MI: Antivirals Flashcards
Describe two approaches to antiviral treatment.
- Viral-encoded proteins are a major target (e.g. protease inhibitors) - these are directly-acting antivirals (DAAs)
- Helping the immune system to clear the virus with the use of immunomodulators (e.g. interferon)
How are viral infections normally detected by the immune system?
Viral replication is detected by pattern-recognition receptors which trigger an innate immune response leading to the production of factors (e.g. IFN)
List some limiting factors for antiviral therapy.
- Host immune response
- Adherene to treatment
- Antiviral drug resistance
- Drug toxicity
What is a possible complication of shingles?
Post-herpetic neuralgia
How might shingles present differently in immunocompromised patients?
Multi-dermatomal distribution or invasive disease
What is the main treatment option for VZV infection?
Aciclovir (PO or IV)
Outline the mechnism of action of aciclovir.
- Nucleoside analogue that is incorporated into growing viral DNA and blocks further elongation
- Requires activation by viral thymidine kinase (which is only present in host cells that are infected by the virus)
- Aciclovir has a higher affinity for viral DNA polymerase than host DNA polymerase
What is the prodrug of aciclovir?
Valaciclovir (PO)
What are two 2nd line treatment options for aciclovir-resistant VZV infection?
- Foscarnet
- Cidofovir
NOTE: they inhibit viral DNA synthesis
HSV encephalitis is a medical emergency. How should it be treated?
- IMMEDIATE treatment with IV aciclovir 10 mg/kg TDS without waiting for test results
- If confirmed, treat for 21 days
What is HSV meningitis and how should it be treated?
- Usually self-limiting
- Immunocompromised patients and those who are unwell enough to require hospital admission require treatment
- IV aciclovir for 2-3 days followed by oral aciclovir for 10 days
List some indications for treatment of VZV.
- Chickenpox in adults (high risk of pneumonitis)
- Shingles in adults > 50 years (risk of post-herpetic neuralgia)
- Infection in immunocompromised patients
- Neonatal chickenpox
- If increased risk of complications (e.g. underlying lung disease)
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What is CMV?
Opportunistic virus that causes severe disease in immunocompromised patients
In which cells does CMV lie dormant?
Monocyte and dendritic cells
List some consequences of CMV infection in immunocompromised patients.
- Bone marrow suppression
- Retinitis
- Pneumonitis
- Hepatitis
- Colitis
- Encephalitis
What is a characteristic histological feature of CMV infection?
Owl’s eye inclusion
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What is the 1st line treatment option for CMV infection?
Ganciclovir (IV)
How is ganciclovir activated?
Requires activation by viral UL97 kinase enzyme
NOTE: ganciclovir is used in conjunction with IVIG in patients with CMV pneumonitis
What is a major side-effect of ganciclovir?
Bone marrow toxicity
NOTE: therefore, its use is limited in bone marrow transplant patients
What is the pro-drug of ganciclovir?
Valganciclovir (PO)
What is the mechanism of action of foscarnet?
- Non-competitive inhibitors of viral DNA polymerase
- NOTE: foscarnet does NOT require activation
- Tends to be used in CMV infections if ganciclovir is contraindicated
What is a major side-effect of foscarnet?
Nephrotoxicity
What is the mechanism of action of cidofovir?
Competitive inhibitors of viral DNA synthesis (nucleotide analogue)
NOTE: does not require activation
What is a major side-effect of cidofovir?
Nephrotoxicity (requires hydration and probenecid)
What are three strategies for the treatment of CMV in transplant patients?
- TREAT established disease
- PROPHYLAXIS with ganciclovir or valganciclovir (mainly in solid organ transplant patients)
- PRE-EMPTIVE THERAPY for bone marrow transplant patients (monitoring for the appearance of CMV in PCR of the blood and starting antiviral therapy when the viral load reaches a threshold)
What is the mechanism of action of maribavir?
Inhibits viral kinase
Effective in vitro, currently undergoing clinical trials
What is the mechanism of action of letermovir?
CMV DNA terminase inhibitor
Approved in the USA for CMV prophylaxis in bone marrow transplant patients
In which cells does EBV cause continuous low-grade viral replication?
B cells
What is post-transplant lymphoproliferative disease?
- Polyclonal expansion of B cells associated with immunosuppression used in organ transplant (due to breakdown of immunosurveillance keeping the B cells and EBV in check)
- This predisposes to lymphoma
How is post-transplant lymphoproliferative disease treated?
- Reduce immunosuppression
- Rituximab (anti-CD20)
What are the roles of haemagglutinin and neuraminidase in the influenza virus?
- Haemagglutinin - mediates viral binding and entry into target cell
- Neuraminidase - allows release of progeny virus particles from the host cell
Name two examples of neuraminidase inhibitors.
- Oseltamivir (Tamiflu) - oral
- Zanamivir (Relenza) - dry powder
What are the 3 indications for use of neuraminidase inhibitors in the community according to NICE?
- National surveillance indicates that influenza is circulating
- Patient is in a risk group
- Within 48 hours of onset of symptoms
What is the most common cause of bronchiolitis?
RSV
List three treatments for bronchiolitis.
- Ribavirin - nucleoside analogue
- IVIG - often used as adjunct to treatment of viral pneumonitis in immunocompromised patients
- Palivizumab - monoclonal antibody against RSV used prophylactically in winter months in high-risk infants (e.g. preterm)
What is BK virus?
A virus that causes minimal symptoms on primary inection but leads to lifelong carriage in the kidneys and urinary tract (causes problems in immunocompromised patients)
What disease states does BK virus cause?
- Bone marrow transplant → haemorrhagic cystitis
- Renal transplants → BK nephritis and ureteric stenosis
Outline the treatment of BK haemorrhagic cystitis.
- Bladder washouts
- Reduce immunosuppression
- Cidofovir IV (may consider intravesical)
Outline the treatment of BK nephropathy.
- Reduce immunosuppression
- IVIG
NOTE: cidofovir cannot be used because it is nephrotoxic
In which subgroup of patients is adenovirus a major issue?
Paediatric transplant patients
Outline the treatment of adenovirus infection in transplant patients.
- Cidofovir IV
- IVIG
- Brincidofovir (prodrug of cidofovir currently undergoing clinical trials)
What is the main cause of antiviral drug resistance?
Inadequate drug levels
How can antiviral drug resistance be prevented?
- Combination drug therapy
- Increase adherence (lower pill burden etc.)
- Sequencing to identify baseline drug resistance
Describe two types of drug resistance assays.
- Genotypic assay - identify drug resistance mutations
- Phenotypic assay - grow the virus in monolayers in the presence of increasing concentrations of antiviral drugs (plaque reduction assay)
What are most cases of HSV drug resistance caused by?
Mutations in viral thymidine kinase
What are most cases of CMV drug resistance caused by?
Mutations in protein kinase gene UL97
In which patient population is HSV and CMV drug resistance most prevalent?
Immunocompromised patients
What are the main treatment ooptions for drug resistant HSV and CMV infection?
Foscarnet and cidofovir