Viral infection and antivirals Flashcards
MOA of aciclovir
Monophosphorylated by viral thymidine kinase (TK) and then further phosphorylation by cellular kinases to ACV-PPP
Affinity of cellular kinases for ACV is poor but activity of these enzymes in virally-infected cells is greatly increased
Affinity of cellular DNA polymerase for ACV-PPP 10- to 30- fold lower than herpesvirus DNA polymerase
Hence inhibition of DNA synthesis by aciclovir in herpesvirus-infected cells is much greater
how is CMV excreted?
in saliva, urine, and breast milk, infection common in childhood, usually minimally symptomatic and self-limiting
what diseases can CMV cause
mononucleosis-like illness
hepatitis
where does CMV lie latent
in monocytic cells (blood and bone marrow)
importance of CMV in transplant
MAJOR pathogen of solid organ and bone marrow transplant patients – marrow suppression, graft rejection, pneumonitis, encephalitis, adrenalitis
transmission of EBV
Salivary transmission, infection common in childhood, usually minimally symptomatic and self-limiting
what diseases is EBV associated with in immunosuppressed patients
Post-transplant lymphoproliferative disease (PTLD)
Burkitt’s lymphoma
Mx of CMV and EBV
Supportive treatment for uncomplicated infection
ACV not effective as treatment
Seek expert guidance for management of immunocompromised patients
Reduction of immune suppression if possible
3 drugs that can be used as CMV antivirals
ganciclovir- nucleoside analogue
cidofovir- nucleoside analogue
foscarnet- inhibits viral DNA pol
When to treat CMV infection
Universal prophylaxis: GCV for all transplant recipients
Pre-emptive therapy: treat viraemia without evidence of end-organ disease (EOD)
molecular basis for drug resistance to ganciclovir
CMV: mutations in protein kinase (UL97) most common; DNA polymerase (UL54) rare
Most likely to occur in context of prolonged therapy in immunocompromised
Can be detected with genotypic tests (UL54 and UL97 mutations)
Suspect if clinical failure despite appropriate therapy and reduction of immune suppression
2nd line for CMV is foscarnet or cidofovir
3 novel anti-CMV drugs
brincidofovir
maribavir
letermovir
symptoms of HHV-6 infection in under 3’s
high fever (+/- febrile convulsions), coryzal symptoms, then sudden rash
symptoms of reactivated HHV6 in immunocompromised
encephalitis, marrow suppression, pneumonitis
Tx for HHV6
Generally supportive – antipyretics
HHV-6 encephalitis in transplant recipients has been treated with Foscarnet and ganciclovir although experience is limited
Important to distinguish chromosomally-integrated HHV-6 – suspect if persistently detectable in every blood sample and confirm with FISH
2 associated malignancies with HHV8
Kaposi sarcoma
multicentric castleman’s disease
4 main types of kaposi sarcoma
Classical – middle-aged Mediterranean men, indolent
Endemic – Africa, skin lesions, aggressive form
Iatrogenic – immune suppression (esp. calcineurin inhibitors), atypical location
AIDS-associated – aggressive, widespread lesions
tx for HHV8
GCV, FOS, CDV (cidofovir) all potentially active in vitro
HHV-8-associated malignancy usually treated by combination of chemotherapy and immunotherapy
HIV-associated KS may improve with HAART and suppression of HIV replication
