Monday, March 13, 2017

Mortality associated with hepatitis C and hepatitis B virus infection

World J Gastroenterol. Mar 14, 2017; 23(10): 1866-1871
Published online Mar 14, 2017. doi: 10.3748/WJG.v23.i10.1866

Mortality associated with hepatitis C and hepatitis B virus infection: A nationwide study on multiple causes of death data
Ugo Fedeli, Enrico Grande, Francesco Grippo, Luisa Frova

To analyze mortality associated with hepatitis C virus (HCV) and hepatitis B virus (HBV) infection in Italy.

Death certificates mentioning either HBV or HCV infection were retrieved from the Italian National Cause of Death Register for the years 2011-2013. Mortality rates and proportional mortality (percentage of deaths with mention of HCV/HBV among all registered deaths) were computed by gender and age class. The geographical variability in HCV-related mortality rates was investigated by directly age-standardized rates (European standard population). Proportional mortality for HCV and HBV among subjects aged 20-59 years was assessed in the native population and in different immigrant groups.

HCV infection was mentioned in 1.6% (n = 27730) and HBV infection in 0.2% (n = 3838) of all deaths among subjects aged ≥ 20 years. Mortality rates associated with HCV infection increased exponentially with age in both genders, with a male to female ratio close to unity among the elderly; a further peak was observed in the 50-54 year age group especially among male subjects. HCV-related mortality rates were higher in Southern Italy among elderly people (45/100000 in subjects aged 60-79 and 125/100000 in subjects aged ≥ 80 years), and in North-Western Italy among middle-aged subjects (9/100000 in the 40-59 year age group). Proportional mortality was higher among Italian citizens and North African immigrants for HCV, and among Sub-Saharan African and Asian immigrants for HBV.

Population ageing, immigration, and new therapeutic approaches are shaping the epidemiology of virus-related chronic liver disease. In spite of limits due to the incomplete reporting and misclassification of the etiology of liver disease, mortality data represent an additional source of information for surveillance.

Key Words: Hepatitis C virus, Hepatitis B virus, Mortality, Epidemiology, Immigrants

Core tip: Multiple causes of death analyses carried out on the Italian National Cause of Death Register showed that 1.6% and 0.2% of all deaths in 2011-2013 were associated with hepatitis C virus (HCV) and hepatitis B virus (HBV) infection, respectively. HCV-associated mortality followed a bimodal distribution, increasing exponentially among the elderly in both genders, with a minor peak in middle-aged subjects, especially among males. The proportion of viral hepatitis-related deaths was higher among Italian citizens and North African immigrants for HCV, and among Sub-Saharan African and Asian immigrants for HBV.

Discussion Only
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Analyses of death certificates are known to be affected by incomplete reporting and misclassification of the etiology of liver diseases, leading to an underestimation of the true mortality burden associated with chronic viral infection[10]. The physicians filling in death certificates may be unaware of HCV or HBV infection in the patient or may not consider that the disease contributed to the death. Furthermore, among elderly patients affected by multiple comorbidities, there may be no simple etiologic chain leading to the identification of a single underlying cause; especially in the contest of ageing populations like in Italy, death often results from a complex interaction between multiple factors. As a consequence, instead of relying only on the underlying cause of death, the MCOD approach allows a more complete identification of the burden of mortality attributable to viral hepatitis infection. The MCOD methodology has been applied in the United States to monitor time trends in HCV-related mortality[10,11], and to assess the burden of HCV-related deaths in high-risk populations such as prison inmates[12]. In Italy, MCOD analyses of virus-related liver diseases have been carried out only at the regional level[13]. This first nationwide report allows for the investigation of variations in mortality by age, gender, area of residence, and immigrant status, thereby providing a raw but comprehensive picture of the contemporary burden of HCV and HBV-related mortality in Italy.

Repeated surveys carried out in a small town in Southern Italy suggest a decreasing prevalence of HCV infection, being mostly confined to the oldest age groups[14]. Moreover, clinical studies found that, although HCV infection still represents the main etiology for chronic liver disease in Italy, its role is declining in more recent years[15,16]. The present data suggest that the current burden of HCV-related disease among elderly Italians is still large, especially in Southern regions. These figures must be interpreted within the frame of the recent availability of safe and effective drugs that will change the approach to the aged HCV patient, with an increasing number of treatment candidates[17]. Furthermore, mortality data confirm the presence of two distinct epidemic waves that have partly been associated with different HCV subtypes[18]. A bimodal distribution of HCV infection has been previously reported by seroprevalence surveys conducted both in Northern[19] as well as in Southern Italy[20], and by analyses of the mention of HCV infection in records from a sample of Italian general practitioners[21]. The peak in middle-aged subjects is most likely associated with intravenous drug abuse as well as with other risk factors (including tattoos and piercing) typical of younger generations[19]. Such a peak is well-recognizable from mortality rates at least in the male gender, and must strictly be monitored in the future: HCV-related liver disease progresses faster with aging, extra-hepatic manifestations of HCV infection are probably worse in the elderly, and the risk of hepatocellular carcinoma increases with age[17]. In the United States, where HCV infection is mostly restricted to the 1945-1965 birth cohort, HCV-related mortality assessed with the MCOD methodology is steeply increasing[10]. The HCV-related mortality wave is rapidly rising in the United States as the age of the affected birth cohort is increasing[22]; a similar unfavorable trend could be observed in Italy in the near future. Furthermore, mortality data suggest that the geographical variation in the burden of HCV differs across age groups, with higher rates observed among middle-aged subjects residing in Northern and Central Italy with respect to the Southern regions.

Mortality among immigrants mirrors the available data on the global epidemiology of viral hepatitis. Estimates for the prevalence of HCV infection range from < 1.0% in Northern Europe to > 2.9% in Northern Africa, with the highest prevalence (15%-20%) reported from Egypt[23]. Similar to Italy, other countries with high HCV prevalence suffered from iatrogenic spread around the middle of the past century. In Egypt, this was due to parenteral antischistosomal therapy through 1961-1986[24]; mass trypanosomiasis therapy before 1951 in the Central Africa Republic, and intravenous treatment with antimalarial drugs and other medical interventions in Cameroon, also caused iatrogenic transmission of HCV[25]. Data on HBV-related mortality are consistent with the rates that have been reported from the countries of origin and with previous studies on immigrants in Italy. Among undocumented immigrants in a city in Northern Italy, 6% tested positive for HBsAg; the only independent predictor was the prevalence of HBV infection in the area of provenance, with higher rates for subjects from Sub-Saharan Africa and Asia[26]. The present mortality analysis was carried out on legal residents with foreign citizenship, representing about 5000000 subjects (8.3% of all residents in Italy, 10.9% in the 20-59-year age band), and was not restricted to selected high-risk groups like undocumented immigrants or asylum seekers. All of the above evidence should guide a re-appraisal of strategies tailored according to the area of provenance for screening, HBV vaccination, HBV and HCV infection treatment of the immigrant population.

In conclusion, population ageing, an increase in the number of immigrants from countries with high HBV and HCV prevalence, and changes in the therapeutic approaches are re-shaping the epidemiology of virus-related chronic liver disease. MCOD data are a useful tool among the multiple information sources needed to monitor this rapidly evolving scenario.

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