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Safety of Hepatitis C Viral Protease Inhibitors in Compensated Cirrhotics: Lingering Concerns Put to Rest?

Safety of Hepatitis C Viral Protease Inhibitors in Compensated Cirrhotics: Lingering Concerns Put... hepatitis C, pharmacokinetics, cirrhosis, hepatotoxicity Historically, treating hepatitis C virus (HCV) in individuals with cirrhosis has been challenging. With pegylated interferon– and ribavirin-based therapies, tolerability was poor and rates of sustained virologic response were low [1]. Interferon-free regimens brought tremendous hope for the safe, simple, and effective treatment of all individuals with HCV, including cirrhotics. However, post-market cases of hepatic failure and death with interferon-free therapies containing an HCV protease inhibitor (PI) reignited concerns about the safety of HCV treatments in those with cirrhosis [2–6]. Fortunately, hepatotoxicity is rarely observed with contemporary, PI-based HCV regimens, and hepatic failure and death have not been reported. The reasons for this are likely 2-fold. First, these PI are unlikely to produce exposures associated with hepatotoxicity in the vast majority of patients at the marketed dose. Second, fewer individuals with advanced liver disease, who are at the greatest risk for complications, are receiving these PI-based therapies, given experience with their predecessors and the availability of a PI-free HCV treatment option. In this issue, Gane and colleagues [7] provide an integrated analysis of the safety, efficacy, and pharmacokinetics of glecaprevir (a PI) and pibrentasvir (an HCV non-structural 5A protein inhibitor; G/P) in compensated cirrhotics across the Phase II/III development program. Cirrhotic patients (n = 308) had similar efficacy compared with non-cirrhotics (n = 2061; 96.4% vs. 97.5%, respectively). An adverse event consistent with hepatic decompensation occurred in a cirrhotic patient. Grade 3 alanine aminotransferase (ALT) elevations (>5 times the upper limit of normal) occurred in 2 patients (0.09%), who were both non-cirrhotic. Grade 3 total bilirubin elevations occurred in 9 patients (0.38%); 3 cirrhotic (0.97%) and 6 non-cirrhotic (0.29%). Overall, with the exception of the 20 cirrhotic patients with stage 4 or 5 chronic kidney disease, safety and tolerability were generally similar between cirrhotics and non-cirrhotics, despite approximately 2.2-fold higher glecaprevir exposures in the cirrhotics. These data are very reassuring on the safety profile of G/P in cirrhotics. However, they do not put all lingering safety concerns about the use of PI-based HCV treatments in cirrhotics to rest. Decompensated cirrhotics remain ineligible for G/P and other PI-based regimens, because of the potential for very high PI concentrations, which may increase the risk for hepatotoxicity. Decompensated cirrhotics were not included in the integrated analysis, and there are very limited real-world data on the safety of these regimens in this population. Among compensated cirrhotics, a blanket determination that no additional clinical or laboratory monitoring is necessary with G/P or other PI-based therapies is unwise. Compensated cirrhosis is not a homogenous condition. Tremendous variation exists in histologic, clinical, hemodynamic, and biological characteristics amongst compensated cirrhotics [8]. These variations affect the pharmacokinetics of the HCV PI and, in turn, the risk for hepatotoxicity and/or decompensating events. The preponderance of evidence indicates that HCV PIs cause concentration-dependent hepatotoxicity [9–11]. For some PIs (including glecaprevir), this exposure-response relationship cannot be readily established, because the concentrations observed with the marketed dose are below those associated with hepatotoxicity in the majority of patients [12]. However, the inability to establish the relationship does not mean it does not exist. Data are limited with higher glecaprevir exposures, but 2 prior pharmacokinetic studies (a dose-ranging study [13] and a drug-interaction study with ritonavir-boosted atazanavir [14]) found increased rates of ALT elevations, with exposures 11.6-fold and 4-fold higher, respectively, than those observed in cirrhotics in the integrated analysis. Though these studies are small, they indicate the potential for an increased risk for hepatotoxicity with higher glecaprevir exposures. Glecaprevir has non-linear pharmacokinetics (as evidenced by the 50-fold increase in exposures between 300 mg and 1200 mg) [13]; thus, the effects of several intrinsic or extrinsic factors on glecaprevir exposures may be more than additive. Factors known to affect the pharmacokinetics of glecaprevir (and other HCV PIs) include renal impairment, drug interactions, advanced age, and female sex. Patients with these factors and compensated cirrhosis require additional clinical and laboratory monitoring for potential hepatotoxicity during PI-based HCV treatment. Although G/P is the HCV treatment of choice in those with impaired renal function, glecapreivr exposures are roughly doubled in renal impairment [12]. In a patient with both renal impairment and cirrhosis, glecaprevir exposures will be higher and the risk for hepatotoxicity increased. There were 20 patients with both renal impairment and compensated cirrhosis included in the integrated analysis, and these patients had a higher rate of serious adverse events (55% vs 6%). This patient population experiences a high rate of adverse events even in the absence of HCV therapy, so these events may not reflect G/P toxicities. Nevertheless, this patient population requires more frequent laboratory and clinical monitoring during HCV treatment. Medications that increase glecaprevir exposures via the inhibition of organic anion transporting polypeptide (OATP1B1) or cytochrome P450 3A4 (CYP3A4) may also predispose to toxicities in cirrhotics. For example, the fixed-dose antiretroviral regimen, including tenofovir alafenamide/emtricitabine/elvitegravir/ cobicistat, increases glecaprevir exposures 3-fold. Cyclosporine increases glecaprevir exposures approximately 5-fold. A population pharmacokinetic analysis found that females have ~39% higher glecaprevir exposures vs males and that increasing age is associated with higher exposures [14]. A 65-year-old will have glecaprevir exposures 32% higher than a 55-year-old. In isolation, these increases are not clinically relevant but, coupled with other factors, they may have clinical significance in a patient with advanced liver disease. Glecaprevir exposures are not different in Han Chinese and Japanese individuals, compared with Caucasians, when given with pibrentasvir [13]. However, exposures of other HCV protease inhibitors are higher in Asian populations, presumably due to the lower expression of the hepatic uptake transporter OATP1B1. These demographic factors should be considered in a patient with compensated cirrhosis who is receiving a PI-based HCV therapy. Cirrhotic patients with certain infectious or non-infectious comorbidities and those taking concomitant hepatotoxic medications may also be predisposed to hepatotoxicity. Patients taking hepatotoxic medications were excluded from the studies included in the integrated analysis, as were those with hepatitis B infection; uncontrolled diabetes, cardiac, respiratory, gastrointestinal, hematologic, neurologic, psychiatric, or other medical diseases and disorders. Thus, results may not be generalizable to all HCV-infected individuals with compensated cirrhosis. In summary, the data by Gane and colleagues [7] suggest there is no need to avoid G/P in compensated cirrhotics, but certain clinical characteristics and conditions can predispose patients to higher glecaprevir exposures and, potentially, to an increased risk of hepatotoxicity. Providers should monitor liver function tests, bilirubin, and signs and symptoms of decompensation, such as ascites, hepatic encephalopathy, and/or variceal hemorrhage, in compensated cirrhotics with the clinical characteristics described above. Fractionated bilirubin is helpful, given HCV PIs may cause benign increases in indirect bilirubin that do not reflect a true liver injury. Instruct patients to contact providers if they develop fatigue, weakness, a loss of appetite, nausea and vomiting, yellowing of the eyes or skin, or light-colored stools. Note Potential conflicts of interest. J. J. K. is supported by the National Institutes of Health (grant R01 DA040499) and reports grants from Gilead Sciences, outside the submitted work. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Bota S , Sporea I , Sirli R , et al. Severe adverse events during antiviral therapy in hepatitis C virus cirrhotic patients: a systematic review . World J Hepatol 2013 ; 5 : 120 – 6 . Google Scholar Crossref Search ADS PubMed 2. Gordon SC , Muir AJ , Lim JK , et al. ; HCV-TARGET study group . Safety profile of boceprevir and telaprevir in chronic hepatitis C: real world experience from HCV-TARGET . J Hepatol 2015 ; 62 : 286 – 93 . Google Scholar Crossref Search ADS PubMed 3. Hezode C , Fontaine H , Dorival C , et al. Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis . Gastroenterology 2014 ; 147 : 132 – 42 e4 . Google Scholar Crossref Search ADS PubMed 4. Stine JG , Intagliata N , Shah NL , et al. Hepatic decompensation likely attributable to simeprevir in patients with advanced cirrhosis . Dig Dis Sci 2015 ; 60 : 1031 – 5 . Google Scholar Crossref Search ADS PubMed 5. Soriano V , Barreiro P , de Mendoza C , Peña JM . Hepatic decompensation with sofosbuvir plus simeprevir in a patient with Child-Pugh B compensated cirrhosis . Antivir Ther 2016 ; 21 : 91 – 2 . Google Scholar Crossref Search ADS PubMed 6. Food and Drug Administration Drug Safety Communication . FDA warns of serious liver injury risk with hepatitis C treatments Viekira Pak and Technivie . Available at: https://www.fda.gov/Drugs/DrugSafety/ucm468634.htm. Accessed 10 December 2018 . 7. Gane E , Poordad F , Zadeikis N , et al. Safety and pharmacokinetics of glecaprevir/pibrentasvir in adults with chronic genotype 1–6 HCV infection and compensated liver disease . Clin Infect Dis . 8. Garcia-Tsao G , Friedman S , Iredale J , Pinzani M . Now there are many (stages) where before there was one: in search of a pathophysiological classification of cirrhosis . Hepatology 2010 ; 51 : 1445 – 9 . Google Scholar Crossref Search ADS PubMed 9. Lin CW , Menon R , Liu W , et al. Exposure-safety response relationship for ombitasvir, paritaprevir/ritonavir, dasabuvir, and ribavirin in patients with chronic hepatitis C virus genotype 1 infection: analysis of data from five Phase II and six Phase III studies . Clin Drug Investig 2017 ; 37 : 647 – 57 . Google Scholar Crossref Search ADS PubMed 10. Jacobson IM , Lawitz E , Kwo PY , et al. Safety and efficacy of elbasvir/grazoprevir in patients with hepatitis C virus infection and compensated cirrhosis: an integrated analysis . Gastroenterology 2017 ; 152 : 1372 – 82 e2 . Google Scholar Crossref Search ADS PubMed 11. Uchida Y , Naiki K , Kouyama JI , et al. Serum asunaprevir concentrations showing correlation with the extent of liver fibrosis as a factor inducing liver injuries in patients with genotype-1b hepatitis C virus receiving daclatasvir plus asunaprevir therapy . PLOS One 2018 ; 13 : e0205600 . Google Scholar Crossref Search ADS PubMed 12. Lin C-W , Zhao W , Ding B , Shulman NS , Mensa FJ , Liu W . Exposure-safety response relationship for glecaprevir and pibrentasvir in hepatitis C Virus-infected subjects in phase 2 and 3 studies [abstract 1189 ]. In: Program and abstracts of The Liver Meeting ( Washington, DC ). Hepatology 2017 ; 66(S1) : 641A . 13. Lin CW , Dutta S , Zhao W , Asatryan A , Campbell A , Liu W . Pharmacokinetic interactions and safety of coadministration of glecaprevir and pibrentasvir in healthy volunteers . Eur J Drug Metab Pharmacokinet 2018 ; 43 : 81 – 90 . Google Scholar Crossref Search ADS PubMed 14. Food and Drug Administration Center for Drug Evaluation and Research . Mavyret clinical pharmacology and biopharmaceutics review . Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209394Orig1s000ClinPharmR.pdf. Accessed 6 December 2018 . © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Infectious Diseases Oxford University Press

Safety of Hepatitis C Viral Protease Inhibitors in Compensated Cirrhotics: Lingering Concerns Put to Rest?

Kiser, Jennifer, J
Clinical Infectious Diseases , Volume Advance Article – Mar 28, 2019
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Oxford University Press
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© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].
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1058-4838
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Abstract

hepatitis C, pharmacokinetics, cirrhosis, hepatotoxicity Historically, treating hepatitis C virus (HCV) in individuals with cirrhosis has been challenging. With pegylated interferon– and ribavirin-based therapies, tolerability was poor and rates of sustained virologic response were low [1]. Interferon-free regimens brought tremendous hope for the safe, simple, and effective treatment of all individuals with HCV, including cirrhotics. However, post-market cases of hepatic failure and death with interferon-free therapies containing an HCV protease inhibitor (PI) reignited concerns about the safety of HCV treatments in those with cirrhosis [2–6]. Fortunately, hepatotoxicity is rarely observed with contemporary, PI-based HCV regimens, and hepatic failure and death have not been reported. The reasons for this are likely 2-fold. First, these PI are unlikely to produce exposures associated with hepatotoxicity in the vast majority of patients at the marketed dose. Second, fewer individuals with advanced liver disease, who are at the greatest risk for complications, are receiving these PI-based therapies, given experience with their predecessors and the availability of a PI-free HCV treatment option. In this issue, Gane and colleagues [7] provide an integrated analysis of the safety, efficacy, and pharmacokinetics of glecaprevir (a PI) and pibrentasvir (an HCV non-structural 5A protein inhibitor; G/P) in compensated cirrhotics across the Phase II/III development program. Cirrhotic patients (n = 308) had similar efficacy compared with non-cirrhotics (n = 2061; 96.4% vs. 97.5%, respectively). An adverse event consistent with hepatic decompensation occurred in a cirrhotic patient. Grade 3 alanine aminotransferase (ALT) elevations (>5 times the upper limit of normal) occurred in 2 patients (0.09%), who were both non-cirrhotic. Grade 3 total bilirubin elevations occurred in 9 patients (0.38%); 3 cirrhotic (0.97%) and 6 non-cirrhotic (0.29%). Overall, with the exception of the 20 cirrhotic patients with stage 4 or 5 chronic kidney disease, safety and tolerability were generally similar between cirrhotics and non-cirrhotics, despite approximately 2.2-fold higher glecaprevir exposures in the cirrhotics. These data are very reassuring on the safety profile of G/P in cirrhotics. However, they do not put all lingering safety concerns about the use of PI-based HCV treatments in cirrhotics to rest. Decompensated cirrhotics remain ineligible for G/P and other PI-based regimens, because of the potential for very high PI concentrations, which may increase the risk for hepatotoxicity. Decompensated cirrhotics were not included in the integrated analysis, and there are very limited real-world data on the safety of these regimens in this population. Among compensated cirrhotics, a blanket determination that no additional clinical or laboratory monitoring is necessary with G/P or other PI-based therapies is unwise. Compensated cirrhosis is not a homogenous condition. Tremendous variation exists in histologic, clinical, hemodynamic, and biological characteristics amongst compensated cirrhotics [8]. These variations affect the pharmacokinetics of the HCV PI and, in turn, the risk for hepatotoxicity and/or decompensating events. The preponderance of evidence indicates that HCV PIs cause concentration-dependent hepatotoxicity [9–11]. For some PIs (including glecaprevir), this exposure-response relationship cannot be readily established, because the concentrations observed with the marketed dose are below those associated with hepatotoxicity in the majority of patients [12]. However, the inability to establish the relationship does not mean it does not exist. Data are limited with higher glecaprevir exposures, but 2 prior pharmacokinetic studies (a dose-ranging study [13] and a drug-interaction study with ritonavir-boosted atazanavir [14]) found increased rates of ALT elevations, with exposures 11.6-fold and 4-fold higher, respectively, than those observed in cirrhotics in the integrated analysis. Though these studies are small, they indicate the potential for an increased risk for hepatotoxicity with higher glecaprevir exposures. Glecaprevir has non-linear pharmacokinetics (as evidenced by the 50-fold increase in exposures between 300 mg and 1200 mg) [13]; thus, the effects of several intrinsic or extrinsic factors on glecaprevir exposures may be more than additive. Factors known to affect the pharmacokinetics of glecaprevir (and other HCV PIs) include renal impairment, drug interactions, advanced age, and female sex. Patients with these factors and compensated cirrhosis require additional clinical and laboratory monitoring for potential hepatotoxicity during PI-based HCV treatment. Although G/P is the HCV treatment of choice in those with impaired renal function, glecapreivr exposures are roughly doubled in renal impairment [12]. In a patient with both renal impairment and cirrhosis, glecaprevir exposures will be higher and the risk for hepatotoxicity increased. There were 20 patients with both renal impairment and compensated cirrhosis included in the integrated analysis, and these patients had a higher rate of serious adverse events (55% vs 6%). This patient population experiences a high rate of adverse events even in the absence of HCV therapy, so these events may not reflect G/P toxicities. Nevertheless, this patient population requires more frequent laboratory and clinical monitoring during HCV treatment. Medications that increase glecaprevir exposures via the inhibition of organic anion transporting polypeptide (OATP1B1) or cytochrome P450 3A4 (CYP3A4) may also predispose to toxicities in cirrhotics. For example, the fixed-dose antiretroviral regimen, including tenofovir alafenamide/emtricitabine/elvitegravir/ cobicistat, increases glecaprevir exposures 3-fold. Cyclosporine increases glecaprevir exposures approximately 5-fold. A population pharmacokinetic analysis found that females have ~39% higher glecaprevir exposures vs males and that increasing age is associated with higher exposures [14]. A 65-year-old will have glecaprevir exposures 32% higher than a 55-year-old. In isolation, these increases are not clinically relevant but, coupled with other factors, they may have clinical significance in a patient with advanced liver disease. Glecaprevir exposures are not different in Han Chinese and Japanese individuals, compared with Caucasians, when given with pibrentasvir [13]. However, exposures of other HCV protease inhibitors are higher in Asian populations, presumably due to the lower expression of the hepatic uptake transporter OATP1B1. These demographic factors should be considered in a patient with compensated cirrhosis who is receiving a PI-based HCV therapy. Cirrhotic patients with certain infectious or non-infectious comorbidities and those taking concomitant hepatotoxic medications may also be predisposed to hepatotoxicity. Patients taking hepatotoxic medications were excluded from the studies included in the integrated analysis, as were those with hepatitis B infection; uncontrolled diabetes, cardiac, respiratory, gastrointestinal, hematologic, neurologic, psychiatric, or other medical diseases and disorders. Thus, results may not be generalizable to all HCV-infected individuals with compensated cirrhosis. In summary, the data by Gane and colleagues [7] suggest there is no need to avoid G/P in compensated cirrhotics, but certain clinical characteristics and conditions can predispose patients to higher glecaprevir exposures and, potentially, to an increased risk of hepatotoxicity. Providers should monitor liver function tests, bilirubin, and signs and symptoms of decompensation, such as ascites, hepatic encephalopathy, and/or variceal hemorrhage, in compensated cirrhotics with the clinical characteristics described above. Fractionated bilirubin is helpful, given HCV PIs may cause benign increases in indirect bilirubin that do not reflect a true liver injury. Instruct patients to contact providers if they develop fatigue, weakness, a loss of appetite, nausea and vomiting, yellowing of the eyes or skin, or light-colored stools. Note Potential conflicts of interest. J. J. K. is supported by the National Institutes of Health (grant R01 DA040499) and reports grants from Gilead Sciences, outside the submitted work. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Bota S , Sporea I , Sirli R , et al. Severe adverse events during antiviral therapy in hepatitis C virus cirrhotic patients: a systematic review . World J Hepatol 2013 ; 5 : 120 – 6 . Google Scholar Crossref Search ADS PubMed 2. Gordon SC , Muir AJ , Lim JK , et al. ; HCV-TARGET study group . Safety profile of boceprevir and telaprevir in chronic hepatitis C: real world experience from HCV-TARGET . J Hepatol 2015 ; 62 : 286 – 93 . Google Scholar Crossref Search ADS PubMed 3. Hezode C , Fontaine H , Dorival C , et al. Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis . Gastroenterology 2014 ; 147 : 132 – 42 e4 . Google Scholar Crossref Search ADS PubMed 4. Stine JG , Intagliata N , Shah NL , et al. Hepatic decompensation likely attributable to simeprevir in patients with advanced cirrhosis . Dig Dis Sci 2015 ; 60 : 1031 – 5 . Google Scholar Crossref Search ADS PubMed 5. Soriano V , Barreiro P , de Mendoza C , Peña JM . Hepatic decompensation with sofosbuvir plus simeprevir in a patient with Child-Pugh B compensated cirrhosis . Antivir Ther 2016 ; 21 : 91 – 2 . Google Scholar Crossref Search ADS PubMed 6. Food and Drug Administration Drug Safety Communication . FDA warns of serious liver injury risk with hepatitis C treatments Viekira Pak and Technivie . Available at: https://www.fda.gov/Drugs/DrugSafety/ucm468634.htm. Accessed 10 December 2018 . 7. Gane E , Poordad F , Zadeikis N , et al. Safety and pharmacokinetics of glecaprevir/pibrentasvir in adults with chronic genotype 1–6 HCV infection and compensated liver disease . Clin Infect Dis . 8. Garcia-Tsao G , Friedman S , Iredale J , Pinzani M . Now there are many (stages) where before there was one: in search of a pathophysiological classification of cirrhosis . Hepatology 2010 ; 51 : 1445 – 9 . Google Scholar Crossref Search ADS PubMed 9. Lin CW , Menon R , Liu W , et al. Exposure-safety response relationship for ombitasvir, paritaprevir/ritonavir, dasabuvir, and ribavirin in patients with chronic hepatitis C virus genotype 1 infection: analysis of data from five Phase II and six Phase III studies . Clin Drug Investig 2017 ; 37 : 647 – 57 . Google Scholar Crossref Search ADS PubMed 10. Jacobson IM , Lawitz E , Kwo PY , et al. Safety and efficacy of elbasvir/grazoprevir in patients with hepatitis C virus infection and compensated cirrhosis: an integrated analysis . Gastroenterology 2017 ; 152 : 1372 – 82 e2 . Google Scholar Crossref Search ADS PubMed 11. Uchida Y , Naiki K , Kouyama JI , et al. Serum asunaprevir concentrations showing correlation with the extent of liver fibrosis as a factor inducing liver injuries in patients with genotype-1b hepatitis C virus receiving daclatasvir plus asunaprevir therapy . PLOS One 2018 ; 13 : e0205600 . Google Scholar Crossref Search ADS PubMed 12. Lin C-W , Zhao W , Ding B , Shulman NS , Mensa FJ , Liu W . Exposure-safety response relationship for glecaprevir and pibrentasvir in hepatitis C Virus-infected subjects in phase 2 and 3 studies [abstract 1189 ]. In: Program and abstracts of The Liver Meeting ( Washington, DC ). Hepatology 2017 ; 66(S1) : 641A . 13. Lin CW , Dutta S , Zhao W , Asatryan A , Campbell A , Liu W . Pharmacokinetic interactions and safety of coadministration of glecaprevir and pibrentasvir in healthy volunteers . Eur J Drug Metab Pharmacokinet 2018 ; 43 : 81 – 90 . Google Scholar Crossref Search ADS PubMed 14. Food and Drug Administration Center for Drug Evaluation and Research . Mavyret clinical pharmacology and biopharmaceutics review . Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209394Orig1s000ClinPharmR.pdf. Accessed 6 December 2018 . © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Clinical Infectious Diseases – Oxford University Press

Published: Mar 28, 2019

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