Anti-viral Pharm for Hep B and C infx (Fitz)

Question 1

list the biological agents used for tx of chronic hep B infx

Answer 1

IFN alpha-2b
PEG-IFN alpha-2b
PEGylated IFN alpha-2a

Question 2

list the nucleos(t)ide reverse transcriptase inhibitors used for tx of chronic hep B infx

Answer 2

Entecavir (guanosine)
Tenofovor (adenosine) for HBV and HIV
Lamivudine (cytosine) for HBV and HIV
Telbivudine (thymidine)

Question 3

this class of hepatitis drugs are primarly used for tx of pts with well-compensated liver disease who do not wish to be on long-term tx or are planning to be pregnant within the next 2 or 3 years

Answer 3

IFN-alpha formulations

Question 4

list some cons for the use of IFN-a or PEG-IFN-a tx of chronic HBV infx:

Answer 4

DANGEROUS IN DECOMPENSATED CIRRHOSIS
parenteral
expensive
side effects such as flu-like syndrome, fever, myalgia

Question 5

the ISGF3:DNA complex upregulates this transcription factor through the use of IFN-a

Answer 5

IFN stimulated genes (ISG)

Question 6

ISG degrades viral RNA through this MOA:

Answer 6

ISG –> 2’5’ OAS –> 2’5’-AAA activates Ribonuclease L

Question 7

ISG inhibits protein synthesis through this MOA:

Answer 7

ISG –> PKR –> Phospho-eIF

Question 8

IFN-a (via IFN-y) favors this immune-mediated phenotype and ultimately leads to this negative effect:

Answer 8

cell-mediated Th1

increased inflammation and fibrosis

Question 9

aside from decompensated cirrhosis, what are some other adverse effects of IFN-a?

Answer 9

Flu-like syndrome after injection
fatigue and mental depression

Dose-limiting toxicity: BM suppression; Neurotoxicity-behavioral changes

Question 10

when are nucleoside or nucleotide analog viral RT inhibitors with potent anti-HBV activity used?

Answer 10

for chronic, suppressive, oral single agent tx

These are much better tolerated than IFN-containing regimens but are NOT USUALLY CURATIVE.

CAN BE USED IN PTS WITH DECOMPENSATED OR COMPENSATED CIRRHOSIS

Question 11

what is the MOA of nucleos(t)ides?

Answer 11

inhibit viral RT/DNA polymerase

Question 12

NRTIs are pro-drugs that require conversion into their corresponding __, which are the ACTIVE anti-viral agents, in hepatocytes harboring HBV

Answer 12

nucleotide tri-phosphates

Question 13

list some HBV resistance mechanisms to nucleos(t)ides

Answer 13

• impaired purine/pyrimidine kinase activity

- mutation of DNA polymerase

Question 14

this nucleotide analog is usueful in pts resistant to lamivudine, telbivudine, and entecavir

Answer 14

tenofovir

Question 15

list the 1st line oral anti-HBV agents

Answer 15

tenofovir

entecavir

Question 16

list the 2nd line oral anti-HBV agents

Answer 16

lamivudine

telbivudine

Question 17

__ is a 1st line tx for wild-type HBV, and as an additional tx in pts with lamivudine, telbivudine, or entecavir resistance

Answer 17

tenofovir

resistant to tenofovir is rare

nephrotoxicity has been encountered at the dose used for HBV tx but occurs more often with higher doses used for HIV tx

Question 18

this 1st line oral anti-HBV agent has potent anti-viral activiy and a low rate of drug resistance. It may be Resistance to this drug occurs in ~50% of lamivudine-resistant pts after 5 yrs of tx. it may be a better option than adefovir or tenofovir in pts with renal insufficiency and in those who are at risk for renal insufficiency

Answer 18

Entecavir

Question 19

long-term efficacy of lamivudine is limited by ___

Answer 19

frequent emergence of drug-resistant HBV (YMDD –> YVDD mutant in catalytic domain of HBV polymerase) and subsequent virological breakthrough

Question 20

list the biological agents used to tx hep C infx

Answer 20

PEG-IFN a-2b

Pegylated IFN a-2a

Question 21

list a nucleoside used to tx hep C infx

Answer 21

Ribavirin

Question 22

list direct acting anti-viral agents used to tx hep C infx

Answer 22

Simeprevir (NS3/4A protease)
Sofosbuvir (NS5B RNA dependent RNA polymerase)
Ledipasvir (NS5A)

Question 23

what is the HCV infx standard of care (through 2011)?

Answer 23

PEG-interferon PLUS ribavirin for 24-48 weeks

Question 24

Ribavirin-monophosphate has what anti-viral effect in hep C tx?

Answer 24

inhibits IMP dehydrogenase –> inhibits purine synthesis and salvage

Question 25

Ribavirin-triphosphate has what anti-viral effect in hep C tx?

Answer 25

inhibits RNA-dependent RNA polymerase –> inhibits RNA replication

Question 26

what is the immunomodulatory MOA of ribavirin?

Answer 26

potentiates IFN action. Alters the balance between proinflammatory (Th1 and Th2) cytokines

Question 27

how is ribavirin metabolized? How is it cleared? where does it tend to get concentrated?

Answer 27

hepatic metabolism

renal clearance (t1/2 ~1 day)

60x concentrated in erythrocytes (t1/2 ~40 days!!)

Question 28

List contraindications of ribavirin:

Answer 28

• causes hemolytic anemia and is contraindicated in pts with anemia
• Pregnancy category X. May cause birth defects and fetal death. Pts must have a negative pregancy test prior to therapy and have monthly pregnancy test during therapy and 6 months post therapy

Question 29

direct-acting anti-viral agents interfere with HCV replication by inhibiting key viral enzymes such as __

Answer 29

NS3/4A serine protease, NS5B polymerase, and NS5A

Question 30

simeprevir is a __ inhibitor

Answer 30

NS3/4A protease inhibitor

Question 31

Ledipsasvir is a __ inhibitor

Answer 31

NS5A inhibitor

Question 32

Sofosbuvir is a ___ inhibitor

Answer 32

NS5B polymerase inhibitor

Question 33

__ block the NS3 catalytic site or the NS3/4A interaction

Answer 33

protease inhibitors

Question 34

__ is a 2nd gen protease inhibitor. Used in combo with PEG-IFN and ribavirin or in combo with sofosbuvir +/- ribavrin for chronic genotype 1 infx

Answer 34

simeprevir

Question 35

these inhibitors play a role in both viral replication and the assembly of the HCV

Answer 35

NS5A inhibitors

Question 36

__ is a potent inhibitor of NS5A, effective across all genotypes, but with a low barrier to resistance. NS5A inhibitors significantly reduce HCV RNA levels when given with PEG-IFN and ribavirin

Answer 36

Ledipasvir

Question 37

__ is the first NS5B inhibitor availabe in the US. It is used in combo with other anti-virals, including Ledipasvir

Answer 37

Sofosbuvir