SHEEHY Viral Pharmacology

Question 1

Asymptomatic carrier
Chronic‐persistent hepatitis
Chronic‐active hepatitis
What should patients with chronic HBV avoid?

Answer 1

Asymptomatic carrier
• Never develops antibodies against HBsAg • Harbors the virus without liver injury
• ~200 million HBV carriers in the world

Chronic‐persistent hepatitis
• Low grade smoldering hepatitis

Chronic‐active hepatitis
• Acute hepatitis state that continues without normal recovery (longer than 6‐12
months)

Avoid EtOh, acetaminophen < 2 gm a day

Question 2

Interferon α and Interferon-α2

1. what are they?
2. what is their function?
3. when are they primarily used?

Answer 2

Interferons are host cytokines

they exert complex antiviral, immunomodulatory, and anti-proliferative actions

Interferon α‐2b:
• PEGylated interferon α‐2b
• PEGylated interferon α‐2a

Primarily used for treatment of patients with well compensated liver disease who does not want to be on long‐term treatment or is planning to be pregnant within the next 2‐3 years

Question 3

Pros of interferons in the tx of HBV

Answer 3

Pros
• Shorter course (24‐48 weeks) 
• Good efficacy
• Decreased HBV DNA
• Decreased HBeAg
• Acquired resistance is rare

Question 4

Cons of interferons in tx of HBV

Answer 4

Parenteral administration
Expensive
LOTs of adverse effects (chills, myalgias, flu like symptoms)
dangerous in decompensated livers

Question 5

how endogenous interferons work

Answer 5

endogenous interferons
• Infected cells release interferons to protect nearby healthy cells by allowing them to mount a defense
• Interferons signal nearby macrophages and natural killer cells (innate immune system) to clear the infected cell
• Interferons act in an autocrine fashion to stimulate lysosome lysis which leads to the lysis of the infected cell

Question 6

pregnant women and HBV

Answer 6

All pregnant women need to be tested for HBV infection.

The immediate administration of hepatitis B immune globulin and HBV vaccination following deliver (<12hrs) is recommended for all infants born to HBsAg(+) women

Question 7

IFN receptor

Answer 7

IFN receptor binding activates JAK1 and Tyk2
→ JAK1 and Tyk2 phosphorylate IFN receptor
→ Phospho-IFN receptor recruits STATs 1 and 2
→ JAK and Tyk2 phosphorylate STATs
→ phospho-STATs “undock” from IFN receptor and dimerize
→ phosph-STATs relocalize to the nucleus
→ ISGF3:DNA complex upregulates transcription of interferon stimulated genes (ISGs)

The proteins encoded by these genes (2’5’-OAS, PKR, ADAR, MxA…) are responsible for the antiviral, cytostatic and immunomodulatory activities of type I IFNs
2’5’ OAS (oligo-adylate synthase) - creates pentamer of oligo-adenylates that activates ribonuclease ⟹ degrades viral ribonuclear proteins
PKR (protein kinase R) - phosphorylates part of translation machinery (elongation initiation factor) ⟹ inhibits protein synthesis

Question 8

ISGF3:DNA complex

Answer 8

→ ISGF3:DNA complex upregulates transcription of interferon stimulated genes (ISGs)
The proteins encoded by these genes (2’5’-OAS, PKR, ADAR, MxA…) are responsible for the antiviral, cytostatic and immunomodulatory activities of type I IFNs
2’5’ OAS (oligo-adylate synthase) - creates pentamer of oligo-adenylates that activates ribonuclease ⟹ degrades viral ribonuclear proteins
PKR (protein kinase R) - phosphorylates part of translation machinery (elongation initiation factor) ⟹ inhibits protein synthesis

Question 9

dangerous in decompensated cirrhosis

Answer 9

Interferon-alpha or PEG-IFNα

Question 10

Influenza-like syndrome after injection (fever, chills, myalgia, arthralgia)
Fatigue and mental depression

Answer 10

Adverse Effects of PEGylated IFNα

80-90% of pts experience some adverse effects- often improve with continued administration

Question 11

Nucleos(t)ides for Tx of HBV infection

Answer 11

Nucleoside or nucleotide analog viral reverse transcriptase and DNA polymerase inhibitors

Question 12

can be used in patients with compensated or decompensated cirrhosis

Answer 12

nucleos(t)ides

Question 13

NTRI

Answer 13

NTRI (nucleotide reverse transcriptase inhibitors) are pro-drugs that require conversion into their corresponding nucleotide triphosphates, which are the active anti-viral agents, in hepatocytes harboring HB

Question 14

NTRI

Answer 14

NTRI (nucleotide reverse transcriptase inhibitors) are pro-drugs that require conversion into their corresponding nucleotide triphosphates, which are the active anti-viral agents, in hepatocytes harboring HB

Question 15

the nucleoside analogs

Answer 15

telbivudine, lamivudine, entacavir

Question 16

nucleotide monophosphates

Answer 16

adefovir, tenofovir

Question 17

adefovir and tenofovir are useful when?

Answer 17

in patients resistant to nucleoside analogs such as lamivudine, entecavir, and telbivudine

Question 18

adefovir, entacovirm

Answer 18

adenosine, guanosine, tenofovir