Dr. Stahelin Hepatitis

Question 1

Ribavirin

Answer 1

• Guanosine analog with incomplete purine ring. Phosphorylated by cellular kinases to the triphosphate form
• SOA: influenza A and B, Hep A/B/C, genital herpes, herpes zoster, measles, hantavirus, Lassa fever virus
• MOA: not definitively known; inhibition of inosine monophosphate dehydrogenase (IMPDH) - reduces GTP levels, direct inhibition of viral RNA polymerase, incorporation into viral RNA leading to error catastrophe

Question 2

Simeprevir and Paritaprevir

Answer 2

• MOA: targets the HCV protease NS3 and blocks cleavage of the HCV polyprotein
• second-generation NS3 inhibitors (P1 and P3 substrate analogs)
• -resistance: mutations in NS3 active site. Low genetic barrier of resistance. Retain activity against some NS3 mutants that are resistant to 1st generation HCV PIs-macrocyclic peptides
• non-covalent inhibitors
• all are substrates of CYP3A4 and are weak inhibitors

Question 3

Grazoprevir ad Voxilaprevir

Answer 3

• MOA: target the HCV protease NS3 and block cleavage of the HCV polyprotein
• second-generation NS3 inhibitor (P2 and P4 substrate analogs)
• resistance: mutations in NS3 active site. Low genetic barrier of resistance. Retain activity against some NS3 mutants that are resistant to 1st generation HCV PIs

Question 4

Sofosbuvir

Answer 4

• NS5B = HCV RNA polymerase
• Nucleoside RNA polymerase inhibitor - pro-drug of 2’-deoxy-2’-fluoro-2’-C-methyluridine monophosphate
• converted to monophosphate by liver enzymes and triphosphorylated by cellular nucleotide kinases (Uridine-cytidine monophosphate kinase (YMPK) and nucleoside diphosphate kinase (NDPK)).
• MOA: incorporated in viral RNA chain and causes chain termination (2’-methyl group is critical)
• genetic barrier for resistance - single mutation in active site (S288T)

Question 5

Dasabuvir

Answer 5

• non-nucleoside RNA polymerase inhibitors
• 7000 fold selectivity for HCV RNA polymerase
• NS5B - has 5 known binding sites; 1 catalytic site and 4 allosteric sites
• MOA: binds to palm I site of HCV RNA polymerase, this prevents conformation changes and blocks nucleotide incorporation into viral RNA
• a genetic barrier for resistance

Question 6

Daclatasvir (1st gen), Velpatasvir (2nd gen), Pibrentasvir (2nd gen)

Answer 6

• NS5A is required for HCV RNA replication, but the exact mechanistic role is unknown. These HCV NS5A inhibitors bind tightly to NS5A and inhibit both viral RNA replication and assembly or release of infectious particles.
• Resistance: occur in the first 100 amino acids. 1st generation has low genetic barriers and it varies between genotypes. SIngle mutations confer high resistance and there are similar resistance patterns among 1st gen. 2nd generations have higher genetic barrier to resistance among the NS5A inhibitors.
• Retains activity against common resistance-associated substitutions (RAS)

Question 7

Lamivudine

Answer 7

incorporated into viral DNA and causes DNA chain termination in HBV

Question 8

HBV reactivation

Answer 8

• HBV reactivation has occurred in patients co-infected with HCV while undergoing treatments with direct acting antivirals.
• HBV reactivation is defined as abrupt increase in HBV replication: rapid increase in serum HBV DNA level and detection of hepatitis B surface antigen (HBsAg) in a person who was previously negative but was positive for HBV core antibody