The Trent HCV cohort is a representative cohort of HCV‐infected individuals in the UK,10,15
with patients recruited from the majority of secondary care centres in the East Midlands, South Yorkshire and Leeds. Referrals of patients from outside the catchment areas to specialist centres were specifically excluded. The cohort therefore reflects the population seen in secondary care across the region. The relatively young age of the cohort compared to the general population is consistent with the known epidemic curve of HCV infection since the 1960s.16
The principal finding of this study is that HCV‐infected persons have a death rate three times higher than that of the general population. Excess mortality is due to significant numbers of deaths from both injecting drug use and liver disease. The 12‐year age difference in deaths from liver disease compared with those from HCC is consistent with the known natural progression of hepatitis C disease.1
There were 58 deaths from unrelated medical causes and suicide (excluding unascertained), very close to the 60 deaths from all causes that would have been expected in this cohort (table 4). Of particular note is the low age at death, which was 51.6 years on average. This is largely a result of lifestyle‐related causes including the illicit use of drugs, murder and suicide, all of which are relatively rare in the general population.
A community‐based study17
from Australia on mortality in HCV patients using very different methodology (linking notified patients with death registrations) also showed a death rate three times higher with HCV infection and that this excess was split equally between drug‐related deaths and liver deaths. The population of New South Wales and the behaviour of those most at risk of HCV infection is likely to be very similar to that in the Trent region.
The causes of death are missing for 14 patients, either because of very recent death or because the patients were lost to follow‐up before they were registered with NHSCR and so had not consented. These deaths were determined from the notes or hospital patient information systems, but cause of death was not recorded. These patients had the same age and sex distribution as those for whom we have a known cause, and therefore the distribution of causes of death in this group is likely to be similar. This will have had the effect of under‐estimating the true incidence of liver and drug‐related death. Further, many patients with HCV are unaware they are infected, and a high proportion of patients known to be infected are not referred to secondary care.18
Patients who have acquired HCV infection from injecting drug use are now the main source of new referrals, reflecting the elimination of blood transfusion and poor medical practice as a route of transmission in the UK and other developed countries.1,16
These drug users are usually referred by drug and alcohol services and we note that attenders at these services are known to survive longer than those who are referred but who do not attend.19
The real risk to the whole HCV‐infected population is therefore likely to be even higher than that evident in our cohort. Our survival analyses did not show an association with injecting drug use after controlling for age. However, a majority of the cohort are drug users which mitigates against demonstrating an “exposure” effect when so many are exposed. Also, there is a major age discrepancy between drug users (younger) and non‐drug users (older) in our cohort, such that deaths in the latter group arising from liver disease and common unrelated medical causes are predominant.
Survival in patients with chronic infection was similar to that in the small cohort of patients exposed to HCV who cleared infection spontaneously (“always PCR negative”). Of the 21 PCR‐negative patients who died, the category of death was lifestyle‐related in six, liver‐related in four, unrelated medical in seven and unknown in four. Of the liver‐related deaths, two death certificates mentioned chronic alcohol use and another patient had chronic hepatitis B. While the numbers are too small for a conclusion to be reached, these results indicate that HCV‐infected patients who spontaneously clear their infection share the same lifestyle risks (including drug‐related complications, suicide, murder, alcohol consumption) as those who become chronically infected. Hepatitis B infection, whether cleared infection or in a chronic carrier, had no effect on survival although there are only 65 HBV surface antigen‐positive patients in this cohort. HBV co‐infection has been suggested by others to worsen prognosis.20
One possible source of bias in an observational study such as ours is the inclusion of patients with more severe liver disease who have HCV diagnosed because they present with liver disease‐related complications, leading to an apparent increase in mortality in the short term. We have minimised this potential bias by ensuring at least 1 year of follow‐up: 26 patients who died within a year of diagnosis were excluded from analysis. The average follow‐up period for the cohort is over 6.7 years and exceeds 10 years for 19%. Further, the substantial proportion of non‐liver‐related deaths suggests this is at best only a partial explanation of the high mortality rate.
Increased age and male gender were associated with all‐cause mortality and age with liver‐related mortality. This is typical of nearly all survival analyses. In addition, there is considerable evidence that women, especially young women, have a good prognosis with respect to HCV infection.7,8
How much this is due to other factors such as low alcohol consumption, and other co‐factors, is less clear. Multivariate analysis demonstrated that more severe liver damage was significantly associated with all‐cause mortality and was the dominant predictor of liver‐related mortality. This effect was seen with an Ishak fibrosis score of 4 or more. This suggests that liver biopsy findings still retain a significant role as a measure of prognosis.
The effect of treatment on survival is difficult to analyse, as there are a number of important confounders. Treatment modalities have changed over time, as have the criteria by which patients qualify for treatment. Early treatment (interferon alone) was reserved only for patients with severe liver disease who are at significantly increased risk of mortality. Thus, any potential small benefit of earlier treatments could have been cancelled out by the worse prognosis of advanced disease. Overall, however, completion of a course of therapy was clearly associated with survival from all‐cause and liver‐related mortality, even in those patients who subsequently relapsed virologically (table 5). This apparently surprising result may be because the ability to complete a course of therapy is a surrogate marker of a health‐conscious patient who adheres to medical advice such as reducing alcohol consumption and adoption of a healthier lifestyle. The most pertinent question, however, is whether combination therapy with pegylated interferons and ribavirin prolongs survival, and the extent to which this is dependent on treatment response. This modality has only been available since 2001 and patients receiving this therapy will therefore be more likely to survive simply because they have undergone shorter periods of follow‐up. In our analyses of 350 treatment‐naive patients who received combination therapy (10 deaths), there was a suggestion of benefit for both full and partial responders similar to that seen for the whole cohort. Long‐term follow‐up will be required to resolve this issue.
Interestingly, current alcohol consumption after diagnosis did not affect overall survival (tables 5 and 6) but unsurprisingly did predict liver mortality independently of liver biopsy findings (tables 7 and 8). We know that many of our cohort patients reduce their alcohol consumption significantly after the diagnosis of HCV infection is made,3
suggesting that alcohol reduction strategies could improve the prognosis of HCV‐infected individuals. We acknowledge that accurate measurement of alcohol intake is notoriously difficult, but any misclassification bias would typically reduce the magnitude of any effect.
A number of variables significant in the univariate analyses did not emerge as independently significant after controlling for liver biopsy and treatment. Many of these factors are likely to act through liver damage and therefore become reflected in the fibrosis score.
Age at infection has been well documented to affect prognosis,3,4,5,10
but for the vast majority of HCV‐infected patients this can only be estimated from knowledge of first exposure to risk. Even this estimate is not possible for a number of our cohort for whom no route of infection has been determined. Most of our cohort are likely to have been infected due to drug use in and around their twenties. With the elimination of most other routes of infection, this age group is most at risk and therefore the most important in which to describe long‐term prognosis.
Knowledge of long‐term disease progression and mortality rates is essential for health planning. An important incidental finding in this study is that, overall, only 23% of deaths had HCV mentioned on the death certificate, rising to just over 50% for deaths from chronic liver disease and HCC, despite the fact that the patients were enrolled in a cohort study for hepatitis C. Further, the majority of patient deaths occurred in the hospital they attended for the management of their HCV infection, and therefore the medical records (paper or electronic) should have been available to the person completing the death certificate. Thus, health planning exercises that rely on data present in death certificates will be highly inaccurate in the specific instance of HCV infection. The recent rise in liver cirrhosis deaths in the UK21
and elsewhere which has been attributed to alcohol may indeed include a significant proportion where HCV was an additional major, but unmentioned, factor, either on its own or as a co‐factor in alcoholic liver disease.
In summary, mortality in HCV‐infected patients is substantially higher than that of control populations, particularly in those younger people where the lifestyles associated with the acquisition of HCV carry increased risk. As patients age, however, there is clear evidence of excess mortality from liver‐related death (fig 1) and this is likely to significantly increase as the cohort ages and liver damage progresses. Further, for the reasons discussed above, mortality rates in our cohort are likely to underestimate the actual rates in the HCV‐infected population in the UK. Our results are important in planning national strategies in response to the burden of HCV infection.