Increased liver-related mortality to hepatitis C viremia defined on the 20th anniversary of its identification

Hepatitis C virus (HCV), which is endemic to most parts of the world, remains the most common cause of posttransfusion hepatitis worldwide, is the leading cause of end-stage liver disease,1 and is one of the 10 leading causes of infectious diseases deaths worldwide. The epidemiology of HCV infection has changed over the past two decades with the near elimination of blood and blood product–related infection in more developed countries and a resulting shift to injection drug use and sexual transmission being the major routes of infection. In less-developed countries, the routes of transmission remain unsafe therapeutic injection practices, inadequate disinfection practices in medical and dental settings, and unscreened blood transfusions as well as sexual transmission and injection drug use.

ALT, alanine aminotransferase; CI, confidence interval; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HR, hazard ratio.

The World Health Organization estimates that 3% of the world's population, or approximately 170 million people, have been infected with HCV with a prevalence of 2%.2, 3 However, there are substantial variations in the prevalence throughout the world, with the highest prevalence being in North America and the Middle East, particularly Egypt (>3%), followed by Africa (3%), Eastern Europe (2.2%), China and other Asian countries (2%), Australia (1.1%), Southeast Asia (1.2%), and Northern Europe and the United Kingdom (1.1%). The incidence data compiled by the national surveillance and NHANES (National Health and Nutrition Examination Survey) shows that the incidence of HCV infection rose in the United States during the 1960s and 1970s, and remained high in the 1980s with estimates of 230,000 new cases per year.3, 4 In the 1990s, the estimated number of new cases decreased, especially among injecting drug users, for reasons that are not clear. It may have been due to the measures, such as needle exchange programs, introduced to prevent human immunodeficiency virus (HIV) transmission.4 In 2004, the estimated number of acute cases of HCV decreased to 26,000.5 Studies in Japan, which has the highest incidence of hepatocellular carcinoma (HCC) in HCV viremic patients (6%–7%),6 estimated that HCV infection was spread there in patients in the 1920s, and that they are now seeing the consequences of this with significant end-stage liver disease and resultant increases in morbidity and mortality.7

Hepatitis C progresses at varying rates,8 and not all infected individuals necessarily develop complications such as HCC and decompensated liver disease.9 Chronicity rates of HCV infection are now well established and can vary with route of transmission. Early studies in cohorts of blood donors, transfusion recipients, and adults acquiring infection through injection drug use reported chronicity rates of 70%–80%,10–12 whereas in cohorts of children infected through blood contamination, only 55%–71% remain chronically infected 15–20 years later.13, 14 In Germany and Ireland, cohorts of young women infected with HCV-contaminated immunoglobulin have chronicity rates of 55% up to 20 years after exposure.15, 16 Racial difference in rates of spontaneous clearance, and thus progression, have been shown with higher rates of HCV viremia and chronicity in HCV antibody–positive African American and Asian Americans than in white Americans.12, 18 Persons who have compromised immune systems and responses are at higher risk of developing persistent infection following exposure, as presented in studies of transplant recipients acquiring HCV from infected organs19 and in studies of persons coinfected with HCV and HIV.12

The factors most consistently associated with the development of progressive disease in chronically infected persons with fibrosis are sex, age at infection, immune status at time of infection, genotype, coinfection with hepatitis B virus, HIV, schistosomiasis, alcohol intake, and the newer emerging entities of steatosis and insulin resistance.20 Studies to date on the development of cirrhosis and HCC indicate rates of cirrhosis at 20 years after infection of 4%–24% and rates of HCC of 1%–7%, depending on the populations studied and the cohort recruitment methods used21–24 (i.e., community cohorts and blood donors as opposed to liver clinic referrals).

Although WHO data provide some epidemiological insights into the global burden of HCV, limited data exist to date on the HCV-related morbidity and mortality, because these data come primarily from natural history studies10, 11, 24–26 rather than from prospectively followed cohorts within community-based settings27 and is limited by the indolent development of progressive and end-stage liver disease. Some investigators have attempted to project the future burden from HCV by utilizing computer modeling, taking into account the proportions of individuals who might develop progressive liver disease and also the fact that some individuals may die from other causes before they develop any significant liver complications.28, 29 Estimates from these studies show liver-related disease mortality at 4%–15%.

In this issue of HEPATOLOGY, Uto et al.30 report the mortality rate and causes of death in a community-based prospective cohort study of individuals positive for HCV antibody in a hyperendemic area of Japan. A total of 1125 individuals were enrolled and were followed in this study between 1995 and the last day of 2005, or to their date of death if earlier. Viremia was assessed by HCV core antigen or HCV RNA. Individuals were classed as carriers if they were viremic and noncarriers if they were not viremic. Serologically defined HCV genotype (HCV serotype) was determined. If the serotype could not be determined, then HCV genotyping was undertaken. HCV genotype 1b was included with serotype 1, and genotypes 2a and 2b with serotype 2. No other genotype was detected in the cohort. Cause of death was assessed by death certificate and was classified into one of seven defined categories: HCC, liver disease excluding HCC, neoplasms excluding HCC, stroke, heart disease, pulmonary disease excluding lung cancer, and unknown/other causes.

The cohort included 758 (67.4%) carriers and 367 (32.6%) noncarriers. The mean age at enrollment was 64.2 and 62.6 respectfully. No statistically significant difference was identified according to sex, the rate of HBsAg surface antigen positivity, history of alcohol intake, or history of blood transfusion within the cohort. The group of carriers were slightly older and had higher levels of alanine aminotransferase (ALT) and γ-glutamyl transferase at baseline. The overall mortality rate was 25.0 per 1000 person-years in the cohort. After having been adjusted for age and sex, HCV carriers had a significantly higher rate of overall mortality (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.13–2.07) compared to noncarriers. This higher rate in overall mortality is explained by the higher rate of liver-related deaths from HCC and non-HCC with a cumulative risk of death of 28.0% in the carrier group as compared to 17.9% in the noncarriers, based on Kaplan-Meier estimates. Subgroup analysis in the carriers indicated a significant association with a higher level of HCV core antigen (>100 pg/mL) (HR, 1.81; 95% CI, 1.08–3.06) to liver-related deaths (HR, 2.58; 95% CI, 1.04–6.41) and weak associations between serotype 1 infection, (HR, 2.21; 95% CI, 0.91–5.33) indeterminate HCV infection (HR, 3.89; 95% CI, 0.97–15.7) and an increase in HCC mortality.

In further subgroup analysis that looked at ALT level and its possible relationship with increased liver-related mortality, 405 of 719 patients were excluded because they had fluctuating levels of ALT. This did not increase the power of these data. However, the inclusion of this category of patients would have answered an important question and provided a more complete picture of what occurs in clinical practice.

This selected Japanese prospective study cohort provides us with valuable additional important information on mortality related to HCV viremia, in particular, the increase in the liver-related mortality, which was clearly defined in this cohort and which was not seen in some of the natural history studies.23 Although racial difference in the incidence of HCC has been previously clearly defined,12, 18 the relatively low proportion of HCC death occurrences in this cohort cannot be explained by possible inaccuracies in death certification alone. The mode of infection and likely age at infection or the prevalence of HIV coinfection were not referred to, and an assumption was likely made that with the high age at enrollment the cohort was likely to have significant progressive disease and cirrhosis although no liver biopsy material was included. The relatively select nature of the population, who all had health insurance, also limits important socioeconomic factors which can affect overall mortality rates.

Considering these study limitations, the main aim of the study was achieved. This should propel us to continue to monitor prospectively and more comprehensively our individual patient cohorts, thus improving our understanding of the mortality risks and data in HCV-infected individuals.