Consideration of ribavirin dose
RBV monotherapy does not induce a significant antiviral response in patients with CHC, but in combination with interferon, RBV markedly improves ETR response, reduces relapse rates and improves SVR rates. A number of mechanisms including direct inhibition of RNA replication, immunomodulation, inhibition of inosine monophosphate dehydrogenase, and enhanced viral mutagenesis have been proposed to explain the action of RBV in CHC as reviewed by Dixit et al. but its overall mode of action remains to be fully elucidated . The main serious adverse event associated with the use of RBV is dose-dependent haemolytic anaemia. The optimal target dose for RBV is not well established.
A recent publication supports the individualization of RBV dosing according to HCV genotype and bodyweight, and highlights a number of clinical variables that influence the likelihood of SVR in contrast to the occurrence of anaemia . The percentage of patients with SVR increased from 40% to 50% when RBV dose was increased from 12 to 16 mg/kg in patients with genotype 1 infection, but was much less influenced by RBV dose in genotype 2 and 3 patients . A higher apparent clearance of RBV, older age and cirrhosis had a negative impact on achieving an SVR. Gender and RBV dose/kg were the most important prognostic factors for anaemia. However, as anaemia is not a universal risk in all treated patients, the initial high dosing strategy of 1000 or 1200 mg, qd, according to bodyweight appears to be appropriate. For heavier patients, RBV doses >1200 mg, qd, may be initiated as they are likely to be associated with additional efficacy and a manageable anaemia risk (provided that the dose does not greatly exceed 15 mg/kg/day) . As discussed above, Lindahl et al. demonstrated in a small pilot study that administration of ultra high-dose RBV (ranging from 1600–3600 mg, qd) in genotype 1 patients according to an individualized schedule is feasible but is associated with more frequent and serious side effects such as anaemia . In this albeit small study, nine of 10 patients achieved an SVR; however, two of 10 patients required blood transfusion for haemoglobin levels <8.0 g/dL and all patients required treatment with erythropoietin (range 9000 to 30 000 IU/week) and oral iron supplements. However, recommendations cannot be made on observations made on such limited patient numbers.
Retrospective analyses of the original study by Hadziyannis et al. showed that in patients without RVR, the lowest rates of relapse were obtained with 48 weeks of treatment and a higher RBV dose . In contrast, treatment duration and RBV dose did not influence SVR in patients with RVR. For genotype 2 and 3 infected patients, higher RBV doses do not improve SVR or relapse rate in patients with RVR on the standard 800 mg, qd, dose . However, for the minority of patients who do not achieve RVR, it is possible that increased RBV dose may improve treatment outcome, although sufficient data are not yet available to make a clear recommendation . A study by Ferenci et al. suggests that, in genotype 2 and 3 infected patients treated with a standard fixed dose of 800 mg, qd, RBV, SVR was greater in patients who were exposed to the highest mean dose of RBV based on body weight . These findings are consistent with a retrospective analysis of data from the peginterferon alfa-2b registration trial . Nonetheless, whether increasing RBV exposure in heavier patients will improve SVR remains uncertain.
A number of studies have shown that erythropoietin can be used to improve quality of life, maintain RBV dose and subsequently improve adherence [60–62]. Although erythropoietin may have a role in the management of RBV-related anaemia, a recent study by Shiffman et al. failed to show an improvement in SVR in genotype 1-infected patients given epoetin alpha at the initiation of therapy to maintain haemoglobin levels between 12 and 15 g/dL . This was a three arm, prospective, open-label, randomized, controlled pilot study comparing 48 weeks of treatment with peginterferon plus standard weight-based RBV with or without erythropoietin (groups 1 and 2), and peginterferon plus higher weight-based RBV plus erythropoietin (group 3). A significantly smaller percentage of group 2 patients had a decline in haemoglobin to less than 10 g/dL (9%vs 34%; P < 0.05) and required that the RBV dose be reduced (10%vs 40%; P < 0.05) compared to group 1 patients. Despite this, SVR was similar in these groups (19–29%). SVR was significantly greater (P < 0.05) in group 3 patients (49%) due to a significant decline in relapse rate (Table 4).
Table 4. Virologic response in patients treated for 48 weeks with standard or higher weight-based doses of ribavirin
|ITT population (n)||48||49||49|
|Mean RBV dose (mg/day) ||1016 ± 170||1102 ± 174||1224 ± 175|
|Dose reduction (%)||40||10||31|
|VR at end of treatment (%)||46||31||53|
|Relapse rate (%)||36||40||8|
It has been suggested that the use of erythropoietin may be an appropriate strategy for managing anaemia, improving quality of life and increasing adherence to therapy, especially in patients with genotype 1 infection . However, its use was not permitted in registration trials of peginterferons and RBV and no recommendation for its use in anaemia associated with RBV is included in the Summary of Product Characteristics. Moreover, its addition to the treatment regimen would be associated with additional costs, inconvenience and potential side effects . In conclusion, the limited data available concerning use of erythropoietin are insufficient to make clear recommendations.
If shortening treatment below the standard duration is to be considered, careful reassessment of RBV dose is necessary, since RBV dose and treatment duration appear to be closely linked. In a prospective Austrian study, reducing the dose of RBV to 400 mg did not adversely affect the rate of SVR compared with the standard 800 mg daily dose in genotype 2 and 3 infected patients treated for 24 weeks . However, due to the limited data available, further studies in RBV dose and treatment duration are warranted before any recommendations can be made. In our opinion, weight-based dosing of RBV is advantageous for genotype 1-infected patients, while its relevance for genotype 2 and 3 infected patients remains to be further elucidated, particularly for shorter treatment duration and for patients without RVR. Generally and independent of HCV genotype, RBV dose is less important in patients with RVR and becomes more and more important if only cEVR or slow response is present. The higher percentage of patients with genotype 2 and 3 achieving RVR in comparison with genotype 1 explains the observed differences between genotypes.
The influence of adherence/dose reduction on sustained virological response
Both adherence and RBV dose have a major impact on SVR rates. Patients who receive the optimal dose of peginterferon and RBV for the planned duration have higher rates of SVR than those who require dose reductions [21,66–68]. Adherence to therapy is important for treatment success, especially in patients with genotype 1 infection who undergo longer-term treatment, as there is evidence that extended therapy may improve SVR in some patients. Adherence during the initial treatment period is especially important, as early viral suppression is a positive predictor of SVR. Therefore, adherence during the early stages of treatment may be more crucial than overall adherence .
Given these findings, physicians should discuss the importance of adherence with patients before initiating therapy. Education of patients, family members and caregivers about potential side effects and their prospective management is an integral aspect of treatment. Frequent monitoring of patients to assess their neuropsychiatric health and social functioning, as well as the clinical side effects of HCV therapy, are important aspects of patient management.
The rapid and effective management of side effects is crucial for treatment success, as adverse events such as anaemia, negatively affect adherence. Identifying and addressing the main side effects of HCV therapy can therefore improve adherence to treatment and potentially allow optimal outcomes to be achieved . Dose reductions are used to manage adverse events encountered during therapy. A recent retrospective study of 569 patients enrolled in phase III trials of 48 weeks’ treatment with peginterferon alfa-2a and RBV, showed that reductions in RBV (≤97% cumulative dose) were more frequent than those of peginterferon alfa-2a (43%vs 27%) . Neither EVR nor SVR were affected adversely by RBV reductions when the cumulative RBV exposure was greater than 60%. However, SVR was reduced significantly (P = 0.0006) in patients with less than 60% cumulative RBV dose. Currently, guidelines suggest that levels of RBV should be reduced to 600 mg, qd, in cases of anaemia (<10 g/dL), which could reduce cumulative RBV levels below the 60% threshold in genotype 1 patients. It has been suggested that more gradual incremental dose reductions of 200 mg may be less likely to impact on SVR than the ad hoc reduction to 600 mg, particularly in patients infected with genotype 1 where RBV dose appears to have a greater impact on SVR compared to other genotypes . Prospective studies, however, would be required to establish more clearly the impact of RBV dose reduction on SVR.
Re-treatment of patients
A major problem for physicians managing patients with CHC is patients with an end-of-treatment virological response but no SVR (relapsers) or patients with HCV RNA detectable at end of treatment with current standard therapy (non-responders). Re-treatment of relapsers is more likely to yield favourable results than re-treatment of non-responders. Re-treatment with peginterferon plus RBV has been investigated in patients who relapsed after interferon monotherapy or interferon plus RBV therapy. Patients who have relapsed following treatment with standard interferon-based regimens often respond to re-treatment with peginterferon plus RBV. In these patients, SVR rates of 41–59% have been reported. Response to re-treatment is most likely in non-genotype 1 patients, patients with mild or moderate fibrosis, and patients with low viral load at baseline [71–77]. Peginterferon plus RBV re-treatment should therefore be considered for all patients who have previously responded to a conventional interferon-based regimen and subsequently relapsed.
Treatment failure can be related to tolerability problems and subsequent discontinuation. It is conceivable that patients non-responsive to one form of peginterferon may be more responsive to treatment with the other form of peginterferon. Furthermore, additional efforts to manage side effects in patients retreated with peginterferon plus RBV may improve adherence and so improve chances of achieving an SVR.
Treatment failure is associated with a higher long-term mortality . Data suggest that selected patients who fail to achieve SVR may benefit from re-treatment with peginterferon-based regimens; however, rates of SVR following re-treatment are far lower than those achieved in treatment-naïve patients. Overall, SVR rates of 4–26% have been reported, with patients who failed to respond to standard IFN monotherapy being most likely to respond to re-treatment with peginterferon plus RBV [71–76,79,80]. Following the results of the ongoing EPIC-3 trial, peginterferon alfa-2b in combination with RBV was recently approved for the re-treatment of relapsers or non-responders to a prior course of interferon alfa (pegylated or non-pegylated) with RBV. In this trial, 1336 patients with moderate to severe fibrosis who failed previous interferon-based treatment received peginterferon alfa-2b plus RBV for up to 48 weeks and were followed for a further 24 weeks. 23% achieved SVR. The authors found a strong correlation between achieving SVR and achieving a cEVR with undetectable HCV RNA levels at week 12 of treatment . In the REPEAT study, which investigated the effects of intensified treatment with higher fixed-dose induction of peginterferon and/or longer treatment duration in previous non-responders to peginterferon alfa-2b plus RBV, re-treatment with fixed-dose induction and longer duration provided the highest SVR rates and the lowest relapse rates .
While some patients are classified as virological relapsers/non-responders, they may have a biochemical response – i.e. reduction or normalization of ALT. Preliminary results from the HALT-C trial showed that peginterferon alfa-2a maintenance therapy led to improvements in ALT level, HCV viral load and necroinflammation. Despite this however, long term maintenance therapy did not show any effect on the rate of disease progression . These findings were in accordance with a long-term study of peginterferon alfa-2b in non-responders which found no difference in the rate of serious long-term liver complications including decompensation and hepatocellular carcinoma despite improvements in fibrosis . In the long-term COPILOT study comparing colchine with low-dose peginterferon alfa-2b, improved disease free survival associated with peginterferon alfa-2b maintenance therapy occurred almost exclusively in patients with portal hypertension . Given these data, the role of long-term, continuous therapy with peginterferon (or RBV or both) for non-responders cannot be generally recommended.
In summary, decisions regarding re-treatment should include consideration of the severity of the underlying liver disease, adherence/compliance and tolerance issues, the previous therapy and type of response to it, viral genotype and other predictive factors for response .