General
Around 170 million throughout the world people have been infected with hepatitis C. The lowest prevalences are found in Western Europe and North America (1%), and it is thought to be very low in the Netherlands (<0.5%). Prevalences in high-risk groups such as (ex-) drug addicts and haemophilia patients may be up to 25-60%.

The disease usually has a mild course and most of the afflicted persons are not even aware of it. About 20% of them show liver cirrhosis 10-20 years after the infection, after which the risk of development of hepatocellular carcinoma has strongly increased. The rate of progression is highly dependent on individual patient characteristics such as age at the time of infection, alcohol use, obesity, and the presence of other infections such as HBV en HIV. Since the discovery of the hepatitis C virus in 1989, therapy potentials have strongly improved. Present-day treatment consists of weekly subcutaneous injections pegylated interferon (peginterferon-alpha) and daily ribavirin tablets. Dependent on the genotype, treatment will last 24 weeks (genotype 2 or 3) or 48 weeks (genotype 1 or 4). Reaction of the hepatitis C virus is monitored during treatment: the treatment period may be shortened in case of a favourable response, whereas delayed response may necessitate longer treatment. The primary endpoint of treatment is achieving a sustained virological response (SVR). This is the situation in which the virus is no longer found in blood 24 weeks after discontinuation of treatment. The risk of virus recurrence is almost nil by then, so SVR can be taken to indicate cure. For patients with genotype 2 or 3 the chance of achieving SVR is about 80%; for those with genotype 1 or 4 patients it is considerably lower, i.e. some 50%. This treatment has a major disadvantage, however, in terms of the many adverse side effects; notably flu-like symptoms, emotional distress and abnormal blood counts.

The clinical scientific research in our department has a focus on improving the current peginterferon-ribavirin therapy. Furthermore, efforts are directed at assessing novel antiviral drugs that perhaps may raise the proportion of successful treatments in the next years. At present there is not yet a vaccine against hepatitis C.

Recently completed studies
Prophylactic treatment of peginterferon-associated psychopathology. A double-blind placebo-controlled trial on the effects of esciatalopram (Lexapro®) in patients with peginterferon and ribavirin (POPS-study).
Significant side-effects that may occur during treatment with peginterferon and ribavirin are psychic complaints including depressive state, anxiety, disturbed concentration and aggression. This study in 80 patients investigated the effect of an antidepressant (escitalopram) or placebo on the development of these complaints as well as the effect on quality of life during standard treatment with peginterferon and ribavirin.

Assessment of the safety, tolerability, pharmacokinetics and pharmacodynamics of SCH 900518 in naïve or treatment-experienced subjects infected with hepatitis C virus genotype 1.
This phase 1 study was done to assess safety and effectiveness of a new drug (a protease inhibitor) that specifically inhibits the activity of a certain viral protein, thus inhibiting multiplication of the hepatitis C virus. A total of 40 patients with genotype 1 were enrolled in this study (published: Hepatology 2010).

Influence of ribavirin and interferon on semen quality (IRIS-study).
Patients treated with (peg)interferon and ribavirin are advised to take strict contraceptive measures during treatment and 6 months thereafter, as harmful effects on the foetus were shown in animal experiments. In order to gain more insight on the effect on semen cells in humans, 20 men on treatment with peginterferon and ribavirin are asked to donate semen samples and extra blood. The validation of elastographic measurement of hepatic fibrosis in chronic viral hepatitis: a comparison between liver biopsy and FibroScanCurrently the extent of liver damage can be diagnosed by doing a liver biopsy. Recently a new machine has become available, the FibroScan, which uses ultrasound to measure liver damage. This study aims at assessing the reliability of the FibroScan in all patients undergoing a liver biopsy.

A phase 1, randomized, double-blind, placebo-controlled, ascending dose study evaluating the safety, tolerability and pharmacokinetics and antiviral activity of JTK-652 administered for four weeks in subjects with chronic hepatitis C infection (JTK-study).
This study evaluates a new antiviral drug, a so-called receptor entry inhibitor, in 20 patients with genotype 1. Inclusion criteria are: no previous treatment with peginterferon and ribavirin, or 6 months elapsed since previous treatment was stopped. The total treatment period is 4 weeks, and patients need to be hospitalized for the first 2 weeks (published: Antiviral Therapy 2010).

Eltrombopag to initiate and maintain interferon antiviral treatment to benefit subjects with hepatitis C related liver disease (ENABLE-study).
Study for hepatitis C patients with any of the genotypes who were never treated with peginterferon and ribavirin and who show an abnormally small number of platelets in the circulating blood. This small number is often observed in cases of severe liver damage liver damage (cirrhosis), so that peginterferon-ribavirin treatment usually cannot be started. In the first instance patients will be given a new drug (eltrombopag) to raise the number of platelets. If this is successful, treatment with standard doses of peginterferon and ribavirin will be started. The study is also open to patients whose previous treatment with peginterferon and ribavirin was unsuccessful because the small number of platelets necessitated low doses.

Subcutaneous continuous infusion of interferon alpha-2b and ribavirin in hepatitis C genotype 1 and 4 nonresponders (SCIN-C study).
This study is in patients with genotype 1 or 4 who previously did not respond to antiviral treatment with (peg)interferon en ribavirin. We intend to include 30 patients. They will receive interferon continuously using a portable mini-pump. This strategy is aimed at continuous suppression of the virus, which possibly could lead to a sustained virological response indeed. Furthermore, we expect that continuous administration will have less severe side effects. Patients will be given ribavirin as well.

Impact of immune responses in chronic hepatitis C genotype 1 virus infected patients during treatment with pegylated interferon alpha-2b and ribavirin (CIRES-study).
This study is in patients chronically infected with hepatitis C genotype 1, 2 or 3 who have never been treated before. They will receive the best therapy available at the moment, i.e. peginterferon combined with ribavirin. The way in which this therapy influences the immune system will be assessed in detail. As hepatitis C mainly affects the liver, we will not only study the immune system in the blood, but also in the liver. Patients are requested therefore to come to the hospital several times for the taking of blood and liver samples. Liver cells will be drawn from the liver using a very fine needle, the so-called ‘fine needle aspiration biopsy' (FNAB). This FNAB procedure should not be confused with the standard liver biopsy in which a relatively larger part of the liver is obtained. Thus, the FNAB procedure is very much less burdensome to the patient. By gaining better understanding of the mechanism underlying this therapy we might eventually improve it (published: Journal of Virology 2011).

Current studies
High-dose versus standard-dose weight-based ribavirin in combination with peginterferon alpha-2a for patients infected with hepatitis C virus genotype 1 or 4 (VIRID-study).
Started in April 2008, this study compares a double dose of ribavirin to the standard dose given. Patients will receive peginterferon in addition. Administration of EPO (erythropoietin) serves to prevent anaemia (mainly on account of ribavirin). Subjects are patients with HCV genotype 1 or 4 whose virus load exceeds 400.000 IU/mL, as standard treatment is known to be less successful in these patients. Ribavirin dosing is studied because there is some evidence that higher doses of ribavirin could help to raise the treatment success rate. As the study is nationwide, patients living outside the Rotterdam region can be included as well in nearby hospitals. Website www.virid.nl provides full information, both for health professionals and patients.

Active Testing!
The Rotterdam-Rijnmond municipal health service (GGD) has initiated a project in which some 850 drug addicts and homeless people with stable condition will be tested for hepatitis C (and hepatitis B and HIV as well). If tested positive, they will be counselled in Erasmus MC on severity of the disease and treatment options. Persons for whom treatment is clearly indicated will receive the standard treatment, while the GGD will provide additional social support.

Study on micro-RNA inhibition in the treatment of HCV: placebo-controlled study of an microRNA-122 inhibitor in naieve patients with genotype 1 hepatitis C virus infection.
Micro-RNA inhibitors are a new class of medicines, which are able to regulate gene-expression. The primary objective of this phase-1 study is to investigate the efficacy of a micro-RNA 122 inhibitor on the reduction in HCV-RNA, and on the safety and tolerability. When proven effective and safe, microRNA-122 inhibition might be an important step towards interferon-free therapeutic regimens in hepatitis C.