Pharmacotherapy of Hepatitis

Question 1

Describe the “natural history” of HCV

Answer 1

From chronic infection it typically takes 20-30 years to become cirrhotic (20%). From there 5% progress to HCC within 1 year.

Question 2

What factors are associated with increased progression of liver injury? Demographic, liver, immune system

Answer 2

Demographic factors: age>40, male, caucasian/hispanic, smoking

Liver injury: alcohol, HBC, obesity, insulin resistance

Immunocompromised: HIV, OLT

Question 3

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

Answer 3

Host: age>40, male, AA, obesity, advanced fibrosis/cirrhosis, HIV, OLT, genetic polymorphism (IL28B)

Viral factors: genotype, viral load

Question 4

What is the gold standard for HCV treatment?

Answer 4

Sustained viral response– absence of detectable HCV in blood 24wks or 12wks after end of course of therapy

Question 5

What was old mainstay of treatment until 2011?

Answer 5

IFN-alpha

Ribavirin

Question 6

What are the MOAs of IFNalpha? (2)

Answer 6

Immune activation: enhances MHC-I expression, amplifies T lymphocytes/NK cells, enhances macrophage activity

Direct antiviral activity: inhibits HCV attachment and uncaring, activation of cellular RNAses

Question 7

What are AE of IFN alpha? (7)

Answer 7

Flu-like symptoms
Depression/suicide
BM suppression 
Activation of autoimmune disease
Weight loss
Bacterial infections
Worsening of liver function in cirrhosis

Question 8

What are MOAs of ribavirin? (4)

Answer 8

Inhibit RNA-dependent RNA polymerase
Induces lethal mutations in HCV RNA
GTP depletion
Modulation of T cell response favoring Th1

Question 9

What are AE of ribavirin? (4)

Answer 9

Non-immune hemolytic anemia
Rash
Dyspnea
Teratogenic

Question 10

What are the differences in genotype in treatment response?

Answer 10

Genotype 1: Longer treatment course (48-72wks), only 40% SVR

Genotype 2/3: 24wks of treatment produces 80% SVR

Question 11

What are categories of currently approved directly acting antiviral drugs? (3)

Answer 11

HCV protease (NS3/4A) inhibitors: telaprevir
Viral RNA-dependent RNA-polymerase (NS5B) inhibitors: Sofosbuvir
Combination pills: Harvoni (ledipasvir+sofosbuvir) and Viekira

Question 12

Describe the current HCV treatment guidelines and the chances of SVR

Answer 12

Genotype 2: sofosbuvir+ribavirin for 12wks
Genotype 3: SOF+RBV for 24wks
SVR=70-90%

Genotype 1: Harvoni/Viekira + ribavirin
SVR=94-99%

Question 13

What is responsible for most of hepatic injury in HBV infection?

Answer 13

Immune response==>the degree of immune tolerance to HBV determines whether a chronic infection will develop

Question 14

Describe phase of immune tolerance in HBV (3)

Answer 14

Normal ALT
High DNA
eAg+, eAb-

Question 15

Describe chronic hepatitis phase of HBV infection

Answer 15

ALT high
High DNA
eAg+, eAb-

Question 16

Describe the changes that occur in eAg seroconversion

Answer 16

ALT transiently high then normal
Low DNA
eAg-/eAb+

Question 17

What is the difference between eAg positive and eAg negative hepatitis B?

Answer 17

eAg negative HBV patients tend to be older (HBV has undergone entire process)

eAg negative HBV infection tends to be harder to treat

Question 18

What are the indications for HBV treatment? (3)

Answer 18

Elevated ALT
Elevated HBV DNA
Patients with cirrhosis and detectable HBV DNA

Question 19

What are endpoints of therapy? (3)

Answer 19

eAg loss (seroconversion associated with decreased risk of hepatic decompensation and HCC)
DNA suppression
Others: normalization of ALT, histological response, HBsAG loss

Question 20

What are two most potent viral polymerase inhibitors?

Answer 20

Entecavir
Tenofovir

Both are oral agents

Question 21

Describe the efficacy of treatment for eAg+ chronic HBV

Answer 21

Goal: eAg seroconversion
Oral agents: 20-50% (increases with duration)
IFN: 30%

Question 22

Describe the efficacy of treatment eAg- chronic HBV.

How long do most patients stay on therapy

Answer 22

Goal: long term DNA suppression
Oral agents: 50-90%
IFN: 20%

Note: There is a high relapse rate so most patients stay on therapy long term

Question 23

What are the pros (2) and cons (4) of IFN for HBV therapy?

Answer 23

Pros: finite course, no viral resistance
Cons: high relapse rate in eAg-, limited efficacy, AE, cannot use in patients with decompensated liver disease

Question 24

Describe the pros (3)/cons (3) of nucleoside analogues in chronic HBV therapy?

Answer 24

Pros: well tolerated, useful for eAg neg patients with long term treatment, useful for decompensated cirrhosis

Cons: development of drug-resistant mutants, need long term therapy, occasional post-withdrawal flares