Effect of HCV RNA suppression during peginterferon alfa-2a maintenance therapy on clinical outcomes in the HALT-C trial

Abstract

Background & aims: The Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial demonstrated that low-dose peginterferon maintenance therapy was ineffective in preventing clinical outcomes in patients with chronic hepatitis C, advanced fibrosis, and failure to achieve a sustained virologic response during lead-in phase treatment with standard dose peginterferon/ribavirin. This analysis was performed to determine whether suppressing HCV RNA during the trial was associated with a reduction in clinical outcomes.

Methods: Seven hundred sixty-four patients treated during the lead-in phase of HALT-C trial were randomized to either peginterferon alfa-2a (90 microg/week) maintenance therapy or no treatment (control) for 3.5 years. Clinical outcomes included an increase in Child-Turcotte-Pugh score, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage, hepatocellular carcinoma, and mortality.

Results: During the lead-in, >or=4-log(10) decline in serum HCV RNA occurred in 178 patients; 82% of whom lost detectable HCV RNA and later broke through or relapsed. These patients had significantly (P = .003) fewer clinical outcomes whether randomized to maintenance therapy or control. Following randomization, serum HCV RNA increased significantly in all 90 control patients and in 58 of 88 receiving maintenance therapy. Only 30 patients had persistent suppression of HCV RNA by >or=4 log(10) during maintenance therapy. No significant reduction in clinical outcomes was observed in these patients.

Conclusions: Viral suppression by >or=4 log(10) with full-dose peginterferon/ribavirin is associated with a significant reduction in clinical outcomes. Continuing low-dose peginterferon maintenance therapy, even in patients with persistent viral suppression, does not lead to a further decline in clinical outcomes.

Trial registration: ClinicalTrials.gov NCT00006164.

Figures

Figure 1

Change in serum HCV RNA level over time. During the lead-in phase (stippled area) patients were treated with peginterferon alfa-2a 180 mcg/ml and ribavirin. (A) Nonresponder group: Patients were serum HCV RNA- positive at week 20. At treatment week 24 (month 0) these patients were randomized to either peginterferon alfa-2a 90 mcg/ml maintenance therapy without ribavirin or to the no treatment control group. (B) Breakthrough/relapse group: Patients had undetectable serum HCV RNA at week 20. These patients received up to 48 weeks of treatment and were randomized (month 0) to either peginterferon alfa-2a 90 mcg/ml maintenance therapy or to the no treatment control group after breakthrough or relapse occurred. For simplicity, and for comparison with the nonresponder group, the time listed on the x-axis corresponds to months after randomization. The wider lead-in phase (stippled area) along the x-axis in the breakthrough/relapse group reflects the longer duration of treatment these patients received prior to randomization.

Figure 2

Number of patients who achieved serum HCV RNA suppression to varying degrees during the lead-in phase. Among patients with a ≥4 log10 decline in serum HCV RNA at the end of the lead-in phase, 77/90 (86%) who entered the control arm and 69/88 (78%) randomized to maintenance peginterferon had undetectable serum HCV RNA at week 20 and received up to 48 weeks of treatment. Numbers at the bottom of each bar represent the number of patients in each group.

Figure 3

Impact of viral suppression during the lead-in phase on clinical (A) and fibrosis (B) outcomes after randomization. Patients were grouped according to the degree of viral suppression during the lead-in phase. Panel A: A significant reduction in clinical outcomes was associated with a decline in serum HCV RNA during the lead-in phase (p=0.003). No difference in clinical outcomes existed between the control and maintenance therapy groups (p=0.56). Panel B: No significant reduction in fibrosis outcome was associated with a decline in serum HCV RNA during the lead-in phase (p=0.42). No difference in outcomes existed between the control and maintenance therapy groups (p=0.88). Numbers at the bottom of each bar represent the number of patients in each group. Error bars indicate the standard error.

Figure 3

Impact of viral suppression during the lead-in phase on clinical (A) and fibrosis (B) outcomes after randomization. Patients were grouped according to the degree of viral suppression during the lead-in phase. Panel A: A significant reduction in clinical outcomes was associated with a decline in serum HCV RNA during the lead-in phase (p=0.003). No difference in clinical outcomes existed between the control and maintenance therapy groups (p=0.56). Panel B: No significant reduction in fibrosis outcome was associated with a decline in serum HCV RNA during the lead-in phase (p=0.42). No difference in outcomes existed between the control and maintenance therapy groups (p=0.88). Numbers at the bottom of each bar represent the number of patients in each group. Error bars indicate the standard error.

Figure 4

Percent of patients with a decline in serum HCV RNA by various log10 amounts from the pretreatment baseline while receiving peginterferon (90 mcg/week) maintenance therapy. The mean log10 HCV RNA over the first 3 years of maintenance therapy was used for this assessment. Patients were grouped according to their decline in serum log10 HCV RNA from the pre-treatment baseline during the lead-in phase. Numbers of patients in each group: < 2 log10 = 210, 2–4 log10 = 80, ≥ 4 log10 = 88.

Figure 5

Impact of serum HCV RNA level during peginterferon (90 mcg/week) maintenance therapy on clinical and fibrosis outcomes (% ± SE). Patients were grouped according to the mean decline in serum HCV RNA level from the pretreatment baseline after randomization. No significant reductions in clinical outcomes (p=0.74) or fibrosis outcomes (p=0.80) were observed with increasing amounts of viral suppression during maintenance therapy. Numbers at the bottom of each bar represent the number of patients in each group.