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GI Week 4 > Lecture 43: Pharmacotherapy of Hepatobiliary disease, viral hepatitis > Flashcards

Lecture 43: Pharmacotherapy of Hepatobiliary disease, viral hepatitis Flashcards

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1
Q

Where do drugs try to intervene to stop decompensated cirrhosis and HCC?

A

From normal to chronic hepatitis/fibrosis
And chronic hepatitis/fibrosis to cirrhosis
Cirrhosis to decompensated cirrhosis and HCC

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2
Q

What are the signs of decompensated cirrhosis?

A
  1. Ascites
  2. Hepatic Encephalopathy
  3. Variceal Bleeding
  4. Jaundice
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3
Q

What are the key characteristics of the HCV viral life cycle?

A
  1. virus binds to receptor
  2. endocytosis of HCV
  3. fusion and uncoating of the HCV, release of ssRNA to form polyprotein precursor
  4. Translation into polyprotein precursor
  5. Polyprotein processing by NS5A, NS3/4A cofactors (cleaves polyprotein from HBV ssRNA)
  6. NS5B RNA dependent RNA polymerase used to form negative template for RNA (to pair with ssRNA)
    This allows virus to proliferate into vesicles
    Leads to release of vesicles
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4
Q

What is the viral replication rate of HCV?

A

10^12

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5
Q

What is the significance of lack of proofreading activity in HCV?

A

High mutation rate because no proof reading activity in RNA polymerase

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6
Q

What are the genotypes of HCV? Significance?

A

Genotype 1 = 75%
Genotype 2 = 15%
Genotype 3, 4, 5, 6 = 10%
No impact on severity of liver injury but helps with HCV therapy

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7
Q

What is the natural history of HCV?

A 
Acute = 15% resolved
85% goes to chronic
Out of those 85% chronic, 80% are stable
20% of chronic go to cirrhosis
About 95% of cirrhotic livers go to 
Slowly progressive
About 5% of cirrhotic livers go to
HCC/decompensated cirrhosis
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8
Q

What are the risk factors for progressing to cirrhotic liver?

A
  1. Age > 40
  2. Male
  3. Caucasian and Hispanic
  4. smoking (cigarettes and cannabis)
  5. concomitant alcohol,, HBV, obesity, insulin resistance, Immunocompromised
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9
Q

What are the factors that determine the likelihood of response of chronic HCV to therapy?

A
  1. Genotype
  2. Viral load
  3. Genetic polymorphism IL28B (very FAVORABLE to be treated)
  4. fibrosis, obesity, HIV = Unfavorable to be treated
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10
Q

What is the significance of the IL28B polymorphism in HCV?

A

It is very FAVORABLE to treatment

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11
Q

What is the gold standard for response to HCV treatment? What is it defined by?

A

Sustained Viral Response (SVR)
Defined as the absence of detectable HCV in blood 6 months after the end of the course of therapy
<1% chance of relapse after SVR
Achieving SVR associated with
i. 5x reduction in risk of HCC
ii. Virtual elimination of the risk of hepatic decompensation

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12
Q

Up to 2011, what was the standard of care for chronic HCV?

A
  1. Pegylated interferon once per week subcutaneously
    +
  2. PO Rivabirin daily
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13
Q

What is the phenomenon of viral interference?

A

The capacity of tissue infected with one virus to resist infection with another

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14
Q

What does the term “interferon” refer to?

A

A substance that mediates the phenomenon of viral interference

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15
Q

What is the MoA of interferon on HCV?

A

Multiple mechanisms

  1. Immune Activation
    i. Enhances MHC-I expression
    ii. Amplification of Tc lymphocytes, NK cells
    iii. Enhanced Macrophage activity
  2. Potential DIRECT antiviral activity
    i. inhibition of HCV attachment and uncoating
    ii. Activation of cellular RNAses
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16
Q

What are the side effects of interferon?

A 
FLU-LIKE SYMPTOMS
Many adverse reactions like
i. depression/suicide
ii. pancytopenia
iii. activation of autoimmune diseases (thyroiditis)
iv. weight loss
v. infection, mostly in cirrhosis
vi. worsening of liver functioning in cirrhosis
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17
Q

What are the key characteristics of Ribavirin (RBV)?

A
  1. Guanosine analogue
  2. Initially developed as potential HIV treatment
    • not effective in HIV but patients had improvement in ALT
  3. Ineffective for HCV as monotherapy but increases the rate of SVR when combined with interferon
    • reduces rate of relapse after stopping treatment
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18
Q

What is the MoA of ribavirin?

A
  1. Inhibition of viral RNA-dep RNA polymerase (NS5B?)
  2. Induction of lethal mutations in HCV RNA
  3. GTP depletion (inhibits IMP dehydrogenase)
  4. Modulations of T cell response favoring TH1
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19
Q

What are the side effects of ribavirin?

A
  1. non-immune hemolytic anemia
  2. rash
  3. dyspnea
  4. teratogenic (women in childbearing age must use contraception)
  5. contraindicated in chronic renal failure
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20
Q

What is predictive of likelihood of SVR (sustained viral response)?

A

Rate of decline in viral load

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21
Q

What is the impact of genotype on treatment?

A

Genotype 1 = 48-72 weeks of treatment, SVR rate = 40%
Genotype 2,3 = 24 weeks of treatment, SVR rate = 80%
This is for interferon + ribavirind

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22
Q

What is the function of NS5B?

A

NS5B is a RNA dependent RNA polymerase (RdRp) that creates a negative strand to pair with the positive strand of HCV’s initial ssRNA

23
Q

What is the function of NS3/4?

A

Protein that cleaves the initial HCV protein into polypeptides fragments before processing for transcription
AKA HCV proteases, so those who target NS3/4 are protease inhibitors

24
Q

What are the types of directly acting antivirals (DAAs)?

A
  1. HCV protease inhibitors
    a. Telaprevir (TPV)
    b. Boceprevir (BOC)
    MoA = inhibiting NS3/4
  2. Viral RNA-polymerase (NS5B) inhibitor)
    Sofusbuvir
  3. Protease inhibitor
    Simeprevir
    2 and 3 = end of 2013
25
Q

What is a drawback in DAA monotherapy for HCV?

A

Mutations in monotherapy = evolution for adaptation

26
Q

What is Boceprevir/Telaprevir used for?

A

ONLY genotype 1
In addition to Peg IFN + RBV
Increases VR to 70%

27
Q

What are the adverse effects of viral protease inhibitors (TPV, BOC)?

A
  1. anemia
  2. rash
  3. dysgeusia
  4. interact with ARVs in HIV patients
  5. interact with calcineurin (immunosuppression given to patients that have liver transplant)
  6. 3 times a day dosing
28
Q

What is calcineurin?

A

A protein phosphatase that is PPP3CA

Activates T cells of immune system and can be blocked by drugs

29
Q

What is the viral structure of HBV?

A

Hepadnaviridiae family

Partially dsDNA

30
Q

What are the key protiens of HBV?

A
  1. Pre-Cor protein
  2. HBcAg
  3. HbeAg
  4. HBsAg
  5. HBx
31
Q

How is the HbeAg formed?

A

The precursor is Pre-Cor protein

It is formed in the golgi

32
Q

What is the siginificance of HbeAg?

A

“e” antigen is a marker of HBV replication

33
Q

What is the most important step of HBV replication?

A

HBV turns into cccDNA (covalently, closed circular DNA)

34
Q

What is the significance of cccDNA?

A

It is very difficult for drugs to eradicate the cccDNA of HBV, so therefore HBV treatments are not very effective

35
Q

What is the difference between HBV and HCV treatment?

A

HBV treatment is a lot less effective because of cccDNA

HCV can be cleared while HBV is hard to clear

36
Q

What is the immune response to HBV?

A
  1. Replication of the virus does little direct damage to hepatocytes
  2. The hepatic injury is mostly due to the immune response to the virus
  3. The degree of immune tolerance to Hep B will determine whether a chronic infection will develop
    • HBsAg positive > 6 months
37
Q

What does an HBsAg positive test mean for HBV infection?

A

It means HBV will last for more than 6 months

38
Q

What are the phases of Chronic Hep B?

A
  1. Inactive carrier state (happens most often when infected as an infant)
  2. eAg positive Hep B (actively replicating)
  3. eAg negative Hep B (not actively replicating)
39
Q

Can patients who are inactive carriers because eAg +/- chorinc hep B?

A

Yes, if they have a FLARE

40
Q

What does the serology profile of ALT nl, High DNA and eAg pos/eAb negative?

A

Tpical INITIAL phase of perinatally acquired infection

41
Q

What are indications for HBV treatment?

A
  1. Elevated ALT
  2. Elevated HBV DNA
  3. Patients with cirrhosis and detectable HBV DNA
42
Q

What is the endpoints of therapy for chronic Hep B?

A
  1. eAg loss/seroconversion
    • because eAg seroconversion is associated with decreased risk of HCC and liver decompensation
  2. DNA suppression
    • because patients with higher DNA levels are more likely to develop HCC and cirrhosis
  3. Biochemical response
    • normalization of ALT associated with improvement in histology and with virologic response
  4. Histological response
    • improvement in liver histology (inflammation/fibrosis) on treatment
  5. HBsAg loss
    • can occur spontaneously and seen rarely on therapy
43
Q

What are the pharmacological agents used for chronic hepatitis B?

A
  1. Viral polymerase inhibitors (oral agents)

2. Pegylated interferon alpha 2a

44
Q

What are the types of viral polymerase inhibitors for HBV therapy?

A
  1. Lamivudine
  2. Telvibudine
  3. Entecavir
  4. Adefovir
  5. Tenofovir
45
Q

What is the treatment of eAg positive chronic HBV?

A
  1. oral agents/viral polymerase inhibitors
  2. pegylated interferon for 12 months
    Goal is to have eAg seroconversion (conver to eAb positive and eAg negative)
46
Q

What is the treatment of eAg negative chronic HBV?

A

Anytime you stop therapy you get a FLARE!!
1. oral agents
2. PegIFN
Goal is long term DNA suppression

47
Q

What are the advantages of interferon in chronic HBV?

A
  1. finite course of therapy

2. no viral resistance

48
Q

What are the disadvantages of interferon?

A
  1. high relapse rate in eAg negative chronic HBV
  2. Limited efficacy in high HBV DNA and low ALT
  3. other side effects (seen above)
  4. cannot use in patients with decompensated liver disease
49
Q

What is the type of HBV that requires constant treatment?

A

eAg NEGATIVE HBV needs continual treatment or else will get a flare

50
Q

What are the advantages of oral agents/nucleoside analogues/viral polymerase inhibitors?

A
  1. well tolerated
  2. useful in eAg negative patients as longterm treatment is needed
  3. useful in patients with decompensated cirrhosis
51
Q

What treatment for HBV do you give for patients with decompensated cirrhosis?

A

Oral agents like Tenofovir

52
Q

What are the disadvantages of oral agents/nucleoside analgoues/viral polymerase inhibitors?

A
  1. development of drug resistant mutants to drugs like Lamivudine
    YMDD mutation, 70% at 4 years
  2. long term therapy required
  3. occasional post-withdrawal flares
53
Q

What is YMDD mutation?

A

The mutation that occurs when you give too much Lamivudine

54
Q

Why is Lamivudine not used?

A

Because of YMDD mutation, HBV has adapted to the drug

GI Week 4 (12 decks)

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