High-dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C†
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Improved treatment regimens for patients with chronic hepatitis C, genotype 1 and high viral load are needed. Increasing the dose of ribavirin has increased the response rate, but experience with doses of more than 1,200 mg/day is limited. The aim of this study was to investigate the safety and tolerance to treatment with a high and individualized dose of ribavirin in combination with peginterferon. Ten patients with chronic hepatitis C, genotype 1 and high viral load were treated with peginterferon alfa-2a and ribavirin for 48 weeks in a prospective trial. The initial ribavirin dose was individualized and calculated from a pharmacokinetic formula based mainly on renal function. Ribavirin plasma concentrations were monitored, and the dose was adjusted to reach the target concentration. Hemoglobin was monitored, and patients were treated with erythropoietin and blood transfusions when indicated. After dose adjustments, the mean dose of ribavirin was 2,540 mg/day (range, 1,600-3,600) at week 24. The main side effect was anemia, which was controlled with erythropoietin. Two patients required blood transfusions. One patient was withdrawn at week 24 because of a lack of viral response, and one patient at week 39 because of side effects, primarily interferon associated. At follow-up (≥24 weeks posttreatment), nine of ten patients had undetectable HCV RNA and thus were cured by standard definitions. In conclusion, a high dose of ribavirin according to an individualized schedule is feasible but associated with more frequent and serious side effects such as anemia. The viral response merits further evaluation. (HEPATOLOGY 2005;41:275–279.)
Although improvements have been made in the antiviral therapy of chronic hepatitis C virus (HCV), patients with genotype 1 infection with a high level of HCV RNA still pose a therapeutic challenge. The standard combination treatment with 12 months of peginterferon combined with ribavirin results in a sustained virological response rate of approximately 40% for this subset of patients.1–3
The mode of action of ribavirin is not firmly established.4 Furthermore, data regarding the correlation between the dose and the resulting concentration of ribavirin are limited, and the optimal dose is not known. For the treatment of chronic HCV, ribavirin is currently dosed according to body weight, usually between 800 and 1,200 mg daily.5 In a recent report by Hadziyannis et al.,3 patients with genotype 1 and a high viral load responded better to a ribavirin dose of 1,000 to 1,200 mg daily than to 800 mg/day combined with peginterferon.3 In contrast to current recommendations, we have recently shown that renal function is of greater importance than body weight for ribavirin clearance, and we therefore have suggested the use of a pharmacokinetic formula based primarily on renal function as a tool to determine the accurate dose of ribavirin for treatment.6
In a previous study, we have shown that with a standard ribavirin treatment dose of 800 to 1200 mg daily, the mean ribavirin concentration was 8.2 μmol/L (range, 0-17.7).7 Other studies have shown a correlation between the ribavirin concentration and viral response.8, 9 We propose that concentrations greater than 15μmol/L may improve the response rate for genotype 1 patients infected with HCV.
The aim of this study was to evaluate safety of and tolerance to a high dose of ribavirin that is selected and adjusted to achieve a high steadystate concentration of ribavirin (>15 μmol/L). We also aimed to prospectively evaluate the use of a pharmacokinetic formula to predict the initial dose of ribavirin required to reach the intended plasma concentration of ribavirin and to measure the viral response to this dose. For this purpose, we conducted an open label study on patients with chronic HCV, genotype 1 and high viral load, with one treatment arm of ribavirin dosed individually, in combination with a standard dose of peginterferon alfa-2a, for 48 weeks.
Patients and Methods
Ten previously untreated patients with chronic HCV, genotype 1 and a viral load of >800 000 International Units (IU)/mL, who were attending the outpatient clinic at the Department of Infectious Diseases, Karolinska University Hospital Huddinge, were enrolled in this open-label, prospective trial. The inclusion criteria were as follows; age >18 years, elevated alanine aminotransferase, positive anti-HCV antibody test, detectable serum HCV RNA, and a liver biopsy consistent with chronic HCV but without cirrhosis. Patients with other forms of liver disease, active hepatitis A or hepatitis B infection, hepatocellular carcinoma, human immunodeficiency virus infection, anemia, a previous diagnosis of severe depression or other psychiatric disease, significant cardiac disease, renal disease, seizure disorders, severe retinopathy, or pregnancy were excluded from the study.
Liver biopsies were classified according to inflammation (grade) and fibrosis (stage) on a noncontinuous scale of 0 to 4.10
The study was approved by the local ethical review board, and all patients gave their informed consent.
The treatment consisted of 180 μg peginterferon alfa-2a (Pegasys, Roche AB, Stockholm, Sweden) subcutaneously once weekly, in combination with ribavirin for 48 weeks. Ribavirin was administered orally with food as 200-mg capsules/tablets, twice or three times daily. Initially the patients were given Rebetol (Schering-Plough AB, Stockholm, Sweden); that is, the first five patients included in the study were treated with Rebetol. Copegus (Roche AB) then became available and was judged to be favorable with regard to compliance because of the smaller size of the tablet, considering the large number of tablets that needed to be taken by the patient. An estimated 90% or more of the ribavirin treatment given throughout the study was Copegus. The change of study drug was decided to be acceptable because the treatment was concentration controlled and not dose controlled; hence, bioequivalence was not an issue.
The initial ribavirin dose was individualized and calculated from a pharmacokinetic formula that is primarily based on renal function and aims to achieve a steady-state concentration of ribavirin of >15 μmol/L.6 When necessary, the dose of ribavirin was increased to reach the target concentration, as indicated by the measured plasma ribavirin concentrations. Creatinine clearance was estimated according to the Cockroft-Gault equation.6 Treatment was discontinued in patients who had detectable virus (>600 IU/mL) after 24 weeks of treatment.
The patients were monitored every 2 to 4 weeks during the entire 48-week treatment period and were followed for an additional 24 weeks, after cessation of treatment. General monitoring included full blood cell counts and hemoglobin level, serum alanine aminotransferase, serum urate, thyroid function tests, and weight.
Plasma samples were collected approximately 12 hours after the dose administration, and ribavirin concentrations were measured by high-performance liquid chromatography11 every 2 to 4 weeks during the first 24 weeks of treatment. During the final 24 weeks of treatment, the ribavirin concentration was measured every 8 weeks or more frequently if dose adjustments were made.
HCV genotyping was done before inclusion by using an in-house method.12 Qualitative (sensitivity <50 IU/mL, Cobas Ampliprep/Cobas Amplicor, HCV test version 2.0, Roche Molecular Systems Inc., Branchburg, NJ) or quantitative (sensitivity <600 IU/mL, Cobas Ampliprep/Cobas Amplicor HCV Monitor version 2.0, Roche Molecular Systems Inc.) HCV polymerase chain reaction tests were conducted at study weeks 0, 4, 12, 24, 48, and 72.
In patients with moderate to severe anemia, treatment options included blood transfusion and reduced treatment doses. Ribavirin was discontinued if the hemoglobin level fell below 8.0 g/dL. To prevent severe anemia, erythropoietin (Neorecormon, Roche AB) and oral iron supplement were used. Dose adjustments of peginterferon were made according to well-established guidelines.1, 2
Ten patients, seven men and three women, mean age 51 years (range, 40-64) were enrolled between November 2002 and April 2003. The patient characteristics are shown in Table 1.
Table 1. Baseline Clinical Characteristics of the 10 Patients With Chronic Hepatitis C Virus Infection Included in the Study
|Age (years), mean (range)||51 (40–64)|
|ALT (μkat/L), mean (range)||2.23 (0.54–5.37)|
|Genotype||1a, n = 7|
| ||1b, n = 3|
|Histology, grade||0, n = 1|
| ||1, n = 3|
| ||2, n = 5|
| ||3, n = 1|
|Histology, stage||0, n = 1|
| ||1, n = 4|
| ||2, n = 3|
| ||3, n = 2|
|Weight (kg), mean (range)||80.6 (66.5–109)|
|Creatinine (μmol/L), mean (range)||68 (42–83)|
|Creatinine clearance (mL/min), mean (range)||96 (77–143)|
The initial daily dose of ribavirin was calculated from the pharmacokinetic formula, which aimed to achieve a steady-state concentration of ribavirin of >15 μmol/L (see Patients and Methods section) and resulted in a mean dose of 1,520 mg/day (range, 1,200-2,200), as shown in Table 2. However, the mean concentration at treatment week 4 was 8.6 μmol/L (range, 6.0-15.7). After a gradual dose escalation, the mean daily dose of ribavirin at treatment week 24 was 2,540 mg/day (range, 1,600-3,600), which in turn resulted in a mean ribavirin concentration of 14.7 (range, 7.8-22.0). The highest individual dose given was 4,000 mg daily.
Table 2. Ribavirin Doses and Corresponding Ribavirin Concentrations, Viral Load, Hemoglobin Levels, and Erythropoietin Treatment in 10 Patients With Chronic HCV Infection During and After Ribavirin and Peg-Interferon Treatment
|Daily ribavirin dose mg, mean (range)||1,520 (1,200–2,200)||1,680 (1,200–2,200)||2,520 (1,600–3,600)||2,540 (1,600–3,600)||2,325 (1,600–3,600)|| |
| || || || || ||n = 8|| |
|Ribavirin concentration μmol/L, mean (range)||—||8.6 (6.0–15.7)||14.7 (10.8–18.7)||14.7 (7.8–22.0)||14.4 (11.9–17.0)|| |
| || || || || ||n = 8|| |
|Viral load IU/mL||Mean: 2.5 × 106||<600 n = 3||<50 n = 5||<50 n = 8||<50||<50|
| || range: 1.6–4.2||Mean: 0.34 × 106||<600 n = 4||<600 n = 1||n = 9||n = 9|
| || ||Range: 0.006–1.2 n = 7||>600 n = 1||>600 n = 1|| || |
|Hemoglobin g/dL, mean (range)||14.4 (12.5–16.0)||12.4 (8.9–15.0)||11.1 (8.6–15.0)||9.7 (8.1–11.3)||9.9 (8.7–11.4)||13.6 (13.0–14.4)|
| || || || || ||n = 8||n = 9|
|Number of patients treated with erythropoietin*||0||8||10||10||8||0|
Table 2 shows the viral response. In one patient, the treatment was discontinued after 24 weeks because of HCV RNA levels >600 IU/mL. The remaining nine patients became HCV RNA negative during treatment and remained negative at follow-up ≥24 weeks after the cessation of treatment, including one patient who was HCV RNA positive (<600 IU/mL) at week 24 and one patient who discontinued the treatment at week 39 because of side effects.
Hemoglobin levels decreased during the treatment, as shown in Table 2. In two patients, the hemoglobin levels decreased to below 8.0 g/dL (nadir, 7.3 and 7.9, respectively). These patients received blood transfusions on two occasions each, and the dose of ribavirin was reduced or temporarily discontinued for 1 week. An additional 5 patients experienced a decrease in hemoglobin to levels between 8.0 and 10.0 g/dL, and two of these patients had minor dose reductions of ribavirin. For shorter periods, in particular during the first 3 to 6 months of treatment, the hemoglobin levels were measured once per week. Nausea caused a minor dose reduction in one additional patient. During the course of treatment, all patients received erythropoietin with doses in the range of 9,000 to 30,000 IU/week as well as an oral iron supplement.
One patient discontinued ribavirin at week 39 because of side effects, mainly associated with concurrent interferon treatment. In four patients peginterferonalfa-2a was discontinued for a short period or a reduced dose was given because of neutropenia.
Important nonhematological side effects are shown in Table 3. Fatigue, nausea, and dermatological problems were, in our opinion, more frequent and severe problems than those usually observed with standard combination treatment. The working capacity was reduced in all patients. One patient, a former drug addict, relapsed into sporadic intravenous amphetamine use 1 month after completing the treatment and was initially lost to follow-up, but came for his follow-up visit 10 months after cessation of treatment. The mean weight (range) in kilograms, at baseline, treatment week 12, and treatment week 20, was 80.6 (66.5-109.0), 79.0 (63.5-110.0), and 78.0 (62.9-110.0), respectively.
Table 3. Important Nonhematological Side Effects in the 10 Patients With Chronic Hepatitis C Virus Infection Included in the Study
|Fatigue||10||Moderate to severe|
|Pruritus or dermatitis||9||Moderate to severe|
|Nausea||7||All patients were treated with ondansetron|
|Aphthous ulcers||3|| |
|Oral candida||2||Responded well to fluconazole|
|Blurred vision||2|| |
|Diabetes mellitus||1||Started at treatment week 10, insulin dependent|
|Brown spots||1||Oral cavity|
|Migraine||1||Severe attack in association with a rapid hemoglobin drop|
Patients with chronic HCV, genotype 1 and high viral load, who were the target group of this study, have a moderate expected outcome with standard combination treatment; improvements in treatment efficacy are needed.1–3 Our hypothesis was that the fraction of patients with sustained virological response could increase with high-dose ribavirin treatment, resulting in high plasma concentration levels. To investigate this, we conducted this pilot study with the primary goal of evaluating safety and tolerance to treatment.
The optimal target concentration for ribavirin is not well established. In a previous study, we found that patients given standard ribavirin dosing, 800 to 1,200 mg daily, had a mean ribavirin plasma concentration of 8.2 μmol/L.7 The probability of response to treatment has been shown to increase with increasing ribavirin concentrations.8, 9 Therefore, we chose a target concentration of >15 μmol/L, based partly on the data of Jen et al.8 and partly on our prior studies in which some patients on standard therapy achieved concentrations above 15 μmol/L. We reasoned that the more effective concentrations achieved in a small proportion of patients on standard therapy should be explored under controlled conditions.
Increases in ribavirin doses from current standard regimens (800-1,200 mg daily) have been discussed. However, the use of high doses of ribavirin as in the current study (1,600-4,000 mg daily) has not to our knowledge been described for treatment of chronic HCV.
Some major limitations of this study were the small number of patients, the lack of controls, and that patients with cirrhosis were excluded. The side effects were more frequent and serious, in particular potentially life-threatening anemia, than those observed with standard combination treatment. However, only minor treatment interruptions occurred among the ten patients who were treated with doses of ribavirin substantially exceeding currently used standard doses.
As expected, anemia was the most challenging side effect to manage. We have previously shown that the degree of anemia is correlated to the plasma ribavirin levels.7 This result was verified in our study, since the patients who were exposed to very high ribavirin concentrations developed severe anemia. In two patients, the hemoglobin dropped below 8.0 g/dL, and they were treated with blood transfusions and discontinuation of ribavirin for a short period. The hemoglobin level dropped to below 10.0 g/L in five patients. Other measures used to limit anemia were minor dose reductions in ribavirin dose and treatment with erythropoietin. Other side effects also seemed to be more frequent and more severe than with standard treatment, in particular fatigue, nausea, and pruritus. Our impression was that this treatment regimen was more demanding for the patients than the standard treatment. Because of the extent and severity of the side effects, closer monitoring and extensive interventions were needed. However, by using these measures to correct anemia and treat other side effects, it was possible, with few exceptions, to maintain the patients on treatment with high doses of ribavirin.
The primary goal of this small pilot study was to determine feasibility and safety of the treatment, and not virological outcome. However, in this difficult-to-treat patient population with genotype 1 and a high viral load, nine of ten patients were cured by standard definitions, which seems to be a better response than that found in studies using standard ribavirin doses.1–3 Absence of patients with cirrhosis in our study population is a potential selection bias. According to current opinion, the major action of ribavirin is to prevent relapse. Interestingly, our impression was that the virological response increased with time and correlated with increasing ribavirin concentrations. Further studies are needed to investigate whether high ribavirin doses could enhance the primary viral response.
An important part of this work was to prospectively analyze the validity of a pharmacokinetic formula, based primarily on renal function, that calculates the dose of ribavirin for any given target concentration.6 Unexpectedly, the formula systematically underestimated the dose of ribavirin. Thus, in general, it was necessary to gradually increase the dose of ribavirin during the first part of the treatment to achieve the chosen target concentration. As a consequence, it took considerably longer to achieve steady state in this study than with the common regimen using the same dose of ribavirin over the entire treatment period. The reasons the formula overestimated the expected concentration of ribavirin for a given dose are being investigated. One possibility is that a small number of samples inappropriately stored in the previous study6 may have biased the model. It is also possible that the absorption of ribavirin is saturable. A third possibility, assuming a difference in the bioavailability of different ribavirin products, is that the use of Copegus in this study instead of Rebetol which was used in the population pharmacokinetic analyses,6 could contribute to the nonoptimal performance of the formula. However, we find this explanation unlikely—firstly, because a recent small study has shown no difference in bioavailability between the two products (bioequivalence study of ribavirin formulations Rebetol and Ro 20-9963 administered orally to individuals with current or previous chronic hepatitis C infection, 2001, Roche, data on file). Secondly, the first two patients in our study received Rebetol during the first 16 weeks with a similar underestimation of ribavirin dose (calculated by the formula) as in the patients treated with Copegus.
In conclusion, we have shown in this small pilot study that it is feasible to treat patients with chronic HCV with high doses of ribavirin without any major treatment interruptions. Side effects were more frequent and serious, in particular potentially life-threatening anemia, than those usually observed with standard combination treatment. Therefore, we do not recommend this treatment regimen outside clinical trials. In particular, patients with coronary heart disease and patients with cirrhosis would be at great risk. The pharmacokinetic formula used to calculate the initial ribavirin dose systematically underestimated the dose. It is still a useful tool, but it needs to be revised. Considering the high proportion of patients cured in this pilot study, additional studies would be of great value to further evaluate safety and side effects as well as the viral efficacy in a controlled fashion. Nonresponders to conventional therapy may be the appropriate target population for future studies.
The professional assistance of research nurses Gunilla Hermann, Anna Hollander, and Mats Christiansen is gratefully acknowledged.