Antivirals Flashcards
Different approaches to Antiviral therapy
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),
Treatment of VZV
Aciclovir (PO or IV) or Valaciclovir (aciclovir pro-drug (inactive precursor), PO)
MOA of aciclovir
• 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
Treatment of HSV encephalitis
Immediate empirical treatment IV Aciclovir 10mg/kg TDS (without waiting for test results)
If confirmed, treat for 21 days
Treatment of HSV meningitis
Treat if immunocompromised or require hospital admission
• IV aciclovir 2-3 days PO for 10 days
Immunocompetent valaciclovir PO at home
CMV infection
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
CMV Consequences in the immunocompromised
Bone marrow suppression Retinitis
Pneumonitis Hepatitis
Colitis Encephalitis
Histology of cmv
Owl’s Eyes” inclusions
Treatment of cmv and its SE
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)
If bone marrow transplant in CMV patient what treatment
Foscarnet (IV or intravitreal)
• Non-competitive viral DNA polymerase inhibitor
SE- nephrotoxicity
3rd line treatment in CMV
Cidofovir (IV)
• Nucleotide analogue competitive inhibitor of viral DNA synthesis – no activation required
SE- nephrotoxic
Strategies for Treatment of CMV in Transplant Patients
(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
Letermovir usage
CMV prophylaxis in CMV + HSCT
Well tolerated and safe
SEs: mainly GI side-effects
CMV DNA terminase inhibitor
EBV infection. mechanism
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
What is Post-Transplant Lymphoproliferative Disease (PTLD) and how is it diagnosed
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
How is PTLD treated
- Reduce immunosuppression
* Rituximab – anti-CD20 monoclonal antibody
2 main surface proteins of Influenza
Haemagglutinin (HA) and neuraminidase (NA)
HA = binding and entry into the target cell
NA = release of progeny virus particles from the host cell
Neuraminidase inhibitor examples and indication
- 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
Treatment of RSV
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
BK virus infection complication in immunocompromised
o HSCT: BK cystitis, nephritis
o Renal transplants: BK nephropathy, ureteric stenosis
Treatment of BK haemorrhagic cystitis
o Bladder washouts
o Reduce immunosuppression
o If significant morbidity Cidofovir (IV)
o If nephrotoxicity Cidofovir (intravesical)
Treatment of BK nephropathy
o Reduce immunosuppression
o IVIG
o NOTE: cidofovir cannot be used because it is nephrotoxic
Adenovirus infection issues
- Issue in paediatric transplant patients
* Can cause severe multi-organ involvement
Treatment of Adenovirus
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
Causes of AVT resistance
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)
Implications of drug resistance
o Treatment failure
o Need to use second-line drugs – less effective and often more toxic
o Cross-resistance with other antivirals
Testing for drug resistance
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
HSV resistance
Resistance to Aciclovir
95% due to mutation in viral thymidine kinase
o TREATMENT foscarnet or cidofovir
CMV resistance
Common mutations in protein kinase gene (UL97)
Seen in prolonged therapy in immunocompromised patients
o TREATMENT foscarnet or cidofovi
Influenza resistance
o Oseltamivir (NA inhibitor) resistance through H275Y mutation
