Term
| What is the antiretroviral line up like? |
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Definition
Nucleoside/-tide Reverse Transcriptase Inhibitors (NRTIs):
Abacavir, Tenofovir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Zidovudine.
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs):
Delavirdine, Efavirenz, Etravirine, Nevirapine.
Protease Inhibitors:
Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir.
Fusion Inhibitors: Enfuvirtide, Maraviroc.
Integrase Inhibitor: Raltegravir |
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Term
| How do the Nucleoside/-tide Reverse Transcriptase Inhibitors (NRTIs) work? |
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Definition
Analog of native ribosides but lack 3`OH thus terminates elongation; renal excretion; A/Es are due to inhibition of mitochondrial DNA polymerase (peripheral neuropathy, pancreatits, lipoatrophy); other A/Es include liver toxicity (lactic acidosis, hepatomegaly with steatosis);
Drug Interactions: Not many (except with zidovudine + tenofovir);
Resistance: Most common mutation at viral codon 184: lamivudine
(restores sensitivity to zidovudine + tenofovir),
Cross-resistance between agents of same analog class can occur |
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Term
| Zidovudine (3'azido-3'deoxythymidine, ZDV, AZT) |
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Definition
Used as prophylaxis and in preventing prenatal infection.
Well absorbed and crosses BBB, T1/2 of 1-3 hrs, Glucuronylated by liver + excreted in urine.
Adverse effects:
Bone marrow suppression (neutropenia, anemia), headaches, GI intolerance
Contraindications:
Toxicity potentiated by coadmin. of probenecid, acetaminophen, lorazepam, indomethacin + cimetidine.
Stavudine + ribavirin activated by same pathways |
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Term
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Definition
Strong inhibitor of β and γ DNA polymerases (decreases
mitochondrial DNA synthesis |
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Term
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Definition
PK:
Absorption best if taken in fasting state (acid labile) or combined with antacid, Penetrates into CSF (less than AZT), 55% excreted in urine.
Adverse Effects:
Pancreatitis (can be fatal – monitor serum amylase),
Dose limiting toxicity – peripheral neuropathy,
GI intolerance
Contraindications(???):
Stavudine (similar toxicities) |
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Term
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Definition
Nucleotide analog. Inhibits HIV reverse transcriptase.
Pharmacokinetics:
Should be taken with food (increase bioavailability),
Long t1/2 |
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Term
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Definition
Terminates synthesis of proviral DNA chain + inhibits HIV + HBV,
RT (DOES NOT affect mitochondrial DNA synthesis or bone marrow precursor cells).
Clinical Applications:
Approved for treatment of HIV in combination with AZT (should not be used with other cytosine analogs)
Resistance:
High level resistance occurs with single amino acid substitutions.
Emtricitabine (FTC) = structural relative of 3TC (can be taken once-a-day) |
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Term
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Definition
Guanosine analog. May be cross-resistance with strains resistant to AZT + 3TC.
Adverse Effects:
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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Term
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Definition
MOA:
Highly selective, noncompetitive inhibitors of HIV-1 RT.
DO NOT REQUIRE ACTIVATION BY CELLULAR
ENZYMES.
Advantages:
Lack of effect on host blood-forming elements,
Lack of cross resistance with NRTIs.
Disadvantages:
Cross-resistance with NNRTIs,
Drug Interactions,
High incidence of hypersensitivity reactions (eg, rash) |
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Term
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Definition
Used in combo to Tx HIV-1, Well absorbed orally w/out effects from food or antacids. Crosses BBB, excreted mainly as a metabolite (CYP 3A4 + CYP 2B6 (?)). A/Es: Severe hepatotoxicity (don’t use in women with CD4+ counts >250 cells/mm3 + men >400 cells/mm3), Rash (16%), fever, headache, Dermatologic effects (Stevens-Johnson syndrome + toxic epidermal necrolysis) 14 day titration period at ½ dose is mandatory to reduce risk of serious epidermal rxn.
Contra: Inducer of CYP3A4. Increases metabolism of PI’s (no dosage adjustment necessary), OC, ketoconazole, methadone, metronidazole, quinidine, theophylline + warfarin
Resistance: Target site is HIV-1 specific + not essential to enzyme |
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Term
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Definition
Preferred NNRTI on DHHS guidelines (results in increased CD4+ counts + decrease in viral load)
PK: Well distributed after oral admin. (bioavailability enhanced when taken with fatty meal), 99% bound to plasma albumin at therapeutic doses, T1/2 >40h (once-a-day dosing), Extensively metabolized to inactive products.
A/Es: Mostly CNS (50%) (dizziness, headache, vivid dreams, loss of concentration) – resolve after few weeks. Rash (25%)
Contra: Potent inducer of CYP P450 enzymes. Pregnancy (D) (can be used after 1st trimester) |
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Term
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Definition
MOA: Reversible inhibitors of HIV aspartyl protease (enzyme responsible for cleavage of viral polyprotein into RT, protease + integrase), Inhibition prevents maturation + results in production of non-infectious virions. PK: Poor oral bioavailability, High-fat meals can increase (nelfanvir + saquinavir) and decrease (indinavir) bioavailability, Substrates for CYP 3A4 (very little excreted unchanged), Substrates for P-glycoprotein pump, Bound to plasma proteins (α1-acid glycoprotein – can increase in response to trauma + surgery).
A/Es: Parathesias, nausea, vomiting, diarrhea; Disturbance in lipid metabolism (diabetes, hypertriglyceridemia, hypercholesterolemia); Chronic admin |
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Definition
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Definition
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Term
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Definition
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Term
| How does Enfuvirtide (T-20) work? |
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Definition
First approved drug that inhibits viral attachment.
Approved for use in treatment-experienced adults with evidence
of HIV replication.
MOA:
Structurally similar to gp41 (HIV protein mediates membrane fusion),
Prevents ability of virion to fuse membranes.
Pharmacokinetics:
Has to be administered parenterally (twice daily subcutaneous injections)
Adverse Effects:
Injection-related (3% discontinue),
Hypersensitivity reactions (rarely),
Eosinophilia has been noted. |
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Term
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Definition
MOA:
Blocks CCR5 coreceptor that works with gp41 to facilitate HIV entry through cell membrane (only CCR5-expressing
virus can be treated with maraviroc)
Pharmacokinetics:
Well absorbed orally,
Metabolized by CYP 3A4 (dose reduced when given with PIs)
Adverse Effects:
Well tolerated, risk of hepatotoxicity |
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Term
| How does Raltegravir work? |
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Definition
Clinical Applications:
In combination with other antiretrovirals is approved for
treatment-experienced and treatment-naive patients with evidence of viral replication.
MOA:
Specifically inhibits final step in integration of viral DNA into host cell DNA.
Pharmacokinetics:
t1/2 = ~9h |
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Term
| What's the Combo therapy? |
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Definition
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Term
| What is the HIV prophylaxis guidelines? |
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Definition
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