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Antiviral treatment Flashcards

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1
Q

Describe the basic viral replication pathway

A
  1. Antiviral binds to a specific receptor
  2. Endocytosis of the antiviral into the cell
  3. Uncoating
  4. Reverse transcription (retroviruses only)
  5. Transport to the nucleus
  6. Genome integration (lysogenic cycle only)
  7. Transcription and translation
  8. Assembly of new virions
  9. Release (cell lysis)
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2
Q

Describe a virus

A
  • Viruses are obligate intracellular parasites
  • Metabolically inert
  • Rely on host cell for replication
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3
Q

What are directly-acting antivirals?

A

DAAs are small molecule inhibitors and can block production or action of viruses encoding specific proteins and inhibit viral replication

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4
Q
  1. What specific proteins do some viruses encode and why?
A

Viruses encode specific proteins required for:

  • cell entry
  • genomic replication
  • transcription
  • assembly and release of progeny virions

Virally encoded including:

  • nucleic acid
  • polymerases
  • proteases
  • integrase
  • CCR5
  • terminase
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5
Q

What is immunomodulation?

A
  • Viral replication detected by pattern-recognition receptors (PPRs, toll-like receptors, RIG-like receptors)
  • Triggers innate immune responses leading to production of restriction factors such as type 1 inteferons (IFNs)
  • Antiviral immune response can be boosted by exogenous immunomodulators. So immunomodulation is when a drug amplifies a response to a virus to trigger the innate immune system, or get a bigger response.
  • Examples:
    • interferon Rx for HBV and HCV,
    • imiquimod for HPV
    • IVIG for viral pneumonitis
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6
Q

What are some of the limiting factors of antiviral therapy?

A
  • Host immune response is critical to achieve suppression of viral replication
    • Transplant patients: if possible reduce immunosuppressive rx
    • HIV patients: start antiretroviral Rx
  • Adherence to treatment/antiviral drug resistance
  • Drug toxicity
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7
Q

What are the classification of human herpes virus?

  1. Subfamily
  2. Viruses examples
  3. Clinical syndromes
  4. Characteristics
A
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8
Q

Describe varicella zoster virus

  1. Primary infection
  2. Reactivation
  3. Complications
A
  1. Primary infection:
  • Chickenpox is the primary infection caused by varicella zoster virus
  • Majority uncomplicated in healthy children
  • Severe disease in the immunocompromised
  1. Reactivation
  • Reactivation of latent infection in the doral root ganglia
  • Chickenpox comes back in later life, or when immunocompromised as shingles
  • Shingles has a dermatoma distribution
  1. Complications
  • Chickenpox - complications include pneumonitis
  • Shingles - complication is post-herpetic neuralgia
  • Immuncompromised can experience multidermatomal or disseminated infection with severe complications
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9
Q

What are the different antiviral drugs for Herpes simplex virus and varicella zoster virus?

A

1st line

  • Aciclovir (po or IV)
  • Valaciclovir (prodrug of aciclovir, po, high bioavaliablity)

Famciclovir

2nd line:

  • Foscarnet or cidofovir for ACV-resistant virus
  • Interfere with viral DNA synthesis
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10
Q
  1. What is aciclovir?
  2. What is aciclovir’s mode of action?
A
  1. Aciclovir is a guanosine analogue
  2. Mode of action:
    • Further elongation of the chain is impossible because acyclovir lacks the 3’hydroxyl group necessary for the insertion of an additional nucleotide
    • It acts as a specific inhibitor of herpes virus DNA polymerase
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11
Q

Describe the selective activity of guanosine analogues like aciclovir

A
  • Monophosphorylated by viral thymidine kinase (TK) and then further phosphorylation by cellular kinases to ACV-PPP (active form)
  • Affinity for herpesvirus DNA polymerase is 10- to 30- fold higher than for cellular (host) DNA polymerase for ACV-PPP
  • Selective activity means reduced drug toxicity
  • Susceptibility: HSV-1> HSV-2 >>VSV
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12
Q

What should be done when HSV encephalitis is suspected?

A

HSV encephalitis:

  • Start empiric treatment immediately with I.V aciclovir 10mg/kg tds WITHOUT waiting for test results
  • If then confirmed, treat for 21 days
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13
Q

Describe the treatment for HSV meningitis

A
  • Most cases are self-limiting
  • Treatment recommended if unwell enough to be admitted to hospital, or if immunocompromised
  • Rx example: Aciclovir IV for 2-3 days, then switch to oral for a further 10 days
  • Alternative in the immunocompetent - valaciclovir to avoid cannulation
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14
Q

What are the indications for treatment with VSV?

A
  • Chickenpox in adults (risk of complication: pneumonitis)
  • Zoster in adults >50 (risk of complication: post-herpetic neuralgia)
  • 1o infection or reactivation in the immunocompromised
  • Neonatal chickenpox
  • If there is an increased risk of complications
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15
Q

Cytomegalovirus (CMV)

  1. Primary infection
  2. Spread
  3. Complications
A
  1. Primary infection with the virus, which can then stay latent in blood monocytes and dendritic cells. Can be reactivated following immunosuppression
  2. Asymptomatic shedding in saliva, urine, semen and cervical secretions
  3. Major pathogens in the immunocompromised causes
    • marrow suppression
    • retinitis
    • pneumonitis
    • hepatitis
    • colitis
    • encephalitis
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16
Q

What are the different CMV antiviral drugs?

A
  • Ganciclovir (GCV) - IV
  • Valganciclovir (VGC) - PO
  • Foscarnet (FOS) - IV/intravitreal
  • Cidofovir (CDV) - IV
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17
Q

Describe how the different CMV antiviral drugs develop resistance

  1. Ganciclovir
  2. Foscarnet
  3. GCV, CDV
A
  1. GCV resistance - alteration in substrate binding or phosphate transfer sites
  2. Foscarnet resistance - Alteration in P-P binding site
  3. GCV, CDV resistance - alteration in catalytic site or relative increase in exonuclease activity
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18
Q

Describe the following about val/Ganciclovir

  1. What is it?
  2. Activity/uses
  3. Route of administration
  4. Excretion
  5. Indications
  6. Side effects
  7. Contraindications
A
  1. Ganciclovir is a guanosine analogue - inhibits viral DNA synthesis
  2. Activity against CMV. However, also against HSV, VZV, EBV, HHV6
  3. GCV - slow IV infusion, valGCV - oral pro-drug
  4. Renal excretion
  5. Indications:
    • CMV disease in immunocompromised (retinitis, pneumonitis)
    • neonates with congenital CMV
    • Given together with IVIG for CMV pneumonitis in Tx patients
  6. Side effects
    • Less well tolerated than ACV
    • Bone marrow toxicity (leucopenia, thrombocytopenia, anaemia, pancytopenia)
    • Renal and hepatic toxicity
  7. Bone marrow suppression
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19
Q

Describe the following about Foscarnet

  1. What is it?
  2. Activity/uses
  3. Route of administration
  4. Indications
  5. Side effects
A
  1. Foscarney is a non-competitive inhibitor of viral DNA polymerase. Does not require activation by phosphorylation
  2. Activity against CMV, and also occassionally used for HSV if ACV resistant. Alos activity against VZV, EBV and HHV6 but seldom used
  3. Route of administration is a slow IV infusion, or intravitreal implants
  4. Indications
    • CMV disease in patients whom GCV is contraindicated i.e. neutropenic patients (e.g. pre-engraftment post-BMT); GCV-resistant CMV, CMV retinitis (intravitreal implants)
  5. Side effects
    • Nephrotoxic
    • Keep well hydrated and monitor electrolytes
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20
Q

Describe the following about Cidofovir

  1. What is it?
  2. Activity
  3. Route of administration
  4. Indication
  5. Side effects
A
  1. Cidofovir is a nucleotide (cytidine) analogue. Is a competitive inhibitor of viral DNA synthesis and does not require activation by phosphorylation
  2. Activity against CMV, and also occassionally HSV (is ACV resistant)
  3. ROA: IV infusion (and comes as a cream)
  4. Indications - third line treatment of CMV disease in the immunocompromised
  5. Side effects - nephrotoxic, and requires hydration and probenicid
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21
Q

Describe the stratergies for management of CMV in transplant patients

A
  1. Treat established disease (ganciclovir & reduce immunosuppression) – high mortality in BMTs
  2. Prophylaxis with GCV/vGCV (or ACV/vACV)
  • SEs include BM toxicity
  • Mostly used for solid organ Tx (eg renal)

3.Pre-emptive therapy:

  • Surveillance (eg weekly blood CMV PCR)
  • vGCV/GCV or foscarnet Rx when PCR +ve
  • Mostly used for stem cell transplant
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22
Q

What is Maribavir?

  • What is it?
  • Uses?
A
  • Oral drug
  • Effective in vitro against CMV and EBV
  • Directly inhibits viral kinase (UL97)
  • Effective in vitro against GCV-resistant CMV strains
  • Well tolerated
  • Does not give rise to either renal or bone marrow toxicity
  • Ongoing clinical trials
23
Q

Describe the following about Letermovir

  1. What is it?
  2. ROA
  3. Side effects
A
  1. Letermovir is a CMV DNA terminase (cleavage and packing of viral progeny DNA into capsids) inhibitor
  2. Remains active against GCV-resistant strains
  3. Well tolerated and safe, mainly GI side effects
24
Q

Describe Epstein-Barr virus

  1. What is it?
  2. Complications in immuncompromised
A
    • EBV is a salivary transmission infection common in childhood, usually minimally symptomatic and self-limiting
    • Classical cause of infectious mononucleosis
    • Lifelong infection - continuous low grade replication in B lymphocytes kept in check by cellular immune system (immunosurveillance)

2.

  • Associated with lymphoproliferative disease in the immunocompromised
25
Q
  1. Describe the association between EBV and Post-transplant lymphoproliferative disease
  2. Diagnosis
  3. Management
A
  1. EBV and PTLD:
  • Associated with EBV infection
  • Breakdown of immunosurveillance
  • Latency infected B cells - polyclonal activation
  • Predispose to lymphoma
  1. Diagnosis
  • EBV viral load in blood
  • Biopsy
  1. Management
  • Reduce immunosuppression
  • Anti-CD20 monoclonal Ab therapy (B cell marker) - rituximab
26
Q

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

a) Oral aciclovir
b) IV foscarnet
c) Oral valaciclovir
d) IV ganciclovir
e) IV aciclovir

A

e) IV aciclovir

Suspected HSV encephalitis

27
Q

What is neuraminidase?

A

Neuraminidase is required for release of new virus to propagate infection

28
Q

Describe how the influenza virus propagates

A
  • Influenza viruses get into the respiratory tract and viruses attach to the outside of respiratory epithelial cells binding to surface proteins. Viral haemagglutin binds to sialic acid on the cell surface. Binding is essential for viral growth
  • Binding to neuroaminidase on the surface is essential for release of new virus to propagate infection
29
Q

Describe neuraminidase inhibitors

  1. Name 2
  2. ROA
  3. Uses
  4. When are they indicated for inpatients?
A
  1. Oseltamivir - Tamiflu - oral, Zanamivir - Relenza, dry powder inhaler
  2. IV and nebulized formulations can also be obtained
  3. Effective for both influenza A and B
  4. For inpatients, indicated for all patients admitted to hospital due to influenza virus-related respiratory disease
30
Q
  1. When are neuroaminidase inhibitors indicated in the community (NICE guidelines)?
  2. What are the risk groups for flu?
A

1.

a) National surveillance indicates influenza is circulating
b) Patient is in a ‘risk-group’ *
c) Within 48 hours of symptom onset (36 hours for zanamivir)
2. Risk groups:

  • Aged >65 years
  • Immunosuppressed
  • Chronic respiratory disease/heart disease/liver disease/neurological disease
  • Diabetes mellitus
  • Pregnant women
  • Morbid obesity
  • Children <6 months
31
Q

What is Peramivir?

A
  • Neuraminidase inhibitor licensed in US, but also available in UK
  • 600mg IV od
  • Evidence mainly for ‘flu A
  • H275Y mutation confers reduced susceptibility à avoid use with oseltamivir resistance
32
Q

Describe Respiratory syncytical virus (RSV)

  1. What is it the most commonest cause of?
  2. What is it associated with in later life?
  3. Risk groups?
A
  1. Commonest cause of severe respiratory tract illness and hospitalisation of infants worldwide (bronchiolitis)
  2. Associated with subsequent wheeze and asthma diagnosis in later life
  3. Other risk groups: Elderly, chronic lung disease and the immunocompromised
33
Q
  1. What is Ribavirin?
  2. How does it work?
  3. Clinical effectiveness
  4. Adverse effects
A
  1. Ribavirin is a guanosine analogue, and is administered PO
  2. Ribavirin acts to inhibit viral RNA synthesis
  3. Broad activity in vitro: effective for Lassa fever and Hepatitis E virus. Clinical effectiveness on RSV is unclear
  4. Adverse effects include anaemia and possible teratogenicity
34
Q

What are the uses for IV Immunoglobulin (IVIG)?

A

IVIG is administered as an adjunct to treatment of viral pneumonitis in the immunocompromised

35
Q
  1. What is Palivizumab?
  2. What are the indications for Palivizumab?
A
  1. Palivizumab is a monoclonal antibody against RSV
  2. Indication: For the prevention of serious lower respiratory tract disease caused by RSV in infants at high risk: eg born preterm and severe underlying heart or lung disease (such as bronchopulmonary dysplasia), SCID or long term ventilation
36
Q

EMQ

The following statements concern the antiviral drugs oseltamivir and zanamivir. Choose the best answer.

a) Oseltamivir directly inhibits the influenza neuraminidase
b) Zanamivir blocks binding of viral haemagglutinin to host cell sialic acid
c) Oseltamivir inhibits influenza virus uncoating
d) Zanamivir is usually given intravenously
e) Zanamivir is usually given by nebuliser

A

A) Ostelamivir directly inhibits the influenza neuroaminidase (enzyme). Therefore, blocking the virus’ ability to propagate

37
Q
  1. What is BK virus?
  2. When does BK virus become problematic?
  3. What can BK cause in the following:

a) Bone marrow transplant
b) Renal transplant

A
  1. Part of Polyomavirus family (related to JC virus)

Primary BK virus infection in childhood with minimal symptoms, but subsequent lifelong carriage in kidneys and urinary tract

  1. BK virus only becomes problematic in the immunocompromised
  2. a) Bone marrow transplant:
  • Haemorrhagic cystitis
  • Less commonly nephritis

b)

  • BK nephritis and ureteric stenosis
38
Q

How is BK haemorrhagic cystitis treated?

A
  • Bladder washouts
  • Reduce level of immunosuppression if possible
  • Cidofovir iv (+ probenicid) if significant morbidity
  • Intravesical cidofovir (5mg/kg/wk) an option if nephrotoxicity
  • (Future: ?brincidofovir)
39
Q

How do you treat BK nephropathy?

A
  • Reduce level of immunosuppression if possible
  • Normal immunoglobulin (IVIG)
  • (Future: ?brincidofovir)
40
Q
  1. Who is most at risk of adenovirus?
  2. What can it cause?
  3. What is the treatment?
A
  1. Adenovirus is most problematic in paeds transplant patients
  2. Adenovirus can cuase severe multi-organ involvement
  3. Treatment:
  • Cidofovir (IV)
  • IVIG
  • Brincidofovir (PO)
41
Q
  1. What is Brincidofovir?
  2. What is the possible main use of this drug?
A
  1. Brincidofovir is a lipid-conjugated oral prodrug of cidofovir, given 100mg twice a week.
  2. Has less toxicity than cidofovir, mainly reduced diarrhoea and mild transaminitis.

Main potential is for treatment of adenovirus and of BK virus disease in the immunocompromised

42
Q

What are the benefits of cellular immunotherapy?

A

Cellular immunotherapy - adoptive immunotherapy/virus-specific cytotoxic T cells/donor lymphocyte infusion

Beneficial for treatment of:

  • CMV
  • Adenovirus
  • BK virus
  • EBV

Especially in transplant recipients

43
Q

Why can treatment fail?

  1. Patient factors
  2. Drugs
  3. Virus
A

•Patient

  • Immunocompromised
  • Poor treatment adherence:
  • Intolerance
  • Side effects

•Drugs

  • Potency
  • Absorption
  • Penetration
  • Activation / inactivation
  • Interactions

•Virus

  • Drug resistance mutations
44
Q

Describe the two mechanisms of drug resistance

  1. Diversity
  2. Selection
A
  1. Diversity - Quasispecies, mutation/recombination
  2. Selection - replication e.g. in the presence of suboptimal drug concentrations
45
Q

What are the implications of drug resistance?

A
  • Treatment failure
  • Change to 2nd line drugs:
  • Less effective
  • More toxic

Example:

Foscarnet or cidofovir are required for GCV-resistant CMV, but nephrotoxicity can be a problem.

•Cross resistance

46
Q

How can drug resistance be prevented?

A
  • Use potent drug regimens to achieve maximal suppression of viral replication (combination Rx / HAART)
  • Increase adherence to treatment (low drug burden, once-daily regimens, patient education…)
47
Q

When does drug resistance occur, when should it be tested for?

A
  • Treatment failure
  • HIV baseline pre-Rx on diagnosis
48
Q

What are drug resistance assays?

A

Drug resistance assays look at genotypic features of viruses looking for resistant mutations. By sequencing/resistance mutations

Also used for HBV, HCV and CMV drug resistance

49
Q

When are phenotypic drug resistance assays routinely used?

A

Phenotypic drug resistance assays such as cell culture, and plaque reduction assay

Routinely used for HSV drug resistance testing

50
Q
  1. What is the main mutation that leads to HSV drug resistance?
  2. When does it most commonly occur?
  3. How are they diagnosed?
  4. How is ACV-resistant HSV treated?
A
  1. Mutations usually in viral thymidine kinase (95%), and rarely in the viral DNA polymerase (5%)
  2. Nearly always occurs in the context of immunosuppression – TK-deficient strains less virulent
  3. Diagnose with viral culture and phenotypic resistance test (plaque reduction assay) – time consuming and requires viable virus to be isolated
  4. Treat ACV-resistant HSV with FOS or CDV

Virus tends to revert to wild type upon cessation of Rx

51
Q
  1. What are the different CMV genetic mutations to GCV?
  2. When are they likely to occur?
  3. When should CMV drug resistanc be suspected?
  4. What is second line treatment for CMV
A
  1. CMV genetic mutations:
  • In protein kinase gene (UL97) - most common
  • In the DNA polymerase gene (UL54) - rare
  1. Most likely to occur in context of prolonged therapy in immunocompromised
  2. Suspect if clinical or virological failure despite appropriate therapy and reduction of immune suppression
  3. 2nd line for CMV is foscarnet or cidofovir
52
Q

Name some different immunoglobulin preparations for the following:

  1. Prophylactic
  2. Post-exposure prophylaxis
  3. Theraputic
A
  1. Prophylactic - palivizumab - for RSV
  2. Post-exposure prophylaxis
  • Varicella zoster IG - for immunocompromised/pregnant/neonates
  • Hepatitis B IG - Unvaccinated recipient exposed to Hep-B positive source/non-responder to vaccine
  • Human rabies IG (HRIG)
  1. Theraputic
  • Human normal IG as adjunctive treatment for viral pneumonitis (e.g. CMV)
  • Rituximab (anti-CD20) for EBV-driven PTLD (Posttransplant lymphoproliferative disease)
53
Q

The following statements concern resistance to antiviral drugs. Choose the best answer.

a) Resistance of HSV to aciclovir is common in the immunocompetent
b) Phenotypic resistance testing is routinely used to detect resistance of CMV to ganciclovir
c) Aciclovir resistance in HSV is most commonly mediated by mutations in the viral thymidine kinase
d) Aciclovir resistance in HSV is most commonly mediated by mutations in the viral DNA polymerase
e) Antiviral drug resistance is most commonly associated with good adherence to treatment

A

c)Aciclovir resistance in HSV is most commonly mediated by mutations in the viral thymidine kinase

Microbiology - Path (12 decks)

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