Antivirals (from CTFs Lecture)

Question 1

What is a virus?

Answer 1

An obligate, intracellular parasite with no cell wall or cell membrane

Question 2

What is a virus capable of doing?

Answer 2

Causing disease in the infected host

Question 3

How big are viruses?

Answer 3

Small - 25-400nm

Question 4

What does the viral genome consist of?

Answer 4

RNA or DNA

Question 5

What does viral replication use?

Answer 5

Host machinery

Question 6

Why does the virus use the host machinery to replicate?

Answer 6

As they don’t have their own organelles (mitochondria, golgi etc)

Question 7

What is the result of the virus using host machinery to replicate?

Answer 7

They hide inside the cell and make it hard to prevent viral replication without injury to the host

Question 8

What are the steps in viral replication?

Answer 8

1. Attachment
2. Penetration
3. Uncoating
4. Replication/protein synthesis
5. Assembly
6. Release

Question 9

What happens in the attachment stage of viral replication?

Answer 9

Virus particles (virons) must first attach to specific receptors on the surface of a host cell

Question 10

How might penetration occur in viral replication?

Answer 10

Direct fusion wiht the cell membrane, or endocytosis and pH mediated fusion

Question 11

What happens in the uncoating stage of viral replication?

Answer 11

The virion disassembles, freeing nucleic acid and viral proteins needed for replication

Question 12

What happens in the replication/protein synthesis stage of viral replication?

Answer 12

Viral proteins and messages are expressed

Question 13

What happens in the assembly stage of viral replication?

Answer 13

New virions containg viral nucleic acid are formed

Question 14

What happens in the release stage of viral replication?

Answer 14

New virions are released from the cell via lysis of the cell, or intra- or extracellular budding

Question 15

What antivirals are used in the treatment of influenza A and B?

Answer 15

• Oseltamivir (Tamiflu)
• Zanamivir

Question 16

How is oseltamivir administered?

Answer 16

Orally

Question 17

How is zanamivir administered?

Answer 17

Inhaled/intranasally

Question 18

What class of antivirals are oseltamivir and zanamivir?

Answer 18

Neuroaminidase inhibitor

Question 19

What is the mechanism of action of neuroaminidase inhibitors?

Answer 19

They block the release of newly formed virions from the host cell

Question 20

How might the influenza virus obtain resistance to oseltamivir and zanamivir?

Answer 20

Mutation of NA (neuroanimidase enzyme), e.g. H275Y mutation so can’t bind oseltamivir

Question 21

When can oseltamivir or zanamivir be used?

Answer 21

• Prophylactically, to prevent infection
• Within 48 hours of infection to reduce intensity and duration of symptoms

Question 22

Is prophylactic use of antivirals the preferred approach in prevention of flu?

Answer 22

No, the preferred approach is yearly vaccinations for those at risk, e.g. elderly, respiratory diease, immunocompromised

Question 23

What diseases are the herpes viruses associated with?

Answer 23

• Cold sores
• Encephalitis
• Genital infections

Question 24

What is used to treat herpes viruses?

Answer 24

Aciclovir (Zovirax)

Question 25

How is aciclovir administered?

Answer 25

* Orally * IV * Topical cream

Question 26

What class of antiviral is aciclovir?

Answer 26

Purine/pyramidine (DNA base) analogue

Question 27

What is the mechanism of action of purine/pyramidine analogues?

Answer 27

They get phosphorylated by viral thymidine kinase, which activates it and inhibits viral DNA synthesis

Question 28

How might aciclovir resistance arise?

Answer 28

Due to thymidine kinase enzyme mutation in the virus, which prevents binding to aciclovir so it can't act as a false substrate in DNA replication anymore

Question 29

What is the limitation of aciclovir treatment for herpes?

Answer 29

It is only effective during the acute phase of the viral infection where the patient is symptomatic, not during the patent phase, and so won't prevent a new outbreak, only control the time/severity of an outbrea

Question 30

What is used to treat cytomegalovirus?

Answer 30

Ganciclovir

Question 31

How is ganciclovir administered?

Answer 31

IV

Question 32

Why does ganciclovir need to be administered IV?

Answer 32

So that it crosses the blood brain barrier

Question 33

Where is gancicolovir currently used to treat CMV?

Answer 33

* CMV retinitis in immunocompromised * CMV prophylaxis in transplant patients

Question 34

What is the mechanism of action of ganciclovir?

Answer 34

It is an analouge of acyclovir, which acts in the same way but is phosphorylated using a different enzyme

Question 35

How does the activity of ganciclovir against CMV differ to that of acyclovir?

Answer 35

It has 10-50 times greater activity

Question 36

What are the potential adverse reactions with ganciclovir?

Answer 36

* Myelosuppression * Carciogenic/teratogenic * Renal failure

Question 37

What antivirals are used in the treatment of hepatitis B and C?

Answer 37

* Lamivudine * Sofosbuvir * Interferon alpha * Ribavirin

Question 38

How is lamivudine administered?

Answer 38

Orally

Question 39

Where is lamivudine used?

Answer 39

In HIV and Hep B

Question 40

What class of antiviral is lamivudine?

Answer 40

Reverse transcriptase inhibitor

Question 41

What is the mechanism of action of reverse transcriptase inhibitors?

Answer 41

Act as false substrate and chain terminator of reverse transcriptase enzyme in viral replication

Question 42

What is the mechanism of action of sofosbuvir?

Answer 42

Blocks action of HCV viral polymerase to prevent production of new virus

Question 43

How is interferon alpha administered?

Answer 43

Intramuscular injection

Question 44

Where is interferon alpha used?

Answer 44

Mainily in the treatment of HepB/C

Question 45

What is the mechanism of action of interferon alpha?

Answer 45

Immunomodulatory effect - *not directly antiviral, but* stimulates proteins to enhance cellular resistance to viral infection

Question 46

What are the adverse effects of interferon alpha?

Answer 46

* Flu-like illness * Fever * Chills * Headache * Malaise * Myalgia * Athralgia * Nausea * Vomiting * Diarrhoea

Question 47

Where is ribavirin used?

Answer 47

* Chronic hepatitis C * Infants with severe RSV infection

Question 48

What is ribavirin used in combination with in chronic hepatitis C?

Answer 48

Interferon alpha

Question 49

How is ribavirin administered?

Answer 49

Oral or IV

Question 50

What class of antiviral is ribavirin?

Answer 50

Guanosine analogue

Question 51

What is the mechanism of action of guanine analogue antivirals?

Answer 51

They inhibit guanine triphosphate formation, preventing viral messenger RNA cappping, and essentially preventing the assembly of viral genome/DNA

Question 52

What are the ADRs of ribavirin?

Answer 52

* Transient anaemia * Teratogenic

Question 53

What drugs are used in the treatment of HIV?

Answer 53

* Nucleoside reverse transcriptase inhibitiors * Non-nucleoside reverse transcriptase inhibitors * Protease inhibitors * Fusion inhibitors * Integrase inhibitors * Receptor inhibitors

Question 54

Give an example of a nucleoside reverse transcriptase inhibitor

Answer 54

Zidovudine

Question 55

What is the mechanism of action of nucleoside reverse transcriptase inhibitors?

Answer 55

Inhibit DNA polymerase, so DNA can't be replicated

Question 56

What are the adverse drug reactions of nucleoside reverse transcriptase inhibitors?

Answer 56

* Hyperlactataemia * Lactic acidosis * Hepatomegaly * Steatosis

Question 57

Give an example of a non-nucleoside reverse transcriptase inhibitor

Answer 57

Nevirapine

Question 58

What is the mechanism of action of non-nucleoside reverse transcriptase inhibitors?

Answer 58

They are non-competitive inhibitors of HIV reverse transcriptase. *They bind at different sites to the nucleoside reverse transcriptase inhibitors, but have the same effect*

Question 59

Are non-nucleoside reverse transcriptase without further phosphylation?

Answer 59

Yes

Question 60

What is the result of non-nucleoside reverse trancriptase inhibitors binding at a different site but having the same effect as nucleoside reverse transcriptase inhibitors?

Answer 60

They can be used as combination therapy

Question 61

What form of HIV do non-nucleoside reverse transcriptase inhibitors work for?

Answer 61

HIV-1, *not HIV-2*

Question 62

Give an example of a protease inhibitor

Answer 62

Ritonavir

Question 63

What is the mechansim of action of protease inhibitors?

Answer 63

They block the cleavage of viral polyproteins by HIV protease enzyme, preventing the production of viral proteins for the formation of final mature virions

Question 64

Give an example of a fusion inhibitor

Answer 64

Enfuvirtide

Question 65

Where are fusion inhibitors used?

Answer 65

Salvage therapy if other treatments havent worked

Question 66

Give an example of an integrase inhibitor

Answer 66

Raltegravir

Question 67

What is the mechanism of action of raltegravir?

Answer 67

Prevents the integration of HIV DNA provirus into the host cell genome

Question 68

Why is antiviral drug resistance testing needed?

Answer 68

* Optimise clinical outcomes * Save costs and adverse effects of ineffective therapy * Reduce pool of drug resistant viruses in the population that may transmit between individuals, reducing the effectiveness of standard therapy

Question 69

When is antiviral drug resistance testing performed?

Answer 69

* When there is evidence of therapeutic failure * As a baseline prior to starting new therapy

Question 70

oWhat could cause therapeutic failure?

Answer 70

* Resistance * Compliance

Question 71

How is antiviral drug resistance testing done?

Answer 71

Phenotypic characterisation linked to genetic mutations; 1. Incubate suspected drug resistant virus with varying concentrationsof drug of interest in culture 2. Look for graded response compared to wild-type virusm 3. Can then look at specific sequencing/genotype of the mutation