ORIGINAL ARTICLE
High-Dose Ribavirin Enhances Early Virological Response in Hepatitis C Genotype 1–Infected Patients Karin Lindahl, MD, PhD,* Erika Hörnfeld, MD,* Lars Ståhle, MD,† Tony Carlsson, MD, PhD,* Ola Weiland, MD, Prof,* Åsa Parke, MD,* and Robert Schvarcz, MD, Assoc Prof*
Background: The aim of the study was to investigate whether patients with a previous nonresponse to standard of care treatment with ribavirin dosed according to body weight would respond to a high individualized dose of concentration-monitored ribavirin.
Methods: Previous nonresponders to standard of care treatment with peginterferon (peg-IFN) and ribavirin were included. Ribavirin was dosed aiming at a plasma concentration of .15 mmol/L. The initial ribavirin dose was calculated from a formula based on renal function and body weight. Erythropoietin treatment was started 2 weeks before antiviral therapy. Results: Twenty patients (16 men and 4 women) with a mean age of 52 years were included. Sixty percent had advanced fibrosis. Eighty percent of patients achieved an early viral response, and 60% were negative for hepatitis C virus ribonucleic acid (HCV RNA) at treatment week 24. High-dose ribavirin resulted in a significantly increased HCV RNA drop at week 12 (mean: 3.13 versus 2.05 IU/mL; P , 0.001). Nine patients were negative for HCV RNA at the end of treatment, and 1 achieved sustained viral response. The final steady-state daily dose of ribavirin varied from 1400 to 4400 mg. Hemoglobin levels decreased during treatment, mean Hb 163, 134, and 110 g/L at week 0, 4, and 12, respectively. Two patients received blood transfusions. No other severe adverse events were recorded. Conclusions: An individualized high ribavirin dose resulted in a more pronounced early viral HCV RNA decline than a standarddose ribavirin scheme. This regime is safe provided that close monitoring of anemia is undertaken and that treatment with erythropoietin is given. Key Words: hepatitis C, nonresponders, ribavirin, pharmacokinetics (Ther Drug Monit 2015;37:745–750)
Received for publication March 12, 2014; accepted March 12, 2015. From the *Division of Infectious Diseases, Department of Internal Medicine, Karolinska Institutet, Karolinska University Hospital; and †Division of Clinical Pharmacology, Department of Medical Laboratory Sciences, Karolinska Institutet, Stockholm, Sweden. Supported by a clinical research grant from the Stockholm County Council and an unrestricted grant from Roche Sweden. Roche Sweden also provided the 2 study drugs ribavirin and epoetin beta but had no role in the study design, data collection, analyses, or report of the study results. The authors declare no conflict of interest. Correspondence: Karin Lindahl, MD, PhD, I73, Clinic of Infectious Diseases, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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INTRODUCTION Until recently, the standard of care (SOC) treatment used for patients with chronic hepatitis C genotype 1 infection has been peginterferon (peg-IFN) combined with ribavirin. Sustained viral response (SVR) has generally been achieved in 40%–50% of patients.1,2 Patients with high ribavirin plasma concentrations have shown higher SVR rates.3 However, increasing the dose of ribavirin has been hampered by the risk for toxicity and side effects, mainly anaemia.4 Optimization of ribavirin plasma concentrations during the first treatment week seems to increase SVR rates.5 Standard dosing of ribavirin according to body weight results in a large variation of ribavirin plasma concentrations. We have demonstrated that an individualized ribavirin dosing, mainly taking renal function into consideration, is a more suitable way to dose ribavirin.6 In a pilot study, we found that very high doses of ribavirin, calculated according to renal function, resulted in seemingly increased SVR rates.7 First-generation protease inhibitors (telaprevir, boceprevir) increase SVR rates in treatment-naive patients with genotype 1 infection by approximately 30% when added to peg-IFN and ribavirin.8,9 Null responders with advanced liver fibrosis/cirrhosis, however, respond less favourable. Hence, only 15% of cirrhotic null responders reach SVR with triple therapy including a protease inhibitor.10 The aim of this study was to investigate whether patients with a previous nonresponse to SOC treatment with ribavirin dosed 1000/1200 mg daily according to body weight would respond to high-dose ribavirin treatment, with the dose individualized and concentration monitored. To this end, we conducted a prospective, open-label, single-centre, pilot study in patients previously failing standard treatment with peg-IFN and ribavirin to investigate the tolerability, the early viral kinetics, and the SVR response of an individualized, concentration-monitored, high-dose ribavirin scheme aiming at a plasma target concentration of more than 15 mmol/L of ribavirin combined with standarddosed peg-IFN.
MATERIALS AND METHODS Study Design The study is a prospective, open-label, single-centre pilot study, including 20 previous nonresponders [patients who failed to reach hepatitis C virus ribonucleic acid
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Lindahl et al
(HCV RNA) , 50 IU m/L] during SOC treatment. All patients were given peg-IFN alpha-2a and an individualized ribavirin dose aiming to reach a plasma concentration of .15 mmol/L during 48 weeks. All patients were also given erythropoietin in an escalating dose 2 weeks before initiation of the antiviral treatment. All patients were closely monitored for development of anemia.
Patients Twenty patients older than 18 years with genotype 1 infection who had failed to achieve a negative HCV RNA (,50 IU/mL Roche Amplicor) during previous treatment with peg-IFN alpha-2a and ribavirin were included. All patients had completed at least a 12-week long previous course of peg-IFN 180 mcg/wk and ribavirin 1200 mg/d. No growth factors were used and no dose modifications were undertaken during this treatment. All patients had a liver biopsy consistent with chronic hepatitis C, excluding iron overload. Liver biopsies were classified according to inflammation (grade) and fibrosis (stage) on a noncontinuous scale from 0 to 4, using the scoring system of Batts and Ludwig.11 All patients were negative for HIV, hepatitis A and B, and had a platelet count of more than 90 · 109/L at screening. Patients with a hemoglobin level of less than 120 g/L in women or 130 g/L in men at screening were excluded. Patients prone to develop anemia or with a low tolerance to an acute decrease in hemoglobin 30–40 g/L were excluded as well as patients with a creatinine clearance of ,50 mL/min at screening.
Treatment All patients were treated with a starting dose of 180 mcg peginterferon alpha-2a (Pegasys; Roche) once weekly. Because of an anticipated saturable absorption of ribavirin,12,13 ribavirin (Copegus; Roche) was given thrice daily. The initial ribavirin dose was calculated from a revised formula based on a regression model in a population pharmacokinetic analyses in which renal function and body weight were included.6
Ribavirin Calculation Formula
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subcutaneously once weekly starting 2 weeks before ribavirin was started; the EPO dose was increased to 30,000 IU weekly. In patients with pronounced anemia, a maximum EPO dose of 60,000 IU per week was given with supplementary oral iron.
Viral Kinetics HCV RNA was assessed at baseline, at treatment week 1, 4, 8, 12, 24, 36, and 48, and after 4, 12, and 24 weeks of follow-up. We defined early viral response (EVR) as having at least a 2 log decline in HCV RNA levels at week 12. Treatment was stopped if HCV RNA was still detectable at treatment week 24. HCV genotyping was performed with an in-house method.15 The viral kinetics during latest SOC treatment episode was chosen as a comparison with the individualized dosing, if the patient had been treated more than once. All HCV RNA analyses were performed with the TaqMan real-time PCR (Roche Diagnostics, Branchburg, NJ) with a detection limit of 15 IU/mL.
Pharmacokinetics Plasma concentrations of ribavirin were obtained at weeks 2, 4, 6, 8, and 12 and hereafter every fourth week during treatment or if dose adjustments were made. Plasma samples were collected 12 hours after ribavirin administration, and ribavirin concentrations were measured using a high-performance liquid chromatography method.6
Safety Assessments All patients were evaluated by physical examination, vital signs, and laboratory test every week or the first 2 weeks and every second week thereafter. After 8 treatment weeks, the patients were monitored every fourth week if there were no adverse events or treatment adjustments. Laboratory tests included hemoglobin, neutrophils, prothrombine complex, bilirubin, creatinine, and transaminases. Safety assessments were made by an independent evaluation board when 10 patients had completed 12-week treatment. Peg-IFN was reduced by steps of 45 mcg in patients who developed interferon-related adverse events, according to label. Ribavirin was discontinued for 1 week, and blood transfusions were given if the hemoglobin level fell below 80 g/L.
0:244 · ribavirin target concentration · dosing interval · ½0:137 · CLcreat þ ð0:0271 · body weightÞ ¼ ribavirin dose:
The target ribavirin concentration was set to 16 mmol/L, the dosing interval to 8 hours, creatinine clearance was estimated according to the Cockroft–Gault equation14 adjusted for the creatinine method used, and body weight was measured in kilograms. When necessary, the ribavirin dose was increased to reach the target concentration, based on plasma concentration monitoring. Ribavirin dose reductions were only undertaken because of adverse events. The starting dose of recombinant erythropoietin (EPO) beta (NeoRecormon; Roche) was 10,000 IU administered
Statistical Analysis
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All patients who received at least 1 dose of the study drugs were included in the analysis. The primary end point was the difference in treatment outcome between SOC treatment and concentration-monitored high-dose ribavirin, measured as SVR. The secondary end point was the viral kinetics during the initial 12 weeks of treatment and evaluation of the performance of the modified ribavirin dosing formula.
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Ther Drug Monit Volume 37, Number 6, December 2015
Paired Student t test was used for the comparison of the HCV RNA log decline during the initial 12-week treatment between the individualized and standard ribavirin dosing scheme. The sample size was based on the assumption that the concentration-monitored high-dose ribavirin scheme would increase the SVR rate to 50% compared with SOC treatment that was estimated to result in an SVR rate of 20% at best. This gave a calculated sample size of 23 patients, all their own controls, and a statistical power of 90% to detect such a difference.
Study Conduct The study was conducted at a single centre according to the criteria of the Declaration of Helsinki, and all patients provided written informed consent before the study was started. The Regional Ethics Review Board in Stockholm and the Swedish MPA approved the protocol. The study is registered at the European Clinical Trials Database, EurdraCT no 2006-003396-13 according to the EMA guidelines.
RESULTS Patient Population All eligible patients identified at the Infectious Diseases Outpatient Department treatment records were informed of the study protocol. Twenty-one patients were screened and all but one were enrolled in the study between November 2006 and January 2008. Sixteen men and 4 women with a mean age of 52 years (range, 34–63 years) and a mean body mass index of 27 kg/m2 (21–33 kg/m2) started treatment. Sixty percent had advanced fibrosis $F3. Baseline demographics of the patients
TABLE 1. Baseline Demographics in 20 Patients (n = 20) With Chronic Hepatitis C Genotype 1 Previous Nonresponders Age, mean (range), yrs Sex males/females (n) Body mass index, mean (range), kg/m2 Creatinine clearance, mean (range), mL/min Genotype 1A/1B (n) Liver histology (n) Mild fibrosis grade I–II Severe fibrosis grade III–IV Baseline HCV RNA, mean (range), IU/mL IL28B (Dukes Single nucleotide polymorphism) (n) CC CT TT Number of previous treatment episodes (n) 1 2 3
52 (34–63) 16/4 27.3 (21.3–33.3) 130 (89–193) 13/6 8 12 6.3 · 106 (217,000–19.9 · 106)
2 14 4
12 5 3
C, cytosine; T, thymine.
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High-Dose Ribavirin
are given in Table 1. No patient was lost during follow-up. Two patients stopped treatment at week 15–17 because of lack of viral response and 1 because of side effects.
Ribavirin Dosing and Plasma Concentrations The initial dose of ribavirin was calculated from the dose estimating formula, which aimed to achieve a steadystate concentration of .15 mmol/L (see Materials and Methods). A mean ribavirin dose of 2130 mg/d (1600–3000 mg/d) was given, as shown in Table 2. At week 4, the mean ribavirin plasma concentration was 12.9 mmol/L (8.7–23.8 mmol/L). Therefore, a gradual dose increase was given to 13 patients, resulting in a mean ribavirin plasma concentration of 16.6 mmol/L at week 12. Five patients reached the target concentration with a minor ribavirin dose adjustment of 200 mg. The dose calculating formula overestimated the final dose in 1 patient. Fifteen patients reached the ribavirin target concentration at treatment week 6, and all patients except 1 reached the target ribavirin concentration of .15 mmol/L before treatment week 12. The final steady-state daily ribavirin dose varied from 1400 to 4400 mg.
Efficacy, Viral Kinetics Viral response is shown in Table 2. With high-dose concentration-monitored ribavirin treatment, 80% of patients (n = 16) achieved an EVR, whereof 2 achieved complete cEVR defined as negative HCV RNA at treatment week 12. Twelve patients (60%) were negative for HCV RNA at treatment week 24. Sixty percent of the patients (n = 12) completed 48 weeks of treatment, and 5 patients stopped treatment at week 25 because of nonresponse. Nine patients were negative for HCV RNA at the end of treatment, and 1 achieved SVR. Concentration-monitored high-dose ribavirin resulted in a mean 3.13 IU/mL log decline and standard-dosed ribavirin resulted in a mean 2.05 IU/mL log decline of HCV RNA at week 12 (P , 0.001) (Fig. 1).
Safety Hemoglobin levels decreased during treatment, as shown in Table 2. Two patients received blood transfusions on 5 and 3 occasions, respectively, because of anemia (nadir Hb level 68 and 71 g/L). On each occasion, ribavirin was temporarily discontinued for 1 week. No blood transfusions were needed before treatment week 13. All patients received 10,000 IU erythropoietin starting 2 weeks before initiation of the antiviral treatment, resulting in a mean 10 g/L increase in hemoglobin levels. For safety reasons, EPO was started 2 weeks before ribavirin acknowledging the fact that it takes at least 2 weeks for the erythropoiesis to respond to EPO and to avoid dramatic onset of ribavirin-induced hemolysis in the first treatment weeks in a setting of patients with advanced liver disease, vulnerable to anemia. Most patients required escalating doses of erythropoietin during treatment to avoid severe anemia (Table 2). One patient stopped treatment because of peg-IFN–related adverse events, mainly fatigue and muscle–joint pain at treatment week 14. No other severe adverse events were recorded. Peg-IFN was reduced in
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TABLE 2. Daily Ribavirin Dose, Ribavirin Concentrations, Viral Load, Viral Response, Hemoglobin Levels, and Erythropoietin Use in 20 Patients With Chronic Hepatitis C, Genotype 1, During Treatment With Peginterferon and High-Dose Ribavirin Treatment Week
0
4
12
24
48
No of patients on treatment Daily ribavirin dose, mean (range), mg Ribavirin concentration, mean (range), mmol/L Viral load, mean (range), IU/mL Viral response
n = 20
n = 20
n = 20
n = 17
n = 13
2130 (1600–3000)
2705 (1800–4000)
2695 (1400–3600)
2825 (1400–4400)
2567 (1200–4000)
—
12.9 (8.7–23.8)
16.6 (10.6–23)
15.7 (9.8–22.4); n = 17
11.2 (0.5–19.2); n = 11
6.6 · 106; n = 20 (217,000–19.9 · 106)
1.4 · 106; n = 20 (11,700–5.6 · 106)
71,200; n = 5 (1730–270,000) HCV RNA = 0 (n = 12)
131,800; n = 3 (2450–354,000) HCV RNA = 0 (n = 9)
101 (73–130)
111 (92–132)
Hemoglobin, mean (range), g/dL Erythropoietin use 10,000 IU/wk 30,000 IU/wk 40,000 IU/wk 60,000 IU/wk
163 (146–184)
134 (87–178)
n=1 n = 19
n=1 n = 19
88,500; n = 18 (30–1.1 · 106) HCV RNA = 0 (n = 2) HCV . 2 log drop (n = 14) 110 (81–160)
n=2 n = 13 n=2 n=3
n=9 n=2 n=6
FU 24
HCV RNA = 0 (n = 1)
n=6 n=1 n=6
FU, follow-up, 24 weeks after treatment.
2 patients because of neutropenia, for 1 or 2 weeks on 3 occasions and for 2 weeks on 1 occasion.
In this study, we found that an individualized concentration-guided high-dose ribavirin scheme increased the initial viral decline as compared with a standard ribavirin scheme dosed according to body weight (1000/1200 mg daily). This is consistent with our earlier finding of an increased SVR rate in a small group of naive patients treated with very high ribavirin doses.7 All our patients served as their own controls, and the response to “high-dose” ribavirin was significantly larger than to the previous response when ribavirin was given at standard doses. At week 12, the mean log drop in HCV RNA with high versus standard-dosed ribavirin was 3.1 and 2.0, respectively (P , 0.001). Furthermore, with high-dose ribavirin treatment, 60% of the patients achieved nondetectable HCV RNA levels at treatment week 24, a remarkable result in this group of patients who previously failed to achieve a response with standard-dosed ribavirin, indicating an antiviral effect of ribavirin when given at higher doses compared with a standard dose. Although the on-treatment effect on HCV RNA increased significantly with high-dose ribavirin, this did not translate in an increased SVR outcome because of only 1 patient achieved this end point. Apparently, the increased virological effect was not sufficient to result in a favorable long-term outcome in this highly selected and difficult-to-treat patient population, consisting of previous nonresponders, many with advanced fibrosis, and the majority with genotype 1a.
A limitation of our study is the relatively small number of patients and the noncontrolled and nonrandomized design. However, the fact that all patients served as their own controls, as well as the negative outcome, suggest that the study was not biased toward a beneficial outcome. Indeed, all patients received the same peg-IFN dose and brand, and the only change in treatment scheme was the ribavirin dose. The main side effect noted among our patients was, as expected, anemia. However, only 2 patients required repeated blood transfusions and short discontinuations of ribavirin dosing, whereas in the other 18 patients, the anemia was controlled by high doses of erythropoietin. No further discontinuations because of anemia were needed, and no severe adverse advents were recorded. In this study, the investigators were highly experienced in therapeutic drug monitoring and utilization of the high-dose ribavirin treatment model, a prerequisite to perform such a study. This treatment model, furthermore, requires access to specialized laboratory analysis, and frequent safety monitoring of the patients, and should only be performed by centers with extensive treatment experience, preferably within the context of a clinical trial. With the introduction of the first-generation protease inhibitors for the treatment of genotype 1 in 2011, a significant improvement of the response rate was achieved. However, in patients with a previous nonresponse with cirrhosis, the cure rate remains low, in the order of 15%. During 2014, new directacting antiviral agents (DAAs) will probably become available, hopefully, further improving response rates for difficult-to-treat patients with chronic hepatitis C. There are, however, so far only scarce data on the results with direct-acting antiviral
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DISCUSSION
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High-Dose Ribavirin
and may be a useful tool when dosing of ribavirin is essential, for instance, patients with end-stage liver disease with no other treatment option besides high-dosed ribavirin, at the time of the study, also when lower levels are aimed at for safety reasons in the posttransplant setting19 and patients with impaired renal function. In some patients, the ribavirin dose had to be adjusted, mostly upwards to reach the intended plasma ribavirin concentration. This highlights the importance of ribavirin plasma concentration monitoring.
CONCLUSIONS We found that an individualized high ribavirin dose scheme resulted in a more pronounced early viral HCV RNA decline than a standard-dose ribavirin scheme during the initial 12 weeks of peg-IFN and ribavirin treatment. This suggest that patients with a previous nonresponse to SOC treatment with ribavirin dosed according to body weight will respond better to a regime using an individualized and concentration-monitored (“high-dose ribavirin”) regimen. This regime is safe provided that close monitoring of anemia is undertaken and that treatment with erythropoietin is given before initiation of the antiviral treatment and can be used in difficult-to-treat patient on an individual basis. FIGURE 1. HCV RNA log drop for 20 patients with chronic hepatitis C. In the figure, each patient is represented by a horizontal bar. The left end shows the log drop at week 12 during previous treatment with ribavirin dosed in a standard fashion, and the right end of the bar shows the log drop at week 12 during the study when patients were given “highdose” ribavirin, dosed individually and concentration monitored.
REFERENCES
agents in the most difficult-to-treat patients, including null responders with cirrhosis; hence, ribavirin will probably be used in many combinations for difficult-to-treat patient in the future. Furthermore, regulatory and financial aspects will probably restrict and reduce treatment options and combinations in many parts of the world, rendering ribavirin and pegIFN much valued alternative treatments. The dosing of ribavirin has been a matter of debate. There are several indications that the response rate improves for patients with genotype 1 with increasing concentrations when used in combination with peg-IFN.3,5,7,16,17 Thus, avoiding dose reductions in order not to jeopardize the response rates has been emphasized when ribavirin is used in combination with peg-IFN. In studies with first-generation protease inhibitors, such as telaprevir, small reductions in the ribavirin dose has not hampered the SVR rates. This might be explained by an interaction between telaprevir and ribavirin, resulting in higher ribavirin concentrations.18 In line with this, we observed higher than normal ribavirin concentrations in patients on triple therapy including a protease inhibitor (unpublished data). In this study, the dosing of ribavirin was individualized, aiming at a high plasma concentration of .15 mmol/L. To reach this, the initial dosing was calculated from a formula taking body weight and renal function into account. The formula performed reasonably well in predicting the correct dose
1. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358: 958–965. 2. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347: 975–982. 3. Jen J, Laughlin M, Chung C, et al. Ribavirin dosing in chronic hepatitis C: application of population pharmacokinetic-pharmacodynamic models. Clin Pharmacol Ther. 2002;72:349–361. 4. Lindahl K, Schvarcz R, Bruchfeld A, et al. Evidence that plasma concentration rather than dose per kilogram body weight predicts ribavirininduced anaemia. J Viral Hepat. 2004;11:84–87. 5. Jin R, Fossler MJ, McHutchison JG, et al. Population pharmacokinetics and pharmacodynamics of ribavirin in patients with chronic hepatitis C genotype 1 infection. AAPS J. 2012;14:571–580. 6. Bruchfeld A, Lindahl K, Schvarcz R, et al. Dosage of ribavirin in patients with hepatitis C should be based on renal function: a population pharmacokinetic analysis. Ther Drug Monit. 2002;24: 701–708. 7. Lindahl K, Stahle L, Bruchfeld A, et al. High-dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C. Hepatology. 2005;41:275–279. 8. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364: 1195–1206. 9. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–2416. 10. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417–2428. 11. Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol. 1995;19:1409–1417. 12. Moss AM, Endres CJ, Ruiz-Garcia A, et al. Role of the equilibrative and concentrative nucleoside transporters in the intestinal absorption of the nucleoside drug, ribavirin, in wild-type and Ent1(-/-) mice. Mol Pharm. 2012;9:2442–2449. 13. Lindahl K. Ribavirin-Dose and Concentration in Treatment of Chronic Hepatitis C Infected Patients. [Doctoral thesis]. Stockholm, Sweden: Karolinska University Press; 2005. ISBN 91-7140-348-5.
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14. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31. 15. Yun Z, Lara C, Johansson B, et al. Discrepancy of hepatitis C virus genotypes as determined by phylogenetic analysis of partial NS5 and core sequences. J Med Virol. 1996;49:155–160. 16. Shiffman ML, Salvatore J, Hubbard S, et al. Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin alpha. Hepatology. 2007;46:371–379.
17. Pawlotsky JM, Dahari H, Neumann AU, et al. Antiviral action of ribavirin in chronic hepatitis C. Gastroenterology. 2004;126:703–714. 18. Hammond K, Jimmerson L, MacBrayne C, et al. Increased Plasma and intracellular ribavirin concentrations associated with telaprevir use. CROI 2013. abstract 34, Atlanta, GA, 3–6 March 2013. 19. Ackefors M, Gjertsen H, Wernerson A, et al. Concentration guided ribavirin dosing with darbepoetin support and Peg-IFN alfa-2a for treatment of hepatitis C recurrence after liver transplantation. J Viral Hepat. 2012:19:635–639.
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High-Dose Ribavirin Enhances Early Virological Response in Hepatitis C Genotype 1–Infected Patients Karin Lindahl, MD, PhD,* Erika Hörnfeld, MD,* Lars Ståhle, MD,† Tony Carlsson, MD, PhD,* Ola Weiland, MD, Prof,* Åsa Parke, MD,* and Robert Schvarcz, MD, Assoc Prof*
Background: The aim of the study was to investigate whether patients with a previous nonresponse to standard of care treatment with ribavirin dosed according to body weight would respond to a high individualized dose of concentration-monitored ribavirin.
Methods: Previous nonresponders to standard of care treatment with peginterferon (peg-IFN) and ribavirin were included. Ribavirin was dosed aiming at a plasma concentration of .15 mmol/L. The initial ribavirin dose was calculated from a formula based on renal function and body weight. Erythropoietin treatment was started 2 weeks before antiviral therapy. Results: Twenty patients (16 men and 4 women) with a mean age of 52 years were included. Sixty percent had advanced fibrosis. Eighty percent of patients achieved an early viral response, and 60% were negative for hepatitis C virus ribonucleic acid (HCV RNA) at treatment week 24. High-dose ribavirin resulted in a significantly increased HCV RNA drop at week 12 (mean: 3.13 versus 2.05 IU/mL; P , 0.001). Nine patients were negative for HCV RNA at the end of treatment, and 1 achieved sustained viral response. The final steady-state daily dose of ribavirin varied from 1400 to 4400 mg. Hemoglobin levels decreased during treatment, mean Hb 163, 134, and 110 g/L at week 0, 4, and 12, respectively. Two patients received blood transfusions. No other severe adverse events were recorded. Conclusions: An individualized high ribavirin dose resulted in a more pronounced early viral HCV RNA decline than a standarddose ribavirin scheme. This regime is safe provided that close monitoring of anemia is undertaken and that treatment with erythropoietin is given. Key Words: hepatitis C, nonresponders, ribavirin, pharmacokinetics (Ther Drug Monit 2015;37:745–750)
Received for publication March 12, 2014; accepted March 12, 2015. From the *Division of Infectious Diseases, Department of Internal Medicine, Karolinska Institutet, Karolinska University Hospital; and †Division of Clinical Pharmacology, Department of Medical Laboratory Sciences, Karolinska Institutet, Stockholm, Sweden. Supported by a clinical research grant from the Stockholm County Council and an unrestricted grant from Roche Sweden. Roche Sweden also provided the 2 study drugs ribavirin and epoetin beta but had no role in the study design, data collection, analyses, or report of the study results. The authors declare no conflict of interest. Correspondence: Karin Lindahl, MD, PhD, I73, Clinic of Infectious Diseases, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Ther Drug Monit Volume 37, Number 6, December 2015
INTRODUCTION Until recently, the standard of care (SOC) treatment used for patients with chronic hepatitis C genotype 1 infection has been peginterferon (peg-IFN) combined with ribavirin. Sustained viral response (SVR) has generally been achieved in 40%–50% of patients.1,2 Patients with high ribavirin plasma concentrations have shown higher SVR rates.3 However, increasing the dose of ribavirin has been hampered by the risk for toxicity and side effects, mainly anaemia.4 Optimization of ribavirin plasma concentrations during the first treatment week seems to increase SVR rates.5 Standard dosing of ribavirin according to body weight results in a large variation of ribavirin plasma concentrations. We have demonstrated that an individualized ribavirin dosing, mainly taking renal function into consideration, is a more suitable way to dose ribavirin.6 In a pilot study, we found that very high doses of ribavirin, calculated according to renal function, resulted in seemingly increased SVR rates.7 First-generation protease inhibitors (telaprevir, boceprevir) increase SVR rates in treatment-naive patients with genotype 1 infection by approximately 30% when added to peg-IFN and ribavirin.8,9 Null responders with advanced liver fibrosis/cirrhosis, however, respond less favourable. Hence, only 15% of cirrhotic null responders reach SVR with triple therapy including a protease inhibitor.10 The aim of this study was to investigate whether patients with a previous nonresponse to SOC treatment with ribavirin dosed 1000/1200 mg daily according to body weight would respond to high-dose ribavirin treatment, with the dose individualized and concentration monitored. To this end, we conducted a prospective, open-label, single-centre, pilot study in patients previously failing standard treatment with peg-IFN and ribavirin to investigate the tolerability, the early viral kinetics, and the SVR response of an individualized, concentration-monitored, high-dose ribavirin scheme aiming at a plasma target concentration of more than 15 mmol/L of ribavirin combined with standarddosed peg-IFN.
MATERIALS AND METHODS Study Design The study is a prospective, open-label, single-centre pilot study, including 20 previous nonresponders [patients who failed to reach hepatitis C virus ribonucleic acid
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Lindahl et al
(HCV RNA) , 50 IU m/L] during SOC treatment. All patients were given peg-IFN alpha-2a and an individualized ribavirin dose aiming to reach a plasma concentration of .15 mmol/L during 48 weeks. All patients were also given erythropoietin in an escalating dose 2 weeks before initiation of the antiviral treatment. All patients were closely monitored for development of anemia.
Patients Twenty patients older than 18 years with genotype 1 infection who had failed to achieve a negative HCV RNA (,50 IU/mL Roche Amplicor) during previous treatment with peg-IFN alpha-2a and ribavirin were included. All patients had completed at least a 12-week long previous course of peg-IFN 180 mcg/wk and ribavirin 1200 mg/d. No growth factors were used and no dose modifications were undertaken during this treatment. All patients had a liver biopsy consistent with chronic hepatitis C, excluding iron overload. Liver biopsies were classified according to inflammation (grade) and fibrosis (stage) on a noncontinuous scale from 0 to 4, using the scoring system of Batts and Ludwig.11 All patients were negative for HIV, hepatitis A and B, and had a platelet count of more than 90 · 109/L at screening. Patients with a hemoglobin level of less than 120 g/L in women or 130 g/L in men at screening were excluded. Patients prone to develop anemia or with a low tolerance to an acute decrease in hemoglobin 30–40 g/L were excluded as well as patients with a creatinine clearance of ,50 mL/min at screening.
Treatment All patients were treated with a starting dose of 180 mcg peginterferon alpha-2a (Pegasys; Roche) once weekly. Because of an anticipated saturable absorption of ribavirin,12,13 ribavirin (Copegus; Roche) was given thrice daily. The initial ribavirin dose was calculated from a revised formula based on a regression model in a population pharmacokinetic analyses in which renal function and body weight were included.6
Ribavirin Calculation Formula
Ther Drug Monit Volume 37, Number 6, December 2015
subcutaneously once weekly starting 2 weeks before ribavirin was started; the EPO dose was increased to 30,000 IU weekly. In patients with pronounced anemia, a maximum EPO dose of 60,000 IU per week was given with supplementary oral iron.
Viral Kinetics HCV RNA was assessed at baseline, at treatment week 1, 4, 8, 12, 24, 36, and 48, and after 4, 12, and 24 weeks of follow-up. We defined early viral response (EVR) as having at least a 2 log decline in HCV RNA levels at week 12. Treatment was stopped if HCV RNA was still detectable at treatment week 24. HCV genotyping was performed with an in-house method.15 The viral kinetics during latest SOC treatment episode was chosen as a comparison with the individualized dosing, if the patient had been treated more than once. All HCV RNA analyses were performed with the TaqMan real-time PCR (Roche Diagnostics, Branchburg, NJ) with a detection limit of 15 IU/mL.
Pharmacokinetics Plasma concentrations of ribavirin were obtained at weeks 2, 4, 6, 8, and 12 and hereafter every fourth week during treatment or if dose adjustments were made. Plasma samples were collected 12 hours after ribavirin administration, and ribavirin concentrations were measured using a high-performance liquid chromatography method.6
Safety Assessments All patients were evaluated by physical examination, vital signs, and laboratory test every week or the first 2 weeks and every second week thereafter. After 8 treatment weeks, the patients were monitored every fourth week if there were no adverse events or treatment adjustments. Laboratory tests included hemoglobin, neutrophils, prothrombine complex, bilirubin, creatinine, and transaminases. Safety assessments were made by an independent evaluation board when 10 patients had completed 12-week treatment. Peg-IFN was reduced by steps of 45 mcg in patients who developed interferon-related adverse events, according to label. Ribavirin was discontinued for 1 week, and blood transfusions were given if the hemoglobin level fell below 80 g/L.
0:244 · ribavirin target concentration · dosing interval · ½0:137 · CLcreat þ ð0:0271 · body weightÞ ¼ ribavirin dose:
The target ribavirin concentration was set to 16 mmol/L, the dosing interval to 8 hours, creatinine clearance was estimated according to the Cockroft–Gault equation14 adjusted for the creatinine method used, and body weight was measured in kilograms. When necessary, the ribavirin dose was increased to reach the target concentration, based on plasma concentration monitoring. Ribavirin dose reductions were only undertaken because of adverse events. The starting dose of recombinant erythropoietin (EPO) beta (NeoRecormon; Roche) was 10,000 IU administered
Statistical Analysis
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All patients who received at least 1 dose of the study drugs were included in the analysis. The primary end point was the difference in treatment outcome between SOC treatment and concentration-monitored high-dose ribavirin, measured as SVR. The secondary end point was the viral kinetics during the initial 12 weeks of treatment and evaluation of the performance of the modified ribavirin dosing formula.
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Ther Drug Monit Volume 37, Number 6, December 2015
Paired Student t test was used for the comparison of the HCV RNA log decline during the initial 12-week treatment between the individualized and standard ribavirin dosing scheme. The sample size was based on the assumption that the concentration-monitored high-dose ribavirin scheme would increase the SVR rate to 50% compared with SOC treatment that was estimated to result in an SVR rate of 20% at best. This gave a calculated sample size of 23 patients, all their own controls, and a statistical power of 90% to detect such a difference.
Study Conduct The study was conducted at a single centre according to the criteria of the Declaration of Helsinki, and all patients provided written informed consent before the study was started. The Regional Ethics Review Board in Stockholm and the Swedish MPA approved the protocol. The study is registered at the European Clinical Trials Database, EurdraCT no 2006-003396-13 according to the EMA guidelines.
RESULTS Patient Population All eligible patients identified at the Infectious Diseases Outpatient Department treatment records were informed of the study protocol. Twenty-one patients were screened and all but one were enrolled in the study between November 2006 and January 2008. Sixteen men and 4 women with a mean age of 52 years (range, 34–63 years) and a mean body mass index of 27 kg/m2 (21–33 kg/m2) started treatment. Sixty percent had advanced fibrosis $F3. Baseline demographics of the patients
TABLE 1. Baseline Demographics in 20 Patients (n = 20) With Chronic Hepatitis C Genotype 1 Previous Nonresponders Age, mean (range), yrs Sex males/females (n) Body mass index, mean (range), kg/m2 Creatinine clearance, mean (range), mL/min Genotype 1A/1B (n) Liver histology (n) Mild fibrosis grade I–II Severe fibrosis grade III–IV Baseline HCV RNA, mean (range), IU/mL IL28B (Dukes Single nucleotide polymorphism) (n) CC CT TT Number of previous treatment episodes (n) 1 2 3
52 (34–63) 16/4 27.3 (21.3–33.3) 130 (89–193) 13/6 8 12 6.3 · 106 (217,000–19.9 · 106)
2 14 4
12 5 3
C, cytosine; T, thymine.
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High-Dose Ribavirin
are given in Table 1. No patient was lost during follow-up. Two patients stopped treatment at week 15–17 because of lack of viral response and 1 because of side effects.
Ribavirin Dosing and Plasma Concentrations The initial dose of ribavirin was calculated from the dose estimating formula, which aimed to achieve a steadystate concentration of .15 mmol/L (see Materials and Methods). A mean ribavirin dose of 2130 mg/d (1600–3000 mg/d) was given, as shown in Table 2. At week 4, the mean ribavirin plasma concentration was 12.9 mmol/L (8.7–23.8 mmol/L). Therefore, a gradual dose increase was given to 13 patients, resulting in a mean ribavirin plasma concentration of 16.6 mmol/L at week 12. Five patients reached the target concentration with a minor ribavirin dose adjustment of 200 mg. The dose calculating formula overestimated the final dose in 1 patient. Fifteen patients reached the ribavirin target concentration at treatment week 6, and all patients except 1 reached the target ribavirin concentration of .15 mmol/L before treatment week 12. The final steady-state daily ribavirin dose varied from 1400 to 4400 mg.
Efficacy, Viral Kinetics Viral response is shown in Table 2. With high-dose concentration-monitored ribavirin treatment, 80% of patients (n = 16) achieved an EVR, whereof 2 achieved complete cEVR defined as negative HCV RNA at treatment week 12. Twelve patients (60%) were negative for HCV RNA at treatment week 24. Sixty percent of the patients (n = 12) completed 48 weeks of treatment, and 5 patients stopped treatment at week 25 because of nonresponse. Nine patients were negative for HCV RNA at the end of treatment, and 1 achieved SVR. Concentration-monitored high-dose ribavirin resulted in a mean 3.13 IU/mL log decline and standard-dosed ribavirin resulted in a mean 2.05 IU/mL log decline of HCV RNA at week 12 (P , 0.001) (Fig. 1).
Safety Hemoglobin levels decreased during treatment, as shown in Table 2. Two patients received blood transfusions on 5 and 3 occasions, respectively, because of anemia (nadir Hb level 68 and 71 g/L). On each occasion, ribavirin was temporarily discontinued for 1 week. No blood transfusions were needed before treatment week 13. All patients received 10,000 IU erythropoietin starting 2 weeks before initiation of the antiviral treatment, resulting in a mean 10 g/L increase in hemoglobin levels. For safety reasons, EPO was started 2 weeks before ribavirin acknowledging the fact that it takes at least 2 weeks for the erythropoiesis to respond to EPO and to avoid dramatic onset of ribavirin-induced hemolysis in the first treatment weeks in a setting of patients with advanced liver disease, vulnerable to anemia. Most patients required escalating doses of erythropoietin during treatment to avoid severe anemia (Table 2). One patient stopped treatment because of peg-IFN–related adverse events, mainly fatigue and muscle–joint pain at treatment week 14. No other severe adverse events were recorded. Peg-IFN was reduced in
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Lindahl et al
TABLE 2. Daily Ribavirin Dose, Ribavirin Concentrations, Viral Load, Viral Response, Hemoglobin Levels, and Erythropoietin Use in 20 Patients With Chronic Hepatitis C, Genotype 1, During Treatment With Peginterferon and High-Dose Ribavirin Treatment Week
0
4
12
24
48
No of patients on treatment Daily ribavirin dose, mean (range), mg Ribavirin concentration, mean (range), mmol/L Viral load, mean (range), IU/mL Viral response
n = 20
n = 20
n = 20
n = 17
n = 13
2130 (1600–3000)
2705 (1800–4000)
2695 (1400–3600)
2825 (1400–4400)
2567 (1200–4000)
—
12.9 (8.7–23.8)
16.6 (10.6–23)
15.7 (9.8–22.4); n = 17
11.2 (0.5–19.2); n = 11
6.6 · 106; n = 20 (217,000–19.9 · 106)
1.4 · 106; n = 20 (11,700–5.6 · 106)
71,200; n = 5 (1730–270,000) HCV RNA = 0 (n = 12)
131,800; n = 3 (2450–354,000) HCV RNA = 0 (n = 9)
101 (73–130)
111 (92–132)
Hemoglobin, mean (range), g/dL Erythropoietin use 10,000 IU/wk 30,000 IU/wk 40,000 IU/wk 60,000 IU/wk
163 (146–184)
134 (87–178)
n=1 n = 19
n=1 n = 19
88,500; n = 18 (30–1.1 · 106) HCV RNA = 0 (n = 2) HCV . 2 log drop (n = 14) 110 (81–160)
n=2 n = 13 n=2 n=3
n=9 n=2 n=6
FU 24
HCV RNA = 0 (n = 1)
n=6 n=1 n=6
FU, follow-up, 24 weeks after treatment.
2 patients because of neutropenia, for 1 or 2 weeks on 3 occasions and for 2 weeks on 1 occasion.
In this study, we found that an individualized concentration-guided high-dose ribavirin scheme increased the initial viral decline as compared with a standard ribavirin scheme dosed according to body weight (1000/1200 mg daily). This is consistent with our earlier finding of an increased SVR rate in a small group of naive patients treated with very high ribavirin doses.7 All our patients served as their own controls, and the response to “high-dose” ribavirin was significantly larger than to the previous response when ribavirin was given at standard doses. At week 12, the mean log drop in HCV RNA with high versus standard-dosed ribavirin was 3.1 and 2.0, respectively (P , 0.001). Furthermore, with high-dose ribavirin treatment, 60% of the patients achieved nondetectable HCV RNA levels at treatment week 24, a remarkable result in this group of patients who previously failed to achieve a response with standard-dosed ribavirin, indicating an antiviral effect of ribavirin when given at higher doses compared with a standard dose. Although the on-treatment effect on HCV RNA increased significantly with high-dose ribavirin, this did not translate in an increased SVR outcome because of only 1 patient achieved this end point. Apparently, the increased virological effect was not sufficient to result in a favorable long-term outcome in this highly selected and difficult-to-treat patient population, consisting of previous nonresponders, many with advanced fibrosis, and the majority with genotype 1a.
A limitation of our study is the relatively small number of patients and the noncontrolled and nonrandomized design. However, the fact that all patients served as their own controls, as well as the negative outcome, suggest that the study was not biased toward a beneficial outcome. Indeed, all patients received the same peg-IFN dose and brand, and the only change in treatment scheme was the ribavirin dose. The main side effect noted among our patients was, as expected, anemia. However, only 2 patients required repeated blood transfusions and short discontinuations of ribavirin dosing, whereas in the other 18 patients, the anemia was controlled by high doses of erythropoietin. No further discontinuations because of anemia were needed, and no severe adverse advents were recorded. In this study, the investigators were highly experienced in therapeutic drug monitoring and utilization of the high-dose ribavirin treatment model, a prerequisite to perform such a study. This treatment model, furthermore, requires access to specialized laboratory analysis, and frequent safety monitoring of the patients, and should only be performed by centers with extensive treatment experience, preferably within the context of a clinical trial. With the introduction of the first-generation protease inhibitors for the treatment of genotype 1 in 2011, a significant improvement of the response rate was achieved. However, in patients with a previous nonresponse with cirrhosis, the cure rate remains low, in the order of 15%. During 2014, new directacting antiviral agents (DAAs) will probably become available, hopefully, further improving response rates for difficult-to-treat patients with chronic hepatitis C. There are, however, so far only scarce data on the results with direct-acting antiviral
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DISCUSSION
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Ther Drug Monit Volume 37, Number 6, December 2015
High-Dose Ribavirin
and may be a useful tool when dosing of ribavirin is essential, for instance, patients with end-stage liver disease with no other treatment option besides high-dosed ribavirin, at the time of the study, also when lower levels are aimed at for safety reasons in the posttransplant setting19 and patients with impaired renal function. In some patients, the ribavirin dose had to be adjusted, mostly upwards to reach the intended plasma ribavirin concentration. This highlights the importance of ribavirin plasma concentration monitoring.
CONCLUSIONS We found that an individualized high ribavirin dose scheme resulted in a more pronounced early viral HCV RNA decline than a standard-dose ribavirin scheme during the initial 12 weeks of peg-IFN and ribavirin treatment. This suggest that patients with a previous nonresponse to SOC treatment with ribavirin dosed according to body weight will respond better to a regime using an individualized and concentration-monitored (“high-dose ribavirin”) regimen. This regime is safe provided that close monitoring of anemia is undertaken and that treatment with erythropoietin is given before initiation of the antiviral treatment and can be used in difficult-to-treat patient on an individual basis. FIGURE 1. HCV RNA log drop for 20 patients with chronic hepatitis C. In the figure, each patient is represented by a horizontal bar. The left end shows the log drop at week 12 during previous treatment with ribavirin dosed in a standard fashion, and the right end of the bar shows the log drop at week 12 during the study when patients were given “highdose” ribavirin, dosed individually and concentration monitored.
REFERENCES
agents in the most difficult-to-treat patients, including null responders with cirrhosis; hence, ribavirin will probably be used in many combinations for difficult-to-treat patient in the future. Furthermore, regulatory and financial aspects will probably restrict and reduce treatment options and combinations in many parts of the world, rendering ribavirin and pegIFN much valued alternative treatments. The dosing of ribavirin has been a matter of debate. There are several indications that the response rate improves for patients with genotype 1 with increasing concentrations when used in combination with peg-IFN.3,5,7,16,17 Thus, avoiding dose reductions in order not to jeopardize the response rates has been emphasized when ribavirin is used in combination with peg-IFN. In studies with first-generation protease inhibitors, such as telaprevir, small reductions in the ribavirin dose has not hampered the SVR rates. This might be explained by an interaction between telaprevir and ribavirin, resulting in higher ribavirin concentrations.18 In line with this, we observed higher than normal ribavirin concentrations in patients on triple therapy including a protease inhibitor (unpublished data). In this study, the dosing of ribavirin was individualized, aiming at a high plasma concentration of .15 mmol/L. To reach this, the initial dosing was calculated from a formula taking body weight and renal function into account. The formula performed reasonably well in predicting the correct dose
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14. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31. 15. Yun Z, Lara C, Johansson B, et al. Discrepancy of hepatitis C virus genotypes as determined by phylogenetic analysis of partial NS5 and core sequences. J Med Virol. 1996;49:155–160. 16. Shiffman ML, Salvatore J, Hubbard S, et al. Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin alpha. Hepatology. 2007;46:371–379.
17. Pawlotsky JM, Dahari H, Neumann AU, et al. Antiviral action of ribavirin in chronic hepatitis C. Gastroenterology. 2004;126:703–714. 18. Hammond K, Jimmerson L, MacBrayne C, et al. Increased Plasma and intracellular ribavirin concentrations associated with telaprevir use. CROI 2013. abstract 34, Atlanta, GA, 3–6 March 2013. 19. Ackefors M, Gjertsen H, Wernerson A, et al. Concentration guided ribavirin dosing with darbepoetin support and Peg-IFN alfa-2a for treatment of hepatitis C recurrence after liver transplantation. J Viral Hepat. 2012:19:635–639.
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