Hepatitis C

by

Benjamin Maasoumy, Markus Cornberg

• LAST REVIEWED: 14 October 2016
• LAST MODIFIED: 28 October 2014
• DOI: 10.1093/obo/9780199756797-0142

Introduction

The hepatitis C virus (HCV) is an uncoated, single-stranded, positive-sense ribonucleic acid (RNA) virus that belongs to the group of Flaviviridae. HCV infection is transmitted between humans mainly via direct blood contact. Therefore, intravenous drug users belong to a high-risk population. Before identification in the late 1980s and the subsequent routine testing of blood products, blood transfusions were an import route of transmission. Here, the introduction of assays to detect antibodies to hepatitis C virus (anti-HCV assays) was a milestone in the prevention of new infections. In the early 21st century more than 185 million people worldwide have been exposed to HCV. Acute HCV infection may be associated with nonspecific symptoms, such as fatigue or abdominal discomfort, while only 20 percent of patients develop jaundice. Fulminant hepatitis C is a rare event. However, the majority of patients remain asymptomatic and thus may not be diagnosed during the acute phase. HCV infection is a self-limited disease in only 10–50 percent of patients, whereas more than half develop chronic infection. Chronic HCV infection is a major reason for the increasing incidence of liver cirrhosis and hepatocellular carcinoma (HCC) in most Western countries. Approximately 15–50 percent of patients with chronic hepatitis C develop liver cirrhosis at some point, approximately 16 percent within twenty years. The progression rate depends on cofactors, such as obesity, older age, alcohol, and coinfections. As soon as HCV-related fibrosis progresses to cirrhosis, the risk of HCC increases to approximately 2–4 percent per year. Successful eradication of the virus through sufficient antiviral treatment can prevent many of these cases and significantly improves the liver-related outcome as well as all-cause mortality. In the acute phase of the infection, monotherapy with pegylated-interferon alfa (Peg-IFN alfa) leads to a sustained virological response (SVR) in up to 90 percent. In chronic HCV infection a dual combination consisting of Peg-IFN alfa and the nucleoside ribavirin (RBV) has been the standard of care in the early 21st century for a long time. Whereas approximately 70 percent of patients infected with genotype 2 or 3 achieve SVR, this regimen cures less than half of patients with genotype 1. In 2011 the protease inhibitors (PIs) boceprevir (BOC) and telaprevir (TLV) were approved for treatment of chronic HCV genotype 1 infection and lead to a significant increase of SVR rates (up to 88 percent under optimal conditions). Still, treatment remained challenging in previous Peg-IFN/RBV null responders, in particular those with liver cirrhosis, in which SVR rates do not exceed 15 percent. In addition, both drugs are accompanied by significant side effects. Both PIs belong to a generation of HCV-specific compounds, so-called direct-acting antivirals (DAA). More recently, a second wave of DAAs has been approved, including the macrocyclic PI simeprevir (SMV) and the NS5B polymerase inhibitor sofosbuvir (SOF). The approval of SOF allowed patients to be treated without IFN for the first time. SOF/RBV dual therapy is highly effective in the majority of genotype 2 and many genotype 3 patients. Several other DAAs are close to coming on the market. Published studies suggest that through a combination of different DAAs belonging to different DAA classes, highly effective IFN-free regimens may become possible for all known HCV genotypes, with cure rates exceeding 90 percent. This article contains a selection of reviews, textbooks, and original papers concerning a variety of hepatitis C, including HCV epidemiology, diagnosis, the natural history, and current and future treatment options in the early 21st century as well as efforts to generate an efficient HCV vaccine.

General Overviews

The selected citations all provide an overview of hepatitis C. European Association for the Study of the Liver 2014 and Ghany, et al. 2009 contain expert recommendations for the optimal management of the disease. They are very useful not only as a guide in clinical practice, but also as an introduction to the field of hepatitis C. The guidelines’ sponsoring organizations (the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases, respectively) decided to offer frequent online updates on this rapidly changing field. Both texts are the result of systematic review by the leading experts in the field and may be considered reference works. Janssen and Craxi 2012, a collection of important reviews, also puts forward a very practical approach to specific aspects of the field. Mauss, et al. 2014 covers the whole range of topics and is updated yearly. A shorter but still very comprehensive source is Tillmann and McHutchison 2012, which includes plenty of helpful figures and tables.

• European Association for the Study of the Liver. 2014. EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. Journal of Hepatology 60.2: 392–420.

  DOI: 10.1016/j.jhep.2013.11.003Save Citation »Export Citation » Share Citation »

  NNNThis is a well-structured, practical guide for the management of HCV patients. The key publications related to HCV have been considered for this publication. Recommendations for treatment with some newer direct-acting antivirals (DAAs) are not yet included but available in the updated online version of the recommendations.

  Find this resource:

• Ghany, M. G., D. B. Strader, D. L. Thomas, and L. B. Seeff. 2009. Diagnosis, management, and treatment of hepatitis C: An update. Hepatology 49.4: 1335–1374.

  DOI: 10.1002/hep.22759Save Citation »Export Citation » Share Citation »

  NNNThis state-of-the-art guide by the American Association for the Study of Liver Diseases gives recommendations for management of the disease. Although somewhat outdated, an update is available online covering the usage of direct-acting antivirals (DAA).

  Find this resource:

• Janssen, H., and A. Craxi, eds. 2012. Special issue: Chronic hepatitis C: Diagnosis and treatment. Best Practice and Research Clinical Gastroenterology 26.4: 369–548.

  Save Citation »Export Citation » Share Citation »

  NNNThis issue contains fourteen reviews concerning the epidemiology, natural history, diagnosis, and treatment of chronic hepatitis C. At the end of each review, the most important practical implications are summarized as bullet points.

  Find this resource:

• Mauss, S., T. Berg, J. Rockstroh, C. Sarrazin, and H. Wedemeyer, eds. 2014. 2014 Flying Publisher short guide to hepatitis C. Flying Publisher.

  Save Citation »Export Citation » Share Citation »

  NNNA German project, written by several experts in the field of viral hepatitis, this comprehensive guide covers the whole field of hepatitis C. Includes chapters on future treatment of DAAs. The section on management of chronic hepatitis C is evidence based and reflects current guidelines. Updated yearly.

  Find this resource:

• Tillmann, H. L., and J. G. McHutchison. 2012. Hepatitis C. In Zakim and Boyer`s hepatology: A textbook of liver disease. Edited by T. D. Boyer, M. P. Manns, and A. J. Sanyal, 564–604. Philadelphia: Saunders/Elsevier.

  Save Citation »Export Citation » Share Citation »

  NNNAn outstanding book chapter that gives a comprehensive overview of HCV. Has a very useful table with suggestions for the management of side effects of interferon (IFN) treatment and a nice figure with recommendations for patient monitoring during treatment.

  Find this resource:

Epidemiology

This section includes a selection of review articles that focus on hepatitis C virus (HCV) epidemiology. Bruggmann, et al. 2014 gives a description of HCV prevalence in selected countries at certain points in time since the mid-1990s. In contrast, Razavi, et al. 2014 presents a view of the future prevalence of the disease. Mohd Hanafiah, et al. 2013 describes changes in antibody to HCV (anti-HCV) prevalence worldwide between 1990 and 2005 which may reflect HCV exposure. Lavanchy 2011 also offers an overview of worldwide prevalence, including local data from several countries. Shepard, et al. 2005 is a state-of-the-art review that also comprehensively analyzes the different routes of viral transmission. Two works mainly look at HCV epidemiology in Europe. Cornberg, et al. 2011 is a compilation of short summaries of local HCV epidemiology in several European countries, whereas Esteban, et al. 2008 particularly concerns changes in the impact of different routes of viral transmission on HCV epidemiology in Europe.

• Bruggmann, P., T. Berg, A. L. Ovrehus, et al. 2014. Historical epidemiology of hepatitis C virus (HCV) in selected countries. Journal of Viral Hepatitis 21, suppl. 1: 5–33.

  DOI: 10.1111/jvh.12247Save Citation »Export Citation » Share Citation »

  NNNThis study was a large international collaboration to determine the epidemiology of HCV infection in sixteen different countries at certain points in time points since the mid-1990s. Different sources were used, including studies as well as national surveys. The authors provide valuable information on the overall rate of HCV-infected individuals, the number of new infections, and treatment uptake.

  Find this resource:

• Cornberg, M., H. A. Razavi, A. Alberti, et al. 2011. A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel. Liver International 31, suppl. 2: 30–60.

  DOI: 10.1111/j.1478-3231.2011.02539.xSave Citation »Export Citation » Share Citation »

  NNNIn this systematic review the authors consider the epidemiology of HCV in Europe, Canada, and Israel. The authors furnish a brief overview of HCV epidemiology in several countries, including country-specific risk factors for infection, prevalence data, number of newly diagnosed cases, proportion of diagnosed HCV cased within the infected population, and local HCV genotype distributions.

  Find this resource:

• Esteban, J. I., S. Sauleda, and J. Quer. 2008. The changing epidemiology of hepatitis C virus infection in Europe. Journal of Hepatology 48.1: 148–162.

  DOI: 10.1016/j.jhep.2007.07.033Save Citation »Export Citation » Share Citation »

  NNNThis review concerns HCV epidemiology in Europe, with a special emphasis on viral transmission routes. The authors nicely summarize how factors including improvement of health-care settings shifted the main transmission routes to intravenous drug users, which subsequently influenced HCV genotype distribution.

  Find this resource:

• Lavanchy, D. 2011. Evolving epidemiology of hepatitis C virus. Clinical Microbiology and Infection 17.2: 107–115.

  DOI: 10.1111/j.1469-0691.2010.03432.xSave Citation »Export Citation » Share Citation »

  NNNThis is a short review concerning the global prevalence of chronic HCV infection. Has a very useful map showing HCV prevalence in different parts of the world and contains prevalence data for many single countries.

  Find this resource:

• Mohd Hanafiah, K., J. Groeger, A. D. Flaxman, and S. T. Wiersma. 2013. Global epidemiology of hepatitis C virus infection: New estimates of age-specific antibody to HCV seroprevalence. Hepatology 57.4: 1333–1342.

  DOI: 10.1002/hep.26141Save Citation »Export Citation » Share Citation »

  NNNA systematic review of studies assessing anti-HCV prevalence. In their analysis the authors demonstrate that HCV prevalence increased between 1990 and 2005, to more than 185 million people worldwide. Includes an excellent table highlighting anti-HCV prevalence in different regions of the world and figures illustrating the respective local increases in the anti-HCV-positive population.

  Find this resource:

• Razavi, H., I. Waked, C. Sarrazin, et al. 2014. The present and future disease burden of hepatitis C virus (HCV) infection with today’s treatment paradigm. Journal of Viral Hepatitis 21, suppl. 1: 34–59.

  DOI: 10.1111/jvh.12248Save Citation »Export Citation » Share Citation »

  NNNThis is an excellent article that calculates the current and future distribution of HCV-related liver fibrosis in selected countries. The authors created a model in order to predict the prevalence up until 2030 of HCV-associated liver cirrhosis, hepatic decompensations, and hepatocellular carcinoma (HCC), which are visualized in very nice figures.

  Find this resource:

• Shepard, C. W., L. Finelli, and M. J. Alter. 2005. Global epidemiology of hepatitis C virus infection. Lancet Infectious Diseases 5.9: 558–567.

  DOI: 10.1016/S1473-3099(05)70216-4Save Citation »Export Citation » Share Citation »

  NNNThis review not only concentrates on HCV prevalence, but also discusses the impact of and changes in different routes of viral transmission.

  Find this resource:

Natural History

A comprehensive knowledge of the natural history of hepatitis C allows understanding of the health burden as well as the urgent need for global screening and therapeutic concepts. The natural course of the infection shows a huge diversity, depending on different risk factors and study design. The following sections contain a collection of general overview articles, a selection of papers mainly considering the risk of liver cirrhosis with chronic hepatitis C virus (HCV) infection, articles concerning the outcome of patients who experienced HCV-related cirrhosis, and, finally, a compilation of manuscripts analyzing the issue of hepatocellular carcinoma (HCC) and its association with HCV infection. The natural history of hepatitis has been reviewed several times, with Leonard Seef writing some of the best reviews. He generally concentrates on the outcome of the disease as well as the characteristics of and controversial data from the different types of studies. A strong suit of his articles is the nice discussion of the problems that exist in this research field. Seeff 1997, in Hepatology, is a reference work, whereas Seeff 2009 provides an update. The two remaining articles offer overviews of HCV. The older review, Hoofnagle 1997, includes very helpful figures that illustrate the course of various serological markers and the onset of symptoms. This article is very useful as a first source, as it is a short and well-structured overview. Maasoumy and Wedemeyer 2012 is a more recent work on the natural history that also discusses the role of genetic markers in the disease and risk factors for the development of HCC.

• Hoofnagle, J. H. 1997. Hepatitis C: The clinical spectrum of disease. Hepatology 26.3, suppl. 1: 15S–20S.

  DOI: 10.1002/hep.510260703Save Citation »Export Citation » Share Citation »

  NNNThe whole spectrum of the disease is reviewed, including acute infection, serological markers, liver-related as well as extrahepatic symptoms, and outcome.

  Find this resource:

• Maasoumy, B., and H. Wedemeyer. 2012. Natural history of acute and chronic hepatitis C. Best Practice and Research Clinical Gastroenterology 26.4: 401–412.

  DOI: 10.1016/j.bpg.2012.09.009Save Citation »Export Citation » Share Citation »

  NNNThis review of the natural history of acute and chronic hepatitis C gives a brief but comprehensive summary of the topic. Details risk factors for chronicity as well as the development of liver fibrosis and cirrhosis, with a balanced discussion of the controversial studies that have been published over the years.

  Find this resource:

• Seeff, L. B. 1997. Natural history of hepatitis C. Hepatology 26.3, suppl. 1: 21S–28S.

  DOI: 10.1002/hep.510260704Save Citation »Export Citation » Share Citation »

  NNNThis reference work concentrates on the outcome of the disease. Seef not only reviews the most important works up until that time, but also nicely describes the difficulties in investigating the natural history of hepatitis C. Different study designs and possible explanations for the different results observed are also considered.

  Find this resource:

• Seeff, L. B. 2009. The history of the “natural history” of hepatitis C (1968–2009). Liver International 29, suppl. 1: 89–99.

  DOI: 10.1111/j.1478-3231.2008.01927.xSave Citation »Export Citation » Share Citation »

  NNNUpdates Seeff 1997. Includes nice figures as well as comprehensive tables.

  Find this resource:

Extrahepatic Manifestations

Hepatitis C virus (HCV) can cause a wide variety of extrahepatic manifestations (EHMs), which include rheumatological, neurological, nephrological, and dermatological symptoms. Sometimes, extrahepatic symptoms may even be the dominant clinical problem. The EHMs with the closest link to HCV are lymphoproliferative disorders, in particular mixed cryoglobulinemia (MC). For many other EHMs a causal relation is less clear. The following sections present some general overviews of EHMs in HCV infection, a selection of articles concerning MC, and, finally, works covering EHMs other than MC. Zignego, et al. 2007 may be considered the major reference work in the field. It is very comprehensive and provides a helpful system for classifying suspected EHMs. Sene, et al. 2004 is also well written and a comprehensive source. For a brief overview, Manns and Rambusch 1999 may be more suitable. El-Serag, et al. 2002 is a landmark study analyzing a huge cohort of US male veterans. This work offers strong epidemiological evidence for several disorders’ being an EHM of HCV infection. Cacoub, et al. 1999 analyzes not only EHMs, but also extrahepatic symptoms. The findings of this study are important, as they help advance understanding of the clinical presentation of chronic hepatitis C.

• Cacoub, P., T. Poynard, P. Ghillani, et al. 1999. Extrahepatic manifestations of chronic hepatitis C. Arthritis and Rheumatology 42.10: 2204–2212.

  DOI: 10.1002/1529-0131(199910)42:10%3C2204::AID-ANR24%3E3.0.CO;2-DSave Citation »Export Citation » Share Citation »

  NNNThis article analyzes the frequency of EHMs and extrahepatic symptoms of chronic hepatitis C in a cohort of more than fifteen hundred patients. The authors also identify risk factors for the development of extrahepatic symptoms, including the stage of liver disease.

  Find this resource:

• Manns, M. P., and E. G. Rambusch. 1999. Autoimmunity and extrahepatic manifestations in hepatitis C virus infection. Journal of Hepatology 31, suppl. 1: 39–42.

  DOI: 10.1016/S0168-8278(99)80372-9Save Citation »Export Citation » Share Citation »

  NNNThis is a shorter review and, as such, gives a brief overview of EHMs. Besides describing several EHMs of HCV infection, the authors place a special emphasis on autoimmunity and autoantibodies.

  Find this resource:

• Sene, D., N. Limal, and P. Cacoub. 2004. Hepatitis C virus–associated extrahepatic manifestations: A review. Metabolic Brain Disease 19.3–4: 357–381.

  DOI: 10.1023/B:MEBR.0000043982.17294.9bSave Citation »Export Citation » Share Citation »

  NNNA well-written and comprehensive summary of the topic. EHMs are divided into two categories: those with a high certainty for an association with HCV infection and those with a low certainty.

  Find this resource:

• El-Serag, H. B., H. Hampel, C. Yeh, and L. Rabeneck. 2002. Extrahepatic manifestations of hepatitis C among United States male veterans. Hepatology 36.6: 1439–1445.

  DOI: 10.1053/jhep.2002.37191Save Citation »Export Citation » Share Citation »

  NNNThis is an epidemiological study on a large cohort of US male veterans. The prevalence several disorders was compared in HCV-infected versus noninfected individuals. Disorders found to be associated with HCV infection were membranoproliferative glomerulonephritis, porphyria cutanea tarda, lichen planus, vitiligo, cryoglobulinemia, and non-Hodgkin’s lymphoma.

  Find this resource:

• Zignego, A. L., C. Ferri, S. A. Pileri, P. Caini, and F. B. Bianchi. 2007. Extrahepatic manifestations of Hepatitis C Virus infection: A general overview and guidelines for a clinical approach. Digestive and Liver Disease 39.1: 2–17.

  DOI: 10.1016/j.dld.2006.06.008Save Citation »Export Citation » Share Citation »

  NNNThis older review article is still the major reference work for EHMs of hepatitis C. The article covers the spectrum of EHMs that have been reported in HCV patients. Zignego and colleagues established four categories, according to strength of evidence for an association with HCV infection. Category A only includes diseases with strong epidemiological as well as pathological evidence.

  Find this resource:

Historical Breakthroughs for the Development of Antiviral Therapies

There have been several important breakthroughs in the history of hepatitis C virus (HCV) research that allowed the development of effective therapies. This section includes a selection of some of these key advances. In the 1970s posttransfusion hepatitis, despite the absence of hepatitis A or B, was a frequent clinical problem. Qui-Lim Choo and colleagues finally ended the intensive search for the hidden infectious particle that causes the so-called non-A/non-B hepatitis by discovering HCV (Choo, et al. 1990). Interestingly, a couple of years earlier Hoofnagle, et al. 1986 reports normalization of transaminases in patients with non-A/non-B hepatitis after treatment with interferon alfa (IFN alfa), which was the start of the development of IFN-based treatments. The authors of Reichard, et al. 1991 were the first to document similar effects during treatment with ribavirin (RBV). Brillanti, et al. 1994 demonstrates that treatment efficacy can be improved with IFN/RBV dual therapy. Finally, Lamarre, et al. 2003 reports the first direct-acting antiviral (DAA) agent, an NS3 protease inhibitor (PI), tested in humans. The development of DAAs would have been impossible without reliable in vitro HCV replicon systems; the lack of such a system or of an animal model was an important hurdle. Here, Lohmann, et al. 1999 contributed an important milestone by establishing the first hepatitis C virus ribonucleic acid (HCV RNA) replicon system in human hepatotoma cells. Blight, et al. 2000 further improved the replicon system by identifying specific mutations within the NS5A gene that increase the replicative ability. Another major milestone was the development of cell culture systems that produced infectious HCV virions, for which Wakita, et al. 2005 is one of the key references.

• Blight, K. J., A. A. Kolykhalov, and C. M. Rice. 2000. Efficient initiation of HCV RNA replication in cell culture. Science 290.5498: 1972–1974.

  DOI: 10.1126/science.290.5498.1972Save Citation »Export Citation » Share Citation »

  NNNThis study helped to ameliorate the HCV replicon system by identifying specific mutations within the NS5A gene that improved the replicative ability. The authors also show, with their cell culture system, that IFN treatment inhibits HCV replication.

  Find this resource:

• Brillanti, S., J. Garson, M. Foli, et al. 1994. A pilot study of combination therapy with ribavirin plus interferon alfa for interferon alfa–resistant chronic hepatitis C. Gastroenterology 107.3: 812–817.

  DOI: 10.1016/0016-5085(94)90131-7Save Citation »Export Citation » Share Citation »

  NNNThis was the first study to investigate an IFN/RBV combination therapy. There was a control arm, in which all twenty patients were treated unsuccessfully with IFN monotherapy. Overall, 40 percent achieved a sustained response in the IFN/RBV arm, whereas none responded after retreatment with IFN monotherapy.

  Find this resource:

• Choo, Q. L., A. J. Weiner, L. R. Overby, G. Kuo, M. Houghton, and D. W. Bradley. 1990. Hepatitis C virus: The major causative agent of viral non-A, non-B hepatitis. British Medical Bulletin 46.2: 423–441.

  Save Citation »Export Citation » Share Citation »

  NNNThis landmark article describes the discovery of HCV and the development of an assay to detect HCV-specific antibodies in order to identify HCV-infected individuals.

  Find this resource:

• Hoofnagle, J. H., K. D. Mullen, D. B. Jones, et al. 1986. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon: A preliminary report. New England Journal of Medicine 315.25: 1575–1578.

  DOI: 10.1056/NEJM198612183152503Save Citation »Export Citation » Share Citation »

  NNNThis was the first study to explore IFN treatment in non-A/non-B hepatitis. Overall, only ten patients were included, of which eight showed a decrease in transaminases after initiation of therapy. Interestingly, the authors documented here the later relapse after treatment cessation.

  Find this resource:

• Lamarre, D., P. C. Anderson, M. Bailey, et al. 2003. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426.6963: 186–189.

  DOI: 10.1038/nature02099Save Citation »Export Citation » Share Citation »

  NNNThis was the first proof-of-concept study to report a working DAA agent against hepatitis C. Oral administration of the investigated NS3 PI BILN 2061 to study participants with chronic HCV infection lead to a decrease in HCV RNA levels.

  Find this resource:

• Lohmann, V., F. Korner, J. Koch, U. Herian, L. Theilmann, and R. Bartenschlager. 1999. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285.5424: 110–113.

  DOI: 10.1126/science.285.5424.110Save Citation »Export Citation » Share Citation »

  NNNA landmark work that established an effective in vitro HCV RNA replicon system. The investigators transfected cloned HCV RNA into human hepatotoma cells, which afterward started to reproduce the full HCV RNA strand as well as viral proteins.

  Find this resource:

• Reichard, O., J. Andersson, R. Schvarcz, and O. Weiland. 1991. Ribavirin treatment for chronic hepatitis C. Lancet 337.8749: 1058–1061.

  DOI: 10.1016/0140-6736(91)91707-2Save Citation »Export Citation » Share Citation »

  NNNIn this pilot trial ten patients with chronic hepatitis C were treated daily with RBV for twelve weeks. Alanine aminotransferase (ALT) values significantly decreased during treatment. However, shortly after treatment, cessation ALT levels relapsed back to levels documented at baseline.

  Find this resource:

• Wakita, T., T. Pietschmann, T. Kato, et al. 2005. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nature Medicine 11.7: 791–796.

  DOI: 10.1038/nm1268Save Citation »Export Citation » Share Citation »

  NNNWakita and colleagues developed a cell culture system that allowed the production of infectious HCV particles. The authors transfected human hepatoma cells (Huh7) with either a full HCV RNA strand or a replication-incompetent mutant. They documented spread of the infection, but only for the full strain. Interestingly, they demonstrate that chimpanzees could be infected with the virus through intravenous injection of medium obtained from the infected cell culture.

  Find this resource:

Impact of Antiviral Treatment

The natural history of hepatitis C virus (HCV) infection has been intensively studied. It seems likely that a viral eradication has a favorable outcome. However, it is absolutely crucial to have clear data on this, as early-21st-century antiviral treatment options are associated with enormous costs as well as a high number of adverse effects. Unfortunately, for quite a long time there was a significant lack of well-performed studies investigating the long-term benefit of sustained virological response (SVR), which equal to viral eradication in the far majority of cases. Bruno, et al. 2007 and Veldt, et al. 2007 are important contributions. Both studies demonstrate the reduced risk of liver-related complications in HCV patients who achieved SVR compared with those who failed to clear the virus. Morgan, et al. 2010 published very important data indicating a decrease in all-cause mortality in SVR patients. Van der Meer, et al. 2012 is possibly the best study looking at this association. In a multicenter study the authors nicely chart the decrease of all-cause mortality, liver-related death, and morbidity (hepatocellular carcinoma [HCC] development) in patients who cleared the virus after an interferon- (IFN-) based treatment. Backus, et al. 2011 also provides valuable data on the impact of SVR on overall survival. However, Deuffic-Burban, et al. 2012 shows that on a population basis, the overall prevalence and, importantly, quality of HCV screening programs have a huge impact on the advantages that can be achieved through improvement of antiviral treatment options. Wedemeyer, et al. 2014 followed a similar approach, but for a greater number of countries and interesting additional end points.

• Backus, L. I., D. B. Boothroyd, B. R. Phillips, P. Belperio, J. Halloran, and L. A. Mole. 2011. A sustained virologic response reduces risk of all-cause mortality in patients with hepatitis C. Clinical Gastroenterology and Hepatology 9.6: 509–516.e1.

  DOI: 10.1016/j.cgh.2011.03.004Save Citation »Export Citation » Share Citation »

  NNNThis study investigated the impact of SVR on all-cause mortality in more than fifteen thousand patients. The data indicate impressively that SVR reduced mortality among patients infected with HCV genotype 1–3 who were being treated using routine medical practice and who had substantial comorbidities. The study also shows that genotype 3 patients without SVR had higher mortality compared with patients with genotype 1 or 2.

  Find this resource:

• Bruno, S., T. Stroffolini, M. Colombo, et al. 2007. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: A retrospective study. Hepatology 45.3: 579–587.

  DOI: 10.1002/hep.21492Save Citation »Export Citation » Share Citation »

  NNNThis is an important study demonstrating that the risk of liver-related complications and death can be reduced through viral clearance in patients with HCV-related liver cirrhosis.

  Find this resource:

• Deuffic-Burban, S., P. Deltenre, M. Buti, et al. 2012. Predicted effects of treatment for HCV infection vary among European countries. Gastroenterology 143.4: 974–985.e14.

  DOI: 10.1053/j.gastro.2012.05.054Save Citation »Export Citation » Share Citation »

  NNNThis study emphasizes the importance of screening for HCV. The authors nicely describe through a mathematical model how advantages of antiviral treatment will transfer into a lower rate of liver cirrhosis. An important finding here is that different European countries benefit differently from improvements in antiviral treatment options, depending on the number of HCV-infected citizens as well as on the quality of HCV screening programs.

  Find this resource:

• Morgan, T. R., M. G. Ghany, H. Y. Kim, et al. 2010. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology 52.3: 833–844.

  DOI: 10.1002/hep.23744Save Citation »Export Citation » Share Citation »

  NNNIlluminates that SVR is associated with lower all-cause mortality and liver-related morbidity in patients with advanced liver fibrosis. Importantly, the authors also observed that even in SVR patients there remains a certain, although significantly decreased, risk of HCC.

  Find this resource:

• van der Meer, A. J., B. J. Veldt, J. J. Feld, et al. 2012. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 308.24: 2584–2593.

  DOI: 10.1001/jama.2012.144878Save Citation »Export Citation » Share Citation »

  NNNThis is the largest study to look at the impact of achieving SVR on all-cause mortality. In this multicenter study the authors found in SVR patients not only a better survival rate, but also a decrease in several other liver-related adverse outcomes. The main factors associated with all-cause-related mortality in patients without SVR were diabetes mellitus, older age, and alcohol, but also genotype 3.

  Find this resource:

• Veldt, B. J., E. J. Heathcote, H. Wedemeyer, et al. 2007. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine 147.10: 677–684.

  DOI: 10.7326/0003-4819-147-10-200711200-00003Save Citation »Export Citation » Share Citation »

  NNNThis is a multicenter, retrospective study that demonstrated a significant reduction in adverse outcomes, defined as death, HCC, or liver failure, if SVR was achieved in patients with advanced liver fibrosis.

  Find this resource:

• Wedemeyer, H., A. S. Duberg, M. Buti, et al. 2014. Strategies to manage hepatitis C virus (HCV) disease burden. Journal of Viral Hepatitis 21, suppl. 1: 60–89.

  DOI: 10.1111/jvh.12249Save Citation »Export Citation » Share Citation »

  NNNA larger, international collaboration in which the authors calculated the future prevalence of HCV infections, HCC, liver cirrhosis, and liver-related death for three different scenarios: (1) no change in antiviral therapy, (2) increased treatment efficacy, (3) increased treatment efficacy and treatment uptake. The interesting results for each individual end point and the different countries are visualized in excellent figures.

  Find this resource:

Treatment of Acute Hepatitis C Virus Infection

More than half of patients with acute hepatitis C virus (HCV) infection fail to clear the virus and develop chronic infection. Several studies show that early interferon (IFN) therapy can prevent chronicity in a significant number of cases. As most patients with acute HCV infection are asymptomatic, recruiting a robust number of patients is often an issue. The first relatively large study to demonstrate the beneficial impact of early IFN therapy was Jaeckel, et al. 2001, a multicenter study conducted by the German Network of Competence on Viral Hepatitis (Hep-Net). Later, other, smaller studies, such as Delwaide, et al. 2004, confirmed these results. Wiegand, et al. 2006 was the second large, German, multicenter acute HCV trial, again by Hep-Net, to illuminate the efficacy of pegylated-interferon (Peg-IFN) in acute HCV and the importance of patient compliance. Wiegand, et al. 2004 determines that SVR24 is a valid marker for the cure of acute HCV infection. De Rosa, et al. 2007 is a smaller but interesting study, as different Peg-IFN dosages and treatment durations are tried. More recently, Deterding, et al. 2013 highlights the results of the third acute HCV study by Hep-Net. This was the first major study to provide valid evidence for the common strategy of delaying antiviral treatment in acute HCV patients until spontaneous clearance of the virus becomes unlikely. Gerlach, et al. 2003 looks at a similar concept in a smaller trial. In the early 21st century, this strategy of delayed treatment is widely recommended, as it helps prevent unnecessary therapy in many patients.

• Delwaide, J., N. Bourgeois, C. Gerard, et al. 2004. Treatment of acute hepatitis C with interferon alpha-2b: Early initiation of treatment is the most effective predictive factor of sustained viral response. Alimentary Pharmacology and Therapeutics 20.1: 15–22.

  DOI: 10.1111/j.1365-2036.2004.02023.xSave Citation »Export Citation » Share Citation »

  NNNA small study indicating that IFN monotherapy may prevent chronicity of HCV infection. Interestingly, a longer duration from the onset of HCV infection to initiation of therapy was associated with higher risk of treatment failure.

  Find this resource:

• De Rosa, F. G., O. Bargiacchi, S. Audagnotto, et al. 2007. Twelve-week treatment of acute hepatitis C virus with pegylated interferon-alpha-2b in injection drug users. Clinical Infectious Diseases 45.5: 583–588.

  DOI: 10.1086/520660Save Citation »Export Citation » Share Citation »

  NNNThis is a small study investigating the efficacy and safety of Peg-IFN therapy in intravenous drug users with acute HCV infection. The authors found that Peg-IFN alfa-2b doses lower than 1.33 micrograms per kilogram may be less successful.

  Find this resource:

• Deterding, K., N. Grüner, P. Buggisch, et al. 2013. Delayed versus immediate treatment for patients with acute hepatitis C: A randomised controlled non-inferiority trial. Lancet Infectious Diseases 13.6: 497–506.

  DOI: 10.1016/S1473-3099(13)70059-8Save Citation »Export Citation » Share Citation »

  NNNThis is the largest randomized trial concerning treatment of acute HCV infection and the first prospectively comparing the strategy of delayed antiviral treatment with immediate therapy. Provides evidence that the delayed strategy helps identify patients who do not require treatment as they appear to be capable of clearing the infection on their own.

  Find this resource:

• Gerlach, J. T., H. M. Diepolder, R. Zachoval, et al. 2003. Acute hepatitis C: High rate of both spontaneous and treatment-induced viral clearance. Gastroenterology 125.1: 80–88.

  Save Citation »Export Citation » Share Citation »

  NNNThis important study was the basis for the third Hep-Net acute study (see Deterding, et al. 2013. The authors found that treatment of only patients who remain hepatitis C virus ribonucleic acid (HCV RNA) positive for more than three months after onset of acute HCV infection led to an overall viral clearance (self-limited and treatment induced) in 91 percent of patients and that unnecessary treatment was avoided in those with spontaneous viral clearance.

  Find this resource:

• Jaeckel, E., M. Cornberg, H. Wedemeyer, et al. 2001. Treatment of acute hepatitis C with interferon alfa-2b. New England Journal of Medicine 345.20: 1452–1457.

  DOI: 10.1056/NEJMoa011232Save Citation »Export Citation » Share Citation »

  NNNThis very important study was the first large, multicenter trial (including forty-four patients with acute HCV infection) to demonstrate that HCV infection can be cured in a large number of patients if treated early in the acute phase of the disease, using IFN monotherapy.

  Find this resource:

• Wiegand, J., P. Buggisch, W. Boecher, et al. 2006. Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: The HEP-NET acute-HCV-II study. Hepatology 43.2: 250–256.

  DOI: 10.1002/hep.21043Save Citation »Export Citation » Share Citation »

  NNNA well-performed study that revealed that monotherapy with Peg-IFN alfa-2b 1.5 micrograms per kilogram is highly efficient in acute HCV infection. A significant finding was that success of treatment strongly depends on adherence to treatment.

  Find this resource:

• Wiegand, J., E. Jackel, M. Cornberg, et al. 2004. Long-term follow-up after successful interferon therapy of acute hepatitis C. Hepatology 40.1: 98–107.

  DOI: 10.1002/hep.20291Save Citation »Export Citation » Share Citation »

  NNNA follow-up study on patients with acute HCV infection treated with Peg-IFN. Importantly, all patients with sustained virological response (SVR) twenty-four weeks after the end of treatment also had negative HCV RNA in blood and in peripheral blood mononuclear cells 52–224 weeks after the end of therapy, supporting that SVR reflects cure of HCV.

  Find this resource:

Current Treatment Options for Chronic Hepatitis C Virus Infection

Dual therapy with pegylated-interferon/ribavirin (Peg-IFN/RBV) has been the standard of care for chronic hepatitis C virus (HCV) infection of all genotypes since 2001. However, treatment duration and doses of antiviral medication have varied, depending on the HCV genotype present. In 2011, treatment of HCV genotype 1 changed with the approval of the first generation of direct-acting antivirals (DAAs), the protease inhibitors (PIs) boceprevir (BOC) and telaprevir (TLV). In several industrial countries triple therapy containing Peg-IFN, RBV, and one of the two PIs became the new standard of care for HCV genotype 1 patients. More recently, two additional DAAs, the NS5B polymerase inhibitor sofosbuvir (SOF) and the second-wave PI simeprevir (SMV), have been approved and have widely replaced TLV and BOC. SMV is labeled for the treatment of HCV genotypes 1 and 4, whereas SOF can be used against all known HCV genotypes. The marketing of SOF allowed for the first time an effective IFN-free antiviral treatment. However, in many countries these new drugs, even the first-generation PIs, are still not available, or access is very limited, owing to cost issues. The following sections cover all available antiviral treatment options for the different HCV genotypes. In addition, European Association for the Study of the Liver 2014 and Ghany, et al. 2009 (both cited under General Overviews) should be used as first references.

Future Treatment Options

Antiviral therapies with the first-generation protease inhibitors (PIs) boceprevir (BOC) and telaprevir (TLV) are limited in terms of efficacy and safety and have a complicated dosing schedule as well as a high risk of drug-drug-interaction. The second-wave direct-acting antivirals (DAAs) sofosbuvir (SOF) and simeprevir (SMV) overcome many of these limitations. In the early 21st century, several other, next-generation DAAs are in advanced clinical development or may soon come on the market. Most of these next-wave DAAs promise a more comfortable dosing schedule and a better safety profile; some, such as SOF, offer pan-genotypic efficacy and even higher efficacy. Most second-generation DAAs have first been tested in combination with pegylated-interferon/ribavirin (Peg-IFN/RBV). However, an increasing number of studies are documenting impressive results with IFN-free regimens through combination of different DAA classes. Many patients are ineligible for IFN. Thus, a highly efficient and well-tolerated IFN-free regimen against all hepatitis C virus (HCV) genotypes will be essential in order to cure all HCV patients in the end. The following sections concern future treatment options, including Peg-IFN-based therapies with second-generation DAAs and IFN-free regimens that might be available by the end of 2014 or in 2015.

Hepatitic C Vaccine

To ultimately eliminate hepatitis C virus (HCV), an efficient HCV vaccine is most likely necessary. However, despite intensive research, the marketing of a clinically applicable vaccine does not seem to be a reality in the near future. The huge genetic diversity, rapid mutation rate, and weak host immune response make the development of an effective vaccine a major challenge. There are a couple of excellent reviews that offer a quick overview of the topic. Houghton 2011 is a very nice review of different strategies for developing an efficient HCV vaccine. Torresi, et al. 2011 is another excellent overview article that describes in detail several different vaccines that have been developed. The review article Liang 2013 includes a comprehensive summary of the interaction of HCV and the host immune system as well as studies regarding the development of an HCV vaccine. Because HCV is able to escape most HCV antibodies, a more promising approach for a vaccine may be to target cell-mediated immunity. Here, Folgori, et al. 2006 was a major study that considered the protective effect of a T cell genetic HCV vaccine in chimpanzees. Park, et al. 2012 was a key study that further characterizes vaccine-induced, HCV-specific T cells. Later, Barnes, et al. 2012 used adenovirus-based vaccines in healthy human volunteers. In addition to protective vaccines, there have also been attempts to generate a therapeutic vaccine. The most advanced study has been Di Bisceglie, et al. 2014. However, given the high efficacy of antiviral treatments with direct acting antivirals, it seems unlikely that therapeutic vaccines will be widely used in the future.

• Barnes, E., A. Folgori, S. Capone, et al. 2012. Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man. Science Translational Medicine 4.115: 115ra1.

  DOI: 10.1126/scitranslmed.3003155Save Citation »Export Citation » Share Citation »

  NNNThe authors studied the safety and efficacy of adenovirus-based HCV vaccines expressing nonstructural HCV genotype 1b proteins in healthy volunteers. The authors found that the vaccines were safe and well tolerated. Furthermore, they showed that the vaccines were able to induce durable HCV-specific T cell responses not only against HCV genotype 1b, but also, although to a lesser extent, against genotypes 1a and 3.

  Find this resource:

• Di Bisceglie, A. M., E. Janczweska-Kazek, F. Habersetzer, et al. 2014. Efficacy of immunotherapy with TG4040, peg-interferon, and ribavirin in a phase 2 study of patients with chronic HCV infection. Gastroenterology 147.1: 119–131.e3.

  DOI: 10.1053/j.gastro.2014.03.007Save Citation »Export Citation » Share Citation »

  NNNThis is a phase 2 study investigating the efficacy of TG4040, a therapeutic vaccine derived from an artificial nonreplicative virus expressing HCV nonstructural proteins. HCV patients who were treated with seven TG4040 injections followed by pegylated-interferon/ribavirin (Peg-IFN/RBV) for forty-eight weeks and six more TG4040 injections had a significantly greater likelihood of achieving a complete early virological response and a numerically higher rate of sustained virological response (SVR), compared with Peg-IFN/RBV only.

  Find this resource:

• Folgori, A., S. Capone, L. Ruggeri, et al. 2006. A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees. Nature Medicine 12.2: 190–197.

  DOI: 10.1038/nm1353Save Citation »Export Citation » Share Citation »

  NNNIn this interesting study the authors used desoxyribonucleic acid (DNA) coding for nonstructural HCV proteins as genetic vaccine. An adenovirus was used as viral vector. The authors observed significant HCV-specific CD8 and CD4 T cell responses. Moreover, acute HCV infection demonstrated a markedly milder course in the vaccinated chimpanzees compared with control animals, indicated by lower alanine aminotransferase (ALT) and HCV RNA levels.

  Find this resource:

• Houghton, M. 2011. Prospects for prophylactic and therapeutic vaccines against the hepatitis C viruses. Immunological Reviews 239.1: 99–108.

  DOI: 10.1111/j.1600-065X.2010.00977.xSave Citation »Export Citation » Share Citation »

  NNNThis is a comprehensive review of the different strategies for creating an HCV vaccine. Covers vaccines developed using recombinant envelope proteins, vaccines targeting T cell responses without neutralizing antibodies, and therapeutic vaccines.

  Find this resource:

• Liang, T. J. 2013. Current progress in development of hepatitis C virus vaccines. Nature Medicine 19.7: 869–878.

  DOI: 10.1038/nm.3183Save Citation »Export Citation » Share Citation »

  NNNThis is an excellent overview of developments regarding an HCV vaccine. The author comprehensively discusses the hurdles that exist, explains possible strategies, and reviews the preclinical and clinical studies. Has very good figures that illustrate the mechanism of the interaction between HCV and the host immune system. The most important studies and HCV vaccines in chimpanzees and human are also summarized in a table.

  Find this resource:

• Park, S. H., E. C. Shin, S. Capone, et al. 2012. Successful vaccination induces multifunctional memory T-cell precursors associated with early control of hepatitis C virus. Gastroenterology 143.4: 1048–1060.e4.

  DOI: 10.1053/j.gastro.2012.06.005Save Citation »Export Citation » Share Citation »

  NNNThis is an important study that allowed the further characterization of vaccine-induced, HCV-specific T cells. Vaccinated and controls were challenged with HCV. The authors identified programmed death (PD)-1 and its ligand PD-L1 as significant mediators of HCV control. Both were downregulated on vaccine-induced T cells, which displayed a high functionality.

  Find this resource:

• Torresi, J., D. Johnson, and H. Wedemeyer. 2011. Progress in the development of preventive and therapeutic vaccines for hepatitis C virus. Journal of Hepatolology 54.6: 1273–1285.

  DOI: 10.1016/j.jhep.2010.09.040Save Citation »Export Citation » Share Citation »

  NNNThe authors examine HCV vaccine development, exploring the hurdles related to neutralizing HCV antibodies. Provides a very helpful figure summarizing the immune responses that are required to clear HCV infection. Several vaccines in preclinical and clinical development are described, together with the available study data.

  Find this resource: