PHARM: Drugs for Hep B and Hep C Flashcards
What is the front-line therapy for chronic HBV?
orally active antivirals:
Tenofovir disoproxil fumarate (PMPA)
Entecavir
What HBV drugs are also good for HIV?
Tenofovir disoproxil fumarate
Entecavir (weakly)
Emtricitabine
Which HBV drug is actually only approved to treat HIV?
Emtricitabine
Which drugs are good for HCV/HBV co-infection?
Ribavirin
Peginterferon alpha-2a
Peginterferon alpha-2b
Why do you use combination treatment to treat HBV?
reduces resistance (not necessarily more effective)
How does resistance to treatment occur in HBV?
mutations in HBV polymerase that is structure specific for the nucleoside/tide structural analogs
How should the first viriologic breakthrough in HBV be managed?
“add-on” strategy rather than by sequential monotherapy
What determines first line therapy for chronic HCV?
Genotype
What is the common treatment factor in all genotypes of HCV?
Peginterferon alpha & Ribavirin (24-48 weeks)
What can you add on for genotype 1 HCV treatment?
HCV NS3/4A protease inhibitors
What are the HCV NS3/4A protease inhibitors (for treatment of genotype 1 HCV)?
Telaprevir or Boceprevir or Simeprevir
What can you add on for genotype 2-4 HCV treatment?
HCV NS5B RNA polymerase inhibitor
What is the HCV NS5B RNA polymerase inhibitor?
Sofosbuvir
MOA: Diphosphate form inhibits HBV polymerase and produces chain termination
Tenofovir Disoproxil
MOA: Guanosine nucleoside analog (triphosphate form inhibits HBV polymerase)
Entecavir
MOA: L-isomer of thymidine (triphosphate form inhibits HBV polymerase and produces chain termination)
Telbivudine
MOA: Adenosine-5-monosphsphate (diphosphate form incorporated into viral DNA producing chain termination)
Adefovir dipivoxil
MOA: L-isomers of cytosine with similar activity, potency, side effects and patterns of resistance (triphosphate form inhibits HBV polymerase).
Lamivudine
Emtricitabine
Should you use lamivudine and emtricitabine together?
Don’t use together (no benefit)
MOA: Binds to cell surface receptor to activate TKs that lead to the production of several enzymes like endoribonucleases (cleave ssRNA of virus), inhibitory effects on dsRNA, inhibition of viral replication cycle, enhance lytic effects of cytotoxic T cells.
interferons
Although HBV oral drugs have NO CYP interactions, where might they have problems with DDIs?
competitive renal secretory mechanisms may be an opportunity for DDIs
Other than viral HBV polymerase, what is inhibited by the HBV oral drugs?
micochondrial DNA polymerase gamma (essential for mitochondrial DNA replication→ organs cannot generate enough energy to work!)
What group of people are most likely to experience hepatic toxicity from HBV drugs?
women, obese patients, and alcoholics with prolonged drug exposure.
What drug has increased bioavailability if taken with fatty foods?
tenofovir disoproxil
TOXICITY: Acute renal failure (pts with systemic/renal disease or concurrent nephrotoxic drugs usually)—test for serum creatinine/BUN and phosphate; avoid NSAIDs; Proximal renal tubulopathy: ask about worsening bone pain, pain in extremities and muscles, and fractures (increased risk of osteoporosis—give vitamin D/ Ca2+); also screen LFTs for hepatic toxicity
tenofovir disoproxil
TOXICITY: risk of renal problems; test for serum creatinine/BUN and phosphate; also screen LFTs for hepatic toxicity
entecavir
adefovir dipivoxil
telvibudine
TOXICITY: risk for renal problems
Lamivudine
Emtricitabine
DOSE LIMITING TOXICITY: neuropsychiatric issues (ex. depression, somnolence, confusion, behavioral changes, seizures (rare); ANEMIA, myelosuppression; thyroid dysfunction; hepatic toxicity (increase hepatic enzymes and TGs)
Interferons
Which type of hepatitis has worse depression with interferons?
HCV> HBV
Which HBV drug has a ~130 hr T1/2?
Entecavir
Oral HBV drugs must have altered doses with what conditions?
renal dysfunction
Why do some antivirals cause chain termination?
lacks the 3’-OH group so nothing can attach
The toxicity of tenofovir is mainly due to what?
accumulation within the cell due to malfunctioning of pump system (drug requires energy dependent pumps to get it into lumen)
What renal receptors take up tenofovir from blood?
OAT1
Mutation of what membrane pump prevents renal cells from emptying tenofovir into lumen for excretion?
Mrp4
What is the only treatment for HBV given by IV injection?
Interferon alpha-2a
MOA: Enhance host T cell immune clearance of HCV, inhibit host IMPDH (depletion of pools of GTP→ none for viral RNA synthesis), direct inhibition of RNA-dependent-RNA poly, and RNA virus mutagenesis (drives HCV to error catastrophe).
Ribavirin
True or false: Ribavirin can return aminotransferase levels to normal
TRUE
MOA: HCV NS3/4A protease inhibitors (prevent formation of several of the critical non-structural proteins).
Boceprevir
Telaprevir
Simeprevir
MOA: HCV NS5B RNA polymerase inhibitor
Sofosbuvir
What drug has synergism with interferon (reduce risk of relapse)?
ribavirin
How does HCV resistance to NS3/4A protease inhibitors occur?
Resistance can occur as the various quasi-species are formed (viral variants with changes in NS proteases).
TOXICITY: HEMOLYTIC ANEMIA is major (within 1-2 weeks of initiation; monitor hematocrit), fatal and non-fatal MI as well as difficulty breathing reported (secondary to anemia
Ribavirin (presents with jaundice, dark urine, etc.)
BBW: DRESS
Telaprevir
TOXICITY: Rash, pruritis, nausea, myalgia, dyspnea.
Boceprevir
Telaprevir
Simeprevir
CONTRAINDICATED: women in pregnancy, women who could become pregnant (use 2 forms of BC during pregnancy and for 6 months after), men whose partners are pregnant.
Ribavirin
Boceprevir
Telaprevir
Simeprevir
In what drugs would you see increased levels of P-gp pumping drug back into lumen and decreasing bioavailability?
Boceprevir
Telaprevir
Simeprevir
Do Boceprevir, Telaprevir, and Simeprevir have potential for CYP interactions?
YES
What drug will NOT have exacerbation of anemia if taken with peginterferon/ribavirin?
simeprevir
What drug for HCV is EXTREMELY expensive?
sofosbuvir
Why does HCV have lots of problems with resistance?
RNA virus
