Absolute bioavailability of the pyrimidinone analog raltegravir has not been established but does not appear to be food-dependent. Terminal half-life is ~ 9 hours. The drug does not interact with the cytochrome P450 system but is metabolized by glucuronidation, particularly UGT1A1. Therefore, concurrent use of inducers or inhibitors of UGT1A1 such as rifampin and rifapentine may necessitate dosage adjustment of raltegravir. The chewable tablets contain phenylalanine, which can be harmful to patients with phenylketonuria.
Raltegravir is one of the antiretroviral agents recommended for use in pregnancy (Table 49–5).
Adverse effects of raltegravir are uncommon but include nausea, headache, fatigue, muscle aches, and increased serum amylase and aminotransferase levels. Severe, potentially life-threatening and fatal skin reactions have been reported, including Stevens-Johnson syndrome, hypersensitivity reaction, and toxic epidermal necrolysis.
The advantages of nucleoside/nucleotide analogs (NA) therapy of hepatitis over interferons (IFN) include fewer adverse effects and a one-pill-a-day oral administration. The main advantages of IFN over NAs are the absence of resistance, and achievement of higher rates of viral agglutinin reduction. However, the disadvantages of IFN are that less than 50% of persons treated will respond, its high cost, administration by injection, and common adverse effects, which preclude its use in many persons, particularly in resource-limited settings. A number of relative and absolute contraindications to IFN also exist, which include the presence of decompensated cirrhosis and hypersplenism, thyroid disease, autoimmune diseases, severe coronary artery disease, renal transplant disease, pregnancy, seizures and psychiatric illness, concomitant use of certain drugs, retinopathy, thrombocytopenia and leucopenia. IFN also cannot be used in infants less than 1 year and in pregnant women.
Interferons are host cytokines that exert complex antiviral, immunomodulatory, and antiproliferative actions (see Chapter 55). Interferon alfa appears to function by induction of intracellular signals following binding to specific cell membrane receptors, resulting in inhibition of viral penetration, translation, transcription, protein processing, maturation, and release, as well as increased host expression of major histocompatibility complex antigens, enhanced phagocytic activity of macrophages, and augmentation of the proliferation and survival of cytotoxic T cells.
Interferon alfa-2b is licensed for the treatment for chronic HBV infection; interferon alfa-2a, interferon alfa-2b, and interferon alfacon-1 are licensed for treatment of chronic HCV infection (Table 49–6). Interferon alfa-2a and interferon alfa-2b may be administered either subcutaneously or intramuscularly; half-life is 2–5 hours, depending on the route of administration. Alfa interferons are filtered at the glomerulus and undergo rapid proteolytic degradation during tubular reabsorption, such that detection in the systemic circulation is negligible. Liver metabolism and subsequent biliary excretion are considered minor pathways.
Pegylation (the attachment of polyethylene glycol to a protein) reduces the rate of absorption following subcutaneous injection, reduces renal and cellular clearance, and decreases
TABLE 49–6 Drugs used to treat chronic hepatitis B virus infection.