Simeprevir is generally well tolerated. Photosensitivity and rash have been reported, occasionally severe; pruritus or nausea may also occur. Transient, mild elevations in bilirubin have been observed with simeprevir due to decreased bilirubin elimination related to inhibition of the hepatic transporters OATP1B1 and MRP2, but no pattern to suggest liver toxicity has been observed. Since simeprevir contains a sulfa moiety, caution should be used in patients with a history of sulfa allergy.
Ribavirin is a guanosine analog that is phosphorylated intracellularly by host cell enzymes. Although its mechanism of action has not been fully elucidated, it appears to interfere with the synthesis of guano-sine triphosphate, to inhibit capping of viral messenger RNA, and to inhibit the viral RNA–dependent polymerase of certain viruses. Ribavirin triphosphate inhibits the replication of a wide range of DNA and RNA viruses, including influenza A and B, parainfluenza, respiratory syncytial virus, paramyxoviruses, HCV, and HIV-1.
The absolute oral bioavailability of ribavirin is 45–64%, increases with high-fat meals, and decreases with co-administration of antacids. Plasma protein binding is negligible, volume of distribution is large, and cerebrospinal fluid levels are about 70% of those in plasma. Ribavirin elimination is primarily through the urine; therefore, clearance is decreased in patients with creatinine clearances <30 mL/min.
Higher doses of ribavirin (ie, 1000–1200 mg/d rather than 800 mg/d) and/or a longer duration of therapy may be more efficacious, but the risk of toxicity is also increased. A dose-dependent hemolytic anemia occurs in 10–20% of patients, usually within the first weeks of therapy. Other potential adverse effects are depression, fatigue, irritability, rash, cough, insomnia, nausea, and pruritus. Contraindications include anemia, end-stage renal failure, ischemic vascular disease, and pregnancy. Ribavirin is teratogenic and embryotoxic in animals as well as mutagenic in mammalian cells. Therefore, two effective forms of contraception should be used by both sexual partners during treatment and for several months thereafter.
The co-administration of ribavirin with didanosine causes significantly increased levels of didanosine; co-administration with azathioprine may result in myelotoxicity due to accumulation of azathioprine.
Influenza virus strains are classified by their core proteins (ie, A, B, or C), species of origin (eg, avian, swine), and geographic site of isolation. Influenza A, the only strain that causes pandemics, is classified into 16 H (hemagglutinin) and 9 N (neuraminidase) known subtypes based on surface proteins. Although influenza B viruses usually infect only people, influenza A viruses can infect a variety of animal hosts, including birds, providing an extensive reservoir. Current influenza A subtypes that are circulating among worldwide populations include H1N1, H1N2, and H3N2. Although avian influenza subtypes are typically highly species-specific, they have on rare occasions crossed the species barrier to infect humans and cats. Viruses of the H5 and H7 subtypes (eg, H5N1, H7N9) may rapidly mutate within poultry flocks from a low to high pathogenic form and have recently expanded their host range to cause both avian and human disease. However, person-to-person spread of these avian viruses to date has been rare, limited, and unsustained.