The Dose-Response Relationship of Peginterferon Alfa-2a and Ribavirin in the Treatment of Patients Coinfected with HIV-HCV
ABSTRACT The relationship between peginterferon/ribavirin exposure and the probability of achieving a sustained virologic response (SVR) in HIV-HCV coinfected patients is not well described. We conducted a retrospective analysis of HIV-HCV coinfected patients randomized to 48 weeks of treatment with peginterferon alfa-2a (40 kD) 180 µg/week and ribavirin 800 mg/day in the multinational APRICOT study to define optimal exposure thresholds.
Actual drug exposure was estimated in 287 patients, taking into consideration dose reductions for adverse events or laboratory abnormalities.
SVR overall and SVR in those completing treatment was, respectively, 29% and 37% among HCV genotype-1 patients and 59% and 68% among genotype non-1 patients. No patients with ≤40% exposure to ribavirin achieved an SVR. Receiver operating characteristic analysis identified that threshold exposures to both drugs of >75% (genotype-1) and >60% (genotype non-1) are associated with SVR. An existing generalized additive model populated with data from HCV monoinfected patients was updated to predict an overall SVR of 37% if genotype-1 patients received ribavirin 1000 or 1200 mg/day but at the cost of a higher incidence of anemia (23%).
Completion of scheduled treatment and exceeding certain thresholds for exposure to peginterferon alfa 2a (40 kD) and ribavirin is associated with higher SVR rates.
Journal of Hepatology 03/2012; 57(1):167-85. DOI:10.1016/j.jhep.2012.02.010 · 10.40 Impact Factor
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ABSTRACT: Ribavirin (RBV) is an integral part of standard-of-care HCV treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 hours on day 1 of weeks 1 and 12 from patients with moderate renal impairment (CrCl 30-50 mL/min; RBV 600 mg daily), severe renal impairment (CrCl<30 mL/min; RBV 400 mg daily), end-stage renal disease (ESRD) (RBV 200 mg daily), or normal renal function (CrCl>80 mL/min; RBV 800-1200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 severely impaired, 13 had ESRD, and 12 had normal renal function. RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups. Despite this modification, patients with moderate and severe impairment had 12-hour (AUC0-12) values of 36% (38, 452 ng⋅h/mL) and 25% (35, 101 ng⋅h/mL) higher, respectively, than those with normal renal function (28,192ng⋅h/mL). Patients with ESRD tolerated a 200 mg daily dose, and AUC0-12 was 20% lower (22,629ng⋅h/mL) compared with patients with normal renal function. PK modeling and simulation (M&S) indicated doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients.Antimicrobial Agents and Chemotherapy 09/2013; DOI:10.1128/AAC.00608-13 · 4.45 Impact Factor
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ABSTRACT: The safety and efficacy of weight-based ribavirin (RBV) dosing regimens in patients with HIV-HCV coinfection has not been demonstrated in randomized clinical trials. This randomized, double-blind, international, parallel-group study in specialist outpatient clinics in the United States, Spain, and Portugal compares the efficacy and safety of 2 RBV dose regimens (800 mg/day and 1000/1200 mg/day) combined with peginterferon alfa-2a (40KD) in patients with HIV-HCV (genotype 1) coinfection. Patients with HIV-HCV coinfection, quantifiable HCV RNA in serum, HCV genotype-1 infection, compensated liver disease, and stable HIV disease (CD4+ count ≥100 cells/µL) with or without ongoing antiretroviral therapy were randomized to 48 weeks' treatment with RBV at standard dose (800 mg/day) or weight-based dose (1000 mg/day for patients weighing <75 kg; 1200 mg/day for patients weighing ≥75 kg) in combination with peginterferon alfa-2a (40KD) 180 µg once a week. Planned enrollment was 400 patients with ≥100 non-Latino African Americans. The primary endpoint was sustained virological response (SVR) (undetectable HCV RNA [<20 IU/mL] at the end of a 24-week untreated follow-up period [week 72]). SVR rates were 19% (26/135) and 22% (60/275) in patients randomized to RBV 800 mg/day and 1000/1200 mg/day, respectively (odds ratio, 1.15; 95% CI, 0.68-1.93; P = .6119). In the 1000/1200 mg/day RBV dose group, the incidence of hemoglobin reductions <100 g/L and anaemia reported as an adverse event were higher versus the standard 800 mg/day RBV dose group. Compared with the standard RBV dose (800 mg/day), weight-based RBV dosing (1000/1200 mg/day) did not significantly increase SVR rates, but did increase the incidence of anemia in HIV-HCV (genotype 1) coinfected patients.HIV Clinical Trials 01/2012; 13(3):142-52. DOI:10.1310/hct1303-142 · 2.14 Impact Factor