RBV
Wk 24: GT 2 or 3 Wk 48: GT 1 or 4 PegIFNa-2a 180 μg/wk + RBV (n=133) PegIFN-l 120 μg/wk + RBV (n=128) Treatment naïve patients with genotype 1-4 HCV infection (n=526) PegIFN-l 180 μg/wk + RBV (n=131) Design of the EMERGE trial for HCV treatment naïve subjects. All patients received RBV 1000/1200 mg/d. The control group received PegIFN α-2a 180 μg weekly. Three experimental groups received different doses of PegIFN-λ. Treatment duration was 48 weeks for GT 1 and 4, 24 weeks for GT 2 and 3. PegIFN-l 240 μg/wk + RBV (n=134) Zeuzem S et al. EASL Abstract 1360 107 107

EMERGE: PegIFN-l/RBV vs. PegIFNa-2a/RBV: Preliminary Results to Week 12
Parameter (%) PegIFNa-2a PegIFN-l 180 μg 120 μg 240 μg GT1/4 RVR 5.8 6.0 14.7* 16.5* GT1/4 cEVR 38 55* 56* GT 2/3 RVR 31 43 76* 67* GT 2/3 cEVR 86 90 97 83 Myalgia 30 11 6.1 9.0 Fever 29 7 6 Hb < 10 g/dL 44 21 15 13 ANC < 750 0.8 PLT < 25 1.5 Conjugated bilirubin 2.3 5.5 8.5 19.7 Results of the EMERGE study to week 12 as presented at EASL EOT and SVR data not yet available. PegIFN lambda appears to result in less fever, myalgia and cytopenias than PegIFN alpha-2a, with perhaps better early antiviral activity vs. GT 1 & 4. PegIFN lambda appears to be associated with a dose-dependent increase in conjugated bilirubin. * p<0.05 compared with PegIFNa-2a Zeuzem S et al. EASL Abstract 1360 108 108

EMERGE: PegIFN-l/RBV vs
EMERGE: PegIFN-l/RBV vs. PegIFNa-2a/RBV: Efficacy and Safety in Genotypes 2 & 3 Fewer hematologic AEs and ALT/AST elevations with pegIFN-l SVR rates comparable in pegIFN- l arm vs. pegIFNa-2a PegIFN-l 180 μg dosage chosen for phase III trials Adverse Event, % Lambda 180 µg (N = 29) Alfa 180 µg (N = 30) Hb < 10 g/dL or ∆ > 3.4 g/dL 6.9 44.8 RBV dose reduction (Hb associated) 23.3 Neutrophils < 750/mm3 27.6 Platelets < 100,000/mm3 24.1 PegIFN dose reduction (hematologic reason) ALT/AST > 5 to 10 x ULN 13.3 100 80 75.9 65.5 60.0 60 53.3 SVR24 (%) 40 20 SVR(24) and safety data in GT 2 and 3 patients in the EMERGE study were presented at EASL RBV dosing was 800 mg. In this phase 2 trial, there were 29 or 30 patients in each of the 4 treatment groups. While the SVR rate in the 180 mcg lambda group was higher, the difference was not statistically significant. The 180 mcg dose of lambda IFN has been selected for phase 3 trials. This regimen has less hematological toxicity than 180 mcg PegIFN-alfa-2a. N = 30 29 29 30 Alfa 180 µg Lambda 120 µg Lambda 180 µg Lambda 240 µg Zeuzem S et al. EASL Abstract 10 109

Proteins encoded by the HCV genome: Three validated targets and four classes of DAAs
5’ UTR region 9.6 kb RNA 3’ UTR region Polyprotein C E1 E2 p7 NS2 NS3 4A NS4B NS5A NS5B Polyprotein Polyprotein processing NS3-4A protease inhibitors 1 NS5B polymerase inhibitors Nucleoside analogs Non-nucleoside analogs 3 4 NS5A inhibitors 2 C E1 E2 p7 NS2 NS3 NS4A NS5A NS5B Core Envelope Glycoproteins Protease Serine Helicase RNA binding RNA-dependent RNA polymerase NS4B Cofactor There are 3 validated targets for DAAs, depicted by the red boxes. NS3/NS4A NS5A NS5B DAAs have been developed against each of these 3 targets. However, in the case of NS5B, there are both nucleoside analogues and non-nucleoside analogues which inhibit the polymerase. The 4 drug classes are depicted by the green boxes. Adapted from Asselah T et al. Liver International 2011; 31 Suppl 1:68-77 110 110

HCV NS3/NS4A Protease Inhibitors (1)
Inhibit cleavage of viral polyprotein chain, essential to HCV replication. Very active against genotype (GT) 1. A single nucleotide mutation in the NS3 region (R155K) results in resistance in GT 1a, but two mutations are required for resistance in GT 1b. Some have activity against non-1 genotypes, but very little clinical data exist. “First generation” NS3 PIs (boceprevir and telaprevir) are linear ketoamides and are associated with anemia; “Second generation” NS3 PIs are macrocyclic and are not associated with anemia. Background on NS3/4A protease inhibitors. Explains why resistance is more frequent in GT1a vs. 1b. Introduces concept of first generation NS3 PI drugs (BOC/TVR) vs. second generation NS3 PIs. 111 111

The two most developed after BOC/TVR are simeprevir (TMC-435)1 and faldaprevir (BI )2. Both are in fully enrolled phase 3 clinical trials vs. dual PegIFN + RBV controls; results are expected in early 2013. Simeprevir and faldaprevir are dosed once daily (150 and 120 mg, respectively) and do not produce additive anemia beyond PegIFN + RBV. Simeprevir is associated with some increase in bilirubin due to reversible inhibition of OATP1B1 and MRP2 transporters. Faldaprevir inhibits glucuronyl transferase and can cause a Gilbert’s like syndrome (similar to the HIV protease inhibitor, atazanavir). Faldaprevir is also associated with rash and photosensitivity. Only two second generation NS3 PIs are currently in clinical phase 3. They are simeprevir (TMC-435) from Tibotec, a division of Johnson and Johnson, and BI from Boehringer Ingelheim. Both are given once daily and do not cause additive anemia to PR. Both are associated with some increase in serum bilirubin. In the case of BI , the increase in bilirubin is only unconjugated bilirubin due to inhibition of uridine glucuronysyl transferase 1A1 (UGT1A1) and the effect is dose dependent. BI is also associated with a skin rash that is largely photosensitivity. 1. Fried MW et al. AASLD Abstract LB-5 2. Sulkowski M et al. EASL Abstracts 60 and 66 112 112

Two NS3 PIs (danoprevir1 and ABT-4502) are being developed for administration with low dose ritonavir. Ritonavir, an HIV protease inhibitor, is a potent inhibitor of CYP3A4; ritonavir increases exposure of drugs metabolized principally via CYP3A4. Other NS3 PIs are under development, including asunaprevir (BMS ), MK-5172, GS-9451, sovaprevir (ACH-1625), whereas the development of several others has been terminated. Danoprevir (Roche) and ABT-450 (Abbott) are NS3 PIs which are being developed only with low dose RTV boosting. Danoprevir on its own was associated with hepatotoxicity at high dose which correlated with AUC. Low dose danoprevir plus low dose RTV appears to be safer while providing adequate danoprevir exposure. Since ABT-450 and RTV are both made by Abbott, it is expected that the two drugs will be coformulated, similar to lopinavir/ritonavir (Kaletra™) for HIV. 1. Rouzier R et al. EASL Abstract 62 2. Lawitz E et al. EASL Abstract 1220 113 113

HCV NS5A Inhibitors NS5A is a protein with no known enzymatic function, but a definite, yet poorly defined role in viral replication. NS5A inhibitors are very potent and pangenotypic in the replicon system1. They are significantly more active vs. genotype 1b than genotype 1a. Daclatasvir, the most developed NS5A inhibitor, is given once daily, and is in phase 3 in treatment naïve patients with genotypes 1 and 4, and in phase 2 for genotypes 2 and 3, and for genotype 1 in the HIV co-infected. NS5A inhibitors in phase 2 are ABT-267 and GS-5885 NS5A inhibitors have no “signature” toxicity to date2. Background on NS5A inhibitors, including reference to sentinel publication in Nature. On a weight basis, NS5A inhibitors are the most potent of the four classes of DAAs. 1. Gao M et al. Nature 2010; 465:96-100 2. Pol S et al. Lancet Infect Dis 2012; 12(9):671-7 114 114

Antiviral Activity of Daclatasvir in Combination with PegIFN2a + RBV in Treatment of Naïve Patients with Chronic HCV Genotype 1 Infection Day 1 Week 48 Week 72 Placebo + PegIFN-2a 180 µg/wk + RBV 1000/1200 mg/d SVR 24 Daclatasvir 3 mg QD + PegIFN-2a 180 µg/wk + RBV 1000/1200 mg/d Treatment naïve HCV GT1 patients n=48 Daclatasvir 10 mg QD + PegIFN-2a 180 µg/wk + RBV 1000/1200 mg/d Design of phase 2a study of NS5A inhibitor daclastasvir plus pegIFN + RBV for HCV GT1 treatment naïve patients. All patients received PegIFNα-2a 180 g/wk + RBV 1000/1200 mg/d x 48 wk. Control patients received additional oral placebo. Experimental arms received 3 doses of daclastasvir given once daily. The DAA was given for 48 wk. Daclatasvir 60 mg QD + PegIFN-2a 180 µg/wk + RBV 1000/1200 mg/d Pol S et al. Lancet Infect Dis 2012; 12(9):671-7 115 115

Daclatasvir (DCV) with PegIFN-2a + RBV: Virologic Response at Weeks 4, 12 & SVR (ITT)
PR PR + DCV 3 mg PR + DCV 10 mg PR + DCV 60 mg 100 92 83 83 83 83 83 80 58 60 (<10 IU/mL by Roche TaqMan) Percent HCV RNA negative 42 42 42 40 25 Phase 2a study of NS5A inhibitor daclastasvir plus pegIFN + RBV for HCV GT1 treatment naïve patients. Virologic results at weeks 4, 12 and SVR(24). The two highest doses of daclastasvir performed extremely well. The 60 mg dose was selected for phase 3. 20 8 RVR cEVR SVR (24) 12 patients per treatment arm; the 60 mg QD dose was selected for phase 3 Pol S et al. Lancet Infect Dis 2012; 12(9):671-7 116 116

HCV NS5B Polymerase Inhibitors
NS5B is a RNA-dependent RNA polymerase, responsible for viral RNA synthesis The viral polymerase is the “classic” target for antiviral drugs (eg. DNA-dependent DNA polymerase in HSV and VZV or RNA-dependent DNA polymerase [reverse transcriptase] in HIV and HBV) As with HIV RT inhibitors, there are two subtypes of NS5B inhibitors, Nucleoside/nucleotide analogues Act as RNA chain terminators High barrier to resistance Pan-genotypic Non-nucleoside inhibitors Least potent class of DAA Low barrier to resistance Background on HCV NS5B target and the two types of inhibitors: nucleoside/nucleotide inhibitors which act as chain terminators, or non-nucleoside inhibitors. Nucs have a high barrier to resistance whereas non-nucs have a low barrier to resistance. Non-nucs are the least potent of the 4 classes of DAAs. 117 117

HCV NS5B Polymerase Inhibitors: Drugs with Antiviral Activity in Humans
Nucleoside/nucleotide analogues Mericitabine (RG-7128) Sofosbuvir (GS-7977/ PSI-7977) VX-135 (ALS-2200) Non-nucleoside inhibitors Tegobuvir (GS-9190) Setrobuvir (ANA-598) ABT-333 (lead Abbott NNI) ABT-072 (back-up Abbott NNI) VX-222 BI This is a list of NS5B inhibitors with activity in humans whose clinical development is still ongoing. Several other nucleosides with antiviral activity in humans have had their clinical development stopped due to toxicity. 118 118

IFN-Free, All Oral Regimens with SVR Data
As of October 2012, 5 pharmaceutical companies have presented pilot data demonstrating that SVR can be achieved in small numbers of patients. The majority of IFN-free regimens to date continue to include ribavirin. Only one study to date has included patients with cirrhosis (SOUND C-2). The most common combination of agents in IFN-free regimens for genotype 1 has been a 3-drug combination of a NS3 PI, a NS5B non-nucleoside (NN) inhibitor and ribavirin. For GT 2 & 3, IFN-free regimens demonstrating SVR are sofosbuvir with either RBV or daclatasvir. 119

Daclatasvir+asunaprevir
IFN Free SVR: The Very First Report (Daclatasvir + Asunaprevir in GT1 Prior Null Responders) Daclatasvir+asunaprevir Follow-up 7 6 5 HCV RNA (log10 IU/mL) 4 3 2 LLOQ LLOD 1 1 2 3 4 6 8 10 12 16 20 24 PT4 PT8 PT12 PT24 PT36 PT48 Week SVR was achieved in 2/9 GT 1a and 2/2 GT 1b prior null responders to PR with 24 weeks of DCV + ASV (all enrolled patients were non-cirrhotic) On therapy breakthrough was common in GT 1a Lok AS et al. EASL 2011; NEJM 2012;366:216-24 120

Dual Oral Therapy with Daclatasvir and Asunaprevir x 24 Weeks for HCV GT1b
Study conducted in Japan All had genotype 1b Treated with asunaprevir (NS3 PI) and daclatasvir (NS5A inhibitor) x 24 weeks Virologic Response (%) Prior Null Responders (n=21) [6 IL-28B CC] IFN Ineligible/Intolerant (n=22) [16 IL-28B CC] Week 4 RVR 52 86 Week 12 cEVR 91 EOTR SVR24 64 It is puzzling that SVR rates appears to be higher in prior null responders to PR than in treatment naïve patients, but the number of treated patients is small. Suzuki F, et al. EASL Abstract 14 121

PILOT: NS3 PI + NN + RBV: Virologic Responses
n = 11, HCV GT1, treatment-naïve, non-cirrhotic; 8 GT1a, 3 GT 1b Only IL-28B CC patients were enrolled, so that they would have a high probability of salvage with PegIFN + RBV in the event that all-oral therapy failed All were treated with ABT-450/r 150/100 mg QD + ABT mg QD + RBV 1000/1200 mg/d 100 100 100 91 91 82 80 HCV RNA Negative (%) In Abbott’s first study of all oral therapy, they chose to restrict it to IL-28B CC subjects, so that there would be a high probability of “rescue” therapy with PegIFN + RBV, in the event that all-oral therapy was unsuccessful. Eight of 11 had GT1a, which is emerging as the more difficult subtype to cure than 1b. One patient relapsed between week 24 and 36 post-treatment. 60 40 20 n/N 11/11 11/11 10/11 10/11 9/11 Wk 4 (RVR) Wk 12 (EOT) SVR12 SVR24 SVR36 Lawitz E, et al. EASL Abstract 13 122

CO-PILOT: NS3 PI + NN + RBV: Virologic Responses
Because of the favorable results in PILOT, CO-PILOT was open to all IL-28B genotypes and explored prior PR non-responders; All had genotype 1 and were non-cirrhotic In CO-PILOT, a different NS5B non-nucleoside inhibitor was used (ABT-333) than in PILOT (ABT-072) RVR eRVR SVR4 SVR12 100 95 95 90 90 93 93 79 79 80 77 59 60 HCV RNA negative (%) 47 47 40 20 ABT-450/r 250/100 mg QD + ABT RBV Treatment naive (n = 19; 17 G1a, 2 G1b) ABT-450/r 150/100 mg QD + ABT RBV Treatment naive (n = 14; 11 G1a, 3 G1b) ABT-450/r 150/100 mg QD + ABT RBV Prior PR Non-responders* (n = 17; 16 G1a; 1 G1b) * 11 partial responders, 6 null responders Poordad F et al. EASL Abstract 1399 123

INFORM-SVR: NS3 PI + Nucleoside + RBV in GT1: SVR12 by HCV Subtype and IL28B Genotype
Data shown are patients treated with 24 weeks of mericitabine + danoprevir/r + ribavirin; all were treatment naïve and non-cirrhotic SVR12 rates were encouraging in GT1b but disappointing in GT1a 100 100 All (n = 64) GT1a (n = 43) GT1b (n = 21) 80 80 76 71 60 60 50 SVR12 (%) 44 This all oral regimen had encouraging SVR12 rates in GT1b, but results were disappointing in GT1a. It is also a 24-week treatment period. It is puzzling that IL-28B CC patients seemed to do worse. 41 40 40 32 27 26 25 20 20 n/N = 26/64 11/43 15/21 n/N = 6/19 4/15 2/4 20/45 7/28 13/17 Overall CC Non-CC IL28B Genotype Gane E et al. EASL Abstract 1412 124

SOUND-C2: NS3 PI + NN ± RBV: SVR12 by Study Arm
N=362; the largest IFN-free study to date All had GT1 and were treatment naïve; 10% had cirrhosis All received faldaprevir 120 mg QD + RBV 1000/1200 mg/d Patients were randomized to 5 arms, 4 containing BI , 600 mg TID (3 arms) or 600 mg BID (one arm) for 3 different durations RBV-free arm was stopped prematurely due to high relapse rate 100 80 68 61 59 SVR12 (%) 60 56 39 40 20 n/N 48/81 49/80 43/77 53/78 18/46 TID 16 wks + RBV TID 28 wks + RBV TID 40 wks + RBV BID 28 wks + RBV TID 28 wks (no RBV) BI Dosing Zeuzem S et al. EASL Abstract 101 125

SOUND-C2 BID Dosing Arm: Higher SVR12 in Patients With GT1b or GT1a-IL28B CC
SVR According to IL28B and HCV Subtype: BID 28 Wks + RBV (ITT) 100 84 82 75 80 60 SVR12 (%) 40 32 20 n/N = 7/22 6/8 31/37 9/11 1a non-CC 1a CC 1b non-CC 1b CC HCV Subtype and IL28B Genotype Boehringer Ingelheim has decided to undertake additional studies of this 3-drug regimen only in patients with GT1b and those with GT1a who are IL-28B CC Zeuzem S et al. EASL Abstract 101 126

Sofosbuvir (GS-7977) Nucleotide NS5B inhibitor
Once daily oral dosing with no food effect No described toxicity to date Pangenotypic No virological breakthroughs reported to date Studied in combination with RBV or daclatasvir or simeprevir* In GT2 & 3, sofosbuvir + RBV x 12 weeks achieved SVR24 in 10/10 patients; sofosbuvir + RBV x 8 weeks achieved SVR12 in 10/10 patients (all non cirrhotic) Two phase 3 RCTs are fully enrolled in GT2 & 3 (including cirrhotics); results expected EASL 2013 FISSION: Treatment naïve patients randomized to sofosbuvir + RBV x 12 weeks vs. PegIFN + RBV x 24 weeks FUSION: Treatment failure patients randomized to 12 wk vs. 16 wk of sofosbuvir + RBV * No data have been presented on sofosbuvir + simeprevir Gane E et al. EASL Abstract 1113 127

Sofosbuvir + RBV x 12 Weeks: Results in GT1 Treatment Naïve Patients
In ELECTRON, 25/25 achieved EOT; 22/25 (88%) achieved SVR4 and 3/25 (12%) relapsed1 In QUANTUM, 17/17 achieved EOT; 10/17 (59%) achieved SVR4, and 7/10 (41%) relapsed2 Combined ELECTRON and QUANTUM SVR in GT1 naives is 32/42 (76%) Only non-cirrhotic patients were enrolled in ELECTRON and QUANTUM Future studies in GT1 will examine Longer treatment durations of Sofosbuvir + RBV The addition of a third antiviral drug 1. Gane E et al. EASL Abstract 1113 2. Gilead Press Release, Apr 19, 2012 128

For more information visit www.liver.ca or call 1-800-563-5483.
The Canadian Liver Foundation gratefully acknowledges the participating health care professionals for their contributions to this project and for their commitment to the liver health of Canadians. The Canadian Liver Foundation (CLF) was the first organization in the world devoted to providing support for research and education into the causes, diagnoses, prevention and treatment of all liver disease. Through its chapters across the country, the CLF strives to promote liver health, improve public awareness and understanding of liver disease, raise funds for research and provide support to individuals affected by liver disease. For more information visit or call This project made possible through the financial support of Merck Canada Inc. The views, information and opinions contained herein are those of the authors and do not necessarily reflect the views and opinions of Merck Canada Inc.

Protease Inhibitors in Chronic Hepatitis C: An Update

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Protease Inhibitors in Chronic Hepatitis C: An Update

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