Box 1 Predictors of response in prior relapsers

To standard interferon Genotype non-1 Low viral load No or mild fibrosis Age greater than 40 Non-African-American ethnicity Early virologic response to therapy

To standard interferon and ribavirin Genotype non-1 Low viral load

Early virologic response to therapy antiviral theapy [33]. An early virologic response is also a strong predictor of a virologic cure [20,25].

Longer duration of treatment (24 versus 48 weeks) [22,23,31], particularly for genotype 1 patients with a high viral load, is associated with a better chance for SVR [27,29] in IFN mono-therapy relapsers given IFN and RBV. Higher doses of IFN have not been associated with higher response rates in most studies [23,29,32]. Saracco et al found that the cumulative dose of IFN during the initial course of therapy or retreatment did not predict a favorable response to therapy [29]. Increased dose or duration of therapy in patients with genotypes 2 and 3 is not associated with higher SVR rates [27,29,31].

Similar predictors of response have been recently reported in relapsers to combination standard IFN and RBV therapy who are retreated with PEG IFN and RBV. Genotype non-1 and low viral load are predictors of a favorable response [43,44]. In one study, the absence of HCV viremia at week 6, as determined by the transcription-mediated amplification assay, was highly predictive of SVR (80% in the overall study population, 92% in genotype non-1 patients) [44].

Adjunctive therapies for patients who have relapsed after interferon and ribavirin combination therapy

In an effort to improve SVR rates in this population, some investigators have evaluated adjunctive therapies in addition to PEG IFN a2b and RBV. Freilich et al assessed the benefit of adding amantadine to PEG IFN and RBV therapy in treating patients who previously had relapsed to therapy [45]. They compared PEG IFN (1.0 mg/kg per week) and RBV (1000 mg per day) with a regimen of PEG IFN (1.0 mg/kg per week) and RBV (1000 mg per day) plus amantadine (200 mg per day). The overall SVR

rate presented from interim data in 23 patients was 43%. The addition of amantadine was not beneficial in genotype 1 relapsers. The SVR rate in genotype 1 relapsers was 25% (2/8) in patients treated with amantadine and 40% (2/5) in those treated with standard PEG IFN and RBV combination therapy. In contrast, the addition of amantadine may have led to superior treatment efficacy in nongenotype 1 patients. All (4/4) of the genotype non-1 patients treated with amantadine had an SVR, compared with only 33% (two of six) of patients treated with PEG IFN and RBV alone, but final data from this study are not available, and the number of patients is too small to draw any definitive conclusions.

In another study, 37 relapsers (to standard IFN monotherapy or standard IFN and RBV combination therapy) were retreated with an induction dose of standard IFN (18 MU daily) in combination with ribavirin (1000 to 1200 mg daily) and amantadine (100 mg daily) for two weeks and then randomized to 22 weeks of continued ribavirin and amantadine with or without IFN (6 MU three times weekly) [44]. The 10 patients who discontinued interferon after the 2 week induction course all relapsed within two weeks. Of the patients who received 24 weeks of interferon, the end-of-treatment response was 63% (17/27) and the SVR rate was 44% (12/27). Twenty nine percent (5/17) of patients with an end-of-treatment response subsequently relapsed.

Herrine et al assessed the efficacy of mycophenolate mofetil and amantadine in addition to PEG IFN and RBV in a pilot study [43]. They treated 124 patients (106 relapsers, 18 breakthrough relapsers) who were randomized to receive PEG IFN alfa-2a 180 mg once weekly in addition to one of four following treatment arms: (1) RBV at 800 to 1000 mg daily, (2) mycophenolate at 1000 mg twice daily, (3) amantadine at 100 mg twice daily, or (4) amantadine at 100 mg twice daily and RBV at 800 to 1000 mg daily. End-of-treat-ment response rates were highest in patients who were treated with PEG IFN and mycophenolate (72.4%) and PEG IFN, RBV, and amantadine (71%). Patients who received PEG IFN, RBV, and amantadine had the highest SVR rates (45%), followed by those who received PEG IFN and RBV (38%). However, the difference in response rates in the two groups did not reach statistical significance. Treatment with PEG IFN and either amanta-dine or mycophenolate alone resulted in lower SVR rates (10% and 17%, respectively), as in other trials. Thus, RBV appears to exact its benefit by preventing relapse. There was a trend towards higher SVR rates in patients with genotype non-1 and low HCV viral load. Tolerance of the medications was similar in the different treatment groups, except for the more significant decline in hemoglobin seen in patients who received ribavirin.

Approach to the retreatment of patients who relapse after interferon and ribavirin combination therapy

Patients who relapse after standard IFN and RBV should be considered strongly for retreatment with PEG IFN and RBV because of their significant chance of SVR (30% to 70%). The available data are derived from studies in which PEG IFN and RBV were administered for 48 weeks. In these studies, however, relapse even after PEG IFN and RBV occurred in significant numbers of patients. Current viral kinetic models suggest that a gradual second phase of HCV-infected cell death occurs, ultimately leading to viral eradication in patients who achieve an SVR [17]. It is thought that patients who relapse may have a more prolonged period of elimination of infected cells, which may not have been completed when a standard course of IFN and RBV therapy ends. Therefore, in these patients with a previously demonstrated proclivity to relapse, longer courses of therapy than the standard duration of 48 weeks may be worth consideration in the retreatment of selected patients, with a goal of maximizing the chance of eventual eradication of all virally infected cells. Such patients might include those with genotype 1, high viral load, and advanced fibrosis, or those with a delayed response to therapy. However, controlled trials demonstrating the efficacy of such prolonged therapy have not been reported.

Adherence to optimal doses of PEG IFN and RBV during prior therapy also should be considered. The superior efficacy (44% versus 41%, P = 0.02) of weight-based (800 mg to 1400 mg) versus fixed (800 mg) RBV dosing has been recently demonstrated in a multicenter, randomized, community based trial of 4913 patients [46]. In treatment naive patients, dose reductions of either drug, and particularly both drugs, have a significant impact on attainment of early virologic response (EVR) after 12 weeks (80% EVR with full doses versus 60% to 70% and 33% with dose reduction of either or both drugs, respectively) [47]. In patients who attain EVR, the chance of SVR is adversely affected by dose reductions or discontinuation of therapy beyond the 12-week timepoint. Although comparable data do not exist for the relapse population, these same principles may well apply. Accordingly, every effort must be made to maintain optimal dosing during the retreatment of patients who have relapsed to a prior course of therapy. Patients who underwent dose reduction during prior therapy for depression, anemia, or neutropenia may be considered for anti-depressants, granulocyte colony stimulating factor therapy, or erythropoie-tin, respectively, as appropriate during retreatment. It must be recognized, however, that while recent studies on erythropoietin show an effect on successful maintenance of ribavirin dose, improvements in hemoglobin levels and quality of life [48], no prospective trials have demonstrated the use of adjunctive factors to enhance SVR.

Treatment of patients who have relapsed after pegylated interferon and ribavirin combination therapy

Patients who have relapsed after a course of PEG IFN and RBV pose a difficult problem, because more effective therapy is not available. There are no data on the efficacy of higher doses of drugs, leaving a repeat course of more prolonged therapy as the major option. Goncales et al treated naive patients with either 24 or 48 weeks of combination PEG IFN alfa-2a and RBV. Patients who received 24 weeks of therapy and relapsed were eligible to enter a retreatment study consisting of PEG IFN alfa-2a (maximum dose of 180 mg per week) and RBV (1000 to 12000 mg per day) for 48 weeks [49]. PEG IFN and RBV doses were adjusted by the investigators according to the patients' tolerance of the medications during the initial course of therapy. Preliminary data from this study on 59 patients indicate high end of treatment virologic response rates of 90% (88% in genotype 1 patients; 93% in patients with genotype 2 and 3) with retreatment. SVR rates from this study are awaited.

Because most patients who relapse after a course of PEG IFN and RBV will have received 48 weeks of therapy, the only realistic option is to consider a repeat course of treatment for a longer duration (eg, 72 to 96 weeks). In apparent conformity with concepts of the kinetics of viral clearance, patients who clear HCV RNA on their initial course of PEG IFN and RBV have an enhanced risk of post-treatment relapse if clearance of HCV RNA requires longer than 12 weeks of therapy [41]. The concept of modifying the duration of therapy according to a patient's virologic response pattern to PEG IFN and RBV therapy has been evaluated in a preliminary study of nine HCV genotype 1, treatment-naive patients [50]. These nine patients all had delayed virologic clearance; they were positive for HCV RNA by PCR but had a 2 log decline in HCV RNA by week 12 of therapy and had cleared virus by week 24. Patients were treated for 72 weeks, and 88% (7/8, with one lost to follow-up) had an SVR. As in patients with relapse after a course of standard IFN and RBV, this approach to therapy needs to be evaluated further in patients who have relapsed after a prior course of PEG IFN and RBV, particularly patients with genotype 1, high viral load, and cirrhosis, or patients in whom clearance of HCV RNA was delayed beyond 12 weeks.

Preliminary data with consensus interferon, a novel recombinant type 1 interferon, suggests sustained virologic response rates of 23-37% in previous nonresponders to pegylated interferon and ribavirin [51,52]. However, data from large multicenter studies is needed to confirm these findings in prior nonresponders. Studies evaluating the efficacy of consensus interferon in prior relapsers to PEG IFN and RBV are currently in progress, including at our center.

Future directions

In addition to the options of PEG IFN and RBV for relapsers to previous combination therapy, or prolonged courses of PEG IFN and RBV in re-lapsers to previous PEG IFN and RBV therapy, new therapies on the horizon for treatment-naive patients with chronic hepatitis C include genome sequence-based therapies, viral enzyme inhibitors, and immunomodulatory agents may be efficacious in patients who have relapsed to previous therapy also [9,53]. Most promising are the protease and polymerase inhibitors which are currently in Phase I and Phase II trials. Preliminary data from both treatment-nai've HCV-infected patients and previous nonresponders have demonstrated marked declines in HCV viremia with these novel compounds [54-57]. Patients with mild liver disease or those who had great difficulty tolerating interferon-based therapy may wish to defer retreatment as novel therapies are awaited. In the authors' practice, however, it is felt that most patients with relapse after standard IFN and RBV should be offered a course of PEG IFN and RBV.


Sustained virologic response rates are significantly higher in patients who have relapsed after a previous course of therapy compared with patients who did not respond. A meta-analysis of combination therapy in patients who failed IFN monotherapy reported SVR rates of 52% in relapsers to prior therapy and 16% in nonresponders [12]. Similarly, relapsers after combination standard IFN and RBV therapy have higher SVR rates than combination of therapy nonresponders when treated with pegylated interferon and ribavirin [34,35-39]. For this reason, patients who relapse after a previous course of therapy should be considered potential candidates for retreatment. Factors that have been associated with SVR in these patients include genotype non-1, low viral loads, and lesser degrees of fibrosis. The course of treatment in all patients who have relapsed after prior therapy should be reviewed to identify possible reasons for failure to achieve an SVR. In particular, optimal dosing of PEG IFN and RBV and the occurrence and timing of treatment dose reductions during prior therapy should be reviewed. The reasons for dose reduction should be addressed before initiating another course of therapy in an effort to optimize the chance for a SVR. Patients who had dose reduction for depression, anemia, or neutropenia, should be considered for antide-pressants, erythropoietin, or, if neutropenia is severe, granulocyte colony stimulating factor therapy, respectively, during retreatment. Prolongation of therapy beyond 48 weeks in patients with relapse after a standard course of PEG IFN and RBV may offer a chance of SVR. Novel agents currently in development, including protease and polymerase inhibitors, may prove to be therapeutic options for these patients in the future.


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