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Respiratory II - Exam 2 > HIV and AIDS Drugs - SRS > Flashcards

HIV and AIDS Drugs - SRS Flashcards

1
Q

What are the classes of drugs we covered that are used for HIV/AIDS?

6

A
  1. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
  2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
  3. Protease inhibitors (PIs)
  4. Entry inhibitors
  5. HIV integrase Strand Transfer Inhibitors
  6. Fixed Dose Combination Products
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2
Q

What are the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) that we must know?

4 RED

7 total

A
  1. Abacavir (ABC)
  2. Emticitabine (FTC)
  3. Lamivudine (3TC)
  4. Tenofovir DF (TDF)
  5. Didanosine (ddl)
  6. Stavudine (d4T)
  7. Zodovudine (ZDV)
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3
Q

What are the Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) that we must know?

Only one RED

Five total

A
  1. Delavirdine (DLV)
  2. Efavirenz (EFV)
  3. Etravirine (ETR)
  4. Nevirapine (NVP)
  5. Rilpivirine (RPV)
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4
Q

What are the protease inhibitors (PIs) we must know?

3 RED

A
  1. Atazanavir (ATV)
  2. Darunavir (DRV)
  3. Fosamprenavir (FPV)
  4. Indinavir (IDV)
  5. Lopinavir/Ritonavir (LPV/RTV)
  6. Nelfinavir (NFV)
  7. Saquinavir (SQV)
  8. Tipranavir (TPV)
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5
Q

What are the entry inhibitor groups?

Name one drug from each.

one red, two drugs total

A
  1. Fusion Inhibitors
    1. Enfuvirtide (T20)
  2. CCR5 Co-Receptor Antagonists
    1. Maraviroc (MVC)
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6
Q

What are the HIV Integrase Strand Transfer Inhibitors (INSTIs) that we need to know?

One RED, three total

A
  1. Dolutegravir (DTG)
  2. Elvitegravir (EVG)
  3. Raltegravir (RAL)
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7
Q

What are the categories of fixed dose combination products?

3

A
  1. NRTI Combinations
  2. NNRTI/NRTI Combinations
  3. Integrase Strand Transfer Inhibitor Combination
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8
Q

What are two examples of NRTI combination products that are used?

A
  1. Emtricitabine/Tenofovir (Truvada)
  2. Zidovudine/Lamivudine (Combivir)
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9
Q

What are two examples of NNRTI/NRTI fixed dose combination products used?

A
  1. Efavirenz/Emtricitabine/Tenofovir (Atripla)
  2. Rilpivirine/Emtricitabine/Tenofovir (Complera)
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10
Q

What is one example of an Integrase Strand Transfer Inhibitor Combination product.

A
  1. Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF (Stribild)
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11
Q

There are about 35 million people living with Human Immunodeficiency Virus (HIV) worldwide. With 2.1 million new cases in 2013. There were 1.5 million deaths in AIDS patients in 2013. Significant advances in drug therapy have been made in a disease that was once uniformly fatal.

What is the medical approach to this disease currently? What are two things physicians need to keep in mind when employing this approach.

A
  1. Combination antiretroviral therapy: Prolongs life and prevents progression of disease.
    1. Must be administered lifelong to control viral replication.
    2. If not used properly, promotes rapid emergence of permanent drug resistance.
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12
Q

What are the steps of the HIV life cycle?

9

A
  1. Attachment and fusion
  2. penetration and uncoating
  3. reverse transcription
  4. integration
  5. transcription
  6. translation
  7. assembly
  8. budding and release
  9. Maturation
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13
Q

What is required for HIV to complete the attachment and fusion stage of its life cycle?

A
  1. HIV binds CD4 receptor of lymphocytes and macrophages to complete attachment
  2. In order to enter the cell co-receptor binding must occur via CCR5 or CXCR4
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14
Q

What occurs during the penetration and uncoating phase?

A

After fusion, full length viral RNA enters the cell cytoplasm

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15
Q

Describe the process of reverse transcription

A
  1. RNA undergoes replication to a short-lived RNA-DNA duplex;
  2. original RNA degraded by RNase H to allow for creation of double stranded DNA.
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16
Q

What incorporates viral genetic material into the host chromosome?

A

Viral integrase

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17
Q

When completing the initial patient evaluation obtain a complete medical history, PE, and lab testing. What should the laboratory testing include?

A
  1. HIV antibody testing
  2. CD4 T-cell count
  3. Plasma HIV RNA (viral load)
  4. Complete blood count, chemistry profile, transaminase levels, blood urea nitrogen (BUN), and creatinine; urinalysis; serologies for Hepatitis A, B, and C viruses.
  5. Fasting blood glucose and serum lipids
  6. Genotypic resistance testing
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18
Q

What is the most important marker of an HIV patients immune function?

A

CD4 T-cell count, this is a strong predictor of disease progression and survival.

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19
Q

CD4 T-cell count should be measured at baseline (first diagnosis) and on a regular basis during treatment. Why should this be done at each of those points?

A
  1. Baseline – determines need to begin prophylaxis against opportunistic infections and urgency of antiretroviral therapy (ART) initiation
  2. Regular basis during treatment – helps assess immunologic response to ART; also, used to determine when prophylaxis against opportunistic infections may be discontinued
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20
Q

What is the most important marker of a patient’s response to ART? (Antiretroviral therapy)

A

Plasma HIV RNA (Viral Load) - critical indicator of initial and sustained response to ART/

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21
Q

When should Plasma HIV RNA (viral load) be measured? Explain why at each point this should be done.

A
  1. Baseline – impacts choice of drug regimen (certain drugs/regimens may be associated with a poor response in a patient with a high viral load)
  2. Initiation of therapy – reductions in viral load following ART initiation associated with decreased risk of progression to AIDs or death
  3. Regular basis during treatment – goal of viral suppression is to maintain viral load below the level of detection (HIV RNA < 20 to 75 copies/mL)
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22
Q

Genotypic resistance testing identifies drug-resistant mutations in viral genes. What can we resistances can we pick up with these?

A
  1. NRTI
  2. NNRTI
  3. PI
  4. Integrase inhibitors
  5. Fusion inhibitors
  6. Co-receptor antagonists
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23
Q

Resistance should be assessed at…

  1. baseline
  2. initiation of therapy
  3. Virologic failure

What benefit is conferred at each stage.

A
  1. Baseline – guides regimen selection to optimize virologic response (do not delay therapy until results final, begin an ART regimen and adjust accordingly)
  2. Initiation of therapy – if treatment initially deferred, repeat resistance testing as patient may have acquired drug-resistant virus
  3. Virologic failure – salvage regimens will produce better virologic response if guided by resistance testing vs. clinical judgement
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24
Q

Antiretroviral drugs, unfortunately, will not eradicate HIV infection. Why?

Consequently, what are the therapeutic goals? 5

A

D/t pool of latently infected CD4 T-cells

  1. Decrease morbitity
  2. prolong duration/quality of survival
  3. restore/preserve immunologic function
  4. suppress viral load
  5. prevent transmission
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25
Q

Although constantly changing, what are the current INSTI-Based Regimen recommended options for ART in treatment-naive patients?

A
  1. Dolutegravir/abacavir/lamivudine [DTG/ABC/3TC] – must be HLA-B*5701 negative
  2. Dolutegravir plus tenofovir/emtricitabine [DTG plus TDF/FTC]
  3. Elvitegravir/cobicistat/tenofovir/emtricitabine [EVG/c/TDF/FTC] – must have CrCl ≥ 70 mL/min
  4. Raltegravir plus tenofovir/emtricitabine [RAL plus TDF/FTC]
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26
Q

What does an “antiretroviral regimen” consist of?

A
  1. Two nucleoside reverse transcriptase inhibitors (NRTIs)
    • One of which is emtricitabine (FTC) or lamivudine (3TC)
  2. Plus one of the following categories
    • integrase strand transfer inhibitor (INSTI)
    • non-nucleoside reverse transcriptase inhibitor (NNRTI)
    • pharmacokinetic enhanced protease inhibitor
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27
Q

What are the current recommended PI based regimens for treatment naive patients?

A
  1. Darunavir/ritonavir plus tenofovir/emtricitabine [DRV/r plus TDF/FTC]
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28
Q

Alternative Regimens for treatment of naive patients may be effective/tolerable but may have disadvantages compared to recommended regimens, and have limitations in certain patient populations, or have less supporting data. What are some examples?

(Based on the formatting of the DSA, probably lower yield stuff here.)

A
  1. NNRTI-Based Regimens
    1. Efavirenz/tenofovir/emtricitabine [EFV/TDF/FTC]
    2. Rilpivirine/tenofovir/emtricitabine [RPV/TDF/FTC] – must have pre-treatment RNA < 100,000 copies/mL and CD4 count > 200 cells/mm3
  2. PI-Based Regimens
    1. Atazanavir/cobicistat tenofovir/emtricitabine [ATV/c TDF/FTC] – must have CrCl ≥ 70 mL/min
    2. Atazanavir/ritonavir plus tenofovir/emtricitabine [ATV/r plus TDF/FTC]
    3. Darunavir/cobicistat or ritonavir plus abacavir/lamivudine [(DRV/c or DRVr) plus ABC/3TC] – must be HLA-B*5701 negative
    4. Darunavir/cobicistat plus tenofovir/emtricitabine [DRV/c plus TDF/FTC]
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29
Q

NRTI’s include abacavir (ABC), didanosine (ddl), emtricitabine (FTC), lamivudine (3TC), stavudine (d4T), tenofovir DF (TDF), zidovudine (ZDV).

What is the MOA for this type of drug? The consequence?

A
  1. competitively inhibit HIV-1 reverse transcriptase;
    1. incorporate into viral DNA and prevent binding with incoming nucleotide (causes premature chain termination).
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30
Q

What do NRTIs require for activation?

A

Intracytoplasmic phosphorylation

31
Q

What are the ADR’s associated with NRTIs?

3

A
  1. Mitochondrial toxicity
  2. lipoatrophy
  3. lactic acidosis with hepatic steatosis (less common, but fatal)
32
Q

Describe the mechanism of NRTI mitochondrial toxicity.

What are the results of this? 4

A

may inhibit mitochondrial DNA polymerase-γ

  1. anemia
  2. granulocytopenia
  3. myopathy
  4. peripheral neuropathy
33
Q

What three NRTIs have low affinity for DNA polymerase, and consequently less risk of mitochondrial toxicity?

A
  1. Emtricitabine
  2. lamivudine
  3. tenofovir
34
Q

Discontinuation of NRTIs is associated with several adverse reactions. What are they? 3

A
  1. rapid rise in aminotransferase levels
  2. progressive hepatomegaly
  3. metabolic acidosis
35
Q

Resistance to NTRIs develops more slowly than to NNRTIs and PIs. How many codon substitutions are required at minimum?

A

3-4 codon substitutions

36
Q

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) include delavirdine (DLV), efavirenz (EFV), etravirine (ETR), nevirapine (NVP), rilpivirine (RPV). What is their MOA?

A
  1. bind HIV-1 reverse transcriptase (near to, but distinct site from NRTIs),
  2. allosterically inhibit RNA- and DNA-dependent DNA polymerase activity.
37
Q

Describe the phosphorylation steps necessary for NNRTIs to become active.

What nucleosides do NNRTIs compete with?

A
  1. Do not require phosphorylation
  2. Do not compete with nucleosides
38
Q

How are NNRTIs metabolised?

A

CYP450 - thus many drug interactions d/t drugs with induction and inhibition of CYP

39
Q

What are the ADRs of NNRTIs?

A
  1. GI disturbances (varied levels)
  2. skin rash
  3. Steven’s Johnson Syndrome - rarely
40
Q

What is Steven’s Johnson syndrome?

A

A form of toxic epidermal necrolysis, is a life-threatening skin condition, in which cell death causes the epidermis to separate from the dermis.

41
Q

Resistance develops relatively easily to NNRTIs. What is the minimum required mutation?

How can we help to minimize consequences of this?

A

High level resistance can occur due to a single point mutation in the binding pocket of the HIV-1 reverse transcriptase.

MUST combine with at least two other active agents to avoid resistance.

42
Q

Protease inhibitors include atazanavir (ATV), darunavir (DRV), fosamprenavir (FPV), indinavir (IDV), lopinavir/ritonavir, (LPV/RTV), nelfinavir (NFV), saquinavir (SQV), tipranavir (TPV).

  1. What is their MOA?
A

Competitively inhibit viral protease

  1. prevents processing of viral proteins into functional conformation
  2. produces immature, noninfectious particles
43
Q

When not inhibited by PIs, what do viral proteases do?

A

Cleave GAG and POL precursor polypeptides - including essential enzymatic and structural viral proteins

44
Q

How are PIs metabolized?

A

CYP450, mostly CYP3A4, so lots of drug interactions

45
Q

Which of the PI drugs has a potent CYP3A4 inhibiting capability?

A

Ritonavir

46
Q

What strategy is Ritonavir used for?

A
  • Used clinically in lower doses to “boost” levels of PIs used in combination.
  • By inhibiting CYP3A4, ritonavir inhibits metabolism of co-administered PIs which increases drug exposure, prolongs t1/2, and allows for reduction in dosing frequency.
47
Q

What are the ADRs of PIs?

9 (dear god)

A
  1. mild to moderate nausea
  2. diarrhea
  3. dyslipidemia
  4. altered fat distribution
  5. hyperglycemia and insulin resistance
  6. elevated serum transaminases
  7. increased risk of cardiovascular disease
  8. hepatotoxicity
  9. increased bleeding in hemophiliacs
48
Q

PI resistance development is intermediate between NRTIs and NNRTIs, what is required for high level resistance?

A

minimum 4-5 codon substitutions

49
Q

Describe the complex process of HIV entry to host cells.

A
  1. The virus attaches to the host, binding the viral envelope glycoprotein complex gp160 (gp120 and gp41) to its cellular receptor CD4.
  2. Binding produces conformational changes in gp120 which allows access to chemokine receptors, CCR5 or CXCR4.
  3. Co-receptor binding provides further conformational change exposing gp41 and leading to viral envelope fusion to host cell membrane and viral entry.
50
Q

One type of entry inhibitor is Enfuvirtide, what is its MOA?

A
  1. binds gp41 subunit; prevents conformational changes necessary for viral and cellular membrane fusion.
51
Q

Maraviroc is an entry inhibitor. What is its MOA?

A

selectively binds CCR5 preventing viral entry into host cell.

52
Q

What strains is Maraviroc active against? Inactive?

A
  1. Only active against viral strains which use CCR5 exclusively;
  2. inactive against those with CXCR4, dual, or mixed tropism. Must undergo specific testing before treatment is initiated.
53
Q

How is Maraviroc metabolised?

A

CYP3A4 - so, will see drug drug interactions

54
Q

What are the ADRs associated with Maraviroc?

7

A
  1. Cough
  2. URI
  3. Muscle and joint pain
  4. diarrhea
  5. sleep disturbances
  6. elevated serum aminotransferases
  7. Theoretical risk of decreased immune surveillance d/t CCR5 binding, leading to increased risk of malignancy or infection. (NO EVIDENCE OF INCREASED RISK SO FAR THOUGH)
55
Q

​HIV Integrase Strand Transfer Inhibitors (INSTIs) include dolutegravir (DTG), elvitegravir (EVG), raltegravir (RAL). What is their MOA?

A

Binds integrase, prevents integration of reverse-transcribed HIV DNA into host cell chromosomes

56
Q

How are the INSTIs metabolized?

A

CYP3A4 and UGT1A1

57
Q

ADR’s of INSTIs?

A

Usually well tolerated

  1. Headache
  2. GI effects
58
Q

In order to reduce risk of acquiring HIV for adults, preexposure prophylaxis (PrEP) can be employed. Who is this recommended for?

A
  1. High risk, sexually-active, adult men who have sex with me (MSM) (copied directly from wallers dsa)
  2. High risk, heterosexually-active, men and women
  3. High risk, injection drug users (IDU)
  4. HIV-discordant couples (heterosexually-active women and men whose partners are known to have HIV infection) to protect the uninfected partner

(Uhhh, Steve, you want to tell us a little bit about #1? Did you mean Michael?)

59
Q

Before starting PrEP, current HIV infection must be excluded. What is the regimen given for this prophylaxis?

A

Combination of Tenofovir DF and Emtricitabine

60
Q

Patients undergoind PrEP must be monitored every three months. What can happen if the patient becomes HIV positive?

A

Two drug regimen becomes inadequate and can produce resistance. Must adjust the patients antiretroviral regimen.

61
Q

Postexposure Prophylaxis (PEP) is also possible, in what situations is this typically employed?

A

Healthcare personnel

Nonoccupational exposure

62
Q

What are the indications for PEP in healthcare personnel?

A
  1. percutaneous,
  2. mucous membrane,
  3. non-intact skin exposure to body fluids of concern (e.g. blood or blood tinged fluids) if patient has known or is suspected of having HIV.
63
Q

If a patient has had a substantial exposure risk for HIV, what is the timeline within which NPEP is recommended?

A

Less than or equal to 72 hours

64
Q

What is the NPEP regimen recommendation?

A

Three-drug regimen for 4 weeks

65
Q

Women of childbearing potential who have HIV may use any form of contraception. However, what must be kept in mind?

A

NNRTIs and PIs have DDI with hormonal contraceptives which can lower contraceptive efficacy.

66
Q

What HIV drugs have no DDI with hormonal conraceptives?

A

NTRIs

Integrase inhibitors

CCR5 antagonists

67
Q

HIV-infected women contemplating pregnancy (why? Just why??) should be approached with what recommended treatment?

A
  1. combination antiretrovirals, maintain undetectable viral load prior to conception.

Goal: prevent progression of patient’s disease and reduce risk of perinatal transmission.

68
Q

To prevent perinatal transmission of HIV, the regimens recommended are generally the same as for non-pregnant women. However, there are risks associated with the drugs, what are three drugs that cause problems?

A
  1. PIs
  2. NRTIs
  3. Efavirenz
69
Q

What problems can PIs cause for a fetus?

A

Lead to hyperglycemia and premature birth

70
Q

NRTIs have what adverse affect that must be taken into account for a pregnant patient and her child?

A

Mitochondrial dysfunction

71
Q

What can Efavirenz do to a fetus?

A

Increased risk of neural tube defects. Should be avoided in first trimester if at all possible.

72
Q

What should women with elevated HIV RNA near delivery recieve?

A

Zidovudine IV

73
Q

What should all HIV exposed neonates recieve? For how long?

Any other things that must be considered?

A

Zidovudine for 6 weeks

breast feeding not recommended

Respiratory II - Exam 2 (13 decks)

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