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CPTP 3 > CPTP 3.9 HIV Treatment > Flashcards

CPTP 3.9 HIV Treatment Flashcards

1
Q

How does HIV bind to and access T-Cells?

A

gp120 protein on the virus binds to CD4 proteins expressed on the surface of T cells

They enter by endocytosis, leaving the envelope in the plasma membrane

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2
Q

What is the nuclear information of HIV kept in? What is found within this?

A

A nuclear capsid made of protein p24

  • RNA
  • Reverse transcriptase
  • Protease
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3
Q

What type of virus is HIV?

A

A retrovirus:
• Starts off as RNA
• Becomes a DNA/RNA hybrid
• This finds other DNA and makes a template which gets expressed by the cell
• The cell expresses the new protein, forming mRNA

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4
Q

Wh y does it take over 100 years of current treatment to eradicate HIV?

A

CD4-containing cells have a very slow turnover rate, virus DNA survives in the cell

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5
Q

Why are vaccines and antivirals not effective in many RNA viruses?

A

Drug resistance:

Millions of copies are made, many with mutations, so they can evolve very quickly compared to bacteria. (Also, HIV attacks the cells that are supposed to defend against them)

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6
Q

What methods can be used against viruses?

A
  • Vaccines
    • Virucides (not ingestible, for cleaning)
    • Antivirals (virus-specific effect, e.g. prevents cell attachment)
    • Immunomodulators (augments host response to pathogen)
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7
Q

What is CI?

A

Chemotherapeutic Index:

Maximum tolerable dose per kg of body weight divided by the minimum dose per kg of body weight which cures the disease

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8
Q

What are the ideal properties of antivirals?

A
  • High CI
    • High bioavailability
    • Good distribution
    • Low ability to induce resistance
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9
Q

How do most antivirals work? What is this poor at combatting?

A

By targetting viral nucleic acid synthesis

This cannot eliminate latent viruses or non-replicative viruses

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10
Q

How can drug resistance to antivirals be minimised?

A
  • Adherence to medication
    • Ensure that mutations gained are likely to make the virus less fit for replication
    • Increase the number of changes the virus must make to become resistant (i.e. less specificity within the virus)
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11
Q

Why do RNA viruses become resistant to medication far easier than DNA viruses?

A

They replicate much faster

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12
Q

Name the co-receptors used by HIV as well as CD4

A
  • CCR5

* CXCR4

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13
Q

What are the stages of the HIV cycle that can be targeted by drugs?

A
  • Binding and fusion
    • Reverse transcription
    • Integration (into DNA)
    • Transcription
    • Assembly
    • Budding
    • Maturation
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14
Q

What happens once the virus RNA is transcribed by the host cell?

A

It is cleaved into the three proteins needed by the virus by protease

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15
Q

What are the three proteins HIV viruses need and what do they do?

A
  • Reverse transcriptase (makes DNA from RNA)
    • Integrase (enables its genetic material to be integrated into the DNA of the infected cell)
    • Protease (cleaves the long protein product into the three separate proteins)

(also needs structural proteins)

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16
Q

What drugs are available

A
  • Nucleoside reverse transcriptase inhibitors
    • Non-nucleoside reverse transcriptase inhibitors
    • Protease inhibitors
    • Integrase inhibitors
    • Fusion inhibitors
17
Q

How are antiviral drugs found?

A

Rational drug design
• Determine the target’s structure and theoretically design an inhibitor

Combinatorial chemistry
• Machine is given several chemical subunits and uses them to make random compounds and test them
• Active compounds are identified and used as a lead compound

18
Q

How do NRTIs work? Name the formulary example. What does it treat?

A

They inhibit reverse transcriptase, stopping the conversion of viral RNA into DNA. They are shaped like nucleotides used to form DNA, and once it is mistaken for one, further growth of the DNA chain stops

Tenofovir

Treats HIV

19
Q

Outline the pharmacokinetics of NRTIs.

A
  • Orally absorbed
    • Become biologically active once inside cells as they become phosphorylated into nucleoside triphosphates
    • Plasma half-life is therefore irrelevant, the intracellular half-life is important
20
Q

What are the adverse cellular effects of NRTIs?

A 
They also inhibit the action of DNA polymerase and so prevent mitochondrial replication, causing disturbance of the respiratory cycle of the cell, leading to:
  •  Lactic acidosis
  •  Steatosis 
  •  Lipoatrophy
  •  Metabolic syndrome
21
Q

How can NRTI resistance occur?

A
  • Mutant reverse transcriptase may remove nucleoside analogues
    • Mutant reverse transcriptase may not bind to the nucleoside analogues (i.e. the NRTIs)
22
Q

Outline the steps in reverse transcription

A
  • The next nucleoside (or nucleoside analogue) triphosphate binds
    • It is incorporated onto the end of the growing viral DNA chain and pyrophosphate is released
    • The incorporated nucleoside is translocated to a different confirmation to allow addition of next nucleoside
23
Q

Name an NNRTI (non-nucleoside reverse transcriptase inhibitor). How do these work?

A

Efavirenz

NNRTIs bind directly to reverse transcriptase, preventing it from adding new nucleotides to the growing DNA chain

24
Q

How can NNRTI resistance occur?

A

Binding site mutation (this is a very easy mutation)

25
Q

Outline the pharmacokinetics of NNRTIs.

A
  • Absorbed orally
    • Long plasma half life (plasma half life is important in this case unlike NRTIs)
    • Metabolised by liver CYP p450 enzyme (therefore interacts with many drugs)
26
Q

What is the most common resistance mutation against NNRTI?

A

K103N

27
Q

Name the formulary protease inhibitor.

A

Darunavir

28
Q

What is the mechanism of action of protease inhibitors?

A

Inhibits the cleavage of the protein product of the DNA (which was integrated into the host cell) by the protease into the building blocks of the new viruses.

29
Q

Outline the pharmacokinetics of protease inhibitors.

A
  • Absorbed orally
    • Metabolised in Liver (CYP p450) therefore many interactions
    • Also metabolised in the small intestine
30
Q

What can the absorption of protease inhibitors be affected by?

A

PPI use (e.g. omeprazole and lansoprazole)

31
Q

How is the half-life of darunavir extended to once-daily? What are the benefits of this

A

Ritonavir boosting:
• Small-dose ritonavir (also another protease inhibitor) inhibit CYP P450

Benefits:
• Better adherence
• Less toxic doses can be used (as the graph of conc is less steep, no need to boost it quite so high initially)

32
Q

How do fusion inhibitors work?

A
  • Prevent the fusion of of HIV virus to CD4 or to CCR5 (both human proteins found on T cells)
    • Therefore, virus entry is refused
33
Q

How does resistance to CCR5 inhibitors occur?

A

The HIV virus switches to be CXCR4-tropic

34
Q

What is the main benefit of integrase inhibitors?

A

They can go past the blood-brain barrier and have excellent distribution

35
Q

How is HIV treated?

A

Either:
• Dual NRTIs and a PR
• Dual NRTIs and an NNRTI
• Dual NRTIs and II

36
Q

Who with HIV is treated?

A

Those with a CD4 count of less than 350

37
Q

How can HIV resistance testing be carried out?

A

First suspected when viral load increases when patient is adherent

Phenotypic
• Take a culture and test resistance
Genotypic
• Look at the genetics of viruses and see what changes are present in people with drug resistance
Virtual phenotype
• Adding the two above methods together

38
Q

What happens when you remove the drug that the viral load has become resistant to?

A

The virus quickly reverts back to its wild type, as this is its fittest state

39
Q

What is the danger of two HIV-infected people having sex?

A

The resistance can be transferred

CPTP 3 (21 decks)

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