Clinical Use of Antiviral Drugs

Question 1

Explain the possible targets for antiviral drugs

Answer 1

Drugs that block or modify host receptor so the virus can’t bind

Inhibit transport of virus, prevent uncoating of viral genome in host cell

Inhibit expression of viral gene/translation

Block viral RNA and DNA strand synthesis

Inhibit full assembly of virus during maturation

Inhibit release of mature virus

Question 2

What are the difficulties in developing a safe anti viral agent?

Answer 2

Antiviral needs to be intracellular

Viruses use host receptors for entry, but blocking these receptors block important host functions

RNA viruses = high mutation rate (quasispecies), so develop fast resistance

Latency common (e.g. Herpes viruses), thus difficult to target

Question 3

Describe the treatment for influenza

Answer 3

Oseltamivir and zanamivir: inhibits neuraminidase which inhibits virus release from infected cells
Oseltamivir –oral
Zanamivir- inhaled or IV, resistance less likely
Amantadine: blocks influenza encoded M2 protein and haemagglutinin assembly- inhibits virus uncoating. Rarely used

Question 4

Describe the effectiveness of Anti influenza drugs, when should they be used, when is resistance more likley?

Answer 4

Treatment must start early BUT, only 25% patients can see their GP within 36hrs of symptom onset

Should be used for “at risk” groups, useful in post-exposure prophylaxis or in the flu season

Resistance rare, more likely in immunocompromised.

Question 5

Describe influenza resistance to antivirals- what kind of mutations cause it, who is resistance seen in? Are there any drugs which influenza remains sensitive to?

Answer 5

Resistance sometimes is a single amino acid change - eg swine flu (H1N1), Tamiflu (oseltamivir)

Point mutation (H275Y; tyrosine replacing histidine)

Seen in immunocompromised patients

Remains sensitive to zanamivir; probs bc of low exposure levels

Question 6

Herpes viruses include…

Answer 6

Herpes simplex (HSV): cold sores, genital ulcers (HSV-1 and HSV-2)

Varicella zoster (VZV): chickenpox and shingles

Cytomegalovirus (CMV)

Epstein-Barr (EBV): glandular fever/infectious mononucleosis

All cause acute infection w subsequent latency and possible re-activation

Question 7

How do you treat herpes viruses?

Answer 7

Question 8

Draw a diagram to describe the mode of action of aciclovir

Answer 8

Aciclovir triphosphate has 30x the affinity for HSV DNA polymerase compared w cellular DNA polymerase

Aciclovir triphosphate= highly polar- difficult to leave/enter cells (but aciclovir is easily taken into cells pre phosphorylation)

Outcompetes guanosine when dNA is being elongated
So when DNA polymerase is inserting a guanosine into the growing chain, acyclovir can replace guanosine
Acyclovir is incorporated into the DNA
Results in chain termination

Question 9

When is Ganciclovir used?

Answer 9

Used to treat CMV

Treats congenital CMV infection

Treats reactivated infection in transplant recipients + immunocomp patients

Prophylaxis in organ transplant recipients

Sometimes used to treat HHV-6 infection

Question 10

Gancciclovir is used to treat CMV
Give the mechanism of action of Ganciclovir

Answer 10

Synthetic analogue of guanosine

Phosphorylated by CMV TKinase (UL97), then more phosphorylation by cellular enzymes

Inhibits polymerase (called UL54 in CMV)

Overall this causes inhibition of viral DNA synthesis – chain termination

Question 11

What is the difference between Valaciclovir and valganciclovir?

Answer 11

Basically the same as acyclovir and ganciclovir but has an attached val group and can be given orally

Question 12

Describe other anti herpes viral agents
When would you use them, when would you NOT use them etc

Answer 12

Foscarnet: for CMV infection in immunocomp e.g. pneumonia in transplants. May be used in ganciclovir resistance/toxicity
Has renal toxicity= not used for renal transplant patients w CMV reactivation unless ganciclovir resistance
Cidofovir= for CMV; but MUCH MORE nephrotoxic

Question 13

Describe the mechanism of action of Foscarnet and cidofovir, and how resistance can arise
Mutations in ? can lead to…

Answer 13

Foscarnet and cidofovir inhibit DNA (NOT HBV) polymerase and thus viral DNA synthesis
Cidofovir- chain terminator
Foscarnet inhibits the pyrophosphate binding site

Mutations in viral thymidine kinase gene can lead to decreased phosphorylation of cidofovir–>drug becomes less effective–>resistance.
Mutations in DNA polymerase gene can impair the ability of the enzyme to be inhibited by drugs like foscarnet

Question 14

Outline the risk of chronic infection from hepB and age

Answer 14

Question 15

Drugs to treat Hep B do not cure it, but they can be used prophylactically and reduce cancer/cirrhosis risk
Describe these drugs used to treat Hep B virus

Note- tenofovir is an NRTI

Answer 15

Lamivudine: triphosphate form competes w cytosine triphosphate in developing vDNA strand–> chain termination

Tenofovir: adenosine analogue. Entecavir: guanosine analogue
Phosphorylated & inhibits HBV polymerase-> chain termination

Adefovir: phosphorylated to adefovir diphosphate–> inhibits HBV polymerase–> chain termination

Question 16

What is the main way in which we treat HIV?

Answer 16

Combination therapy reduces risk of resistance
Adherence to treatment is ESSENTIAL
Use up to 5 drugs may be combined in one pill
Once a day tablets best

Question 17

What is the difference between NRTI and NNRTIs?
Give examples of NRTIs and NNRTIs

Answer 17

NRTIs act as chain terminators, while NNRTIs bind allosterically to the reverse transcriptase enzyme to inhibit viral replication.

(NRTIs): emtricitabine, tenofovir, used in HIV PreP
(NNRTIs): Efavirenz, Rilpirivine: (no action against HIV-2)

Question 18

Describe other anti retrovirals apart from NRTIs and NNRTIs

Answer 18

Protease inhibitors: inhibit polyprotein cleavage. Atazanivir (usually “boosted” with ritonavir)
Integrase inhibitors: inhibits proviral DNA formation. Dolutegravir, elvitegravir (“boosted” with cobicistat)
CCR5 inhibitors: maraviroc (blocks cell surface receptor)
Capsid inhibitors: Lenacapavir (stops viral capsid uncoating)

Question 19

Describe why there are high levels of HIV resistance and how we can test for resistance

Answer 19

Selection pressure and high mutation frequency in HIV (and HCV)
Most RNA viruses have no proof reading capacity, so mutations are not fixed
Can test for resistance by cell culture (plaque assay), but slow process, or molecular methods in anti-viral sensitivity testing

Question 20

When is someone given PEP? What about PrEP?

Answer 20

Pre-exposure prophylaxis (PrEP):
Truvada = emtricitabine and tenofovir
For those at risk of HIV from sexual exposure
Can lead to increase rates of other STDs

Question 21

Which viral infections are currently untreatable?

Answer 21

Rabies
Dengue
Common cold (many viruses)