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Pharm S2015 > Antiretrovirals > Flashcards

Antiretrovirals Flashcards

1
Q

Course of HIV infection

A

Goal of pharmacotherapy is to extend clinical latency

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2
Q

HIV treatment

A

Therapy is usually initiated when CD4+ cells ≤500 cellsmm3

Regardless of CD4 count, initiation of therapy is strongly recommended for individuals with the following conditions:

• Pregnancy

  • History of an AIDS-defining illness
  • HIV-associated nephropathy (HIVAN)
  • HIV/hepatitis B virus (HBV) co-infection

Current Rx recommendation for HIV: PI + 2 NRTI

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3
Q

Current HIV drugs

A

**Nucleoside/-tide Reverse Transcriptase Inhibitors (NRTIs): **Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine,Tenofovir, Zidovudine

  • Zidovudine (ZDV): T analog; formerly AZT
  • Stavudine (d4T): T analog
  • avoid Zidovudine and Stavudine combinations
  • avoid didanosine and Stavudine combinations: additive neuropathy and potentially fatal pancreatitis
  • Emtricitabine (FTC): C analog
  • Lamivudine (3TC): C analog
  • avoid FTC and 3TC combinations
  • Abacavir (ABC): G analog

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs): Delavirdine, Efavirenz, Etravirine, Nevirapine

Protease Inhibitors: Atazanavir, Darunavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Tipranavir

Entry Inhibitors: Enfuvirtide, Maraviroc

**Integrase Inhibitor: **Raltegravir

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4
Q

NRTI

A
  • Analogs of native ribosides (lack 3’OH)
  • includes Didanosine, Tenofovir, Abacavir
  • Require intracytoplasmic activation via phosphorylation by cell enzymes and incorporated into viral DNA by reverse transcriptase
  • Lack of 3’OH terminates DNA elongation, ie. they are competitive inhibitors of reverse transcriptase
  • Most have activity against HIV-2 as well as HIV-1

Resistance/PK

  • Emerges rapidly if used alone
  • Most common mutation at viral codon 184: lamivudine (restores sensitivity to zidovudine & tenofovir)
  • Cross-resistance between agents of same analog class can occur
  • PK: Dosage adjustments required with renal insufficiency
  • Note: require oral drugs since HIV + Pt take drugs the rest of the life (IV is impractical)
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5
Q

NRTI - Adverse & interactions

A
  • inhibit mitochondrial DNA polymerase γ (didanosine & stavudine highest affinity)
  • AE mainly due to inhibition of mitochondrial DNA polymerase: peripheral neuropathy, myopathy, lipoatrophy & lactic acidosis
  • Pancreatitis, myelosuppression & cardiomyopathy can also occur
  • Liver toxicity is rare but fatal (lactic acidosis, hepatomegaly with steatosis).
  • Zidovudine & stavudine may be particularly associated with dyslipidemia & insulin resistance.

Drug interactions

  • Didanosine & tenofovir: Tenofovir increases plasma didanosine levels ~60%.
  • Doses of didanosine have to be reduced.
  • NRTIs are not generally metabolized by cytochrome enzymes
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6
Q

Zidovudine (ZDV, AZT)

A

Nucleoside Analog: Thymidine

Pharmacokinetics

  • Oral
  • Penetrates well across BBB
  • Dosage adjustments required in patients with cirrhosis
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7
Q

Zidovudine - Adverse effects

A
  • Bone marrow suppression (neutropenia, anemia)
  • Concurrent administration with ganciclovir can result in additive neutropenia.
  • GI intolerance, headaches, insomnia

Contraindications

  • Toxicity potentiated by coadmin. of probenecid, acetaminophen, lorazepam, indomethacin & cimetidine.
  • Stavudine & ribavirin activated by same pathways (might reduce active levels of zidovudine)
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8
Q

Stavudine (d4T)

A
  • Strong inhibitor of beta and gamma DNA polymerases (high affinity for mitochondrial DNA polymerase, which can lead to toxicity)
  • Nucleoside Analog: Thymidine

Pharmacokinetics

  • Oral
  • Dosage adjustment required in renal insufficiency
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9
Q

Stavudine (d4T) - Adverse

A
  • Peripheral neuropathy, lactic acidosis
  • Hyperlipidemia, neuromuscular weakness
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10
Q

Didanosine (DDL)

A

Nucleoside Analog: Adenosine

Pharmacokinetics

  • Absorption best if taken in fasting state (acid labile) or combined with antacid
  • Penetrates into CSF
  • Dosage adjustment required in renal insufficiency
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11
Q

Didanosine - Adverse

A

High affinity for mitochondrial DNA polymerase

  • Pancreatitis (esp. alcoholics and patients with hypertriglyceridemia)
  • Peripheral neuropathy, diarrhea, hepatic dysfunction
  • CNS effects
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12
Q

Tenofovir (TDF)

A
  • One of preferred NRTIs in currently recommended regimens
  • Nucleotide Analog: Adenosine

Fixed-Dose Combinations Available

  • Tenofovir + emtricitabine
  • Tenofovir + emtricitabine + efavirenz

PK

  • Should be taken with food to increase bioavailability
  • Long t1/2 (can dose once daily)
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13
Q

Tenofovir - Adverse & contraindications

A

Adverse Effects: GI (nausea, diarrhea, vomiting, flatulence)

Contraindications

  • Serum creatinine monitored with renal insufficiency
  • Only NRTI with sig. drug interactions (increases didanosine concentrations and dosage reductions are usually required)
  • Decreases concentrations of atazanavir. Atazanavir can be ‘boosted’ with ritonavir
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14
Q

Lamviduine (3TC) including adverse

A
  • DOES NOT affect mitochondrial DNA synthesis or bone marrow precursor cells
  • Nucleoside Analog: Cytosine
  • Resistance: High level resistance occurs with single amino acid substitutions

PK: Dosage adjustment required with renal insufficiency

Adverse: Few significant (headache, dry mouth)

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15
Q

Emtricitabine (FTC) including Adverse

A
  • Structural relative of lamivudine
  • One of preferred NRTIs in currently recommended regimens
  • Nucleoside Analog: Cytosine
  • Pharmacokinetics: Once-a-day administration
  • Adverse: Hyperpigmentation of palms and soles (occurs most frequently in dark-skinned people)
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16
Q

Abacavir (ABC) including Adverse

A
  • Nucleotide Analog: Guanosine
  • Resistance: HIV resistance requires several mutations and tends to develop slowly.

Adverse

  • GI, headache, dizziness
  • 5% - ‘hypersensitivity’ reaction (one or more of rash, GI, malaise, respiratory distress).
  • Sensitized individuals should NEVER be rechallenged (can be genetically screened)
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17
Q

NNRTIs

A
  • includes Nevirapine, Efavirenz, Delaviridine, Etravirine, Rilpivirine

MOA

  • Highly selective, noncompetitive inhibitors of HIV-1 RT
  • Bind at a distinct site away from active site (NNRTI pocket)
  • All NNRTI’s bind within the same pocket
  • All result in inhibition of RNA- and DNA-dependent DNA polymerase
  • DO NOT REQUIRE PHOSPHORYLATION BY CELLULAR ENZYMES
  • Lack in vitro activity against HIV-2

Advantages

  • Lack of effect on host blood-forming elements
  • Lack of cross resistance with NRTIs (binding sites are distinct)

Disadvantages

  • Cross-resistance with NNRTIs
  • Drug interactions
  • High incidence of hypersensitivity reactions (eg, SJS rash)
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18
Q

NNRTI Adverse

A
  • Skin rash (including Stevens-Johnson syndrome)
  • GI intolerance
  • All are CYP3A4 substrates and can act as inducers, inhibitors or both of CYPs
    • inducers (nevirapine)
    • inhibitors (delavirdine)
    • mixed inducers and inhibitors (efavirenz, etravirine).
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19
Q

Nevirapine (NVP) including contraindications

A

Pharmacokinetics: Excreted mainly in urine as metabolites (CYP 3A4 & CYP 2B6)

Adverse Effects

  • Potential severe hepatotoxicity (don’t use in women with CD4+ counts >250 cells/mm3 & men >400 cells/mm3)
  • Rash (16%), dermatologic effects (Stevens-Johnson syndrome & toxic epidermal necrolysis)
  • 14 day titration period at 1⁄2 dose is mandatory to reduce risk of serious epidermal reactions

Resistance: Target site of nevirapine is HIV-1 specific & not essential to enzyme (reverse transcriptase), thus mutations and resistance can develop rapidly

Contraindications

  • Inducer of CYP 3A4
  • Increases metabolism of PI’s (no dosage adjustment necessary), oral contraceptives, ketoconazole, methadone, metronidazole, quinidine, theophylline & warfarin
20
Q

Delaviridine (DLV)

A

Clinical Applications: Not as widely used as other NNRTIs due to short t1/2 Pharmacokinetics

  • Well absorbed orally (especially at pH <2; antacids, H2 blockers etc may decrease absorption)
  • Excreted mainly in urine as metabolites (CYP 3A4 & 2D6)
  • Non-linear PK (t1/2 increases with increasing doses)
21
Q

Delaviridine - Adverse

A

Adverse Effects

  • Rash (18-36%), Stevens-Johnson syndrome & toxic epidermal necrolysis
  • Fever, headache & depression also common
  • Teratogenic

Contraindications

  • Inhibitor of and substrate of CYP3A4
  • CYP 3A4 inducers (eg, rifampin, phenytoin) may decrease delavirdine concentrations
  • Pregnancy (Cat C)

Resistance: Target site of delavirdine is HIV-1 specific & not essential to enzyme (reverse transcriptase) therefore resistance develops rapidly

22
Q

Etravirine (ETV)

A

Clinical Applications

  • Approved for use in treatment-experienced patients
  • May be effective against HIV strains resistant to first-generation NNRTIs

Pharmacokinetics

  • Metabolized by CYP 3A4, 2C9 and 2C19
  • Metabolites have ~10% HIV activity of parent compound
23
Q

Etravirine - Adverse

A
  • Rash (normally resolves within 1-2 weeks), nausea, diarrhea
  • Transaminase elevations (esp. in patients co-infected with hepatitis)

Contraindications

  • CYP 3A4 inducer
  • CYP 2C9 and 2C19 inhibitor
  • Some interactions are difficult to predict
24
Q

Efavirenz (EFV)

A

Clinical Applications

  • Preferred NNRTI on DHHS guidelines
  • Results in increased CD4+ counts & decreased viral load

Pharmacokinetics

  • Oral
  • t1/2 >40h (once-a-day dosing)
  • Extensively metabolized to inactive products
25
Q

Efavirenz - Adverse

A

Adverse Effects

  • Mostly CNS (50%) (dizziness, headache, vivid dreams, loss of concentration) – resolve after few weeks.
  • Rash (25%)
  • Increased triglycerides, HDL and total cholesterol (lipid levels must be monitored at beginning of and during therapy)
  • also teratogenic

Contraindications

  • Potent inducer of CYP P450 enzymes.
  • Pregnancy (D) (can be used after 1st trimester if considered best choice)
26
Q

Protease inhibitors (PI)

A

MOA

  • Reversible inhibitors of HIV aspartyl protease (enzyme responsible for cleavage of viral polyprotein into RT, protease & integrase)
  • Protease inhibition prevents virus maturation & results in production of non-infectious virions
  • DO NOT REQUIRE INTRACELLULAR ACTIVATION
  • Active against both HIV-1 and HIV-2

PK

  • includes ritonavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, tipranavir
  • Poor oral bioavailability
  • High-fat meals can increase (nelfinavir) or decrease (indinavir) bioavailability
  • Substrates for CYP 3A4
  • Substrates for P-glycoprotein pump
  • Bound to plasma proteins (alpha1-acid glycoprotein which can increase in response to trauma & surgery)

Resistance: Accumulation of stepwise mutations of protease gene. Can lead to high levels of resistance.

27
Q

Protease Inhibitors - Adverse & Interactions

A
  • Parathesias, nausea, vomiting, diarrhea
  • Disturbances in carb & lipid metabolism (diabetes, hypertriglyceridemia, hypercholesterolemia); all PI cause diabetes
  • Chronic admin -> similar to cushingnoid appearance; fat redistribution & accumulation resulting in central obesity, dorsocervical fat enlargement (buffalo hump), peripheral & facial wasting, breast enlargement and a cushingoid appearance
  • Atazanavir has less side effects than other PI’s

Drug interactions

  • Potent inhibitors and substrates of CYP isoforms including 3A4 eg, rhabdomyolysis (simvastatin or lovastatin), excessive sedation (midazolam or triazolam), respiratory depression (fentanyl)
  • Warfarin, sildenafil & phenytoin require dosage adjustments
  • Rifampin & St.Johns Wort are contraindicated
28
Q

Atazanavir (ATV)

A

Clinical application: ATV + RTV are only once-daily preferred PIs

PK:

  • Structurally unrelated to other PIs
  • Well absorbed with food
  • Highly protein bound

**Contraindications: Less incidence of side-effects than other PIs **

  • Metabolized by & inhibits CYP3A4
  • PPI
  • Admin. must be > 12h apart from H2- blockers & antacids
29
Q

Ritonavir

A
  • PI
  • Clinical application: PK enhancer/ booster of other PI’s
  • PK: Potent inhibitor of CYP3A4
  • Contraindications: Numerous (due to inhibition of CYP)
30
Q

Darunavir (DRV)

A
  • PI
  • Clinical application: Inhibits HIV protease resistant to other PIs
  • PK: Well absorbed with food
  • Contraindications: Metabolized & inhibits CYP3A4
31
Q

Indinavir (IDV)

A
  • PI
  • Clinical application: Given with RTV

PK:

  • Least protein bound (60%)
  • Absorption
  • decreased when taken with meals

Contraindications: Dosage should be reduced with hepatic insufficiency

  • Special adverse effects: Well-tolerated, Nephrolithiasis & hyperbilirubinemia (adequate hydration important)
32
Q

Lopinavir (LPVr)

A

PI

Clinical application:

  • One of preferred PIs.
  • Given with RTV

PK: Poor intrinsic bioavailability

Contraindications:

  • Enzyme inducers (St Johns Wort) should be avoided.
  • Oral solution contains EtOH (avoid disulfiram or metronidazole)
33
Q

Nelfinavir (NFV)

A

PI

**Clinical application: **Cannot be boosted by RTV

**PK: **

  • Metabolized by several CYPs
  • Major metabolite (CYP2C19) has antiviral activity equal to parent compound

**Contraindications: **Numerous (due to inhibition of CYP)

**Specific adverse effects: **Diarrhea (controlled by loperamide), nausea, flatulence

34
Q

Tipranavir (TPV)

A

PI

**Clinical application: **

  • Inhibits HIV protease resistant to other PIs
  • Twice-daily with RTV

**PK: **Well absorbed with food

**Contraindications: **Inducer of CYP P450

**Specific Adverse Effects: **Severe and fatal hepatitis; fatal & nonfatal intracranial hemorrhages

35
Q

Entry/Fusion inhibitors

A
  • Fusion Inhibitor: Enfuvirtide
  • Entry Inhibitor: Maraviroc
36
Q

Enfuvirtide (T-20)

A
  • First approved drug that inhibits viral fusion
  • Approved for use in treatment-experienced adults with evidence of HIV replication
  • No activity against HIV-2

MOA

  • Structurally similar to gp41 (HIV protein mediates membrane fusion)
  • Binds to gp41 subunit of the viral envelope glycoprotein, preventing ability of virion to fuse cell membrane

PK: Parenteral admin. only

37
Q

Enfuvirtide (T-20) - Adverse

A
  • Injection-related (3% discontinue)
  • Hypersensitivity reactions & eosinophilia rarely
  • No drug interactions with other antiretrovirals have been noted
38
Q

Maraviroc including Adverse

A

MOA

  • Binds specifically and selectively to CCR5 (one of two coreceptors necessary for entrance of HIV into CD4+ cells)
  • Result in blocking HIV entry (only CCR5-tropic virus can be treated with maraviroc)

**PK: **Metabolized by CYP 3A4 (reduce dose when given with PIs)

**Adverse: **Well tolerated, risk of hepatotoxicity

39
Q

Integrase Strand Transfer Inhibitor (INSTI) - Raltegravir (RAL)

A

Clinical applications: In combination with other antiretrovirals, raltegravir is approved for treatment-experienced and treatment- naive patients with evidence of viral replication

40
Q

Raltegravir (RAL)

A

INSTI

MOA

  • Binds integrase (enzyme essential to the replication of both HIV-1 and HIV-2)
  • Leads to specific inhibition of the final step in integration of viral DNA into host cell DNA

PK: Metabolism via UGT1A1-mediated glucuronidation

41
Q

Raltegravir (RAL)

A

Adverse Effects

  • Well tolerated (nausea, headache, diarrhea)
  • Can cause increases in creatine phosphokinase

Drug Interactions

  • Rifampin, tipranavir & efavirenz may decrease [raltegravir]
  • PPI’s may increase [raltegraivr]
42
Q

Current recommendations for treatment-naive Pt

A

Start with one of the following regimens:

(1) NNRTI & 2 x NRTI
(2) PI (preferably boosted with ritonavir) & 2 x NRTI (3) INSTI & 2 x NRTI

Selection is based on:

  • Avoiding the use of 2 agents of the same nucleotide analog
  • Avoiding overlapping toxicities and genotypic and phenotypic characteristics of the virus
  • Patient factors such as disease symptoms and concurrent illnesses
  • Impact of drug interactions; and
  • Ease of adherence to a frequently complex administration regimen

Preferred regimens

  • **NNRTI-based regimen: **Efavirenz + tenofovir + emtricitabine
  • PI-based regimen
  • (1) Ritonavir-boosted atazanavir + tenofovir + emtricitabine
  • (2) Ritonavir-boosted darunavir + tenofovir + emtricitabine
  • INSTI-based regimen: Raltegravir + tenofovir + emtricitabine
  • For pregnant Pt: Ritonavir-boosted lopinavir (twice daily zidovudine/lamivudine)
  • HIV infected mother: Zidovudine (start immediately after birth, 6 wk admin)
43
Q

HIV prophylaxis following needle stick

A
  • Postexposure prophylaxis regimen containing at least 3 antiretroviral drugs.
  • Preferred regimen (09/2013): Raltegravir + tenofovir + emtricitabine; given for 28 days and can be stopped if source is shown to be HIV-negative.
  • no longer require assessing the severity of exposure.
44
Q

HIV Prophylactic Vaccines

A
  • Streptococcus pneumoniae
  • Hepatitis A
  • Hepatitis B and
  • Influenza
  • are generally recommended for all HIV-infected patients
45
Q

Vaccines contraindicated in HIV+ Pt w CD4+ < 200 cells/mm3

A

Live vaccines eg,

  • MMR
  • Varicella and
  • Zoster

Other vaccines may be administered without regard to the patient’s CD4+

Pharm S2015 (47 decks)

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