Page 6 - EASL Recommendations on Treatment of Hepatitis C 2014
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and nature of therapy is debatable, and treatment may be deferred. Simeprevir should be administered at the dose of 150 mg (one The decision to defer treatment for a specific patient should consider capsule) once per day. No dose recommendation can be given the patient’s preference and priorities, the natural history and risk of for patients with Child-Pugh Class B or C cirrhosis, due to higher progression, the presence of co-morbidities including HIV coinfection, simeprevir exposures (particularly in Child-Pugh C patients) that and the patient’s age. Patients who have treatment deferred should be may be associated with increased frequency of adverse reactions. assessed on a regular basis for evidence of progression, to reconsider Simeprevir is well tolerated. Adverse reactions with at least 3% the indication for treatment, and to discuss new therapies as they higher frequency in patients receiving simeprevir in combination emerge. with pegylated IFN-α and ribavirin were rash (including IFN-free, ideally ribavirin-free therapy may also be considered photosensitivity), pruritus and nausea. Because simeprevir is in patients with decompensated cirrhosis. Although scarce data is an inhibitor of the transporters OATP1B1 and MRP2 [15], mild, available in that population, these patients are those who may benefit transient hyperbilirubinaemia not accompanied by changes in other more from HCV eradication in the short-term. IFN-free treatment liver parameters was observed in approximately 10% of cases. in patients with decompensated disease should only be attempted Co-administration of simeprevir with substances that are in experienced centers until further safety and efficacy data have moderate or strong inducers or inhibitors of cytochrome P450 3A accumulated. (CYP3A) is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively. A number of compounds are contra-indicated in patients receiving simeprevir, Recommendations including anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), antibiotics (erythromycin, Recommendations clarithromycin, telithromycin, rifampin, rifabutin, rifapentine), systemically administered antifungals (itroconazole, ketoconazole, posaconazole, fluconazole, voriconazole), systemically • All treatment-naïve and -experienced patients with administered dexamethasone, cisapride, herbal products (milk compensated disease due to HCV should be considered thistle, St John’s wort) and a number of antiretroviral drugs, for therapy (Recommendation A1) including cobicistat-based regimens, efavirenz, delavirdine, etravirine, nevirapine, ritonavir, and any HIV protease inhibitor, • Treatment should be prioritized for patients with boosted or not by ritonavir. Raltegravir, maraviroc, rilpivirine, significant fibrosis (METAVIR score F3 to F4) tenofovir, emtricitabine, lamivudine, and abacavir have no (Recommendation A1) interactions with simeprevir and can thus be safely used in patients receiving this drug. Dose adjustments are needed with some • Treatment is justified in patients with moderate fibrosis antiarythmics, warfarin, calcium channel blockers, HMG Co-A (METAVIR score F2) (Recommendation A2) reductase inhibitors and sedative/anxiolytics. No dose changes are required when used in combination with immunosuppressants, • In patients with no or mild disease (METAVIR score such as cyclosporine and tacrolimus, based on studies in healthy F0-F1), the indication for and timing of therapy can be volunteers [16]. individualized (Recommendation B1) Daclatasvir should be administered at the dose of 60 mg (one • Patients with decompensated cirrhosis who are on the tablet) once per day. It is overall well tolerated. Dose adjustments transplant list should be considered for IFN-free, ideally are not needed in patients with Child B or C disease. The most ribavirin-free therapy (Recommendation A1) frequently reported side effects with daclatasvir were fatigue, headache, and nausea. Little information has been released on daclatasvir drug-drug interactions. Daclatasvir is a substrate of CYP34A and a substrate and inhibitor of P-gp. The daclatasvir dose should be adjusted 4.6. Available drugs (approved by EMA before the end of 2014) to 30 mg daily in HIV-infected patients receiving atazanavir/ ritonavir and to 90 mg daily in those receiving efavirenz. No dose Pegylated IFN-α2a should be used at the dose of 180 µg/week, adjustment is needed with tenofovir. No information on other whereas pegylated IFN-α2b should be used at the weight-based antiretroviral drugs is available yet. No dose adjustments are dose of 1.5 µg/kg/week. Ribavirin dose should be 1000 or 1200 mg/ required with cyclosporine or tacrolimus. Total daclatasvir AUC is day, based on body weight (<75 kg or ≥75 kg, respectively). decreased by 40% and 43% in patients with mild or moderate liver impairment, respectively. However, the unbound pharmacologically Sofosbuvir should be administered at the dose of 400 mg (one tablet) active fraction is unchanged, thus dose adjustment is not needed once per day. Currently, no dose recommendation can be given for patients in patients with liver impairment. with severe renal impairment (estimated glomerular filtration rate <30 ml/ 2 min/1.73m ) or with end-stage renal disease due to higher exposures (up 4.7. Treatment of chronic hepatitis C to 20-fold) of the predominant sofosbuvir metabolite. Sofosbuvir is well tolerated over 12 to 24 weeks of administration. The In 2014, treatment-naïve and -experienced patients with most common adverse events (≥20%) observed in combination with ribavirin compensated disease will benefit from a broad choice of drug were fatigue and headache. The most common adverse events (≥20%) combinations. Indications will depend on the HCV genotype/ observed in combination with pegylated IFN-α and ribavirin were fatigue, subtype and, eventually, the severity of liver disease, the results headache, nausea, insomnia, and anaemia. of prior therapy or the presence at baseline of detectable, pre- Drugs that are potent P-gp inducers significantly decrease sofosbuvir existing amino acid substitutions known to confer resistance to a plasma concentrations and may lead to a reduced therapeutic effect. given DAA. The indications are the same in HCV-monoinfected Thus sofosbuvir should not be administered with other known inducers of and HIV-coinfected patients. However, treatment alterations or P-gp, such as rifampin, carbamazepine, phenytoin or St. John’s wort. No dose adjustments may be needed in the latter due to drug-drug other significant drug-drug interactions have been reported, in particular interactions (see above, drug-drug interactions). Acceptance, with all of the antiretroviral agents tested, including emtricitabine, tenofovir, tolerance, and contraindications to IFN will be a factor. ralpivirine, efavirenz, darunavir/ritonavir, and raltegravir, and there are no potential drug-drug interactions with the remaining antiretrovirals. Sofosbuvir AUC is not significantly changed in patients with mild liver impairment, but it For each genotype, the available options will be described, is increased 2.3 fold in those with moderate liver impairment. followed by a summary of the data available for the given option. 4
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