Antivirals

Question 1

Different approaches to Antiviral therapy

Answer 1

Directly Acting Antivirals / Small Molecule Inhibitors
-cell entry, genomic replication/transcription, assembly and release of progeny
E.G. nucleic acid polymerases, proteases, integrase CCR5, terminase

Immunomodulators
o Viral replication is detected by PRRs (i.e. TLRs, RIG-like receptors) - trigger innate immune responses
o This antiviral immune response can be boosted by giving immunomodulators
 E.G. interferon (tx HBV, HCV), IVIG (viral pneumonitis),

Question 2

Treatment of VZV

Answer 2

 Aciclovir (PO or IV) or Valaciclovir (aciclovir pro-drug (inactive precursor), PO)

Question 3

MOA of aciclovir

Answer 3

• Nucleoside (guanosine) analogue (incorporated into the growing chain of viral DNA  blocks)
o AKA ‘chain terminators’

• Requires activation by viral thymidine kinase (only found in infected host cells)
• Aciclovir has a higher affinity for viral DNA polymerase than the host DNA polymerase

Question 4

Treatment of HSV encephalitis

Answer 4

 Immediate empirical treatment  IV Aciclovir 10mg/kg TDS (without waiting for test results)
 If confirmed, treat for 21 days

Question 5

Treatment of HSV meningitis

Answer 5

 Treat if immunocompromised or require hospital admission
• IV aciclovir 2-3 days  PO for 10 days

 Immunocompetent  valaciclovir PO at home

Question 6

CMV infection

Answer 6

an opportunistic virus  cause severe disease in immunocompromised
o Primary infection  latent in blood monocytes and dendritic cells  reactivated following immunosuppression
o Shed in asymptomatic patients via saliva, urine, semen and cervical secretions

Question 7

CMV Consequences in the immunocompromised

Answer 7

 Bone marrow suppression Retinitis
 Pneumonitis Hepatitis
 Colitis Encephalitis

Question 8

Histology of cmv

Answer 8

Owl’s Eyes” inclusions

Question 9

Treatment of cmv and its SE

Answer 9

 Ganciclovir (IV) or Valganciclovir (PO)
• Guanosine analogue
• Needs activation by viral UL97 kinase

• SEs: bone marrow toxicity, renal and hepatic toxicity (not in HSCT patients)

Question 10

If bone marrow transplant in CMV patient what treatment

Answer 10

 Foscarnet (IV or intravitreal)
• Non-competitive viral DNA polymerase inhibitor

SE- nephrotoxicity

Question 11

3rd line treatment in CMV

Answer 11

 Cidofovir (IV)
• Nucleotide analogue  competitive inhibitor of viral DNA synthesis – no activation required

SE- nephrotoxic

Question 12

Strategies for Treatment of CMV in Transplant Patients

Answer 12

 (A) TREAT established disease (GCV and reduce immunosuppression) – high mortality in HSCT
 (B) PROPHYLAXIS with GCV/vGCV
• Indication: solid organ transplant (i.e. renal)
• SEs: bone marrow toxicity
 (C) PRE-EMPTIVE THERAPY with Foscarnet > GCV/vGCV
• Indication: HSCT

Question 13

Letermovir usage

Answer 13

CMV prophylaxis in CMV + HSCT
 Well tolerated and safe
 SEs: mainly GI side-effects
 CMV DNA terminase inhibitor

Question 14

EBV infection. mechanism

Answer 14

o Salivary transmission
o Common childhood infection; minimally symptomatic  infectious mononucleosis  life-long infection
 Continuous low-grade viral replication in B lymphocytes kept in check by the cellular immune system
 Associated with lymphoproliferative disease in the immunocompromised

Question 15

What is Post-Transplant Lymphoproliferative Disease (PTLD) and how is it diagnosed

Answer 15

 Polyclonal expansion of B cells associated with the immunosuppression used in organ transplants
 Due to a breakdown of immunosurveillance keeping the B cells and EBV in check
 Predisposes to lymphoma
 DIAGNOSIS: high EBV viral load in blood, biopsy

Question 16

How is PTLD treated

Answer 16

• Reduce immunosuppression

* Rituximab – anti-CD20 monoclonal antibody

Question 17

2 main surface proteins of Influenza

Answer 17

Haemagglutinin (HA) and neuraminidase (NA)
 HA = binding and entry into the target cell
 NA = release of progeny virus particles from the host cell

Question 18

Neuraminidase inhibitor examples and indication

Answer 18

• Oseltamivir (Tamiflu) – ORAL
• Zanamivir (Relenza) – Dry Powder
• Those unwell enough to be admitted to hospital
• Risk groups – i.e. age >65yo, immunosuppressed, chronic resp. disease

Question 19

Treatment of RSV

Answer 19

o Ribavirin (PO):
 Nucleoside/Guanosine analogue - inhibits viral RNA synthesis
 Indications: Lassa fever, HEV, HCV (not sure if effective in RSV)

o IVIG:
 Derived from pooled donors
 Often used as an adjunct to treatment of viral pneumonitis in the immunocompromised

o Palivizumab:
 Monoclonal antibody against RSV
 Used prophylactically in the winter months for the prevention of serious lower respiratory tract disease caused by RSV in high risk infants

Question 20

BK virus infection complication in immunocompromised

Answer 20

o HSCT: BK cystitis, nephritis

o Renal transplants: BK nephropathy, ureteric stenosis

Question 21

Treatment of BK haemorrhagic cystitis

Answer 21

o Bladder washouts
o Reduce immunosuppression
o If significant morbidity  Cidofovir (IV)
o If nephrotoxicity  Cidofovir (intravesical)

Question 22

Treatment of BK nephropathy

Answer 22

o Reduce immunosuppression
o IVIG
o NOTE: cidofovir cannot be used because it is nephrotoxic

Question 23

Adenovirus infection issues

Answer 23

• Issue in paediatric transplant patients

* Can cause severe multi-organ involvement

Question 24

Treatment of Adenovirus

Answer 24

o Cidofovir (IV) or Brincidofovir (PO)
 Brincidofovir is the prodrug or cidofovir
 Indications: adenovirus, BK virus in the immunocompromised
 Less toxic on the GI tract
o IVIG

Question 25

Causes of AVT resistance

Answer 25

o Selection  selection of pre-existing resistant strains due to inadequate drug levels
o Diversity  quasispecies (a population of the virus are genetically heterogenous rather than clonal)

Question 26

Implications of drug resistance

Answer 26

o Treatment failure
o Need to use second-line drugs – less effective and often more toxic
o Cross-resistance with other antivirals

Question 27

Testing for drug resistance

Answer 27

o Genotypic assays – sequencing genome  identify known drug resistance mutations
o Phenotypic assays – culturing in cell monolayers in presence of increasing concentrations of antiviral drugs

Question 28

HSV resistance

Answer 28

Resistance to Aciclovir
95% due to mutation in viral thymidine kinase
o TREATMENT  foscarnet or cidofovir

Question 29

CMV resistance

Answer 29

 Common  mutations in protein kinase gene (UL97)
Seen in prolonged therapy in immunocompromised patients
o TREATMENT  foscarnet or cidofovi

Question 30

Influenza resistance

Answer 30

o Oseltamivir (NA inhibitor) resistance through H275Y mutation