Posted: 08/11/2010; Alimentary Pharmacology & Therapeutics. 2010;31(12):1346-1353.
© 2010 Blackwell Publishing
Abstract and Introduction
Abstract
Background The optimal dose of ribavirin to be used in combination with Peg-IFN in patients with HCV genotypes 2 and 3 undergoing short treatment has not been established.
Aim To explore the relationship between starting ribavirin doses, expressed as mg/kg body weight and both rapid viral response at treatment week 4 (RVR) and sustained virological response (SVR) in patients treated for 12–14 weeks with peg-interferon α-2b and ribavirin.
Methods A post hoc analysis of data collected from two multicenter clinical trials was performed. Multiple regression analyses were employed to identify independent baseline and on-treatment predictors of RVR and SVR. For each dose of ribavirin, the empirical estimated probability of response was computed and the continuous exposure index was dichotomized by using a recursive partitioning and amalgamation method.
Results A nonlinear relationship was ascertained between ribavirin dose and RVR, but not SVR. A dose of 15.2 mg/kg was selected as the best splitting value for discriminating RVR vs. non-RVR. Regression analysis identified low baseline viraemia, genotype 2 and high ribavirin dose as independent prognostic factors for RVR. The likelihood of an SVR was not correlated with baseline ribavirin dose, but was independently predicted by adherence to the full dose throughout treatment and normal platelet counts.
Conclusions Starting high ribavirin doses appears capable of increasing the rate of RVR in patients with HCV genotypes 2 and 3 undergoing short treatment. Maintenance of the full planned dose throughout treatment is essential for achieving optimal SVR rates.
Introduction
The benefit of short (12 or 14 weeks) therapy with Peg-Interferon (Peg-IFN) in combination with ribavirin for patients with chronic HCV genotype 2 or genotype 3 infection has been documented in recent clinical investigations.[1–6] Patients who will benefit the most by short therapy are lean, noncirrhotic individuals capable of clearing the virus at treatment week 4.[7] This experimental evidence has been incorporated in some, but not all, treatment guidelines issued by scientific societies[8–10] and hence, uncertainties still remain about implementing short therapy in everyday clinical practice. Indeed, a clear-cut benefit of short therapy in comparison with the standard 24-week treatment did not emerge in some other clinical trials.[11, 12]
A controversial issue in genotypes 2 and 3 therapy that might explain part of previous inconsistencies across trials is the optimal dose of ribavirin to be used in combination with Peg-IFN: whenever ribavirin was given at higher dosage (800–1400 mg daily, according to body weight) than the one currently recommended (800 mg daily), the benefit of short therapy appeared evident;[1–4] on the contrary, when the administered dosage was the fixed 800 mg daily dosage,[11, 12] the benefit waned off.
The predominant mechanism(s) of ribavirin action against HCV is (are) yet to be established. Although ribavirin monotherapy imposes a transient HCV decline early on therapy, the drug has no apparent long-term effect on serum HCV RNA levels;[13, 14] however, in combination with interferon, it dramatically improves the success of therapy. In naïve patients undergoing treatment with conventional interferon and ribavirin, higher ribavirin concentrations were associated with a higher likelihood of response.[15] Plasma ribavirin concentrations have been shown to correlate with the starting dose of the drug,[15] and therefore selecting appropriate starting dose and maintaining it throughout treatment impact positively on therapeutic outcome. In genotype 1 patients, the probability of achieving a sustained virological response (SVR) increased as a function of the ribavirin dose (mg/kg of body weight), with a 40–50% increase for a 12–16 mg/kg dose.[16] Data are less clear for genotypes 2 and 3 infection, as a single study failed to prove a correlation between probability of SVR after 24 weeks of treatment and the ribavirin dose.[16] Although debate is ongoing as to which ribavirin dosage should be administered in combination with Peg-IFN, it is clear that ribavirin activity is dose/exposure-dependent[15, 16] and selecting and maintaining the optimal dose of the drug might be crucial for a successful therapy. This concept might apply particularly when considering short treatment duration. The objective of this analysis was to explore the relationship between starting ribavirin and both rapid viral response at treatment week 4 (RVR) and SVR in patients with genotypes 2 and 3 undergoing short (12 or 14 weeks) therapy with ribavirin and Peg-IFN α-2b.
Patients and Methods
Study Subjects
Data used in this analysis were collected from two multicentre clinical trials, run in Italy and Scandinavia, in naïve patients with genotypes 2 and 3. The complete inclusion and exclusion criteria, study design and primary results are available elsewhere.[5, 7] The primary efficacy objective of these trials was to compare SVR following Peg-IFN α-2b (Peg-Intron; Schering-Plough, Kenilworth, NJ, USA) plus ribavirin administered for short (12 or 14 weeks respectively) or standard (24 weeks) duration. All patients received Peg-IFN α-2b 1.5 μg/kg subcutaneously weekly together with ribavirin administered orally. In the study by Mangia et al.,[7] 718 patients were treated with Peg-IFN α-2b plus ribavirin 1000 or 1200 mg/day on the basis of body weight higher or lower than 75 kg; 496 patients with week 4 viral clearance (labelled as rapid virological responders, RVR) were allocated to 12-week treatment duration, whereas those without RVR were given therapy for 24 weeks. Italian patients with missing serum creatinine values at baseline were not included in the present analysis. In the 428 patients enrolled in the trial by Dalgard et al.,[5] ribavirin dose varied according to body weight as follows: 800 mg for body weight <65 kg, 1000 mg for body weight ranging from 65 to 85 kg, 1200 for body weight ranging from 85 to 105 kg and 1400 for body weight >105 kg. For the sake of homogeneity with the design of the Italian study, of the original 428 Scandinavian patients, only 148 individuals with RVR who were treated for 14 weeks and 130 non-RVR patients whose treatment lasted 24 weeks were considered eligible for the present investigation; the remaining 150 patients with RVR who were treated for the standard 24 weeks were excluded. Among Scandinavian patients considered eligible, only 10 had body weight >105 kg and required 1400 mg; therefore, the combined database allowed us to evaluate a large series of patients, including a comparable number of genotypes 2 and 3, who received similar dosages of ribavirin.
Per protocol, the ribavirin dose had to be reduced by 200 mg daily in patients who experienced a decrease in haemoglobin level of more than 2 g/dL during treatment, and by 400 mg daily if haemoglobin levels decreased to less than 10 g/dL. Ribavirin was discontinued if haemoglobin levels decreased to less than 8.5 g/dL. The use of erythropoietin was not allowed. Anaemia was defined as haemoglobin concentration <10 g/dL documented on at least one occasion during the studies. For patients who were intolerant to Peg-IFN α-2b, dose reductions in decrements of 12% of the assigned dose were allowed.
Analytical Methods
Definitions: The HCV RNA level was measured using the COBAS AMPLICOR HCV Test [(Roche Molecular Systems, Branchburg, NJ, USA), version 2.0; limit of detection 50 IU/mL]. Rapid virological response (RVR) was defined as undetectable serum HCV RNA at treatment week 4. End-of-treatment response (ETR) was defined as undetectable HCV RNA at weeks 12, 14 or 24 according to the different therapeutic regimens and SVR was defined as undetectable HCV RNA at the end of a 24-week follow-up period.
Statistical Analysis
As the primary objective of the present study was to explore the impact of ribavirin dose on both RVR and SVR, only patients who could tolerate anti-viral drugs for the planned length of therapy were retained in the analysis. Patients who had reduction in ribavirin and/or Peg-IFN at some point during treatment but completed the planned treatment duration were retained. Consequently, of the total 905 eligible patients enrolled in the two previous trials, only 673 patients (405 from the Italian cohort and 268 from the Scandinavian cohort) were retained. Of the 232 excluded patients, 120 had no serum creatinine available for glomerular filtration (GFR) rate calculation and 112 (10 among patients treated for 12–14 weeks and 102 among those treated for 24 weeks) had a premature treatment discontinuation for major side effects or were lost to follow-up.
Baseline patient characteristics were reported as frequencies and groups were compared with Pearson chi-square. Multiple logistic regression analyses were employed to identify independent baseline and on-treatment predictors of RVR and SVR, with age, gender, body mass index, genotype, baseline viraemia, platelet count, aspartate aminotransferase-to-platelet ratio index (APRI) score[17, 18] and starting ribavirin dose as dependent variables. An exploratory analysis was made to assess the nature of the relationship between dose of ribavirin adjusted for GFR and response probability: for each dose, the empirical estimated probability of response was computed. Moreover, the continuous exposure index was dichotomized using the best splitting value by using a Recursive Partitioning and Amalgamation (RECPAM) method.[19] All analyses were performed using SAS release 9.1 (SAS Institute, Cary, NC, USA). Two-tailed P-values <0.05 were considered significant.
Results
Characteristics of Patients
Baseline features of patients derived from the two studies are outlined in Table 1. There were differences in demographics, serum biochemistry and virological features of patients from the two cohorts: in the Scandinavian cohort, patients were as a mean 10 years younger, had a prevalent genotype 3 infection and lower frequency of advanced liver damage, as indicated by the lower proportion of individuals with low platelet counts and APRI score >2. Conversely, a higher proportion of Italian patients received a high (≥15 mg/kg) dose of ribavirin, a finding that might be related to differences in the schedule of ribavirin administration between the two studies: a more stringent weight-related dosing in the Scandinavian trial, and a looser relation to body weight in the Italian study.
Sustained virological response rates and predictability of SVR by RVR in accordance with the different duration of treatment are reported in Table 2.
Impact of Ribavirin Dosing on Rapid Virological Response
No patient had to reduce the ribavirin dose by treatment week 4, so that the relationship between starting ribavirin dose and the probability of RVR could be detailed. As shown in Figure 1, the dose of ribavirin, expressed in mg/kg of body weight, may be a determining factor of RVR in genotype 2 and 3 patients: the probability of RVR increased with increasing ribavirin dose. However, the relationship was a nonlinear one and the probability increased from approximately 54% to 80% for a ribavirin dose increase from 13 to 15.2 mg/kg. The dose of 15.2 mg/kg was determined as the best splitting value for discriminating RVR vs. non-RVR: among the 147 patients receiving a dose of ribavirin higher than 15 mg/kg, an 80% probability of achieving an RVR was observed, while for the 528 patients who received a lower dose, the RVR rate was 67%. At the univariate analysis of predictors of RVR, body mass index, genotype, viral load and ribavirin dose were significantly associated with RVR (Table 3). Multiple logistic regression analysis identified low baseline viraemia (<400 000 IU/mL) (OR = 2.5; 95% CI 1.6–3.8), genotype 2 (OR = 1.7; 95% CI 1.2–2.5) and high ribavirin dose (15 mg/kg) (OR = 1.6; 95% CI 1.1–2.6) as independent prognostic factors.
Figure 1. Probability of rapid virological response (RVR) in patients with hepatitis C virus genotypes 2 and 3 as a function of the ribavirin dose per kilogram of body weight after 12–14 weeks treatment. Observed values are presented as circles. The dashed lines are the 95% point-wise confidence intervals.
Predictors of RVR at the univariate analysis are shown separately for HCV genotypes 2 and 3 in Table 4. At multivariate analysis, young age and low viraemia were independent predictors of RVR in genotype 2 patients, OR = 2.06, 95% CI 1.16–3.64 and OR = 2.01 (1.18–3.40) respectively. For genotype 3 patients, independent predictors of RVR were low viraemia (OR = 2.84, 95% CI 1.60–5.01), high ribavirin dose (OR = 2.13, 95% CI 1.07–4.26) and young age (OR = 2.91, 95% CI 1.77–4.80).
Impact of Ribavirin Dosing on Sustained Virological Response
As per protocol, anti-viral therapy lasted 12–14 weeks in 473 patients with RVR and 364 of them (77.0%) attained an SVR. The likelihood of an SVR was not correlated with baseline ribavirin dose, expressed in mg/kg of body weight, but rather with the inability to adhere to the prescribed dose of the drug. Low viral load (P = 0.033), normal platelet count (P = 0.0001) and maintenance of full dose of ribavirin throughout treatment were associated with SVR (P = 0.0001). Decreasing ribavirin dose relative to target during treatment was a predictor of relapse: of patients who achieved an SVR, only 7% had to reduce the dose of ribavirin after the initial 4 weeks of therapy with a consequent 25% of total amount of ribavirin reduction, whereas 19% of those who failed to clear the virus did so. At multivariate analysis, independent predictors of SVR in patients with RVR were no ribavirin dose reduction (OR = 3.1; 95% CI 1.6–5.9) and normal platelet counts (OR = 2.75; 95% CI 1.6–4.7).
Two hundred patients without RVR were treated per protocol for the standard 24 weeks of therapy and 134 of them achieved an SVR (67%). At univariate analysis, female gender (P = 0.09) and high baseline ribavirin dose (P = 0.05) emerged as the only two predictors of SVR. In particular, of 30 patients without RVR who received ribavirin at dose of ≥15 mg/kg of body weight, 23 (78.7%) individuals attained an SVR, as opposed to 110 of 170 patients in the lower ribavirin dose (64.7%). Dose reduction of ribavirin only occurred in 2% of those without RVR and was not associated with response. At the multivariate analysis, no factor was independently associated with SVR.
Ribavirin-related Side Effects
Sixty four of 673 patients with RVR required modification of the ribavirin dose because of a drop in haemoglobin levels below 10 g/dL. Anaemia was more frequently detected among patients treated with ribavirin dose of ≥15 mg/kg than in those who were treated with lower doses (9.5 vs. 4.4%), but the difference was not significant (P = 0.11). Other ribavirin related side effects as cutaneous rash, cough and dry skin were not differently distributed among patients in the low and high ribavirin dosage: 3% vs. 2.4% (P = 0.35).
Discussion
Current analysis evaluated the impact of ribavirin dosing on the therapeutic outcome in patients with genotypes 2 and 3 infection who received Peg-IFN α-2b in combination with ribavirin for a short treatment duration. Original data were derived from two clinical trials where patients were allocated to short or standard treatment duration depending on whether or not they attained an RVR.[5, 7] We could ascertain a relationship between the dose of ribavirin, expressed as mg/kg of body weight, and the likelihood of achieving an RVR. The relationship held true particularly for patients infected with HCV genotype 3. Furthermore, in RVR patients, the SVR rate was higher among those who were compliant with the initially assigned ribavirin dose throughout treatment.
Weight-based dosing of ribavirin has been extensively utilized in patients with genotype 1, in whom a relationship between ribavirin dose and SVR has been established when the drug was administered in association with either Peg-IFN α-2a or α-2b.[20–25] Based on these data, the ribavirin dose of 15 mg/kg was selected as the best balance between efficacy and a manageable safety profile. Data are less clear for genotypes 2 and 3. When administered in combination with Peg-IFN α-2a for 48 weeks, ribavirin doses of 800 or 1000–1200 mg daily produced equivalent outcomes.[22] Similarly, a comparative trial of fixed-dose (800 mg daily) or weight-based doses of ribavirin (800–1400 mg daily) in combination with Peg-IFN α-2b showed equal SVR rates: 67.7% vs. 65.0%.[23] This study also documented that responses were consistent across all body weight categories in the weight-based group, but lower SVR were attained with increasing weight.[22] However, a randomized study of Peg-IFN α-2a plus ribavirin for 24 weeks at doses of either 400 or 800 mg claimed no decrease in SVR rates in the lower dose group among patients with genotype 3 infection, but SVR rates declined from the 67.5% rate in the 800 mg group to 63.9% in the 400 mg group.[24]
It needs to be reminded that all previous trials administered therapy for at least 24 weeks. In principle, it might be conceivable that for the overall population of genotype 2 and 3 patients, a fixed 800 mg/day dose of ribavirin could be enough to achieve optimal response rates after 24 weeks of therapy. However, as shorter treatment courses may be viable in select genotype 2 and 3 patients, such as those with RVR, it could be speculated that much more promising results could be obtained by weight adjustment of ribavirin dose when considering abbreviated treatment. Indirect evidence supports this claim. In the NORDynamIC trial, patients who achieved SVR had significantly lower body weight than those who did not; as a fixed dose of 800 mg of ribavirin was administered to all patients, it is plausible that SVR patients had been exposed to higher dose of ribavirin than those who did not achieve SVR.[13] A post hoc analysis of the trial showed that the chance of achieving an SVR was associated with higher median serum ribavirin concentrations at week 4.[25]
In a study from Taiwan, an RVR rate of 86% was registered following therapy with Peg-IFN alpha-2a and weight-based ribavirin (1000–1200 mg daily); considering that the mean body weight of patients included in the study was 68 kg, a mean dose of 15–20 mg/kg was administered and could be one factor that might have impacted on the pronounced RVR rate.[4] In opposition, the ACCELERATE trial administered a fixed dose of 800 mg to patients whose mean body weight was 81.5 kg; consequently, they received a low ribavirin dose (9.8 mg daily, as a mean) and attained an RVR at a rate as low as 65.5%.[12] We acknowledge that although suggestive, all mentioned lines of evidence should be interpreted with caution because they were derived from secondary analyses with potential confounding variables.
The present analysis has added new evidence to the ongoing debate on the optimal ribavirin dosage. We found a relationship between body weight and RVR, an observation suggesting that the dose of ribavirin per kilogram may contribute substantially to response to therapy in patients undergoing short therapy. It is important to note that the type of the relationship was nonlinear, but S-shaped, with a low and a high threshold value for dosing of ribavirin. From our analysis, it turned out that a threshold value of ≥15.2 mg/kg was expected to result in a better outcome of therapy when considering short treatment. In previous studies,[16] the concept that ribavirin clearance is linearly dependent on renal function was not incorporated into the analysis, at variance in our patients as suggested by Bruchfeld,[25] the renal effect could be excluded after the adjustment for GFR. As a matter of fact, 80% of patients given ribavirin dose ≥15.2 mg/kg achieve an RVR as compared to 54% of those who were given 13 mg/kg.
Reddy et al. reported that as long as patients achieved RVR, ribavirin dose reduction had minimal impact on SVR after standard treatment duration.[26] Our findings on RVR patients who were treated with only 12–14 weeks of therapy demonstrate lower SVR rates when the initial dosage of ribavirin had to be reduced. Indeed, 46 of 473 patients with RVR required dose modification because of a drop in haemoglobin levels below 10 g/dL, and 54% of them attained an SVR as opposed to a 79% rate in those who could tolerate the starting dose of ribavirin throughout treatment. Although data modelling suggests that RVR increases with ribavirin doses that equate to ≥15 mg/kg, there is also a simultaneous increase in the rate of anaemia. To contrast anaemia development, the use of off-label erythropoietin has been implemented,[27–29] but the drug was not allowed in our patients for cost-saving considerations.
In summary, the results of our study suggest that in patients with HCV genotypes 2 and 3 infection completing short therapy with Peg-IFN α-2b in combination with weight-based doses of ribavirin, a high starting dose of ribavirin appeared one of the factors influencing the rate of RVR. We would recommend administering ribavirin at a dose of ≥15 mg/kg when considering short treatment duration. Larger prospective studies would be required to confirm the role of higher ribavirin doses on SVR, as both the need of maintaining the full planned dose of ribavirin throughout treatment to achieve an optimal SVR rate and the improvement of SVR in patients still viremic at treatment week 4 after an intensified ribavirin dosing suggest that higher ribavirin dosage affects SVR. Finally, the evidence that genotype 3 may derive more benefit from high dosages of ribavirin warrants further confirmation of the present post hoc analysis.
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