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Antivirals Flashcards

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1
Q

What poses a problem for antivirals?

A

Intracellular replication and use of host enzymes poses difficulties for selective toxicity

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2
Q

What leads to a virus’ cellular tropism and host range?

A

Binding to receptor

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3
Q

What are the 9 processes for virus replication?

A 
Binding to specific receptor 
Endocytosis 
Uncoating 
Reverse transcription (retro only) 
Transport to nucleus 
Genome integration (lysogenic cycle only) 
Transcription and translation 
Assembly of new virions 
Release
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4
Q

How is viral replication detected by pattern recognition receptors?

A

Toll like receptors - conserved areas of single strand RNA

Rig like receptors

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5
Q

How does detection of PRRs trigger innate immune response?

A

Leads to production of restriction factors such as type 1 interferons, broadly acting, can induce antiviral state in host and neighbouring cells

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6
Q

How can the antiviral response be boosted?

A

Exogenous interferons or stimulation of PRRs- immunomodulation
Effective against numerous different viruses
Eg- peginterferon a2a for HCV or imiquimod for HPV

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7
Q

How do small molecule inhibitors or DAA work?

A

Production or action of Virally encoded proteins can be blocked
Inhibit viral replication
Generally highly virus specific
Restricted to one group of viruses
Host immunity still crucial for viral elimination

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8
Q

How can virus be diagnosed?

A

Clinical- characteristic rash
virus detection- viral nucelic acid amplification test NAAT, includes PCR, or antigen detection. Can be direct from lesions or blood/body fluid
Viral serology- identify host response to virus by detecting antibodies, usually in serum

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9
Q

What are the issues with nucelic acid tests and serology?

A

Nucelic acid test- sensitive for detecting viral mediated disease, non specific. Detecting a virus does not necessarily mean it is causing the disease or clinical syndrome

Serological response- may take days/weeks, to become detectable and canon it reliably distinguish primary infections from re infection
Moral:clinical correlation is essential

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10
Q

How many families of herpes viruses are there?

A

3- alpha, beta, gamma

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11
Q

What is in the alpha family?

A

Disease- HSV 1,2, VZV
Syndrome- herpes labialis, herpes genitalis, chicken pox shingles
Characteristics- rapid growth, latency in sensory ganglia

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12
Q

What is the beta family?

A

Disease- CMV, HHV 6,7
Clinical syndromes- mononucleosis retinitis colitis oesophagitis, 6th dresses encephalitis, ex anthem subitum
Characteristics- slow growth, restricted host range

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13
Q

What is in the gamma family?

A

Disease- EBV, hhv8
Clinical syndrome- infectious mononucleosis burkitts nasopharyngeal carcinoma , kaposi sarcoma, multicentric castlemans syndrome
Characteristics- oncogenic

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14
Q

What is herpes labialis?

A

Cold sores, HSV 1 nearly always
Spread by direct contact with lesions, asymptomatic shedding frequent
Primary infection- frequently asymptomatic, may experience pharyngitis, fever, mouth ulceration and lymphadenopathy
Recurrence- common, classically prodromal tingling followed by localised painful blisters that resolve over 5-7 days

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15
Q

What is herpes genitalis?

A

Classically HSV 2 but 50-80% in some settings
Primary infection- frequently asymptomatic, may experience painful ulceration, fever, lymphadenopathy and urianry retention (radiculitis)
Recurrence- localised ulceration, HSV2 more than 1

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16
Q

What is herpes simplex encephalitis?

A

Severe, life threatening infection of CNS
Virus spreads via neurons
Sporadic, no seasonal
SIGNS- fever, fits, funny behaviour
Disturbed conscious level, focal neurology
Distinct clincal syndrome from meningitis- headache, photophobia, meningism +/- fever

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17
Q

What is the rash like for chicken pox?

A

Generalised vesicular rash on trunk, rash and arms
Lesions are superficial and itchy
Lesions of all stages present at the same time
Shingles- localised dermatomal, do not cross mid line, lesions similar stage

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18
Q

What is varicella?

A

Caused by primary infection with varicella zoster virus
Sporadic, spring summer peak
Highly infectious, resp droplets and shedding from lesions
Most infectious 1-2 days before rash onset
Infectious until all lesions crusted over
Adults more risk of severe disease and pneuminitis
Immunocompromised can experience disseminated infection

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19
Q

What is the pathogenesis of varicella?

A

Initial localised infection in resp tract, primary viraemia and seeding of reticuloendothelial organs
Secondary viraemia- dissemination to all tissues, skin and mucosal lesion- chicken pox

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20
Q

What is the pathogenisis of shingles?

A

Retrograde transport along neurons from skin permits entry to spinal cord where virus becomes latent
Reactivation and anterograde transport back to innervated skin lead to shingles

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21
Q

What is the antiviral treatment for HSV and VZV?

A

Virally encoded enzymes are key targets, thymidine kinase and DNA polymerase
Aciclovir- prototype drug
Valacyclovir- prodrug of acicylovir, high bioavailability
Famciclovir- prodrug of pencicolvir, high bioavailability

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22
Q

How is the antiviral treatment for HSV and VZV tolerated?

A

Oral doses well tolerated, bioavailability of ACV is 15-30% half life 3 hours, renally excreted
Poorly soluble in urine, crystallisation of drug in tubules can occur at high iv doses, and in renal failure

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23
Q

How does DNA replication occur?

A

Triphosphate deoxyribonucleotides are incorporated into growing DNA molecule by enzymatic removal of 2 phosphates yielding energy to link new nucleotide via ribose group

24
Q

What are viruses and what is the basic principle for their replication?

A

Obligate intracellular parasites, metabolically inert
Rely on host cell for replication
May encode specific proteins for genomic replication or transcription (nucelic acid polymerises, proteases)

25
Q

What is the mode of action for ACV?

A

ACV and guanosine both coastline purine base guanine
ACV has acyclic side chain in place of ribose moiety
Further elongation of the chain is impossible because ACV mono phosphate lacks the 3’ hydroxyl group necessary for the insertion of an additional nucleotide

26
Q

How does the selective toxicity of guanosine analogies work?

A

They are monophosphorylated by viral thymidine kinase, then further phosphorylated by cellular kinase 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 is 10-30 times lower than herpesvirus DNA polymerase
Hence inhibition of DNA synthesis by acyclovir in herpes virus infected cells is much greater

27
Q

What is the susceptibility of guanosine analogues to HSV and VZV?

A

HSv1 >hsv2> VZV

28
Q

What is the general treatment for HSV and VZV?

A

Supportive treatment alone may be sufficient for single ep of orogenital HSV, uncomplicated chickenpox and shingles
Antivirals drugs reduce symptoms, duration of illness, viral shedding, reduce complications
ALWAYS treated immunocompromised, pneuminitis, encephalitis, eye disease

29
Q

What is the antiviral treatment for orogenital HSV?

A

ACV 5 times a day, double dose in immunocompromised, consider iv if extensive
Treat for longer if new lesions appear
Prevention of recurrence ACV and vacv

30
Q

What is the antiviral treatment for VZV?

A

ACV 5 times a day/ vacv
In immunocompromised, iv ACV 10mg/kg 8 hourly for 5-7 days
HSV encephalitis: iv ACV 10mg/kg 8 hourly for 14-21 days, within 6 hours admission - get nephrotoxicity

31
Q

What is CMV?

A

Excreted in saliva, urine, breast milk, infection common in childhood, normally self limiting
Mononucleosis like illness and hepatitis
15% aged 1-4 years, 80% in those above 65 years
Remains latent in monocytic cells (blood and bone marrow), can reactivate in context of immune suppression
CMV retinitis rare due to HAART
Major pathogen of solid organ and bone marrow not transplant patients - marrow suppression, graft rejection, pneuminitis, encephalitis, adrenalitis

32
Q

What is EBV?

A

Salivary transmission, infection common in childhood, usually minimally symptomatic and self limiting
Classical cause of infectious mononucleosis, glandular fever, kissing disease
Associated with lymphoproliferative disease in immunocompromised- ptld, burkitts

33
Q

What is the general treatment for CMV and EBV?

A

Supportive
ACV not effective
Expert guidance for immunocompromised
Reduction of immune suppression

34
Q

How do CMV antiviral drugs work?

A

Ganciclovir- monophosphorylated by viral protein kinase
Cidofovir- DI and triphosphorylated by cellular enzymes
Foscarnet- inhibition of viral DNA polymerase, pyrophosphate analogue

35
Q

What is the pharmaco of each CMV antiviral?

A

Ganciclovir- iv, valganciclovir are effective , longer intracellular half life 18 hours. Drawback- toxicity, marrow suppression with neutropenia, and thrombocytopenia
Foscarnet- iv only, side fx of renal impairment, electrolyte disturbabc
Cidofovir- nucleoside analogue, broad activity against DNA viruses, iv or topical. Iv given weekly, nephrotoxic, contraindicated in renal impairment, requires prior iv hydration, co treatment with probenicid
all 3 effective against HSV, VZV, EBV, hhv6

36
Q

When should CMV be treated?

A

Universal prophylaxis- gcv for all transplant patients
Pre emptive therapy- treat viraemia, without evidence of end organ disease
Some controversy about which strategy is best

37
Q

What drugs do you use for CMV treatment?

A

Tx divided into induction and and maintenance
1st line- iv gcv, iv gcv or iv fos
Choice of initial agent often depends on relative importance of side fx
2nd line- iv cdv, then for maintenance

38
Q

What is the treatment for EBV lymphoma?

A

Seek expert guidance
DAA not effective
Chemo and surgery may be required
Immunotherapy B cell depletion with anti c20 monoclonal antibody, rituximab effective

39
Q

What is the rash for HHV 6?

A

Pink/red, macular, can be raised patches, non itchy

40
Q

What is hhv6?

A

Cause of exanthem subitum 6th disease, roseola infantum
Children under 3 years, high fever, possibly convulsions, coryzal symptoms, sudden rash
Self limiting, virus remains latent
Can reactivate in immunocompromised- encephalitis, marrow suppression, pneuminitis

41
Q

How does hhv6 interact with DNA?

A 
Integration of viral DNA into host chrosome can occur 
Frequency is 1 % population 
Every cell affected 
Can be inherited from either parent 
Biological significance unclear
42
Q

What is the treatment for hhv6?

A

Generally supportive- antipyretic
Encephalitis- in transplant patients has been treated with fos and gcv
Important to distinguish chromosomally integrated hhv6

43
Q

What is the rash like for HHV 8?

A

Multiple raised, red/violet macules

Diffuse plasma cell proliferation

44
Q

What is HHV 8?

A

Infection acquired in early life, asymm
2 main malignancies- kaposi, multicentric castlemans
Usually detectable in biopsy but not detectable in blood and biopsies
Mcd- HHV 8 usually detectable in blood biopsies, but non HHV related forms exist

45
Q

What are the 4 types of kaposi sarcoma?

A

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

46
Q

What is the treatment for HHV 8?

A

Gcv, fos, cdv all potentially active in vitro
No definitive clinical role for DAA
Chemo and immunotherapy
May approve with HAART if associated with HIV

47
Q

What drug resistance can occur with ACV?

A

Mutations in viral TKs, and DNA polymerase, mediates cross resistance to gcv
Resistance stains selected out by drug treatment
Nearly always occurs in immune suppression-TK deficient strains less virulent

48
Q

How do we treat drug resistance of ACV?

A

Diagnose with viral culture, phenotypic resistance test-plaque reduction assay- time consuming and requires viable virus to be isolated
Characterisation of resistance mutations may permit genotype testing in the future
Treat ACV resistance HSV with fos or cdv

49
Q

What’s is the resistance with gcv?

A

Mutations in protein kinase most commone, DNA poly are most rare
Most likely to occur in context of prolonged therapy in immunocompromised
Difficult to identify- phenotypic tests rely on viral culture and genotypic mutations incompletely characterised
Suspect if clinical failure despite appropriate therapy and reduction of immune suppression
2nd line- fos or cdv

50
Q

What are the 3 major resp viruses detected at imperial?

A

Influenza a spring, rsv xmas, rhinovirus

51
Q

How does the influenza virus mediate infection?

A

Major surface glyocoproetins haemagluttinin qnd neuramindase.
HA facilitates attachment via host cell sialic acid and causes membrane fusion, NA cleaves sialic acid and allows virion to exit host cell
HA binding antibodies can neutralise infection and are the focus of current influenza vaccines

52
Q

What neuramindase inhibitors are used?

A

Oseltamivr oral, zanamivir- dry powder inhaler
Iv and nebulised zanamivir can be used
Effective for influenza a and b
Indicated if all 3 apply- influenza is circulating, patient is in risk group, within 48 hours of symptom onset (36 hours for zanamivir)
Severely unwell should always be treated
Vaccination is better than antiviral

53
Q

What is amantidine and rimantidine?

A

Antiparkinsonian drug- also antiviral activity
Inhibit influenza A matrix protein M2
Prevent virus uncoating
Orally absorbed only effective for influenza a
Not currently recommended or used in UK

54
Q

What is Rsv?

A

Commonest cause of severe respiratory tract illness and hospitalisation of infants in the world
Associated with subsequent wheeze and asthma diagnosis in later life
Elderly, chronic lung disease and immunocompromised

55
Q

What can be used for Rsv? (No effective antiviral)

A

Ribavarin- guanosine analogue
Inhibits viral RNA synthesis- exact mechanism unclear, broad activity in vitro
Clinical efficacy unclear- effective for Lassa fever, used in combination with interferon for HCV, weak data for nebulised ribavarin for Rsv
Can have anaemia and mitochondrial toxicity

56
Q

What is palivizumab?

A

Human monoclonal antibody against fusion protein
Given prophylactic ally for Rsv, prevents Rsv infection, and reduces later life wheezing but in ineffective for treatment of Rsv
Promising drug- given day after rsv detected, oral gs- 5806

Microbiology (15 decks)

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