Studies on the epidemiology of hepatitis B and C virus infections are still needed
Authors: Pierre Deltenre
Journal: Journal of Hepatology (2015)

Prevalence of elevated ALT values, HBsAg, and anti-HCV in the primary care setting and evaluation of guideline defined hepatitis risk scenariosJournal of HepatologyVol. 62Issue 6PreviewTherapy options for patients infected with chronic hepatitis B (HBV) or hepatitis C (HCV) viral infections have changed substantially over the last years. Full-Text PDF Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are major public health problems. Approximately 350–400 million people worldwide are chronic hepatitis B surface antigen (HBsAg) carriers, and HBV is a leading cause of cirrhosis and associated liver failure, hepatocellular carcinoma (HCC) and death. Indeed, one half to one million deaths are estimated to be related to HBV every year [[1]EASL clinical practice guidelines: management of chronic hepatitis B virus infection.J Hepatol. 2012; 57: 167-185Abstract Full Text Full Text PDF PubMed Scopus (2719) Google Scholar]. HCV infects an estimated 130–170 million persons worldwide and is responsible for 350,000–500,000 deaths per year [2Perz J.F. Armstrong G.L. Farrington L.A. Hutin Y.J. Bell B.P. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide.J Hepatol. 2006; 45: 529-538Abstract Full Text Full Text PDF PubMed Scopus (1997) Google Scholar, 3WHO, Hepatitis C, Fact sheet N°164, Updated April 2014. Available from <http://www.who.int/mediacentre/factsheets/fs164/en/>.Google Scholar]. In Europe, where an estimated 7.3–8.8 million people are infected with HCV, the overall prevalence of the infection is 1.1–1.3%, ranging from 0.6% in Germany to 4% in Italy [4Deuffic-Burban S. Deltenre P. Buti M. Stroffolini T. Parkes J. Muhlberger N. et al.Predicted effects of treatment for HCV infection vary among European countries.Gastroenterology. 2012; 143 (e14): 974-985Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 5Muhlberger N. Schwarzer R. Lettmeier B. Sroczynski G. Zeuzem S. Siebert U. HCV-related burden of disease in Europe: a systematic assessment of incidence, prevalence, morbidity, and mortality.BMC Public Health. 2009; 9: 34Crossref PubMed Scopus (189) Google Scholar]. Chronic hepatitis C is one of the main causes of HCC and the most common indication for liver transplantation in many European countries. Great progress has been made in the management of chronic hepatitis B and C at the individual level. Thanks to recent therapeutic advances, current treatments are able to control HBV replication and to eradicate HCV in almost all cases. Thus, further improvements in the management of HBV and HCV infections will be possible mainly by focusing on treatment impact at a population level. In this field, attention should be given to the dynamics of infection, natural history, screening, and therapeutic access which influence the impact of antiviral therapy on morbidity and mortality [4Deuffic-Burban S. Deltenre P. Buti M. Stroffolini T. Parkes J. Muhlberger N. et al.Predicted effects of treatment for HCV infection vary among European countries.Gastroenterology. 2012; 143 (e14): 974-985Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 5Muhlberger N. Schwarzer R. Lettmeier B. Sroczynski G. Zeuzem S. Siebert U. HCV-related burden of disease in Europe: a systematic assessment of incidence, prevalence, morbidity, and mortality.BMC Public Health. 2009; 9: 34Crossref PubMed Scopus (189) Google Scholar]. The epidemics of HBV and HCV are continuously evolving, mainly because of increased safety of blood donations, improvements in health care conditions, continuous expansion of intravenous drug use, and immigration to Europe from endemic areas. Thanks to vaccination programs and blood donor testing, the incidence of HBV infection has decreased significantly in Europe and the United States (US) during the past two decades [[6]Kim W.R. Epidemiology of hepatitis B in the United States.Hepatology. 2009; 49: S28-S34Crossref PubMed Scopus (167) Google Scholar]. However, this has not translated into a reduced HBV burden, since the absolute number of HBsAg-positive persons continues to increase [6Kim W.R. Epidemiology of hepatitis B in the United States.Hepatology. 2009; 49: S28-S34Crossref PubMed Scopus (167) Google Scholar, 7Ott J.J. Stevens G.A. Groeger J. Wiersma S.T. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity.Vaccine. 2012; 30: 2212-2219Crossref PubMed Scopus (1369) Google Scholar]. Regarding HCV infection, despite a marked decrease in the incidence of new HCV infections since the beginning of the 1990s due to systematic testing of blood donations, it is anticipated that the incidence of cirrhosis and HCC will continue to increase over the next decade [4Deuffic-Burban S. Deltenre P. Buti M. Stroffolini T. Parkes J. Muhlberger N. et al.Predicted effects of treatment for HCV infection vary among European countries.Gastroenterology. 2012; 143 (e14): 974-985Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 8Ly K.N. Xing J. Klevens R.M. Jiles R.B. Ward J.W. Holmberg S.D. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007.Ann Intern Med. 2012; 156: 271-278Crossref PubMed Scopus (615) Google Scholar]. However, although chronic hepatitis C is a curable disease, treatment uptake rates have remained low. The reasons are manifold and include financial issues, fear of possible side effects of interferon-based therapies and low detection rates. On the other hand, prognostic models have demonstrated that combined improvements in screening, treatment access, and sustained virological response (SVR) rates have a much greater impact on HCV-related mortality than the improvement of SVR rates alone [4Deuffic-Burban S. Deltenre P. Buti M. Stroffolini T. Parkes J. Muhlberger N. et al.Predicted effects of treatment for HCV infection vary among European countries.Gastroenterology. 2012; 143 (e14): 974-985Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 9Davis G.L. Alter M.J. El-Serag H. Poynard T. Jennings L.W. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression.Gastroenterology. 2010; 138 (521 e1-6): 513-521Abstract Full Text Full Text PDF PubMed Scopus (775) Google Scholar, 10Gane E. Kershenobich D. Seguin-Devaux C. Kristian P. Aho I. Dalgard O. et al.Strategies to manage hepatitis C virus (HCV) infection disease burden – volume 2.J Viral Hepat. 2015; 22: 46-73Crossref PubMed Scopus (50) Google Scholar, 11Wedemeyer H. Duberg A.S. Buti M. Rosenberg W.M. Frankova S. Esmat G. et al.Strategies to manage hepatitis C virus (HCV) disease burden.J Viral Hepat. 2014; 21: 60-89Crossref PubMed Scopus (179) Google Scholar]. Screening is a prerequisite to improve access to care. Current national and international guidelines for the management of HCV infection recommend that screening for HCV infection should be performed in individuals with well-known risk factors (risk-based screening) or individuals within a certain age group (birth cohort screening) [12Fretz R. Negro F. Bruggmann P. Lavanchy D. De Gottardi A. Pache I. et al.Hepatitis B and C in Switzerland – healthcare provider initiated testing for chronic hepatitis B and C infection.Swiss Med Wkly. 2013; 143: w13793PubMed Google Scholar, 13Lok A.S. McMahon B.J. Chronic hepatitis B: update 2009.Hepatology. 2009; 50: 661-662Crossref PubMed Scopus (2428) Google Scholar]. Although data are limited, it is estimated that around 50% of infected persons were identified in Europe in 2011, ranging from 34–35% in the United Kingdom and Spain to 64% in France [[4]Deuffic-Burban S. Deltenre P. Buti M. Stroffolini T. Parkes J. Muhlberger N. et al.Predicted effects of treatment for HCV infection vary among European countries.Gastroenterology. 2012; 143 (e14): 974-985Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar]. In the US, a similar estimated 45–85% of HCV-infected individuals are unaware of their infection [14Smith B.D. Morgan R.L. Beckett G.A. Falck-Ytter Y. Holtzman D. Teo C.G. et al.Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965.MMWR Recomm Rep. 2012; 61: 1-32PubMed Google Scholar, 15Smith B.D. Morgan R.L. Beckett G.A. Falck-Ytter Y. Holtzman D. Ward J.W. Hepatitis C virus testing of persons born during 1945–1965: recommendations from the Centers for Disease Control and Prevention.Ann Intern Med. 2012; 157: 817-822Crossref PubMed Scopus (235) Google Scholar]. These data indicate that current recommendations for screening individuals with a known risk factor are not as effective as they should be. In line with these data, a recent study observed that in one third of patients in whom a diagnosis of HCV infection was just made, a blood transfusion received before 1990 was documented as the route of transmission, which demonstrates the gap existing between the theoretical efficacy of a screening strategy based on the presence of a common risk factor and its applicability in real life [[16]De Vroey B. Moreno C. Laleman W. van Gossum M. Colle I. de Galocsy C. et al.Hepatitis B virus and hepatitis C virus infections in Belgium: similarities and differences in epidemics and initial management.Eur J Gastroenterol Hepatol. 2013; 25: 613-619Crossref PubMed Scopus (11) Google Scholar]. These findings underline the need for new screening policies. For HCV infection, much interest has recently been given to birth cohort screening. The rationale for this is evident when considering the epidemiology of the infection. In Europe as well as in the US, most infections occurred by blood transfusion in the late 1980s, before blood products were systematically screened for HCV. Accordingly, those who were susceptible to receive blood products before 1990 were at the highest risk of being infected. Recent epidemiological data in the US indicated that individuals born between 1945 and 1965 represent one fourth of the general population but harbor three fourths of HCV infections. Consequently, the Centers for Disease Control and Prevention recommended screening of this age group [14Smith B.D. Morgan R.L. Beckett G.A. Falck-Ytter Y. Holtzman D. Teo C.G. et al.Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965.MMWR Recomm Rep. 2012; 61: 1-32PubMed Google Scholar, 15Smith B.D. Morgan R.L. Beckett G.A. Falck-Ytter Y. Holtzman D. Ward J.W. Hepatitis C virus testing of persons born during 1945–1965: recommendations from the Centers for Disease Control and Prevention.Ann Intern Med. 2012; 157: 817-822Crossref PubMed Scopus (235) Google Scholar]. With full implementation of this strategy, 800,000 persons currently unaware of their HCV infection are expected to be identified and thus potentially eligible for treatment. It is unknown if similar screening strategies could be applied to other countries. In this issue of the Journal, Wolffram and colleagues assessed the prevalence of HBV and HCV infections in a primary care setting in Germany [[17]Wolffram I, Petroff D, Bätz O, Jedrysiak K, Kramer J, Tenckhoff H, et al. for the German “Check-Up 35+“ Study Group, Prevalence of elevated ALT values, HBsAg, and anti-HCV in the primary care setting and evaluation of guideline defined hepatitis risk scenarios. J Hepatol 2015;62:1256–1264.Google Scholar]. They investigated a large cohort of individuals attending their primary care physician for a general check-up. By doing so, the authors did not identify an age group with a particularly high prevalence of HBV or HCV infection and concluded that immigration, infection in household or male gender for HBV, and immigration, intravenous drug use or a history of blood transfusion before 1992 for HCV helped to identify previously unknown infected persons. These results deserve several comments. Firstly, this study is remarkable for a number of reasons: It includes a huge cohort of more than 21,000 persons included in a preventive medical program in 51 primary care practices. A high proportion of individuals who attended their physicians accepted to participate to this study. The authors focused on the best strategy for identifying individuals unaware of their infection, which is relevant from a public health point of view. As previously noted, this study found that blood transfusion before 1992 was still a common route of transmission in patients unaware of their HCV infection in 2012. However, this study also has a limitation, as acknowledged by the authors: it suffers from a selection bias, as individuals had to attend their general practitioner to have a chance to be included in the study. In addition, this study was restricted to persons with an appropriate medical insurance older than 35 years, and few patients older than 75 years were included. Thus, the conclusions of this study apply to the study population, which is not fully representative of the general population. This bias is frequent and almost unavoidable in this kind of epidemiological studies. With this limitation taken into account, should a birth cohort screening strategy for the screening for chronic viral hepatitis be dismissed in Germany? Differences in dynamics and natural history of HCV infection could explain why a birth cohort strategy could be efficient in one country and not another. Such differences explain substantial discrepancies between European countries in terms of HCV burden. As an example, the peak of the HCV epidemic in Italy occurred 20–30 years earlier than in other European countries and was mainly associated with unsafe invasive procedures such as vaccinations or injections of antibiotics and vitamins [[4]Deuffic-Burban S. Deltenre P. Buti M. Stroffolini T. Parkes J. Muhlberger N. et al.Predicted effects of treatment for HCV infection vary among European countries.Gastroenterology. 2012; 143 (e14): 974-985Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar]. In the United Kingdom, intravenous drug use seems to be a more frequent route of transmission than in other parts of Europe [[4]Deuffic-Burban S. Deltenre P. Buti M. Stroffolini T. Parkes J. Muhlberger N. et al.Predicted effects of treatment for HCV infection vary among European countries.Gastroenterology. 2012; 143 (e14): 974-985Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar]. However, available data indicate that the epidemiology of HCV infection follows a comparable course in the US and in several European countries including Germany, Belgium and France [4Deuffic-Burban S. Deltenre P. Buti M. Stroffolini T. Parkes J. Muhlberger N. et al.Predicted effects of treatment for HCV infection vary among European countries.Gastroenterology. 2012; 143 (e14): 974-985Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 5Muhlberger N. Schwarzer R. Lettmeier B. Sroczynski G. Zeuzem S. Siebert U. HCV-related burden of disease in Europe: a systematic assessment of incidence, prevalence, morbidity, and mortality.BMC Public Health. 2009; 9: 34Crossref PubMed Scopus (189) Google Scholar]. In these countries, the peak of HCV infections was observed in the late 1980s, and the majority of new infections are since related to intravenous drug use and immigration from countries of high HCV prevalence. Thus, Germany seems to present a similar pattern of the HCV epidemic as compared to the one predicted by Davis and colleagues in the US [4Deuffic-Burban S. Deltenre P. Buti M. Stroffolini T. Parkes J. Muhlberger N. et al.Predicted effects of treatment for HCV infection vary among European countries.Gastroenterology. 2012; 143 (e14): 974-985Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 9Davis G.L. Alter M.J. El-Serag H. Poynard T. Jennings L.W. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression.Gastroenterology. 2010; 138 (521 e1-6): 513-521Abstract Full Text Full Text PDF PubMed Scopus (775) Google Scholar]. In an attempt to explain differences that could exist between Germany and the US, the authors advocated that the population they screened comprised a lower proportion of non-Hispanic Black or Mexican Americans, two populations with high HCV prevalence. Overall, the question as to whether birth cohort screening may be useful for the screening for HCV infection in the general German population remains open. Additional epidemiological studies including large samples of individuals representative of the whole population are still needed. Independently from their outcome, screening based on known risk factors will always remain indicated. Up until now, therapeutic guidelines have mainly been elaborated for patient care at an individual level while little attention has been given to treatment impact at a population level. New public health policies should aim to improve HBV and HCV screening to reduce the burden of these infections. While Wolffram and colleagues have to be commended on their important contribution, additional studies will be required to settle the issue of risk based vs. birth cohort screening in Europe and to inform decision making for health policies. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this editorial.