"The slower initial HCV RNA decline, in patients with advanced fibrosis, was despite receiving similar cumulative dosages of PEG-IFNα-2a and ribavirin to patients without advanced fibrosis, indicating that differences in treatment tolerability in relation to dose modifications and/or discontinuations are not the explanation for the lower initial HCV RNA decline or higher relapse rates seen in advanced fibrosis. A potential explanation for our findings is the relationships between fibrosis stage, intrahepatic HCV RNA replication, and HCV clearance. Although patients with advanced fibrosis do not have higher serum HCV RNA levels, they have a higher percentage of hepatocytes with evidence of HCV RNA replication [19]. Viral kinetic studies have shown that patients with HCV genotype 1 and advanced fibrosis have slower second phase HCV RNA decline than those with less fibrosis [20], consistent with our week 4 and 8 response findings. Further, recent HCV modeling based on HCV genotype 1 patients indicates that patients with cirrhosis have lower SVR rates due to a higher percentage of HCV-infected hepatocytes [21]. An additional explanation would relate to potential immunological differences by extent of liver disease. Immunological characteristics including up-regulation of intrahepatic Th1-like cytokines and interferon-stimulated genes (ISGs) are known to influence both fibrosis progression and IFN-based treatment response [22], [23]. Finally, the recently reported association, between IL28B genetic polymorphisms and PEG-IFN/RBV treatment outcome in treatment naïve patients with chronic HCV genotype 1, indicates that host genetic characteristics are important for treatment responsiveness [24], [25]. If IL28B genetic polymorphisms associated with poor HCV treatment response are also found to be linked to liver disease progression, host genetic characteristics could explain the differential response by fibrosis stage."
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Articles in Press
Low virological response and high relapse rates in hepatitis C genotype 1 patients with advanced fibrosis despite adequate therapeutic dosing
Wendy S.C. Cheng1, Stuart K. Roberts2, Geoffrey McCaughan3, William Sievert4, Martin Weltman5, Darrell Crawford6, William Rawlinson7, Philippa S. Marks8, James Thommes9, Bishoy Rizkalla10, Motoko Yoshihara10, Gregory J Dore811Corresponding Author Informationemail address, on behalf of the CHARIOT Study Group
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ABSTRACT
Background & Aims
The impact of fibrosis stage on chronic hepatitis C virus (HCV) treatment response was explored in CHARIOT, a study of high dose peginterferon alfa-2a (PEG-IFNα-2a) induction therapy in treatment naïve genotype 1 infection.
Methods
Eight hundred and ninety-six patients were randomised 1:1 to 360µg (n=448) or 180µg (n=448) PEG-IFNα-2a weekly with RBV 1000-1200mg/day for 12weeks followed by 36weeks of 180µg PEG-IFNα-2a weekly plus RBV 1000-1200mg/day. Virological responses were assessed at week 4, 8, 12, 24, 48 (end of therapy), and 24weeks following therapy (sustained virological response, SVR). As previously reported, there was no significant difference in SVR in the induction (53%) and standard (50%) arms, therefore the pooled study population was used for analysis of SVR and relapse.
Results
A marked step-wise decline in SVR was evident by fibrosis stage: F0 (70%); F1 (60%); F2 (51%); F3 (31%); F4 (10%) (p<0.0001). Early virological responses were lower among F3/4 patients, including rapid virological response (RVR) (21% vs. 34% for F3/4 and F0-2, respectively) (p=0.0072), and the RVR positive predictive value was also lower (63% vs. 80%). Virological relapse rates were similar in early disease stages (F0, 16%; F1, 23%; F2, 26%), but increased markedly in advanced fibrosis (F3, 50%; F4, 80%) (p<0.0001). Cumulative PEG-IFNα-2a and ribavirin doses were similar among patients with F3/4 and F0-2 within treatment arms through week 4, 8, 12, and week 24.
Conclusions
Low virological response in hepatitis C genotype 1 patients with advanced fibrosis is not explained by inadequate cumulative PEG-IFN and ribavirin doses.
Introduction
Pegylated interferon and ribavirin therapy for chronic hepatitis C virus (HCV) infection achieves a sustained virological response (SVR) in 70-80% in genotype 2/3, but only 40-55% in genotype 1 infected patients [1], [2], [3]. Treatment response rates are particularly poor among patients with genotype 1 infection and advanced fibrosis (bridging fibrosis and compensated cirrhosis), with SVR rates of 15-40% [2], [3], [4], [5], [6], [7] reported from generally small study populations.
HCV-related cirrhosis is associated with a high risk of progression to hepatic decompensation, hepatocellular carcinoma (HCC), and liver-related mortality [8], [9], [10]. Although interferon-based HCV viral clearance is more difficult to achieve in patients with advanced fibrosis, there are clear benefits for those who do, with lower risk of progression to advanced liver disease complications [11], [12], [13], and regression of fibrosis in many [14], [15].
The CHARIOT trial was a large international randomized controlled trial of peginterferon (PEG-IFN) alfa-2a induction dosing in combination with ribavirin in treatment naïve patients with chronic HCV genotype 1 infection [16]. Despite enhanced early virological responses, induction therapy provided no improvement in SVR (53% and 50% in induction and standard therapy arms, respectively). Preliminary analyses of the influence of fibrosis stage on treatment outcomes, following induction and standard therapy, demonstrated poor SVR rates among patients with advanced fibrosis (28% and 24%) compared to those with moderate (51% and 50%) and no or minimal fibrosis (64% and 60%) [16]. The aim of this analysis was to further evaluate the impact of fibrosis stage on treatment response within CHARIOT, including the predictive value of week 4, 8, and 12 responses, and virological relapse. In particular, the contribution of cumulative PEG-IFNα-2a and ribavirin dose to the lower virological responses observed in patients with advanced fibrosis was explored.
Discussion
This comprehensive evaluation of the impact of fibrosis stage on PEG-IFNα-2a and ribavirin treatment response, within a large randomized trial population of treatment naïve patients with chronic HCV genotype 1 infection, has demonstrated several important findings. A marked difference in response by fibrosis stage was found, with very encouraging responses for patients with early liver disease, but poor responses for those with advanced fibrosis. High virological relapse was also seen in patients with advanced fibrosis. The predictive values of early virological responses for SVR differed by fibrosis stage grouping, with the major finding that patients with advanced fibrosis appear unlikely to achieve a SVR without a RVR, and very unlikely if HCV RNA is detectable at week 8 or 12. Only small differences in cumulative PEG-IFNα-2a and ribavirin dose by fibrosis stage were apparent, including through to week 48 among patients with an end-of-treatment response. Thus, low HCV treatment response and high virological relapse rates among patients with advanced fibrosis are not explained by inadequate cumulative therapeutic dosing.
These further analyses within the CHARIOT study provide robust evidence for the influence of fibrosis stage on treatment response. SVR was as high as 70% among patients with no fibrosis, declining in a step-wise fashion to rates of 31% for those with bridging fibrosis (n=97), and only 10% for those with cirrhosis (n=30). We have combined patients with bridging fibrosis and cirrhosis because of the relatively smaller number of patients with cirrhosis. An Italian randomized controlled trial, in a treatment naive genotype 1 population, demonstrated similar trends among patients receiving PEG-IFNα-2b and ribavirin, with SVR rates declining from 60% for Ishak stage 1 to 7% for stage 6 [7]. However, the influence of fibrosis stage on PEG-IFN and ribavirin therapy outcomes in other studies has been based on two disease stage groupings only (generally advanced fibrosis and earlier disease) [2], [3], [18]. Further, key studies have not provided genotype-specific SVR by disease stage, including the pivotal studies of PEG-IFN and ribavirin therapy by Fried et al. [18] and Manns et al. [3].
Low treatment response rates have been described in other studies of PEG-IFN and ribavirin involving treatment naïve patients with genotype 1 and advanced fibrosis, with SVR rates generally 15-40% [2], [3], [4], [5], [6], [7]. In the Hadziyannis et al. study of PEG-IFNα-2a and ribavirin treatment duration and ribavirin dosing, SVR for patients with genotype 1 receiving 48weeks therapy and higher ribavirin dose (1000-1200mg/day) was 41% and 57% among those with and without advanced fibrosis, respectively [2]. A French randomized controlled trial within a METAVIR F3/4 population (51% with cirrhosis) demonstrated SVR rates among the sub-group of treatment naïve genotype 1 patients (n=104) of 24% and 17%, respectively, for standard (1.5µg/kg/week) and low dose (0.75µg/kg/week) PEG-IFNα-2b in combination with ribavirin (800mg/day) for 48weeks [5]. Another randomized controlled trial of PEG-IFNα-2b and ribavirin (800-1200mg/day), in patients with established cirrhosis, showed an SVR of 24% in the genotype 1 sub-group [6].
The low SVR rates among patients with advanced fibrosis in the CHARIOT study were characterized by two clearly outlined virological patterns: (1) slower early virological responses and (2) considerably higher virological relapse. Although SVR and relapse rates were considerably lower and higher, respectively, among patients with advanced fibrosis, when non-SVR patients were analyzed separately within the two fibrosis groupings, the proportions failing therapy due to non-response at week 12, virological breakthrough, and virological relapse were similar.
The slower initial HCV RNA decline, in patients with advanced fibrosis, was despite receiving similar cumulative dosages of PEG-IFNα-2a and ribavirin to patients without advanced fibrosis, indicating that differences in treatment tolerability in relation to dose modifications and/or discontinuations are not the explanation for the lower initial HCV RNA decline or higher relapse rates seen in advanced fibrosis. A potential explanation for our findings is the relationships between fibrosis stage, intrahepatic HCV RNA replication, and HCV clearance. Although patients with advanced fibrosis do not have higher serum HCV RNA levels, they have a higher percentage of hepatocytes with evidence of HCV RNA replication [19]. Viral kinetic studies have shown that patients with HCV genotype 1 and advanced fibrosis have slower second phase HCV RNA decline than those with less fibrosis [20], consistent with our week 4 and 8 response findings. Further, recent HCV modeling based on HCV genotype 1 patients indicates that patients with cirrhosis have lower SVR rates due to a higher percentage of HCV-infected hepatocytes [21]. An additional explanation would relate to potential immunological differences by extent of liver disease. Immunological characteristics including up-regulation of intrahepatic Th1-like cytokines and interferon-stimulated genes (ISGs) are known to influence both fibrosis progression and IFN-based treatment response [22], [23]. Finally, the recently reported association, between IL28B genetic polymorphisms and PEG-IFN/RBV treatment outcome in treatment naïve patients with chronic HCV genotype 1, indicates that host genetic characteristics are important for treatment responsiveness [24], [25]. If IL28B genetic polymorphisms associated with poor HCV treatment response are also found to be linked to liver disease progression, host genetic characteristics could explain the differential response by fibrosis stage.
A further feature of the virological response patterns, between patients with and without advanced fibrosis, was the differential outcomes within similar virological response groupings. Patients with advanced fibrosis with initial undetectable HCV RNA at week 4, 8, 12, were less likely to achieve an SVR compared to those in the corresponding virological response group without advanced fibrosis. Among patients without advanced fibrosis and a RVR, the proportion with a SVR (PPV) was 80%, within the 77-90% RVR PPV range from other studies [26], [27], [28]. However, only 63% of patients with advanced fibrosis and RVR achieved a SVR. The high NPV of RVR for SVR among patients with advanced fibrosis (84%) makes extension of therapy a potential strategy for evaluation in this group. Extension of PEG-IFN and ribavirin therapy, from 48 to 72weeks among patients with HCV genotype 1 and non-RVR, has reduced relapse rates and increased SVR [29], [30], but data on this specific strategy among patients with advanced fibrosis is not available.
Although combination therapy with PEG-IFN, ribavirin, and direct acting antivirals (DAA) such as protease or polymerase inhibitors has shown great promise in phase I and II evaluation, most of these trials have enrolled relatively few patients with advanced fibrosis (patients with established cirrhosis have generally been excluded) and disease stage-specific response data is not available [31], [32]. Pivotal studies among genotype 1 patients for the protease inhibitors telaprevir and boceprevir have included individuals with advanced fibrosis, therefore data on efficacy and safety in this sub-group is eagerly awaited.
Results
Patient characteristics
A total of 871 patients were enrolled, randomized (1:1) to induction and standard therapy, and received study drug (intention to treat analysis population). Baseline liver histology was obtained in 625 of 871 patients (71.8%). Fibrosis stage was F3/4 in 127 patients (14.6%), F0-2 in 498 patients (57.2%), and missing in 246 patients (28.2%). F3/4 patients were older with higher body weight and baseline ALT levels compared to F0-2 patients (Table 1). All F3/4 patients had compensated liver disease (Child-Pugh Score 5 in 124 and 6 in 3 patients). The distribution of patient characteristics for those with biopsy staging were similar to those with missing staging, apart from a lower proportion of Caucasians (80% vs. 90%), and a higher baseline ALT level (median: 54 vs. 44U/L) in those with biopsy (Table 1). Laboratory markers of advanced fibrosis were similar among those with and without biopsy staging including AST/ALT ratio, serum albumin, serum total bilirubin, INR, and platelet count (Table 1). Only six (2.4%) patients with missing biopsy had a Child-Pugh Score of >5.
Virological responses
Induction therapy provided approximately 10% higher early virological responses including undetectable HCV RNA proportions at week 4, 8, and 12 for both F3/4 and F0-2 groups (Fig. 1). However, early virological responses were lower among F3/4 patients in both induction and standard groups compared to corresponding F0-2 patient groups; this difference was apparent by week 4. A rapid virological response (RVR) was achieved in 25% and 18% of F3/4 patients on induction and standard therapy, respectively, compared to 39% and 28% in F0-2 patients.
Fig. 1. Rates of undetectable HCV RNA (<15IU/ml) during treatment (week 4, 8, 12, 24, 48) and at 24weeks post-treatment follow up in both the induction and standard dose treatment groups according to fibrosis group (F0-2, F3/4).
The randomized groups were combined (given similar SVR rates) to explore the impact of individual fibrosis stage on treatment responses. A marked trend in SVR by fibrosis stage was evident with progressive declines in response with increasing fibrosis: F0 (70%); F1 (60%); F2 (51%); F3 (31%); F4 (10%) (p<0.0001) (Fig. 2A). Virological relapse rates were similar in early disease stages (F0, 16%; F1, 23%; F2, 26%), but increased markedly in advanced fibrosis (F3, 50%; F4, 80%) (p<0.0001) (Fig. 2B). Among patients without SVR, the percentage with non-response at week 12, virological breakthrough, and virological relapse was similar for patients with F0-2 (n=216; 27%, 36%, 37%, respectively) and patients with F3/4 (n=94; 30%, 28%, 42%, respectively).
Fig. 2. Sustained virological response and virological relapse by fibrosis stage. (A) Rates and their 95% confidence intervals of sustained virological response by individual fibrosis stage in the combined induction and standard treatment arm population. The total number of patients in each fibrosis sub-group is given at the bottom of each column. (B) Rates and their 95% confidence intervals of virological relapse by individual fibrosis stage in the combined induction and standard treatment arm population. The total number of patients with an end-of-treatment response in each fibrosis sub-group is given at the bottom of each column.
The impact of early treatment response was further characterized in the overall population by determining SVR among fibrosis groups (F0-2, F3/4) within four mutually exclusive response groups based on the week of initial undetectable HCV RNA (week 4, 8, 12, 24). A lower proportion of F3/4 patients reached undetectable HCV RNA by week 4 (21% vs. 34%) and week 8 (19% vs. 26%) (p<0.0001 for comparison of time to undetectable HCV RNA) (Fig. 3A). Furthermore, the SVR rates for each treatment response group were lower for F3/4 patients compared to F0-2 patients, including the rapid virological response group (week 4, 63% vs. 80%) (Fig. 3B). Thus, patients with advanced fibrosis had both slower initial viral decline and lower likelihood of SVR within each early treatment response group.
In a multivariate analysis among patients with all baseline parameters available for inclusion (n=507), METAVIR fibrosis score was associated with SVR (p=0.0194). Adjusted odds ratios for SVR in comparisons with F4 patients were 8.9 (1.8-43.8), 6.3 (1.5-26.6), 5.7 (1.4-23.6), and 2.7 (0.6-11.5) for patients with F0, F1, F2, and F3, respectively.
Predictors of response
The predictive value of early virological response in determination of SVR was also examined, among fibrosis groups and randomized arms (Table 2). The positive predictive value (PPV) of RVR for SVR was lower among F3/4 patients in induction (60%) and standard (67%) arms compared to F0-2 patients (79% and 82%, respectively). Of note, the negative predictive value (NPV) of RVR for SVR was considerably higher among F3/4 patients (83-84%) compared to F0-2 patients (55-57%) (Table 2). Among F3/4 patients the PPV for SVR was lower and NPV higher at week 8. Also, the PPV of week 12 response for SVR, both EVR and cEVR, were considerably lower among F3/4 patients compared to F0-2 patients (Table 2), while NPV of EVR was 100% for all groups (note that patients in both arms without an EVR, continued therapy to week 24 then to week 48 if HCV RNA was undetectable at week 24).
Cumulative therapeutic dosing
The proportions of patients receiving >80% and >95% of planned PEG-IFNα-2a dose by week 12 and 24 were lower among patients on induction therapy, but similar among patients with F3/4 and F0-2 (Table 3). There was a marginally lower proportion with >95% cumulative dosage of PEG-IFNα-2a among F3/4 patients compared to F0-2 patients in the standard arm by week 12 (83.6% vs. 89.3%) and 24 (76.1% vs. 81.0%). The proportions with receipt of >80% and >95% of planned ribavirin dose were similar across randomized and fibrosis groupings, including >95% receipt by week 12 (F0-2: induction 80.1%, standard 83.9%; F3/4: induction 83.3%, standard 83.6%) and week 24 (F0-2: induction 74.6%, standard 74.8%; F3/4: induction 75.0%, standard 73.1%) (Table 3).
Further analyses were undertaken among patients who received greater than or equal to 80% of cumulative PEG-IFN and ribavirin dosage. A marked trend in SVR by fibrosis stage remained with progressive declines in response with increasing fibrosis: F0 (78%); F1 (75%); F2 (70%); F3 (46%); F4 (13%). Virological relapse rates were similar in early disease stages (F0, 19%; F1, 23%; F2, 26%), but again increased markedly in advanced fibrosis (F3, 53%; F4, 85%).
In a logistic regression analysis the odds ratio for SVR was 0.55 (95% CI 0.46-0.66, p<0.0001) per one stage increase in fibrosis stage.
Safety and tolerability
The serious adverse event rate was 12-15% for patients with F3/4 compared to 9-10% for patients with F0-2 (Table 4). Treatment discontinuation due to adverse events or laboratory abnormalities was similar among patients with F3/4 (8-9%) and F0-2 (7-9%) (p=0.86). Although dose modification of PEG-IFNα-2a was more common among patients in the induction than standard treatment group (26% vs. 19%) (p=0.040), there was no significant difference by fibrosis group (p=0.44). In contrast, no significant difference in ribavirin dose modification was seen for both treatment (p=0.21) or fibrosis group stratification (p=0.47). Hemotological toxicity was greater among patients with F3/4, with significantly higher rates of thrombocytopenia (platelets<50x109/L) (p<0.0001) and severe anemia (hemoglobin <8.5g/dl) (p=0.009).
Methods
CHARIOT study population
The CHARIOT trial methods and patient population have been described in detail [16]. Eligible subjects included treatment naïve adults aged 18-75years with chronic HCV genotype 1 infection and compensated liver disease (Child-Pugh Score <7). Initial recruitment (in Australia from August 2004) excluded patients with cirrhosis. The protocol was revised in mid-2006 to allow inclusion of patients with normal serum ALT level and absence of liver biopsy staging of disease consistent with changes to Australian subsidized treatment requirements for serum ALT elevation (December 2005) and pre-treatment liver biopsy (April 2006). In addition, patients with compensated cirrhosis were able to enroll. Also, from mid-2006, recruitment commenced through several other countries (New Zealand, Thailand, Canada, Mexico, Argentina), with pre-treatment liver biopsy staging required in all these countries apart from New Zealand.
Patients meeting screening eligibility criteria were randomly assigned 1:1 to receive PEG-IFNα-2a either in an induction dose or standard dose regimen. The induction regimen consisted of 360µg of PEG-IFNα-2a weekly, for the first 12weeks, followed by 180µg of PEG-IFNα-2a weekly, for 36weeks and 1000/1200mg of ribavirin daily for 48weeks. The standard dose regimen involved 180µg of PEG-IFNα-2a weekly and 1000/1200mg of ribavirin daily for 48weeks. Patients in both arms without an early virological response (EVR) at week 12 continued therapy to week 24; patients with detectable HCV RNA at week 24 ceased therapy.
Cumulative exposure to PEG-IFNα-2a and ribavirin was determined by calculation of the percentage of planned dose received through week 4, 8, 12, 24, and 48. Reductions from maximum dose occurred through both clinician-directed dose modification and patient non-adherence, with adherence assessed via recording the injections and doses of PEG-IFNα-2a and ribavirin at each visit according to the patient's detailed statements, and via documentation of drugs dispensed through pharmacy records.
Assessments and efficacy endpoints
Quantitative serum HCV RNA levels were measured at baseline and at weeks 4, 8, 12, 24, 48, and 72 (Roche Ampliprep/Cobas TaqMan HCV Test with a detection limit of 15IU/ml). Treatment response endpoints were defined as undetectable HCV RNA, including the primary endpoint at week 72, and were based on Taqman results below the level of detection (both undetectable and detectable <15IU/ml).
Liver biopsies were taken within 36months of treatment and scored by local pathologists. Fibrosis stage was classified according to the METAVIR system [17] as F0 (no), F1 (mild), F2 (moderate), F3 (severe), and F4 (cirrhosis). Advanced fibrosis included patients with either F3 or F4 fibrosis stage.
Statistical analysis
The intent-to-treat analysis population was defined as all patients randomized who received at least one dose of study medication. Percentages are calculated for categorical parameters. Means are calculated for the continuous variables. Area under the curve (AUC) of HCV RNA through week 24 is calculated and has been analyzed with F3/4 vs. F0-2 and treatment groups as factors in ANCOVA. A logistic regression analysis was conducted for SVR with METAVIR score as a prognosis factor. A multivariate logistic regression analysis was also conducted to evaluate the independent impact of fibrosis stage on SVR, with the following baseline variables included: treatment group, age, gender, race, body weight, METAVIR fibrosis score, screening HCV RNA level, subtype (1b or non-1b), ALT, AST/ALT ratio, hemoglobin, white blood cell count, platelet count, serum creatinine, serum albumin, total bilirubin, alkaline phosphatase, gamma-glutamyl transferase (GGT), and international normalized ratio (INR). Due to the exploratory nature of the analyses, no alpha-adjustments were applied to account for multiple significance testing.
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