January 31, 2012

Ribavirin Rather than PEG-interferon Pharmacodynamics Predict Nonresponse to Antiviral Therapy in Naive Chronic Hepatitis C Patients

From Journal of Viral Hepatitis

L. G. van Vlerken; E. J. Huisman; H. van Soest; G. J. Boland; J. P. H. Drenth; P. D. Siersema; D. M. Burger; K. J. van Erpecum

Posted: 01/30/2012; J Viral Hepat. 2012;19(1):39-46. © 2012 Blackwell Publishing

Abstract and Introduction
Abstract

Twenty to fifty per cent of patients with chronic hepatitis C (CHC) experience nonresponse to current antiviral therapy, which may relate in part to ribavirin or PEG-interferon pharmacodynamics. We evaluated potential relevance of various factors for nonresponse. Two hundred forty-two naive CHC patients who received in a previous trial at least 24 weeks of antiviral therapy, including PEG-interferon alfa-2b and ribavirin, were analysed. Of them, 53% were infected with hepatitis C virus (HCV) genotype 1–4, 71% exhibited high viral load and 32% had severe fibrosis/cirrhosis. After 24 weeks of treatment, 39 patients (16%) were nonresponders. In multivariate analysis, lower serum ribavirin concentrations, HCV genotype 1–4 and higher baseline γ-GT predicted nonresponse. Week-24 ribavirin concentrations (2.2 vs 2.8 mg/L, P < 0.001), average ribavirin doses (14.5 vs 15.2 mg/kg per day, P = 0.03) and week-24 haemoglobin decreases (1.7 vs 2.0 mm, P = 0.02) were lower in nonresponders. Nonresponse rates increased progressively at decreasing ribavirin concentrations: 4%, 11%, 13% and 36% in case of serum ribavirin concentrations ≥4, 3–4, 2–3 and ≤2 mg/L, respectively (P = 0.001). Ribavirin concentrations correlated with both week-24 haemoglobin decreases (r = 0.42, P < 0.001) and ribavirin doses (r = 0.17, P = 0.01). Subgroup analysis in HCV genotype 1–4 patients revealed essentially the same results. Nonresponse was exceptional in HCV genotype 2–3 patients and associated with ribavirin concentrations <2 mg/L. Presumed interferon-related factors (average PEG-interferon doses and decreases in leucocytes, granulocytes, platelets and body weight) did not differ between nonresponders and responders. In conclusion, ribavirin- rather than PEG-interferon-related factors are independent and potentially modifiable predictors of nonresponse in treatment-naive CHC patients.

Introduction

Current treatment for chronic hepatitis C (CHC), consisting of PEG-interferon and ribavirin, is not effective in 20–50% of cases.[1,2] Several baseline patient and viral characteristics have been described as predictive factors for nonresponse to PEG-interferon and ribavirin treatment in previous studies, such as hepatitis C virus (HCV) genotype, viral load, patient weight, presence of cirrhosis and African American race.[3] It is important to explore which modifiable on-treatment factors affect nonresponse rates, in order to develop effective strategies to improve outcome of antiviral treatment. Adherence to at least 80% of the prescribed (PEG) interferon and ribavirin doses has been associated with better response rates, especially in HCV genotype 1 patients.[4] Inter-individual variability in plasma concentrations of ribavirin during treatment is high,[5,6] and low plasma concentrations of ribavirin could be important predictors of nonresponse.[5,7–10] Interferon-related factors could also be relevant: in a recent post hoc analysis of the HALT-C trial in previous nonresponders with advanced fibrosis or cirrhosis undergoing PEG-interferon and ribavirin re-treatment, presumed interferon-related factors (less pronounced reductions in body weight, leucocytes or platelets) were significantly associated with null response (≤1 log decrease in HCV RNA at week 24) in multivariate analysis.[11] The underlying mechanism could be systemic interferon resistance. The aim of the current study was therefore to evaluate the influence of various baseline and on-treatment factors, including serum ribavirin concentrations, on nonresponse in treatment-naive CHC patients.

Patients and Methods
Patients

In this study, we analysed a subgroup of patients who participated in a multicentre, double-blind randomized placebo-controlled trial on potential benefit of adding amantadine to PEG-interferon alfa-2b and ribavirin combination therapy in 297 treatment-naive hepatitis C patients: the CIRA trial. Details of this study have been published previously.[12] Of the 297 patients included in this trial, 242 patients received therapy for at least 24 weeks and are included in the current analysis. All patients received induction therapy (from day 1 combined with ribavirin), consisting of interferon alfa-2b (Schering Plough B.V., Maarssen, the Netherlands) 10 MIU/day subcutaneously during the first 6 days, followed by 5 MIU/day for the next 6 days, followed by PEG-interferon alfa-2b (Schering Plough B.V.) 1.5 μg/kg per week subcutaneously up to 26 weeks and 1.0 μg/kg per week from week 26 to 52, regardless of HCV genotype. Oral ribavirin (Schering Plough B.V.) was given from day 1 during the entire 52-week treatment period in two different doses: 1000 mg/day for body weight <75 kg and 1200 mg/day for body weight ≥75 kg. There were no differences in the amantadine and placebo groups regarding virological response. Therefore, data of both groups are combined in the following analyses.

Methods

Follow-up occurred at 0, 1, 2 and 4 weeks and monthly thereafter during 1 year of treatment and at 3-month intervals during 1 year after the end of treatment. During each visit, laboratory tests, including haemoglobin, leucocytes, granulocytes and platelet counts, were performed. Body weights and doses of ribavirin and PEG-interferon alfa-2b were also recorded at each visit. Average ribavirin and PEG-interferon alfa-2b doses during the first 24 weeks of therapy were calculated for each individual patient. Baseline creatinine clearance was calculated according to the Cockcroft–Gault equation.[13] Quantitative serum HCV RNA testing (Cobas Amplicor HCV Monitor Test, version 2.0, detection limit 615 IU/mL; Roche Diagnostics, Almere, the Netherlands) and genotyping [sequence analysis of the 5' untranslated region of the HCV genome by TrueGene Hepatitis C Assay (Visible Genetic, Suwanee, GA, USA)] were performed before inclusion by the central study laboratory. Baseline HCV RNA values >800 000 IU/mL were considered high viral loads. Baseline liver biopsies were performed in 215 patients (89%) and assessed according to the METAVIR scoring system.[14] Qualitative serum HCV RNA testing was performed at weeks 24, 52 and 104 (Cobas Amplicor HCV test, version 2.0; detection limit 50 IU/mL; Roche Diagnostics) by the central study laboratory. Treatment was terminated if qualitative HCV RNA test was positive after 24 weeks of treatment. Detailed information concerning dose reduction policy and definitions of virological response has been published previously.[12]

Fifty-five of 297 patients discontinued treatment before week 24 because of patient preference (n = 13), noncompliance (n = 2), loss to follow-up (n = 9) or WHO grade 4 or persistent/recurrent grade 3 toxicity [n = 31: decompensated cirrhosis (n = 1), death because of drug overdose (n = 1), leucopenia or granulocytopenia (n = 16), anaemia (n = 2), psychiatric side effects (n = 7), miscellaneous (n = 4)].

Ribavirin Measurements

Serum samples of all patients were prospectively collected and stored at −80 °C. For the current analysis, all available week-24 samples (98% of all patients) were thawed, mixed and tested for ribavirin concentrations simultaneously using high-pressure liquid chromatography with UV detection (4.6 × 150 mm Atlantis T3 5 μm reverse-phase C18 column, autosampler column oven 35 °C: mobile phase 20 mm phosphate buffer pH 3.23 with flow rate 1.0 mL/min, λ 235 nm). Accuracy values were 104.6%, 105.2%, 101.5%, 100.9% and 100.8% at 0.300, 1.00, 4.00, 10.0 and 12.0 mg/L, respectively. At the same concentrations, the precision values (within and between days, coefficient of variation) were all below 6.0%. The calibration curve was linear over a concentration range of 0.3–12.0 mg/L. One hundred six possible co-medications were tested on this assay, none interfered with ribavirin.

Statistics

SPSS for Windows, version 15.0.1 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. We analysed patients according to per-protocol principle: for analysis of nonresponse, only patients who were treated for at least 24 weeks were included, and for analysis of final outcome, only patients who reached a primary study endpoint (i.e. completion until end of follow-up or detectable HCV RNA after 24 or 52 weeks of treatment) were included. Values are expressed as means ± SD for data with Gaussian distribution; otherwise medians with range are used. Differences in potential predictors for virological response were tested for statistical significance with the Student's t-test, Mann–Whitney U-test, Pearson's chi-square test and Fisher's exact test, as appropriate. Differences between patients with nonresponse, relapse and sustained viral response (SVR) were tested with ANOVA with post hoc LSD test. Baseline and week-24 factors that were associated with nonresponse/SVR in univariate analysis at the 0.1 level were entered in a multivariate logistic regression model with stepwise backward selection to identify independent predicting factors for these two outcomes of interest. A two-sided P-value <0.05 was considered statistically significant.

Results
Patient and Treatment Characteristics

Baseline patient characteristics of the 242 patients who received antiviral therapy during at least 24 weeks are given in Table 1. Fifty-three per cent of patients were infected with HCV genotype 1–4, 71% had high viral loads (>800 000 IU/mL), 32% exhibited severe fibrosis or cirrhosis on liver biopsy and 54% had elevated γ-GT levels at baseline. Dose reductions of ribavirin were applied in 18 patients (7%: five patients WHO grade 3 toxicity of haemoglobin, 13 patients other reasons). Dose reductions of PEG-interferon were applied in 49 patients (20%: 30 patients WHO grade 3 toxicity of granulocytes and/or leucocytes, two patients WHO grade 3 platelet toxicity, 17 patients other reasons).

Ribavirin Concentrations

Average ribavirin dose during 24 weeks of treatment was [median (range)] 1033 mg/day (467–1200 mg/day). Median week-24 serum ribavirin concentration was 2.7 mg/L (range 0.2–7.4 mg/L). Serum ribavirin concentrations were higher in female than male patients (median 2.9 vs 2.6 mg/L, P = 0.045). Serum ribavirin concentrations were not affected by HCV genotype, baseline viral load, fibrosis severity or baseline body weight. By multivariate linear regression analysis with backward stepwise selection, only higher average ribavirin dose during the first 24 weeks of therapy (in mg/kg per day) was identified as an independent predictive factor for higher week-24 serum ribavirin concentrations (coefficient 0.07, 95% CI 0.02–0.13, P = 0.01) However, only 3% (r2 = 0.029) of variability in serum ribavirin concentrations could be ascribed to differences in ribavirin doses. Week-24 serum ribavirin concentrations tended to negatively correlate with baseline creatinine clearance (r = −0.12, P = 0.07) and baseline haemoglobin (r = −0.12, P = 0.06). Furthermore, a significant correlation of serum ribavirin concentrations with week-24 haemoglobin decreases (r = 0.42, P ≤ 0.001) was found. In contrast, average ribavirin doses did not correlate with week-24 haemoglobin decreases (r = −0.05, P = 0.40).

Factors Associated with Nonresponse

After 24 weeks of therapy, 203 of 242 patients (84%) exhibited negative qualitative serum HCV RNA (responders). HCV RNA was positive in the remaining 39 patients (16%; nonresponders). Of the 128 patients with HCV genotype 1–4, 36 had a nonresponse (28%). In contrast, only three of the 113 patients (3%) infected with HCV genotype 2–3 were nonresponders.

Results of univariate analysis of baseline and on-treatment factors associated with nonresponse in the total group are summarized in Table 2. Baseline factors significantly associated with nonresponse were male gender, HCV genotype 1–4 infection and higher gamma-glutamyl transpeptidase (γ-GT) levels. Week-24 serum ribavirin concentrations, average ribavirin doses during 24 weeks of therapy and week-24 haemoglobin decrease were significantly lower in nonresponders than responders.

Nonresponse rates increased progressively at decreasing serum ribavirin concentrations: 4%, 11%, 13% and 36% in case of serum ribavirin concentrations ≥4, 3–4, 2–3 and ≤2 mg/L, respectively (P = 0.001). Figure 1 shows the nonresponse rates as a function of serum ribavirin concentrations, according to HCV genotype. Interestingly, all HCV genotype 2 or 3 nonresponder patients exhibited week-24 serum ribavirin concentrations <2 mg/L.

756035-fig1

Figure 1. Nonresponse rates in naive chronic hepatitis C patients after 24 weeks of antiviral therapy as a function of week-24 serum ribavirin concentrations. Bars represent the percentage of patients with nonresponse after 24 weeks of antiviral treatment: grey bars represent patients with hepatitis C virus (HCV) genotype 1–4, white bars represent patients with HCV genotype 2–3.

Multivariate logistic regression analysis identified infection with HCV genotype 1–4, higher pretreatment levels of γ-GT and lower week-24 serum ribavirin concentrations as independent predicting variables for nonresponse at 24 weeks of therapy (Table 3). Uni- and multivariate analysis in the subgroup of HCV genotype 1–4 patients revealed essentially the same results as in the total group, again with lower serum ribavirin concentrations, lower ribavirin doses and higher baseline γ-GT levels as independent risk factors for nonresponse (Tables S1 and S2). As in the total population, week-24 serum ribavirin concentrations in the subgroup of HCV genotype 1–4-infected patients significantly correlated with week-24 haemoglobin decreases (r = 0.50, P < 0.001). In contrast, no significant correlation between serum ribavirin concentrations and average ribavirin doses (in mg/kg per day) was found (r = 0.15, P = 0.11). In HCV genotype 2–3 patients, serum ribavirin concentrations correlated with both week-24 haemoglobin decreases (r = 0.32, P = 0.001) and average ribavirin doses (r = 0.20, P = 0.03).

PEG-interferon-related Factors

Presumed interferon-related factors (leucocytes, granulocytes, platelets and body weight) did not differ significantly between nonresponders and responders, nor did PEG-interferon doses (Table 2). In the subgroup of HCV genotype 1–4 patients, also no significant differences in interferon-related factors were found between responders and nonresponders (Table S1).

Factors Associated With Null or Partial Virological Response After 24 Weeks of Therapy

Quantitative HCV RNA at week 24 in the nonresponders revealed <1 log10 decrease of viral load (null response) in six cases, ≥1 log10 decrease (partial response) in 30 cases and could not be determined in three cases because of absence of serum samples. Decreases from pretreatment levels of leucocytes (2.1 vs 3.7 × 109/L, P = 0.09), granulocytes (0.8 vs 2.2 × 109/L, P = 0.22), platelets (4 vs 48 × 109/L, P = 0.08) and body weight (3.3 vs 5.0 kg, P = 0.11) and serum ribavirin concentrations (1.6 vs 2.3 mg/L, P = 0.18) tended to be less in null responders. Week-24 haemoglobin decreases and average ribavirin or PEG-interferon alfa-2b doses during antiviral therapy were not significantly different between the null and partial responders (data not shown).

Final Treatment Outcome

Of the 203 patients with negative qualitative HCV RNA at week 24, 145 patients (71%) reached SVR, 13 patients (6%) relapsed, 10 patients (5%) exhibited viral breakthrough and 35 patients (17%) were dropouts at later stages for various reasons. Characteristics for a more favourable treatment outcome generally increased progressively in the order: nonresponse, relapse and SVR groups, including week-24 serum ribavirin concentrations (2.2, 2.6 and 2.9 mg/L: Table S3). SVR rates increased progressively at increasing serum ribavirin concentrations: 47%, 69%, 76% and 95% in case of serum ribavirin concentrations ≤2, 2–3, 3–4 and ≥4 mg/L, respectively (P = 0.001, Fig. 2). By multivariate analysis, HCV genotype 2–3, lower baseline γ-GT levels and higher serum ribavirin concentrations were identified as independent predictors of SVR (Table S4). Highly similar findings were found in the subgroup of HCV genotype 1–4 patients (Tables S5 and S6).

756035-fig2

Figure 2. Sustained viral response (SVR) rates in naive chronic hepatitis C patients as a function of week-24 serum ribavirin concentrations (per-protocol analysis). Bars represent the percentage of patients with SVR: grey bars represent patients with hepatitis C virus (HCV) genotype 1–4, white bars represent patients with HCV genotype 2–3.

Discussion

In this study, we explored the potential influence of various baseline and on-treatment factors, including serum ribavirin concentrations, on nonresponse to PEG-interferon alfa-2b and ribavirin in treatment-naive CHC patients. Our main finding is that lower week-24 serum ribavirin concentrations are an independent risk factor for nonresponse.

This finding indicates the importance of adequate exposure to ribavirin, especially in HCV genotype 1–4 patients. Only 3% of patients with HCV genotype 2–3 were nonresponders, but all had a serum ribavirin concentration below 2 mg/L. Although one could speculate that a certain threshold in serum ribavirin concentrations has to been reached to exclude an unfavourable outcome in patients with HCV genotype 2–3, the low numbers of genotype 2–3 patients with nonresponse preclude any conclusion in this respect.

Inter-patient variability in serum ribavirin concentrations is known to be high.[5,6] Body weight, renal function, gender and age are associated with ribavirin clearance at various time points but can only explain a small part of the variability.[5,15,16] In our study, only higher average ribavirin doses (in mg/kg per day) were an independent predictor of higher serum ribavirin concentrations (r2 = 0.029). Determinants not studied in the current analysis such as nonadherence[17] and factors influencing absorption, transport and intracellular metabolism of ribavirin could contribute to the high variability.

Ribavirin has a narrow therapeutic index: while low ribavirin concentrations increase the risk of nonresponse, high ribavirin concentrations increase the risk of toxicity, especially haemolytic anaemia.[5,7,8,18,19] In line with these data, week-24 haemoglobin decreases in the current study were significantly correlated with week-24 ribavirin concentrations (r = 0.42, P < 0.001).

A potential bias in our analysis is that only patients who completed 24 weeks of treatment were included. However, only two patients stopped therapy before week 24 because of anaemia. We were interested in week-24 serum ribavirin concentrations, because we aimed at identifying factors determining risk of nonresponse rather than to adapt ribavirin dose at an early point during antiviral therapy. However, according to previous literature, steady state concentrations are already reached after 4–8 weeks.[20] Another possible limitation of this study is that we did not measure serum PEG-interferon concentrations. It should also be noted that some aspects of the study protocol differ from current practice, because the design of the CIRA study dated from 1999–2000.[12] Patients received high-dose induction therapy with interferon, which is currently not advised. PEG-interferon alfa-2b dose was decreased in the second half of the treatment period from 1.5 to 1.0 μg/kg per week. However, PEG-interferon doses 1.0 μg/kg per week appear not to compromise SVR rates.[21,22] Also, in our series of 236 patients with ribavirin determinations, there was one outlier, with ribavirin concentration of 7.4 mg/L. Although we cannot exclude some haemolysis associated with antiviral therapy in this patient, all available clinical data would suggest that ribavirin exposure was considerable: the patient received a high ribavirin dose (17.5 mg/kg per day), with corresponding drop in haemoglobin (3.6 mm at week 24 compared to basal). Finally, patients were not checked after 12 weeks of treatment for early viral response,[23] and patients with HCV genotype 2–3 were treated for 1 year.

Apart from lower serum ribavirin concentrations, infection with HCV genotype 1–4 and higher baseline γ-GT levels were identified as independent risk factors for nonresponse. HCV genotype 1 has extensively been described as the predominant risk factor for nonresponse to combination therapy for CHC. In our study, HCV genotype 1–4 was the predominant predictor for nonresponse. In contrast, elevated γ-GT levels have not been described as an independent predictive factor for nonresponse in patients with hepatitis C before. However, low or normal γ-GT levels have been associated with SVR,[24–26] and our findings suggest that lower nonresponse rates under these circumstances could be the explanation of this finding. Elevated γ-GT levels are associated with more severe hepatic fibrosis or cirrhosis.[27,28] In the current analysis, 54% of patients exhibited elevated γ-GT levels, similar to other reports,[25,26,29,30] and γ-GT levels were significantly correlated with severe fibrosis or cirrhosis (median of γ-GT level 70 (range 16–700) in case of severe fibrosis or cirrhosis vs 48 (5–575) in case of less severe fibrosis scores, P = 0.004). Severe fibrosis or cirrhosis could not be identified as a predictive factor for nonresponse, and one may speculate that γ-GT is a more sensitive marker for fibrosis than classification according to the METAVIR scoring system.

We also compared various on-treatment factors suggested to be different on re-treatment between patients with partial response and null response in the HALT-C trial[11] to evaluate whether similar differences could be found in treatment-naive patients. The predictive value of less reduction in body weight, leucocytes and platelets for nonresponse was not confirmed in our treatment-naive patients. Nevertheless, when comparing partial responders with null responders, a trend towards less reduction in body weight, leucocytes, granulocytes and platelets was observed, suggesting type II error. Alternatively, interferon-related factors may predict null response, especially during re-treatment of previous nonresponder patients and/or patients with severe fibrosis/cirrhosis. No other relevant studies on this topic have been published.

In conclusion, our results indicate that ribavirin rather than PEG-interferon pharmacodynamics determine in part the chance of nonresponse in treatment-naive CHC patients. This is especially the case in patients with HCV genotype 1–4, although HCV genotype 2–3 patients with serum ribavirin concentrations below a threshold of 2.0 mg/L may also experience nonresponse.

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