lamivudine

1. lamivudine

2. Lamivudine • The first of the nucleoside analogues to be approved • inhibits reverse transcriptase activity of both HIV and HBV • a potent and effective agent for patients with chronic hepatitis B • conversion from HBeAg-reactive to anti-HBe-reactive • Clinical and laboratory side effects of lamivudine are negligible

3. MOA • It can inhibit both types (1 and 2) of HIVreverse transcriptase and also the reverse transcriptase of hepatitis B. It needs to be phosphorylated to its triphosphate form before it is active. 3TC-triphosphate also inhibits cellular DNA polymerase. • Lamivudine is administered orally, and it is rapidly absorbed with a bio-availability of over 80%. • Lamivudine is often given in combination with zidovudine, with which it is highly synergistic.

4. Long-term monotherapy with lamivudine is associated with methionine-to-valine (M204V) or methionine-to-isoleucine (M204I) mutations, • primarily at amino acid 204 in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of HBV DNA polymerase • managed by adding another antiviral to which YMDD variants are sensitive : adefovir • lamivudine has been eclipsed by more potent antivirals that have superior resistance profiles • patients with cirrhosis or advanced fibrosis: effective in reducing the risk of progression to hepatic decompensation. • Because lamivudinemonotherapy can result universally in the rapid emergence of YMDD variants in persons with HIV infection • patients with chronic hepatitis B should be tested for anti-HIV prior to therapy • if HIV infection is identified, lamivudinemonotherapy at the HBV daily dose of 100 mg is contraindicated • These patients should be treated with triple-drug antiretroviral therapy, including a lamivudine daily dose of 300 mg.

5. The safety of lamivudine during pregnancy has not been established; however, the drug is not teratogenic in rodents and has been used safely in pregnant women with HIV infection and with HBV infection.

6. AdefovirDipivoxil • oral daily dose of 10 mg • equally effective in treatment-naïve patients and IFN nonresponders • In HBeAg-reactive chronic hepatitis B, a 48-week course of adefovirdipivoxil was shown to achieve • histologic improvement (and reduce the progression of fibrosis) and normalization of ALT in half of patients • HBeAgseroconversion in 12%, HBeAg loss in 23%, and suppression to an undetectable level of HBV DNA in 20–30%, as measured by PCR

7. Adefovir works by blocking reverse transcriptase, an enzyme that is crucial for the hepatitis B virus (HBV) to reproduce in the body. • It is approved for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (primarily ALT) or histologically active disease.

8. Adefovir contains a flexible acyclic linker instead of the L-nucleoside ring of lamivudine, avoiding steric hindrance by mutated amino acids. • In addition, the molecular structure of phosphorylatedadefovir is very similar to that of its natural substrate; therefore mutations to adefovir would also affect binding of the natural substrate, dATP. • Hypothetically, these are among the reasons that resistance to adefovirdipivoxil is much less likely than resistance to lamivudine;

9. Among patients co-infected with HBV and HIV and who have normal CD4+ T cell counts, adefovirdipivoxil is effective in suppressing HBV dramatically (by 5 logs10 in one study). • Moreover, adefovirdipivoxil is effective in lamivudine-resistant, YMDD-mutant HBV and can be used when such lamivudine-induced variants emerge. • Adverse effect: nephrotoxicity

10. For patients with underlying renal disease, adefovir dipivoxil dose reductions are recommended: • administration reduced to every 48 h for creatinine clearances of 20–49 mL/min • every 72 h for creatinine clearances of 10–19 mL/min • once a week, following dialysis, for patients undergoing hemodialysis.

11. Pegylated Interferon • treatment of hepatitis C and chronic hepatitis B • once-a-week PEG IFN was more effective than the more frequently administered, standard IFN

12. PEG-interferon alfa-2a • his drug is approved around the world for the treatment of chronic hepatitis C (including patients with HIV co-infection, cirrhosis, 'normal' levels of ALT) and has recently been approved (in the EU, U.S., China and many other countries) for the treatment of chronic hepatitis B. • Peginterferon alfa-2a is a long acting interferon. Interferons are proteins released in the body in response to viral infections. Interferons are important for fighting viruses in the body, for regulating reproduction of cells, and for regulating the immune system

13. PEG-interferon alpha-2b • One of the major mechanisms of PEG-interferon alpha-2b utilizes the JAK-STAT signaling pathway. • PEG-interferon alpha-2b will bind to its receptor, interferon-alpha receptor 1 and 2 (IFNAR1/2). • Upon ligand binding the Tyk2 protein associated with IFNAR1 is phosphorylated which in turn phosphorylates Jak1 associated with IFNAR2. This kinase continues its signal transduction by phosphorylation of signal transducer and activator of transcription (STAT) 1 and 2 via Jak 1 and Tyk2 respectively. The phosphorylated STATs then dissociate from the receptor heterodimer and form an interferon transcription factor with p48 and IRF9 to form the interferon stimulate transcription factor-3 (ISGF3). This transcription factor then translocates to the nucleus where it will transcribe several genes involved in: cell cycle control, cell differentiation, apoptosis, and immune response.[4][5] • PEG-interferon alpha-2b acts as a multifunctional immunoregulatory cytokine by transcribing several genes, including interleukin 4 (IL4). • This cytokine is responsible for inducing T helper cells to become type 2 helper T cells. • This ultimately results in the stimulation of B cells to proliferate and increase their antibody production. • This ultimately allows for an immune response, as the B cells will help to signal the immune system that a foreign antigen is present.[6] • Another major mechanism of type I interferon alpha (IFNα) is to stimulate apoptosis in malignant cell lines. Previous studies have shown that IFNα can cause cell cycle arrest in U266, Daudi, and Rhek-1 cell lines.