Microbiology 21 - Antivirals

Question 1

How is VZV reactivation different in immunocompetent and immunocompromised?

Answer 1

immunocompetent

Dermatomal distribution (may lead to post-herpetic neuralgia)

immunocompromised

multidermal/disseminated disease

Question 2

What is the treatment for VZV?

Answer 2

1. Aciclovir (PO or IV) or Valaciclovir (aciclovir pro-drug, PO)
2. Famciclovir (Foscarnet or Cidofovir for aciclovir-resistant strains)

Question 3

What is the mechanism of action of acyclovir?

Answer 3

Guanosine analogue that

further elongation of chain impossible as it lacks 3’ hydroxyl group → chain terminator

Question 4

Why is aciclovir associated with low toxicity?

Answer 4

selective to viral vs human components:

Requires activation by viral thymidine kinase (only in infected host cells)

higher affinity for viral DNA polymerase than host DNA polymerase

Question 5

Which viruses is acyclovir particularly useful for?

Answer 5

VZV
HSV 1 + 2

HSV1 > HSV2 >> VZV

VZV less sensitive so ↑ dose required

Question 6

What are some Indications for Treatment of VZV:

Answer 6

adults: chickenpox (pneumonitis) or zoster (post-herpetic neuralgia in >50)

Primary infection or reactivation in immunocompromised patient

Neonatal chickenpox

↑ risk complications (e.g. underlying lung disease, eye involvement)

Question 7

Which antiviral is used in HSV encephalitis?

Answer 7

EMERGENCY = Immediate empirical treatment

IV Aciclovir 10mg/kg TDS (before test results)

If confirmed, treat for 14-21 days

Question 8

Which antiviral is used in HSV meningitis?

Answer 8

Treat if immunocompromised or require hospital admission

IV aciclovir 2-3 days → PO for 10 days

Immunocompetent → valaciclovir PO at home

Question 9

where does asymptomatic shedding occur in CMV?

Answer 9

saliva, urine, semen and cervical secretions

Question 10

CMV consequences in immunocompromised:

Answer 10

Bone marrow suppression

Retinitis

Pneumonitis

Hepatitis

Colitis

Encephalitis

Question 11

Which viral infection are Owl’s eye inclusions indicative of?

Answer 11

CMV

Question 12

Which antivirals are effective against CMV?

Answer 12

Ganciclovir (slow IV) or Valganciclovir (PO)

Foscarnet (IV or intravitreal)

Cidofovir (IV)

Question 13

What is ganciclovir used for?

Answer 13

Pretty much only for treatment of CMV in the imunocompromised and neonates

Question 14

MOA ganciclovir

Answer 14

guanosine analogue

activateion via viral UL97 kinase

Question 15

when is ganciclovir contraindicated?

Answer 15

bone marrow suppression - neutropoenia

Question 16

MOA of foscarnet

Answer 16

Non-competitive viral DNA polymerase inhibitor – no activation required

Question 17

What is the main side effect of ganciclovir?

Answer 17

Bone marrow toxicity

also renal and hepatic toxicity

Question 18

When is foscarnet used?

Answer 18

To treat CMV in patients where ganciclovir is contra-indicated (eg neutropaenic patients)

GCV resistant CMV

CMV retinitis

Question 19

MOA codofovir

Answer 19

Nucleotide analogue - competitive inhibitor of viral DNA synthesis – no activation required

Question 20

What is the treatment of CMV in transplant patients?

Answer 20

PROPHYLAXIS with GCV/vGCV

Indication: solid organ transplant (i.e. renal)

SEs: bone marrow toxicity, may develop resistance

PRE-EMPTIVE THERAPY

monitoring (weekly CMV PCR)

Foscarnet or GCV/vGCV when PCR +ve

Indication: HSCT

Question 21

MOA of Letermovir

Answer 21

CMV DNA terminase inhibitor

Question 22

What treatment can clear chronic hep B in 3-7% of patients?

Answer 22

48 week course of pergolated interferon gamma

Question 23

What drug is given to infant groups at high risk of RSV?

Answer 23

Palivizumab - Monoclonal antibody against RSV

Nirsevimab - single IM injection to provide protection for whole winter

Question 24

side effects of cidofovir

Answer 24

nephrotoxic (requires hydration and probenicid (inhibitor of renal tubular transport)

Question 25

How to treat PTLD

Answer 25

Reduce immunosuppression Rituximab – anti-CD20 monoclonal antibody

Question 26

Which antiviral is most useful for treating haemophagocytic lymphohistiocytosis in covid?

Answer 26

Anakinra (IL-1 receptor agonist)

Question 27

Which antiviral is most useful for treating RSV (bronchiolitis in children)?

Answer 27

Ribavarin - but there is a lack of good evidence for its efficacy Nucleoside/Guanosine analogue - inhibits viral RNA synthesis

Question 28

MOA ribavirin

Answer 28

Nucleoside/Guanosine analogue - inhibits viral RNA synthesis

Question 29

side effects of ribavirin

Answer 29

anaemia possible teratogenicity

Question 30

Which antivirals are used in COVID?

Answer 30

Question 31

Which mAbs are used in SARS Cov2?

Answer 31

target S protein 0 bind ACE2 and stop virus entering cells

Question 32

Which immunomodulators are used in SARS Cov2

Answer 32

Question 33

how to treat BK virus?

Answer 33

Bladder washouts ↓ immunosuppression significant morbidity → Cidofovir (IV) (+ probenicid) nephrotoxicity → Cidofovir (intravesical) - Avoids nephrotoxicity if direct into bladder IVIG

Question 34

What is the best treatment for paediatric adenovirus infection?

Answer 34

Cidofovir (IV) or Brincidofovir (PO) * Brincidofovir is prodrug or cidofovir * Indications: adenovirus, BK virus in immunocompromised * Less toxic on GIT IVIG

Question 35

What is the cause of drug resistance in HSV?

Answer 35

almost always in immunosuppression - TK deficient strains less virulent ## Footnote 95% - mutation in viral thymidine kinase (mediates cross resistance to GCV) 5% - mutations in viral DNA polymerase

Question 36

What is the cause of CMV drug resistance?

Answer 36

mutations in ## Footnote protein kinase gene (UL97) Rare - DNA polymerase gene (UL54) More likely prolonged therapy in immunocompromised

Question 37

What is the cause of influenza A drug resistance?

Answer 37

oseltamivir (NA inhibitor) resistance through H275Y mutation zanamivir resistance rare

Question 38

When are genotypic vs phenotypic assays used for drug resistance?

Answer 38

**Genotypic assays – sequencing genome → identify known drug resistance mutations:** For… HIV, HBV, HCV, CMV **Phenotypic assays – culturing in cell monolayers in presence of increasing concentrations of antiviral drugs:** AKA: Plaque Reduction Assay For… HSV