Antivirals Flashcards
Which parts of the viral replication cycle do antivirals target?
Reverse transcription (retroviruses only)
Transcription and translation
Release (cell lysis)
What are examples of viral encoded proteins?
Nucleic acid polymerases
Proteases
Integrase
CCR5
Terminase
What are limiting factors of antiviral therapies?
Host immune response is critical to achieve suppression of viral replication.
Adherence to treatment/antiviral drug resistance.
Drug toxicity
Drug interactions
Which human herpesviruses are classified as alpha-type?
HSV1 + HSV2
VZV
What are the characteristics of alpha-type human herpesviruses?
Rapid growth, latency in sensory ganglia
Which human herpesviruses are classified as beta-type?
CMV
HHV-6
HHV-7
What are the characteristics of beta-type human herpesviruses?
Slow growth, restricted host range
Which human herpesviruses are classified as gamma-type?
EBV
HHV-8 (KSHV)
What are the characteristics of gamma-type human herpesviruses?
Oncogenic
What is chickenpox?
Caused by primary infection with varicella-zoster virus (VZV).
Majority uncomplicated in healthy children.
Adults at risk of complications including pneumonitis.
Severe disease in the immunocompromised.
What is shingles?
Reactivation of latent infection (dorsal root ganglia).
Immunocompetent:
- Dermatomal distribution
- Complication: Post-herpetic neuralgia
Immunocompromised: Can experience multidermatomal or disseminated infection with severe complications.
What is 1st line treatment for HSV and VZV?
Acyclovir
Varicyclovir (prodrug of acyclovir)
What is second line treatment for HSV and VZV and why is it used?
Famciclovir
Used for ACV-resistant strains
What is the mode of action of acyclovir?
Further elongation of the chain is impossible because acyclovir lacks the 3’ hydroxyl group necessary for the insertion of an additional nucleotide.
What is the pharmacological activity of guanosine analogues?
Monophosphorylated by viral thymidine kinase (TK) and then further phosphorylation by cellular kinases to ACV-PPP (active form).
Affinity for herpesvirus DNA polymerase is 10- to 30- fold higher than for cellular (host) DNA polymerase for ACV-PPP.
Selective activity means reduced drug toxicity.
What is the efficacy of guanosine analogues against the alpha-type human herpesviruses?
Susceptibility: HSV-1 > HSV-2 >> VZV
VZV 10x less sensitive so higher doses required
What is the management for HSV encephalitis?
On clinical suspicion:
Start empiric treatment immediately with iv ACV 10mg/kg tds without waiting for test results.
If confirmed, treat for 14 - 21 days.
When is treatment indicated for VZV?
Chickenpox in adults (risk of complication: pneumonitis)
Zoster in adults >50 (risk of complication: post-herpetic neuralgia)
1o infection or reactivation in the immunocompromised
Neonatal chickenpox
If there is an increased risk of complications
What is CMV?
MAJOR pathogen in the immunocompromised (including solid organ and bone marrow transplant patients) – causes bone marrow suppression, retinitis, pneumonitis, hepatitis, colitis, encephalitis.
What are the treatments for CMV?
Ganciclovir - IV
Valganciclovir - PO
Foscarnet - IV/Intravitreal
Cidofovir - IV
+ Letermovir
Which viruses does Ganciclovir have activity against?
Activity against CMV
Also activity against HSV, VZV, EBV and HHV6, but seldom used
What are specific indications for ganciclovir?
CMV disease in immunocompromised (retinitis, pneumonitis), and neonates with congenital CMV.
Given together with IVIG for CMV pneumonitis.
What are side effects of ganciclovir?
Less easily tolerated than ACV.
Bone marrow toxicity (leukopenia, thrombocytopenia, anaemia, pancytopenia).
Renal and hepatic toxicity.
What are contraindications for ganciclovir?
Bone marrow suppression (neutropenia)
What is Foscarnet?
Non-competitive inhibitor of viral DNA polymerase
Does NOT require activation by phosphorylation
What viruses does Foscarnet have activity against?
Activity against CMV, and also occasionally used for HSV (eg if ACV-resistance).
Also activity against VZV, EBV and HHV6, but seldom used.