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van der Meer AJ, Veldt BJ, Feld, JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association between sustained virologic response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 2012;308:2584–2593. (Reprinted with permission.)

Abstract

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  2. Abstract
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Context: Chronic hepatitis C virus (HCV) infection outcomes include liver failure, hepatocellular carcinoma (HCC), and liver-related death. Objective: To assess the association between sustained virological response (SVR) and all-cause mortality in patients with chronic HCV infection and advanced hepatic fibrosis. Design, Setting, and Patients: An international, multicenter, long-term follow-up study from 5 large tertiary care hospitals in Europe and Canada of 530 patients with chronic HCV infection who started an interferon-based treatment regimen between 1990 and 2003, following histological proof of advanced hepatic fibrosis or cirrhosis (Ishak score 4-6). Complete follow-up ranged between January 2010 and October 2011. Main Outcome Measures: All-cause mortality. Secondary outcomes were liver failure, HCC, and liver-related mortality or liver transplantation. Results: The 530 study patients were followed up for a median (interquartile range [IQR]) of 8.4 (6.4-11.4) years. The baseline median (IQR) age was 48 (42-56) years and 369 patients (70%) were men. The Ishak fibrosis score was 4 in 143 patients (27%), 5 in 101 patients (19%), and 6 in 286 patients (54%). There were 192 patients (36%) who achieved SVR; 13 patients with SVR and 100 without SVR died (10-year cumulative all-cause mortality rate, 8.9% [95% CI, 3.3%-14.5%] with SVR and 26.0% [95% CI, 20.2%-28.4%] without SVR; P < .001). In time-dependent multivariate Cox regression analysis, SVR was associated with reduced risk of all-cause mortality (hazard ratio [HR], 0.26; 95% CI, 0.14-0.49; P < .001) and reduced risk of liver-related mortality or transplantation (HR, 0.06; 95% CI, 0.02-0.19; P < .001), the latter occurring in 3 patients with SVR and 103 without SVR. The 10-year cumulative incidence rate of liver-related mortality or transplantation was 1.9% (95% CI, 0.0%-4.1%) with SVR and 27.4% (95% CI, 22.0%-32.8%) without SVR (P < .001). There were 7 patients with SVR and 76 without SVR who developed HCC (10-year cumulative incidence rate, 5.1%; 95% CI, 1.3%-8.9%; vs 21.8%; 95% CI, 16.6%-27.0%; P < .001), and 4 patients with SVR and 111 without SVR experienced liver failure (10-year cumulative incidence rate, 2.1%; 95% CI, 0.0%-4.5%; vs 29.9%; 95% CI, 24.3%-35.5%; P < .001). Conclusion: Among patients with chronic HCV infection and advanced hepatic fibrosis, sustained virological response to interferon-based treatment was associated with lower all-cause mortality.

Comment

  1. Top of page
  2. Abstract
  3. Comment
  4. References

It is becoming clear that the incidence of hepatitis C virus (HCV)-related cirrhosis and its complications will continue to increase in the coming years unless substantial improvements are made in both access to and effectiveness of HCV antiviral treatment.[1, 2] The effectiveness of antiviral treatment has historically been evaluated by the surrogate endpoint of sustained virologic response (SVR) 24 weeks after cessation of antiviral medication. In numerous studies, SVR has been associated with a reduced occurrence of liver failure, hepatocellular carcinoma (HCC), and liver-related deaths in patients with HCV.[3, 4]

Whether the beneficial effects of SVR also result in reduced all-cause mortality, however, is the more essential question to answer. Because all-cause mortality is the most definite clinical endpoint with clear interpretation, demonstrating direct clinical benefits of SVR on all-cause mortality would better justify the use of intensive and costly antiviral therapy. Knowing the effect of HCV antiviral treatment on all-cause mortality is also important for considering broader clinical questions such as the utility of birth cohort screening for HCV. In the largest prior effort, a study of 16,864 U.S. Veterans analyzed separately by genotype found reduced all-cause mortality among patients with HCV genotypes 1, 2, and 3 who were treated in routine medical practice.[5] Because the majority of these patients were treated without liver biopsy, there was limited information about the impact of SVR on all-cause mortality in patients with severe fibrosis or cirrhosis.

The current article by van der Meer et al.[6] seeks to add to the information about the impact of SVR on all-cause mortality, particularly in patients with severe fibrosis or cirrhosis. Van der Meer et al. report on long-term outcomes from 530 patients from five large tertiary care hospitals in Europe and Canada. The patients started an interferon-based regimen between 1990 and 2003 following histologic proof of advanced hepatic fibrosis or cirrhosis (Ishak score of 4 in 27% of patients, Ishak score of 5 in 19% and Ishak score of 6 in 54%). In all, 175 patients started interferon monotherapy, 148 patients started interferon/ribavirin, and 176 patients started pegylated interferon/ribavirin with resulting SVR rates of 5.1%, 23.6%, and 42.1%, respectively. An additional 14 patients started pegylated interferon monotherapy and 17 patients started consensus interferon with or without ribavirin. A total of 204 patients with initial non-SVR were retreated, of whom 67 subsequently achieved SVR. Ultimately, 192 of 530 patients (36%) achieved SVR. The patients with successful retreatment were considered as patients without SVR in the analysis until after successful treatment, at which point they were treated as patients with SVR for the remainder of the follow-up. Thirteen patients with SVR and 100 patients without SVR died (10-year cumulative all-cause mortality rate 8.9% [95% confidence interval (CI) 3.3%-14.5%] with SVR and 26.0% [95% CI 20.2%-28.4%] without SVR P < 0.001) (Fig. 1). In multivariate analysis including age, sex, SVR, and variables with P < 0.20 in univariate analyses, Cox proportional hazards regression analysis showed that SVR was associated with a statistically significant reduction in the hazard of overall death (adjusted hazard ratio [HR] 0.26, 95% CI 0.14-0.49, P < 0.001). Of the deaths that occurred, 70% of the deaths in patients without SVR were determined to be liver-related deaths, whereas only 23% of deaths were liver-related in patients who achieved SVR. This suggests that much of the benefit that achieving SVR affords in reducing all-cause mortality is manifested in the decrease of liver-related deaths—which is often used as a surrogate endpoint.

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Figure 1. Survival outcomes for all-cause mortality in patients with HCV and advanced hepatic fibrosis with and without sustained virologic response (SVR).

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Other baseline factors significantly associated with increased risk of all-cause mortality in multivariate analysis were older age, HCV genotype 3 (compared to nongenotype 3), Ishak score of 6 (compared to 4), diabetes, and a history of severe alcohol use. Patients with HCV genotype 3 had an ∼2-fold increased risk of all-cause mortality (adjusted HR 2.08, 95% CI 1.18-3.66, P = 0.01) and HCC (adjusted HR 2.07, 95% CI 1.06-4.05, P = 0.03) but not the combined endpoint of liver-related mortality or liver transplantation (adjusted HR 1.18, 95% CI 0.62-2.27, P = 0.62). Genotype 3 infection has previously been associated with more rapid fibrosis progression and a higher risk of HCC, the latter of which may be explained by the more frequent presence of hepatic steatosis in patients with HCV genotype 3 infection, which, independent of cirrhosis, is a risk factor for HCC.[7-10] In the Veteran study, all-cause mortality rates were similarly elevated in patients with genotype 3 who did not have SVR compared to patients with genotype 1 or 2 who did not have SVR.[5] This study by van der Meer et al. further substantiates increased all-cause mortality in patients with HCV genotype 3 compared to other HCV genotypes. Data such as these should prompt clinicians to treat this population sooner rather than delaying therapy while awaiting newer antiviral agents for HCV genotype 3.

With regard to the other liver-related outcomes, van der Meer et al. found SVR was associated with reduced risk of HCC (adjusted HR 0.19, 95% CI 0.08-0.44, P < 0.001), liver failure (adjusted HR 0.07, 95% CI 0.03-0.20, P < 0.001) and the composite endpoint of liver transplantation/liver-related mortality (adjusted HR 0.06, 95% CI 0.02-0.19, P < 0.001). SVR reduced but did not eliminate the risk of HCC. Seven patients with SVR were diagnosed with HCC up to 6.8 years after SVR. Seventy-six patients without SVR developed HCC (10-year cumulative incidence rate, 5.1% [95% CI 1.3%-8.9%] with SVR versus 21.8% [95% CI 16.6%-27.0%, P < 0.001]). This finding of continued, although markedly diminished, risk of HCC after SVR raises questions about whether continued screening for HCC in patients with SVR would be beneficial or cost-effective.

In August 2012, the U.S. Centers for Disease Control and Prevention (CDC) recommended one-time HCV screening, without prior ascertainment of HCV risk, for all persons born during 1945-1965.[11] Conversely, the U.S. Preventive Services Task Force (USPSTF) issued a draft Recommendation Statement in November 2012 that gave such birth-cohort screening only a grade C recommendation.[12] Grade C is defined as clinicians may provide this service to selected patients depending on individual circumstances; however, for most individuals without signs or symptoms there is likely to be only a small benefit from this service. One issue that likely led to the unexpected grade C recommendation by the USPSTF was the scant evidence that birth cohort screening would lead to decreased all-cause mortality—the ultimate clinical outcome. The present work by van der Meer et al. further contributes to the body of evidence that SVR achieved from HCV antiviral treatment is associated with significant reduced all-cause mortality. These data, however, face the limitation of all such observational outcome data that patients cannot be randomized to SVR versus no SVR. Thus, SVR may be a marker for some other unmeasured residual confounder responsible for the lower all-cause mortality. Given the extent of the effect demonstrated by van der Meer et al.—the risk of all-cause mortality was almost 4-fold lower in patients with SVR compared with patients without SVR—however, it is difficult to envision what such a confounder could be.

Although extrapolating these data as support for expanded birth cohort testing is enticing, one must also consider the issue of how the patients followed in the present study were initially identified as being HCV-positive and whether that can be extrapolated to other populations. Given the time of first antiviral therapy (1990-2003), it is likely that patients were identified through HCV testing prompted by high-risk behavior, symptoms, or laboratory abnormalities. Hence, it is conceivable that the observed reduction in all-cause mortality would not have been as pronounced in a cohort identified through other criteria, such as birth cohort, where no specific clinical indicator prompted HCV testing. The population reported on by Van der Meer et al. may represent a different population than that which would have been identified by broad-based birth cohort screening in terms of risk of HCV disease progression and necessity of antiviral therapy.

Nevertheless, the well-designed, long-term follow-up study by van der Meer et al. has several key strengths that provide strong evidence on the association between virologic and clinical outcomes and, in particular, all-cause mortality. With strengths such as a median follow-up duration of 8.4 years and 86% of patients completing follow-up in addition to the evaluation of all-cause mortality as a single outcome, the prolonged survival in those patients with histologic proof of advanced fibrosis or cirrhosis experiencing SVR lends credence to the ultimate value of antiviral therapy with peginterferon plus ribavirin. Given the even higher SVR rates observed with direct-acting antiviral agents, now the standard of care for genotype 1 HCV infection, one might expect even more of a benefit in reduction of all-cause mortality with these more potent regimens.

  • Lisa I. Backus, M.D., Ph.D1

  • Pamela S. Belperio, Pharm.D.2

  • Office of Public Health/Population Health

  • Department of Veterans Affairs

  • 1Palo Alto Health Care System

  • Palo Alto, CA

  • 2Greater Los Angeles Health Care System

  • Los Angeles, CA

References

  1. Top of page
  2. Abstract
  3. Comment
  4. References