Antiviral Pharm for Hepatitis B and C Infections Flashcards
Interferons are host cytokines that exert complex antiviral, immunomodulatory, and antiproliferative actions. In what patient population are these used to tx hepatitis?
Primarily used for tx of patients with well compensated liver disease — especially in pts who do not want to be on long-term tx, or those planning to be pregnant within 2-3 years
Pros of interferons in tx of chronic HBV
Shorter course (24-48 wks) Good efficacy Decreased HBV DNA Decreased HBeAg Acquired resistance is rare
Cons of interferons in tx of chronic HBV
Parenteral administration
Expensive
Side effects in 80% (flu-like syndrome)
Dangerous in decompensated cirrhosis
Primary difference between interferon alpha-2b and PEGylated interferons alpha-2a/2b
PEGylated interferons require less frequent dosing to maintain serum concentration
The non-PEGylated versions require additional doses more frequently because the levels tend to rapidly drop between doses
MOA of interferons in tx of chronic HBV
Infected cells release interferons to protect nearby healthy cells by allowing them to mount a defense
Interferons signal nearby macrophages and NK cells to clear infected cell
Interferons act in autocrine fashion to stimulate lysosome lysis —> lysis of cell itself
Molecular mechanism of interferon alpha
Binds type 1 interferon receptor and activates JAK1 and TYK2, which then phosphorylate intracellular domains of receptor
Phosphorylation of receptor —> recruitment, phosphorylation, and dimerization of STAT1 and STAT2, which translocate to nucleus and activate transcription of interferon stimulated genes (ISGs)
ISGs inhibit multiple steps of viral protein synthesis and translation — ZAP, IFIT family, OAS-RNAseL pathway, and PKR
Interferon alpha inhibits HBV replication and depends on immune clearance of HBV infected cells, meaning that for a period of time during treatment there is increased ____ and _____ prior to clearance of those infected cells
Inflammation; fibrosis
PEGylated interferon alpha treatment induces an increase in _____ during seroconversion, which is a good sign meaning that the tx is working
ALT
Contraindications and AEs of interferon tx of HBV
Contraindication: dangerous in decompensated cirrhosis
AEs occur in 80-90%: flu-like syndrome with HA, fever, chills, myalgia, malaise, fatigue
Dose limiting toxicities = bone marrow suppression, neurotoxicity (behavioral changes)
Nucleosides and nucleotides can be used for tx of HBV infection and act as HBV DNA RT/DNA polymerase inhibitors. How do these treatments compare to interferons in terms of patient tolerability and response rate?
Better tolerated and higher response rate than interferon alpha treatment
Can also be used in pts with decompensated liver cirrhosis
What 2 functions of viral replication are inhibited by nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)?
Plus-strand synthesis by DNA polymerase
Minus-strand synthesis by reverse transcriptase
NRTIs require conversion into their corresponding ____ _____, which constitute the active antiviral agents
Nucleotide triphosphates
Name the NRTIs used in HBV tx
Nucleosides:
Lamivudine
Telbivudine
Entecavir
Nucleotide:
Tenofovir
Adefovir
Which NRTI would you give to a pt that has impaired purine/pyrimidine kinase activity?
These pts are resistant to nucleoside analogs: lamivudine, entecavir, telbivudine)
They are responsive to nucleotide analogs — would give Tenofovir!
[resistance is d/t slow or low conversion of nucleosides into nucleotide monophosphate form]
Besides impaired purine/pyrimidine kinase activity, what is another mechanism of resistance to NRTI therapy?
Mutation of DNA polymerase — so the virus is able to continue replicating even in the presence of nucleosides/nucleotides
Factors affecting selection of antiviral nucleosides/nucleotides for HBV
Resistance profile
Efficacy (clearance of HBV DNA)
Usefulness with HIV co-infection
Pregnancy (category B — no proven risk)
Tenofovir is a nucleotide analog of _____ and is the first line tx for wild-type HBV. With chronic use, and adverse effect is ______
Adenosine; nephrotoxicity
Entecavir is a _____ nucleoside analog used as first line HBV infection agent
It is a better choice than adefovir or tenofovir in pts with _____ _____
Guanosine
Renal insufficiency
What is the main limitation to long-term efficacy of lamivudine?
Frequent emergence of drug resistance — d/t YMDD to YVDD mutant in catalytic domain of HBV polymerase —> subsequent virological breakthrough
T/F: relapse of hepatitis induced by HBV is always possible
True! Even with apparently succesful therapy, there is failure to fully eradicate the virus
HCV can be cured using what tx?
PEGylated interferon alpha + Ribavirin
[24-48 wk regimen]
MOA of Ribavirin
Ribavirin is nucleoside analog of guanosine
It interferes with synthesis of GTP, inhibits capping of viral mRNA, and inhibits viral RNA-dependent polymerase of certain viruses [other parts of mechanism unknown]
It also potentiates the action of PEGylated interferon alpha-2a/2b as well as ISGs
Contraindications to ribavirin use
Patients with anemia
Pregnancy
What are the protease inhibitors used to tx HCV?
Simeprevir
Telaprevir
Boceprevir (and grazoprevir)
MOA of protease inhibitors for HCV
Block the NS3 catalytic site or the NS3/NS4A interaction —> inhibit generation of new viral particles
Second generation protease inhibitor
Simeprevir — best option because more potent and better tolerated
Administered in combination:
Simeprevir + PEGylated interferon alpha-2a/2b + Ribavirin
Simeprevir + sofosbuvir +/- Ribavirin (chronic type 1 infection)
First generation protease inhibitors and how they are administered
Telaprevir and boceprevir
Administered in combo with PEGylated interferon alpha-2a/2b + ribavirin (chronic type 1 infection)
____ is a nucleotide analog that inhibits NS5B (RNA dependent RNA polymerase needed for HCV replication)
Sofosbuvir (note that it is used in combo with ledipasvir and disrupts all genotypes of HCV)
3 NS5A inhibitors
Ledipasvir
Elbasvir
Velpatasvir
Ledipasvir, elbasvir, and velpatasvir are NS5A inhibitors. What is the NS5A protein and how are these drugs administered?
NS5A = important for viral replication and assembly of HCV
Ledipasvir, elbasvir, velpatasvir inhibit NS5A and are effective against all genotypes of HCV; traditionally given in combo with ribavirin and PEGylated interferon alpha-2a/2b —> significant reduction in HCV RNA levels
Interferon and ribavirin-free regiments used to tx genotype 1 HCV infection
Ledipasvir + sofosbuvir
Interferon and ribavirin-free regiments used to tx genotype 1, 2, and 3 HCV infections
Velpatasvir + sofosbuvir
Elbasvir + grazoprevir
How do you manage patients co-infected with both HBV and HCV?
Treatment directed at predominant virus with overall goal of eliminating HCV and managing HBV
Some studies suggest PEGylated interferon alpha 2a/2b + Ribavirin for 48 weeks (effective against HBV infection - but just as effective with co-infection)
