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PT 2 > Block 10 - L4 > Flashcards

Block 10 - L4 Flashcards

1
Q

What is the major target of HIV?

A

CD4+ or T-helper lymphocytes

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2
Q

What is a normal CD4 cell count?

A

800-1500 cells/mm^3

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3
Q

CD4 cells counts less than ___ cells/mm^3 are associated with the development of opportunistic infections.

A

500 (and especially 200)

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4
Q

What are the goals of ART therapy in HIV-infected patients?

A
  1. Maximal and durable suppression of viral load to reduce the risk of disease progression
  2. Restoration and/or preservation of immunologic function
  3. Improvement in quality of life
  4. Reduction in HIV-related morbidity and mortality
  5. Prevent transmission of HIV
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5
Q

The viral load assessment predicts what three things?

A
  1. Course of disease
  2. Which ART to use
  3. Clinical response to ART
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6
Q

What is the goal of resistance testing and when should it be performed?

A

To identify the resistance mechanism; prior to initiating ART and after ART fails

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7
Q

When should ART be initiated?

A

Upon diagnosis of HIV-infection, regardless of CD4 T-lymphocyte cell count

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8
Q

What are the 6 major drug classes of drugs available for treatment of HIV infection?

A
  1. Nucleoside/nucleotide reverse transcriptase inhibitors
  2. Non-nucleoside reverse transcriptase inhibitors
  3. Protease inhibitors
  4. Viral integrase inhibitors
  5. Fusion inhibitors
  6. CCR5 antagonists
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9
Q

What viral function is targeted by CCR5 antagonists and fusion inhibitors?

A

Attachment/fusion of the virus with the host cell

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10
Q

What viral function is targeted by NRTI’s and NNRTI’s?

A

Reverse transcription

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11
Q

What viral function is targeted by integrase inhibitors?

A

Integration

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12
Q

What viral function is targeted by protease inhibitors?

A

Maturation

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13
Q

Where is HIV-2 infection seen geographically?

A

Endemic to west Africa

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14
Q

List the 7 NRTI’s.

A
  1. Abacavir
  2. Didanosine
  3. Emtricitabine
  4. Lamivudine
  5. Stavudine
  6. Tenofovir
  7. Zidovudine
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15
Q

What is the general MOA of the NRTIs?

A

NRTIs are nucleoside or nucleotide analogs that lack a 3’-hydroxyl group; they enter the cells, are phosphorylated, and form synthetic substrates for viral reverse transcriptase. These molecules compete with native nucleotides for incorporation into the viral genome, and when inserted, terminate proviral DNA.

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16
Q

What is the major AE of NRTIs?

A

Some (Didanosine > Stavudine > Zidovudine) inhibit DNA polymerase gamma, blocking production of mitochondrial DNA and inhibiting oxidative phosphorylation complexes. This promotes production of cytosolic lactate and may induce lactic acidosis-hepatic steatosis syndrome. NRTIs can also inhibit beta-oxidation, leading to accumulation of triglycerides

Other - anemia, myopathy, pancreatitis, HBV flare

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17
Q

What is HBV flare?

A

Discontinuation of certain NRTI’s (Emtricitabine, Lamivudine, Tenofovir), which have anti-HBV activity, is associated with increase in HBV titer

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18
Q

What is a major AE/contraindication of Abacavir?

A

Hypersensitivity, especially in HLA-B 5701+ patients (contraindicated in these patients)

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19
Q

What are the major AE of Tenofovir?

A

Well-tolerated overall, potential renal toxicity and bone density changes; can reduce these when using a TAF prodrug

Also HBV flare

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20
Q

Which NRTIs are preferred for naive patients?

A
  1. Emtracitabine

2. Tenofovir

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21
Q

Which NRTIs can cause an HBV flare (AE)?

A
  1. Emtracitabine
  2. Lamivudine
  3. Tenofovir
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22
Q

Which NRTIs can cause lactic acidosis (AE)?

A
  1. Didanosine
  2. Stavudine
    [3. Zidovudine]
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23
Q

Which NRTI can cause anemia and neutropenia (AE)?

A

Zidovudine

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24
Q

List the 5 non-nucleotide reverse transcriptase inhibitors.

A
  1. Delavirdine
  2. Efavirenz
  3. Etravirine
  4. Nevirapine
  5. Rilpivirine
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25
Q

What is the MOA of NNRTIs?

A

Non-competitive inhibitors bind to RT and induce a conformational change that greatly reduces enzyme activity

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26
Q

What is the major AE of NNRTIs?

A

All influence cytochrome P450 enzyme activity - drug interactions are common

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27
Q

What are the major AE and contraindiations of Efavirenz?

A

Birth defects, transient CNS effects; contraindicated in 1st trimester of pregnancy or in women planning to conceive

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28
Q

Discuss the drug interactions of Efavirenz.

A

Efavirenz is a CYP3A4 inducer; lowers exposure to some PIs, methadone

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29
Q

What is the major AE of Nevirapine?

A

Severe hepatotoxicity

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30
Q

What are the contraindiations of Nevirapine?

A

Womenw ith pre-treatment CD4>250 cells/mm and men with CD4>400 cells/mm

31
Q

Discuss the drug interactions of Nevirapine.

A

Nevirapine is a CYP3A4 inducer; lowers exposure to some PIs, methadone

32
Q

List the 8 protease inhibitors.

A
  1. Ritonavir
  2. Fosamprenavir
  3. Atazanavir
  4. Indinavir
  5. Nelfinavir
  6. Saquinavir
  7. Tipranavir
  8. Darunavir
33
Q

What is the MOA of PIs?

A

Inhibit HIV aspartyl protease, which blocks processing of viral proteins required to produce a mature viral particle

34
Q

What are the major AE of PIs?

A
  1. Metabolic syndrome
  2. Chronic use leads to lipodystrophy
  3. N/V, diarrhea, paresthesias
  4. CYP substrates and inhibitors - significant drug interactions
35
Q

List 4 important CYP3A4 substrates that should not be co-administered with PIs due to CYP-dependent metabolism.

A

Quinidine (antiarrhythmic)
Ergotamine (ergot derivative)
Midazolam (benzodiazepine)
Warfarin (anticoagulant)

36
Q

List 4 important CYP3A4 inducers that should not be co-administered with PIs due to CYP-dependent metabolism.

A
  1. Rifampin (antimycobacterial)
  2. Phenobarbitol (barbiturate)
  3. St. Johns’ Wart (herbal)
37
Q

Ritonavir is not effective - why is it used?

A

Ritonavir is a potent CYP3A4 inhibitor; co-administration of low dose ritonavir boosts exposure of CYP3A4 substrates (other PIs) - allows for reduced dose and dosing frequency

38
Q

What is an alternative boosting agent?

A

Cobicistat

39
Q

Which statins are CYP3A4 substrates?

A

Simvastatin
Atorvastatin
Lovastatin

40
Q

Which statins are not CYP3A4 substrates?

A

Pravastatin

Fluvastatin

41
Q

List the 3 integrase inhibitors.

A
  1. Raltegravir
  2. Elvitegravir
  3. Dolutegravir
42
Q

List the 1 fusion inhibitor.

A
  1. Enfuvirtide
43
Q

List the 1 CCR5 antagonist.

A

Maraviroc

44
Q

What is the MOA of integrase inhibitors?

A

BLocks the insertion of reverse-transcribed viral DNA into the host DNA by binding the Mg2+ cofactors required for the strand transfer.

45
Q

What are the major AE of integrase inhibitors?

A

Diarrhea, headache, nausea

46
Q

What is the MOA of Enfuviritide?

A

The drug binds to HIV surface glycoprotein gp41 to block conformation required for membrane fusion with the host cell

47
Q

What are the major AE/contraindications of Enfuviritide?

A

Injection site reaction/inflammation, hypersensitivity; contraindicated in patients with known hypersensitivity to enfuviritide

48
Q

What is the MOA of Maraviroc?

A

Reversible antagonist of the CCR5 interaction with gp120, blocking CCR5-tropic HIV-1 entry

49
Q

What are the major AE and contraindications of Maraviroc?

A

Hepatotoxicity and possible hypersensitivity; use with caution in patients with liver dysfunction

50
Q

Why should rifampin not be coadministered with all PIs and many NNRTIs?

A

Rifampin is a potent inducer of CYP activity and dramatically reduces exposure to the ART drugs.

51
Q

How is active TB treated in patients infected with HIV? Latent TB?

A

Rifapentine (only efavirenz or raltegravir-based regimens); isoniazid

52
Q

What are the recommended starting regimens of ART for treatment-naive patients?

A
  1. 1 INSTI + 2 NRTI, or
  2. 1 PI (boosted with RTV) + 2 NRTI

INSTI recommendations - dolutegravir, elvitegravir, raltegravir

PI recommendations - darunavir + ritonavir

NRTI recommendations - Tenofovir prodrug + emtricitabine

Note - this applies to HIV2 as well, with darunavir, lopinavir, and saquinavir being the most effective PI options

53
Q

What is an alternative PI option for ART in treatment-naive patients? When is this contraindicated?

A

Atazanavir + ritonvir or cobicistat; patients who require high dose PPIs

54
Q

What is an alternative Dual-NRTI option for ART in treatment-naive patients? When is this contraindicated?

A

Abacavir + lamivudine; do not use when positive for HLA-B 5701

Caution when HIV RNA >100,000 copies/mL or in high risk of cardiovascular disease

55
Q

What are the contraindications of tenofovir prodrug + emtricitabine?

A

Do not use with unboosted atazanavir; use with caution with nevirapine or in patients with underlying renal insufficiency

56
Q

When should the ART drug regiment be changed?

A

Virologic suppression failure or immunologic failure

57
Q

Define virologic suppression failure.

A

The inability to achieve or maintain suppression of viral replication to levels below the limit of detection (<50 copies/mL); may manifest as -

  1. Incomplete virologic response (HIV RNA > 400 copies/mL after 24 weeks of therapy or >50 copies/mL by 48 weeks)
  2. Virologic rebound (after virologic suppression, repeated detection of HIV RNA above the assay limit of detection)
58
Q

Define immunologic failure.

A

The inability to achieve and maintain an adequate CD4 T-cell response despite virologic suppression

59
Q

List the 3 ART regimens that should not be used.

A
  1. Monotherapy with NRTI
  2. Dual NRTI regimens
  3. Triple NRTI regimens
60
Q

Why should monotherapy and dual NRTI regimens be avoided?

A
  1. Rapid resistance development

2. Inferior antiretroviral activity

61
Q

Why should triple NRTI regimens by avoided?

A

High rate of non-response in treatment-naive patients

62
Q

When are triple NRTI regimens permitted?

A

Abacavir/zidovudine/lamivudine or tenofovir/zidovudine/lamivudine in patients form whom other options are worse

63
Q

Why should atazanavir + indinavir be avoided?

A

Potential hyperbilirubinemia

64
Q

Why should didanosine + stavudine be avoided?

A

High incidence of toxicity, potential serious lactic acidosis

65
Q

Why should a double NNRTI combo be avoided?

A

EFV + NVP has more adverse effects than separate and both reduce ETV

66
Q

Why should EFV be avoided in the first trimester of pregnancy?

A

Teratogenic

67
Q

Why should emtricitabine + lamivudine be avoided?

A

Similar resistance profile

68
Q

Why should etravirine + unboosted PI be avoided?

A

Induced PI metabolism

69
Q

Why should etravirine + boosted ATV, FPV, or TPV be avoided?

A

Induced PI metabolism

70
Q

Why should nevirapine be avoided in navie women with CD4>250 and men with CD4>400?

A

High incidence of hepatoxicity

71
Q

Why should stavudine and zidovudine be avoided?

A

Antagonistic

72
Q

Why should unboosted darunavir, saquinavir, or tipranavir be avoided?

A

Inadequate bioavailabiltiy

73
Q

What are the two types of cure of HIV?

A

Functional cure (prevent virus from inducing immune deficiency) and sterilizing cure (complete elimination of virus)

PT 2 (15 decks)

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