Managing drug-drug interactions with new direct-acting antiviral agents in chronic hepatitis C.

Several direct-acting antiviral agents (DAAs) have marketing authorization in Europe and in the USA and have changed the landscape of hepatitis C treatment: each DAA has its own metabolism and drug-drug interactions (DDIs), and managing them is a challenge. To compile the pharmacokinetics and DDI data of the new DAA and to provide a guide for management of DDI. An indexed MEDLINE search was conducted using the keywords: DAA, hepatitis C, simeprevir, daclatasvir, ledipasvir, sofosbuvir, 3D regimen (paritaprevir/ritonavir, ombitasvir, dasabuvir), DDI and pharmacokinetics. Data were also collected from hepatology, and infectious disease and clinical pharmacology conferences abstracts. Food can play a role in the absorption of DAAs. Most of the interactions are linked to metabolism (cytochrome P450-3 A4 [CYP3A4]) or hepatic and/or intestinal transporters (organic anion-transporting polypeptide and P-glycoprotein [P-gp]). To a lesser extent other pathways can be involved such as breast cancer resistance protein transporter or UDP-glucuronosyltransferase metabolism. DDI are more likely to occur with 3D regimen, daclatasvir, simeprevir and ledipasvir, as they are all both substrates and inhibitors of P-gp and/or CYP3A4, than with sofosbuvir. They can increase concentrations of coadministered drugs and their concentrations may be influenced by P-gp or CYP3A4 inducers or inhibitors. Overdosage or low dosage can be encountered with potent inducers or inhibitors of CYP3A4 or drugs with a narrow therapeutic range. The key to interpret DDI data is a good understanding of the pharmacokinetic profiles of the drugs involved. Their ability to inhibit CYP450-3A4 and transporters (hepatic and/or intestinal) can have significant clinical consequences.

Prospective study comparing hepatic steatosis assessment by magnetic resonance imaging and four ultrasound methods in 105 successive patients.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming a major health problem, resulting in hepatic, metabolic and cardio-vascular morbidity. AIM: To evaluate new ultrasonographic tools to detect and measure hepatic steatosis. METHODS: We prospectively included 105 patients referred to our liver unit for NAFLD suspicion or follow-up. They underwent ultrasonographic measurement of liver sound speed estimation (SSE) and attenuation coefficient (AC) using Aixplorer MACH 30 (Supersonic Imagine, France), continuous controlled attenuation parameter (cCAP) using Fibroscan (Echosens, France) and standard liver ultrasound with hepato-renal index (HRI) calculation. Hepatic steatosis was then classified according to magnetic resonance imaging proton density fat fraction (PDFF). Receiver operating curve (ROC) analysis was performed to evaluate the diagnostic performance in the diagnosis of steatosis. RESULTS: Most patients were overweight or obese (90%) and had metabolic syndrome (70%). One third suffered from diabetes. Steatosis was identified in 85 patients (81%) according to PDFF. Twenty-one patients (20%) had advanced liver disease. SSE, AC, cCAP and HRI correlated with PDFF, with respective Spearman correlation coefficient of -0.39, 0.42, 0.54 and 0.59 (P < 0.01). Area under the receiver operating characteristic curve (AUROC) for detection of steatosis with HRI was 0.91 (0.83-0.99), with the best cut-off value being 1.3 (Se = 83%, Sp = 98%). The optimal cCAP threshold of 275 dB/m, corresponding to the recent EASL-suggested threshold, had a sensitivity of 72% and a specificity of 80%. Corresponding AUROC was 0.79 (0.66-0.92). The diagnostic accuracy of cCAP was more reliable when standard deviation was < 15 dB/m with an AUC of 0.91 (0.83-0.98). An AC threshold of 0.42 dB/cm/MHz had an AUROC was 0.82 (0.70-0.93). SSE performed moderately with an AUROC of 0.73 (0.62-0.84). CONCLUSION: Among all ultrasonographic tools evaluated in this study, including new-generation tools such as cCAP and SSE, HRI had the best performance. It is also the simplest and most available method as most ultrasound scans are equipped with this module.