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Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

The objective of this study is to determine the efficacy and safety of peginterferon alfa-2a (40KD)/ribavirin in patients with advanced fibrosis. Data from 341 genotype 1/4 patients (99 with bridging fibrosis/cirrhosis) treated for 48 weeks and 1547 genotype 2/3 patients (380 with bridging fibrosis/cirrhosis) treated for 16 or 24 weeks enrolled in three randomized international studies were analyzed. Sustained virological response (SVR) rates decreased progressively from 60% in genotype 1/4 patients without advanced fibrosis to 51% in those with bridging fibrosis and 33% in those with cirrhosis (trend test P = 0.0028); and from 76% to 61% and 57%, respectively, in genotype 2/3 patients treated for 24 weeks (trend test P < 0.0001). Irrespective of genotype, patients without advanced fibrosis were more likely to have an earlier response to treatment that was associated with higher SVR rates and lower relapse rates during untreated follow-up. Among patients with or without a diagnosis of advanced fibrosis, rates of SVR and relapse were similar for patients with similar responses in the first 12 weeks. Conclusion: Compared with patients with less severe disease, SVR rates are significantly lower in patients with advanced fibrosis. However, irrespective of genotype and degree of fibrosis, the time to become hepatitis C virus (HCV) RNA undetectable was the strongest predictor of SVR. (HEPATOLOGY 2010.)

More than 170 million people are infected with hepatitis C virus (HCV) worldwide.1 Complications of chronic hepatitis C include cirrhosis, liver failure, and hepatocellular carcinoma. Approximately 25% of all cases of cirrhosis and hepatocellular carcinoma are attributable to chronic hepatitis C.2 Moreover, chronic hepatitis C is the leading reason for liver transplantation worldwide.1

Despite the declining incidence of HCV infection, the prevalence of serious complications continues to increase because of the slow progression of the disease.3 The patients with the greatest need for treatment, those with advanced fibrosis and in particular those with cirrhosis, have unsatisfactory sustained virological response (SVR) rates.4, 5 Nevertheless, achievement of an SVR in these individuals significantly reduces the incidence of hepatic decompensation, development of hepatocellular carcinoma, and death.6–8 Thus, improvements in the treatment of this “difficult to treat and manage” population are vital.

The concept of response-guided therapy has recently been introduced, although it has not yet been incorporated into consensus guidelines. This treatment paradigm involves monitoring the virological response during treatment, identifying patients with a higher or lower likelihood of achieving an SVR, and adjusting the therapeutic regimen accordingly.

Large clinical trials of combination therapy for chronic hepatitis C have generally included only a small proportion of patients with advanced fibrosis and cirrhosis. Indeed, only two randomized trials of antiviral therapy have been conducted exclusively in patients with cirrhosis or bridging fibrosis.4, 5 Therefore, few data are available about the efficacy, safety, and the overall value of response-guided therapy in this subset of patients.

The clinical trial program for peginterferon alfa-2a (40KD) plus ribavirin included a large subgroup of patients with advanced fibrosis and cirrhosis. This has allowed us to determine the efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in patients with advanced fibrosis and cirrhosis and the impact of rapid virological response (RVR) at week 4 and early virological response (EVR) at week 12 on treatment outcomes.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

Data included in this analysis were obtained from three large randomized international phase III studies in which patients were treated with the combination of peginterferon alfa-2a (40KD) plus ribavirin. The complete study design and primary efficacy and safety results of these trials are published elsewhere.9–11 Patients with HCV genotype 1 or 4 infection were included in the analysis if they were randomized to receive peginterferon alfa-2a (40KD) 180 μg/week plus a standard dose of ribavirin (1000 mg/day if their body weight was <75 kg or 1200 mg/day if their body weight was ≥75 kg) for 48 weeks.9, 10 Patients with HCV genotype 2 or 3 infection were included if they were randomized to receive peginterferon alfa-2a (40KD) 180 μg/week plus low-dose ribavirin (800 mg/day) for 16 or 24 weeks.10, 11

Patients

Patients eligible for enrollment in these studies were required to have chronic hepatitis C as evidenced by a positive HCV antibody test, quantifiable HCV RNA in serum (>600 IU/mL), elevated serum ALT levels, and a liver biopsy result consistent with the diagnosis of chronic hepatitis C. Patients with cirrhosis were eligible provided that they had compensated liver disease (in other words, a Child-Pugh score <7). Patients co-infected with human immune deficiency virus or hepatitis B virus were excluded, as were those with serious concomitant chronic diseases or liver disease attributable to a cause other than HCV infection.

Outcomes

The primary efficacy outcome in each study was SVR, defined as undetectable HCV RNA by qualitative polymerase chain reaction (PCR) assay (<50 IU/mL) at the end of a 24-week untreated follow-up period.

Several secondary (post-hoc) efficacy outcomes were evaluated in this analysis. RVR was defined as undetectable HCV RNA by qualitative PCR assay (<50 IU/mL) after 4 weeks of treatment. In the original analyses, EVR at week 12 was defined as undetectable HCV RNA by qualitative PCR (<50 IU/mL) or a 2-log10 or more decrease in serum HCV RNA by quantitative PCR (limit of quantitation, 600 IU/mL). In this analysis, patients without an RVR but who achieved an EVR were divided into two groups: (1) those with a complete EVR, defined as detectable HCV RNA (≥50 IU/mL) at week 4, but undetectable HCV RNA (<50 IU/mL) at week 12; and (2) those with a slow response (SR) at week 12, defined as detectable HCV RNA (≥50 IU/mL) at week 4 and at week 12, but a 2-log or more decline in serum HCV RNA by week 12. End-of-treatment virological response was defined as undetectable HCV RNA (<50 IU/mL) by qualitative PCR at the end of the planned treatment duration. The positive predictive value and the negative predictive value of RVR for the achievement of SVR were also calculated. Exposure to peginterferon alfa-2a (40KD) and ribavirin was expressed as the percentage of the planned dose. Thus, a patient with exposure of 100% to either agent would have received the total dose as specified in the protocol. Dose reductions resulting from patient nonadherence (as indicated by pill counts and diaries), or physician-initiated dose reductions, were considered in the exposure analysis.

Safety was assessed by reports of adverse events and laboratory abnormalities, and by reductions in the dose of either study drug for adverse events or laboratory abnormalities.

Statistical Methods

In all analyses, patients were grouped according to the fibrosis score on the baseline liver biopsy assigned by the local pathologist. Those without advanced fibrosis (assigned scores of 2 or less on the Metavir and Knodell scales or 3 or less on the Ishak scale) were grouped together. Patients with bridging fibrosis, but without cirrhosis (assigned a score of 3 on the Metavir or Knodell scales, or 4 on the Ishak scale), and patients with cirrhosis (assigned a score of 4 on the Metavir or Knodell scales, or 5 or 6 on the Ishak scale) were considered separately. Patients with bridging fibrosis or cirrhosis are referred to collectively as having “advanced fibrosis.”

Differences in baseline characteristics, and efficacy and safety outcomes, between patients with and without advanced fibrosis were examined by chi-squared test or Fisher's exact test (categorical variables), Mantel-Haenszel chi-squared test (ordinal variables), or t test (continuous variables) as appropriate. The Cochran-Armitage trend test was used to investigate whether the severity of fibrosis (no advanced fibrosis, bridging fibrosis, and cirrhosis) was associated with a trend in treatment response. All statistical tests were two-sided, and a P-value below 0.05 was considered significant. Because of the exploratory nature of these analyses, no alpha-adjustments were applied to account for multiple significance testing.

Baseline and on-treatment (in other words, virological response) factors predictive of SVR in patients with advanced fibrosis were identified by multiple logistic regression (MLR) analysis. Baseline factors (sex, race, fibrosis status [bridging fibrosis versus cirrhosis], age, weight, body mass index, pretreatment serum HCV RNA level, ALT quotient, creatinine clearance, serum albumin, platelet count, and neutrophil count) were selected in a stepwise fashion with a threshold value of P = 0.1 for inclusion in the model and a threshold value of P = 0.05 for retention in the final model. In subsequent models, the on-treatment virological response (RVR or complete EVR versus slow response or no RVR, complete EVR, or slow response) and cumulative exposure to peginterferon alfa-2a (40KD) and ribavirin were included. In a final step, only patients who completed treatment were considered. This ensured that lower cumulative drug doses in some patients are not attributable to treatment discontinuation for insufficient virological response. MLR models for patients infected with genotype 2 or 3 included data from 729 patients (191 with advanced fibrosis) randomly assigned to 16 weeks of treatment in the trial by Shiffman et al.11 Treatment for 16 or 24 weeks was included as a potential predictor of SVR in genotype 2/3 patients to allow us to confirm whether abbreviated therapy is appropriate in these patients.

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

A total of 341 genotype 1 or 4 patients were included in the analysis, of whom 242 (71%) did not have advanced fibrosis, and 99 (29%) had advanced fibrosis on a pretreatment liver biopsy. A total of 1547 genotype 2 or 3 patients were included in the analysis, of whom 1167 (75%) did not have advanced fibrosis and 380 (25%) had advanced fibrosis on a pretreatment liver biopsy. Among patients with genotype 2 or 3 infection, 818 (189 with advanced fibrosis) were randomly assigned to 24 weeks of treatment, and 729 (191 with advanced fibrosis) were randomly assigned to 16 weeks of treatment.

Preliminary analyses showed that genotype 2 or 3 patients with cirrhosis randomly assigned to 16 weeks showed overall lower rates of SVR (48% versus 57%) and higher rates of relapse (49% versus 32%) compared with 24 weeks of treatment, respectively. This was also evident among patients with an RVR (SVR: 67% versus 79%, respectively). These observations were confirmed in the MLR analysis, suggesting that patients with cirrhosis should not be considered for an abbreviated duration of therapy irrespective of baseline characteristics or on-treatment responses. For this reason we have restricted detailed analysis to genotype 2 or 3 patients randomized to the standard 24-weeks treatment duration.

Baseline characteristics of patients with and without advanced fibrosis are presented in Table 1. Patients infected with any HCV genotype (1, 2, 3, or 4) with advanced fibrosis were typically older, heavier, and had higher baseline ALT levels and lower platelet and neutrophil counts than patients without advanced fibrosis. In addition, patients with HCV genotype 2 or 3 with advanced fibrosis were more likely to be male and to have lower serum albumin levels than patients without advanced fibrosis.

Table 1. Baseline Characteristics of Patients Included in the Analysis
 Patients with HCV Genotype 1 or 4 InfectionPatients with HCV Genotype 2 or 3 Infection
Treated for 48 WeeksTreated for 24 Weeks
Without Advanced Fibrosis (n = 242)With Advanced Fibrosis (n = 99)PWithout Advanced Fibrosis (n = 629)With Advanced Fibrosis (n = 189)P
  1. Values are mean ± SD unless otherwise specified. Advanced fibrosis is defined as a score of 3 or 4 on the Metavir or Knodell scales or 4 to 6 on the Ishak fibrosis scale.

  2. χ2-test for categorical data and t-test for continuous data.

  3. NS, not significant (P 0.05).

Male sex, n (%)157 (64.9)74 (74.7)NS384 (61.0)135 (71.4)0.009
Age, years41.4 ± 10.248.6 ± 9.0<0.00143.8 ± 10.348.7 ± 8.4<0.001
Weight, kg77.2 ± 16.381.2 ± 15.10.03279.9 ± 18.185.4 ± 18.3<0.001
BMI, kg/m226.3 ± 4.627.4 ± 4.50.03827.1 ± 5.428.6 ± 5.5<0.001
Race, n (%)      
 Caucasian205 (84.7)92 (92.9)NS554 (88.1)165 (87.3)NS
 Black12 (5.0)2 (2.0)19 (3.0)4 (2.1)
 Other25 (10.3)5 (5.1)56 (8.9)20 (10.6)
Serum ALT, IU/L82.1 ± 72.8102.5 ± 62.10.01079.5 ± 55.7107.7 ± 57.8<0.001
Serum ALT quotient2.7 ± 2.43.4 ± 2.10.0102.6 ± 1.93.6 ± 1.9<0.001
Serum albumin, g/dL43.3 ± 4.342.6 ± 4.5NS42.2 ± 3.140.7 ± 3.7<0.001
Platelets, cells/mm3 × 1000223.8 ± 63.7172.3 ± 53.7<0.001244.4 ± 61.5190.8 ± 56.7<0.001
Neutrophils, cells/mm3 × 10003.6 ± 1.43.3 ± 1.10.0134.1 ± 1.63.7 ± 1.50.007
Creatinine clearance, mL/min97.4 ± 25.195.4 ± 25.1NS102.0 ± 27.7103.2 ± 25.6NS
HCV RNA level, IU/mL × 1062.03 ± 2.141.96 ± 1.98NS5.21 ± 6.545.46 ± 7.44NS

Virological Outcomes

End of Treatment and SVR Rates According to Histological Diagnosis.

Among patients infected with genotype 1 or 4, the end-of-treatment virological response was higher in patients without advanced fibrosis (74%) and among those with bridging fibrosis (73%) than in patients with cirrhosis (53%) (trend test: P = 0.0197; Fig. 1A). Among patients infected with genotype 2 or 3, there were no statistically significant differences in the rate of virological responses at the end of treatment between patients without advanced fibrosis (89%), patients with bridging fibrosis (86%), and those with cirrhosis (84%) (trend test: P = 0.1332; Fig. 1B).

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Figure 1. Virological response rates at end of treatment and end of untreated follow-up in patients without advanced fibrosis, those with bridging fibrosis, and those with cirrhosis. (A) Patients infected with genotype 1 or 4 treated for 48 weeks with peginterferon alfa-2a (40KD) 180 μg/week plus ribavirin 1000 or 1200 mg/day. (B) Patients infected with genotype 2 or 3 treated for 24 weeks with peginterferon alfa-2a (40KD) 180 μg/week plus ribavirin 800 mg/day.

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Among patients infected with HCV genotype 1 or 4, the SVR rate was highest in patients without advanced fibrosis (60%) and was progressively lower in patients with bridging fibrosis (51%) and in those with cirrhosis (33%) (trend test: P = 0.0028; Fig. 1A).

SVR rates were also highest among patients infected with HCV genotype 2 or 3 without advanced fibrosis (76%) compared with those with bridging fibrosis (61%) and those with cirrhosis (57%) (trend test: P < 0.0001; Fig. 1B).

SVR According to On-Treatment Virological Response.

The rate of viral clearance at weeks 4 (RVR) and 12 (complete EVR) was higher in genotype 1 or 4 patients without advanced fibrosis than in those with advanced fibrosis (Table 2). Among genotype 1 or 4 patients with an RVR, SVR rates were very high and not significantly different in those without advanced fibrosis (95%) and those with bridging fibrosis (89%). Only two patients with cirrhosis achieved an RVR, and one of these patients achieved an SVR; nevertheless, the trend test for SVR rates across the three fibrosis categories was significant (P = 0.0398; Fig. 2A). The positive predictive value of an RVR in genotype 1 or 4 patients was 94.7% in those without advanced fibrosis, 81.8% in those with advanced fibrosis and 50.0% in those with cirrhosis. The corresponding negative predictive value was lower: 50% in those without advanced fibrosis, 60.5% in those with advanced fibrosis, and 67.6% in those with cirrhosis. There were no statistically significant decreases in SVR rates, with increasing fibrosis status in patients who achieved a complete EVR (range, 68%-72%, trend test; P = 0.7597) or who had a slow response (range, 20%-26%, trend test; P = 0.6892; Fig. 2A).

Table 2. Virological Response During Treatment
 Patients with HCV Genotype 1 or 4 infectionPatients with HCV genotype 2 or 3 infection
Treated for 48 WeeksTreated for 24 weeks
Without Advanced Fibrosis (n = 242)With Advanced Fibrosis (n = 99)**With Cirrhosis (n = 36)Without Advanced Fibrosis (n = 629)With Advanced Fibrosis (n = 189)*With Cirrhosis (n = 70)
  • *

    P = 0.031;

  • **

    P = 0.0044;

  • P = 0.053 versus patients without advanced fibrosis (Mantel-Haenszel χ2-test).

  • Rapid virological response (RVR) = HCV RNA <50 IU/mL at week 4; complete early virological response (cEVR) = HCV RNA ≥ 50 IU/mL at week 4 and <50 IU/mL at week 12; slow response (SR) = HCV RNA ≥50 IU/mL at week 4 and at week 12, but ≥2-log10 decrease in HCV RNA between baseline and week 12.

  • Advanced fibrosis is defined as a score of 3 or 4 on the Metavir or Knodell scales or 4 to 6 on the Ishak fibrosis scale.

Patients with an RVR, n (%)57 (23.6)11 (11.1)2 (5.6)428 (68.0)109 (57.7)33 (47.1)
Patients with a complete EVR, n (%)111 (45.9)39 (39.4)10 (27.8)155 (24.6)62 (32.8)30 (42.9)
Patients with slow response SR, n (%)38 (15.7)33 (33.3)18 (50.0)13 (2.1)5 (2.6)2 (2.9)
Patients with no RVR or EVR, n (%)36 (14.9)16 (16.2)6 (16.7)33 (5.2)13 (6.9)5 (7.1)
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Figure 2. Sustained virological response rates in patients without advanced fibrosis, those with bridging fibrosis, and those with cirrhosis according to the on-treatment virological response. RVR (rapid virologic response) = undetectable HCV RNA (<50 IU/mL at week 4; cEVR (complete early virologic response) = detectable HCV RNA (≥50 IU/mL) at week 4 and undetectable HCV RNA (<50 IU/mL) at week 12; SR (slow response) = detectable HCV RNA (≥50 IU/mL) at week 4 and week 12; ≥2-log10 drop in HCV RNA at week 12; no RVR/cEVR/SR = none of the criteria for RVR, cEVR, or SR are fulfilled. (A) Patients infected with genotype 1 or 4 treated for 48 weeks with peginterferon alfa-2a (40KD) 180 μg/week plus ribavirin 1000 or 1200 mg/day. (B) Patients infected with genotype 2 or 3 treated for 24 weeks with peginterferon alfa-2a (40KD) 180 μg/week plus ribavirin 800 mg/day.

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Among patients with genotype 2 or 3 infection, more patients without advanced fibrosis achieved an RVR (68%) when compared with patients with advanced fibrosis (58%). However, the proportion of patients with a complete EVR was higher with advanced fibrosis, indicating that the average time to achieve undetectable HCV RNA levels is longer in patients with advanced fibrosis. A small proportion of patients with or without advanced fibrosis achieved a slow response (2%-3% across histological categories) or failed to achieve an RVR, complete EVR, or a slow response (range, 5%-7% across all categories) (Table 2).

Overall SVR rates were considerably higher in genotype 2 or 3–infected patients who achieved an RVR than among those who achieved a complete EVR (Fig. 2B). The positive predictive value of an RVR in genotype 2 or 3 patients treated for 24 weeks was 87.1% in those without advanced fibrosis, 81.7% in those with advanced fibrosis, and 78.8% in those with cirrhosis. Consistent with the results for genotype 1 or 4 patients, the negative predictive value was lower for each category: 45.2% in those without advanced fibrosis, 71.8% in those with advanced fibrosis, and 63.9% in those with cirrhosis.

Of note, none of the 18 genotype 2 or 3 patients with a slow response achieved an SVR, and few patients who did not achieve an RVR, complete EVR, or a slow response achieved an SVR (Fig. 2B). No patients with bridging fibrosis or cirrhosis achieved an SVR in the absence of an RVR, complete EVR, or a slow response, irrespective of genotype (Fig. 2A, B).

Among genotype 2 or 3 patients who achieved an RVR, there were no significant trends in SVR rates in patients without advanced fibrosis (87%) and those with bridging fibrosis (83%) or cirrhosis (79%) (trend test; P = 0.1132, Fig. 2B).

Among patients with a complete EVR, SVR rates were 65% in those without advanced fibrosis, 31% in those with bridging fibrosis, and 47% in those with cirrhosis (trend test: P = 0.0043; Fig. 2B). Although this trend was significant, it did not mirror the severity of fibrosis.

Virological Relapse According to On-Treatment Virological Response.

Among all patients, relapse rates were significantly higher in patients with bridging fibrosis or cirrhosis than in those without advanced fibrosis (trend test: P = 0.0381 for genotype 1/4, P < 0.0001 for genotype 2/3; Fig. 3).

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Figure 3. Virological relapse rates between the end of treatment and end of untreated follow-up according to on-treatment virological response in patients without advanced fibrosis, those with bridging fibrosis, and those with cirrhosis. Only patients with an end-of-treatment response are in included. (A) Patients infected with genotype 1 or 4 treated for 48 weeks with peginterferon alfa-2a (40KD) 180 μg/week plus ribavirin 1000 or 1200 mg/day. (A) Patients infected with genotype 2 or 3 treated for 24 weeks with peginterferon alfa-2a (40KD) 180 μg/week plus ribavirin 800 mg/day RVR (rapid virologic response) = undetectable HCV RNA (<50 IU/mL at week 4; cEVR (complete early virologic response) = detectable HCV RNA (≥50 IU/mL) at week 4 and undetectable HCV RNA (<50 IU/mL) at week 12; SR (slow response) = detectable HCV RNA (≥50 IU/mL) at week 4 and week 12; ≥2-log10 drop in HCV RNA at week 12; no RVR/cEVR/SR = none of the criteria for RVR, cEVR, or SR are fulfilled.

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Relapse was typically uncommon in patients with an RVR, occurring more frequently in those with a complete EVR and a slow response (Fig. 3). However, within each time to response category (RVR, complete EVR, and slow response) the proportion of patients who experienced a relapse was similar regardless of histological diagnosis (Fig. 3).

Treatment Exposure.

Overall, the percentage exposure of the target dose was lower in genotype 1/4 patients than in genotype 2/3 patients, indicating that both the percent exposure of peginterferon alfa-2a (40KD) and ribavirin decreased with longer duration of treatment or higher starting dose of ribavirin. However, there were no consistent differences in exposure to peginterferon alfa-2a (40KD) or ribavirin between patients with and without advanced fibrosis (Fig. 4).

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Figure 4. Exposure to study drugs in patients with and without advanced fibrosis (advanced fibrosis = bridging fibrosis and cirrhosis combined).

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Predictors of SVR in Patients with Bridging Fibrosis or Cirrhosis.

When both baseline and on-treatment factors were considered in the MLR analysis of data from genotype 1 or 4 patients, the only significant predictors of achieving an SVR were the on-treatment virological response (RVR or complete EVR versus slow response or no EVR; odds ratio [OR] 22.40; 95% confidence interval [95%CI] 6.87-73.03, P < 0.0001) and cumulative ribavirin dose (OR 24.04 for receipt of ≥60% versus <60% of the planned dose, 95%CI 4.32-133.94, P = 0.0003). The results were similar (data not shown) when the analysis was restricted to patients who completed the planned duration of treatment.

When both baseline and on-treatment factors were considered, significant predictors of achieving an SVR in patients with advanced fibrosis and genotype 2 or 3 infection included on-treatment virological response (RVR versus no RVR; OR 11.35, 95%CI 6.56-19.61; P < 0.0001), female sex (OR 2.12 versus male, 95%CI 1.19-3.78, P = 0.0111); lower pretreatment serum HCV RNA level (OR 1.49 per 1-log10 IU/mL decrement, 95%CI 1.04-2.13; P = 0.0278); higher ALT quotient (OR 1.27 per 1-unit increment, 95% CI 1.10-1.47; P = 0.0009); higher serum albumin (OR 1.12 per 1-g increment, 95% CI 1.04-1.20, P = 0.0025); higher cumulative ribavirin dose (OR 9.79 for receipt of ≥60% versus <60% of the planned dose, 95%CI 2.64-36.36; P = 0.0007); and assignment to 24 weeks' treatment (OR 2.52 versus assignment to 16 weeks' treatment, 95%CI 1.47-4.29, P = 0.0007). When the analysis was restricted to patients who completed the planned duration of treatment, the predictors were similar with the exception of cumulative ribavirin dose, which was not retained in the final model (data not shown).

When both baseline and on-treatment factors were considered, significant predictors of achieving an SVR in patients with advanced fibrosis and genotype 2 infection included on-treatment virological response (RVR versus no RVR; OR 8.54, 95% CI 4.22-17.30; P < 0.0001); higher ALT quotient (OR 1.26, 95%CI 1.05-1.50; P = 0.0118); higher serum albumin (OR 1.14, 95%CI 1.03-1.26; P = 0.0141); higher cumulative peginterferon alfa-2a dose (OR 10.30 for receipt of ≥60% versus <60% of the planned dose, 95%CI 2.24-47.23; P = 0.0027); and assignment to 24 weeks' treatment (OR 2.24, 95%CI 1.11-4.51).

When both baseline and on-treatment factors were considered, significant predictors of achieving an SVR in patients with advanced fibrosis and genotype 3 infection included on-treatment virological response (RVR versus no RVR; OR 21.26, 95%CI 8.97-50.40; P < 0.0001); higher ALT quotient (OR 1.28, 95%CI 1.03-1.59; P = 0.0278); and assignment to 24 weeks' treatment (OR 3.16, 95%CI 1.36-7.33).

Safety and Tolerability.

There were no significant differences between patients with and without advanced fibrosis with respect to the incidence of serious adverse events, withdrawals for adverse events or laboratory abnormalities (neutropenia, thrombocytopenia), or the incidence of hemoglobin less than 8.5 g/dL or neutrophils less than 0.5 × 103 cells/mm3 (Table 3). However, there was a statistically significant difference in the incidence of platelet counts <50 × 103/mm3 during treatment between patients with and without bridging fibrosis/cirrhosis (Table 3). This difference was attributable largely to a significantly higher incidence of thrombocytopenia in patients with cirrhosis.

Table 3. Safety and Tolerability
 Patients with HCV Genotype 1 or 4 InfectionPatients with HCV Genotype 2 or 3 Infection
Treated for 48 WeeksTreated for 24 Weeks
Without Advanced Fibrosis (n = 242)With Advanced Fibrosis (n = 99)With Cirrhosis (n = 36)Without Advanced Fibrosis (n = 629)With Advanced Fibrosis (n = 189)With Cirrhosis (n = 70)
  • *

    P = 0.0056;

  • **

    P<0.0001 versus without advanced fibrosis;

  • P = 0.0002,

  • ††

    P <0.0001 versus all patients without cirrhosis (Fisher's exact test). Advanced fibrosis is defined as a score of 3 or 4 on the Metavir or Knodell scales or 4 to 6 on the Ishak fibrosis scale.

Patients with ≥1 serious adverse event, n (%)24 (9.9)10 (10.1)5 (13.9)36 (5.7)15 (7.9)7 (10.0)
Discontinued therapy due to an adverse event, n (%)29 (12.0)11 (11.1)7 (19.4)30 (4.8)10 (5.3)4 (5.7)
Discontinued therapy due to a laboratory event, n (%)      
 Neutropenia3 (1.2)001 (<0.1)00
 Thrombocytopenia00001 (0.5)1 (1.4)
Completed therapy, n (%)195 (80.6)75 (75.8)25 (69.4)554 (88.1)168 (88.9)64 (91.4)
Laboratory abnormalities, n (%):      
 Hemoglobin <8.5 g/dL4 (1.7)2 (2.0)2 (5.6)3 (<0.1)1 (0.5)1 (1.4)
 Neutrophils <0.5 × 103 cells/mm310 (4.1)3 (3.0)2 (5.6)23 (3.7)4 (2.1)1 (1.4)
 Platelets <50 × 103/mm35 (2.1)9 (9.1)*7 (19.4)7 (1.1)18 (9.5)**9 (12.9)††

Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

Here we describe treatment outcomes in the largest group of patients with advanced fibrosis reported to date. The results confirm that SVR rates are consistently and significantly higher in patients without advanced fibrosis than in those with bridging fibrosis and in particular those with cirrhosis. The trend is consistent in patients infected with genotype 1 or 4 and in those infected with genotype 2 or 3. The reason for the lower SVR rates appears to relate to a slower overall virological response rate in patients with advanced fibrosis, which in turn contributes to progressively higher rates of virological relapse during follow-up in these individuals.

The analysis shows that RVR and complete EVR are the most important predictors of SVR regardless of genotype and baseline histological diagnosis. When genotype 1 or 4 patients with an RVR or complete EVR and genotype 2 or 3 patients with an RVR are considered, there was no consistent difference in SVR rates between patients with and without bridging fibrosis or cirrhosis treated for the recommended duration (48 weeks in those with genotype 1 or 4, and 24 weeks in those infected with genotype 2 or 3). Consistent with this observation, relapse rates were low overall in patients with an RVR and were not influenced by genotype or histological diagnosis. Thus, achievement of an RVR and complete EVR are indicators of treatment success regardless of baseline predictors of response. It must be noted that patients with cirrhosis have greatly reduced rates of RVR, although the mechanism underlying this phenomenon remains to be elucidated.

Interestingly, in genotype 2 or 3 patients with a complete EVR, SVR rates were significantly higher in those without bridging fibrosis or cirrhosis, which suggests that treatment for 24 weeks may not be sufficient to maximize SVR in patients with advanced fibrosis who do not achieve an RVR. Few genotype 2 or 3 patients did not experience viral clearance by week 12, and among such patients almost none achieved an SVR. This suggests that treatment for 24 weeks is insufficient to eradicate HCV in slow responders with genotype 2 or 3 and that alternative treatment strategies such as extending therapy to 48 weeks and using higher doses of ribavirin may be required. Limited data suggest that treatment for 48 weeks may be beneficial in these individuals.12

Exposure to therapy is an important determinant of outcomes regardless of genotype and histological status. Fewer genotype 1 or 4 patients with advanced fibrosis had an exposure level of 80% or more of the planned doses of peginterferon alfa-2a (40KD) and ribavirin than those without advanced fibrosis. In contrast, the proportion of genotype 2 or 3 patients with this extent of exposure was similar regardless of histological diagnosis.

The MLR models show that on-treatment factors are important predictors of SVR in patients with advanced fibrosis. When on-treatment predictors were included in the analysis of data from genotype 1 or 4 patients, ribavirin exposure and viral clearance by week 4 or 12 superseded all baseline factors as predictors of SVR. This suggests that measures to maintain drug exposure and the monitoring of the on-treatment virological response are very important in patients with advanced fibrosis. More factors were retained in the model for patients infected with genotypes 2 or 3, perhaps reflecting the increased statistical power associated with the greater number of genotype 2 or 3 patients. Consistent with the model for genotype 1 or 4 patients, cumulative ribavirin exposure and achievement of an on-treatment response were strong predictors of SVR in genotype 2 or 3 patients with advanced fibrosis.

Perhaps the most striking finding of this analysis is the observation that the proportion of patients with a nonresponse in the first 12 weeks (in other words, no RVR, complete EVR, or slow response) was relatively constant across genotype and fibrosis groups. For those infected with genotypes 1 or 4, the rate of nonresponse was 15% to 17% regardless of fibrosis stage at baseline. The rate of nonresponse was lower but relatively constant (5%-7%) in those infected with HCV genotypes 2 or 3. This suggests that complete insensitivity to interferon treatment is determined by genetic factors and that the degree of fibrosis contributes little to this phenomenon.

In general, treatment was similarly tolerated in patients with and without bridging fibrosis or cirrhosis. The exception was the significantly greater impact of treatment on platelet counts in patients with bridging fibrosis or cirrhosis, although only one patient in the entire dataset discontinued treatment because of thrombocytopenia.

Most of the efficacy and safety data for combination therapy has come from studies that have recruited a broad spectrum of patients, most of whom did not have cirrhosis. Data collected exclusively in patients with advanced fibrosis are sparse. SVR rates of 18% (genotype 1), 61% (genotype 2 or 3), and 33% (genotype 4) have been reported in patients with bridging fibrosis or cirrhosis after treatment with pegylated interferon alfa-2b (12KD) plus ribavirin.13 In patients with more advanced disease—cirrhosis and portal hypertension—RVR was reported to be the best on-treatment predictor of SVR.14 In another trial, in which patients with cirrhosis were treated with peginterferon alfa-2b (12KD), 1.0 μg/kg/week plus ribavirin 800 to 1200 mg/day SVR rates of 24%, 80%, and 56% were obtained in patients infected with HCV genotypes 1, 2, and 3, respectively.8

The results of this analysis expand our understanding of the implications of a rapid response to treatment in the management of chronic hepatitis C. Patients who achieve an earlier response to treatment have a universally lower probability of relapse and a universally higher probability of achieving an SVR regardless of genotype or histological diagnosis. The use of viral response at both weeks 4 and 12 to guide therapy is a recent advance in the management of patients with chronic hepatitis C. SVR rates are similar after 24 or 48 weeks of treatment in noncirrhotic patients with genotype 1 or 4 infection who achieve an RVR; thus, this parameter may be used to select patients for abbreviated treatment.15–19 Similarly, patients with genotype 2 or 3 infection may be treated with abbreviated 12- to 16-week regimens provided they achieve an RVR and have a low baseline HCV RNA level.11, 20–22 Achievement of an RVR translates into a high probability of achieving an SVR in patients infected with HCV genotype 1 or 4 and advanced fibrosis, although the results of this analysis do not provide any insight as to whether abbreviated therapy is suitable in this setting. Thus, the full 48-week regimen must continue to be recommended in these individuals. In contrast, patients with advanced fibrosis who do not achieve an RVR have a low probability of achieving an SVR with the standard regimen and may be candidates for extended treatment.23 The implications of this analysis for genotype 2 or 3 patients with advanced fibrosis are clear. These individuals should not receive abbreviated regimens even if they achieve an RVR, because the probability of relapse is significantly higher and the probability of an SVR is significantly lower when compared with patients who receive the standard 24-week regimen.

In conclusion, peginterferon alfa-2a (40KD) plus ribavirin is effective and well tolerated in patients with bridging fibrosis or cirrhosis. Overall SVR rates are lower in such individuals than in patients without advanced fibrosis; however, achievement of an RVR overrides the effects of fibrosis stage. Response-guided therapy, which involves monitoring of the on-treatment virological response, can be used to identify patients with the highest chance of an SVR. Future studies should focus on strategies to increase viral eradication rates in genotype 1 or 4 non-RVR patients with a slow response by week 12 and genotype 2 or 3 non-RVR patients with a complete or slow response by week 12.

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information
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