Journal of Antimicrobial Chemotherapy Advance Access published February 10, 2016

J Antimicrob Chemother doi:10.1093/jac/dkw009

Plasma and intracellular ribavirin concentrations are not significantly altered by abacavir in hepatitis C virus-infected patients Edward J. Fuchs1†, Jennifer J. Kiser2†, Craig W. Hendrix1, Mark Sulkowski1, Christine Radebaugh1, Lane Bushman2, Michelle L. Ray2 and Adriana Andrade1* Department of Medicine, Johns Hopkins University, Baltimore, MD, USA; 2Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA *Corresponding author. Tel: +1-410-614-4036; E-mail: [email protected] †E. J. F. and J. J. K. contributed equally to this work.

Received 22 July 2015; returned 27 August 2015; revised 21 December 2015; accepted 9 January 2016 Objectives: The objective of this study was to evaluate the effects of abacavir on intracellular ribavirin triphosphate and plasma ribavirin trough concentrations. Methods: Hepatitis C virus-infected subjects who had been cured or failed prior treatment were randomized to 8 weeks of ribavirin alone (N¼14; weight-based dosing) or weight-based ribavirin+ abacavir (N¼14; 300 mg orally every 12 h). Ribavirin trough concentrations were measured on days 14, 28, 42 and 56; PBMCs for ribavirin triphosphate determination were sampled on days 28 and 56, pre-dose and at 6 and 12 h post-dose. ClinicalTrials.gov: NCT01052701. Results: Twenty-six subjects completed the study (24 males, 17 Caucasians, median age 52 years); 2 were excluded for missed pharmacokinetic visits. Fourteen subjects received ribavirin+abacavir and 12 received ribavirin alone. Mean+SD plasma ribavirin trough concentrations (mg/mL) on days 14, 28, 42 and 56, respectively, were not significantly different with coadministration of abacavir (1.54+0.60, 1.93+0.54, 2.14+0.73 and 2.54+1.05) compared with ribavirin alone (1.48+0.32, 2.08+0.41, 2.32+0.47 and 2.60+0.62) (P.0.40). Mean ribavirin triphosphate intracellular concentrations (pmol/106 cells) on days 28 and 56, respectively, did not differ statistically between abacavir users (11.98+9.86 and 15.87+12.52) and non-users (15.91+15.58 and 15.93+12.69) (P.0.4). Adverse events were mild or moderate, except for three grade 3 occurrences of transaminitis, cholecystitis and low absolute neutrophil count that resolved and were judged not attributable to study medications. Conclusions: Abacavir did not significantly alter ribavirin or ribavirin triphosphate concentrations.

Introduction Coinfection with hepatitis C virus (HCV) and HIV is common in the USA.1 – 4 Chronic liver disease associated with HCV infection is a significant cause of morbidity and mortality in HIV-infected individuals. HCV infection is more severe in HIV-infected persons, and can be associated with impaired immune reconstitution and antiretroviral-mediated hepatotoxicity.3 – 5 Many individuals treated for HCV achieve a sustained virological response (SVR). However, treatment in HIV/HCV coinfection is constrained by drug interactions.6,7 Ribavirin, a guanosine analogue, shares intracellular metabolic phosphorylation pathways with anti-HIV NRTIs.8 Antagonistic interactions through these pathways may compromise antiviral safety and efficacy.8 Despite expansion in drugs available for HCV, ribavirin remains in use to increase the probability of achieving SVR. Several studies retrospectively identified an association between use of abacavir, an NRTI, and reduced response to ribavirin-based HCV treatment.9 – 12 It has been suggested that pharmacokinetic

interactions involving competitive phosphorylation might be the underlying mechanism for loss of ribavirin efficacy. Other studies have failed to corroborate an association between abacavir use and lower rates of SVR in individuals receiving ribavirin.13 – 15 While no studies to date have examined the intracellular pharmacology of ribavirin with this combination, ribavirin trough concentrations were similar in patients receiving abacavir-based ART versus patients receiving non-abacavir-containing regimens.16 Conflicting results suggest the need for prospective studies with more pharmacokinetic sampling, including measurement of ribavirin triphosphate, the major intracellular metabolite of ribavirin. We conducted a prospective pharmacokinetic study in HCV-infected subjects to determine whether abacavir affected plasma and intracellular concentrations of ribavirin and ribavirin triphosphate, respectively.

Methods HCV monoinfected individuals, 18– 64 years of age, who previously completed or failed ribavirin-based treatment for HCV infection and were not

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Results Twenty-eight subjects were enrolled; 2 subjects were excluded because of missed visits. The 26 who completed the study were included in the analysis; 24 were male, including 16 Caucasian and 8 African-American, with a median age and weight of 52 years and 86 kg, respectively. Of the 14 subjects randomized

to the ribavirin + abacavir arm, 13 were male; 9 were Caucasian and 4 were African-American. Of the 12 subjects randomized to the ribavirin-alone arm, 11 were male; 7 were Caucasian and 5 were African-American (Table 1). Ribavirin and abacavir were well tolerated with no unexpected adverse events (AEs). One hundred and forty-six AEs were reported: 119 and 24 were grade 1 and grade 2, respectively. There were three grade 3 AEs, including neutropenia associated with a tooth abscess, an episode of pancreatitis that resolved with passage of a common duct stone and an episode of transaminitis in the setting of alcohol use. None of these events was attributed to study medications. All AEs normalized or returned to baseline. A total of 23 of the 26 evaluable subjects in both treatment arms had 100% adherence. One subject randomized to the ribavirin + abacavir arm missed one dose of ribavirin and a second subject missed one dose of abacavir and ribavirin. Of the subjects randomized to ribavirin alone, one subject missed a single dose. Mean plasma ribavirin trough and ribavirin triphosphate intracellular concentrations were not significantly different between the treatment arms (P .0.4; Table 2). Ribavirin triphosphate concentrations 6 and 12 h post-dose were not significantly different by treatment group on days 28 and 56 (data not shown).

Discussion In this prospective study of subjects who previously completed ribavirin-based treatment, we found abacavir coadministration did not significantly impact plasma ribavirin or intracellular ribavirin triphosphate concentrations. There are conflicting data on whether HCV SVR rates are lower in those receiving abacavir.9 – 15 These reports were based on retrospective analysis of parent cohort studies. A recent retrospective pharmacokinetic analysis failed to detect an effect of abacavir on ribavirin Cmin or HCV treatment outcome.16 These results are supported by other studies indicating a lack of association between abacavir use and substandard virological response in HIV/HCV-coinfected patients treated with ribavirin.13 – 15 Our study confirms the findings by Solas et al.,16 who did not find a difference in ribavirin plasma concentrations between abacavir users and non-users, and goes further in demonstrating no effect of abacavir on intracellular ribavirin triphosphate. Together, these findings do not support a ribavirin – abacavir interaction as the cause for the poor virological response to ribavirin-based therapy in HIV/HCV-coinfected patients also receiving abacavir.

Table 1. Baseline characteristics Variable Sex, n Race/ethnicity, n

male female Caucasian African-American

Weight (kg), median (IQR) Age (years), median (IQR)

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male female male female

Total, N¼26

Ribavirin+abacavir arm, N ¼14

Ribavirin-alone arm, N ¼12

24 2 16 1 8 1 86 (78 – 102) 52 (49 – 58)

13 1 9 1 4 0 94 (78 –106) 54 (50 –58)

11 1 7 0 4 1 79 (78 –93) 50 (48 –54)

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currently receiving HCV treatment, were eligible to participate in this two-arm, parallel-design, multiple-dose, pharmacokinetic study of ribavirin with and without abacavir. HCV-infected subjects were selected because giving ribavirin to this population was deemed an acceptable risk by the FDA since they had already completed ribavirin-based therapy. Exclusion criteria included pregnancy, cirrhosis, history of ribavirininduced anaemia, haemoglobinopathy or any other cause of haemolysis, non-reactive HIV-1 antibody, positive HLA-B*5701 and creatinine clearance ,50 mL/min. Individuals with normal haemoglobin, AST, ALT and alkaline phosphatase ,5-fold below the upper limit of normal (ULN) and direct bilirubin ,1.5-fold below ULN were eligible for entry. The study was approved by the Johns Hopkins Institutional Review Board. Participants provided written informed consent. ClinicalTrials.gov: NCT01052701. Following screening, participants completed study visits for 84 days. Participants were randomly assigned to a 1 : 1 open-label regimen with either ribavirin alone or ribavirin +abacavir for 56 days. Ribavirin dose was based on body weight.8 Participants weighing .75 kg received 600 mg orally every 12 h; those weighing ≤75 kg received 600 mg each morning and 400 mg each evening. Subjects randomized to dual study drug therapy were given abacavir 300 mg twice daily to match administration with the ribavirin dose. Adherence was assessed at each visit by participant self-report (medication diaries) and pill count. Laboratory and clinical assessments occurred every 2 weeks. Whole blood was collected in EDTA tubes for measurement of ribavirin plasma trough concentrations on days 14, 28, 42 and 56. Whole blood was collected in sodium heparin cell preparation tubes for measurement of ribavirin triphosphate concentrations in PBMCs on days 28 and 56. Ribavirin was measured in plasma using a validated HPLC-UV method. Ribavirin triphosphate was measured in PBMCs using a validated LC-MS/ MS method.17 At the time of study design, data were unavailable describing ribavirin triphosphate pharmacokinetics. Therefore, the sample size calculation was based on published intracellular triphosphate pharmacokinetics for lamivudine, since this agent has an intracellular phosphorylation pathway similar to that of ribavirin.18 Assuming a coefficient of variation (CV) of 50%, a 40% decrease in a pharmacokinetic parameter at 80% power and using a two-sided t-test with 0.05 level of significance, we estimated 14 subjects would be required in each study arm. Ribavirin trough and ribavirin triphosphate concentrations were compared using a two-group t-test in SPSS Statistics, Version 22.0 (IBM, Armonk, NY, USA).

JAC

Abacavir does not affect ribavirin pharmacokinetics

Table 2. Mean plasma ribavirin trough and ribavirin triphosphate intracellular concentrations with and without abacavir coadministration at study visits Study arm Plasma ribavirin (mg/mL) ribavirin only (N ¼12) ribavirin+abacavir (N ¼14) P value

Day 14

Day 28

Day 42

Day 56

1.48+0.32 1.54+0.60 0.76

2.08+0.41 1.93+0.54 0.43

2.32+0.47 2.14+0.73 0.46

2.60+0.62 2.54+1.05 0.85

15.91+15.58 11.98+9.86 0.44

15.93+12.69 15.87+12.52 0.99

Data are mean+SD. P value is for comparison of ribavirin only to ribavirin+abacavir using t-test. Only plasma ribavirin and intracellular ribavirin triphosphate trough concentrations results are included in this table. Ribavirin triphosphate concentrations 6 and 12 h post-dose were not statistically significant different on days 28 and 56 when comparing the two treatment groups (data not shown).

This study had some limitations. Although both men and women were eligible to participate, only two women were enrolled in the study. Our population was composed of onethird African-American subjects. We are not aware of data indicating that metabolism and pharmacokinetics of ribavirin and ribavirin triphosphate are affected by race. There have been studies describing sex-based differences in ribavirin pharmacology, with women having higher ribavirin plasma levels due to a smaller volume of distribution.19,20 However, no sex-based differences were observed in ribavirin triphosphate concentrations in these studies. This study was conducted in HCV monoinfected subjects who had been cured or previously failed hepatitis C treatment. HIV/ HCV-coinfected patients were not included in this study to minimize risk, since it was not known at the time whether a clinically relevant drug interaction existed with ribavirin and abacavir coadministration. We are not aware of any data to suggest that the ribavirin and ribavirin triphosphate pharmacokinetics reported in our study would significantly differ in either HCV-infected patients receiving ribavirin treatment19 or in HIV-infected patients receiving concomitant abacavir-based therapy. Adherence to abacavir was quantified by self-report and pill count, which are adherence measures known to have a degree of imprecision. We did not measure abacavir pharmacokinetics, which might have provided a more objective adherence measure. Because participants were not being treated for HCV, we did not measure plasma HCV RNA levels and, therefore, did not assess the impact of ribavirin pharmacokinetics on HCV infection. Finally, ribavirin triphosphate variability was higher than anticipated, ranging from 79% to 98%, though consistent with a subsequent study.19 However, with this variability our study could only robustly exclude a difference .40%. In conclusion, this prospective study in HCV-infected subjects found no evidence of a significant effect of abacavir on plasma ribavirin or intracellular ribavirin triphosphate concentrations. An abacavir and ribavirin pharmacokinetic drug interaction is unlikely to be the cause for the lower SVR rates in HIV/HCV-coinfected persons. Current treatment guidelines recommend the use of ribavirin and abacavir as components for treatment of HCV and HIV infection, respectively. Our pharmacokinetic findings indicate

that they can be administered safely, with no pharmacological basis to advise against coadministration.

Acknowledgements This study was presented at the Twentieth Conference on Retroviruses and Opportunistic Infections, Atlanta, GA, USA, 2013 (Poster 538). We are grateful to Drs Courtney Fletcher and Susan Rosenkranz for providing invaluable input in the design of this study. We thank GlaxoSmithKline for providing an investigator-initiated grant to support this study.

Funding This work was supported by GlaxoSmithKline (grant number COL112055). National Institutes of Health/National Institute of Drug Abuse (grant number K24DA034621) provided funding support to M. S.

Transparency declarations J. J. K. received research support from ViiV and Janssen. A. A. received support from DKBmed for a CME programme. All other authors: none to declare.

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with pegylated interferon and weight-adjusted ribavirin. Antivir Ther 2008; 13: 953–7.

Plasma and intracellular ribavirin concentrations are not significantly altered by abacavir in hepatitis C virus-infected patients.

The objective of this study was to evaluate the effects of abacavir on intracellular ribavirin triphosphate and plasma ribavirin trough concentrations...
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