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Biochemical Pharmacology > HIV & AIDS > Flashcards

HIV & AIDS Flashcards

1
Q

How many people are living with HIV globally?

A

Approx. 38 million people

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2
Q

What percentage of people with HIV know their status?

A

81%

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3
Q

How many people are receiving antiretroviral therapy (ART)?

A

25.4 million people

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4
Q

What are the WHO targets to end the HIV epidemic?

A
  • New guidelines to increase ART coverage,
  • New set targets for 2020
  • The 90-90-90 strategy
  • Ending the AIDS epidemic by 2030.
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5
Q

What is the 90-90-90 strategy?

A
  • 90% of people with HIV are aware of their infection
  • 90% of those people are receiving ART
  • 90% of those receiving ART have no detectable virus in their bloodstream.
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6
Q

When was the first cases of AIDS diagnosed?

A

1981

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7
Q

Where are approximately 68% of all current cases of HIV?

A

Sub-Saharan Africa due to lack of resources.

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8
Q

What age group is most likely affected by HIV?

A

15-24 age group

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9
Q

What is HIV?

A

Human Immunodeficiency Virus

  • Invades the helper T cells in the body of the host
  • Preventable & manageable
  • NOT curable.
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10
Q

What is AIDS?

A

Acquired Immune Deficiency Syndrome

  • Occurs when the immune system becomes weakened by HIV.
  • Used to describe a number of potentially life-threatening infections and illnesses
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11
Q

What happens during acute HIV?

A
  • Presents as flu-like symptoms
  • Reported by half of those who contract HIV
  • It generally occurs between 2 and 6 weeks after infection
  • Dramatic drop in CD4+ T cell count in early weeks - this is what causes flu symptoms
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12
Q

What is chronic HIV?

A

aka clinical latent infection

  • HIV-positive but asymptomatic
  • Lasts for several years
  • Viral replication occurring up to 10 billion virions per day
  • CD4 counts drop to 500-600 cells/ml
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13
Q

What is chronic lymphadenopathy?

A

Swelling of the lymph nodes and is a characteristic of chronic HIV.

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14
Q

What is the average time between HIV infection and AIDS?

A

Approximately 10 years.

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15
Q

What is the CD4 count in chronic HIV?

A

500-600 cells/mL.

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16
Q

What is the CD4 count in AIDS?

A

<200 cells/mL

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17
Q

What happens during progression to AIDS?

A
  • CD4 count drops to <200 cells/mL
  • makes it easier to overwhelm the immune system.

Majority of manifestations occur due to opportunistic infections resulting from immunosuppression rather than direct injury by virus.

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18
Q

What subfamily of retroviruses does HIV belong to?

A

Lentivirus subfamily.

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19
Q

What is the structure of HIV?

A
  • An enveloped virus composed of two copies of positive-sense single-stranded RNA
  • Enclosed by a conical capsid composed of 2,000 copies of the viral protein p24.
  • The RNA is tightly bound to nucleocapsid proteins p7.
  • A matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle.
  • A lipid viral envelope is composed of proteins gp41 and gp120.
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20
Q

What is the function of retroviruses?

A

Transcribe RNA into DNA.

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21
Q

What is the composition of the HIV genome?

A

Two copies of positive-sense single-stranded RNA.

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22
Q

What is the composition of the clonal capsid that incodes viral DNA?

A

Composed of 2000 copies of viral protein p24

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23
Q

What are the enzymes required for the development of the virion?

A
  • Ribonuclease
  • Reverse transcriptase
  • Proteases
  • Integrase.
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24
Q

What is the function of ribonuclease in HIV?

A

Degrades RNA during HIV replication.

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25
Q

What is the function of reverse transcriptase in HIV?

A

Transcribes RNA into proviral DNA.

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26
Q

What is the role of proteases in HIV?

A

Cleave viral polyproteins into functional proteins.

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27
Q

What is the function of integrase in HIV?

A

Integrates proviral DNA randomly into the host genome.

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28
Q

What is the purpose of the matrix in HIV?

A
  • Composed of the viral protein p17
  • Surrounds the capsid
  • Maintains the integrity of the virion particle.
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29
Q

What is the composition of the lipid viral envelope in HIV?

A

Composed of proteins gp41 and gp120.

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30
Q

What are the roles of proteins gp41 and gp120 in HIV?

A

gp41 anchors the HIV envelope to the viral membrane
gp120 is involved in the attachment and binding to host cell receptors.

31
Q

What is the difference between HIV-1 and HIV-2?

A

Have slightly different genetic variations

HIV-2:

  • clinically demonstrating a slower clinical course,
  • a longer asymptomatic phase
  • a lower infectivity rate.
  • possesses the gene vpx instead of vpu.
32
Q

What are some transmission risk factors for HIV?

A
  • Blood transfusion/organ transplants
  • Breastfeeding, anywhere with a mucus membrane.
  • Sharing injecting equipment
33
Q

What immune cells can HIV infect?

A
  • CD4+ T cells
  • Macrophages
  • Microglial cells.
34
Q

How does HIV-1 enter macrophages and CD4+ T cells?

A

Mediated through interaction of gp120 and gp41 with the CD4 molecule on the target cells membrane.

35
Q

What are the steps of HIV pathogenesis?

A

Include:
1. Entry
2. Replication and transcription
3. Assembly and release.

36
Q

What are the entry steps of HIV pathogenesis?

A
  1. Adsorption of gp to surface receptors on target cell
  2. Fusion of viral envelope with target cell membrane
  3. Release of HIV capsid into the cell
37
Q

What are the replication and transcription steps of HIV pathogenesis?

A
  1. Reverse transcriptase liberates ssRNA genome from attached viral proteins
  2. Viral DNA (cDNA) is formed, transported accross nucleus and integrated into host DNA
38
Q

What are the assembly and release steps of HIV pathogenesis?

A
  1. Assembly of new HIV-1 virons at plasma membrane of the host cell
  2. Proteases creates cleaves proteins to produce mature virions
39
Q

What are the methods used to provide evidence of HIV infection?

A
  • Virus isolation
  • Measurement of viral nucleic acid
  • Detection of viral antigen
  • Detection of viral antibody
40
Q

What are the key tests used for HIV diagnostics?

A

ELISA and PCR based.
Detection of viral antigen and detection of viral antibody using western blotting are also used.

41
Q

Which viral protein is detected in the detection of viral antigen?

A

p24 capsid protein.

42
Q

What is the role of CD4+ T cell count in recognizing immunodeficiency in HIV?

A

CD4+ T cell count is used to assess the level of immunodeficiency in HIV-infected individuals.

43
Q

What is the window period in HIV diagnosis?

A
  • The period early in infection when the blood of an infected person can contain HIV but antibodies are not detectable.
  • Generally 4-6 weeks in duration.
44
Q

What is antiretroviral therapy (ART)?

A

A treatment that may assist in controlling viral loads and activity in the body.
There are six classes

45
Q

Who should receive HIV ART?

A

Everyone
Particularly important in:

  • Severe symptoms
  • Presence of an opportunistic infection
  • CD4 T-cell count under 350 cells/µL
  • Pregnant women
  • HIV-related kidney disease
  • Presence of hepatitis B or C.
46
Q

Why is HIV a difficult virus to treat?

A
  • It is extremely adaptable
  • High resistance rate
  • High adaptable rate
47
Q

What are the six classes of ART drugs?

A
  1. Entry inhibitors - Maraviroc
  2. Fusion inhibitors - Enfuvirtide
  3. Reverse transcriptase inhibitors
    1. Nucleoside-based - Zidovudine (AZT)
    2. Non-nucleoside-based - Efavirenz
  4. Integrase inhibitors - Dolutegavir
  5. Protease inhibitors - Ritonavir
  6. PK enhancers - Ritonavir
48
Q

What is the mechanism of action of Entry/Fusion Inhibitors?

A

Prevent HIV from entering healthy cells in the body.

49
Q

What is an example of an entry inhibitor?

A

Maraviroc

50
Q

What is an example of a fusion inhibitor and how does it work?

A

Enfuvirtide

  • A synthetic peptide
  • Structurally similar to a section of gp41
  • Blocks conformational changes in gp41,
  • Blocking the entry of the virus
  • Targets CCR5 & CXCR4

works antagonistically - not allowing fusion

51
Q

What are NRTIs?

A
  • Reverse Transcriptase Inhibitors that require intra-cytoplasmic activation via phosphorylation by cellular enzymes.
52
Q

How do NRTIs work?

A

They inhibit reverse transcriptase by incorporating into viral DNA and causing chain termination

53
Q

Why are NRTIs preferred as first-line drugs for HIV treatment?

A

Because of their:

  • Favourable PK profile,
  • Long intracellular half-life,
  • High oral bioavailability,
  • Convenient once or twice daily dosage schedule,
  • Low risk for drug-drug interactions.
54
Q

What is an example of an NRTI drug, and what are its uses?

A

Zidovudine (AZT)

  • It is a thymidine analogue
  • Rapid oral absorption
  • 65% bioavailability
  • Half life: 1 h
  • Exctreted unchanged in urine

Uses:

  • Palliative treatment of HIV-1 and HIV-2 with other two ART drugs,
  • Post exposure prophylaxis (PEP)
  • Mother to offspring transmission
55
Q

What are NNRTIs?

A

Reverse Transcriptase Inhibitors that do not require activation through phosphorylation.

56
Q

How do NNRTIs inhibit viral replication?

A

They bind directly to the catalytic site of viral reverse transcriptase

  • Cause enzyme inactivation
    &
  • inhibition of viral DNA synthesis.
57
Q

What is an example of an NNRTI drug, and what are its adverse effects?

A

Efavirenz

  • 50% bioavailability
  • Metabolized mainly by CYP2B6, and lesser by CYP3A4.

Shown to reduce HIV-1 viral load to below 400copies/ml within 6 months in 60-80% of people who have not previously taken HIV treatments
Adverse effects:

  • Headache
  • Insomnia
  • Dizziness
  • Rashes
  • Neuropsychiatric symptoms.
58
Q

What is the mechanism of action of Protease Inhibitors?

A
  • Competitively inhibit the viral protease enzyme,
  • Preventing cleavage of gag-pol polyproteins
    (necessary for mature viron production)
  • Results in the production of immature, non-infectious virions.
59
Q

What is the limitation of using protease inhibitors as a first-line regimen?

A

Avoided as first line regime
reserved for failure class
due to:

  • Insulin resistance
  • hypertriglyceridemia
  • High risk of coronary heart disease
  • Clinically significant interactions
60
Q

What is the recommendation when using protease inhibitors?

A

use in combination with either:
two NRTIs
or
one NRTI & one NNRTI

61
Q

What is the “boosted PI regimen,” and how does it work?

A

Combines with a low and subtherapeutic dose of Ritonavir (100 mg).
Ritonavir reduces the first pass metabolism,
increasing bioavailability and
higher concentration within the bloodstream that’s able to carry out action, and
slows systemic metabolism,
decreasing clearance, and keeping the drug in the body for a longer time.

62
Q

What is the mechanism of action of Integrase Inhibitors in HIV treatment?

A
  • Inhibit the viral enzyme integrase
  • Preventing the insertion of HIV genetic material into chromosomes of the host cells
  • Halting the viral replication process.
63
Q

What is an example of an integrase inhibitor?

A

Dolutegravir

  • Superior to Raltegravir.
  • Increased absorption in the presence of food
  • Metabolized by UDP-glucuronyltransferase
  • Can distribute in the CSF and plasma.
64
Q

What is HAART, and why is combination therapy important in HIV treatment?

A

Highly Active Antiretroviral Therapy

  • involves the combination of different antiretroviral drugs
  • from at least two different classes
  • to suppress the replication of the HIV virus
  • control the progression of the disease.

Combination therapy is important because it decreases the emergence of resistance and toxicity.

65
Q

What are the preferred agents for initial HIV treatment?

A

combination of
NRTI/NtRTI: Tenofovir and Emtricitabine,
and either:

  • NNRTI: Efavirenz,
  • a ritonavir-boosted PI: Atazanavir/Ritonavir,
  • INSTI: Raltegravir, Dolutegravir, or Bictegravir.
66
Q

What is the composition of Biktarvy?

A
  1. Bictegravir
  2. Tenofovir alafenamide (AF)
  3. Emtricitabine
67
Q

What is the role of bictegravir in Biktarvy?

A
  • Bictegravir is an integrase strand transfer inhibitor (INSTI)
  • Helps prevent the integration of HIV-1 into the host’s DNA,
  • Inhibiting viral replication.
68
Q

What is the significance of Biktarvy having a high genetic barrier to HIV-1 resistance?

A
  • It is less likely for the virus to develop resistance to the medication
  • allows patients to stay on the treatment for a longer duration.
69
Q

How does Biktarvy compare to dolutegravir-based therapy in clinical trials?

A

In phase III trials
was found to be noninferior to dolutegravir-based therapy
in achieving virological suppression
in treatment-naïve adults over 96 weeks of treatment.

70
Q

What were the findings regarding Biktarvy in treating treatment-experienced patients?

A

Found to be noninferior to ongoing dolutegravir/abacavir/lamivudine or boosted protease inhibitor (PI)-based therapy
in preventing virological rebound over 48 weeks in treatment-experienced patients.

71
Q

What are some strategies for toxicity management in HIV treatment?

A
  • Alternating therapies before resistance or adverse reactions occur
  • Using combination therapy
    decreased emergence of resistance
    decreased risk of toxicity.
72
Q

How can pharmacogenomics impact the toxicity of select antiretroviral therapies?

A

Polymorphisms identified may impact the toxicity of select antiretroviral therapies.
CYP2B66 allele

  • increased risk of adverse events when treated with efavirenz,

HLA-B57:01:01 allele

  • Increased risk of hypersensitivity to abacavir,

* 6 and * 28 allele

  • in combination with a normal or decreased function allele may have an increased likelihood of hyperbilirubinemia when treated with atazanavir.
73
Q

What are some HIV prevention strategies?

A
  • Vaccines (although none have been successful so far),
  • Education, counseling, and behavior change, safer sex practices, food and water safety, skin and mucous membrane integrity,
  • Free needles for IV drug users,
  • Screening and treating pregnant women.
74
Q

What is PrEP and PEP?

A

PrEP (Pre-Exposure Prophylaxis)

  • a single daily pill (combination of tenofovir/emtricitabine)
  • can reduce the risk of contracting HIV by 99.99%.

PEP (Post-Exposure Prophylaxis)

involves taking antiretroviral medications (such as AZT) after potential exposure to HIV within 72 hours for 28 days

Biochemical Pharmacology (9 decks)

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