Pharmacotherapy of Hepatitis Flashcards
Describe the “natural history” of HCV
From chronic infection it typically takes 20-30 years to become cirrhotic (20%). From there 5% progress to HCC within 1 year.
What factors are associated with increased progression of liver injury? Demographic, liver, immune system
Demographic factors: age>40, male, caucasian/hispanic, smoking
Liver injury: alcohol, HBC, obesity, insulin resistance
Immunocompromised: HIV, OLT
What are factors that determine likelihood of response of chronic HCV to therapy?
Host: age>40, male, AA, obesity, advanced fibrosis/cirrhosis, HIV, OLT, genetic polymorphism (IL28B)
Viral factors: genotype, viral load
What is the gold standard for HCV treatment?
Sustained viral response– absence of detectable HCV in blood 24wks or 12wks after end of course of therapy
What was old mainstay of treatment until 2011?
IFN-alpha
Ribavirin
What are the MOAs of IFNalpha? (2)
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
What are AE of IFN alpha? (7)
Flu-like symptoms Depression/suicide BM suppression Activation of autoimmune disease Weight loss Bacterial infections Worsening of liver function in cirrhosis
What are MOAs of ribavirin? (4)
Inhibit RNA-dependent RNA polymerase
Induces lethal mutations in HCV RNA
GTP depletion
Modulation of T cell response favoring Th1
What are AE of ribavirin? (4)
Non-immune hemolytic anemia
Rash
Dyspnea
Teratogenic
What are the differences in genotype in treatment response?
Genotype 1: Longer treatment course (48-72wks), only 40% SVR
Genotype 2/3: 24wks of treatment produces 80% SVR
What are categories of currently approved directly acting antiviral drugs? (3)
HCV protease (NS3/4A) inhibitors: telaprevir
Viral RNA-dependent RNA-polymerase (NS5B) inhibitors: Sofosbuvir
Combination pills: Harvoni (ledipasvir+sofosbuvir) and Viekira
Describe the current HCV treatment guidelines and the chances of SVR
Genotype 2: sofosbuvir+ribavirin for 12wks
Genotype 3: SOF+RBV for 24wks
SVR=70-90%
Genotype 1: Harvoni/Viekira + ribavirin
SVR=94-99%
What is responsible for most of hepatic injury in HBV infection?
Immune response==>the degree of immune tolerance to HBV determines whether a chronic infection will develop
Describe phase of immune tolerance in HBV (3)
Normal ALT
High DNA
eAg+, eAb-
Describe chronic hepatitis phase of HBV infection
ALT high
High DNA
eAg+, eAb-
Describe the changes that occur in eAg seroconversion
ALT transiently high then normal
Low DNA
eAg-/eAb+
What is the difference between eAg positive and eAg negative hepatitis B?
eAg negative HBV patients tend to be older (HBV has undergone entire process)
eAg negative HBV infection tends to be harder to treat
What are the indications for HBV treatment? (3)
Elevated ALT
Elevated HBV DNA
Patients with cirrhosis and detectable HBV DNA
What are endpoints of therapy? (3)
eAg loss (seroconversion associated with decreased risk of hepatic decompensation and HCC)
DNA suppression
Others: normalization of ALT, histological response, HBsAG loss
What are two most potent viral polymerase inhibitors?
Entecavir
Tenofovir
Both are oral agents
Describe the efficacy of treatment for eAg+ chronic HBV
Goal: eAg seroconversion
Oral agents: 20-50% (increases with duration)
IFN: 30%
Describe the efficacy of treatment eAg- chronic HBV.
How long do most patients stay on therapy
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
What are the pros (2) and cons (4) of IFN for HBV therapy?
Pros: finite course, no viral resistance
Cons: high relapse rate in eAg-, limited efficacy, AE, cannot use in patients with decompensated liver disease
Describe the pros (3)/cons (3) of nucleoside analogues in chronic HBV therapy?
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
