Antivirals

Question 1

How do antiviral drugs get developed?

Answer 1

Look at expenses vs need vs resistance
Burden of disease and clinical need
Understanding virology: what too target
Drug development: Screening compounds or drug design
Clinical trials and impact: Adverse effects and monitoring of resistance.

Question 2

What are the three types of influenza?

Answer 2

Influenza A - multiple host specifies, antigenic drift and shift

Influenza B - No animal reservoir, Lower mortality

Influenza C - Like the common cold

Question 3

What are the influenza related complications?

Answer 3

Most complications occur in otherwise healthy persons

• Bronchitis
• Sinusitis
• Exacerbations of underlying disease

60-80% received antibiotics if they had complications

Antibiotics prescribed for 30-45% of patients presenting with influenza or ILI

Question 4

What is the structure of influenza A virus?

Answer 4

RNA inside
Surrounded by lipid envelope and a protein envelope
Proteins (Haemagglutinin) on outside which sticks to resp cells
Neuraminidase also on outside

Question 5

Describe the influenza virus life cycle

Answer 5

Bind to Salic acid receptor on resp cells (Usally upper) 
Engulfed into cell (endosome)
embrace fusion
RNA transfer into nucleus 
Protein synthesis 
Viral budding and protolytic cleavage

Question 6

What are amatadines and rimantadine?

Answer 6

They are tricyclics primacy amine which block M2 channel to inhibit viral incoating.

Anti-Parkinsonism activity

Available since 1960’s

Active against influenza A

Question 7

What are the problems with M2 inhibitors?

Answer 7

Infuenza A only.

CNS and renal side effects

Single point mutation in M2 gene: S31N.
High level, rapid emergence resistance
Transmissible viruses

Question 8

How do yo design new drugs?

Answer 8

Gene sequencing of protein
X-Ray crystallography
Nuclear Magnetic Resonance

Question 9

What is neuraminidase?

Answer 9

Neuraminidase is essential for virus replication

Surface of influenza highly variable but neuraminidase active site is conserved across subtypes. 
-Human and non-human influenza-A
Influenza B
M2 resistant viruses 
Avian strains including H5N1
Reconstructed 1918 pandemic H1N1

Question 10

How does neuraminidase work?

Answer 10

NA cleaves HA binding

Binding of virus with NA inhibition

Question 11

What is Zanamavir?

Answer 11

Low bioavailability 
Acid degrades 
Dry powder aerosol
Remains detectable in sputum up to 24 hours post dosing 
Renal excreted

Question 12

What is oseltamivir?

Answer 12

Tablet
Pro-drug
80% bio-availability
Active site changes shape

Question 13

Oseltamivir studies. Does it work?

Answer 13

Earlier treatment - 36% reduction in symptoms.

Yes, you have a 2/3 reduction in likelihood of death.

3. 5 times less likely to die if in nursing home.
4. 1 times less likely to die if over 65

Question 14

Does oseltamivir work as seasonable prophylaxis?

Answer 14

Yes, prevent flu!

Question 15

What is the safety profile of oseltamivir?

Answer 15

Vomiting
Abdominal pain
Epistaxis

No drug related serious events

Low rate of discontinuation in studies

Question 16

How is oseltamivir used in H5N1 (bird flu) infection?

Answer 16

Bird flu = 70% mortality

But, rarely moves from birds to people so many people infected (luckily).

People treated with oseltamivir are more likely to live.

Question 17

Olsetamivor resistance

Answer 17

Does get resistance but little resistance.

But, a close to 1/3 of virus resistant (Potential to be resistant…)

Question 18

H1N1 Pandemic

Answer 18

Swine flu

Pandemic

Replaced 2008 human H1N1 circulating viruses which had developed oseltamivir resistance

The ‘swine’ derived H1N1 viruses remain oseltamivir sensitive.

Question 19

What are the guideline for use of oselsetamivir

Answer 19

NICE

Cochrane review …

Question 20

What are human herpes viruses?

Answer 20

Large family 150 species
DNA viruses
Widespread across animal kingdom 
High rates of infection
Generally mild primary infection
Established latent infection
Secondary infection / reactivation

Question 21

How do you classify herpes viruses?

Answer 21

Biological properties
Appearance
Genetic analysis

Question 22

What some common herpes viruses?

Answer 22

Herpes simplex 1
Herpes simplex 2
Viracella-Zoster

Cytomegalovirus
Epstein-Barr Virus
Kaposi Sarcoma Virus

Question 23

Describe the structure of Herpes Viruses

Answer 23

Nucleocapsid
Regiment (space)
Lipid bilayer with glycoproteins spikes (peplomers)

Question 24

Where about do soem for he herpes viruses remain latent?

Answer 24

HSV1/2: Neurones (trigeminal / sacral)
VZV: Donal root ganglia
EBV: B cells

Question 25

Describe the oncogenic potential of some of the Herpes Viruses

Answer 25

HSV1 and 2 CMV carcinogenic in animals

HHV6 and Kaposi’s Sarcoma

EBV is linked to tumours in humans:
B cell lymphoma (aids)
Burketts lymphoma
Nasopharyngeal carcinoma

Question 26

How can you treat herpes viruses?

Answer 26

Specific antiviral therapy

Supportive care - Bacterial complications

Nucleoside analogues inhibiting herpes viral DNA polymerase:

• Acyclovir and valacyclovir (HSVm VZV)
• Cidofovir (CMV, resistant HSV)
• Gancyclovir (CMV, EBV)