| |
Randomized comparison of 12 or 24 weeks of peginterferon a-2a and ribavirin in chronic hepatitis C virus genotype 2/3 infection
|
| |
| |
Hepatology June 2008
Martin Lagging 1 *, Nina Langeland 2, Court Pedersen 3, Martti Farkkila 4, Mads Rauning Buhl 5, Kristine Morch 2, Amar P. Dhillon 6, Asa Alsio 1, Kristoffer Hellstrand 1, Johan Westin 1, Gunnar Norkrans 1, NORDynamIC Study Group
1Department of Infectious Diseases, Goteborg University, Goteborg, Sweden
2Department of Infectious Diseases, Haukeland University Hospital and Institute of Medicine, University of Bergen, Bergen, Norway
3Department of Infectious Diseases, University of Southern Denmark, Southern Denmark, Denmark
4Department of Gastroenterology, Helsinki University, Helsinki, Finland
5Department of Infectious Diseases, Aarhus University, Aarhus, Denmark
6Department of Histopathology, Royal Free Hospital, London, United Kingdom
"The post hoc analyses identified two groups of patients who responded favorably to short-term treatment: (1) patients younger than 40 years of age achieving RVR and (2) patients 40 years old or older with a very rapid virological response (that is, HCV-RNA below 1000 IU/mL on day 7 in addition to achieving RVR)......The age of the patients impacted significantly on treatment efficacy, with markedly better outcome in those younger than 40 years (Fig. 4). When analyzed by means of a receiver operating characteristic curve for age, 40 years was identified as a threshold above which SVR declined noticeably in the 12-week treatment arm. Patients younger than 40 years (who constituted 40% of the ITT population) were less likely to have cirrhosis (2% versus 20%, P < 0.0001) and showed a nonsignificant trend toward a higher likelihood to achieve RVR (72% versus 56%) in comparison with those >/=40 years old......In conclusion, our findings demonstrate that the efficacy of 12 weeks of combination therapy is overall inferior to 24 weeks in patents infected with genotype 2 or 3. Post hoc analyses, however, suggested that 12 weeks of treatment is equally efficacious in patients younger than 40 years achieving RVR and in those >/=40 years old with a very rapid clearance of virus. However, larger prospective studies will be needed to confirm these findings."
Abstract
Previous trials investigating the efficacy of treatment durations shorter than the standard of 24 weeks for chronic hepatitis C virus (HCV) genotype 2/3 infections have yielded discordant results. The aims of this investigator-initiated phase III study were to compare the efficacy of 12 or 24 weeks of treatment and to identify patients suitable for short-term therapy. Three hundred eighty-two genotype 2/3-infected patients [intention-to-treat (ITT) population] at 31 centers in Denmark, Finland, Norway, and Sweden were randomized to 12 or 24 weeks of peginterferon a-2a (180 ug/week) plus ribavirin (800 mg/day). Twelve weeks of therapy was inferior to 24 weeks in the ITT population (sustained viral response [SVR] rates: 59% versus 78%, P < 0.0001) and in the subgroups of patients infected with genotype 2 (56% versus 82%, P = 0.006) or 3 (58% versus 78%, P = 0.0015). These differences were observed regardless of the fibrosis stage. Age and HCV-RNA levels on days 7 and 29 were independent predictors of SVR. Short-term treatment was useful in patients < 40 years old, especially if HCV-RNA was undetectable on day 29, and also in patients 40 years old, provided that HCV-RNA was below 1000 IU/mL on day 7 in addition to being undetectable on day 29. If neither of these two criteria were met for patients >40 years old, 24 weeks of therapy was superior (P < 0.0001).
Conclusion: Peginterferon/ribavirin treatment for 12 weeks in HCV genotype 2/3 infection is overall inferior to 24 weeks of treatment but may be useful in some patients with a rapid initial clearance of virus.
Hepatitis C virus (HCV) is the foremost cause of parenterally transmitted non-A, non-B hepatitis.[1][2] Chronic infection is associated with liver fibrosis, cirrhosis, and hepatocellular carcinoma.[3][4] Treatment with pegylated interferon a and ribavirin yields sustained viral response (SVR) rates of 50%-80%,[5-7] with higher SVR rates seen in patients infected with HCV of genotypes 2 and 3. The current standard of care for patients carrying these viral genotypes is 24 weeks of treatment. Because of the severe side effects and the high cost of therapy, shorter treatment duration with retained efficacy is desirable, but recent trials investigating the effectiveness of treatment for less than 24 weeks have yielded discordant results. Although several trials with treatment durations of 12-16 weeks[8-10] have demonstrated outcomes compatible with that obtained with 24 weeks in patients who achieve a rapid virological response (RVR; defined as undetectable serum HCV-RNA after 4 weeks of therapy), the largest trial to date (the Accelerate trial) reported significantly lower SVR rates with 16 weeks of therapy in comparison with 24 weeks even in patients who had achieved RVR.[11] The aims of this phase III study were to compare the efficacy of 12 or 24 weeks of therapy with 180 ug of peginterferon a-2a once weekly in combination with 800 mg of ribavirin and to identify patients potentially suitable for short-term therapy.
Patients and Methods
Patients.
Between February 2004 and November 2005, 392 patients with chronic HCV genotype 2/3 infection were screened for inclusion in a phase III, open-label, randomized, multicenter, investigator-initiated trial conducted by the NORDynamIC study group at 31 centers in Denmark, Finland, Norway, and Sweden (Fig. 1). Three hundred eighty-two enrolled patients met all inclusion criteria and constituted the intention-to-treat (ITT) population. All patients were adults (age >18 years), had compensated liver disease, were treatment-naive for hepatitis C, were seronegative for hepatitis B surface antigen and for antibodies to human immunodeficiency virus, and fulfilled the following additional inclusion criteria: a positive test for anti-HCV antibody, infection with HCV genotypes 2 and/or 3 but not genotypes 1, 4, 5, or 6, and HCV-RNA > 600 IU/mL (quantified with the Roche Amplicor HCV monitor, version 2.0) within 6 months of treatment initiation. A liver biopsy consistent with chronic hepatitis C within 24 months of entry was also required. At randomization, the study groups were stratified for age, genotype, and presence of cirrhosis in the liver biopsy as judged by the local pathologist. Three hundred three patients (79%) received at least 80% of the target dose of peginterferon a-2a and at least 80% of the target dose of ribavirin for at least 80% of the target treatment duration and were included in the per protocol analysis. Fifty-eight patients prematurely terminated treatment (12 in the 12-week arm versus 46 in the 24-week arm), chiefly because of adverse events in both arms. In the 24-week arm, 39 of 46 premature terminations of therapy occurred between study weeks 13 and 24. However, these terminations were primarily due to adverse events, and none were due to treatment failure because no HCV-RNA plasma samples were analyzed until after the 24-week posttreatment follow-up period. Twenty-six patients (15 in the 12-week arm and 11 in the 24-week arm) failed to have a plasma sample drawn 24 weeks after completion of therapy; these latter patients were censored as treatment failures. These censored patients were classified as nonresponse or relapse on the basis of whether or not HCV-RNA was detectable in the end-of-treatment plasma.
Treatment.
At study entry, patients were randomized to either 12 or 24 weeks of therapy with 180 ug of peginterferon a-2a once weekly (Pegasys, F. Hoffmann-La Roche, Basel, Switzerland) and ribavirin twice daily (Copegus, F. Hoffmann-La Roche) at a total daily dose of 800 mg daily. The result of the randomization was not disclosed to patients or treating physicians until after 12 weeks of therapy.
Study Endpoints.
The primary trial endpoint was a comparison of the SVR rates after 12 or 24 weeks of combination therapy. The sample size was calculated to detect a difference of >12% (SVR rates) between treatment arms with a power of 80%. Secondary objectives included evaluation of the impact of viral kinetics (by means of HCV-RNA quantification) and liver biopsy scores on SVR.
HCV-RNA Quantification.
Plasma was obtained with PPT tubes, and HCV-RNA was determined by reverse-transcription polymerase chain reaction of plasma with the Cobas AmpliPrep/COBAS TaqMan HCV test (Roche Diagnostics, Branchburg, NJ), which quantifies HCV-RNA with a limit of detection of <15 IU/mL. HCV-RNA quantification was performed on days 0, 3, 7, 8, and 29 and in weeks 8, 12, and 24 (for those receiving 24 weeks of therapy) and 24 weeks after completion of therapy. All samples were frozen (-70°C) and subsequently analyzed at the central laboratory (Department of Virology, Goteborg, Sweden).
Classification of Treatment Outcome.
Patients were classified as achieving SVR if plasma HCV-RNA was undetectable (i.e., <15 IU/mL) 24 weeks after completion of therapy, as having relapsed if plasma HCV-RNA was undetectable at the end of treatment but detectable 24 weeks after completion of therapy, and as being nonresponders if plasma HCV-RNA was detectable at the end of treatment. Patients were classified as having an RVR if HCV-RNA was undetectable on day 29.
Genotyping.
Genotyping of HCV was initially performed at the local centers and subsequently confirmed at the central laboratory (Department of Virology, Goteborg, Sweden) with a TaqMan primer-specific reverse-transcription polymerase chain reaction method[12] and, if needed, INNO-LiPA HCV II (Innogenetics N.V., Ghent, Belgium). Two patients had dual infections with genotypes 2 and 3.
Liver Biopsies.
Liver biopsies were obtained from all patients within 24 months prior to study entry. Only biopsies with a length exceeding 1.5 cm and containing more than 6 portal tracts were evaluated. In total, liver biopsies from 354 patients were retrieved and scored. For each biopsy, a hematoxylin-eosin stain and a Sirius Red stain were centrally staged and graded by two independent observers (J.W. and M.L. under the supervision of A.P.D) experienced in pseudo-numerical scoring of liver biopsies with a documented acceptable interobserver variability.[13-15] The evaluation was performed in a blinded fashion according to the Ishak protocol.[16] Equivocal issues were debated after the independent scores were noted, and a consensus score was obtained. In addition, steatosis was graded as follows: absent = 0, less than 30% of hepatocytes involved = 1, 30%-70% of hepatocytes involved = 2, and more than 70% of hepatocytes involved = 3.[17]
Statistical Methods.
The chi-square test and Fisher's exact test were used to evaluate differences in frequencies of SVR, relapse, and nonresponse between treatment groups. In order to evaluate factors associated with SVR, univariate analyses of covariates were performed. All covariates with a P value of 0.10 or less in the univariate analysis were considered for inclusion in a multivariate logistic regression model. The potential explanatory variables included in the multivariate analysis were as follows: HCV-RNA levels at baseline, day 3, day 7, day 8, day 29, week 8, and week 12; second slope (as measured by the decline in HCV-RNA between days 3 and 7); age; gender; fibrosis stage; steatosis grade; body mass index; weight; height; baseline a-2-macroglobulin; baseline gamma glutamyl transpeptidase; baseline bilirubin; baseline procollagen type 2 N-terminal propeptide; baseline hyaluronic acid; baseline cholesterol; alcohol intake during the year prior to enrollment; depression score at baseline; duration of infection; ribavirin trough levels at day 29 and week 12; and percentage of the target dose of pegylated interferon taken. A stepwise procedure with forward selection and backward elimination was performed for each study arm separately and for the study arms combined through a comparison of the difference in deviance between nested models. All statistical analyses were performed with SAS for Windows (version 8.02, SAS Institute, Inc., Cary, NC) by K.W. and C.A. (Pharma Consulting Group, Uppsala, Sweden) or with StatView for Macintosh (version 5.0, SAS Institute) by M.L. (Goteborg, Sweden). All reported P values are two-sided, and P values < 0.05 were considered significant.
Results
No significant differences were noted regarding the baseline characteristics of the patients in the 12- and 24-week treatment arms (Table 1). Interestingly, however, the genotype 2-infected patients were significantly older than those infected with genotype 3 (47.2 versus 39.8 years; P < 0.0001), but they did not differ significantly in fibrosis stage, gender, or other characteristics.
Twelve weeks of combination therapy was in general inferior to 24 weeks with respect to both a lower SVR rate (ITT population: 59% versus 78%, P < 0.0001) and a higher relapse rate (33% versus 12%, P < 0.0001), and this held true for genotypes 2 and 3 in both the ITT (Fig. 2) and per protocol analyses (data not shown). In the 24-week treatment arm, 37 of the 177 patients completed 24 weeks of posttreatment follow-up but failed to be included in the per protocol analysis (that is, they had not taken at least 80% of both study medications for at least 80% of the planned treatment duration). Interestingly, despite this, 27 of these 37 patients (73%) achieved SVR.
The SVR rate in the 12-week arm was inferior to that in the 24-week arm, regardless of the stage of liver fibrosis as assessed in the liver biopsies (Fig. 3). This difference was statistically significant for patients with nonsignificant fibrosis (Ishak fibrosis stage 0-2) as well as bridging fibrosis (Ishak fibrosis stage 3-4), and an analogous trend (P = 0.074) was noted for patients with cirrhosis (Ishak fibrosis stage 5-6). Interestingly, as shown in Fig. 3, only 57% of the patients with cirrhosis achieved SVR despite 24 weeks of treatment. For patients with steatosis, regardless of severity, 24 weeks was superior (P = 0.0002).
The age of the patients impacted significantly on treatment efficacy, with markedly better outcome in those younger than 40 years (Fig. 4). When analyzed by means of a receiver operating characteristic curve for age, 40 years was identified as a threshold above which SVR declined noticeably in the 12-week treatment arm. Patients younger than 40 years (who constituted 40% of the ITT population) were less likely to have cirrhosis (2% versus 20%, P < 0.0001) and showed a nonsignificant trend toward a higher likelihood to achieve RVR (72% versus 56%) in comparison with those >40 years old.
The pretreatment viral load also significantly impacted on treatment outcome (Table 2). The 102 patients (27%; 51 patients in each study arm) with baseline HCV-RNA below 400,000 IU/mL had an SVR rate of 80% with 12 weeks of therapy and 90% with 24 weeks versus 51% and 74%, respectively, for patients with baseline HCV-RNA >400,000 IU/mL (P < 0.0001). Of the patients with a low baseline viral load, 54% were younger than 40 years, and 83% achieved RVR. Eight of the patients with baseline HCV-RNA < 400,000 IU/mL had cirrhosis, 6 of whom achieved SVR.
Outcome was significantly better in the 24-week treatment arm, regardless of whether or not patients had achieved RVR (Fig. 5). This held true both for patients infected with genotype 2 (P = 0.008) and for patients infected with genotype 3 (P = 0.0042). However, this difference was most pronounced for patients 40 years old or older.
When the predictors of SVR that had been identified in the univariate analysis were included in a multivariate analysis, three independent predictors of SVR in the 12-week arm emerged: HCV-RNA on day 7 (<1000 versus >/=1000 IU/mL, odds ratio 7.98; P < 0.0001), age (<40 versus >/=40 years, odds ratio 4.84; P < 0.0001), and HCV-RNA on day 29 (detectable versus undetectable, odds ratio 2.13; P = 0.0454). Similarly, two independent predictors of SVR were identified in the 24-week arm: HCV-RNA on day 29 (detectable versus undetectable, odds ratio 5.44; P = 0.0002) and age (<40 versus >/=40 years, odds ratio 3.50; P < 0.0001).
When combining the independent predictive factors identified in the multivariate analysis, we noted that for patients younger than 40 years of age, 86% achieved SVR in the 12-week study arm and 93% achieved SVR in the 24-week arm if the patients had achieved RVR. The majority of these younger patients (72%) achieved RVR. Not surprisingly, we observed lower SVR rates if RVR was not achieved among younger patients. However, within this small group of patients (n = 22 and n = 19 in the 12- and 24-week arms, respectively), no significant benefit of extending the duration of therapy to 24 weeks was noted in the ITT population (SVR: 73% for the 12-week arm versus 63% for the 24-week arm), with similar results observed in the per protocol population (SVR: 73% in both arms).
For patients 40 years old or older, monitoring RVR alone was not helpful in identifying patients suitable for shorter therapy. However, an HCV-RNA level below 1000 IU/mL on day 7, suggestive of a very rapid clearance of virus, was predictive of successful short-term treatment also in these patients (Fig. 6). Of the 23% of patients with age >/=40 years with such a very rapid clearance of HCV, 91% achieved SVR with 12 weeks of therapy versus 89% with 24 weeks of treatment. In patients with HCV-RNA exceeding 1000 IU/mL on day 7, 24 weeks of therapy was clearly advantageous (SVR: 35% in the 12-week arm versus 70% in the 24-week arm, P < 0.0001). All patients 40 years old or older in the 12-week arm with HCV-RNA below 1000 IU/mL on day 7 (n = 23) also achieved RVR. However, 3 patients in the 24-week arm with such early clearance of virus did not achieve RVR; 1 patient prematurely terminated therapy and subsequently relapsed, whereas the other 2 achieved SVR. Notably, all 5 patients with cirrhosis in the 12-week arm with HCV-RNA below 1000 IU/mL on day 7 eventually achieved SVR.
The vast majority of patients reported adverse events during the study (92% versus 94% for the 12- and 24-week arms, respectively). Adverse events leading to premature termination of therapy were more common in the 24-week arm than in the 12-week arm (20 versus 2, P < 0.0001). The total number of reported adverse events was also higher in the 24-week arm (1099 events versus 1352 for the 12- and 24-week arms, respectively). The nature of the observed adverse events was in agreement with previous reports.[5][6][10]
Discussion
In our study, 12 weeks of combination therapy with peginterferon and ribavirin for patients with HCV of genotype 2 or 3 was overall inferior to 24 weeks of treatment, even in patients achieving RVR, and this was in large part due to a significant increase in the relapse rate following shorter term therapy. This finding differs from previous reports on treatment shorter than 24 weeks for patients with these genotypes,[8-10] including the Accelerate study, which reported lower SVR rates following shorter term therapy even in patients achieving RVR, although this latter finding was statistically significant only in patients infected with genotype 2.[11]
There are several conceivable explanations for this difference in outcome in comparison to prior reports, including baseline patient demographics, differences in treatment duration, and differences in ribavirin dosage. Fifty-three percent of our patients had bridging fibrosis or cirrhosis versus 18% in the study by Mangia et al.,[9] 23% in that by Dalgard et al.,[8] and 24% in the Accelerate trial.[11] Von Wagner et al.[10] reported a mean Ishak fibrosis stage of 1.6 in the 16-week treatment arm, indicating that their study population may have had less advanced disease. As well as having more advanced liver fibrosis, our patients were older than those in prior studies of short-term treatment: the mean age of our patients was 42 years versus 37 years in the study by Dalgard et al. and 38 years in the von Wagner study. Mangia et al. reported a higher mean age of 46.6 years; however, in addition to having less advanced fibrosis, these patients had a mean weight 8.8 kg below that of the patients in this study. Given the documented impact of liver fibrosis, age, and body weight on treatment outcome,[5-7] it may be hypothesized that the poorer outcome of short-term therapy in our study may, at least in part, be explained by a higher frequency of unfavorable baseline features.
Despite the unfavorable baseline characteristics, the proportion of patients achieving RVR in our study (62%) was in agreement with previous reports (62%-93%).[8-11] The limit of detection of the HCV-RNA assay reported in this study was
It is possible that a higher dose of ribavirin, as used in several other studies,[8-10] would have decreased the relapse rate and increased the fraction of patients achieving SVR in our study. It would also likely have entailed increasing numbers of adverse events and a substantially higher cost. An alternative to giving all patients higher doses would be to restrict the use of additional ribavirin to those with suboptimal concentrations of this drug; this issue likely will be addressed in forthcoming studies.
The post hoc analyses identified two groups of patients who responded favorably to short-term treatment: (1) patients younger than 40 years of age achieving RVR and (2) patients 40 years old or older with a very rapid virological response (that is, HCV-RNA below 1000 IU/mL on day 7 in addition to achieving RVR). Because our study population had a relatively high proportion of unfavorable prognostic features, we hypothesize that the proposed criteria for identifying suitable candidates for short-term therapy may be applicable also to populations with more favorable characteristics. Interestingly, in this study, no apparent benefit of extending therapy beyond 12 weeks was observed among the relatively few patients younger than 40 years who did not achieve RVR. However, because the Accelerate study has reported significantly lower SVR rates among such patients following short-term treatment,[11] 24 weeks of therapy may be preferential in this group.
If patients with a favorable viral kinetic response to therapy were selected for 12 weeks of therapy as suggested previously and the treatment population had demographics similar to ours, approximately 40% of the total population would likely be suitable for short-term therapy, which subsequently would lead to a 20% reduction in pharmaceutical costs as well as a substantial reduction in side effects along with a minimal infringement on SVR rates. It must be emphasized, however, that our study was not powered to evaluate the efficacy of short-term therapy in subgroups of patients suitable for shorter term therapy. Therefore, it may be prudent to prospectively monitor outcome if current treatment durations are modified in accordance with the aforementioned guidelines.
Liver fibrosis and steatosis influenced the treatment outcome in both the 12- and 24-week arms. However, our results indicate that the viral kinetic response is of greater importance and that a liver biopsy is not helpful in assessing whether a patient is suitable for short-term therapy. Indeed, all 5 patients with cirrhosis and 13/14 patients with bridging fibrosis with HCV-RNA below 1000 IU/mL on day 7 achieved SVR following 12 weeks of therapy.
In conclusion, our findings demonstrate that the efficacy of 12 weeks of combination therapy is overall inferior to 24 weeks in patents infected with genotype 2 or 3. Post hoc analyses, however, suggested that 12 weeks of treatment is equally efficacious in patients younger than 40 years achieving RVR and in those 40 years old with a very rapid clearance of virus. However, larger prospective studies will be needed to confirm these findings.
|
|
| |
| |
|
|
|
