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Hepatitis C virus – A teacher of clinical research, cell biology and immunology

  • Xavier Forns
    Correspondence
    Corresponding authors. Addresses: Hospital Clínic, Liver Unit, Villarroel 170, Barcelona 08036, Spain. Tel.: +34 932275753 (X. Forns), or Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Sektion Hepatologie, Liebigstr. 20, Leipzig 04103, Germany. Tel.: +49 3419712330 (T. Berg).
    Affiliations
    Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain
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  • Thomas Berg
    Correspondence
    Corresponding authors. Addresses: Hospital Clínic, Liver Unit, Villarroel 170, Barcelona 08036, Spain. Tel.: +34 932275753 (X. Forns), or Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Sektion Hepatologie, Liebigstr. 20, Leipzig 04103, Germany. Tel.: +49 3419712330 (T. Berg).
    Affiliations
    Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Leipzig, Germany
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      The recent development of direct acting antivirals (DAA) has changed the field of hepatitis C and probably of hepatology. Since the discovery of the hepatitis C virus (HCV) in 1989, a hallmark in molecular biology, the efforts to obtain robust in vitro systems and the search for a cure have run in parallel and have certainly driven high quality basic and clinical research. After only a couple of decades we have now the tools to cure chronic HCV infection. There are no cases in medicine of such an achievement in a chronic infection caused by a virus. The safety and great efficacy of the new antivirals, after years of suboptimal, interferon-based therapies has been accompanied by enthusiasm in the scientific community and, most importantly, by patients and their families.
      Despite this excitement, the fact that we now have an efficacious treatment has also led to the distressing feeling that research in the HCV field has come to an end. Some top research groups have changed their field of research since they fear a lack of sufficient funding to continue their future projects in this field.
      Nevertheless, there are still many unanswered questions where further research is needed. From an epidemiological point of view HCV incidence is growing in some risk groups (men who have sex with men, for example) and, since previous infection does not elicit protective immunity, intervention in potentially exposed individuals is mandatory. From a clinical point of view, there are also still some areas of uncertainty. Viral clearance is not always associated with liver function improvement in patients with end-stage liver disease: we need to understand why in some individuals, fibrosis regresses and tissue remodeling occurs, whereas in others the disease progresses (“point of no return”). Indeed, the impact of DAA therapy on the waiting list of liver transplantation has still not been assessed in depth. Another relevant issue refers to the impact of HCV cure on hepatocellular carcinoma (HCC) in cirrhotic patients. It seems intuitive to think that the incidence of HCC will decrease in cirrhotic patients achieving sustained virological response, as shown in the interferon era. While these results are awaited, controversy on the potential increase in HCC recurrence in patients who have undergone DAA treatment after HCC remission is open. Finally, it will be important to follow-up on the few individuals who develop resistant associated substitutions; second-generation DAA appear to overcome this potential issue but current information is still scarce.
      As treatments for HCV will regretfully not be affordable to all parts of the world in the coming years, and treatment alone not able to eliminate this virus globally, the search for a prophylactic vaccine still remains a search for the ‘Holy Grail’. Yet, vaccine development is complicated by – among other reasons - the high degree of virus variability. Despite this, the significant success in our understanding of the immune responses elicited by HCV infection over the last few years now allows us to study new vaccine strategies (in early phase clinical trials). Moreover, restoration of immune functions seen after DAA-induced cure of the HCV infection, may guide further protective vaccine development.
      From a translational point of view, there are many lessons to be learned from studying HCV that have significantly contributed to recent advances in basic science and our understanding of the molecular biology of other viral and non-viral diseases. Targeting other parts of the virus life cycle or host factors involved in viral propagation may be important for developing new efficacious strategies to treat related viruses like Dengue or West Nile fever virus, which cause significant morbidity worldwide. In addition, research in other areas, such as improving current cell culture systems (with new full-length viral strains) or advancing in the knowledge of specific steps of the HCV life cycle, will also be relevant for other viral diseases. Studies to unravel mechanisms involved in HCV-related hepatocarcinogenesis are also deemed essential, and may become a basis for preventive strategies; taking into account the upcoming burden of HCV-related liver cancer that is anticipated to occur over the next two decades.
      In this supplement issue of Journal of Hepatology, the readers will have the opportunity to gain profound insights into the most important fields of HCV research, and also to share a vision on the future demands related to this chronic viral infection. A number of well-known experts have worked together in producing this supplement issue and their work not only provides state of the art knowledge, but also suggests ways how further studies may help to continue this success story of modern medicine towards worldwide eradication of HCV and translating the knowledge gained beyond hepatitis C.