Drugs for HCV & HBV

Question 1

Treatment of Chronic HBV

Answer 1

The 5 orally active antivirals are front-line therapy:
–Tenofovir (preferred)
–Entecavir (preferred)
–Telbivudine
–Adefovir
–Lamivudine
Emtricitabine In HIV/HBV co-infected patients

Question 2

The orally active antivirals for HBV Better:

Answer 2

– Better tolerated (than interferons)

– Better suppression of the virus

Question 3

Nucleoside/tide Structural Analogs

L-nucleosides

Answer 3

Lamivudine (3TC)

Telbivudine (LdT)

Question 4

Nucleoside/tide Structural Analogs

Acyclic Phosphonates

Answer 4

Adefovir (ADV)

Tenofovir (TDF)

Question 5

Nucleoside/tide Structural Analogs

d-cyclopentane

Answer 5

Entecavir (ETV)

Question 6

Antiviral drug resistance tends to be

Answer 6

structure (sugar residue) specific

Arises from mutations in HBV polymerase

Question 7

Tenofovir

Mechanism of Action

Answer 7

Pro-drug for tenofovir, a nucleotide analog
of adenosine-5-monophosphate
Diphosphate form inhibits HBV polymerase & produces chain termination

Question 8

Entecavir

Mechanism of Action

Answer 8

Guanosine nucleoside analog

Triphosphate form inhibits HBV polymerase

Question 9

Telbivudine

Mechanism of Action

Answer 9

L-isomer of thymidine

Triphosphate form inhibits HBV polymerase & produces chain termination

Question 10

Adefovir

Mechanism of Action

Answer 10

Adenosine-5-monophosphate

Diphosphate form incorporated into viral DNA producing chain termination

Question 11

Lamivudine

Mechanism of Action

Answer 11

L-isomers of cytosine with similar activity, potency, side effects & patterns of resistance
Triphosphate form inhibits HBV polymerase

Question 12

Emtricitabine

Mechanism of Action

Answer 12

L-isomers of cytosine with similar activity, potency, side effects & patterns of resistance
Triphosphate form inhibits HBV polymerase

Question 13

HBV antivirals ADME

Answer 13

NO CYP interactions of note, BUT competitive renal secretory mechanisms may be opportunity for drug-drug interactions (GFR + RTS)

Question 14

Tenofovir Bioavailability

Answer 14

Taken with high fat meal increases bioavailability

Question 15

Entecavir Bioavailability

Answer 15

Food delays absorption; coordinate meals &

dosing

Question 16

Telbivudine, Adefovir, Lamivudine, & Emtricitabine Bioavailability

Answer 16

Food has no substantial effect upon bioavailability

Question 17

Tenofovir Adverse Effects:

Answer 17

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.

Question 18

Serum creatinine/BUN tests also recommended for

Answer 18

lamivudine, adefovir, & entecavir

Question 19

Interferons

Answer 19

Pleiotropic biological effects including antiviral,

antiproliferative and immunomodulatory actions

Question 20

Interferon Highpoints

Answer 20

• 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

Question 21

Interferon Dose-Limiting Toxicity

Answer 21

• 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

Question 22

Treatment of Chronic HCV

Genotype 1

Answer 22

• Peginterferon-alfa
• • Ribavirin for 24 – 48 weeks
• • Telaprevir or Boceprevir – HCV NS3/4A protease inhibitors

Question 23

Treatment of Chronic HCV

Genotype 2 & 3

Answer 23

• Peginterferon-alfa

* + Ribavirin for 24 – 48 weeks

Question 24

Ribavirin:

Mechanisms of action include:

Answer 24

– 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)

Question 25

Ribavirin:

ADME

Answer 25

• Bioavailability: Increase by high fat meal
• Extensive uptake into cells, including erythrocytes
• No CYP action - renal elimin -> accumulation possible

Question 26

Ribavirin:

Toxicity

Answer 26

• The primary toxicity of oral ribavirin therapy is
hemolytic anemia
• Fatal & non-fatal MI & difficulty breathing reported, 2° to ribavirin-induced anemia

Question 27

Male-Mediated Teratogenicity

Answer 27

Ribavirin, Boceprevir, & Telaprevir
Contraindicated in:
– Women in pregnancy
– Women who could become pregnant
– Men whose partners are pregnant

Question 28

Telaprevir & Boceprevir

Mechanisms of action:

Answer 28

The NS3/4A serine protease cleaves several key sites in the polyprotein precursor. The inhibitors prevent formation of several of the critical nonstructural proteins.

Question 29

Telaprevir & Boceprevir Somewhat less effective in

Answer 29

African Americans

Question 30

Telaprevir & Boceprevir

Side Effects:

Answer 30

Both drugs produce fatigue, anemia* and nausea

– *Additive anemia over and above the combination drug effects

Question 31

Telaprevir & Boceprevir

SERIOUS SIDE EFFECT:

Answer 31

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

Question 32

Telaprevir & Boceprevir

ADME

Answer 32

• 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

Question 33

Telaprevir & Boceprevir

Contraindicated:

Answer 33

Co-administration with strong CYP3A4 inducers (rifampin) or with drugs reliant on CYP3A4 or P-gp contraindicated.

Question 34

Vidarabine

Mechanism:

Answer 34

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.

Question 35

Vidarabine:

Answer 35

Excreted kidneys.