Viral infection and antivirals

Question 1

MOA of aciclovir

Answer 1

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

Question 2

how is CMV excreted?

Answer 2

in saliva, urine, and breast milk, infection common in childhood, usually minimally symptomatic and self-limiting

Question 3

what diseases can CMV cause

Answer 3

mononucleosis-like illness

hepatitis

Question 4

where does CMV lie latent

Answer 4

in monocytic cells (blood and bone marrow)

Question 5

importance of CMV in transplant

Answer 5

MAJOR pathogen of solid organ and bone marrow transplant patients – marrow suppression, graft rejection, pneumonitis, encephalitis, adrenalitis

Question 6

transmission of EBV

Answer 6

Salivary transmission, infection common in childhood, usually minimally symptomatic and self-limiting

Question 7

what diseases is EBV associated with in immunosuppressed patients

Answer 7

Post-transplant lymphoproliferative disease (PTLD)

Burkitt’s lymphoma

Question 8

Mx of CMV and EBV

Answer 8

Supportive treatment for uncomplicated infection
ACV not effective as treatment
Seek expert guidance for management of immunocompromised patients
Reduction of immune suppression if possible

Question 9

3 drugs that can be used as CMV antivirals

Answer 9

ganciclovir- nucleoside analogue

cidofovir- nucleoside analogue

foscarnet- inhibits viral DNA pol

Question 10

When to treat CMV infection

Answer 10

Universal prophylaxis: GCV for all transplant recipients

Pre-emptive therapy: treat viraemia without evidence of end-organ disease (EOD)

Question 11

molecular basis for drug resistance to ganciclovir

Answer 11

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

Question 12

3 novel anti-CMV drugs

Answer 12

brincidofovir
maribavir
letermovir

Question 13

symptoms of HHV-6 infection in under 3’s

Answer 13

high fever (+/- febrile convulsions), coryzal symptoms, then sudden rash

Question 14

symptoms of reactivated HHV6 in immunocompromised

Answer 14

encephalitis, marrow suppression, pneumonitis

Question 15

Tx for HHV6

Answer 15

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

Question 16

2 associated malignancies with HHV8

Answer 16

Kaposi sarcoma

multicentric castleman’s disease

Question 17

4 main types of kaposi sarcoma

Answer 17

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

Question 18

tx for HHV8

Answer 18

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