Evolving drug therapies for chronic hepatitis C Immunomodulation and beyond Jilling Bergmann stellingen // PROEfSCHRIfT Stellingen behorende bij het proefschrift Evolving drug therapies for chronic hepatitis C Immunomodulation and beyond Jilling Bergmann, 23 november 2011 1 Behandeling met een hoge dosis peginterferon alfa in HCV geïnfecteerde patiënten is over het algemeen veilig maar leidt niet tot verbetering van de behandeluitkomst in vergelijking met de standaard dosis peginterferon. (dit proefschrift) 2 Continue subcutane toediening van standaard interferon alfa in combinatie met ribavirine kan leiden tot een blijvende virologische repons in eerdere peginterferon non-responders. (dit proefschrift) 3 Endogene inductie van interferon alfa na toediening van een orale toll-like receptor agonist kan leiden tot een significante HCV RNA daling. (dit proefschrift) 4 Behandeling met narlaprevir (een NS3 proteaseremmer) gedurende 7 dagen leidt tot een meer dan 4 log10 HCV RNA daling in zowel naïeve patiënten als eerdere non-responders. (dit proefschrift) 5 Toevoeging van ritonavir leidt tot een verbetering van het farmacokinetisch profiel van narlaprevir door remming van cytochroom P450-3A4 waardoor tweemaal daags doseringen mogelijk zijn in plaats van driemaal daags. (dit proefschrift) 6 Over 10 jaar is chronische hepatitis C mogelijk een zeldzame aandoening in de Westerse wereld mits we bereid zijn om ruwweg x 75.000,- voor een antivirale behandeling neer te tellen. 7 Wetenschap lost nooit problemen op zonder 10 nieuwe problemen te creëren. (George Bernard Shaw) 8 Niemand heeft bezwaar tegen evidence-based medische richtlijnen zolang er maar te allen tijde van afgeweken kan worden. 9 De mens gebruikt de eerste helft van zijn leven om zijn gezondheid te ruïneren, terwijl hij de tweede helft op zoek gaat naar genezing. (Leonardo da Vinci) 10 Het beste argument tegen democratie is een conversatie van vijf minuten met een gemiddelde stemgerechtigde. (Winston Churchill) 11 Ik weet niets van muziek, in mijn vakgebied is dat ook niet nodig. (Elvis Presley) Later in the evenin’ As you lie awake in bed With the echoes from the amplifiers Ringin’ in your head You smoke the day’s last cigarette Rememberin’ what she said Here I am, on the road again There I am, up on the stage Here I go, playin’ star again There I go, turn the page (Turn the page, Bob Seger, 1972) Voor Francesca, Sara en Maurits Evolving drug therapies for chronic hepatitis C Immunomodulation and beyond Jilling Bergmann Colofon © 2011 Jilling Bergmann, the Netherlands ISBN 978-90-818186-0-5 Graphic design studio Tineke Wieringa bno, Haren Printing Het Grafisch Huis, Groningen Financial support for design and printing was kindly given by the Department of Gastroenterology and Hepatology of the Erasmus University Medical Center Rotterdam, Erasmus University Rotterdam, Nederlandse Vereniging voor Hepatologie, PRA International, Gilead, MSD, Janssen-Cilag, Roche, Zambon, Ferring, Vifor, Tramedico, Abbott, Glaxosmithkline and studio Tineke Wieringa. All rights reserved. No part of this thesis may be reproduced or transmitted in any for or by any means, without prior written submission of the author. The work presented in this thesis was conducted at the Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands. Evolving drug therapies for chronic hepatitis C Immunomodulation and beyond Therapeutische ontwikkelingen voor chronische hepatitis C Immunomodulatie en meer Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. H.G. Schmidt en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 23 november 2011 om 13.30 uur door Jilling Frederik Bergmann geboren te Groningen Promotiecommissie Promotor Prof.dr. H.L.A. Janssen Overige leden Prof.dr. C.A.B. Boucher Prof.dr. M. Peppelenbosch Dr. H.W. Reesink Copromotor Dr. R.J. de Knegt ConTEnTS // 7 Contents Chapter 1 8 General introduction Chapter 2 16 What is on the horizon for treatment of chronic hepatitis C? Chapter 3 34 Gamma-glutamyltransferase and rapid virological response as predictors of successful treatment with experimental or standard peginterferon alfa-2b in chronic hepatitis C non-responders Chapter 4 48 Continuous interferon alfa-2b infusion in combination with ribavirin for chronic hepatitis C in treatment-experienced patients Chapter 5 63 Viral kinetics and immune activation during continuous subcutaneous administration of high-dose interferon alfa-2b in treatment-experienced chronic hepatitis C patients Chapter 6 76 Randomized clinical trial: anti-viral activity of ANA773, an oral inducer of endogenous interferons acting via TLR7, in chronic HCV Chapter 7 92 Potent immune activation in chronic hepatitis C patients upon administration of an oral inducer of endogenous interferons that acts via TLR7 Chapter 8 106 Safety and antiviral activity of JTK-652: a novel HCV infection inhibitor Chapter 9 120 Antiviral activity of narlaprevir combined with ritonavir and pegylated interferon in chronic hepatitis C patients Summary and discussion 136 Samenvatting en discussie 144 List of publications 153 PhD portfolio summary 154 Dankwoord 156 Curriculum Vitae 159 Chapter 1 General introduction GEnERal inTRoduction // 9 Introduction Chronic hepatitis C infection is a major health problem and a leading cause of chronic liver disease. The hepatitis C virus was discovered in 1989 (1, 2). The virus is a small, enveloped, single-stranded, positive sense Rna virus and is a member of the hepacivirus genus in the family Flaviridae (3). Six major genotypes have been identified with several subtypes within each genotype (4). Viral replication occurs predominantly within hepatocytes in the liver but there is some evidence that it might also replicate outside the liver, in peripheral blood mononuclear cells, in lymphoid cells and in neurons (5, 6). Chronic hepatitis C infection can cause cirrhosis, digestive hemorrhage, liver failure and liver cancer. Transmission of the hepatitis C virus (HCV) is mainly related to parenteral contact with blood and blood products. Blood transfusions and the use of shared, nonsterilized needles and syringes have been the main causes of the spread of HCV. after the introduction of routine blood screening for HCV antibody (1992 in most countries), transfusion-related hepatitis C virtually disappeared (7, 8). at present in the developed world, injection drug use is the most common risk factor. Body piercing, tattoos and sharing tooth brushes or razors with an infected person have also been described as risk factors for transmission (9, 10). High-risk sexual behavior of HiV-infected gay men might be a risk factor as well, whereas sexual transmission of HCV between monogamous partners is uncommon (11, 12). There is a small risk of transmission during delivery of a child from an infected mother (13). an estimated 180 million people worldwide are infected with hepatitis C (14). The prevalence of chronic hepatitis C in Europe and north america is 1.0 to 1.7 percent. The prevalence is higher in Southern Europe, in asia and in Egypt. in the netherlands approximately 0.1 to 0.4% of the population is chronically infected (15). Hepatitis C is most prevalent among hemophiliacs who received plasma derived clotting factor concentrates before 1987 (after which time viral inactivation procedures were implemented), among intravenous drug users and among prison inmates (16). acute HCV infection is often subclinical and only 20-40% of the patients experience symptoms such as jaundice, nausea, abdominal pain or general unwellness (17). acute icteric patients are more likely to spontaneously clear the infection than patients with a subclinical infection (18). The virus persists in 60-85% of infected patients, leading to chronic inflammation of the liver. During the early phase of chronic infection, patients are often asymptomatic or experience aspecific symptoms such as fa- tigue. it may take years or even decades before patients discover that they have chronic hepatitis C infection. Patients may be identified when routine blood tests show elevated liver enzyme values or if there are known risk factors. a small proportion of infected patients (1-2%) develop extrahepatic manifestations of hepatitis C, such as porphyria cutanea tarda, glomerulonephritis, or vasculitis due to cryoglobulinemia (19, 20). Chronic hepatitis C leads to slow but progressive increasing degrees of fibrosis (21). Fibrosis is the de- leterious but variable consequence of chronic inflammation. it is characterized by the deposition of an extracellular matrix component, leading to the distortion of the hepatic architecture with impairment of liver microcirculation and liver cell functions. Usually, HCV infection is lethal only when it leads to cirrhosis, the last stage of liver fibrosis. The rate of fibrosis progression is affected by some host-related characteristics such as the duration of the infection, alcohol abuse and factors like co-infection with hepatitis B virus (HBV) or HiV. Shortly after the discovery of the hepatitis C virus, interferon alfa was approved as anti-HCV treatment. although the mechanism of action of interferon has not been fully clarified, it has been shown that interferon has both a direct antiviral effect as well as important interactions with the adaptive and 10 // GEnERal inTRoduction innate immune reponses (22). Clearance of hepatitis C virus is associated