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Ribavirin Levels Too High or Low in Most Patients Taking DAAs
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17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC
Mark Mascolini
Most HCV patients in a 100-person Netherlands analysis had ribavirin concentrations above or below the target range when taking the drug with direct-acting antivirals (DAAs) [1]. Ribavirin starting doses appeared to be too high in people with an estimated glomerular filtration rate (eGFR) below 70 mL/min.
DAAs have become the mainstay of treatment for HCV infection, but Dutch collaborators noted that regimens for certain patients still include ribavirin. Because elevated ribavirin concentrations may cause anemia, they conducted a prospective analysis of ribavirin levels in contemporary DAA patients at four centers in the Netherlands.
The Dutch team enrolled all patients taking ribavirin with any DAA regimen. Participating centers centrifuged all ribavirin samples within 2 hours of collection to prevent misleadingly high ribavirin concentrations caused by ribavirin leakage from erythrocytes. The researchers analyzed week-8 ribavirin levels with a t-test for gender and weight (below or above 75 kg). They defined the ribavirin target range as 2.2 to 3.6 mg/L and anemia as hemoglobin below 10 g/dL.
The 100 study participants included 78 men, 65% infected with HCV genotype 1, 55% with cirrhosis, and 72% treated with a 12-week DAA regimen. Most participants, 55%, had an eGFR above 90 mL/min, and eGFRs ranged from 17 to above 90 mL/min. The DAAs most frequently used with ribavirin were sofosbuvir/daclatasvir (45%), sofosbuvir/simeprevir (32%), and sofosbuvir alone (23%).
People with a baseline eGFR below 50 mL/min (n = 5), 50 to 89 mL/min (n = 37), or 90 mL/min or higher (n = 55) had respective median week-8 ribavirin concentrations of 2.62, 3.49, and 2.46 mg/L (P = 0.001). Median ribavirin starting doses in the three groups were 14.70, 14.34, and 13.53 mg/kg/day. Week-8 doses for the three groups were 7.47, 10.73, and 13.51 mg/kg/day. Respective week-8 hemoglobin levels in these three groups were 9.3, 11.0, and 12.8 g/dL.
While 29% of ribavirin concentrations lay below the target range, 26% lay above that range, and the remaining 45% were on target. Ribavirin concentrations did not differ by gender, weight, or DAA regimen. Anemia developed in 21% of these people during treatment.
Compared with patients who had normal renal function (eGFR 90 mL/min or higher), those with eGFR between 50 and 89 mL/min were more likely to take reduced-dose ribavirin (57% versus 31%), to have elevated ribavirin levels (46% versus 16%), and to have anemia (41% versus 4%). Anemia developed in 9 of 13 people with eGFR between 50 and 70 mL/min and 6 of 24 with eGFR between 70 and 90 (69% versus 25%).
The researchers concluded that people with an eGFR below 50 mL/min--and possibly those with 50 to 70 mL/min-"would benefit from a lower starting dose" of ribavirin. They suggested that "therapeutic drug monitoring could be beneficial to improve ribavirin concentrations during DAA treatment," especially in people with moderately reduced renal function, "so sustained virologic response can be achieved without unnecessary toxicity."
Reference
1. Smolders EJ, van Tilborg M, Lieveld FI, et al. Steady state ribavirin pharmacokinetics in chronic hepatitis C infected patients with moderate renal impairment taking modern DAA combinations: are we dosing too high? 17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC. Abstract O7.
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