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Do Higher Doses of Anti-HCV Treatment Increase Responses? A Tale of 3
Studies Results from the largest hepatitis C trial performed so far in the US were the subject of a late breaking presentation at this meeting. Based on the finding of a relationship between ribavirin (RBV) dose in mg/kg and sustained virological response (SVR) in a previous trial (evaluating pegylated interferon (pegIFN)-a-2a combined with RBV for the treatment of chronic hepatitis C [1]), the aim of the study was to compare, combined with the same type of pegIFN, flat doses of RBV (800 mg/day) (FD arm) versus weight-based RBV (800-1,400 mg/day) (WD arm) [2]. The investigators also addressed the effects of duration of therapy through randomization of patients infected by HCV genotypes 2/3 to receive either 24 or 48 weeks of therapy. This randomized trial, named WIN-R, was performed at 225 US sites (academic and community hospitals) and enrolled 4,913 patients (2,444 FD and 2,469 WD) chronically infected by HCV and with at least one elevated ALT value within the prior 6 months. The study seemed to include an adequate representation of each weight group (<65 Kg, 14%; 65-<85 Kg, 41 %; 85-<105 Kg, 34%; 105-125, 11%) as to find differences between the FD and WD arms if there were any. However, a downside of the study was the unacceptably high number of discontinuations due to side effects or non-medical reasons (30%). This was reflected in the low figures obtained for SVR in both groups in the intent-to-treat (ITT) analysis: 41% FD vs. 44% WD; p=0.02. With the large number of patients enrolled, differences were still found between the FD and the WD dosages, but undoubtedly the effect of the randomization weakens with such a high proportion of drop-outs. On-treatment analysis resulted in higher SVR (51% FD vs. 56% WD) and more pronounced differences between groups (p=0.005). Supporting previous data, maximizing RBV dose according to weight was only relevant for genotype 1, as shown in the table 1 (ITT analysis). Moreover, higher RBV doses seem to impact on SVR by reducing relapses after treatment discontinuation. Among patients with HCV-1 genotype, differences in SVR between FD and WD were only found in patients with high baseline HCV RNA levels (FD 27% vs. WD 32%; p=0.047), but not in those with lower viral loads (FD 34% vs. 39%; p>0.05). African-American patients with HCV-1 (N=362) had also higher SVR in the WD group (21%) compared to the FD group (10%). Data from HCV-4-infected patients were not given. Table 1. Efficacy of anti-HCV therapy according to RBV arm and genotype.
ns: non-signifficant. The use of higher doses of RBV in the WD arm entailed a significantly more frequent development of anemia (nadir hemoglobin levels < 10 g/dL: 12% FD vs. 19% WD), which caused more dose reductions but no more discontinuations. Overall, serious adverse events were similar for both arms (11%). Nevertheless, reported discontinuations of therapy were higher (15%). In addition, 15% of patients discontinued therapy for “non-medical reasons”. It seems therefore that there were a significant number of drop-outs that might have been avoidable. "Concerning
the duration of therapy in subjects with HCV genotypes 2/3, there were
no significant differences between the 24 and 48-week groups in SVR (table
2)."
In conclusion, use of higher RBV doses according to weight is well tolerated and increases SVR in patients with chronic hepatitis caused by HCV genotype 1, especially in the presence of factors predictive of non-response (high viral load and African-American race), but not in subjects carrying HCV-2/3 genotypes. Extending therapy to 48 weeks, according to the results of this trial, does not seem to improve SVR among HCV-2/3-infected patients either, supporting recommendations in current guidelines. Flat- versus Weight-based Ribavirin in Nonresponders and Relapsers There was another oral presentation at the 56th AASLD (San Francisco, November 11-15, 2005) dealing with FD versus WD RBV, this time in patients failing previous therapy (non-responders and relapsers). The study was non-randomized, and compared to consecutive cohorts: A) 247 patients enrolled between June and December 2000: 1.5 mcg/kg/week pegIFN-a-2b and 800 mg/day RBVB) 207 patients enrolled between February 2001 and January 2005: 1.5 mcg/kg/week pegIFN-a-2b and 800 mg/day RBV and WD RBV (as described in the WIN-R study) A significantly greater percentage of women and African Americans were represented in the WD RBV cohort. There was a trend to have more patients with advanced liver fibrosis in the WD RBV group (18%) compared to the FD group (9%) (p=0.08). Dose decreases (24% FD and 18% WD) and treatment discontinuations (21% both FD and WD) were comparable for both groups. Overall, SVR was 19%, with no differences between the FD (17%) versus the WD (20%) arms. Better responses were achieved in relapsers (33% vs. 14% non-responders), non-1 HCV genotype and prior monotherapy. However, no differences between the FD and the WD RBV arms were found across the different subgroups of patients (table 3). Table 3. SVR in the different subgroups according to RBV dosage
In their conclusions the authors state that SVR is approximately 20% in this re-treatment study, is not improved with higher RBV dosing, and that important limitations of this study might have impacted the results, such as its non-randomized character, and the disbalanced representation of African Americans and patients with more advanced fibrosis in the two cohorts. Higher-dose Peginterferon alfa-2b in Nonresponders: The REPEAT Study Another strategy to increase responses to anti-HCV therapy in patients who had no response to prior treatment (pegIFN-a-2b/RBV), giving higher doses of pegIFN, was assessed by the REPEAT study team [4]. Most subjects in this randomized study were Caucasians and infected by HCV-1 genotype, and around one forth in each arm had cirrhosis. The trial also evaluates different durations of therapy, but only early virological responses (EVR) were presented at this meeting. Patients were randomized to receive along with RBV (100/1200 mg/day), either 360 mg/week of pegIFN-a-2a (PEGASYS®) for the first 12 weeks of therapy followed by the standard 180 mg/week, or 180 mg/week for the whole study period. Compared to the standard dose arm, significantly more patients in the induction arm had an EVR, defined as HCV RNA <50 IU/mL (20% vs. 13%; p=0.003), HCV RNA <600 IU/mL (42% vs. 25%; p<0.0001), and ³2log decrease (62% vs. 45%; p<0.0001). By histology, patients with less fibrosis showed superior response (66% with the high dose and 48% with the standard dose) than subjects with advanced fibrosis or cirrhosis (50% with the high dose and 38% with standard dose). Tolerance was similar for both groups, with similar proportions of decreases in platelet counts, dose reductions, and treatment discontinuations (3-5%). The authors concluded that in a difficult-to-treat population non-responding to pegIFN-a-2b/RBV, better early responses were obtained by giving 360 mg/week during the first 12 weeks of therapy compared to the standard 180 mg/week dose, even in patients with advanced fibrosis or cirrhosis. While these results are promising, it is necessary to await SVR data. It is also unclear what dose of RBV subjects included in this study had received during their prior treatment, and therefore the role of higher doses of pegIFN-a-2a in the superior response remains uncertain. Double-dose Peginterferon alfa-2b (PegIntron): The RENEW Trial Double dose of pegIFN (3 m g/Kg/week), this time pegIFN-a-2b, was compared to standard doses (1.5 mg/Kg/week), given both with 800-1400 mg/day of RBV, for the treatment of non-responders to prior therapy with standard IFN plus RBV [5]. There was a high number of drop-outs between randomization and the initiation of therapy, which might have had a negative impact in the analysis of data: 411 randomized and 352 starting therapy in the 1.5 mg/Kg/week arm, and 415 randomized and 352 starting therapy in the 3 mg/Kg/week arm. End-of-treatment (EOT) responses were comparable for the two groups (24% each), but SVR were significantly higher in the double dose arm (17%) compared to the single dose arm (12%) (p=0.03). Patients with advanced fibrosis responded better to double dose than to standard dose (SVR 12% vs. 8%), as well as African American patients (16% vs. 4%). Although there was a trend towards higher frequency of adverse effects on the higher dose of pegIFN-a-2b, differences were not significant, and treatment discontinuations due to adverse events were comparable for both groups. The authors state in their conclusions, “Among patients who never cleared HCV RNA on previous IFN and RBV therapy, pegIFN-a-2b 3 mg/Kg/week was more effective than 1.5 mg/Kg/week, especially among African Americans and those with advanced fibrosis, with similar tolerance”. In summary, according to these studies, increased doses of RBV and of pegIFN seem to be safe and may be of help in the treatment of difficult-to-treat patients. The results of some of these studies are promising, but they have several limitations, and there are multiple factors involved in the response to anti-HCV therapy which make interpretation of some of these data difficult. Therefore, further studies are needed to clarify several uncertainties. It would be also of interest to assess the role of higher doses of pegIFN in patients naïve to anti-HCV treatment. 11/21/05 References
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