Waller Pharm CIS Flashcards
Agents for Hepatitis B Virus (HBV)
Nucleoside/Nucleotide Analogs (NAs):
Adefovir
! Entecavir*
Lamivudine* (3TC)
Telbivudine
! Tenofovir*
* anti-HIV activity
! Peginterferon alfa
Agents for Hepatitis C Virus (HCV)
Direct-Acting Antivirals (DAAs): ! Daclatasvir (Daklinza) ! Ledipasvir-sofosbuvir (Harvoni) ! Ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak) ! Simeprevir (Olysio) ! Sofosbuvir (Sovaldi)
Peginterferon alfa
Protease Inhibitors (PIs)
- Boceprevir (Victrelis)
- Telaprevir (Incivek)
! Ribavirin
Viral serology testing
Suspect acute viral hepatitis
Obtain LFTs
Elevations in serum aminotransferases? AST and ALT
Determine cause: viral serologic tests - IgM antibody to HAV HBsAg IgM antibody to hepatitis B core (IgM anti-HBc) Antibody to HCV (anti-HCV)
HBeAg seroconversion
development of antibodies
indicates lower levels of HBV; good predictor of viral clearance
treatment goals for HBV include
HBeAg seroconversion
Prevention of complications of viral hepatitis (cirrhosis, HCC, hepatic failure)
Suppress viral replication (has been associated with normalization of serum ALT, loss of HBeAg with or without detection of anti-HBe, and improvement in liver histology)
No viral cure for B. Hep C does, however, have a cure possibility
decompensated cirrhosis
symptoms of cirrhosis:
encephalopathies, ascites, coagulopathies, jaundice, etc.
HBV disease course
HBV has a fluctuating disease course. One high HBV DNA level is a poor predictor of prognosis – must have regular disease monitoring to determine need for antiviral therapy.
treatment options for pt with chronic Hep B (6 months)
Peginterferon and the nucleoside/ nucleotide analogs (adefovir, entecavir, lamivudine, telbivudine, telbivudine, tenofovir)
2 agents only used for Hep C
Ribavirin, sofosbuvir
How does entecavir work?
NA; inhibits DNA polymerase
Ribavirin works how?
inhibits RNA polymerase
Sofosbuvir works how?
Inhibits NS5B dependent RNA polymerase
Tenofovir works how?
NA; inhibits DNA polymerase
advantages of peginterferon compared to interferon?
given subcutaneously, slower clearance with complexed polyethylene glycol, less frequent dosing, higher SVR rate
can give once weekly
advantages of peginterferon compared to nucleoside (-tide) analogs?
finite duration of treatment, resistance not a problem, more durable responses.
analogs can be very long-term treatment.
agent preferred ifi pt has decompensated (hep B) liver disease?
nucleotide or -side analogs;
peginterferon is contraindicated
pegintereron contraindications
psych issues
autoimmunity
decompensated liver disease
Which NAs are preferred for first-line treatment of HBV?
Entecavir and Tenofovir
lower potential for resistance and better treatment response
drawbacks to adefovir
slow response, low likelihood of seroconversion
drawbacks of lamivudine
high rate of resistance
drawbacks of telbivudine
high rate of resistance
What is an SVR?
sustained virologic response
absence of HCV RNA by PCR 3 months after completion of therapy
associated with improved liver histology, decreased HCC, sometimes cirrhosis regression
Which of the following does not have activity against HCV? Dasabuvir Ombitasvir Paritaprevir Ribavirin Ritonavir
Ritonavir; we’re using it for it’s CYP 3A inhibitory activity; increases plasma concentrations of paritaprevir and overall drug exposure
Direct-Acting Antivirals: NS5A
Involved in organization of replication complex, regulating replication, viral particle assembly
Daclatasvir Elbasvir Ledipasvir Ombitasvir Velpatasvir
Direct-Acting Antivirals: NS5B
RNA-dependent RNA polymerase necessary for viral replication
Dasabuvir
Sofosbuvir
Direct-Acting Antivirals: NS3/4A protease
Grazoprevir
Paritaprevir
Simeprevir
daclatasvir, how does it work
–> NS5A
peginterferon, how does it work
–> viral penetration, translation, and viral maturation
ribavirin, how does it work
-> inhibits initiation/ elongation of RNA
ritonavir, how does it work
–> inhibits CYP3A, used for “boosting” properties
ribavirin drawbacks
chance of hemolytic anemia
peginterferon drawbacks
flu-like symptoms
chronic HBV infection, best course of action?
tenofovir
Lamivudine is not first-line due to high rate of drug resistance.
Ribavirin is not indicated in HBV
chronic HBV, Resistance testing reveals the presence of a drug mutation.
The drug most appropriate for treatment, inhibits viral:
DNA polymerase
This question is asking for the mechanism of action of tenofovir. Tenofovir is a nucleotide analog which competitively inhibits DNA polymerase, incorporates into viral DNA, and causes chain termination.
agent which allosterically inhibits NS5B RNA-dependent RNA polymerase.
Which of the following was most likely prescribed? A daclatasvir. B dasabuvir. C peginterferon. D sofosbuvir. E tenofovir.
Correct Answer: dasabuvir. Explanation: Daclatasvir (Choice A, incorrect) binds NS5A inhibiting viral RNA replication and virion assembly. Peginterferon (Choice C, incorrect) exerts complex antiviral, immunomodulatory, and anti-proliferative actions but is not linked to the HCV non-structural (NS) proteins. Sofosbuvir (Choice D, incorrect) inhibits NS5B RNA-dependent RNA polymerase but does so through competition with nucleotides resulting in chain termination vs. allosteric inhibition. Tenofovir (Choice E, incorrect) is a nucleotide analog which inhibits DNA polymerase. This leaves dasabuvir (Choice B, correct), as the most appropriate answer, which through allosteric modification of NS5B interferes with viral replication. OK
Why has ritonavir been added to this regimen?
A
Alleviates adverse effects of the HCV regimen
B
Covers HBV in an at-risk patient
C
Inhibits CYP3A enhancing overall drug exposure
D
Provides HIV coverage in an at-risk patient
E
Targets HCV by inhibiting viral protease
Inhibits CYP3A enhancing overall drug exposure
Explanation:
Ritonavir does not have activity against HBV, HCV, or HIV. It is used solely for its potent CYP3A inhibitory effects (“boosting” properties) which increase plasma concentrations of paritaprevir (and other viral protease inhibitors) to increase overall drug exposure.
