Treating chronic hepatitis C with pegylated interferon alfa-2a (40 KD) and ribavirin in clinical practice

Authors


  • 1

    The other contributing members of the Canadian Pegasys Study Group given in the appendix.

Dr S. S. Lee, 3330 Hospital Drive, NW, Calgary, AB, T2N 4N1, Canada.
E-mail: samlee@ucalgary.ca

Abstract

Summary

Background

Pegylated interferon alfa-2a (40 KD) plus ribavirin therapy induces sustained virological response rates up to 63% in randomized-controlled trials.

Aim

To conduct a prospective open-label programme to examine the efficacy and safety of this therapy in routine clinical practice.

Methods

Treatment-naive patients with chronic hepatitis C received, at the discretion of the investigator, pegylated interferon alfa-2a 180 μg/week + ribavirin 800 mg/day for 24 or 48 weeks. In total, 508 patients were enrolled [334 non-cirrhotic; 174 cirrhotic (defined as stage F3 and F4)].

Results

In genotype 1 patients treated for 48 weeks, sustained virological response rates were 41% in non-cirrhotics and 34% in cirrhotics. Sustained virological response rates in genotype 2 or 3 non-cirrhotics were 79% (24 weeks) and 72% (48 weeks). Corresponding values for cirrhotic genotype 2/3 were 66% and 44%. The negative predictive value of an early virological response at week 12 was 94%. Predictive factors for sustained virological response on multivariate analysis were genotype (2/3 vs. 1), low viral load and degree of fibrosis. Rates of serious adverse events (≤5%) and adverse events inducing withdrawal (≤8%) were comparable with the phase III trials.

Conclusion

Efficacy and safety of pegylated interferon alfa-2a + ribavirin in clinical practice is comparable with results of randomized-controlled trials.

Introduction

Chronic infection with the hepatitis C virus (HCV) is thought to be the leading cause of death from liver disease in the USA.1 In Canada, up to 250 000 persons are currently estimated to be infected with HCV,2, 3 and a marked increase in HCV-related deaths due to end-stage liver disease has been projected over the period 1998–2008.2

The current treatment of choice for chronic hepatitis C is the combination of pegylated interferon (peginterferon) plus ribavirin,1, 3, 4 which has superseded the use of conventional interferon plus ribavirin in everyday clinical practice. In randomized-multinational phase III clinical trials, peginterferon alfa-2a (40 KD) (Pegasys, F. Hoffmann La Roche Ltd, Basel, Switzerland) plus ribavirin (Copegus, F. Hoffmann La Roche Ltd) has produced overall sustained virological response (SVR) rates of 56%5 and 63%6 in treatment-naïve patients with chronic hepatitis C.

While such response rates with peginterferon plus ribavirin combination therapy have been achieved in phase III randomized-controlled trials, it is unclear if these results can be replicated in routine clinical practice. It is well known that patients selected for studies represent a motivated, compliant subgroup with less comorbidities and associated problems. In effect, these study subjects represent the ‘cream’ of the patients seen in clinical practice. Thus, a large multinational expanded access program was initiated to determine the efficacy and safety of peginterferon alfa-2a plus ribavirin in HCV-infected patients in a routine practice setting. This program was designed to be representative of ‘real world’ clinical practice; the duration of treatment (24 or 48 weeks) was determined by the investigator. The current paper presents the results of the Canadian patient subgroup of the international expanded access program, measuring efficacy, safety and tolerability.

Methods

Patients

This prospective multicentre, open-label, non-randomized study was conducted at 18 centres in Canada between April 2001 and June 2004. The study was conducted in accordance with the principles of the Declaration of Helsinki and International Conference of Harmonization guidelines for Good Clinical Practice. The protocol was approved by local independent Ethics Committees at each site and all patients provided written informed consent prior to entry.

The general eligibility, inclusion and exclusion criteria mirrored those of the two large multicentre phase III trials of peginterferon alfa-2a plus ribavirin in treatment-naïve patients.5, 6 The patient cohort of the present study consisted of treatment-naïve male and female patients aged ≥18 years, with serological evidence of chronic hepatitis C by an anti-HCV antibody test and detectable serum HCV RNA (Cobas Amplicor HCV Monitor, version 2.0, Roche Diagnostics, Laval, QC, Canada). There was no upper age limit in this study. Patients with elevated serum alanine aminotransferase (ALT) activity and liver biopsy findings consistent with the diagnosis of hepatitis C infection with or without compensated cirrhosis were eligible for inclusion. Patients with advanced fibrosis (METAVIR stage F3) or cirrhosis (F4) could be enrolled only if they had compensated liver disease (Child-Pugh class A). For ease of expression, this group (F3 and F4) will hereafter be referred to as the ‘cirrhotic’ or ‘cirrhosis’ group.

Exclusion criteria included the following: coinfection with hepatitis B and/or human immunodeficiency virus; evidence of a chronic liver disease other than HCV; bleeding from oesophageal varices, presence of ascites, hepatocellular carcinoma or other conditions consistent with decompensated liver disease; neutrophil count <1500 cells/mm3, platelet count <90 000 cells/mm3 or serum creatinine level >1.5 times the upper limit of normal. Pregnant or breastfeeding women, those with a history of severe psychiatric disease, chronic pulmonary or cardiac disease, prior organ transplantation or a history of substance abuse (including excessive alcohol consumption) were excluded from participating.

Study design

The study was designed and initiated before the optimal treatment regimens for HCV genotype 1 (48 weeks treatment; 1000/1200 mg/day ribavirin) and genotypes 2/3 (24 weeks treatment; 800 mg/day ribavirin) were determined.

During initial screening (conducted up to 8 weeks prior to study start), eligible patients provided a medical history and underwent physical examination and measurement of laboratory parameters. Patients underwent a liver biopsy generally within 1 year prior to screening, and the results were graded using the METAVIR scale by an experienced liver histopathologist in each centre. Patients were then allocated to one of three treatment arms, at the discretion of the investigator, as follows:

  • 1Peginterferon alfa-2a 180 μg/week monotherapy for 48 weeks
  • 2Group A: peginterferon alfa-2a 180 μg/week plus ribavirin 400 mg twice daily, for 24 weeks
  • 3Group B: peginterferon alfa-2a 180 μg/week plus ribavirin 400 mg twice daily, for 48 weeks.

The mandatory clinic visits for group A patients were at weeks 0, 12, 24 and 48, and for group B, weeks 0, 12, 24, 48 and 72. Visits at other times were at the discretion of the investigator, for clinically indicated reasons.

In total, 509 patients were enrolled. Only one patient, with F4 cirrhosis, was enrolled into the peginterferon monotherapy arm, and did not achieve SVR. Therefore this group will not be further mentioned, and analysis is restricted to the 508 patients who received combination therapy (groups A and B).

Outcome measures

Efficacy

The primary efficacy outcome was SVR, defined as undetectable HCV RNA (<50 IU/mL) by qualitative polymerase chain reaction (PCR) assay (Cobas Amplicor HCV Test, v2.0) at the end of untreated follow-up (week 48 in group A and week 72 in group B). Serum HCV RNA levels were determined by quantitative PCR [Cobas Amplicor Monitor HCV Test, v2.0, limit of quantitation >600 IU/mL)] at baseline and week 12 and by qualitative PCR at week 24 and 48 for all patients, and week 72 for group B. All HCV RNA PCR assays were performed in a central facility, the B.C. Centre for Disease Control Virology Lab.

Early virological response (EVR) at week 12 was defined as undetectable HCV RNA by qualitative PCR assay or a ≥2-log10 decrease from baseline in serum HCV RNA by quantitative PCR assay.

Safety

Assessments of laboratory and biochemical parameters were conducted at regular intervals throughout the study and a physical examination was conducted at the end of treatment. Adverse events were monitored throughout the treatment period and up to 6 months after treatment.

Stepwise dose reductions of peginterferon alfa-2a (to 135 μg, 90 μg and 45 μg) were permitted to manage adverse events or laboratory abnormalities. Dose reduction was recommended for cases of neutropenia (neutrophils <750 cells/mm3), thrombocytopenia (platelets <50 000 cells/mm3) or if serum ALT progressively increased from baseline. When ALT level remained significantly elevated from baseline, or was accompanied by conjugated hyperbilirubinemia or evidence of hepatic decompensation, discontinuation of therapy was recommended. Treatment was suspended for absolute neutrophil counts <500 cells/mm3 or for platelet counts <25 000 cells/mm3, until recovery.

The dose of ribavirin could be reduced to 600 mg/day if haemoglobin (Hb) fell to between >8.5 and <10 g/dL or decreased from baseline by >2 g/dL. Ribavirin was discontinued if Hb fell to <8.5 g/dL. In the event of ribavirin being discontinued, the patient could continue to receive peginterferon alfa-2a monotherapy, but ribavirin could be re-introduced at the investigator's discretion.

Statistical analysis

No formal sample size calculation was performed. Data were grouped and analysed according to baseline histological status: non-cirrhotic (patients with F0–F2 fibrosis) and cirrhotic (F3 or F4), and by HCV genotype. Statistical analysis was conducted on intent to treat (ITT) population. All patients who received at least one dose of study medication were included in the efficacy population (ITT). Early terminations and missed follow-ups were considered as non-responders (see Figure 1). The safety population included patients who received ≥1 dose of study medication and had at least one post-baseline safety assessment. Descriptive statistics were used to present the efficacy and safety results. Baseline factors predictive of SVR were identified by multiple logistic regression analysis. Categorical variables analysed included HCV genotype (1 vs. 2 or 3), race (Caucasian vs. non-Caucasian), and gender (female vs. male). Numerical continuous or semi-continuous variables included baseline viral load, body mass index, body weight, age and Metavir fibrosis score.

Figure 1.

Patient disposition.

Results

Patient disposition is shown in Figure 1. A total of 508 treatment-naive patients were enrolled, of whom 334 were non-cirrhotic (≤F2) and 174 were cirrhotic (F3 or F4).

The demographic and baseline characteristics of the study population were generally well-matched between the treatment groups (Table 1). Although the proportion of patients with a viral load of HCV RNA >850 000 IU/mL was greater among non-cirrhotic patients in Group B compared with the other groups, stratification by viral load with a cut-off of HCV RNA 500 000 IU/mL showed similar percentages in the four groups. All patients infected with HCV genotype 1 were assigned to receive 48-week treatment, and the majority of patients with genotypes 2/3 received 24-week treatment.

Table 1.  Demographic and baseline characteristics
 Patients without cirrhosis (n = 334)Patients with cirrhosis (F3/F4) (n = 174)
Group A (n = 93)Group B (n = 241)Group A (n = 35)Group B (n = 139)
  1. BMI, body mass index; Group A, peginterferon alpha-2a plus ribavirin for 24 weeks; Group B, peginterferon alpha-2a plus ribavirin for 48 weeks.

Gender M/F n/n (% male)53/40 (57)169/72 (70)23/12 (66)90/49 (65)
Age, (years) mean ± SD41.1 ± 8.943.2 ± 8.248.1 ± 10.448.3 ± 8.0
Race, n (%)
 Caucasian68 (73)207 (86)28 (80)119 (86)
 African-American1 (1)4 (2)0 (0)2 (1)
 Asian or Pacific Islander15 (16)18 (7)5 (14)14 (10)
 Other9 (10)12 (5)2 (6)4 (3)
 Height (cm)170 ± 10172 ± 10168 ± 11171 ± 10
 Weight (kg)77 ± 1780 ± 1677 ± 1782 ± 17
 BMI, kg/m2; mean ± SD26.7 ± 4.326.9 ± 4.627.3 ± 5.028.0 ± 4.8
HCV genotype, n (%)
 10 (0)196 (81)0 (0)118 (85)
 2/391 (98)36 (15)35 (100)18 (13)
 Other2 (2)9 (4)0 (0)3 (2)
 HCV RNA >850 000 IU/mL n (%)39 (42)68 (28)12 (34)38 (27)
 HCV RNA >500 000 IU/mL n (%)52 (56)127 (53)21 (60)71 (51)
Histological diagnosis n (%)
 Bridging fibrosis0 (0)0 (0)19 (54)78 (56)
 Cirrhosis0 (0)0 (0)16 (46)61 (44)

Growth factors were permitted, but because of regional regulatory restrictions on their use, only a few sites in Quebec and Ontario used erythropoietin. In total 34 patients (7%) received erythropoietin.

Sustained virological response

The overall SVR rate by ITT analysis was 55% in non-cirrhotic patients, and 42% for cirrhotic (F3/F4) patients (Table 2). Only 14 patients (3% of the entire cohort) were not infected with genotypes 1, 2 or 3. Most of these were genotype 4, with some genotype 6 patients; the overall SVR in this group was 50%. Because these numbers are so small, and it remains unclear whether such patients’ antiviral responses are similar to patients with genotype 1 or 2/3,7 the remainder of the analysis is limited to our cohort with genotypes 1, 2 or 3.

Table 2.  Multiple logistic regression model: analysis of deviance
Predictive factorWald t-statistic P-value
  1. The Wald t-statistic is equal to the ratio of the coefficient from the model divided by its standard error.

  2. * Analysed as a continuous numeric variable.

Genotype (1 vs. 2/3)2.1400.032
Viral load*−2.0890.037
BMI*−1.6100.107
Weight*0.4100.682
Age*0.2240.823
Sex0.3340.738
Race−1.0940.274
Fibrosis*−3.0600.002
Genotype by viral load−2.3380.019
Genotype by body mass index0.7150.475
Genotype by weight−1.3640.173
Genotype by age−1.7260.084
Genotype by sex−1.1950.232
Genotype by race−0.2430.808
Genotype by fibrosis1.9140.056

In non-cirrhotic patients with genotypes 2/3, 24 or 48 weeks’ treatment produced similar SVR rates (79% and 72%). In non-cirrhotic genotype 1 patients treated for 48 weeks, the SVR rate was 41%.

In cirrhotic genotype 2/3 patients, therapy for 24 weeks produced a statistically insignificant greater response rate (66%) than 48 weeks’ treatment (44%) (P = 0.15). In cirrhotic genotype 1 patients, an SVR of 34% was observed.

Predictability of response at week 12

Figures 2 and 3 show predictability of response based on week 12 EVR data. We used the standard definition of EVR as either an undetectable HCV RNA by qualitative PCR testing, or >2log10 drop compared with the baseline HCV RNA value.

Figure 2.

Week 12 predictability of response for patients with (bottom) and without cirrhosis (top). Patients in groups A (24-week treatment) and B (48-week treatment) were combined in this analysis. EVR, early virological response; NPV, negative predictive value.

Figure 3.

Week 12 predictability of response for patients with (a) hepatitis C virus (HCV) genotype 1 and (b) HCV genotype 2/3. Data presented for patients with and without cirrhosis.

Of 323 non-cirrhotic patients, EVR status was unknown in 14 patients. Of the remaining 309 patients, 83% overall had an EVR. Of these patients, 57% who had an EVR achieved a SVR, resulting in a positive predictive value (PPV) of 68%.

Of the non-cirrhotic genotype 1 patients, 74% had an EVR, with 42% going on to achieve SVR (PPV = 57%). Of non-cirrhotic genotype 2/3 patients, 96% had an EVR, with 78% going on to achieve SVR (PPV = 82%). Of the 53 non-cirrhotic patients who did not attain EVR, three (6%) achieved SVR (NPV = 94%). Subgroup analysis showed that all three of these patients were genotype 1 (from a total of 48 genotype 1 patients who did not have EVR) resulting in a NPV of 94% for genotype 1 patients without cirrhosis.

Of 171 cirrhotic patients, EVR status was unknown in seven patients. A total of 121 patients (74%) had an EVR, including 65% of those with genotype 1 and 94% of those with genotype 2/3. In total, 41% of cirrhotic patients who achieved an EVR had a SVR (PPV = 56%).

In total, 65% of genotype 1 cirrhotic patients had an EVR, with 33% going on to achieve SVR (PPV = 51%). Of genotype 2/3 cirrhotic patients, 94% had an EVR, with 60% going on to achieve SVR (PPV = 64%).

Of the 43 patients with cirrhosis who did not attain EVR, three (7%) achieved an SVR (NPV = 93%). Two of these patients were HCV genotype 1 (from a total of 40 genotype 1 patients who did not have an EVR) resulting in a NPV of 95% for HCV genotype 1 patients with cirrhosis.

Baseline factors predictive of sustained virological response

A multiple logistic regression model was used to identify the significant predictors of SVR. The analysis of deviance for the multiple logistic regression model is illustrated in Table 2. The Wald t-statistic is equal to the ratio of the coefficient from the model divided by its standard error; it should have a standard normal distribution under the null hypothesis. The model included terms to account for possible interactions between predictors [baseline viral load, body mass index (BMI), weight, age, sex, race, fibrosis score] and genotype and revealed the presence of significant effects of fibrosis score (P = 0.002), and genotype, viral load and their interaction (P = 0.032 for genotype 1 vs. 2/3, P = 0.037 for viral load, and P = 0.019 for their interaction.

Figure 4a displays the relationship between genotype and fibrosis in a simpler, two-way graphical summary; the interaction between these factors was not significant in the logistic regression model (P = 0.056), suggesting that the impact of fibrosis is similar for both genotypes 1 and 2/3. The probability of SVR is significantly reduced with higher fibrosis scores. Figure 4b shows the nature of the strong interaction between genotype and viral load, which was detected by the model. The odds of SVR are essentially unaffected by viral load in patients with genotype 2 or 3; whereas in genotype 1 patients, the odds of SVR drop rapidly as viral load increases to approximately 500 000–1 000 000 IU/mL. Viral loads above this range have virtually no further impact on the odds of SVR.

Figure 4.

Logistic regression analysis of independent factors associated with sustained virological response (SVR). (a) SVR by genotype by fibrosis stage. (b) SVR vs. viral load by genotype. Dotted lines represent 95% confidence intervals. Vertical dotted lines indicate 500 000 and 1 000 000 IU/mL. Small lines just above the x-axis represent the number of observations; each line represents one patient.

Table 3 shows the interpretation of the logistic regression model wherein we analysed viral load, BMI, weight, age and fibrosis score as continuous numeric rather than categorical variables. The standardised odds ratios are expressed as comparisons of the odds of SVR for patients at the 25th and 75th percentiles of the predictive factor. The estimated odds ratios are adjusted for a typical 45-year-old male Caucasian subject with a BMI of 27, weighing 79 kg with a baseline viral load of 531 500 and a fibrosis score of 2; these are the median or modal values of these predictive factors.

Table 3.  Interpretation of logistic regression model
Predictive factorComparingOR*95% Confidence interval
LowerUpper
  1. * The standardized odds ratios (OR) are expressed as comparisons of the odds of SVR for patients at the 25th and 75th percentiles of the predictive factor. The estimated odds ratios are adjusted for a typical 45 yr old male Caucasian with a BMI of 27, weight of 79 kg with a baseline viral load of 531 500 and a fibrosis score of 2; these are the median or modal values of these predictive factors.

Genotype2/3 vs. 14.352.118.95
Genotype 1
 Viral load240 000 vs. 1 649 0001.941.352.79
 BMI24 vs. 301.320.662.65
 Weight (kg)68 vs. 911.430.643.19
 Age (years)39 vs. 501.270.891.80
 Fibrosis score1 vs. 31.290.822.05
 SexFemale vs. male0.750.381.49
 RaceNon-Caucasian vs. Caucasian1.570.723.43
Genotype 2 or 3
 Viral load240 000 vs. 1 649 0000.960.611.53
 Body mass index24 vs. 302.080.755.74
 Weight (kg)68 vs. 910.510.151.78
 Age (years)39 vs. 500.730.441.23
 Fibrosis score1 vs. 33.061.446.51
 SexFemale vs. male1.660.554.99
 RaceNon-Caucasian vs. Caucasian1.330.463.82

Safety

The overall incidence of adverse events was similar in both cirrhotic and non-cirrhotic patients and across the three treatment arms, ranging from 42 to 47% (Table 4). The most common adverse events were typical of interferon/ribavirin treatment and included neutropenia, anaemia and thrombocytopenia. Serious adverse events were similar in cirrhotic patients (4%) and non-cirrhotics (5%). The frequency of serious adverse events was similar in patients treated for 24 weeks or 48 weeks, and between patients with genotype 1 (3–5%) vs. those with genotype 2/3 (5–6%; data not shown). No deaths were attributed to the drug treatment.

Table 4.  Adverse events and laboratory abnormalities, n (%)
 Patients without cirrhosis (n = 334)Patients with cirrhosis (n = 174)
Group A (n = 93)Group B (n = 241)Group A (n = 35)Group B (n = 139)
  1. Grade 3, neutrophil counts 500–750 cells/mm3; Grade 4, neutropenia counts <500 cells/mm3 thrombocytopenia, Grade 3, platelet count <50 000 cells/mm3.

Adverse events39 (42)112 (47)14 (40)62 (45)
Serious adverse events4 (4)13 (5)1 (3)6 (4)
Non-serious laboratory abnormalities25 (27)72 (30)13 (37)46 (33)
Neutropenia
 Grade 311 (12)45 (19)6 (17)16 (12)
 Grade 40 (0)9 (4)0 (0)2 (1)
 Not graded3 (3)3 (1)2 (6)5 (4)
Thrombocytopenia
 Grade 30 (0)3 (1)1 (3)7 (5)
 Not graded3 (3)1 (0.4)2 (6)5 (4)
Anaemia (Hb)
 <10 g/dL6 (6)22 (9)2 (6)16 (12)
 ≥10 g/dL4 (4)5 (2)1 (3)1 (1)
Alanine aminotransferase elevation3 (3)3 (1)0 (0)4 (3)

The incidence of non-serious laboratory abnormalities was similar between treatment groups A and B in both cirrhotic and non-cirrhotic patients (29–34%). Grade 4 neutropenia was rare and occurred only in patients receiving treatment for 48 weeks. Grade 3 thrombocytopenia was slightly more common in cirrhotic patients (3–5%) than in non-cirrhotic patients (1%). The occurrence of anaemia (Hb <10 g/dL) was similar between cirrhotic and non-cirrhotic patients and was slightly higher in the 48-week group (9–12%) than in the in 24-week group (6%). Peginterferon dose reduction was most commonly because of neutropenia (17–21% of patients). Fewer patients required dose reduction because of thrombocytopenia and this was more common in cirrhotic (6–8%) than non-cirrhotic (2–3%) patients. Elevated ALT rarely necessitated peginterferon dose modification (≤2% of patients). Ribavirin dose reduction was required in 11% of patients because of anaemia.

In total, 107 (32%) non-cirrhotic and 70 (40%) cirrhotic patients prematurely discontinued treatment (Figure 1). Patients treated for 48 weeks had a higher rate of premature treatment withdrawal; 44% overall, and 41% in non-cirrhotics and 48% in cirrhotic patients. Adverse events accounted for discontinuation in ≤8% of patients in the combination therapy groups. In the 48-week groups, non-response was the most common individual reason for discontinuation in patients without cirrhosis (15% of patients) and in those with cirrhosis (25% of patients) (Figure 1).

Discussion

In this expanded access program, although the inclusion/exclusion criteria were identical to the randomized-controlled trials, several other factors differed, reflecting the ‘real world’ nature of this program. First, investigators could choose the treatment duration. Second, monitoring and clinic visits were only mandated at certain time points that are generally used in clinical practice; thus the frequency of visits/monitoring was much less than in the RCTs. Third, the stepwise dose reductions of peginterferon and ribavirin were similar to routine clinical practice, and differed from the dose reduction schedules of the Fried and Hadziyannis studies.

Considering that patients who volunteer for randomized-clinical trials are a highly selected subgroup of motivated, compliant and committed patients, it is not surprising that results in routine clinical practice usually fail to achieve the success rates of therapeutic trials. This phenomenon has been well demonstrated for many different types of patients and conditions, including asthma,8 acute coronary syndromes9 and congestive heart failure.10 Thus the current results that show comparable efficacy and tolerability of peginterferon alfa-2a plus ribavirin combination therapy in a ‘real world’ clinical practice setting, are somewhat surprising. Using an 800 mg daily ribavirin dose combination regimen, SVR rates in treatment-naïve chronic hepatitis C patients in our study were generally comparable with those previously reported in controlled-clinical trials where standard doses of ribavirin were used.5, 6 Moreover, these rates are very close to the results from those treatment arms of the Hadziyannis trial that used 800 mg of ribavirin dosing.6

We believe that several factors may explain this somewhat unexpectedly good result in our ‘real world’ program. First, all participating centres were highly experienced with the use of interferon-based antiviral therapies. Most were academic centres that had previously participated in multicentre RCTs in viral hepatitis, and in most cases, patients in this early access program were managed by the same study coordinator-nurses who run the phase II and III clinical trials. Moreover, following the same eligibility criteria for the phase III RCTs excluded potentially problematic patients such as those with decompensated cirrhosis or ongoing substance abuse.

However, we believe that our patients do indeed represent ‘real world’ populations because some subtle clues suggest that they are not the ‘cream’ of patients who usually enter RCTs. One such clue is the relatively high number of patients lost to follow-up. In the two phase III studies, a remarkably consistent tiny fraction of the ITT population failed to return for follow-up, 1.3% in the Fried study 5 and 1.4% in the Hadziyannis study.6 This contrasts to our study wherein 24 of 508 patients (5%) were lost to follow-up. Another clue suggesting a less motivated population in our program compared with subjects in RCTs is the higher dropout rate. The premature withdrawal rate of 44% in our 48-week treatment group contrasts unfavourably with the rate of 26% in the peginterferon + ribavirin arm of the Fried study and 32% in the 48-week 800 mg ribavirin arm of the Hadziyannis trial.

In the present study, overall SVR rates were higher in patients without cirrhosis/bridging fibrosis (55%) than in those with cirrhosis/bridging fibrosis (42%). Traditionally, the number of patients with advanced fibrosis or cirrhosis enrolled in clinical trials of peginterferons has been relatively small, and only one large randomized, phase III trial of antiviral therapy has been conducted specifically in this patient population.11 In that study, the SVR rate in patients receiving peginterferon alfa-2a 180 μg/week monotherapy (30%) was significantly higher than in patients receiving conventional interferon monotherapy (8%).

Subsequent clinical trials of peginterferon alfa-2a in combination with ribavirin that included a proportion of patients with bridging fibrosis or cirrhosis have demonstrated that overall response to treatment is lower in this group than in the overall patient population.5, 6 In the study by Fried et al. in which a standard dose of ribavirin (1000/1200 mg/day) was administered, the SVR rates were 56% in the overall population and 43% in patients with cirrhosis or bridging fibrosis. These results are almost identical to the SVR rates obtained in the current study. In the Hadziyannis trial, SVR rates were 45% among non-cirrhotic genotype 1 patients receiving low-dose ribavirin (800 mg/day) for 48 weeks compared with 28% in the cirrhotic group, which are also consistent with our findings.

Although this study was started before the optimal treatment regimens for genotype 1 and genotype 2/3 patients were known, all patients with HCV genotype 1 in our study were treated for 48 weeks, which is in line with current treatment guidelines.1, 3 Moreover, the majority of genotype 2/3 patients (70%) were assigned to 24 weeks of therapy. As expected, the SVR rate was higher among genotype 2/3 patients (58–77%) than among those infected with HCV genotype 1 (34–41%). The SVR rate achieved in the most ‘difficult to treat’ patient group, genotype 1 patients with cirrhosis, was higher than in patients who received 48 weeks’ therapy with low dose ribavirin in the Hadziyannis trial (34% vs. 28%).6 In the latter study, the SVR rate increased to 41% in patients treated with a standard dose (1000/1200 mg/day) of ribavirin. One could therefore speculate that the SVR rate for all genotype 1 patients in our study might have been higher had the optimal dose of ribavirin been used.

Our results in genotype 2/3 patients agree with those of Hadziyannis et al., confirming that 24-week treatment is sufficient, and that doubling the duration of therapy adds no additional benefit in such patients. The SVR rates for our cirrhotic genotype 2/3 patients (44%) treated for 48 weeks are lower than the 70% reported in the Hadziyannis study, but the sample size in this subgroup was very small (n = 18).

We also assessed the predictability of an EVR at week 12. Previous studies of peginterferon plus ribavirin combination therapy have shown that the absence of an EVR at week 12 has a high negative predictive value for the probability of achieving an SVR.5,12–15 In clinical practice, the absence of an EVR at week 12 is being increasingly used to guide treatment decisions.1, 3, 12, 15 Assessing response at week 12 allows some patients to discontinue treatment early, as almost all patients who fail to achieve an EVR will not achieve an SVR.12–15 In the current study, the NPV was 93% in cirrhotic and 94% in non-cirrhotic patients. Thus, the utility of the week-12 EVR stopping rule suggested by RCTs also appears to hold in a ‘real world’ setting.

For the multiple logistic regression analyses, we treated all numeric variables as continuous rather than categorical or binary variables. Previous studies had arbitrarily split these numerical variables at some point, for example, weight >85 kg or <85 kg, then treated these as categorical variables. We felt that this method of analysis might run a greater risk of committing a type II error than our method. The multivariate regression analysis thus determined that 3 baseline factors were more likely to be associated with a chance of obtaining SVR: genotype, viral load and degree of fibrosis. There were also significant interaction associations between genotype and viral load. Although it is known that genotype, viral load and extent of fibrosis (F3/F4 vs. F1/F2) are predictive factors, treating variables, where possible, as numeric rather than categorical allowed some novel insights to emerge from our data.

For example, we found that the degree of fibrosis linearly corresponds to the chance of obtaining SVR. Previous studies had merely used the split of F1/F2 vs. F3/F4. When analysed in this manner, we found that the higher the degree of fibrosis at baseline, the less the likelihood of SVR. Although this result seems logical and coherent, to our knowledge the observation that fibrosis is such a linearly distributed baseline predictive factor has not previously been reported.

Analysing the predictive effect of baseline viral load as a continuous variable also showed an interesting novel finding. In patients with genotype 1 infection, the continuous response curve demonstrates a plateau effect, i.e. the predictive value of viral load is much more useful at lower viral loads (up to about 500 000–1 000 000 IU/mL), and that above this range, the predictive value declines. Moreover, in patients with HCV genotype 2 or 3, the baseline viral load showed a flat effect, i.e. no predictive value. Previous studies that arbitrarily split viral load at 2 million copies/mL (which corresponds to approximately 850 000 IU/ml by the Cobas Amplicor Monitor assay) for definition of ‘high’ vs. ‘low’ viral load had failed to detect this plateau effect.

The relatively high discontinuation rates in the 48-week groups may have led to an artifactually better adverse event profile in our study, when comparing the 48-week arms of the RCTs where all patients, including non-responders, were treated and monitored for adverse events for the entire 48-week period.

Patients with cirrhosis had been previously thought to be more susceptible to severe side effects with interferon-based therapies. In this study, the incidence of adverse events was comparable in cirrhotic and non-cirrhotic patients. As expected, the incidence was higher in group B (48 week) compared with group A. Serious adverse events were rare in all treatment groups (≤5%), and the rate of dose modifications was similar among cirrhotic and non-cirrhotic patients. The frequency of premature discontinuations was higher in cirrhotic groups (40 vs. 32%); however, the discontinuation rate was substantially higher among the 48-week group compared with the 24-week group. Notwithstanding these relatively high dropout rates, the adverse effect profiles in this study suggest that even patients with advanced fibrosis or cirrhosis can be safely treated in routine clinical practice, as long as they do not have decompensated liver disease.

In conclusion, the results of this Canadian open-label study confirm the efficacy and tolerability of peginterferon alfa-2a plus ribavirin combination therapy in both cirrhotic and non-cirrhotic treatment-naïve HCV patients in a ‘real world’ clinical practice setting. Moreover, higher SVR rates might have been achieved with a treatment regimen employing a standard ribavirin dose for genotype 1 patients.

Acknowledgements

This study was funded by Roche Canada. The authors gratefully acknowledge the expert data analysis help of Dr Robert Balshaw, Amanda Yu and Rohinish Gunadasa of Syreon Corp., and Trisha Hutzul (Roche Canada) for help with logistical issues in the early phases of the study.

Appendix

Frank Anderson, MD – Liver and Intestinal Research Centre, Vancouver, BC; Victor Feinman, MD – Mt Sinai Hospital, Toronto, ON; Susan Greenbloom, MD – Toronto Digestive Disease Associates, Inc, Toronto, ON; Nir Hilzenrat, MD – Jewish General Hospital, Montreal, QC; Kelly Kaita, MD – John Buhler Research Centre, Winnipeg, MB; Paul Marotta, MD – London Health Sciences Centre, London, ON; Linda Scully, MD – Ottawa Civic Hospital, Ottawa, ON; Bernard Willems, MD – CHUM – Hopital St-Luc, Montreal, QC; Helga Witt-Sullivan, MD – Hamilton Health Sciences Corp. General Site, Hamilton, ON; Lawrence Worobetz, MD – Royal University Hospital, Saskatoon, SK.

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