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YEAR 5: MICRO > MI: Antivirals > Flashcards

MI: Antivirals Flashcards

1
Q

Describe two approaches to antiviral treatment.

A
  • 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)

can also give IVIG or IFN

target step 4,7,9

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2
Q

How are viral infections normally detected by the immune system?

A

Viral replication is detected by pattern-recognition receptors which trigger an innate immune response leading to the production of factors (e.g. IFN)

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3
Q

Main difference between anti viral and anti bacterial therapy

A

Antiviral therapy relies on HOST to clear infection

whereas Abx essentially clear the infection themselves

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4
Q

List some limiting factors for antiviral therapy.

A
  • Host immune response
  • Adherene to treatment
  • Antiviral drug resistance
  • Drug toxicity
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5
Q

difference between chickenpox and shingles infection

A

chickenpox - primary infection

zoster/shingles - reactivation in dorsal root ganglia
immunocompetent - dermatomal distribution
immunosupprressed - multidermatomal or dissemeninated infection

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6
Q

What is a possible complication of shingles?

A

Post-herpetic neuralgia

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7
Q

How might shingles present differently in immunocompromised patients?

A

Multi-dermatomal distribution or invasive disease

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8
Q

What is the main treatment option for VZV infection?

A

Aciclovir (PO or IV)

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9
Q

Main complication of chickenpox in adults

A

pneumonitis

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10
Q

Outline the mechnism of action of aciclovir.

A
  • Guanosine 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
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11
Q

Why do you need to give higher dose of guanosine analogues in VZV than HSV

effect of this

A

affinity to HSV DNA polymerase is much higher than to VZV DNA polymerase

So in shingles/chickenpox you need to give higher dose –> more risk of side effects

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12
Q

What is the prodrug of aciclovir?

A

Valaciclovir (PO)

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13
Q

What are two 2nd line treatment options for aciclovir-resistant VZV infection?

A
  • Foscarnet
  • Cidofovir

NOTE: they inhibit viral DNA polymerase –> inhibits synthesis

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14
Q

HSV encephalitis is a medical emergency. How should it be treated?

A
  • IMMEDIATE treatment with IV aciclovir 10 mg/kg TDS without waiting for test results
  • If confirmed, treat for 21 days
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15
Q

What is HSV meningitis and how should it be treated?

A
  • 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
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16
Q

List some indications for treatment of VZV.

A
  • 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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17
Q

What is CMV?

A

Opportunistic virus that causes severe disease in immunocompromised patients

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18
Q

In which cells does CMV lie dormant?

A

Monocyte and dendritic cells

reactivated following immunosuppression

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19
Q

List some consequences of CMV infection in immunocompromised patients.

A
  • Bone marrow suppression
  • Retinitis
  • Pneumonitis
  • Hepatitis
  • Colitis
  • Encephalitis
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20
Q

What is a characteristic histological feature of CMV infection?

A

Owl’s eye inclusion

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21
Q

What is the 1st line treatment option for CMV infection?

A

Ganciclovir (IV)

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22
Q

How is ganciclovir activated?

WHat is its mechanism

A

Requires activation by viral UL97 kinase enzyme

Guanosine nucleoside anlalogue - prevents DNA synthesis

NOTE: ganciclovir is used in conjunction with IVIG in patients with CMV pneumonitis

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23
Q

What is a major side-effect of ganciclovir?

A

Bone marrow toxicity - leukopaenia, thrombocytopenia, anaemia

NOTE: therefore, its use is limited in bone marrow transplant patients - so Foscarnet is used 1st line instead

24
Q

What is the pro-drug of ganciclovir?

A

Valganciclovir (PO)

25
What is the mechanism of action of foscarnet? Side effects
* Non-competitive inhibitors of viral DNA polymerase * NOTE: foscarnet does NOT require activation * Tends to be used in CMV infections in immunosuppressed/transplant patient Prolongs QTc, AKI
26
What is a major side-effect of foscarnet?
Nephrotoxicity Proloongs QTc
27
What is the mechanism of action of cidofovir? What is it used for
Competitive inhibitors of viral DNA synthesis (nucleotide analogue) NOTE: does not require activation 3rd line for CMV in immunocompromised
28
What is a major side-effect of cidofovir?
Nephrotoxicity (requires hydration and probenecid) | VERY TOXIC
29
What are three strategies for the treatment of CMV in transplant patients?
1. TREAT established disease 2. PROPHYLAXIS with ganciclovir or valganciclovir (mainly in solid organ transplant patients) 3. 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)
30
What is the mechanism of action of maribavir?
Inhibits viral kinase (UL97) Effective *in vitro*, against CMV and EBV currently undergoing clinical trials
31
What is the mechanism of action of letermovir?
CMV DNA terminase inhibitor - prevents virion formation --> virus can't leave cell Approved for CMV prophylaxis in bone marrow transplant patients - to prevent reactivation in CMV IgG+ patients
32
In which cells does EBV cause continuous low-grade viral replication?
B cells
33
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) * There is uncontrolled B cell polyclonal expansion * This predisposes to lymphoma
34
How is post-transplant lymphoproliferative disease treated?
* Reduce immunosuppression * Rituximab (anti-CD20)
35
Herpes, influenza viruses - DNA or RNA
Herpes - DNA virus Influenza - RNA virus
36
What are the roles of haemagglutinin and neuraminidase in the influenza virus?
* Haemagglutinin - mediates binding + entry to target cell (binds to sialic acid) * Neuraminidase - allows release of new virus particles from the host cell | Most influenza drugs are neuraminidase inhibitors
37
Name two examples of neuraminidase inhibitors. What are they used for
* Oseltamivir (Tamiflu) - oral * Zanamivir (Relenza) - dry powder for influenza A and B | Peramivir - only in US for influenza A, H275Y mutation reduces activity
38
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 | Given to ALL patients in hospitla with influenza respiratory disease
39
What is the most common cause of bronchiolitis?
RSV
40
List three treatments for bronchiolitis.
* **Ribavirin** - nucleoside (guanosine) analogue - not a lot of evidence for it * **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) | Vaccine for pregnant women
41
List drugs for Sars-Cov2
Antivirals - All target RNA polymerase Remdesevir, Paxlovid, Monulpiravir Monclonal antibodies - prevent virus binding to host cells ACE2 receptors by binding to spike proteins, administer early Ronapreve, Sotrovimab Immunomodulaltors - steroids, toculizumab (IL-6), Sarilumab, Anakinra (TNF-alpha)
42
WHat drugs for Monkeypox
Tecovirimat Cidofivir
43
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) | polyoma virus - related to JC virus
44
What disease states does BK virus cause?
* Bone marrow transplant → haemorrhagic cystitis * Renal transplants → BK nephritis and ureteric stenosis
45
Outline the treatment of BK haemorrhagic cystitis.
* Bladder washouts * Reduce immunosuppression * Cidofovir IV (may consider intravesical)
46
Outline the treatment of BK nephropathy.
* Reduce immunosuppression * IVIG NOTE: cidofovir cannot be used because it is nephrotoxic
47
In which subgroup of patients is adenovirus a major issue?
Paediatric transplant patients
48
Outline the treatment of adenovirus infection in transplant patients.
* Cidofovir IV * IVIG * Brincidofovir (prodrug of cidofovir currently undergoing clinical trials)
49
What is the main cause of antiviral drug resistance?
Inadequate drug levels
50
How can antiviral drug resistance be prevented?
* Combination drug therapy * Increase adherence (lower pill burden etc.) * Sequencing to identify baseline drug resistance
51
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) | phenotypic - used for HSV drug resistance
52
What are most cases of HSV drug resistance caused by?
Mutations in viral thymidine kinase
53
What are most cases of CMV drug resistance caused by?
Mutations in protein kinase gene UL97
54
In which patient population is HSV and CMV drug resistance most prevalent?
Immunocompromised patients
55
What are the main treatment ooptions for drug resistant HSV and CMV infection?
Foscarnet and cidofovir

YEAR 5: MICRO (24 decks)

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