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Background Monitoring ribavirin concentrations during hepatitis C treatment with dual therapy can help optimize treatment response and minimize anaemia. A defined therapeutic range for ribavirin during direct-acting antiviral-based therapies is lacking. This analysis explores whether a therapeutic range for ribavirin concentrations can be defined in patients treated with boceprevir- or telaprevir-based triple therapies.Methods Treatment-naive patients from ADVANCE, ILLUMINATE, OPTIMIZE and SPRINT-2, and treatment-experienced patients from RESPOND-2 were included. Multivariable logistic regression analyses were performed to evaluate whether ribavirin concentrations were an independent predictor of sustained virological response or anaemia. Optimal cutoff values and the percentage of patients within the proposed therapeutic range were determined, along with the associated chance of response.Results Overall, 1,502 patients were included. In both regimens, ribavirin concentrations were significantly associated with anaemia (haemoglobin level <10 g/dl) at all time points (1.75 < odds ratio [OR] <2.45) and sustained virological response was associated with ribavirin concentrations at week 8 (OR=1.43 for telaprevir and 1.78 for boceprevir). A therapeutic range for ribavirin at week 8 of 2.2–3.5 mg/l was defined for telaprevir treatment. Of the 48% of patients with a concentration within this range, 81% achieved sustained virological response and only 5.1% reported anaemia. For boceprevir treatment, the week 8 optimal range was defined as 2.2–3.6 mg/l and 50% of patients had a concentration within this range, of whom 69% achieved sustained virological response and 46% developed anaemia.Conclusions We established the therapeutic range for ribavirin in boceprevir- and telaprevir-based therapy that balances safety and efficacy.

Interferon-free regimens are needed to treat hepatitis C virus (HCV) infections. We investigated the efficacy of combined simeprevir and sofosbuvir.

Although the addition of the HCV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa plus ribavirin has improved sustained virological response (SVR) in treatment-naive and treatment-experienced patients infected with hepatitis C virus (HCV) genotype 1, the regimens have a high pill burden and are associated with increased rates and severity of adverse events, such as anaemia and rash. The efficacy and safety of the combination of simeprevir, a one pill, once-daily, oral HCV NS3/4A protease inhibitor, plus peginterferon alfa 2a plus ribavirin were assessed in treatment-naive patients with HCV genotype 1 infection.

Pegylated interferon (peginterferon) alfa 2a or 2b plus ribavirin regimens were the standard of care in patients with hepatitis C virus (HCV) infection, but the sustained virological response can be suboptimum in patients with HCV genotype 1 infection. The efficacy, safety, and tolerability of the combination of simeprevir, a one-pill, once-daily, oral HCV NS3/4A protease inhibitor versus placebo, plus peginterferon alfa 2a or 2b plus ribavirin was assessed in treatment-naive patients with HCV genotype 1 infection.

To assess the role of GST’s (glutathione S-transferases) in the (de)toxification of their substrates, an in vivoactive inhibitor based on the structure of glutathione (GSH), γ-L-glutamyl-α-(D-2-aminoadipyl)-N-2-heptylamine monoethyl ester (Et-R-Hep), was developed. To increase its effectivity, analogues esterified with alkyl chains of varying lengths and one diesterified derivative (DiEt-R-Hep) were synthesized. The unesterified analogue, R-Hep, was also tested. Their isoenzyme selectivity was characterized using purified rat GST isoenzymes. Furthermore, the extent of inhibition of the GSH conjugation of (RS)-2-bromoisovalerylurea (BIU) was evaluated in rat liver cytosol, isolated hepatocytes, and in liver perfusions. All compounds inhibited Alpha- (1–1 and 2–2) more effectively than Mu (3–3 and 4–4) class GSTs; Pi-(5–5) and Theta (7–7) classes were minimally inhibited. The unesterified R-Hep was the most effective inhibitor towards purified isoenzymes; its Kivalue towards GST 3–3 (S-BIU as substrate) was 27 μM. The mono ethyl ester derivative, Et-R-Hep (Ki270 μM for 3–3), was the most potent inhibitor in hepatocytes and in the perfused liver: 50 μM inhibited the conjugation of (S)-BIU by 50%. Longer ester chains or diesterification did not increase the inhibitory potency; R-Hep had less inhibitory activity. In all systems, only the (S)-enantiomer of BIU, which is conjugated mainly by Alpha class GSTs, was inhibited, confirming Alpha isoenzyme selective inhibition.

ABSTRACTInteractions between simeprevir (hepatitis C virus [HCV] NS3/4A protease inhibitor) and ledipasvir (HCV NS5A replication complex inhibitor) were investigated in treatment-naive HCV genotype 1-infected patients without cirrhosis, treated with simeprevir-sofosbuvir-ledipasvir in a two-panel, phase 2, open-label study. Patients had stable background treatment with sofosbuvir (400 mg once daily [QD]). In panel 1 (n= 20), the effect of ledipasvir (90 mg QD) on simeprevir (150 mg QD) was studied. Patients received simeprevir and sofosbuvir from days 1 to 14; steady-state pharmacokinetics (PK) of simeprevir was assessed (day 14). On day 15, ledipasvir was added and steady-state PK of simeprevir in the combination was evaluated (day 28). In panel 2 (n= 20), the effect of simeprevir on ledipasvir was investigated. From days 1 to 14, patients received ledipasvir and sofosbuvir and steady-state PK of ledipasvir was assessed (day 14). On day 15, simeprevir was added and a full PK profile was obtained (day 28). The least-squares mean maximum plasma concentration and area under the concentration-time curve (90% confidence interval) increased 2.3-fold (2.0- to 2.8-fold) and 3.1-fold (2.4- to 3.8-fold) for simeprevir, respectively (panel 1), and 1.6-fold (1.4- to 1.9-fold) and 1.7-fold (1.6- to 2.0-fold) for ledipasvir, respectively (panel 2), in the presence versus the absence of the other drug. All patients achieved sustained virologic responses 12 weeks after treatment end. Adverse events, mainly grade 1/2, occurred in 80% of patients; the most common was photosensitivity (45%). Due to the magnitude of interaction and the limited amount of safety data available, the use of this treatment combination is not recommended. (This study has been registered at ClinicalTrials.gov under registration no. NCT02421211.)