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Medical Microbiology and Virology > 34 Attacking the enemy: antivirals > Flashcards

34 Attacking the enemy: antivirals Flashcards

1
Q

Antiviral drugs do not kill viruses, but stop viral replication. Monitor progress with therapeutic drug level monitoring, and viral loads.

Replication pathways if DNA viruses, RNA viruses and retroviruses differ upon entering host cell, so different antivirals attack different targets.

Antivirals difficult to classify, so often classified by disease they treat e.g anti-HIV

Where do different viruses replicate?

A

DNA viruses - nucleus e.g CMV, HBV, HPB, HSV, VSV

Retro viruses - nucleus e.g HIV, HTLV

RNA virus - cytoplasm. e.g HCV, RSV, influenza

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2
Q

How do these classes of anti-virals work?

1 5-substituted 2’-deoxyuridines

2 Nucleoside analogues

3 pyrophosphate analogues

A

1 5-substituted 2’-deoxyuridines - inhibit viral DNA synthesis in nucleus

2 Nucleoside analogues - inhibit viral DNA synthesis in nucleus, inhibit viral reverse transcriptase

3 pyrophosphate analogues - inhibit viral DNA synthesis in nucleus

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3
Q

How do these classes of anti-virals work?

4 NRTIs

5 NNRTIs

6 Protease inhibitor

A

4 NRTIs - inhibit reverse transcriptase in cytoplasm

5 NNRTIs - inhibit reverse transcriptase in cytoplasm

6 Protease inhibitor - inhibits viral protease, preventing protein formation, and viral maturation

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4
Q

How do these classes of anti-virals work?

7 Integrase inhibitor

8 entry inhibitor

9 acyclic guanosine analogues

A

7 Integrase inhibitor - inhibit viral integration of DNA in host DNA

8 entry inhibitor - prevent entry of virion (endocytosis)

9 acyclic guanosine analogues - inhibit viral DNA synthesis in nucleus

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5
Q

How do these classes of anti-virals work?

10 acyclic nuceloside phosphonate analogues (2)

11 HCV NS5A/ NS5G polymerase inhibitor

12 influenza virus inhibitors

A

10 acyclic nuceloside phosphonate analogues - inhibit viral DNA synthesis in nucleus, - inhibit reverse transcriptase in cytoplasm

11 HCV NS5A/ NS5G polymerase inhibitor - inhibit viral polymerase

12 influenza virus inhibitors - prevent viral uncoating, prevent exocytosis, inhibit viral polymerase

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6
Q

What are examples of drugs that target DNA viruses?

A

CMV -
Ganciclovir
Valganciclovir
Foscarnet

HSV/ VZV -
Aciclovir
Ganciclovir
Foscarnet

HBV - 
Emtrictabine
Lamivudine
Tenofovir
INF alpha
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7
Q

What are examples of drugs which target RNA viruses?

Influenza A + B

Influenza A

RSV

A

Influenza A + B - oseltamivir, zanamavir

Influenza A - amantadine, rimantadine

RSV - ribavirin

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8
Q

Which broad classes target HIV?

A 
NRTIs
NNRTIs
Fusion inhibitor
CCR5 inhibitor
Integrase inhibitors
Protease inhibitor
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9
Q

HIV treatment. What are examples which belong to these classes?

NRTIs

A 
Abacivir
Emtricitabine
Lamivudine (3TC)
Stavudine (d4T)
Tenofovir
Zidovudine (AZT)
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10
Q

HIV treatment. What are examples which belong to these classes?

NNRTIs

A

Efavirenz
Nevirapine
Rilpivirine

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11
Q

HIV treatment. What are examples which belong to these classes?

Fusion inhibitor

CCR5 inhibitor

A

Fusion inhibitor -
Enfuvirtide (T20)

CCR5 inhibitor -
MAraviroc

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12
Q

HIV treatment. What are examples which belong to these classes?

Integrase inhibitors

A

Dolutegravir

Raltegravir

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13
Q

HIV treatment. What are examples which belong to these classes?

Protease inhibitors

A

Atazanavir
Indinavir
Lopinavir + ritonavir (kaletra)

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14
Q

HCV is RNA virus. Treatment with NS3 protease inhibitor, and NS5 polymerase inhibitors.

What are examples of NS3 protease inhibitor?

A

Simeprivir

Telaprivir

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15
Q

HCV is RNA virus. Treatment with NS3 protease inhibitor, and NS5 polymerase inhibitors.

What are examples of NS5 polymerase inhibitor?

A

Sofosbuvir
Ribavirin
IFN alpha

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16
Q

What are examples of drugs that target viral DNA polymerase?

A 
Aciclovir
Valaciclovir
Famciclovir
Ganciclovir
Valganciclovir
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17
Q

What is mechanism of action of aciclovir?

A

Enters as prodrug - inactive

Phosphorylated by enzyme thymidine kinase carried only by HSV/ VZV, and the monophosphate is converted by cellular kinases to the triphosphate.

This acts as false substrate causing chain termination. It has higher affinity for viral polymerase than host polymerase.

Thymidine kinase only present in infected cells, so aciclovir only targets infected cells

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18
Q

Oral bioavailability aciclovir is 20%, so often given IV

What are sides effects of aciclovir

A

Excreted renally

Can crystallise in renal tract, and cause acute tubular necrosis

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19
Q

Ganciclovir has similar mechanism of aciclovir

What are benefits?

What are draw backs?

A

Wider range of action - also effective CMV DNA polymerase

Selective toxicity not seen, so can cause myelosuppression

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20
Q

What are indications for ganciclovir?

What are benefits of valganciclovir?

A
  • CMV retinitis, encephalitis, GI disease in immunocompromised
  • Pre-emptive therapy in bone marrow/ solid organ transplant
  • Valganciclovir is similar to ganciclovir, but can be given orally. Has revolutionised outpatient management
21
Q

How do pyrophosphate analogues work, and give an example

A

Foscarnet

Direct inhibitor of polymerase - blocks pyrophosphate-binding (nucleotide) site on viral DNA polymerase

22
Q

What are uses for pyrophosphate analgoues?

A

Foscarnet effective against:

HSV
VSV
CMV

23
Q

Anti-retroviral drugs - there are six classes named after their mechanism of action.

What are they?

A

NRTI - Nuceloside and nucleotides reverse transcriptase inhibitors

NNRTI - non-nucleoside reverse transcriptase inhibitors

PI - protease inhibitor

Fusion inhibitors

INSTIs - integrase inhibitors

Chemokine receptor antagonists

24
Q

What are examples of NRTIs?

A 
Abacavir
Zidovudine (azidothymidine) - AZT
Emtricitabine
Didanosine - ddl
Lamivudine - 3TC
Tenofovir
Stavudine - d4T
25
Q

What are nucleosides and nucleotides formed from?

A

Bases include:

  • pyrimidines - cytosine, thymine, uracil
  • purines - adenine, guanine

Nucleoside is base + sugar (ribose or deoxyribose)
Nucleotide is base + sugar + phosphate group

Sugar is ribose for RNA, deoxyribose for DNA

26
Q

What are functions of nucleotides/ nucleosides?

A

The biological functions of nucleotides are:

Data storage - as part of DNA/RNA
Energy Currency - ATP
Cellular communication (cAMP; ATP allosteric regulator)
Co-enzyme catalysis

Nucleoside is phosphorylated to nucleotide, it can then be used in metabolic functions.

27
Q

In general, how do NRTIs work?

A

Analogues of nucleosides use cellular kinases to convert to nucleotide.

Nucleotides then act as substrate for reverse transcriptase, which inhibits it.

NRTIs and protease inhibitors can be used for HIV-2

28
Q

What are common side effects with NRTIs?

A 
Bone marrow suppression
Nausea
Headache
Myalgia
Lactic acidosis
Hyperlipidaemia
Lipoatrophy
Diabetes mellitus
29
Q

What are these combination NRTIs composed of?

Combivir

Trizivir

Truvada

A

Combivir - AZT and 3TC

Trizivir - AZT, 3TC and abacavir

Truvada - emtricitabine and tenofovir

30
Q

What is the mechanism of action of NNRTIs?

A

Non-competitive inhibitors of HIV-1 RT. Bind and inhibit RT directly (instead of acting as false substrates)

Inactive against HIV-2

31
Q

What are side effects and resistance problems NNRTI?

A

Inducer of cytochrome p450
Skin rash
Vivid dreams

Single gene mutation in RT leads to resistance, and means drug class cannot be used

32
Q

What is mechanism of action of protease inhibitors?

A

protease enzyme acts on post-translational cleavage of the gag and gag-pol polyproteins

Defective HIV virions produced

Resistance to one protease inhibitor, usually confers resistance to others

33
Q

What are side effects of protease inhibitors?

A

GI disturbance
Lipodystrophy
Diabetes mellitus

34
Q

What is an example of a fusion inhibitor?

How does it work?

A

Enfuvirtide (T20)

Competitively binds

35
Q

What is mechanism of action of integrase inhibitors?

A

They prevent integration of viral encoded DNA into host DNA

36
Q

How does maraviroc work (CCR5 antagonist)?

A

HIV-1 gains entry by binding viral envelope protein gp120 to CD4 receptor, and subsequently to chemokine co-receptor (CCR5 and CXCR4)

Maraviroc is CCR5 chemokine co-receptor antagonsit used for patiented who are R5-tropic

R5-tropic - display CCR5
X4- tropic - display CXCR4
Dual/mixed - display both

37
Q

What are indications for ribavirin use?

A

Hep C/ E
RSV infection infants
Measles
Lassa fever - post exposure prophylaxis

38
Q

What is mechanism of action of ribavirin?

A

Guanosine analogue inhibits production of guanosine triphosphate required for nucleic acid synthesis.

Additionally, once ribavirin phosphorylated, it can directly intefere with viral RNA polymerase

39
Q

How do amatandine and rimatadine work?

A

Work in influenza A only - so not often used

Inhibit penetration of virus into cell, and it’s uncoating

40
Q

How to neuraminidase inhibitors work?

Work on influenza A + B

A

Neuraminidase is one of two surface gylcoproteins on influenza surface. It normally cleaves N-acetylneuraminic acid (siliac acid) from host cell, thus releasing virus and allowing further spread in respiratory tract

Drugs are N-acetlyneuraminic acid analgoues, and act as competitive reversible inhibitors of neuraminidase enzyme

Drugs reduce viral shedding, disease severity, duration of symptoms if given early in infection

41
Q

Goal of hepatisis B treatment is to reduce HBV DNA levels and reduce risk of cirrhosis/HCC.

What are drug options?

A

NRTIs

Pegylated-IFN

42
Q

How does pegylated IFN work?

Classified as an immune modulator

A

Binds to type 1 interferon receptor, which leads to up-regulation of IFN–stimulated genes, which inhibit viral replication

Polyethylene glycol (PEG) is added to interferon to form PEG-IFN, which has longer half life. Can be given as weekly injection, instead of daily

43
Q

Hepatitis C treatment previously included ribavirin and IFN-alpha.

Which drugs are now used for 3 months to give complete clearance?

Monitor HCV RNA to look for sustained virologic response

A

NS5B inhibitor e.g sofosubuvir and velpatasvir in combination

Specific combination depends on which genotype of virus

44
Q

What are reasons antiviral drug may not be working?

A

Poor compliance

Malabsorption

Incorrect treatment - e.g wrong genotype HCV

Resistance - some mutations are well known, and can be tested for prior to treatment starting with nucleic acid sequencing. Resistant strains e.g HIV can be transmitted in populations

45
Q

Why do fast/ slow viral replications rates make it difficult to treat viral infection?

A

Rapid replication leads to mutation/ resistance. Viral RNA polymerases including reverse transcriptases lack proffreading capacity, so large numbers of errors accumulate during replciation process

Slow replication/ latency - cannot be targeted by current anti-virals

46
Q

Which gene mutations cause resistance in these infections?

HSV/VZV

CMV

A

HSV/ VZV - enzyme thymidine kinase

CMV - UL97

47
Q

52 year old man with renal failire receives cadaveric renal transplant. CMV seronegative, donor CMV seropositie. HLA mismatch, so requires high level immunosuppression.

What is best strategy to prevent CMV disease?

Monitor CMV viral load, treat IV ganciclovir when viral load detectable

Oral ganciclovir prophylaxis 3 months

Oral valaciclovir prophylaxis 3 months

Oral valganciclovir prophylaxis 3 months

A

Oral valganciclovir for 3 months as high risk patient.

Can use prophylaxis, or alternatively monitor viral load and give pre-emptive treatment

ganciclovir needs IV line

valaciclovir for HSV/ VZV

48
Q

32 year old man HIV with efavirenz, emtricitabine, tenofovir develops virological failure after initial successful viral control.

Genotyping shows presence of M184V and K103N in RT

What is most likely to be successful?

Add maraviroc
Add raltegravir
Switch efavirenz to ritonavir boosted darunavir
switch emtricitabine to lamuvidine
switch tenofovir to abacavir
A

Emtricatibine and and efavirenza have low genetic barrier to resistance, so likely to be cause of failure.

M184V predicts resistance to lamivudine and emtricabine, so switching will not help.

K103N predicts resistance to efavirenz, with cross-resistance to nevirapine.

Adding new class to failing regimen not recommended.

Swtich efavifenz to ritonavir boosted darunavir is treatment option. Although M184V reduces susceptibility to emtricitabine, it also makes virus less fit, so most physicians will leave emtrictabine/ lamivudine in regimen despite presence of resistance

Medical Microbiology and Virology (60 decks)

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