Therapeutic Uses

Adefovir dipivoxil is approved for treatment of chronic HBV infections. In patients with HBV e-antigen (HbeAg)—positive chronic hepatitis B, adefovir dipivoxil (10 mg/day) results in >100-fold reduced serum HBVDNA levels and, in about one-half of patients, improved hepatic histology and normalizes aminotransferase levels by 48 weeks. Continued therapy is associated with increasing frequencies of aminotransferase normalization and HbeAg seroconversion. In patients with HbeAg-negative chronic HBV, adefovir is associated with similar biochemical and histological benefits. Regression of cirrhosis may occur in some patients.

In patients with lamivudine-resistant HBV infections, adefovir dipivoxil results in sustained reductions in serum HBVDNA levels, but lamivudine alone or added to adefovir is not beneficial. In patients with dual HIV and lamivudine-resistant HBV infections, adefovir dipivoxil (10 mg/day) significantly reduces HBVDNA levels and also has been used successfully in patients with lamivudine-resistant HBV infections both before and following liver transplantation. The optimal duration of treatment in different populations, possible long-term effects on HBV complications, and combined use with other anti-HBV agents are under study.

Interferons classification and antiviral activity Interferons (IFNs) possess antiviral, immunomodulating, and antiproliferative activities (see Chapter 52). They are synthesized by host cells in response to various inducers and stimulate an antiviral state in cells. There are three major classes of human interferons with antiviral activity: a, b, and g. Clinically used recombinant a IFNs (Table 49-2) are nonglycosylated proteins of ~19,500 Da.

IFN-a and IFN-b are produced by nearly all cells in response to viral infection and a variety of other stimuli, including double-stranded RNA and certain cytokines (e.g., interleukin 1, interleukin 2, and tumor necrosis factor a). IFN-g production is restricted to T-lymphocytes and natural killer cells responding to antigenic stimuli, mitogens, and specific cytokines. IFN-a and IFN-b have antiviral and antiproliferative actions; stimulate the cytotoxic activity of lymphocytes, natural killer cells, and macrophages; and up-regulate class I major histocompatibility complex (MHC) antigens. IFN-g has less antiviral activity but more potent immunoregulatory effects. Most animal viruses are inhibited by IFNs, although DNA viruses are relatively insensitive.

mechanisms ofaction Following binding to specific cellular receptors, IFNs activate the JAK-STAT pathway and stimulate the transcription of specific genes, leading to synthesis of >20 proteins that contribute to viral resistance at different stages of viral infection (Figure 49-3). For many viruses, the major effect is inhibition of protein synthesis. IFN-induced proteins include 2'-5'-oligoadenylate [2-5(A)] synthetase and a protein kinase, either of which can inhibit protein synthesis in the presence of double-stranded RNA. The protein kinase selectively phosphorylates and inactivates eukaryotic initiation factor 2 (eIF-2). Certain viruses counter IFN effects by blocking production or activity of selected IFN-inducible proteins. For example, IFN resistance in HCV is attributable to inhibition of the IFN-induced protein kinase. IFNs also may modify the immune response; IFN-induced expression of MHC antigens may enhance lytic effects of cytotoxic T-lymphocytes.

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Diabetes 2

Diabetes 2

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