the al. Flying Publisher Guide to t e u c Hepatitis C s e n r e C Treatment 2011 Cernescu, Ruta, Gheorghe, Iacob, Popescu, Wanless R e h s 4 i l b u P g # n i y l F Flying PublisheR Cernescu – Ruta – Gheorghe – Iacob – Popescu – Wanless The Flying Publisher Guide to Hepatitis C Treatment The PDF of the 2011 Flying Publisher Guide to Hepatitis C Treatment is freely available from www.FlyingPublisher.com thanks to an educational grant provided by www.boehringer-ingelheim.com Costin Cernescu Simona Ruta Liana Gheorghe Speranṭa Iacob Irinel Popescu Richard Sebastian Wanless The Flying Publisher Guide to Hepatitis C Treatment 2011 Edition Flying Publisher 4 | Correspondence: [email protected] Disclaimer Hepatitis C treatment management is an ever-changing field. The publishers and authors of “The Flying Publisher Guide to Hepatitis C treatment “ have made every effort to provide information that is accurate and complete as of the date of publication. However, in view of the rapid changes occurring in Hepatitis C management, as well as the possibility of human error, this site may contain technical inaccuracies, typographical or other errors. It is the responsibility of the physician who relies on experience and knowledge about the patient to determine the most adequate treatment. The information contained herein is provided “as is” and without warranty of any kind. The contributors to this book, including Flying Publisher & Kamps, disclaim responsibility for any errors or omissions or for results obtained from the use of information contained herein. Gentium Basic and Gentium Book Basic font software by J. Victor Gaultney. Gentium font software is licensed under the SIL Open Font License, Version 1.1. This license is available at http://scripts.sil.org/OFL This work is protected by copyright both as a whole and in part. © 2011 by Flying Publisher & Kamps Copy-editing: Simona Ruta and Richard Sebastian Wanless ISBN: 978-3-942687-04-1 | 5 Preface Affecting around 200 millions people worldwide, chronic Hepatitis C is the leading cause of cirrhosis and liver cancer and the first reason for liver transplants. The current standard therapy for chronic HCV infection – combined pegylated interferon and ribavirin – is successful in only 50% of the cases and is associated with frequent and sometimes serious side effects. Fortunately, there is huge potential to increase the number of successfully treated patients if we take into account pre-treatment and on-treatment host and virus characteristics that may lead to therapy failure. This Guide will discuss the available strategies for those who interrupt, fail or relapse after treatment, in particular – the benefits and risks of current therapeutic options – the categories of patients with therapeutic failure that should be re-treated – the appropriate measures for therapy monitoring and outcomes assessment As a growing number of non-responders and relapsers are seen in clinical practice there is a permanent search for new antiviral, anticellular and immunomodulator drugs. Year 2011 has brought the approval of the first generation of viral protease inhibitors that will offer higher cure rates for non-responders and open the door for the eventual testing of interferon-free regimens. The Editors June 2011 6 | Contributing Authors Simona Ruta Speranṭa Iacob Carol Davila University of Gastroenterology and Medicine and Pharmacy Hepatology St. S. Nicolau Institute of Fundeni Clinical Institute Virology 258, sos. Fundeni 285, sos. Mihai Bravu 22328, Bucharest, Romania 030304, Bucharest, Romania Irinel Popescu Costin Cernescu Center of Digestive Diseases St. S. Nicolau Institute of and Liver Transplantation Virology Fundeni Clinical Institute 285, sos. Mihai Bravu 258, sos. Fundeni 030304, Bucharest, Romania 22328, Bucharest, Romania Liana Gheorghe Richard Sebastian Wanless Gastroenterology and Baylor International Pediatric Hepatology AIDS Initiative Carol Davila University of 6621 Fannin Street, MC-A1150 Medicine and Pharmacy 77030 Houston, Texas, USA Fundeni Clinical Institute Baylor Black Sea Foundation, 258, sos. Fundeni Constanta, Romania 22328, Bucharest, Romania | 7 Abbreviations ACR: acute cellular rejection INR: international normalized AEs: Adverse side effects ratio ALT: alanine aminotransferase IR: insulin resistance ANC: absolute neutrophil IU: international unit count LT: liver transplant AST: aspartate MELD: Model for End-Stage aminotransferase Liver Disease BMI: body mass index MMF: mycophenolate mofetil CP: Child-Pugh NAT: nucleic acid tests Anti-HCV: antibody to PCR: polymerase chain hepatitis C virus reaction cEVR: complete early virologic PegIFN: pegylated interferon response pEVR: partial early virologic CIFN: consensus interferon response CHC: chronic hepatitis C PKR: interferon-inducible DAA: direct-acting antivirals proteinkinase DILI: drug-induced liver PT: prothrombin time injuries QoL: quality of life EMEA: European Medicines QALY: quality adjusted life- Agency year EoTR: end of treatment RBV: ribavirin virologic response RGT: response-guided therapy EVR: early virologic response RVR: rapid virologic response FDA: US Food and Drug SNP: single nucleotide Administration polymorphism HBV: hepatitis B virus SoC: standard of care antiviral HCV: hepatitis C virus therapy HCV RNA: ribonucleic acid of SSRI: selective serotonin hepatitis C virus reuptake Inhibitor HCC: hepatocellular carcinoma STAT-C: Specifically targeted HIV: human immunodeficiency antiviral therapy for HCV virus SVR: sustained virologic IDUs: injecting drug users response IFN: interferon TSH: thyroid stimulating IL28B: interleukin 28B hormone IMPDH: inosine ULN: Upper limit of normal monophosphate VL: viral load dehydrogenase 8 | | 9 Table of Contents 1. Antiviral Therapy: The Basics..................................................13 Antiviral therapy – Standard of Care (SoC).........................13 Predictors of response before treatment............................17 Virus factors......................................................................17 Host factors........................................................................18 Co-morbidities...................................................................19 Treatment related factors................................................20 Adverse effects associated with therapy.............................21 Response-guided therapy (RGT)...........................................24 Nonresponders and relapsers...............................................27 Outlook...................................................................................28 Links........................................................................................29 2. Patients’ monitoring during and after treatment..................30 Basic knowledge....................................................................30 Viral kinetics: methodology.................................................32 Viral load monitoring.......................................................32 Real-time PCR tests...........................................................32 HCV genotyping................................................................34 Assessment of hepatic fibrosis.............................................35 Liver biopsy.......................................................................35 Non invasive methods......................................................37 Correlation between biochemical, histological and virological markers and HCV treatment.............................40 Outlook...................................................................................41 Links........................................................................................42 3. Antiviral therapy in non-responders, relapsers and special populations......................................................................................43 How to manage genotype 1 non-responders and relapsers ? .................................................................................................43 Therapy selection: monitoring vs. retreatment.............43 10 | Therapeutical strategies...................................................45 Practical approach to retreatment..................................49 How to manage genotype 2 and 3 non-responders and relapsers ?..............................................................................50 Nonresponders/relapsers infected with HCV G2/3.......50 Retreatment of HCV genotype 2 and 3 patients.............51 Special categories of patients...............................................52 Injecting drug users (IDUs)..............................................52 Hemodialysis patients......................................................53 Patients with psychiatric comorbidities.........................54 Patients with inherited anemias......................................54 African Americans............................................................55 HIV-HCV coinfection........................................................55 Outlook...................................................................................57 Links........................................................................................57 4. Searching for new antiviral therapies.....................................58 Candidates for new therapeutic approaches.......................58 New IFN formulations...........................................................59 Alternative RBV formulation................................................64 Direct-Acting Antivirals (DAAs)...........................................65 Protease inhibitors (PIs)...................................................65 Triple therapy...................................................................66 Other investigational HCV PIs.........................................69 HCV polymerase inhibitors..............................................70 NS5A inhibitors.................................................................72 Host cyclophilins inhibitors.............................................73 Emergence of drug resistant mutations..........................73 What does the future hold?..................................................74 Outlook...................................................................................76 Links........................................................................................77