3. Viral Hepatitis Drugs Flashcards
Drugs for HBV aim to slow the development of liver disease. Chronic HBV infection in the asymptomatic carrier - never develops antibodies against HBsAg, harbors the virus without liver injury. Chronic persistent hepatitis is a low grade?
smoldering hepatitis (treated differently)
What is an acute hepatitis state that continues without normal recovery (longer than 6-12 months)?
Chronic acitve hepatitis
Interferon alpha is a host cytokine that exert complex antiviral, immunomodulatory, and antiproliferative actions and include interferon a-2b, PEGylated interferon a-2b and?
PEGylated interferon a-2a
Interferon alpha drugs for HBV are primarily used for treatment of patients with well compensated liver disease, also patients who dont want to be on long term treatment (>48weeks) and patients planning to be?
Pregnant in the next 2-3 years
Some pros of treatment of chronic HBV with interferons is that it utilizes a shorter course, has good efficacy, decreases HBV DNA and HBeAg, and resistance is?
RARE
Some cons of treatment of chronic HBV with interferons is that it needs to be given via IV, expensive, 80%* get flu-like side effects with fever, headache, chills, myalgia, and malaise… NOTE: this drug is dangerous in what group of people?***
Dangerous in decompensated cirrhosis **dont give to more advanced HBV patients
The main difference between intereferon a-2b and the pegylated intereferon a-2a/2b is that the 1/2 life of interferon is about 36hrs and then goes away, where as pegylated have?
a slower clearance and a longer 1/2 life - lasting over 200hrs!
Endogenous intereferons are released from infected cells to protect nearby healthy cells by allowing them to mount defense (protects), they also go to mø and NK cells to do what?
have them come and clear the infected cell (activated)
IFNs act autocrinely to stimulate lysosomal lysis which leads to lysis of infected cell, as well
The MOA of interferon alpha is that it binds to type 1 interferon receptor (plasma membrane) and activates JAK1 and TYK2, which then phosphorylate intracellular domains of type 1 IFN receptor, leading to recruitment, phosphorylation and dimerization of? (2)
signal transducer and activator of transcription 1 (STAT1) and STAT2
STAT1 and STAT2 then translocated to the nucleus and activate transcription of interferon stimulated genes (ISGs). ISGs particularly will do what?
They inhibit multiple steps of viral replication/ viral protein synthesis and translation (ZAP, IFIT, OAS-RNAse, PKR)
Interferon alpha also inhibits HBV replication and depends on immune clearance of HBV infected cells, the increase in dead HBV cells waiting to be cleared (takes weeks) leads to what in the liver?2
Initial increased inflammation and fibrosis (in response to ISGs killing HBV)
What IFN treatment induces an initial increase in ALT, known as hepatitis flare which can be a sign that seroconversion is progressing?
PEGylated interferon alpha increases ALT initially
What is the MAIN contraindication associated with interferon alpha and PEGylated interferon alpha?
DO NOT USE in decompensated cirrhosis (can make liver dz worse)
Adverse effects of interferons occur in MOST patients (80-90%), always a flu like syndrome with HA, fever, chills, myalgia, malaise. There are dose limiting toxicities including neurotoxicity (behavioral changes) and?
Bone marrow suppression* if too much is given
Nucleosides and Nucelotides are used for treatment of HBV, they are HBV DNA reverse transcriptase/ DNA polymerase inhibitors given orally, they are better tolerated and have a higher response rate than IFNs and can be used in what type of patient?**
Can be used in patients with decompensated cirrhosis*
IFNs CANNOT be used in these patients
What is the main structural difference between a nucleotide and nucleoside?
Nucleotide is a nucleoside with a phosphate group attached
Nucleoside/Nucleotide reverse transcriptase inhibitor (NRTI) have a MOA that inhibits plus strand synthesis by DNA polymerase as well as minus strand?
synthesis by reverse transcriptase
Active NRTIs require conversion into nucleotide *triphosphates- which is the active antiviral agents, What will covert both synthetic and endogenous nucleosides into nucleotides?
Cellular kinases (cytosine kinase more energy needed for first P+ to be added, then mono and di kinases for the last phosphates to be added)
Sort the following as nucleosides or nucleotides... Tenofovir Telbivudine Adefovir Lamivudine Entecavir
Tenofovir, Adefovir has P+ = Nucleotide
Lamivudine, Telbivudine, Entecavir = No P+ = Nucleoside
HBV resistance to nucleosides and nucleotides can occur via impaired pruine/pyrimidine kinase activity, if this is the case, then they are resistant to nucleoside and responsive to nucleotides (since already have first phosphate so dont need to purine kinase activity). Resistance is due to slow or low conversion of nucleosides into?
nucleotide monophosphate form
Resistance also may be via mutations in DNA polymerase
HBV viral breathrough (med doesnt work) is either commonly due to resistance or due to patient?
non-compliance (doesnt complete entire course of drug)
There are many factors influencing selection of NRTI for HBV treatment including resistance, efficacy - clearance of HBV DNA as well as usefulness with what coinfection?
HIV** (some NRTIs treat both HIV and HBV)
What drug is a nucleotide analog of adenosine and is first line tx for wild type HBV, used in patients with nucleoside resistance?
Tenofovir
Resistance to Tenofovir is rare (along with adefovir) however a major complication/side effect is what, causing occuring the proximal renal tubule?
NEPHROTOXICITY
