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HCV Viral Load Reduction Improved Inflammation, Fibrosis, Clinical Outcomes with PegIFn Lead-In Maintenance therapy in HALT-C
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[from Jules: I don't know how many of you recall I protested and disagreed with the original report by the HALT-C investigators when they said in their initial presentation at AASLD several years ago that maintenance therapy was not useful & provided no improvement. I vehementky disagreed & said they were wrong, finally this publication agrees with me.]
"Our previous intention-to-treat analysis of the HALT-C Trial demonstrated no effect of long-term half-dose maintenance peginterferon treatment on the occurrence of clinical outcomes and fibrosis progression in 1,050 previous interferon nonresponders with advanced hepatic fibrosis (7). The current post-hoc analysis of a subset of HALT-C Trial patients expands and extends early observations on the impact of interferon-induced reduction of hepatic inflammation on fibrosis progression (6) owing to our focus on patients with advanced hepatic fibrosis, the measurement of clinical outcomes, the long duration of the follow-up period (up to 8.5 years), and the large sample size. We report that improved hepatic inflammation was associated with marked reductions in serum HCV RNA during the preceding 24-week lead-in phase of full-dose peginterferon/ribavirin treatment."
Of note, these results also suggest potential benefit for patients with advanced liver disease currently being treated with direct-acting antiviral agents in combination with peginterferon/ribavirin, regardless of whether they achieve SVR. We conclude that reduction of hepatic inflammation appears to be an important target for future therapeutic interventions to retard the progression of hepatitis C-related liver disease.........the 54 patients who were able to maintain ≥2 log10 suppression of HCV RNA levels during both lead-in and randomized phases (Figure 3a, third column) were more likely to have improved HAI (74%) compared with the remaining 274 patients who had less virological suppression during the same time period (31%, P<0.0001, Figure 3a, columns 1 and 2). Similarly, the same 54 patients who maintained ≥2 log10 suppression of HCV RNA levels during both lead-in and randomized phases were more likely to have improved ALT (54%) than the 274 patients who had less virological suppression (34%, P=0.007).
Fewer clinical outcomes occurred in patients with improved hepatic inflammation compared to patients without improved inflammation at year 1.5, regardless of whether patients were randomized to the control (HR 0.60, 95% CI 0.36-0.99, P=0.05) or treated groups (HR 0.63, 95% CI 0.41-0.95, P=0.03) (Figure 6a)........In the group randomized to maintenance peginterferon therapy, fibrosis progression occurred in 29% with worse HAI, in 18% with unchanged HAI, and in only 7% with improved HAI......The relationship between improved HAI and reduced fibrosis progression was also evident on the year-3.5 biopsy. We analyzed changes in inflammation and fibrosis in the same biopsies at year 1.5 (Figure 5a) or year 3.5 (Figure 5b). However, we also investigated whether improved HAI on the year-1.5 biopsy was associated with reduced fibrosis progression on the year-3.5 biopsy or on either the year-1.5 or year-3.5 biopsies considered together. In both cases, the association between improved HAI and reduced fibrosis progression held, with overall odds ratios of 0.54 (95% CI 0.32-0.92, P=0.02, N=427) and 0.52 (95% CI 0.33-0.81, P=0.004, N=511), respectively (the control and treated groups combined).
DISCUSSION
Our previous intention-to-treat analysis of the HALT-C Trial demonstrated no effect of long-term half-dose maintenance peginterferon treatment on the occurrence of clinical outcomes and fibrosis progression in 1,050 previous interferon nonresponders with advanced hepatic fibrosis (7). The current post-hoc analysis of a subset of HALT-C Trial patients expands and extends early observations on the impact of interferon-induced reduction of hepatic inflammation on fibrosis progression (6) owing to our focus on patients with advanced hepatic fibrosis, the measurement of clinical outcomes, the long duration of the follow-up period (up to 8.5 years), and the large sample size. We report that improved hepatic inflammation was associated with marked reductions in serum HCV RNA during the preceding 24-week lead-in phase of full-dose peginterferon/ribavirin treatment. Thus, improved hepatic inflammation in subsets of both the maintenance peginterferon and control groups could be explained by the fact that all of these patients were pretreated with full-dose peginterferon/ribavirin. Patients with profound virological suppression during the lead-in phase who were also able to maintain substantially suppressed viral levels during the randomized half-dose maintenance phase were most likely to experience improvement in hepatic inflammation. Most importantly, improved inflammation was associated with fewer clinical outcomes and less fibrosis progression compared to patients without such improvement.
We previously showed that maximal suppression of HCV RNA levels (≥4 log10) during lead-in therapy was the most important variable associated with a reduced frequency of subsequent clinical decompensation outcomes, although no direct relationship was found between HCV RNA suppression and histological fibrosis progression (8). Here we report that HCV RNA suppression during lead-in therapy was associated with reduction of hepatic inflammation and, separately, reduced hepatic inflammation was associated with less fibrosis progression. Overall, these data confirm the close association between HCV RNA levels and hepatic inflammation and suggest that amelioration of these factors is crucial to limiting liver disease progression (6,16).
The effect of virological suppression during lead-in therapy on reduction of hepatic inflammation appeared to be surprisingly durable even in patients with subsequent viral recrudescence, as reduced hepatic inflammation was found in a subset of patients randomized to the untreated-control group as long as 3.5 years after the cessation of peginterferon/ribavirin treatment. This observation confirms the notion that peginterferon therapy has two distinct effects that may be separable: (1) reduction of viremia and (2) long-term reduction of hepatic inflammation. This clinical observation is consistent with the many reports of the direct effects of interferon-alfa on viral replication (17), distinct from effects on proinflammatory lymphocyte function (18) and on inhibition of collagen production by hepatic stellate cells (19).
What could be the biological basis for the durability of the reduced hepatic inflammation induced by peginterferon/ribavirin treatment? The reduction in the hepatic inflammatory cell infiltrate and of hepatocyte death as documented in the year-1.5 and year-3.5 HAI scores, even with viral recurrence to near baseline levels, suggests the possibility that peginterferon/ribavirin may have had durable epigenetic molecular effect(s) on cells within the liver that have a role in liver inflammation. Whatever these effects might have been, peginterferon/ribavirin clearly had direct or indirect (downstream) effects on lymphocyte recruitment and activity in the liver, as indicated by reductions in portal and periportal inflammation and parenchymal injury in the HAI scores. Future detailed studies of liver samples from patients who experience maximal HCV RNA suppression will be necessary to determine what durable molecular events could account for the post-treatment effects we describe.
Worth emphasizing is the observation that the HALT-C Trial was dominated by patients who were null (virological) responders-who experienced <2 log10 HCV RNA reduction with full-dose peginterferon/ribavirin lead-in treatment (Figure 2, N=360 of 657). By contrast, most patients in this analysis with improved hepatic inflammation derived from the subset with profound virological suppression (≥4 log10) by week 20 of lead-in therapy who experienced subsequent virological breakthrough during or relapse after up to 24 more weeks of full-dose peginterferon/ribavirin treatment compared with the true nonresponders. Whether such profound and mostly sustained virological suppression (≥4 log10) by peginterferon/ribavirin treatment in this small subset was related to common host or viral characteristics among these patients is not known. Our findings are consistent with the possibilities that virological suppression can result in reduction of hepatic inflammation, that virological suppression serves as a marker of persons more likely to reduce hepatic inflammation as a consequence of treatment, or both. Moreover, our data are consistent with the notion that patients who can achieve profound virological suppression and reduction of hepatic inflammation may have the potential to benefit from longer-term pharmacological suppression of HCV replication. On the other hand, we also identified a potential cost of maintenance peginterferon therapy: almost 50% of patients who experienced worsening of hepatic inflammation with therapy had clinical outcomes (Figure 6a). Although the increased inflammation may have been a marker for those destined to have a poor outcome rather than a result of maintenance interferon therapy, these latter findings support our previous conclusion that the use of long-term interferon maintenance therapy in HCV-infected nonresponder patients with advanced liver disease cannot be recommended at this time.
Our findings may help to explain why we were unable to demonstrate clinical benefit of maintenance peginterferon among the 1,050 patients enrolled in the overall HALT-C Trial. The majority of patients were true null virological responders with a <2 log10 decrease of HCV RNA during full-dose peginterferon/ribavirin therapy. Among these patients, few demonstrated improvement of hepatic inflammation, most demonstrated no change, and some demonstrated worsening inflammation during therapy. During subsequent randomized-phase treatment with half-dose peginterferon, the vast majority of patients exhibited <2 log10 virological suppression and relatively few patients experienced substantial virological suppression (7). Thus, based upon the data presented here and elsewhere (8), if virological suppression is required for clinical benefit to occur, then we speculate that the degree of virological suppression with half-dose peginterferon therapy during the maintenance phase was insufficient to reduce hepatic inflammation and clinical and fibrosis outcomes in the entire treated group. Alternatively, the durable histological impact of short-term virological suppression during lead-in therapy might have had an overwhelming, confounding effect that might have obscured a difference in fibrosis progression and clinical outcomes between the randomized control and maintenance-peginterferon groups in the HALT-C Trial.
In conclusion, analysis of laboratory data and paired serial liver biopsies from a subset of well-pedigreed patients with advanced hepatic fibrosis enrolled in the HALT-C Trial demonstrates the associations between peginterferon/ribavirin-induced virological suppression, hepatic inflammation, serum ALT levels, hepatic fibrosis progression, and liver disease outcomes (of hepatic decompensation, liver cancer, and death). Although maximal virological suppression during the lead-in phase of the Trial was shown to have no direct impact on fibrosis progression (8), profound suppression of HCV RNA, achieved in a small minority of patients, was found to be associated with decreased hepatic inflammation. Decreased hepatic inflammation, in turn, appeared to be a critical factor that was associated with reduced fibrosis progression and, to a lesser extent, fewer clinical outcomes. The surprisingly durable beneficial effect of peginterferon/ribavirin (3.5 years later) on hepatic inflammation was also associated with a sustained improvement of ALT, despite viral recrudescence at the time of repeat biopsy and serum laboratory measurements. Of note, these results also suggest potential benefit for patients with advanced liver disease currently being treated with direct-acting antiviral agents in combination with peginterferon/ribavirin, regardless of whether they achieve SVR. We conclude that reduction of hepatic inflammation appears to be an important target for future therapeutic interventions to retard the progression of hepatitis C-related liver disease.
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Reduction in Hepatic Inflammation Is Associated With Less Fibrosis Progression and Fewer Clinical Outcomes in Advanced Hepatitis C
The American Journal of Gastroenterology (12 June 2012)
Chihiro Morishima, Mitchell L Shiffman, Jules L Dienstag, Karen L Lindsay, Gyongyi Szabo, Gregory T Everson, Anna S Lok, Adrian M Di Bisceglie, Marc G Ghany, Deepa Naishadham, Timothy R Morgan, Elizabeth C Wright and for the HALT-C Trial Group15
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.
Introduction
Treatment with pegylated interferon-alfa plus ribavirin cures 40-50% of persons with chronic hepatitis C. The remaining patients have persistent viremia and the potential for progressive hepatic inflammation and fibrosis (1). Although some patients with untreated chronic hepatitis C may have nonprogressive liver disease, insidious progression to cirrhosis occurs in at least 20-25% of patients over 2 decades, increasing the risk for hepatic decompensation, hepatocellular carcinoma, and liver-related death (2).
The achievement of a sustained virological response (SVR), i.e., the absence of detectable hepatitis C virus (HCV) RNA for at least 24 weeks following a course of antiviral therapy, is associated with a marked reduction in the incidence of end-stage liver disease and its consequences of decompensated liver disease and death (3). Even in the absence of SVR, 40-75% of treated patients have been reported to achieve histological benefit from interferon-based therapy (4,5). In a key study, investigators analyzed 53 patients with a wide range of liver fibrosis who exhibited reduction of HCV RNA levels (but not SVR) and improvement in hepatic inflammation during an initial course of interferon monotherapy. Among these patients, 2 years of additional maintenance therapy was associated with continued suppression of hepatic necroinflammatory activity but not with significantly reduced fibrosis progression (6).
These early observations provided the rationale for the prospective, multicenter Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. The primary goal of the HALT-C Trial was to determine whether 3.5 years of treatment with half-dose maintenance peginterferon-alfa therapy could prevent fibrosis progression and/or the development of hepatic decompensation and other clinical outcomes in previous interferon nonresponders with advanced hepatic fibrosis (Ishak fibrosis score ≥3). Our intention-to-treat analysis of the 1,050 patients enrolled in the HALT-C Trial indicated that maintenance peginterferon treatment did not yield clinical benefit (7). In a recent sub-analysis of this cohort, however, we demonstrated that patients with ≥4 log10 virological suppression during full-dose peginterferon/ribavirin lead-in therapy had fewer clinical outcomes over the 3.5 years after randomization compared to those without such profound virological suppression (8). In the current analysis, we investigated the relationship between peginterferon/ribavirin-induced virological suppression and changes in hepatic inflammation based on serial liver biopsies separated by 1.5 and 3.5 years in this large cohort of patients with advanced liver disease. Furthermore, we evaluated improvement in hepatic inflammation as a potential mechanism by which reduced alanine aminotransferase (ALT) levels, hepatic fibrosis progression, and clinical outcomes (up to 8.5 years) could have occurred in a subset of HALT-C Trial patients.
RESULTS
Characteristics of the study cohort
All patients in this analysis were required to have had a year-1.5 liver biopsy. Table 1 shows the baseline clinical, demographic, laboratory, and histological characteristics of this cohort (N=834) according to treatment status. Patients in the treatment group were older and more likely to have HCV genotype 1 infection, but the differences were small.
Although our previous intention-to-treat analysis of 1,050 HALT-C Trial patients demonstrated no clinical benefit of maintenance peginterferon treatment, we reported modest but statistically significant reductions in hepatic inflammation (HAI), and serum ALT and HCV RNA levels in treated patients (7). Figure 1 shows, by treatment group, the frequency of patients who experienced improvement, no change, or worsening of HAI on their year-1.5 biopsy compared with baseline as well as changes in serum ALT to year 1.5 compared with baseline. For all analyses involving histological liver inflammation, we chose to focus mainly on the year-1.5 results (N=834; N=414 control and N=420 treated) because the sample size was substantially smaller at year 3.5 (N=652); however, the analyses of the year-3.5 data were consistent with those found at year 1.5, as discussed below.
The mean change in HAI from baseline to year 1.5 was 0.12 (95% CI -0.12 to 0.35) in the control group and -0.87 (95% CI -1.10 to -0.64) in the treated group (P<0.0001 for control vs. treated). The significant difference between the control and treated groups involved three of the four components of the HAI (12) (parenchymal injury P<0.0001, periportal inflammation P<0.0001, and portal inflammation P=0.002). The fourth component, confluent necrosis, could not be analyzed because only one patient had any necrosis scored on the year-1.5 biopsy. Similar results were found for the change to year 3.5.
Relationships between HCV RNA suppression and hepatic inflammation and serum ALT levels
The majority of patients in this analysis underwent lead-in treatment with full-dose peginterferon/ribavirin therapy immediately preceding randomization to maintenance peginterferon or observation (N=657). To investigate the relationships between virological suppression and improvement in hepatic inflammation and/or ALT levels, we analyzed HAI improvement according to randomization status and the degree of HCV RNA suppression at week 20 of lead-in therapy (Figure 2a). A higher proportion of patients with improved HAI had greater reduction in HCV RNA levels during the preceding lead-in phase in both the control (P<0.0001) and treated groups (P<0.0001). This finding was also reflected in greater mean HAI improvement according to greater HCV RNA level reduction. A substantial proportion of patients in both the treated and control groups (31-53%), including those with maximal virological suppression (≥4 log10) during lead-in treatment (31 and 40%), demonstrated no change in hepatic inflammation on the year-1.5 biopsy. Other patients experienced worsening of hepatic inflammation in both the control (19-32%) and peginterferon (5-23%) groups. Worth noting, HCV RNA levels in 94% of control-group patients and 57% of treated-group patients were within 0.5 log10 of baseline levels by year 0.5 (6 months after completion of lead-in therapy); moreover, HCV viremia persisted at this level through collection of the year-1.5 and -3.5 biopsies.
Hepatitis C virus (HCV) RNA suppression during lead-in therapy is associated with improvement in hepatic inflammation and alanine aminotransferase (ALT) level 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 Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial (x-axis): <2 log10, 2-<4 log10, and ≥4 log10 decrease between baseline and week 20. (a) 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. The mean change in hepatic activity index (HAI) and associated s.e. for the group of patients represented by each column is shown below the x-axis. (b) 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. The mean change in ALT and associated s.e. 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 percent improved. The number of patients represented by each column are as follows: peginterferon/ribavirin (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.
A larger reduction in HCV RNA levels during lead-in treatment was also associated with improvement in serum ALT between years 0.5 and 1.5 after randomization compared with baseline (Figure 2b) in both the control (P<0.0001) and treated groups (P=0.0002). Virological response to peginterferon/ribavirin treatment during lead-in for patients included in Figure 2 was associated with expected clinical and demographic factors, as previously published (11) and shown in Supplementary Tables 1 and 2 online.
Among the 516 lead-in patients who had biopsy results at both year 1.5 and year 3.5, virological suppression during lead-in treatment was significantly associated with improvement of hepatic inflammation on the year-3.5 biopsy in both the control and treated groups (P=0.01 and P=0.001, respectively). The mean (SE) changes in HAI at year 3.5 were 0.16 (0.23), 0.33 (0.37), and -0.82 (0.33) in the control group (P=0.03) and -0.64 (0.22), -1.05 (0.34), and -2.23 (0.30) in the treated group (P=0.0002) for HCV RNA decreases of <2, 2-<4, and ≥4 log10, respectively. Similarly, greater HCV RNA reduction during lead-in treatment was associated with a more substantial reduction in ALT levels between years 0.5 and 3.0 of the study in both the randomized control and treated groups (P<0.0001 and P=0.0003, respectively). The mean ALT changes according to HCV RNA decline during lead-in treatment were -0.21 (0.09), -0.14 (0.16), and -0.88 (0.15) in the control group (P=0.0002) and -0.32 (0.10), -0.57 (0.17), and -0.79 (0.15), in the treated group (P=0.03).
Virological suppression during maintenance peginterferon therapy was modest; however, among patients randomized to treatment (N=328), those with maximal and persistent virological suppression exhibited the greatest improvement in HAI and ALT (Figure 3). Specifically, the 54 patients who were able to maintain ≥2 log10 suppression of HCV RNA levels during both lead-in and randomized phases (Figure 3a, third column) were more likely to have improved HAI (74%) compared with the remaining 274 patients who had less virological suppression during the same time period (31%, P<0.0001, Figure 3a, columns 1 and 2). Similarly, the same 54 patients who maintained ≥2 log10 suppression of HCV RNA levels during both lead-in and randomized phases were more likely to have improved ALT (54%) than the 274 patients who had less virological suppression (34%, P=0.007). Clinical and demographic information for patients included in Figure 3 demonstrated only differences in racial composition between the groups (see Supplementary Table 3 online).
For patients randomized to maintenance peginterferon, persistent hepatitis C virus (HCV) RNA suppression during both lead-in and randomized phases is associated with the greatest improvement in hepatic inflammation (HAI) and alanine aminotransferase (ALT) level. 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 Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial (x-axis): (1) <2 log10 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. (a) 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. (b) 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. Percent ALT change was calculated as in Figure 1. P values are based on a chi-square test for trend in the percent improved. HAI, hepatic activity index.
Relationship between improvement in hepatic inflammation and serum ALT
The relationship between improved serum ALT and hepatic inflammation is shown in Figure 4. Patients with improved HAI had significantly greater improvement in mean ALT than patients without improved HAI in both the control and treated groups (P<0.0001 both groups). Similar results were found when ALT data through year 3 and the year-3.5 HAI were evaluated (P=0.004 in the control group and P=0.02 in the treated group).
Relationship between hepatic inflammation and histological fibrosis progression
We reported previously that virological suppression during the lead-in or randomized phases of the HALT-C Trial did not influence fibrosis progression (data not shown) (8). Here we explored the relationship between HAI change and fibrosis progression in the same biopsies among patients with Ishak fibrosis scores of 3 and 4 at study entry (Figure 5). Patients with Ishak fibrosis stages 5 and 6 were excluded from this analysis because they could not progress by ≥2 points. The majority of patients (71-84%) demonstrated no change from baseline to year 1.5 in their fibrosis scores (Figure 5a). Fibrosis progression was significantly associated with change in hepatic inflammation in both the control and treated groups (P for trend=0.02 and 0.0003). In the control group, fibrosis progression occurred in 26% with worse HAI, in 13% with unchanged HAI, and in 11% with improved HAI. In the group randomized to maintenance peginterferon therapy, fibrosis progression occurred in 29% with worse HAI, in 18% with unchanged HAI, and in only 7% with improved HAI. The odds ratios for the association between improved HAI and fibrosis progression were 0.55, 95% CI 0.23-1.32, P=0.18 in the control group and 0.27, 95% CI 0.12-0.65, P=0.003 in the treated group. Mean changes in the Ishak fibrosis score also reflected the association between HAI improvement and lack of fibrosis progression. The relationship between improved HAI and reduced fibrosis progression was also evident on the year-3.5 biopsy (Figure 5b, P=0.01 and 0.0001 in the control and treated groups, respectively). We analyzed changes in inflammation and fibrosis in the same biopsies at year 1.5 (Figure 5a) or year 3.5 (Figure 5b). However, we also investigated whether improved HAI on the year-1.5 biopsy was associated with reduced fibrosis progression on the year-3.5 biopsy or on either the year-1.5 or year-3.5 biopsies considered together. In both cases, the association between improved HAI and reduced fibrosis progression held, with overall odds ratios of 0.54 (95% CI 0.32-0.92, P=0.02, N=427) and 0.52 (95% CI 0.33-0.81, P=0.004, N=511), respectively (the control and treated groups combined). In this analysis, no relationship was found between the treatment group and fibrosis progression. As previously reported for the full cohort (7), no significant effect of half-dose maintenance peginterferon therapy on fibrosis progression was found at either year 1.5 (P=0.77) or year 3.5 (P=0.78).
In the patient subgroup with cirrhosis (Ishak stages 5 and 6) at baseline, we found a trend towards improvement in hepatic fibrosis by ≥2 points among patients with reduced hepatic inflammation by ≥2 points (fibrosis improved in 15% with worse HAI, in 21% with unchanged HAI, and in 26% with improved HAI); however, the sample sizes were relatively small (N=61, 156, and 106, respectively), and the trend fell short of statistical significance (P=0.08). When analyzed separately by the treatment group, we found that the trend towards significance was present in the control group (P=0.07) but not in the treated group (P=0.44).
Improvement in hepatic inflammation and serum ALT and relationships with clinical outcomes
We evaluated whether improvement in hepatic inflammation and/or ALT was associated with the occurrence of predefined clinical outcomes (hepatic decompensation, hepatocellular carcinoma, or death) during follow-up to 8.5 years. Fewer clinical outcomes occurred in patients with improved hepatic inflammation compared to patients without improved inflammation at year 1.5, regardless of whether patients were randomized to the control (HR 0.60, 95% CI 0.36-0.99, P=0.05) or treated groups (HR 0.63, 95% CI 0.41-0.95, P=0.03) (Figure 6a). Maintenance therapy had no impact on reducing clinical outcomes (P=0.67), as reported previously (7).
We also examined the relationship between ALT change to year 1.5 and clinical outcomes (Figure 6b). Fewer patients with year-1.5 improvement in ALT had clinical outcomes compared to patients without improvement in ALT in the control group (HR 0.56, 95% CI 0.34-0.91, P=0.02) but not in the treated group (HR 0.85, CI 0.57-1.28, P=0.44).
Consistent with our earlier report up to year 3.5 (8), maximal virological suppression (≥4 log10) during lead-in treatment was associated with fewer clinical outcomes to year 8.5 in both the control (HR 0.50, 95% CI 0.27-0.92, P=0.03) and treated groups (HR 0.37, 95% CI 0.18-0.73, P=0.004). When HAI change and week 20 lead-in virological suppression (<2 log10 vs. ≥2 log10) were analyzed in multivariate Cox regressions for the control and treated groups combined, both HAI improvement (HR 0.67, 95% CI 0.47-0.98, P=0.04) and virological suppression during the lead-in (HR 0.57, 95% CI 0.42-0.79, P=0.001) were associated with reduced clinical outcomes. However, when ALT improvement and week-20 lead-in virological suppression were both analyzed as predictors of outcomes, only virological suppression remained a significant predictor of outcomes. The 54 patients with persistent virological suppression ≥2 log10 during both the lead-in and randomized phases had fewer clinical outcomes compared to those with virological suppression <2 log10 during lead-in or ≥2 log10 during the lead-in phase and <2 log10 during the randomized phase (P=0.007). Finally, when both HAI improvement and ALT improvement were included in a Cox regression analysis for prediction of clinical outcomes, the HR for HAI improvement remained statistically significant (HR 0.64, 95% CI 0.46-0.89, P=0.007), but the HR for ALT improvement was no longer statistically significant (HR 0.79, 95% CI 0.58-1.08, P=0.14).
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