What is Killing People With Hepatitis C Virus Infection?

JasonGrebely, B.Sc., Ph.D.; Gregory J.Dore, M.B.B.S., Ph.D., F.R.A.C.P., M.P.H.


Semin Liver Dis. 2011;31(4):331-339. 

In This Article

Natural History of Chronic HCV Infection

An estimated 75% of people who acquire HCV infection progress to development of persistent of chronic HCV infection,[22] with associated risk of progressive liver disease, cirrhosis, liver failure, or hepatocellular carcinoma.[23] The remaining 25% of people achieve spontaneous HCV clearance;[22] however, these individuals may be reinfected in the setting of ongoing HCV exposure. Although many of those with reinfection undergo subsequent spontaneous viral clearance, others develop persistent infection.[24–30]

As reviewed elsewhere,[31] the risk of HCV-related liver disease morbidity and mortality depends on several factors: (1) the duration of HCV infection;[32–34] (2) the presence of cofactors for development of liver fibrosis (such as male gender,[35–37] ethnicity,[38,39] older age at infection,[37,40–42] heavy alcohol intake,[43–45] HIV[46–49] or chronic hepatitis B virus (HBV) co-infection,[50,51] diabetes,[52,53] obesity,[54,55] and hepatic steatosis[56,57]); (3) access to HCV therapy and a favorable treatment response;[58] and (4) competing mortality risk (such as HIV[7,49] and illicit drug-related overdose[2,6,7,8,49]). The generally slowly progressive nature of chronic HCV, with limited advanced liver disease in the initial 10 to 15 years of infection (even in those individuals with cofactors for fibrosis development), means that duration of HCV infection and its surrogate, age, are key determinants of mortality risk.[31] Thus, a 50-year-old individual with 30 years chronic HCV is likely to have a higher HCV-related mortality risk, even in the absence of liver disease cofactors, than a 30-year-old individual with 5 to 10 years infection and several cofactors. However, the 50-year-old individual with 30 years infection, with heavy alcohol intake, obesity, and regular cannabis smoking (recently shown to be a liver fibrosis cofactor[59]) will be at particularly high risk.

The risk of HCV-related cirrhosis based on duration of infection has recently been estimated through large systematic reviews of disease progression studies in HCV mono-infected and HIV/HCV co-infected populations (Fig. 1).[33,34] The exponential relationship between duration of infection and cirrhosis relates to the generally protracted disease course (few very fast progressors), the cumulative nature of cirrhosis prevalence (even linear rates of progression lead to a nonlinear/upward curve for cirrhosis), and the potential for more rapid fibrosis progression at older age.

Figure 1.

Risk of hepatitis C virus- (HCV-) related cirrhosis based on duration of infection as estimated through large systematic reviews of disease progression studies in HCV mono-infected and human immunodeficiency virus (HIV)/HCV co-infected populations.33,34

Without therapeutic intervention, an estimated 7 to 18% of HCV mono-infected individuals will develop cirrhosis over a 20-year infection period,[31,34] and be at considerable risk of HCC (1–6% per annum) or liver failure (2–3% per annum).[31] Thus, a significant minority of people with chronic HCV (possibly 10–20%) are likely to have shortened life expectancy through HCV-related mortality. A further large proportion will have HCV-related morbidity with reduced quality of life.[60]


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