Reduction in Hepatic Inflammation Is Associated With Less Fibrosis Progression and Fewer Clinical Outcomes in Advanced Hepatitis C

Abstract

Objectives: During the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial, 3.5 years of maintenance peginterferon-alfa-2a therapy did not affect liver fibrosis progression or clinical outcomes among 1,050 previous interferon nonresponders with advanced fibrosis or cirrhosis. We investigated whether reduced hepatic inflammation was associated with clinical benefit in 834 patients with a baseline and follow-up biopsy 1.5 years after randomization to peginterferon or observation.

Methods: Relationships between change in hepatic inflammation (Ishak hepatic activity index, (HAI)) and serum alanine aminotransferase level, fibrosis progression and clinical outcomes after randomization, and hepatitis C virus (HCV) RNA decline before and after randomization were evaluated. Histological change was defined as a ≥ 2-point difference in HAI or Ishak fibrosis score between biopsies.

Results: Among 657 patients who received full-dose peginterferon/ribavirin "lead-in" therapy before randomization, year-1.5 HAI improvement was associated with lead-in HCV RNA suppression in both the randomized treated (P<0.0001) and control (P=0.0001) groups, even in the presence of recurrent viremia. This relationship persisted at year 3.5 in both the treated (P=0.001) and control (P=0.01) groups. Among 834 patients followed for a median of 6 years, fewer clinical outcomes occurred in patients with improved HAI at year 1.5 compared with those without such improvement in both the treated (P=0.03) and control (P=0.05) groups. Among patients with Ishak 3-4 fibrosis at baseline, those with improved HAI at year 1.5 had less fibrosis progression at year 1.5 in both the treated (P=0.0003) and control (P=0.02) groups.

Conclusions: Reduced hepatic inflammation (measured 1.5 and 3.5 years after randomization) was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized treatment.

Trial registration: ClinicalTrials.gov NCT00006164.

Figures

Figure 1. Distribution of Changes in Hepatic Inflammation and ALT Between Baseline and Year 1.5 According to Randomized Treatment Status

Patients were categorized according to their randomization to observation or treatment (x-axis) and whether hepatic inflammation improved or worsened by ≥2 points or did not change (within 2 points) on the modified Ishak HAI score between baseline and year-1.5 liver biopsies (A). ALT improvement was defined as ALT decrease by >25%, ALT worsening as ALT increase by >25%, and no change as ALT change ≤25% between baseline and year 1.5 (B). Serum ALTs were measured every 3 months and ALT change was calculated using the formula: [(mean ALT between year 0.5 through year 1.5 – mean baseline ALT) / mean baseline ALT] x 100%. The percentage of patients in each group is shown. P values are based on a comparison between control (n = 414) and treated groups (n = 420) in the percentage of patients with improved HAI or ALT.

Figure 2. HCV RNA Suppression During Lead-in Therapy is Associated with Improvement in Hepatic Inflammation and ALT During the Randomized Phase

Patients were categorized according to their randomized untreated control (left) or treated status (right) and their degree of HCV RNA suppression during the lead-in phase of the HALT-C Trial (x-axis): 10, 2-<4 log10, and ≥4 log10 decrease between baseline and week 20. Percentages of patients with improvement or worsening of hepatic inflammation by ≥2 points or with no change between baseline and year-1.5 biopsies are indicated on the y-axis and by the numbers in the columns (A). The mean change in HAI and associated standard error for the group of patients represented by each column is shown below the x-axis. The percentage of patients with ALT improvement (ALT decrease by >25%), ALT worsening (ALT increase by >25%) and no change (ALT change ≤25%) between baseline and year 1.5 are shown on the y-axis and by the numbers in the columns (B). The mean change in ALT and associated standard error for the group of patients represented by each column is shown below the x-axis. Percent ALT change was calculated as described for Figure 1. P values are based on a chi-square test for trend in the % improved. The number of patients represented by each column are as follows: PEG-RBV/Control groups <2 log10 reduction n = 185, 2 to <4 log10 reduction n = 66, ≥4 log10 reduction n = 78; PEG-RBV/PEG groups <2 log10 reduction n = 175, 2 to <4 log10 reduction n = 68, ≥4 log10 reduction n = 85.

Figure 3. For Patients Randomized to Maintenance Peginterferon, Persistent HCV RNA Suppression During Both Lead-in and Randomized Phases is Associated with the Greatest Improvement in Hepatic Inflammation and ALT

Patients were categorized according to their degree of HCV RNA suppression during the lead-in (week 20) and randomized phases (mean of years 0.5, 1.0, and 1.5) of the HALT-C Trial (x-axis): (1) 10 between baseline and week 20 (lead-in), n = 175; (2) ≥2 log10 decrease (lead-in) and <2 log10 (randomized), n = 99; and (3) ≥2 log10 decrease (lead-in) and ≥2 log10 (randomized), n = 54. Percentages of patients with improvement or worsening of hepatic inflammation by ≥2 points or with no change between baseline and year-1.5 biopsies are indicated by the numbers in the columns and y-axis (A). The percentage of patients with ALT improvement (ALT decrease by >25%), ALT worsening (ALT increase by >25%) and no change (ALT change ≤25%) between baseline and year 1.5 are shown by the numbers in the columns and y-axis (B). Percent ALT change was calculated as in Figure 1. P values are based on a chi-square test for trend in the % improved.

Figure 4. Change in Hepatic Inflammation and Serum ALT Over Time are Related Factors

Patients were categorized according to their randomization to observation or treatment (x-axis) and whether hepatic inflammation improved, did not change, or worsened between baseline and the year-1.5 liver biopsy by ≥2 points. Change in ALT (y-axis) was calculated as the average of the differences between the baseline ALT and the mean ALT (obtained every 3 months and averaged from year 0.5 to 1.5) for all patients in each category. The total number of patients in each column is shown. Mean ALT values were estimated by least squares regression and were adjusted for baseline ALT level. Error bars represent one standard error. Patients with improvement in hepatic inflammation had greater mean reduction in ALT than those without improvement, in both the treatment (P

Figure 5. Improvement in Hepatic Inflammation Is Associated with Fibrosis Progression

Only patients with precirrhotic fibrosis (Ishak fibrosis score 3 or 4) at study entry were included in these analyses. Patients were categorized according to their randomized untreated control (left) or treated status (right) and also according to their change in Ishak HAI between baseline and year-1.5 biopsies (A, x-axis) or between baseline and year-3.5 biopsies (B, x-axis). Percentages of patients with improvement in hepatic fibrosis (Ishak scale), worsening in hepatic fibrosis by ≥2 points (i.e., fibrosis progression), or no change (≤2 points) between baseline and year 1.5 (A) or year 3.5 (B) biopsies are shown. The percentage of patients in each group is indicated. The mean change in Ishak fibrosis score and associated standard error for each group of patients represented by a column is shown below the x-axis. Improved HAI was associated with less fibrosis progression in the same biopsy at years 1.5 and 3.5 in both control (P = 0.02 and 0.02 respectively) and treatment groups (P = 0.0003 and 0.0001), based on separate analyses for each group. P values are based on a chi-square test for trend in the % with fibrosis progression. The number of patients represented by each column are as follows: (A) change in HAI to year 1.5/control groups worse n = 73, same n = 114, improved n = 64; change in HAI to year 1.5/PEG-IFN groups worse n = 48, same n = 111, improved n = 101; (B) change in HAI to year 3.5/control groups worse n = 65, same n = 85, improved n = 61; change in HAI to year 3.5/PEG-IFN groups worse n = 32, same n = 89, improved n = 95.

Figure 6. Decreased Frequency of Clinical Outcomes to Year 7 in Both Untreated Control and Treated Groups is Associated with Improvement in Hepatic Inflammation at Year 1.5

The cumulative percentage of patients with clinical outcomes (defined in Materials and Methods) from Kaplan-Meier life table analyses are shown. Patients were categorized according to their randomized untreated control or treated status and the change in hepatic inflammation between baseline and year 1.5 (y-axis) (A) or change in serum ALT between baseline and year 1.5 (y-axis) (B). For panel A, sample sizes in the control group were: HAI worse (n = 109), HAI same (n = 203), HAI improved (n = 102) and in the treated group were: HAI worse (n = 73), HAI same (n = 178), HAI improved (n = 169). For panel B, sample sizes in the control group were: ALT worse (n = 61), ALT same (n = 248), ALT improved (n = 105) and in the treated group were: ALT worse (n = 73), ALT same (n = 200), ALT improved (n = 147). P values for differences among the three groups were derived from a Cox regression analysis for the control and treated groups evaluated separately.