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
What is a guanosine nucleoside analog, first line HBV agent, with potent antiviral activity and a low rate of drug resistance, which is usually low in naive (new) patients with HBV? (resistance is 50% in patients resistant to lamivudine)
Entecavir
Entecavir is a better choice for HBV than adefovir or tenofovir with RENAL insufficiency, as it has not been reported to cause renal impairment, it is well tolerated with?
limitied side effects
Long term efficacy of lamivudine is limited by drug resistance, there is a YMDD to YVDD mutant in the catalytic domain of HBV polymerase leading to?
virological breathrough (resistance) over years (70% resistant after 5 years treatment)
Therapies for HBV fail to fully eradicated the virus, relapse of heptatitis induce HBV is always possible even with apparently?
successful therapy
HCV can be cured! it is an RNA virus and is not incorporated into the host DNA (like HBV), the older drug from 2011 that is/was used for tx is PEGylated interferon plus ribavirin which was a 24 to 48 weeks regimen and cured less than?
50% of patients (new agents cure almost 90% now!)
Ribavirin is a nucleoside analog of guanosine, whose mechanism of action has not be figure out. It is known that is interferes w synthesis of GTP, inhibits capping of viral messenger RNA and inhibits viral RNA-dependent ?
polymerase of certain viruses
Ribavirin POTENTIATES actions of PEGylated IFN a-2a/2b and also upregulates interferon stimulated genes (ISGs), it covers a broad spectrum of HCVs and has what two major contraindications?
Anemia Pregnancy (causes birth defects so need a pre-tx, during-tx, and post-tx pregnancy tests to make sure not preggers)
The main target for the new HCV drugs that have replaced most of the 2011 HCV drugs is translation and processing of RNA replication, treated now via structural and?
nonstructural proteins
Nonstructural protein (NS) 3/4A protease inhibitors inhibit NS3/4A serine protease which inhibits HCV post-translational processing and replication, these drugs include grazoprevir, paritaprevir, and?
simeprevir
Grazoprevir MC SE are fatigue, headache and nausea. What drug causes CYP3A drug-drug interactions, is ‘boosted’ when combined with ritonavir, and SE include nausea, pruritus and insomnia*?
Paritaprevir
What is the main point of giving ritonavir with paritaprevir?
Ritonavir is a CYP3A blocker, so it makes the paritaprevir, which uses CYP3A, last longer
Which NS3/4A protease inhibitor must be taken with fod to maximize absorption and is generally well tolerated?
Simeprevir
NS5B RNA polymerase inhibitors inhibit RNA dependent RNA polymerase needed for HCV replication- effective against all 6 HCV genetypes. What drug is a nucleotide analog, PRODRUG, and generally well tolerated?
Sofosbuvir
What NS5B RNA polyermase inhibitor is a non-nucleoside NS5B allosteric inhibitor, causes drug interaction via CYP3A with SE of nausea, pruritus and insomnia?
Dasabuvir
NS5A inhibitors inhibit NS5A which is important for viral replication and assembly of HCV - mechanism unknown. Which NS5A inhibitor has SE with combination with sofosbuvir including fatigue, headache and asthenia?
Ledipasvir
What NS5A inhibitor has MC SE with grazoprevir including fatigue, headache and nausea, and is metabolized by CYP3A = potential drug drug interactions?
Elbasvir
What NS5A inhibitor can be combined with paritaprevir, ritonavir, or dasabuvir which are metabolized via CYP3a to prolong its effects, and MC SE are nausea, pruritis and insomnia?
Ombitasvir
What NS5A inhibitor is combine with sofosbuvir as the FIRST once daily single tablet regimen with pangenotypic activity (active against all HCV genotypes), with SE including headache and fatigue?
Velpatasvir
20% of patients are coinfected with HBV and HCV, have severe liver disease, and a higher probability of cirrhosis and hepatic decompensation, what a greater incidence of HCC than pts with a single infection… treatment is directed at?
The predominant virus
HBV reactivation tx with HBV targeting drugs
NOTE: post treatment: HCV cured, HBV is handled but then comes back, what two drugs are used to treat both?
Interferons and Ribavirin
