Chronic hepatitis C virus infection increases risk of death from both liver disease and non-liver-related causes

As well as increasing the risk of death from liver disease, chronic hepatitis C virus infection increased the risk of death from circulatory and kidney disease as well as several non-liver-related cancers, investigators report in the August 15^th edition of the Journal of Infectious Diseases.

Researchers in Taiwan compared mortality rates between three groups of people: those who had never been infected with hepatitis C virus (HCV); individuals who had antibodies to hepatitis C but who had cleared the infection; and people with chronic hepatitis C infection, indicated by detectable levels of virus.

Mortality rates were similar for the first two groups. However, people with chronic hepatitis C infection were significantly more likely to die of liver disease and a number of other causes.

“We found that anti-HCV seropositives with detectable HCV RNA had an increased risk of dying from all causes of death, whereas the risk for anti-HCV seropositives with negative HCV RNA was similar to the risk for anti-HCV seronegatives,” write the investigators.

The study’s findings underline the importance of detecting and treating chronic hepatitis C virus infection. New guidance was recently issued in the US recommending routine screening for people born between 1945 and 1965, the age group that has the highest hepatitis C prevalence.

There are an estimated 170 million hepatitis C virus infections worldwide. The prevalence of infections in richer countries is around 1% and is twice that level in resource-limited settings.

It is well recognised that infection with hepatitis C increases the risk of death from liver disease, including cirrhosis and liver cancer. There is some evidence that the infection also increases the risk of death from non-liver-related causes.

However, hepatitis C can be cured with antiviral therapy and previous research has suggested that this can reduce the risk of death from both liver disease and other causes. The studies showing this have been limited by their size or duration of follow-up. Investigators in Taiwan therefore wanted to establish a clearer understanding of the relationship between chronic hepatitis C virus infection and mortality.

They analysed data gathered during the prospective Risk Evaluation of Viral Load and Associated Liver Disease/Cancer (REVEAL) study.

Individuals who were uninfected with hepatitis B virus were recruited to this study between 1991 and 1992 and were followed until the end of 2008.

They were tested for the presence of hepatitis C antibodies and hepatitis C RNA.

A total of 1095 participants had antibodies to hepatitis C and 69% of these individuals had detectable virus.

Overall, people who were hepatitis C virus-positive were significantly more likely to die of liver-related causes (HR = 12.48; 95% CI, 9.34-16.66) as well as non-liver related causes (HR = 1.38; 95% CI, 1.15-1.16).

These non-liver-related causes included circulatory diseases (HR = 1.50; 95% CI, 1.10-2.03), kidney disease (HR = 2.77; 95% CI, 1.49-5.15) and several cancers, including cancer of the esophagus (HR = 4.08; 95% CI, 1.38-12.08), prostate cancer (HR = 4.19; 95% CI, 1.18-14.94) and thyroid cancer (HR = 8.22; 95% CI, 1.36-49.66).

The investigators then looked at the relationship between ongoing hepatitis C virus replication and mortality risk.

After 18 years of follow-up, 0.3% of hepatitis C-negative participants had died of liver disease. The mortality rate for people who had cleared hepatitis C virus infection was non-significantly higher at 1.6%. In contrast, 10% of participants with chronic infection died of liver-related causes.

“There was no case that died from chronic liver diseases and cirrhosis among participants seropositive for anti-HCV with undetectable serum HCV RNA,” note the authors.

A similar relationship between chronic hepatitis C virus and increased mortality was apparent when the investigators looked at non-liver-related caused of death.

In all, 3% of hepatitis C-negative participants died of cardiovascular disease, as did 3.5% of those who had cleared hepatitis C and 5% of people with ongoing viral replication, a significant difference (p < 0.01).

A detectable hepatitis C viral load was also associated with an increased risk of death from kidney disease (p < 0.01).

“There was no death from chronic liver disease and cirrhosis, esophagus cancer, prostate cancer, and thyroid cancer among anti-HCV seropositives with undetectable serum HCV RNA at study entry,” emphasise the investigators. “The consistent findings suggest active infection (seropositive for HCV RNA) rather than prior infection (seropositive for anti-HCV) is more important in predicting the long-term risk of mortality from liver disease.”

They therefore believe that hepatitis C screening programmes should include tests for both antibodies to the infection and hepatitis C RNA. “Anti-HCV seropositives, particularly those with detectable HCV RNA, should be encouraged to modify health behaviors, including weight reduction, tobacco cessation, or eating a balanced diet, in order to decrease the risk of cancers, circulatory diseases, and renal disease.”

The author of an editorial accompanying the study highlighted recent data showing that hepatitis C is now a more important cause of death in the US than HIV. “Now is the time for chronic HCV infections to be taken more seriously as an important public health problem.”

However, separate US research published in the online edition of the Journal of Infectious Diseases suggests that the pace of liver disease associated with chronic hepatitis C virus infection is slow. A total of 384 people were monitored 15 years after they were diagnosed and an estimated 25 years since they were first infected with hepatitis C.  Liver biopsies showed that 33% had no liver fibrosis, 52% had only mild fibrosis, 12% had intermediate fibrosis and only 2% had cirrhosis.

The investigators were encouraged by these results, which they believe could inform hepatitis C treatment strategies: “It is probable that those who have shown no or little fibrosis progression over 25 years will have a nonprogressive or slowly progressive course that will provide time for more effective and safer therapies to emerge and induce sustained virologic responses that appear tantamount to a cure.”

Mei-Hsuan Lee et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatitis diseases: a community-based long-term prospective study. J Infect Dis 206: 469-77, 2012.

Nelson KE. The impact of chronic hepatitis C virus infection on mortality. J Infect Dis 206: 461-63, 2012.

Allison RD et al. A 25-year study of the clinical and histologic outcomes of hepatitis C virus infection and its modes of transmission in a cohort of initially asymptomatic blood donors. J Infect Dis, online edition. DOI: 10/1093/infdis/jis410, 2012.