HCV and HBV drugs Flashcards
Preferred antivirals for HBV?
Tenofovir and Entecavir
where does HBV antiviral resistance arise from?
mutations in HBV DNA polymerase – tends to be structure (sugar residue) specific
Tenofovir: MOA, uses, metabolism, bioavailability, AEs
MOA: prodrug (intracellular hydrolysis) –> nucleotide analog for AMP, 17 hr t1/2
Uses: HBV AND HIV!
**SECRETED PRIMARILY UNCHANGED IN URINE (no cyp interaction)
Bioavailability: take w/ high fat meal
AEs: OSTEOPOROSIS (inc turnover, dec bone mineral density), rare RENAL toxicity (esp w/ concurrent renal disease or renal toxic drugs like NSAIDs)
Entecavir: MOA, Metabolism, bioavailability
MOA: guanosine nucleoside analog, 130 hr t1/2
**Excreted primarily unchanged in urine, no cyp interaction
Bioavailability: food delays absorption – coordinate opposite of meals
Telbivudine, adefovir, lamivudine, emtricitabine
MOA:
– telbivudine = Thymidine isomer, 45 hr half life!
– adefovir = adenosine-5-monophophate
– lamivudine / emtricitabine = cytosine isomers – DON’T USE TOGETHER! too similar of structure to have synergistic response
Which HBV antiviral do you need to ask the pt about bone pain and fracture?
Tenofovir > stavudine/abacavir: due to osteoporosis and/or renal tubulopathy
- *measure Cr / BUN!
- *Administer Ca and Vit D for HIV patients on prolonged tx
which antivirals require LFTs?
TENOFOVIR, ENTECAVIR, adefovir, telbivudine
– suspend treatment if: Lactic acidosis / pronounced hepatotoxicity w/ hepatomegaly or steatosis
Which antivirals can be used in co-infection of HBV and HIV?
TENOFOVIR (AMP analog), emtricitabine (cytosine analog), ~entecavir (weakly active, guanosine analog)
What drugs should be used for co-infection of HCV and HBV?
Peginterferon and Ribavirin – target HCV first
Interferons: MOA, administration, AEs
MOA:
Activate TKs –> INF stimulation/inc IFN stimulated enzymes –> x ssRNA and dsRNA
–> x viral penetration, assembly and release
–> inc cytotoxic T cell effects
Administration: SC or IM
AEs: DLT = NEUROPSYCHIATRIC ISSUES (depression, somnolence/confusion +/- rare seizures),
acute influenza like syndrome, anemia, myelosuppression (granulocytes and thrombocytopenia), inc hepatic enzymes/triglycerides
are pegylated interferon products better or worse tolerated?
BETTER - lower rates of discontinuance, longer t1/2
Which hep virus drug class causes immune mediated destruction of thyroid tissue in genetically predisposed patients?
Interferons
**temporary thyrotoxicosis (wks to mo’s)
Tx: discontinue IFN until euthyroid
Chronic HCV treatment? (genotype 1 vs. 2, 3, 4)
Genotype 1 (most common in US): -- peginterferon-alfa and Ribavirin (24-48 wks) \+ telaprevir or boceprevir or simeprivir (protease inhibitors)
Genotype 2, 3, 4:
Peginterferon- alfa + Ribavirin (24-48 wks)
+ Sofosbuvir (RNA polymerase inhibitor)
Ribavirin: MOA, use w/ interferons?, bioavailability, AEs
MOA:
- enhances T cell immune clearance of HCV
- depletes GTP pools (essential for viral RNA replication)
- direct HCV RNA polymerase inhibition
**SYNERGIZES w/ interferon = greatly enhances activity/reduces risk of relapse
Bioavailability: inc w/ Fatty meal
Metabolism: renal excretion, no Cyp interaction
AEs: HEMOLYTIC ANEMIA (monitor hematocrit/for signs of jaundice), MI,
Which HCV drugs cause teratogenicity? male or female?
RIBAVIRIN + boceprivir and telaprevir (combo theryapy = “guilty by association”)
– male and female teratogen!
Teleprevir and Boceprevir: MOA, whats special about their administration?, AEs
MOA: xNS3/4A serine protease
(HCV RNA is translated into single polypeptide and then segmented/cleaved by NS2/3 and NS3/4A serine proteases)
- *ALWAYS ADMINISTERED W/ RIBAVIRIN –> AE = TERATOGEN
- *Short t1/2 = daily/twice daily dosing
AEs: interaction w/ concurrent drugs (cyp3A4 and P gp metabolism), exacerbation of ANEMIA, rash/pruritis/myalgia/dyspnea/DRESS
BBW for protease inhibitors?
DRESS (drug rash w/ eosinophilia and systemic symptoms)
**especially TELAPREVIR > boceprevir
Protease inhibitors and resistance?
***RAPID DEVELOPMENT OF RESISTANT OF HCV:
— high mutation rate / RNA VIRUS
**especially w/ boceprevir
which hepatitis drug is the only one w/ CNS involvement?
INTERFERONS – Dose limiting tox = neuropsych issues
which viral hepatitis drugs cross interact w/ mitochondrial DNA polymerase?
nucleoside analog antivirals
Ex) tenofovir, entecavir, telbivudine, adefovir
–> renal and hepatic toxicity (lactic acidosis)
what is a common AE of interferon and small molecule hepatitis drugs like ribavirin?
ANEMIA!
HAV: structure, #serotypes, reservoir/transmission, common places of transmission
ssRNA virus, Nonenveloped, icosahedral capsid
1 serotype (ie vaccine available)
Human reservoir – Entero Transmiss/Fecal oral
Risk: Daycares, prisons, travel to 3rd world, Diners (outbreaks), (less common IVDU, MSM)
Which Hepatitis viruses are considered to be sexually transmitted? which cause chronic hepatitis?
Sexually transmitted: HBV, HCV
Chronic: HCV (40%), HBV (20%, HDV (5%)
HBV: structure, #serotypes, replication, reservoir/transmission, common places of transmission
partial dsDNA genome, enveloped (Dane particle), filam surface ag
Rep: Genome length RNA used as template for REVERSE TRANSCRIPTION, maintained extrachromosomally during chronic infection but can integrate into genome
SEXUALLY TRANSMITTED (blood, semen, vag secretions)
Risk: IVDU/needle sticks, sexual, perinatal / vertical trans, MSM, Heamophiliacs/transfusions
what is the significance of HBV filams?
surface ag particles, really high concentration in blood during infection – acts as a “smoke screen” to distract immune system from actual virus
what are HBV’s 5 major proteins? Order of presentation during infection?
DNA polymerase (source of resistance), Surface Ag, Core Ag, E ag (derivative of core Ag), X ag (influences gene expression)
Surface Ag –> HBeAg / HBV DNA –> Anti HBeAg –> Anti HBsAg
HDV: structure, method of infection w/ HBV, common places of transmission/risk
ssRNA + must incorporate HBsAg to infect hepatocytes!, encodes delta Ag
Co infection = severe, acute, low risk for chronic HDV
Super Infection = prior HBV infection, HIGH risk for severe chronic liver disease
Risk:
HCV: structure, pathogenesis, risk
ssRNA (+), enveloped icosahedral capsid, 6 genotypes! (1a and 1b most common in US)
Pathogenesis: acute = mild, chronic = multiple bouts of Reinfection / emergence of quasi species
risk: IVDU, sexual contacts, baby boomers, vertical spread, transfusions, alcohol abusers, dialysis, HIV
Quasi Species of HCV?
E2 protein = immuno neutrolizing epitope – where Abs bind to neutrolize has HIGH FREQUENCY OF MUTATION
Tx: Have generated T cell response to Surface protein instead
what causes hepatocyte destruction in hepatitis virus infection?
IMMUNE DESTRUCTION by cytotoxic cells – not the virus
which age of infection is more prone to chronic HBV development?
5 = 2% rate of chronicity
Younger = higher risk, die mostly in 6th decade
what are the 3 phases of chronic HBV infection?
- immune tolerance phase
- Immune clearance phase
- residual phase
Recommendations for HBV/HCV chronic hep pts?
Immunize against HAV, discourage alcohol,
HBV vaccine /Immunoglobulin mech
Yeast expressed HBsAg –> create Anti HBs Abs
HBIg –> short term Immune protection for travelers
