Yay, Dx

Question 1

RF for progression of chronic HBV infection

Answer 1

• elevated HBV DNA -and- elevated serum ALT
  
  • liver fxn measure
• male, older, fhx of HCC (3)
• co-infxn w/: HDV, HCV, HIV

Question 2

Recommendations for antiviral therapy

Answer 2

• liver failure, cirrhosis, HBV DNA+
• reactivation of chronic HBV after immunosuppression

Question 3

specific recommendation for therapy

Answer 3

• HBV DNA >10^5/mL; HBeAg-; elevated ALT for >3mo
• HBV DNA >10^4/mL; HBeAg+; elevated ALT for >3mo
  
  • blood marker for infectiousness

Question 4

Pharmacologic management of chronic HBV infection

Answer 4

• PegIFN-antiviral, some HBV unresponsive to IFN
• **ENTECAVIR-guanosine analog; inhibits viral polymerase
• TENOFOVIR-adenosine analog; inhibits viral polymerase

Question 5

ENTECAVIR to tx HBV

Answer 5

• **inhibit more than one pt: more potent
• MOA: inhibits THREE fxns of HBV replication cycle: HBV DNA priming, RT and DNA pol
• Activity spectrum: HBV, lamuvidine-resistant HBV variants
• PK: Entec-PPP has a long half-life; excreted in glomeruli
  
  • daily oral, one of the MOST POTENT anti-HBV dx
• SE: lactic acidosis, rebound hepatitis
• DDI: do NOT use in conjunction w/ HAART (for HIV)

Question 6

TENOFOVIR to tx HBV

Answer 6

• *disoproxil moiety INC Teno F; cleaved following adsorption
• MOA: PRO-DRUG hydrolyzes to nucleoTIDE analog
  
  • converted repidly to Ten-P by esterases
  • phosphorylated to Ten-PPP (by cellular kinsaes) + blocks HBV DNA pol
• Activity spectrum: HBV and HIV inhibitor
• PK: 25% oral bioavailability
  
  • 18h half-life
• Clinical Uses: oral daily, one of the MOST POTENT anti-HBV drugs
• SE: GI, fatigue, HA, **renal failure
• DDI: RENAL TOXICITY and LACTIC ACIDOSIS

Question 7

AMANTADINE-Anti-influenza dx

Answer 7

• MOA: plug the M2 ion channel=protons cannot enter virus
  
  • RNAs will not release from virion proteins
  • infection blocked at uncoating (disassembly) stage
• Indications: influenza type A infections
  
  • 70% of flu dz f/m type A
  • 30% type B and C
• Steps:
  
  • low pH: activates M2 channel, protons enter virions
    
    • contacts altered-loosens proteins
    • HA conformational changed triggered, fusion peptide translocated, HA fusion
  • liberation of RNPs to cytoplasm (NO LIBERATION W/ AMANTADINE)
  • RNPs transported to nucleus

Question 8

AMANTADINE and RIMANTADINE

Answer 8

• MOA: inhibit virion M2 ion channels (no acid entry); prevents RNPs dissociating from virus entry site
• CI: Influenza A (not B or C)
• PK: well-absorbed
  
  • half-life: 15h
  • renal elimination
  • oral admin
  • for IAV-susceptible (influenza-A) individuals–most of them are RESISTANT
    
    • reduces duration of flu by 1 day
• SE: neurological-anxiety, disorientation, HA (Amantadien was first used for PD in elderly)
• DDI: emergence of dx-resistant mutants limits clinical utility

Question 9

Neuraminidase Inhibitors

Answer 9

• active against influenza A and B viruses
• who?: Zanamivir (Tamiflu), Oseltamivir
• MOA: NA cleaves sialic acids from infected cells and from virions
  
  • they RETARD virus dissemination-blocks guy that cleaves receptor=no virion release
  • selective (competitive) inhibitor
• PK: [peak] in 1 hr (v. rapidly A), well tolerated, renal elim
  
  • oseltamivir (oral prodrug)
  • Zanamivir- (active) aerosol inhalant
  • preventive for pts who cant tolerate vaccination, or are v. susceptivle to severe influenza respiratory dz
  • post-exposure prophylaxis-start within 2d of exposure
    
    • continue daily-10 days (6weeks d/r outbreaks; LT to pts in NH)
    • shorten dz by 1-2 days
• SE: N/V; GI; insomnia; vertigo
• drug resistant mutant viruses exist

Question 10

Anti-RSV dx

Answer 10

• passive immunotherapy (RSV Ig: PALIVIZUMAB)-anti RSV F protein Ab are most effective
• RIBAVIRIN
  
  • active vs. RNA viruses
  • treat RSV infections (aerosol admin for RSV)
• susceptible pop: RSV-infected babies

Question 11

Why are there so few approved ANTI-virals?

Answer 11

• if used as monotherapy, at wrong doses at wrong time=expansion of drug resistant viruses
  
  • =render the drug useless
• drug stockpiles aimed at mitigating influenza pandemic must include more than AMANTADINE and OSELTAMIVIR (via just ONE missense mut=resistance; barrier to drug resistance-low barrier means single nucleotide sub–>drug resistance)
  
  • S31N mut in M2=AMANTADINE resistance
  • H274Y mut in NA=OSELTAMIVIR resistance

Question 12

Drug resistance calculations

Answer 12

• reagrde NUMERO!
• mut rate: 1/10^4 nucleotide incorporations
  
  • =each base is substituted in 1/10^4 viruses
• infected person can make 10^10 viruses
  
  • =an infected person can make 10^10/10^4=10^6 drug-resisant viruses in one day

Question 13

Combination Therapy

Answer 13

• simultaneously apply multiple drugs, each inhibit a distinct, essential viral fxn
• pt compliance is required to limit development of drug-resistant variant viruses ESPECIALLY for persistent infections (HIV)
• ex of places targeted:
  
  • recognition/attachement: Ab receptor ANTagonists
  • uncoating: Amantadine, Rimantadine
  • transcription: IFN
  • protein synthesis: IFN
  • replication: nucleotide analogs
  • assembly: protease inhibitors
  • lysis and release

Question 14

HIV control

Answer 14

• NRTI
• NNRTI
• PI

Question 15

transmission of HBV

Answer 15

• perinatally
• STD
• direct blood transmission