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Randomized Controlled Trial
, 52 (3), 833-44

Outcome of Sustained Virological Responders With Histologically Advanced Chronic Hepatitis C

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Randomized Controlled Trial

Outcome of Sustained Virological Responders With Histologically Advanced Chronic Hepatitis C

Timothy R Morgan et al. Hepatology.

Abstract

Retrospective studies suggest that subjects with chronic hepatitis C and advanced fibrosis who achieve a sustained virological response (SVR) have a lower risk of hepatic decompensation and hepatocellular carcinoma (HCC). In this prospective analysis, we compared the rate of death from any cause or liver transplantation, and of liver-related morbidity and mortality, after antiviral therapy among patients who achieved SVR, virologic nonresponders (NR), and those with initial viral clearance but subsequent breakthrough or relapse (BT/R) in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) Trial. Laboratory and/or clinical outcome data were available for 140 of the 180 patients who achieved SVR. Patients with nonresponse (NR; n = 309) or who experienced breakthrough or relapse (BT/R; n = 77) were evaluated every 3 months for 3.5 years and then every 6 months thereafter. Outcomes included death, liver-related death, liver transplantation, decompensated liver disease, and HCC. Median follow-up for the SVR, BT/R, and NR groups of patients was 86, 85, and 79 months, respectively. At 7.5 years, the adjusted cumulative rate of death/liver transplantation and of liver-related morbidity/mortality in the SVR group (2.2% and 2.7%, respectively) was significantly lower than that of the NR group (21.3% and 27.2%, P < 0.001 for both) but not the BT/R group (4.4% and 8.7%). The adjusted hazard ratio (HR) for time to death/liver transplantation (HR = 0.17, 95% confidence interval [CI] = 0.06-0.46) or development of liver-related morbidity/mortality (HR = 0.15, 95% CI = 0.06-0.38) or HCC (HR = 0.19, 95% CI = 0.04-0.80) was significant for SVR compared to NR. Laboratory tests related to liver disease severity improved following SVR.

Conclusion: Patients with advanced chronic hepatitis C who achieved SVR had a marked reduction in death/liver transplantation, and in liver-related morbidity/mortality, although they remain at risk for HCC.

Trial registration: ClinicalTrials.gov NCT00006164.

Figures

Figure 1
Figure 1
Flow-diagram of HALT-C subjects included in the current analysis. Of the 1145 patients entering the lead-in phase and receiving treatment with peginterferon alfa-2a 180 ug/week and ribavirin 1–1.2 grams/day, 180 achieved an SVR. Of these, 140 participated in the current study (SVR group). 813 patients from the HALT-C lead-in phase and 237 patients who were non-responders or relapsers to peginterferon/ribavirin given outside of the HALT-C Trial (Express) were randomized to either no treatment (control arm) or to peginterferon alfa-2a 90ug/week for 3.5 years, and then followed without treatment. For the current analysis, we excluded all patients randomized to receive peginterferon 90 ug/week in order to eliminate a possible effect of long-term interferon on outcomes. Among the 533 patients randomized to no treatment, 120 patients from the Express arm were excluded because data on whether the patients were NR or BT/R was not available. Of the remaining 333 nonresponders in the control arm, 24 were eliminated because they were not followed after randomization (17), received interferon treatment after randomization (6) or had undetectable HCV RNA during follow-up (1). Three of the 80 patients with BT/R were eliminated because they were not followed after randomization (2) or received treatment with peginterferon (1).
Figure 2
Figure 2
Cumulative proportion of patients with death from any cause or liver transplantation, or with liver-related clinical outcomes, during 7.5 years for patients with SVR, BT/R and NR, adjusted for variables that were significant in the Cox-proportional hazard analysis. (a) death from any cause or liver transplantation, (b) any liver related outcome, (c) decompensated liver disease, (d) HCC and (e) liver-related death or liver transplantation.
Figure 3
Figure 3
Mean (± standard error of the mean) value of laboratory tests at baseline, Month 18, and Month 72/84 for patients with SVR, BT/R and NR. (a) platelet count (× 1,000/mm3) (n=100 (SVR), 54 (BT/R) and 181 (NR)), (b) serum albumin (g/dL) (n=102 (SVR), 54 (BT/R) and 184 (NR)), (c) serum total bilirubin (mg/dL) (n=102 (SVR), 54 (BT/R) and 184 (NR)), and (d) INR (n=85 (SVR), 54 (BT/R) and 179 (NR)). Statistical comparisons within each group are between two adjacent time points (i.e., baseline vs. M18 and M18 vs. M72/84). *p<0.05; **p<0.001; +p<0.0001.

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