Clinical course of infection with hepatitis C

Although around 170 million people worldwide are currently infected with hepatitis C virus (HCV), its course is still not well understood. Predicting the course of infection is essential to deciding who and when to treat with the powerful available drugs—pegylated interferons and ribavirin—and anticipating the need for liver transplants and other interventions for end stage liver disease.

Several factors influence the clinical course of HCV infection. Being older than 40 at the time of infection, male sex, coinfection with hepatitis B virus or HIV, steatohepatitis, immunosuppression, and predisposing human leukocyte antigen (HLA) haplotypes have all been associated with progression of fibrosis and possible development of cirrhosis. The main risk factor for faster progression to cirrhosis in HCV infection remains, however, the consumption of alcohol.¹,² Moreover, many intravenous drug users, the main population still at risk of HCV infection in developed countries, consume alcohol regularly.

Despite this evidence about risk factors, studies of the course of HCV infection have so far led to conflicting conclusions, and the two most recent studies are no exceptions. Wiese et al extended the follow-up of a cohort of 1980 women infected in the former East Germany from a single source (anti-D immunoglobulin contaminated by HCV genotype 1b) in 1978 and 1979 and found that, after 25 years, only 48% of untreated women still had HCV RNA in their blood. Of those untreated women who developed chronic hepatitis C, 1.3% had cirrhosis, 4.4% had marked hepatic fibrosis, and 0.1% had hepatocellular carcinoma.³ Liver associated mortality was 0.5% in viraemic women (half of them had serious comorbidities).

Another recent study gives an entirely different picture of prognosis. D'Souza et al studied 206 first generation and second generation adult Asian immigrants to northeast London who were, according to history and extrapolation of linear regression analyses, most probably infected with HCV in childhood or by the age of 20. The investigators selected 143 patients for analysis and compared them with 239 white patients. Liver biopsies showed cirrhosis in 11% of Asians aged 26-40, 33% of those aged 41-60, and 78% of those older than 60.⁴ Although only 25% of white patients aged 61-80 had cirrhosis, on the basis of multivariable linear analysis the authors concluded that prolonged infection for over 50 years leads to cirrhosis in most patients in other populations too. Can we then conclude that white European women are almost immune from cirrhosis induced by HCV, whereas the prognosis is very poor for Asians likely to be infected in childhood? We cannot.

The clinic based, cross sectional study by D'Souza et al looked at a highly selected group of individuals who were ascertained because they had HCV infection. Prone to detection bias and largely depending on extrapolation of regression lines, the study overestimates the risk of cirrhosis and reports the highest rate ever recorded for any such population of patients. Still, the data by D'Souza et al confirm that people can survive for more than 60 years with HCV infection, even when they have developed cirrhosis.

How should we put into context these two conflicting reports? Studies of the clinical course of HCV infection transmitted vertically or acquired early in life clearly show that progression of the disease is usually very slow, at least in the first three decades of life.⁵ The study by D'Souza et al is therefore exceptional in showing rapid progression in 11% of patients aged under 40.⁴ On the other hand, cohort studies with long term follow-up of people who acquired HCV in adulthood⁶ confirm and extend in time the data of Wiese et al.³ Finally, although the progression of hepatic fibrosis in hepatitis C seems to be non-linear,⁷ and the virus seems to be more fibrogenic in older people,⁸ population based studies show that infection with HCV is highly prevalent in asymptomatic people who live to old age.⁹,¹⁰ Overall, the study by D'Souza et al adds little to our knowledge of the course of HCV infection. The cohort study by Wiese et al is more robust, but it may underestimate the occurrence and progression of liver disease because it is confined to young, healthy women, who are already at reduced risk of liver disease related to HCV. Most low income countries cannot afford antiviral drugs. Worldwide, antiviral treatment for HCV infection is therefore underused, and treatment does not have a marked impact on the course of this infection in populations.¹¹ We should urgently aim to reduce the spread of HCV infection by strictly avoiding reuse of syringes and needles (still practised in many poor countries), and to limit the main cofactor of disease progression through well designed public health campaigns and interventions capable of reducing alcohol intake. In addition, measures should be taken to reach people in prisons and intravenous drug addicts, still at high risk for disease acquisition and spread. At the same time, researchers and epidemiologists should continue to study the clinical course of HCV infection in those countries where the disease is still actively spreading in the general population.¹²