Early HCV Treatment?: Chronic and cleared hepatitis C viral infection:

Early HCV Treatment?: Chronic and cleared hepatitis C viral infection:
A nationwide cohort study - pdf attached


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Jnl of Hepatology July 2010

"Five-year survival was 86% (95% CI: 84-87%) among patients in the chronic HCV group and 92% (95% CI: 91-94%) among those in the cleared HCV group (Fig. 1)...... In HCV RNA positive patients, the 8-year risks of death were: 5.5% from liver-related death, 5.5% from non-liver-related natural death, 8.8% from unnatural death, and 0.8% from other death. In HCV RNA negative patients these estimates were 2.0%, for liver-related death, 5.0% for non-liver-related natural death, 6.6% for unnatural death, and 0.2% for other death (Fig. 2).....Chronic HCV-infection was primarily associated with liver-related death (SDHR: 2.42, 95% CI: 1.51-3.88)"

Lars Haukali Omland1Corresponding Author Informationemail address, Henrik Krarup2, Peter Jepsen3, Jorgen Georgsen4, Lene Holm Harritshoj5, Kirsten Riisom6, Svend Erik Hove Jacobsen7, Per Schouenborg8, Peer Brehm Christensen9, Henrik Toft Sorensen310, Niels Obel1, On behalf of the DANVIR Cohort Study

ABSTRACT

Background & Aims

It is unknown whether mortality differs between patients with chronic hepatitis C virus (HCV) replication and those who cleared the virus after infection. We examined the impact of chronic HCV replication on mortality among Danish patients testing positive for HCV antibodies.

Methods

This nationwide cohort study focused on Danish patients with at least one HCV RNA measurement available after testing positive for HCV antibodies between 1996 and 2005. To capture long-term prognosis, eligible patients needed to be alive 1year after HCV RNA assessment. We estimated mortality rate ratios (MRRs) using Cox regression (for overall mortality) and subdistribution hazard ratios (SDHRs) for cause-specific mortality, controlling for gender, age, comorbidity, calendar period, alcohol abuse, injection drug use, and income.

Results

Of the 6292 patients under study, 63% had chronic HCV-infection and 37% had cleared the virus. Five-year survival was 86% (95% confidence interval (CI): 84-87%) in the chronic HCV group and 92% (95% CI: 91-94%) in the cleared HCV group. Chronic HCV-infection was associated with higher overall mortality (MRR: 1.55, 95% CI: 1.28-1.86) and liver-related death (SDHR: 2.42, 95% CI: 1.51-3.88). Chronic HCV-infection greatly increased the risk of death from primary liver cancer (SDHR: 16.47, 95% CI: 2.24-121.00).

Conclusions

Patients with chronic HCV-infection are at higher risk of death than patients who cleared the infection. The substantial association found between chronic HCV-infection and death from primary liver cancer supports early initiation of antiviral treatment in chronically HCV-infected patients.

Results

From the DANVIR cohort we identified 13,005 patients diagnosed with HCV, of whom 6292 met the studyÕs inclusion criteria. Of these, 3969 patients (63%) were classified as chronically HCV-infected and 2323 (37%) as having cleared the infection. Compared to patients in the cleared group, patients with chronic HCV-infection were more likely to be male, and they also were older and had lower income, more hospitalizations, and a higher prevalence of non-HCV-related liver disease (Table 1).

Overall mortality

During 23,648 person-years of observation (PYR), a total of 601 patients died (MR: 25.4/1000 PYR, 95% CI: 23.5-27.5) with 448 deaths in the chronic group and 153 deaths in the cleared group. Five-year survival was 86% (95% CI: 84-87%) among patients in the chronic HCV group and 92% (95% CI: 91-94%) among those in the cleared HCV group (Fig. 1). The adjusted MRR was 1.55 (95% CI: 1.28-1.86). Chronic HCV-infection was associated with increased mortality in most subgroups, except among patients with severe comorbidity (Table 2). Restricting the cohort to patients whose positive HCV antibody test was confirmed by a 3rd generation diagnostic test prior to HCV RNA measurement (n=2753) did not change the estimated association between chronic HCV-infection and mortality (data not shown).

Specific causes of death

In HCV RNA positive patients, the 8-year risks of death were: 5.5% from liver-related death, 5.5% from non-liver-related natural death, 8.8% from unnatural death, and 0.8% from other death. In HCV RNA negative patients these estimates were 2.0%, for liver-related death, 5.0% for non-liver-related natural death, 6.6% for unnatural death, and 0.2% for other death (Fig. 2). The risk of death other than liver-related death (i.e. non-liver-related death, unnatural death and other death) thereby far exceeded the risk of liver-related death for both HCV RNA positive and negative patients (15.1% vs. 5.5% and 11.8% vs. 2.0%, respectively). The corresponding causes for specific MRs are provided in Supplementary Table 1.

Chronic HCV-infection was primarily associated with liver-related death (SDHR: 2.42, 95% CI: 1.51-3.88), and to some extent with non-liver-related natural causes of death (SDHR: 1.24, 95% CI: 0.91-1.71) and unnatural causes of death (SDHR: 1.28, 95% CI: 0.97-1.69). In the non-liver-related natural death category, none of the detailed causes of death were notably associated with chronic HCV-infection (Table 3). Except for primary liver cancer, there was no substantially increased risk of death due to neoplasms (SDHR: 1.28, 95% CI: 0.65-2.54).

Of the liver-related deaths, death due to alcoholic liver disease was the most frequent (2.3% vs. 1.4% after 8years of follow-up for patients with chronic vs. cleared HCV-infection). Chronic HCV-infection was substantially associated with death from primary liver cancer (SDHR: 16.47, 95% CI: 2.24-121). However, death from primary liver cancer was rather infrequent (28 events vs. 1 event for patients with chronic vs. cleared HCV-infection, corresponding to an 8-year risk of 1.4% in patients with chronic HCV-infection and of 0.0% in patients with cleared HCV-infection) (Fig. 3). There were no deaths due to oesophageal or gastric varices.

Discussion

We observed an increased mortality among patients with chronic HCV-infection compared to patients with cleared infection, based on HCV RNA testing. This effect was observed in all patient subgroups except in those with severe comorbidity. Chronic HCV-infection was associated with liver-related mortality, and in particular death from primary liver cancer. However, the risk of deaths other than liver-related deaths by far exceeded the risk of liver-related deaths in both HCV RNA positive and HCV RNA negative patients. To our knowledge, no previous study has addressed the impact of chronic HCV replication on mortality in an equivalent nationwide setting with a long and complete follow-up and with an extensive control of confounders.

Our study has several limitations. We had access to the exact date of HCV diagnosis, but not the date of HCV-infection [6]. For a substantial proportion of study participants, HCV-infection could have preceded study inclusion by several years, since most HCV-infections occur subclinically [6]. Thus patients in the chronic group could have had more liver damage at the time of study inclusion than patients in the cleared group. We did not have access to liver biopsies or liver function tests, so we could not directly address this question. More patients in the chronic HCV group than in the cleared group were diagnosed with liver diseases other than HCV. However, we were able to demonstrate that chronic HCV-infection was associated with mortality in patients both with and without pre-existing liver diseases, which indicates that severity of liver disease did not explain our findings. Our analyses did not account for spontaneous or treatment-related viral clearance nor HCV re-infection during follow-up. Most patients are IDUs, and probably as a result, regular testing for HCV RNA subsequent to an initial diagnosis is not performed systematically in Denmark. Modelling HCV viraemia as a time-updated variable thus was not possible in this study. However, spontaneous clearance of HCV-infection subsequent to the initial acute phase of the disease occurs infrequently [25] and only a minority of Danish patients receive antiviral treatment [11]. Finally, despite the large study population and long-term follow up, our study had too small power to make statistically significant estimates for most of the detailed categories of causes of death.

Patients with chronic HCV-infection were at an increased risk of liver-related death, with the strongest association observed between chronic HCV-infection and primary liver cancer. This information is important, and suggests that clearance of the virus almost eliminates the risk of developing primary liver cancer, thus confirming the potential benefit of antiviral treatment. However, one patient in the cleared group developed primary liver cancer. This observation agrees with recent findings of cases of hepatocellular carcinoma in long-term viral suppression responders [26]. These data suggest that clearance of the virus substantially decreases but not fully eliminates the risk of primary liver cancer. Chronic HCV-infection was also associated with other liver-related causes of death (viral hepatitis, alcoholic liver disease and non-alcoholic liver disease), also emphasising the potential for antiviral treatment.

The associations between chronic HCV-infection and non-liver-related natural deaths, unnatural deaths and other deaths diminished when we adjusted for confounders. However, we cannot exclude the possibility of unmeasured or residual confounding. The fact that patients with chronic HCV-infection were at increased risk of unnatural deaths (and to some extent death due to infections) indicates certain risk-taking behaviour in this group. As we were unable to adjust for this factor in our models, this could have resulted in unmeasured confounding. We find it likely that the associations found between chronic HCV-infection and non-liver-related natural deaths, unnatural deaths, and other deaths result from unmeasured confounding. In particular, from more injection drug use among chronically HCV-infected patients than among patients who cleared the virus.

The Trent HCV Cohort Study examined predictors of survival among HCV-infected patients treated in secondary care centres. That study, unlike ours, reported no substantial association between HCV RNA positive status (compared to HCV RNA negative status) and an increased all-cause mortality (MRR: 1.1, 95% CI 0.7-1.8) [5]. These inconsistent findings might be a result of lack of precision in the Trent study, which included only 157 deaths in the HCV RNA positive group and 21 deaths in the HCV negative group. More likely, however, these inconsistencies stem from differences in the study populations, as the Trent HCV Cohort only included patients from referral sites, while our study included nearly all patients tested for HCV RNA in Denmark. The patients in the Trent study therefore may have been at a more advanced stage of their liver disease and may have had more comorbidity. In that case, results for the Trent HCV Cohort should be compared to results for the most diseased subgroup of our study population. In fact, we did not observe a substantial impact of chronic HCV-infection among patients with a high comorbidity index, those with alcohol abuse or those who had been hospitalized recently. In a previous study from our group focusing on Danish HIV-infected IDUs with a high level of comorbidity, we also observed no association between chronic vs. cleared HCV-infection and mortality [27]. These findings suggest that chronic HCV-infection, compared to cleared HCV-infection, is associated with increased mortality in most patient groups. However, in high-risk study populations characterised by substantial mortality, the relative impact of chronic HCV-infection is limited.

We conclude that based on HCV RNA assessment, patients with chronic HCV-infection have higher mortality and, in particular, a higher risk of liver-related death than patients who cleared the virus. The pronounced association between chronic HCV-infection and death from primary liver cancer provides a rationale for antiviral treatment in chronically HCV-infected patients. However, our data also underline the importance of a balanced decision, as subgroups characterised by substantial mortality probably have less potential for a treatment benefit.