TREATMENT OF LIVER DISEASES (HEPATITIS ‘B’ & HEPATITIS’C )’

1. TREATMENT OF LIVER DISEASES (HEPATITIS ‘B’ & HEPATITIS’C )’ DR.FAROOQ ALAM M.B.B.S-M.Phil 10 février 2012

2. Treatment • The complicated Hepatitis – Chronic hepatitis requires expensive treatment – antiviral drugs – Lamivudine and immune modulators – Interferons. • Unfortunately such treatments are not with good success. • Once Cirrhosis is established or Liver cancer starts the treatment is only Liver transplantation which is the most expensive therapy.

3. Therapies for Chronic Hepatitis B Mechanism of action of Interferon

4. These interferons induce about 20-30 proteins, three of the proteins that appear to play an important role in the induction of the anti-viral effects are; • Expression of one of these proteins (2’5’ oligo A synthase) results in activation of the • second of these proteins (a ribonuclease) which can break down mRNA • Expression of the third protein (a protein kinase) results in inhibition of the initiation step of protein synthesis.

5. These activities target viral protein synthesis, but also result in inhibition of host protein synthesis. Thus it is important that these proteins are only made and activated when needed. • Double-stranded RNA is needed for activation of these proteins. • Thus, these potentially toxic pathways are only activated in the interferon-treated cell if double-stranded RNA is made, this will usually only happen if virus infection actually occurs. • The activation of these proteins may sometimes result in the death of the cell.

7. INTERFERON Uses: Side effects: Flu-like symptoms. Depression and suicide. Renal Adverse Events . Hematologic Adverse Events. Cardiovascular Adverse Events Ophthalmic Adverse Events. Endocrine Adverse Events. Infections . Autoimmune Adverse Events. Injection side reaction. • Antiviral, antiseptic and antioncogenic properties when administered as drugs.

8. Contraindication • History of major depressive illness. • Active alcohol use. • Cytopenia (more than one type of blood cell deficiency) . • Hyperthyroidism (overactivity of the thyroid gland) . • Renal transplantation. • Autoimmune disease .

9. Adefovir DipivoxilProposed Indication • Adefovirdipivoxil is indicated for the treatment of chronic hepatitis B in adults with evidence of active liver disease • Oral prodrug of adefovir • Nucleotide analog of adenosine monophosphate • Potent in vitro activity against hepadnaviruses, retroviruses, and herpes viruses • Competitive inhibitor of HBV DNA polymerase • Long intracellular half-life (12-36 hours)

10. Adefovir Dipivoxil Pharmacokinetics • Oral bioavailability 59%, T1/2  7 hours • Pharmacokinetics not affected by food, chronic hepatitis B disease, demographic characteristics • Not substrate or inhibitor of CYP450 • No clinically relevant drug-drug interactions • Change in dosing interval required in patients with moderate to severe renal impairment • Increased exposure with CLcr < 50 mL/min • Lamivudine, acetaminophen, ibuprofen, trimethoprim/sulfamethoxazole • No dose alteration for hepatic impairment

11. Lamivudine (3TC, Epivir) • Nucleoside analog • Well-tolerated and cheap • High rates of resistance! • 47% develop YMDD (YMDD locus of the HBV reverse transcriptase gene) mutation at 2 yrs, 90% at 4 yrs

12. Entecavir (Baraclude) • Nucleoside analog • Good for LAMIVUDINE failures • Cross-resistance can occur with LAMIVUDINE • Entecavir is use in HBV patients

13. TREATMENT OF HEP-C

14. Boceprevir (Victrelis) Indications • In combination with Peg-interferon alfa (Pegylation is the process of covalent attachment of polyethyleneglycol (PEG) polymer chain to another molecule { normally a drug OR therapeutic protein} and Ribavirin • Chronic HCV genotype 1 infection • Adults (> 18 years of age) with compensated liver disease, including cirrhosis • Treatment-naïve or failed prior interferon & ribavirin therapy

15. Adverse Effects: • Anemia • nausea • dysgeusia (distortion of the sense of taste)

16. Drug Interactions Potential for Boceprevir to Affect Other Medications -Bocepreviris strong inhibitor of CYP3A4/5 enzyme-Bocepreviris potential inhibitor of p-glycoprotein (P-gp) Potential for Other Medications to Affect Boceprevir-Boceprevirprimarily metabolized by aldo-ketoreductase (AKR)- Boceprevir may be co-administered with aldo-ketoreductase inhibitors- Partially metabolized by CYP3A4/5- Potential for interactions with drugs that inhibit or reduce CYP3A4/5

17. Ribavirin • Synthetic nucleoside analogue • Structurally resembles guanosine • Broad spectrum antiviral - DNA & RNA • Also used in Rx of respiratory syncitial virus

18. Ribavirin - mechanisms of action • Antiviral -inhibits 5’CAP (is a specially altered nucleotide on the 5th end of precursor mRNA & some other primary RNA transcripts as found in eukaryotes. The presence of 5 capping is vital to creating mature mRNA, which is then able to undergo translation) - inhibits RNA polymerase - inhibits IMP dehydrogenase

19. Telaprevir (Incivek) Indications • In combination with Peg-interferon-alfa and Ribavirin (PR) • Chronic HCV genotype 1 infection • Adults (> 18 years of age) with compensated liver disease, including cirrhosis • Treatment-naïve or prior interferon-based treatment Adverse Effects. • Rash, anemia, nausea, fatigue, headache, diarrhea, pruritus, and anal or rectal irritation and pain

20. Interferons • Interferons (IFN) are glycoproteins which stimulate the immune system. IFN-α can be injected into the bloodstream as a treatment of HCV. • More recently PEGylated-IFN-α’s have been used. • PEG gives the IFN- α better PK properties such as solubility and half-life.