Drugs for HCV & HBV Flashcards
Treatment of Chronic HBV
The 5 orally active antivirals are front-line therapy:
–Tenofovir (preferred)
–Entecavir (preferred)
–Telbivudine
–Adefovir
–Lamivudine
Emtricitabine In HIV/HBV co-infected patients
The orally active antivirals for HBV Better:
– Better tolerated (than interferons)
– Better suppression of the virus
Nucleoside/tide Structural Analogs
L-nucleosides
Lamivudine (3TC)
Telbivudine (LdT)
Nucleoside/tide Structural Analogs
Acyclic Phosphonates
Adefovir (ADV)
Tenofovir (TDF)
Nucleoside/tide Structural Analogs
d-cyclopentane
Entecavir (ETV)
Antiviral drug resistance tends to be
structure (sugar residue) specific
Arises from mutations in HBV polymerase
Tenofovir
Mechanism of Action
Pro-drug for tenofovir, a nucleotide analog
of adenosine-5-monophosphate
Diphosphate form inhibits HBV polymerase & produces chain termination
Entecavir
Mechanism of Action
Guanosine nucleoside analog
Triphosphate form inhibits HBV polymerase
Telbivudine
Mechanism of Action
L-isomer of thymidine
Triphosphate form inhibits HBV polymerase & produces chain termination
Adefovir
Mechanism of Action
Adenosine-5-monophosphate
Diphosphate form incorporated into viral DNA producing chain termination
Lamivudine
Mechanism of Action
L-isomers of cytosine with similar activity, potency, side effects & patterns of resistance
Triphosphate form inhibits HBV polymerase
Emtricitabine
Mechanism of Action
L-isomers of cytosine with similar activity, potency, side effects & patterns of resistance
Triphosphate form inhibits HBV polymerase
HBV antivirals ADME
NO CYP interactions of note, BUT competitive renal secretory mechanisms may be opportunity for drug-drug interactions (GFR + RTS)
Tenofovir Bioavailability
Taken with high fat meal increases bioavailability
Entecavir Bioavailability
Food delays absorption; coordinate meals &
dosing
Telbivudine, Adefovir, Lamivudine, & Emtricitabine Bioavailability
Food has no substantial effect upon bioavailability
Tenofovir Adverse Effects:
Rare Renal Toxicity: Avoide Systemic/renal disease or concurrent nephrotoxic drugs NSAIDs. Serum creatinine/BUN & phosphate testing recommended.
Osteoporosis: shown to produce decrease bone
mineral density & increase markers of bone turnover.
Serum creatinine/BUN tests also recommended for
lamivudine, adefovir, & entecavir
Interferons
Pleiotropic biological effects including antiviral,
antiproliferative and immunomodulatory actions
Interferon Highpoints
- IM or SC administration
- Cellular effect, exceed persistence of drug in body
- The 2 PEG products differ in the structure of the PEG; straight chain vs. branched chain
- Acute influenza-like syndrome following injection
- Use antipyretics
- Pegylated products usually better tolerated – lower rates of discontinuance
Interferon Dose-Limiting Toxicity
• Neuropsychiatric issues – Depression
• Higher in HCV infected patients than in HBV infections – Somnolence, confusion, behavioral changes, & rarely, seizures
• Effect on serotonin and/or corticotropin?
• Myelosuppression with granulocytopenia &
thrombocytopenia
• Increase hepatic enzymes & triglycerides– Monitor thyroid function & LFTs during IFN therapy
• Infrequent development of serum neutralizing antibodies– Loss of clinical responsiveness
Treatment of Chronic HCV
Genotype 1
- Peginterferon-alfa
- Ribavirin for 24 – 48 weeks
- Telaprevir or Boceprevir – HCV NS3/4A protease inhibitors
Treatment of Chronic HCV
Genotype 2 & 3
- Peginterferon-alfa
* + Ribavirin for 24 – 48 weeks
Ribavirin:
Mechanisms of action include:
– enhanced host T-cell immune clearance of HCV
– inhibition of the host inosine monophosphate dehydrogenase (IMPDH), with depletion of pools of guanosine triphosphate, an essential substrate for viral RNA synthesis
– direct inhibition of HCV replication (RNA-dependent RNA polymerase)
Ribavirin:
ADME
- Bioavailability: Increase by high fat meal
- Extensive uptake into cells, including erythrocytes
- No CYP action - renal elimin -> accumulation possible
Ribavirin:
Toxicity
• The primary toxicity of oral ribavirin therapy is
hemolytic anemia
• Fatal & non-fatal MI & difficulty breathing reported, 2° to ribavirin-induced anemia
Male-Mediated Teratogenicity
Ribavirin, Boceprevir, & Telaprevir Contraindicated in: – Women in pregnancy – Women who could become pregnant – Men whose partners are pregnant
Telaprevir & Boceprevir
Mechanisms of action:
The NS3/4A serine protease cleaves several key sites in the polyprotein precursor. The inhibitors prevent formation of several of the critical nonstructural proteins.
Telaprevir & Boceprevir Somewhat less effective in
African Americans
Telaprevir & Boceprevir
Side Effects:
Both drugs produce fatigue, anemia* and nausea
– *Additive anemia over and above the combination drug effects
Telaprevir & Boceprevir
SERIOUS SIDE EFFECT:
Telaprevir but NOT boceprevir associated with pruritis, rash; sometimes serious rash
– DRESS (Drug Rash w/ Eosinophilia & Systemic Symptoms
– Stevens-Johnson syndrome (SJS)
– Toxic epidermal necrolysis (TEN)
– Erythema multiforme (EM
Telaprevir & Boceprevir
ADME
• Take BOTH with food – increases bioavailability
– High fat for telaprevir; no preference w/ boceprevir
• Boceprevir & telaprevir extensively bind plasma proteins
• BOTH undergo hepatic metabolism w/ elimination primarily in stool
Telaprevir & Boceprevir
Contraindicated:
Co-administration with strong CYP3A4 inducers (rifampin) or with drugs reliant on CYP3A4 or P-gp contraindicated.
Vidarabine
Mechanism:
Vidarabine works by interfering with the synthesis of viral DNA. It is a nucleoside analog & therefore has to be phosphorylated to be active (X3). Both an inhibitor & a substrate of viral DNA polymerase.
Vidarabine:
Excreted kidneys.
