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MICRO - Abbie > 15. Antivirals > Flashcards

15. Antivirals Flashcards

1
Q

What are two main approaches of antivirals?

A
  1. Block production or action of viral-encoded proteins and inhibit viral replication
  2. help the immune system to clear the virus or to try and reduce inflammation
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2
Q

How do antivirals block production or action of viral-encoded proteins and inhibit viral replication?

A

Viral-encoded proteins are a target for antiviral drugs (e.g. protease inhibitors, polymerase inhibitors, integrase inhibitors). Small molecule inhibitors (directly-acting antivirals (DAAs)) can block production or action of the above and inhibit viral replication.

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3
Q

How do antivirals help the immune system to clear the virus or to try and reduce inflammation?

A

This is achieved by giving exogenous immunomodulators (e.g. interferon, IVIG)

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4
Q

What is viral replication normally detected by?

A

Normally, viral replication is detected by pattern-recognition receptors which trigger innate immune responses leading to production of factors such as type 1 interferons

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5
Q

How can the normal antiviral response be boosted?

A

This antiviral immune response can be boosted by giving immunomodulators

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6
Q

What are limiting factors in antiviral therapy?

A

The host immune response is CRITICAL so treating transplant patients and HIV patients can be difficult. Other limiting factors: adherence to treatment; antiviral drug resistance; drug toxicity

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7
Q

What is chickenpox caused by?

A

VZV

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8
Q

What does reactivation of VZV cause?

A

Shingles

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9
Q

Possible complication of VZV?

A

Post-herpetic neuralgia

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10
Q

Tx for VZV shingles

A

Aciclovir (PO or IV); valaciclovir - prodrug of aciclovir (PO); famciclovir. 2nd line: foscarnet or cidofovir for aciclovir-resistant strains (High toxicity). These drugs work by interfering with viral DNA synthesis.

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11
Q

How does aciclovir act against VZV?

A

Nucleoside analogue that gets incorporated into the growing chain of viral DNA. When this happens, further gene elongation becomes blocked. So, this class of drugs is also known as ‘chain terminators’. It requires activation by viral thymidine kinase (which is only found in host cells that are infected by the virus). Aciclovir has a higher affinity for viral DNA polymerase than the host DNA polymerase.

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12
Q

How to treat HSV encephalitis?

A

Medical EMERGENCY. Start empirical treatment IMMEDIATELY with IV Aciclovir 10 mg/kg tds without waiting for test results. If confirmed, treat for 21 days

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13
Q

How to treat HSV meningitis?

A

Usually self-limiting. TREAT if immunocompromised or if they are unwell enough to require hospital admission. Treatment: IV aciclovir for 2-3 days, then switch to oral for another 10 days. In the immunocompetent, valaciclovir can be used as an alternative to avoid cannulation.

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14
Q

Indications for VZV treatment?

A

Chickenpox in adults (risk of pneumonitis); shingles in adults > 50 years (risk of post-herpetic neuralgia); primary infection or reactivation in an immunocompromised patient; neonatal chickenpox; if increased risk of complications (e.g. underlying lung disease, eye involvement).

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15
Q

What does CMV do after latent infection?

A

CMV tends to lie latent in blood monocytes and dendritic cells. Reactivated following immunosuppression

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16
Q

What are consequences of CMV in immunocompromised?

A

Bone marrow suppression, retinitis, pneumonitis, hepatitis, colitis, encephalitis

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17
Q

What does histology of CMV typically show?

A

Typically shows owl’s eye inclusions

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18
Q

CMV Tx?

A
  1. Ganciclovir (IV) - In patients with CMV pneumonitis, ganciclovir is used in conjunction with IVIG.
  2. Foscarnet (IV/intravitreal) - tends to be used in CMV infection where ganciclovir is contraindicated (e.g. neutropaenia)
  3. Cidofovir (IV) - 3rd line treatment of CMV disease in the immunocompromised
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19
Q

What is ganciclovir (IV) used for?

A

Requires activation by the viral UL97 kinase enzyme (like aciclovir). Effective against a range of herpesviruses but tend to mainly be used to treat CMV infection in immunocompromised patients

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20
Q

What are side effects of ganciclovir (IV)?

A

Side-effects: bone marrow toxicity, renal and hepatic toxicity. NOTE: this limits its use in bone marrow transplant patients

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21
Q

What are side effects of foscarnet?

A

Nephrotoxicity

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22
Q

How does foscarnet work?

A

Non-competitive inhibitor of viral DNA polymerase. Does NOT require activation. Effective against many herpesviruses

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23
Q

How does cidofovir work?

A

Nucleotide analogue - Competitive inhibitor of viral DNA synthesis. Does NOT require activation.

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24
Q

What is a side effect of cidofovir?

A

Nephrotoxicity. Requires hydration and probenicid (inhibitor of renal tubular transport that helps protect against the nephrotoxic effects of cidofovir)

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25
Q

What are strategies for CMV Tx in transplant patients?

A

TREAT established disease once it has been developed (high mortality in bone marrow transplant patients).
PROPHYLAXIS with ganciclovir or valganciclovir
(Side-effects: bone marrow toxicity - Mostly used for solid organ transplant).
PRE-EMPTIVE THERAPY (for bone marrow transplant patients) - monitoring for the appearance of CMV on PCR in the blood. Starting ganciclovir, valganciclovir or foscarnet when the viral load reaches a certain threshold.

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26
Q

What are new drugs for CMV?

A

Maribavir, letermovir

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27
Q

How does maribavir work?

A

New drug. Inhibits viral kinase, effective in vitro against CMV and EBV (but no others)

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28
Q

Why is new drug maribavir potentially beneficial?

A

Does not cause bone or renal toxicity. On going clinical trials (but they have been disappointing)

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29
Q

How does letermovir work?

A

New drug. CMV DNA terminase inhibitor; terminase is involved in later stages of the viral replication cycle (this is a viral protein - NO human counterpart)

30
Q

Why is new drug letermovir potentially beneficial?

A

Well tolerated and safe; mainly GI side-effects. Approved in the USA for CMV prophylaxis in bone marrow transplant patients.

31
Q

How is EBV transmitted?

A

Saliva

32
Q

What is a classical cause of infectious mononucleosis?

A

EBV

33
Q

What are the effects of EBV infection?

A

Causes life-long infection - continuous low-grade viral replication in B lymphocytes kept in check by the cellular immune system. Associated with lymphoproliferative disease in the immunocompromised.

34
Q

What is Post-Transplant Lymphoproliferative Disease in EBV patients?

A

This is a polyclonal expansion of B cells associated with the immunosuppression used in organ transplants. This is due to a breakdown of immunosurveillance keeping the B cells and EBV in check. This predisposes to lymphoma.

35
Q

How is Post-Transplant Lymphoproliferative Disease diagnosed?

A

EBV viral load in blood

36
Q

Treatment for Post-Transplant Lymphoproliferative Disease in EBV patients

A

Reduce immunosuppression

and give Rituximab - anti-CD20 monoclonal antibody

37
Q

A 42 year old lady is admitted with a 2 day Hx of fever and confusion and presents with new onset seizures. What antiviral medication should she receive as soon as possible?

A

HSV encephalitis? ANSWER: IV Aciclovir (10 mg/kg tds without waiting for test results. If confirmed, treat for 21 days ??)

38
Q

What are the TWO main surface proteins of influenza and what do they do?

A

Haemaglutinin (HA) and neuraminidase (NA). HA mediated virus binding and entry into the target cell. NA allows release of progeny virus particles from the host cell.

39
Q

What is the target of the current generation of anti-influenza drugs?

A

neuraminidase (NA)

40
Q

What are examples of neuraminidase inhibitors?

A 
Oselatmivir (Tamiflu) - ORAL
and zanamivir (Relenza) - Dry Powder. Effective against influenza A and B. Indicated for all patients who are unwell enough to be admitted to hospital with an influenza virus-related respiratory disease. Also, peramivir (IV) - NOT licensed in the UK; few indications.
41
Q

What are treatments for RSV?

A

Ribavarin, IVIG, pavilizumab

42
Q

What is ribavarin?

A

Nucleoside analogue; oral; inhibits viral RNA synthesis; clinical efficacy is in doubt

43
Q

What is IVIG?

A

Derived from pooled donors; often used as an adjunct to treatment of viral pneumonitis in the immunocompromised.

44
Q

What is palivizumab?

A

Monoclonal antibody against RSV. Used prophylactically in the winter months for the prevention of serious lower respiratory tract disease caused by RSV in high risk infants (e.g. preterm, heart or lung disease, SCID)

45
Q

Choose the best answer. A. Oseltamivir directly inhibits the influenza NA. B. Zanamavir blocks binding of viral haemagglutinin to host cell sialic acid. C. Oseltamivir inhibits influenza virus uncoating. D. Zanamavir is usually given IV. E. Zanamavir is usually given by nebuliser.

A

A. Oseltamivir directly inhibits the influenza

46
Q

What are the effects of BK virus?

A

Polyomavirus. Primary BK infection in childhood causes minimal symptoms but leads to lifelong carriage in the kidneys and urinary tract. Causes problems in the immunocompromised. Bone marrow transplants: haemorrhagic cystitis and sometimes nephritis. Renal transplants: BK nephritis and ureteric stenosis.

47
Q

What are treatments for BK haemorrhagic cystitis?

A

Bladder washouts, reduce immunosuppression, Cidofovir IV, may consider intravesical cidofovir.

48
Q

What are Tx for BK nephropathy?

A

Reduce immunosuppression, IVIG, NOTE: cidofovir cannot be used because it is nephrotoxic.

49
Q

What are effects of adenovirus?

A

Issue in paediatric transplant patients. Can cause severe multi-organ involvement

50
Q

What is Tx for adenovirus?

A

Cidofovir IV; IVIR; brincidofovir PO

51
Q

What is brincidofovir?

A

Orally available prodrug of cidofovir. Less toxicity (mainly GI). NOT currently licensed and is still undergoing clinical trials. Main potential is for the treatment of adenovirus and BK virus disease in the immunocompromised.

52
Q

What are quasispecies?

A

Quasispecies = a population of the virus are genetically heterogenous rather than clonal

53
Q

implications of AV drug resistance

A

o Treatment failure
o Need to use second-line drugs
o Cross-resistance with other antivirals

54
Q

Prevention of drug resistance

A

o Combination drug therapy can achieve maximal suppression of viral replication (this is standard for HIV and hepatitis treatment)
o Increase adherence to treatment (lower pill burden etc.)
o In HIV, the virus is sequenced to identify the baseline resistance in order to select the optimum treatment regimen

55
Q

What drug resistance assays can be used?

A

o Genotypic assays - identify known drug resistance mutations
o Phenotypic assays - growing the virus in cell monolayers in the presence of increasing concentrations of antiviral drugs (plaque reduction assay)

56
Q

HSV drug resistance cause?

A

o Majority are due to mutation in viral thymidine kinase
• 5% of cases are due to mutations in viral DNA polymerase
o Most of these will show cross-resistance with ganciclovir
o Nearly always occur in immunocompromised patients

57
Q

How is HSV drug resistance diagnosed?

A

Diagnosed using viral culture and plaque reduction assays (although genotypic assays are also becoming available)

58
Q

Treatment for HSV drug resistance?

A

TREATMENT: foscarnet or cidofovir

59
Q

CMV drug resistance cause

A

o Most commonly caused by mutations in protein kinase gene (UL97)
• Mutations in DNA polymerase are rare
o More likely to occur in the context of prolonged therapy in immunocompromised patients

60
Q

Treatment for CMV drug resistance

A

TREATMENT: foscarnet or cidofovir

61
Q

Prophylactic Ig e.g.

A

Palivizumab for RSV

62
Q

Post-exposure prophylaxis e.g.

A

VZ Ig; Hep B Ig; Human Rabies Ig

63
Q

Therapeutic Ig e.g.

A

Human normal immunoglobulin (IVIG) as adjunctive Tx for viral pneumonitis (e.g. CMV). Rituximab (anti-CD20) for EBV driven PTLD

64
Q

Resistance of HSV to aciclovir is common in the immunocompetent true or false?

A

Not sure if common but nearly always occur in immunocompromised patients

65
Q

Phenotypic resistance testing is routinely used to detect resistance of CMV to ganciclovir - true or false?

A

False? Use genotypic assays - identify known drug resistance mutations ?? I.e. Most commonly caused by mutations in protein kinase gene (UL97)

66
Q

Aciclovir resistance in HSV is most commonly mediated by mutations in the viral thymidine kinase true or false?

A

True

67
Q

Aciclovir resistance in HSV is most commonly mediated by mutations in the viral DNA polymerase true or false?

A

False -only 5% of cases

68
Q

Antiviral drug resistance is most commonly associated with good adherence to Tx true or false

A

false??

69
Q

What types of therapies used in SARS CoV-2?

A

Antiviral drugs, neutralising monoclonal antibodies(nMabs), immunomodulators

70
Q

What are antiviral drugs against SARS CoV-2?

A

Remdesevir: Broad spectrum adenosine nucleotide analogue pro-drug. iv..

Molnupiravir: Broad spectrum. induces viral RNA mutagenesis.

Paxlovid: Protease inhibitor nirmatrelvir (administered together with low dose ritonavir to increase drug t1/2).

71
Q

What are examples of neutralising monoclonal Abs - “nMabs” in SARS CoV-2?

A

Ronapreve: (combination casirivimab + imdevimab), 2.4g iv once only.
Sotrovimab: 500mg iv once only - Strategy to treat patients who have mild to moderate disease, but who are at high risk of severe disease. Administer as early in the disease process as possible!

72
Q

Examples of immunomodulators against SARS CoV-2?

A

Steroids (eg dexamethasone). Cytokine Release Syndrome (CRS):
tocilizumab: IL-6 receptor antagonist; sarilumab: IL-6 receptor antagonist; anakinra: IL-1 receptor antagonist. (+ Thromboprophylaxis – heparin)

MICRO - Abbie (19 decks)

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