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72 Weeks Pegasys/RBV Improves SVR for When HCV-RNA is Detectable at Week 4
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Peginterferon-Alfa2a (Pegasys) Plus Ribavirin for 48 Versus 72 Weeks in Patients With Detectable Hepatitis C Virus RNA at Week 4 of Treatment
Gastroenterology Volume 131, Issue 2, Pages 451-460
(August 2006)
"....In conclusion, extension of the duration of treatment with peginterferon-alfa2a plus ribavirin up to 72 weeks significantly increased the likelihood of achieving SVR in patients without virologic response at week 4. The virologic response at week 4, measurement of viremia at baseline, and consideration of HCV kinetics during treatment provide useful information for individualizing therapy. However, further studies are necessary to better delineate optimal, highly individualized, and more cost-effective therapeutic strategies...."
Authors: TeraViC-4 Study Group. Jose M. Sanchez-Tapias_, Moises Diago, Pedro Escartin, Jaime Enriquez, Manuel Romero-Gomez, Rafael Barcena#, Javier Crespo Raul Andrade, Eva Martinez-Bauer, Ramon Perez, Milagros Testillano, Ramon Planas, Ricard Sola, Manuel Garcia-Bengoechea, Javier Garcia-Samaniego, Miguel Munoz-Sanchez, Ricardo Moreno-Otero
Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer,
ABSTRACT
Background & Aims: Patients with chronic hepatitis C who do not respond rapidly to therapy have a low chance of developing a sustained virologic response (SVR) when treated for 48 weeks. This study investigated whether treatment for 72 weeks increases the rate of SVR in patients with detectable hepatitis C virus (HCV)-RNA levels at week 4 of treatment.
Methods: A total of 510 treatment-naive patients were treated with peginterferon-alfa2a (180 μg/wk) plus ribavirin (800 mg/day). Patients with detectable HCV-RNA levels at week 4 (n = 326) were randomized to complete 48 (group A, n = 165) or 72 weeks (group B, n = 161) of treatment.
Patients with undetectable HCV-RNA levels at week 4 (n = 184) were allocated into group C (n = 148) or group D (n = 36), according to HCV genotype and baseline viremia, and treated for 24 or 48 weeks, respectively. All patients were followed-up for 24 weeks after the end of treatment.
Results:
The end-of-treatment response rate (61%) was similar in groups A and B, but the SVR rate was higher in group B (45% vs 32% in A; P = .01). In genotype 1-infected patients randomized to group A (n = 149) or B (n = 142), SVR rates were 28% and 44%, respectively (P = .003). The incidence of adverse events was similar in all groups. Treatment discontinuation was more frequent in group B (36%) than in group A (18%) (P = .0004).
SVR rates in groups C and D were 79% and 64%, respectively.
Conclusions: Extension of treatment with peginterferon-alfa2a plus ribavirin from 48 to 72 weeks significantly increases the rate of SVR in patients with detectable viremia at week 4 of treatment.
Discussion
Despite recent developments, the treatment of chronic hepatitis C is unsuccessful in a significant proportion of patients. In the absence of alternative antiviral agents that are effective against HCV, further exploration of the therapeutic potential of currently available drugs seems justified. In the present study we evaluated the therapeutic efficacy and safety of increasing the total duration of treatment with peginterferon-alfa2a plus ribavirin from 48 to 72 weeks in patients with detectable HCV RNA after 4 weeks of combination therapy.
This study was undertaken because previous observations suggested that extending the duration of treatment may increase the efficacy of antiviral therapy in patients with CHC. Conventional interferon monotherapy of 3 million IU 3 times weekly for 18 months produced greater histologic and biochemical benefits than regimens that included lower doses or shorter treatment duration.13 Similar observations were reported from Australia in patients treated with conventional interferon monotherapy for 2 years.14 More recently, treatment with conventional interferon plus ribavirin for 18 months was shown to reduce the relapse rate and significantly increase the SVR rate compared with conventional interferon monotherapy given for 18 months or combination therapy for 6 months.15
In this study, patients were selected for randomization according to HCV-RNA status after 4 weeks of therapy. This decision was based on several observations indicating that clearance of serum HCV RNA at week 4 of treatment is associated closely with SVR, as it was shown in patients treated with either conventional interferon,15, 16, 17 consensus interferon,18 or combination therapy with conventional7 or pegylated interferon8, 9, 10 plus ribavirin. This approach ensured that patients most likely to respond favorably to less aggressive therapy were excluded from randomization and not exposed to potential risks associated with prolonged therapy. In addition, assessment of extended-duration therapy would focus on those patients less likely to respond to standard-duration therapy.
This study shows that, in this particular population, extension of treatment duration up to 72 weeks significantly increases the efficacy of peginterferon-alfa2a plus ribavirin in comparison with the currently recommended 48-week treatment duration. The number of patients who discontinued therapy and who thus were considered to be nonresponders was significantly greater among those randomized to prolonged therapy. Nevertheless, the intention-to-treat analysis showed that the SVR rate was 45% in patients treated for 72 weeks and 32% in those treated for 48 weeks, a difference that was statistically significant. However, it must be stressed that our study focused on patients who did not achieve a virologic response within 4 weeks of initiating therapy and, as such, the possible benefits of prolonged therapy cannot be generalized to all patients with CHC.
The virologic response rate at the end of therapy was identical in patients treated for 48 or 72 weeks. After discontinuation of treatment, virologic relapse was significantly less frequent in patients treated for 72 weeks and, as a consequence, the proportion of patients with SVR was significantly greater in patients undergoing prolonged therapy. These findings are in line with the results of a previous randomized study in which a decreased relapse rate was observed in patients treated with standard interferon plus ribavirin for 18 months as compared with patients treated for 6 months.15
Ribavirin plays an important role in the treatment of CHC,2, 19, 20, 21 and adequate dosing of ribavirin is important as well. Retrospective analysis of data from a large trial showed that patients treated with pegylated interferon alfa-2b (12 kilodaltons) plus a ribavirin dose of 10.6 mg/kg/day or more had a greater chance of developing an SVR than patients treated with pegylated interferon alfa-2b (12 kilodaltons) and a lower daily dose of ribavirin.1 More recently, it was shown that combination therapy with peginterferon-alfa2a plus ribavirin for 48 weeks was more effective in patients infected with HCV genotype 1 if the ribavirin dose was 1000 or 1200 mg/day rather than 800 mg/day.3 This information was not available at the time the present study was designed and the dose of 800 mg/day was chosen. Nevertheless, regression analysis showed that more prolonged therapy rather than higher-dose ribavirin, according to body weight, was associated with an increased likelihood of SVR. Whether prolonged therapy also may provide more benefit in patients treated with the currently recommended higher doses of ribavirin deserves further study.
Despite prolonging treatment up to 72 weeks, 55% of patients without RVR at week 4 did not achieve SVR. In this study a significant increase of SVR was achieved with prolonged therapy in patients with a viral load less than 800,000 IU/mL at baseline but not in those with a higher level of viremia. A subanalysis of the patients infected with genotype 1, who accounted for about 90% of patients randomized to standard or an extended duration of therapy, led to the same conclusion. The potential benefit of prolonged therapy in highly viremic patients is unclear and deserves further investigation.
The negative predictive value for SVR of HCV RNA decrease lower than 2-log10 at week 12 for patients treated for 72 weeks was only 85%, suggesting that some of these particular patients may benefit from prolonged therapy. This finding is in apparent contradiction to the widely accepted 12-week stopping rule stated in previous studies.2, 11 However, it should be noted that our study focused on a different patient population (week 4 nonvirologic responders), that the ribavirin dose used (800 mg/day) was different, and that the duration of treatment was different as well. In contrast, an insufficient decrease of HCV-RNA level at week 24 of treatment had a 95% negative predictive value for SVR, irrespective of treatment duration. Thus, baseline viremia and viral kinetics during treatment provide information that may be useful for therapeutic decisions concerning treatment duration in patients with detectable HCV-RNA levels after 4 weeks of treatment.
The type and incidence of adverse events observed in this trial did not differ from those reported in other studies. Interestingly, previously unreported adverse events were not observed in patients treated for 72 weeks. The proportion of patients who discontinued treatment as a result of adverse events was similar in groups A and B. However, significantly more patients randomized to group B discontinued therapy prematurely because of refusal of further treatment or failure to return, which occurred mostly between weeks 24 and 48 of therapy.
Among patients who did not discontinue treatment, the SVR rate was 40% in the 48-week treatment group and 64% in the 72-week treatment group (per protocol analysis). These data highlight the relevance of encouraging adherence to therapy in patients with CHC.22
The SVR rate observed in patients with virologic response at week 4 who received treatment for 24 or 48 weeks was 79% and 64%, respectively. This observation supports the value of qualitative determination of HCV RNA at week 4 of therapy as a tool for differentiating more difficult from less difficult to treat patients with CHC. Several studies have suggested that this approach may be appropriate to reduce the duration of treatment in patients infected with HCV genotype 2 or genotype 3.23, 24, 25 Interestingly, the high SVR rate observed in genotype 1-infected patients with low viral load and virologic response at week 4 when treated for 24 weeks only is in keeping with the observations made in a recent study evaluating 24 weeks of therapy in these particular patients.9
In conclusion, extension of the duration of treatment with peginterferon-alfa2a plus ribavirin up to 72 weeks significantly increased the likelihood of achieving SVR in patients without virologic response at week 4. The virologic response at week 4, measurement of viremia at baseline, and consideration of HCV kinetics during treatment provide useful information for individualizing therapy. However, further studies are necessary to better delineate optimal, highly individualized, and more cost-effective therapeutic strategies.16
Study Design
In this partially randomized, open-label, parallel-group, multicenter study all patients received subcutaneous peginterferon-alfa2a (PEGASYS; Roche, Basel, Switzerland) 180 μg/week plus oral ribavirin (COPEGUS; Roche) 800 mg/day during the treatment phase of the study. To identify subjects with a rapid virologic response (RVR), all patients were tested for HCV RNA after 4 weeks of treatment using a qualitative polymerase chain reaction assay with a limit of detection of 50 IU/mL (COBAS AMPLICOR HCV Test, v2.0; Roche Diagnostics). RVR was defined as undetectable HCV-RNA levels at week 4 of therapy.
Patients without an RVR were randomized in a 1:1 ratio to continue therapy for 44 additional weeks (group A; total treatment duration, 48 wk) or for 68 additional weeks (group B; total treatment duration, 72 wk). The computerized randomization list (by blocks of 4 patients, without stratification) was generated automatically by SAS software (SAS Institute, Cary, NC). PRA-Staticon International S.L. (Madrid, Spain) managed the centralized randomization procedure, maintained the randomization list, and communicated with study centers by phone and confirmed by fax.
Patients who had a RVR at week 4 were allocated to receive further treatment according to their virologic profile at baseline. Patients infected with HCV genotypes 2 or 3 and patients infected with genotype 1 or genotype 4 who had serum HCV-RNA levels of 800,000 IU/mL or less at baseline continued treatment for 20 additional weeks (group C; total treatment duration, 24 wk). Patients infected with HCV genotype 1 or 4 and an HCV-RNA level greater than 800,000 IU/mL at baseline continued treatment for 44 additional weeks (group D; total treatment duration, 48 wk). All patients were followed-up for 24 weeks after treatment withdrawal. The use of growth factors such as erythropoietin or granulocyte colony-stimulating factor was not allowed.
The study was designed by a panel of expert hepatologists and delegates of the sponsor. The institutional human research review committee from each participating center reviewed the study protocol and approved the study. Written informed consent was obtained from each patient before inclusion in the study, and the trial adhered to the principles outlined in the guidelines for Good Clinical Practice (International Conference on Harmonization), the Spanish Royal Decree 561/93, the Roche standard operating procedures on clinical trials, and the ethical principles of the World Medical Association Declaration of Helsinki and its amendments (Tokyo, Venice, Hong Kong, and Republic of South Africa).
Background
A large proportion of patients with chronic hepatitis C (CHC) can achieve a sustained virologic response (SVR) when treated with pegylated interferon plus ribavirin for 24 or 48 weeks,1, 2, 3 which is the currently recommended therapy for this condition.4, 5 However, there is an ongoing need to refine treatment strategies because many patients do not respond or relapse after treatment.
Hepatitis C virus (HCV) kinetics during the early phase of treatment is being recognized as a predictor of the final therapeutic outcome. Studies in patients treated with interferon monotherapy6 or with ribavirin in combination with interferon7 or pegylated interferon8, 9 have shown consistently that the rate of SVR inversely correlates with the time on treatment that is necessary to clear HCV RNA from serum. After 48 weeks of treatment, the likelihood of SVR was about 90% in patients who cleared HCV RNA at week 4 of treatment,7, 8 even in subjects infected with HCV genotype 1,10 whereas the probability of relapse was greater in patients responding later.8, 9 Furthermore, patients with less than a 2-log10 HCV-RNA decrease from baseline at week 12 had virtually no chance of developing SVR.2, 11
On the other hand, a recent analysis based on a mathematic model suggested that the rate of SVR in patients infected with HCV genotype 1 directly correlates with the duration of treatment once HCV RNA has been cleared from serum.12 Therefore, it is possible that extension of treatment would decrease the rate of relapse, and therefore increase the rate of SVR, in those patients who do not clear HCV RNA from serum early during therapy.
We report the results of a prospective, partially randomized, multicenter study comparing the efficacy and the safety of peginterferon-alfa2a plus ribavirin administered for 48 or 72 weeks in patients who did not clear HCV RNA from serum within 4 weeks of starting treatment.
Results
The study was conducted at 28 centers in Spain. Patients were enrolled between April and September 2001. The flow of patients through the trial is presented in Figure 1. A total of 522 patients were recruited, 517 received at least 1 dose of study medication and 510 returned at week 4 for qualitative HCV-RNA assessment to identify patients with or without RVR.
The HCV-RNA level became undetectable after 4 weeks of therapy in 184 patients, including 18 of 20 (90%) with HCV genotype 2, 75 of 90 (83%) with genotype 3, 11 of 27 (41%) with genotype 4, and 80 of 371 (22%) with genotype 1.
The 326 patients with detectable HCV-RNA levels at week 4 were randomized to group A (n = 165) or group B (n = 161). Among randomized patients, 89%, 5%, 5%, and .61%, were infected with HCV genotypes 1, 2, 3, and 4, respectively. There were no significant differences between patients in groups A and B regarding demographic, clinical, biochemical, or virologic characteristics at baseline (Table 1). At week 4 of therapy there were no significant differences in mean HCV-RNA serum concentrations between group A (121 ± 199 X 103 IU/mL) and group B (140 ± 333 X 103 IU/mL), or in the proportion of patients who had a 2-log10 or more decrease in serum HCV-RNA concentration from baseline (57/165 patients in group A and 62/161 patients in group B).
Of the 184 patients with undetectable HCV-RNA levels at week 4, 148 were enrolled in group C and 36 in group D. The main features of these patients are shown in Table 1.
Outcomes in Patients Without an RVR at Week 4
Virologic response
At the end of therapy, the HCV-RNA level was undetectable in 61% of patients from both groups A and B. At the end of the follow-up period, virologic response was sustained in 32% of patients in group A and 45% of patients in group B (P = .014; Table 2). The difference in SVR rates between these 2 groups is related to the significant difference in relapse rates observed in patients treated for 48 weeks (48%) compared with those treated for 72 weeks (26%, P = .003).
The rate of SVR among HCV genotype 1-infected patients was significantly higher in patients treated for 72 weeks than in those treated for 48 weeks (44% vs 28%; P = .003).
Among patients with a baseline serum HCV-RNA level of 800,000 IU/mL or less, the rate of SVR was significantly higher in patients treated for 72 weeks than in those treated for 48 weeks (53% vs 32%; P = .004). Among patients with a baseline serum HCV-RNA level greater than 800,000 IU/mL, there was no significant difference in the rate of SVR between the 2 groups (36% vs 32%, P = .23). By logistic regression analysis, duration of treatment (odds ratio, 1.805; 95% confidence interval, 1.14-2.84; P = .01) but not baseline viremia (odds ratio, .66; 95% confidence interval, .416-1.06; P = .08) was significantly associated with SVR.
Among patients with genotype 1 and baseline viremia less than 800,000 IU/mL, SVR rate was significantly greater (P = .007) in patients treated for 72 weeks (51%) as compared with patients treated for 48 weeks (27%) (Table 2). This difference was not observed in patients with genotype 1 and baseline viremia higher than 800,000 IU/mL (37% for group B vs 28% for group A, p= .15).
A logistic regression analysis aimed to explore the possible influence of the flat ribavirin dose (800 mg/day) used in this study showed that duration of treatment (odds ratio, 1.696; 95% confidence interval, 1.08-2.67; P = .02) but not the dose of ribavirin by body weight (odds ratio, 1.023; 95% confidence interval, 91-1.15; P = .7) was associated significantly with SVR.
Prediction of SVR during therapy
The predictive value of the on-treatment virologic response, defined as an undetectable serum HCV-RNA level or a 2-log10 or more decrease from baseline in serum HCV-RNA levels, at weeks 12 or 24 of treatment, for an SVR is depicted in Figure 2. At week 12, the negative predictive value of the absence of virologic response was 92% and 85% in groups A and B, respectively. The absence of virologic response at week 24 had a negative predictive value of 94% and 95% in groups A and B, respectively.
Outcomes in Patients With an RVR at Week 4
The SVR rate in patients allocated to groups C (79%) and D (64%) was higher than in patients who did not have an RVR at week 4 (groups A and B). SVR rates in these rapid responders were remarkably high, ranging from 64% (23/36) in patients with genotype 1 and baseline HCV-RNA level greater than 800,000 IU/mL, who were treated for 48 weeks, to 94% (44/47) in patients with genotype 2 or 3 and baseline HCV-RNA levels of 800,000 IU/mL or less, who were treated for 24 weeks.
Safety
The incidence of adverse events in the 4 treatment groups is presented in Table 3. Asthenia, headache, fever, and neutropenia were the most frequently reported adverse events. The incidence of adverse events reported in patients randomized to groups A and B was similar. Depression and insomnia were reported more often by patients in group B, whereas flu-like symptoms and anorexia were more frequent in group A. The incidence of serious adverse events was slightly higher among patients in group B (8%) than in group A (4.8%). However, none of these differences were statistically significant.
Note from Jules Levin: depression was 12% in Group A & 19% in group B; 3% in group C and 14% in group D).
Details of treatment outcome in the 4 groups of patients are summarized in Table 4. Treatment was discontinued in 18% of patients in group A and in 36% of patients in group B (P = .0002). The discontinuation rate, which was similar in both groups during the initial 24 weeks of treatment, clearly increased on extension of treatment in patients from group B. The proportion of patients who discontinued treatment because of adverse events was similar in the 2 groups. However, the proportion of patients who voluntarily discontinued treatment or failed to return was higher in group B (39/161) than in group A (15/165) (P = .0004).
Note from Jules Levin: treatment discontinuations were higher in group D than group C (25% vs 6%) and most of them occurred between weeks 24-48. Dose reductions for Pegasys were 33% in group D vs 17% for group C, which occurred between week 12-24 (17% vs 4%) and between week 24-48 0% vs 5%).
The proportion of patients who necessitated reduction of the dose of peginterferon or ribavirin in groups A and B was similar. The timing of dose reduction was similar as well. In all groups the most frequent cause for dose reduction was anemia for ribavirin and neutropenia and thrombocytopenia for peginterferon.
Patients
Treatment-naive patients with CHC consecutively referred to 28 specialist hepatology centers in Spain were eligible for the study if they fulfilled the following criteria: age older than 18 years, persistent increase of serum alanine transaminase levels during the past 6 months, positive anti-HCV antibody test, serum HCV-RNA concentration greater than 600 IU/mL (COBAS AMPLICOR HCV MONITOR Test, v2.0, Roche Diagnostics, Branchburg, NJ), histologic evidence of chronic hepatitis in a liver biopsy specimen obtained within the preceding 24 months, and provision of written informed consent to participate in the study. Exclusion criteria included decompensated liver disease; co-existing serious medical or psychiatric illness; liver disease other than that caused by HCV infection; neutrophil count less than 1.5 X 109/L; platelet count less than 90 X 109/L; hemoglobin concentration less than 12 g/dL in women or less than 13 g/dL in men; serum creatinine level greater than 1.5 times the upper limit of the normal range; and presence of co-infection with hepatitis A virus, hepatitis B virus, or the human immunodeficiency virus. Patients also were excluded if they had received any systemic antiviral, antineoplastic, or immunomodulatory therapy within 6 months before the study. Pregnant and breast-feeding women and male partners of pregnant women also were excluded. All participants had to use 2 forms of effective contraception during treatment and throughout the 24-week follow-up phase of the study.
Assessments and End Points
Patients were assessed at 4-week intervals during treatment, at weeks 4, 12, and 24 during posttreatment follow-up evaluation, and when clinically indicated. Vital signs, clinical symptoms, and adverse events were recorded and biochemical and hematologic determinations were performed at each visit. Serum HCV-RNA level was determined by qualitative HCV-RNA test at baseline; at treatment weeks 4, 12, and 24 in all groups; at treatment week 48 in groups A, B, and D; at treatment week 72 in group B; and at weeks 12 and 24 during the untreated follow-up phase in all patients. All samples that were positive for HCV RNA according to the qualitative test were retested with the quantitative HCV-RNA assay. Routine laboratory analyses including HCV-RNA determinations were performed locally at each center.
Only randomized patients (groups A and B) were included in the efficacy analysis. The primary efficacy end point was SVR, which was defined as undetectable serum HCV-RNA levels by qualitative polymerase chain reaction assay at the end of the 24-week posttreatment follow-up period. Patients with missing data were considered to be nonresponders.
The safety population included all patients who received at least 1 dose of study medication and underwent at least 1 safety assessment. Measures of safety included adverse events, clinical signs and symptoms, and biochemical and hematologic variables.
Statistical Analysis
The primary objective of the study was to compare SVR rates achieved with 48 and 72 weeks of therapy (group A vs group B) in patients who did not have an RVR at week 4. The trial was planned to have 80% power to detect a difference of at least 15% in the rate of SVR with a 2-tailed α level of 5%. An enrollment of 504 patients was planned based on the assumption that 40% of patients would have an RVR at week 4. This would result in 304 patients being randomized to 48 or 72 weeks of treatment.
The efficacy analysis was conducted on an intention-to-treat basis. The SAS software was used throughout. All patients who received at least 1 dose of study medication and had at least 1 postbaseline efficacy assessment were included in the intention-to-treat population. The baseline characteristics of patients randomized to groups A and B were compared using the Wilcoxon rank-sum test for quantitative variables and the x 2 test for differences in the proportion of qualitative variables. The Maentel-Haenszel test was used to test the null hypothesis that there was no difference between groups A and B in the probability of achieving an SVR or a sustained biochemical response. To explore the possible influence of ribavirin dose on response, a logistic regression analysis was performed in which SVR was the dependent variable and the dose of ribavirin by body weight (mg/kg/day) and the duration of treatment (48 or 72 weeks) were entered as independent continuous and categoric variables, respectively. A similar analysis was performed to explore the relative influence of viral load at baseline and treatment duration on SVR.
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