Antiretrovirals Flashcards
When should you start HIV treatment?
when CD4+ count drops below 500; or in pregnant women, patient with AIDS-defining illness, HBV-HIV co-infection, or nephropathy
MOA of Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Analogs of native ribosides; lack 3’OH group –> chain termination (act as reversible competitive inhibitors of RT)
Require phosphorylation by cellular enzymes –> incorporated into DNA by RT
Which viruses are NRTIs active against?
HIV-1 and HIV-2
Most common resistance mechanisms of NRTIs
Mutation at viral codon 184
Resistance to which drug restores sensitivity to Zidovudine and Tenofovir?
Lamivudine (Nucleoside/Nucleotide analog used against Hepatic infections)
Which NRTI is especially associated with myelosuppression?
Zidovudine
Which NRTI increases levels of Didanosine? (Drug Interaction)
Tenofovir
AE of NRTIs
inhibition of mitochondrial DNA polymerase ==> peripheral neuropathy, lipoatrophy, myopathy, and lactic acidosis
Pancreatitis, Cardiomyopathy
Which NRTIs are particularly associated with insulin resistance and dyslipidemia?
Zidovudine and Stavudine
What must be monitored while taking NRTIs?
serum creatinine
True or False: NRTIs are metabolized by CYP450 enzymes.
False
Contraindications of Zidovudine
Co-administration with Probenicid, Acetaminophen, Lorazepam, Indomethacin, and Cimetidine;
Since Stavudine and Ribavirin are activated by same pathways as Zidovudine, might reduce active levels of Zidovudine
AE of Zidovudine
Bone marrow suppression, insomnia, insulin-resistance
Thymidine analog (for HIV treatment) that crosses BBB
Zidovudine; doses must be adjusted in patients with cirrhosis
Thymidine analog (for HIV treatment) whose dosage must be adjusted in renal insufficiency
Stavudine
MOA of Stavudine
Strongly inhibits beta and gamma DNA polymerases; has high affinity for mitochondrial DNA polymerase, which can lead to toxicity
PK/PD of Stavudine and Zidovudine
Oral administration
AE of Stavudine
Peripheral neuropathy, lactic acidosis, insulin-resistance, neuromuscular weakness, hyperlipidemia
Adenosine analog (for HIV treatment) that crosses the BBB and penetrates the CSF
Didanosine
Acid labile Antiretroviral best taken with antacid or while fasting
Didanosine
AE of Didanosine
Pancreatitis in alcoholics and patients with hypertriglyceridemia
Which 2 NRTIs have a high affinity for mitochondrial DNA polymerase?
Didanosine and Stavudine
NRTI; Adenosine analog preferred in current regimens (for HIV treatment)
Tenofovir
Fixed dose combinations of Tenofovir
Tenofovir + Emtricitabine & Tenofovir + Emtricitabine + Efavirenz
Tenofovir drug interactions
Increases Didanosine concentration ; decreases Atazanavir concentration (give Ritonavir as booster)
NRTIs
Tenofovir, Stavudine, Didanosine, Zidovudine, Lamivudine, Emticitabine, Abacavir
NRTI taken with food to increase oral bioavailability
Tenofovir
Cytosine analog (for HIV treatment) that does not affect mitochondrial synthesis or bone marrow
Lamivudine
AE of Lamivudine
Headache, dry mouth
Cytosine analog; preferred NRTI used in current regimens
Emtricitabine
AE of Emtricitabine
Hyperpigmentation of palms and soles (especially in dark skinned individuals)
Guanosine analog that is an NRTI
Abacavir
AE of Abacavir
Hypersensitivity Rxns; should not rechallenged sensitized individuals
Non-competitive Inhibitors of HIV-1 Reverse Tramscriptase
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
MOA of NNRTIs
Inhibit RNA and DNA-dependent DNA Polymerase; bind at same allosteric site (NNRTI pocket). DO NOT REQUIRE PHOSPHORYLATION by cellular enzymes
CYP3A4 substrates that act as inhibitors, inducers, or both
NNRTIs
True or False: NNRTIs have cross resistance with NRTIs.
False; they have different binding sites.
Common AE of NNRTIs
Steven-Johnson syndrome (rash), hypersensitivity rxns
Dosing for Emtricitabine
Once a day
NNRTIs extensively metabolized to inactive products
Rilvipirine and Efavirenz
AE of Rilvipirine
Insomnia, depression, increased liver enzymes, rash
PK/PD of Rilvipirine
Oral administration
NNRTI that induces CYP3A4; metabolized by CYP3A4 and CYP2D6
Nevirapine
AE of Nevirapine
Severe hepatotoxicity, Steven Johnson syndrome (titrate at half dose for 14 days to reduce risk)
Contraindications of Nevirapine
Women with CD4 > 250 and Men with CD4 > 400
Drug interactions of Nevirapine
Increases metabolism of Protease Inhibitors, oral contraceptives, Ketoconazole, Methadone, Metronidazole, Quinidine, Theophylline, and Warfarin
Oral NNRTI with long half-life
Efavirenz –> once daily dosing
NRTI that is potent CYP inducer and results in reduced viral load and increased CD4 count
Efavirenz
AE of Efavirenz
Vivid dreams, possible suicidality, rash, increased TGs, HDL, and cholesterol
Contraindications of Efavirenz
Pregnancy (Category D) –> use after 1st trimester
Protease Inhibitors (for HIV treatment)
Ritonavir, Atazanavir, Indinavir, Nelfinavir, Lopinavir, Darunavir
MOA of Protease Inhibitors
Reversibly inhibit aspartyl protease that cleaves polyprotein into Integrase, Reverse Transcriptase, and Protease
Prevent virus maturation, leading to production of non-infectious visions
Which viruses are Protease Inhibitors active against?
HIV-1 and HIV-2
True or False: Protease Inhibitors require intracellular activation
False
PK/PD of Protease Inhibitors
Poor oral bioavailability affected by fatty foods;
Substrates for CYP3A4 and P-glycoprotein pump;
Bound to plasma proteins (alpha 1 acid glycoprotein, which is increased after trauma/surgery)
AE of Protease Inhibitors
Paresthesias, disturb lipid metabolism, fat redistribution and accumulation–> buffalo hump and cushingoid appearance
Contraindications of Protease Inhibitors
Rifampin and St. John’s Wort
Drug Interactions of Protease Inhibitors
Inhibitors and Substrates for CYP isoforms; Rhabomyolysis with statins, excessive sedation with Midazolam and Triazolam, Respiratory depression with Fentanyl;
Adjust doses of Warfarin, Sildenafil, and Phenytoin
Resistance mechanisms against Protease Inhibitors
Stepwise accumulation of mutations in protease gene
PK Enhancers
Ritonavir and Cobicistat
MOA of PK Enhancers
Inhibit CYP3A4 to increase Antiretroviral concentration –> lower and less frequent dosing; improve tolerability of Antiretrovirals
How is Ritonavir administered?
In combination with Protease Inhibitors except Nelfavinir; never used alone
How is Cobicistat administered?
In combination with the Integrase Strand Transfer Inhibitor (INSTI) Eltegravir; also in combination with Atazanavir and Darunavir
Protease Inhibitor contraindicated in patients with a Sulfa-allergy
Darunavir
PK of Atazanavir
Well absorbed with food; structurally unrelated to other Protease Inhibitors; metabolized and inhibits CYP3A4
True or False: Atazanavir can be co-administered with H2- blockers and antacids.
False; Atazanavir must be administered more than 12 hours apart from H2-blockers and antacids
AE of Atazanavir
PR interval prolongation, rash, nephrolithiasis, hyperbilirubinemia
Clincal application of Atazanavir`
Given with Ritonavir
Clinical application of Darunavir
Inhibits HIV protease resistant to other Protease Inhibitors
PK of Darunavir
Well absorbed with food; metabolized and inhibits CYP3A4
Drug interactions of Atazanvir
Inhibits PPIs
Clinical Application of Indinavir (same as Atazanavir)
Given with Ritonavir
PK of Indinavir
Absorption decreased when taken with food, especially fatty meals
Contraindications of Indinavir
Reduce dose in hepatic insufficiency
AE of Indinavir
Blurred vision, Nephrolithiasis, hyperbilirubinemia, rash
One of preferred Protease Inhibitors; given with Ritonavir
Lopinavir
PK of Lopinavir
Poor intrinsic bioavailability
Contraindications of Lopinavir
Enzyme inducers such as St. John’s Wort; avoid Disulfiram and Metronidazole (oral solution contains alcohol)
AE of Lopinavir
GI effects
Protease Inhibitor that cannot be boosted by Ritonavir
Nelfinavir
PK of Nelfinavir
Metabolized by several CYPs; oral bioavailability increased by fatty meals
Protease Inhibitor whose metabolite has equal antiretroviral activity to parent compound
Nelfinavir
Metabolite of Nelfinavir
CYP2C19
Contraindications of Nelfinavir
Numerous!
AE of Nelfinavir
Diarrhea (controlled by Loperamide), nausea, flatulence
Antiretroviral that acts as Fusion Inhibitor
Enfuviritide (T-20)
Activity of Enfuviritide
HIV-1
MOA of Enfuviritide
Structurally similar to gp41; binds gp41 on viral envelope to prevent virion fusion with cell membrane
AE of Enfuviritide
Injection-related (discontinue), hypersensitivity rxns, and eosinophilia; no drug interactions with other Antiretrovirals
PK of Enfuviritide
Parenteral administration only
Antiretroviral that acts as Entry Inhibitor
Maraviroc
MOA of Maraviroc
Binds selectively and specifically to CCR5 co-receptor, blocking HIV entry
PK of Maraviroc
Metabolized by CYP3A4 –> reduce dose when given with Protease Inhibitors
AE of Maraviroc
Well-tolerated; risk of hepatotoxicity
True or False: Enfuviritide is approved for treatment-experienced adults with evidence of HIV replication
True
Antiretroviral class with good side effect profile and favorable effects on lipid metabolism
Integrase Strand Transfer Inhibitors (INSTIs)
True or False: INSTIs are approved for treatment-experienced and treatment-naive patients with evidence of viral replication
True
MOA of INSTIs
Bind Integrase (in HIV-1 and HIV-2) and inhibit last step in integration of viral DNA in to host DNA
AE of INSTIs
Generally well tolerated (rash, nausea, headache, insomnia, diarrhea) or increases creatinine phosphokinases
INSTIs
Dolutegravir, Elvitegravir, Raltegravir
PK of Dolutegravir
Primarily eliminated by glucuronidation by UGT1A1 and some contribution from CYP3A4
AE of Dolutegravir
Well tolerated; discontinue if organ dysfxn occurs
Why do drug interactions occur with Dolutegravir?
Due to CYP3A4 interactions
PK of Elvitegravir
Primarily metabolized by CYP3A and may require enhancing via Cobicistat
Protease Inhibitor and PK Enhancer
Ritonavir
Why do drug interactions occur with Elvitegravir?
Due to CYP interactions
PK of Raltegravir
Primarily eliminated by glucuronidation by UGT1A1 enzyme (like Doltegravir)
AE of Raltegravir
Well tolerated; can cause increases in creatinine phosphokinases
Drug interactions of Raltegravir
Rifampin, Tipranavir, and Efavirenz may decrease Raltegravir concentration; PPIs may increase Raltegravir concentration
Current Recommendations for Treatment-naive patients
2NRTIs + INSTI or 2NRTIs + Protease Inhibitor
INSTI-based regimens for Treatment-naive patients
Raltegravir or Dolutegravir + Tenofovir + Emtricitabine
Protease-based regimen for Treatment-naive patients
Ritonavir-boosted Darunavir + Tenofovir + Emtricitabine
Treatment recommended for Infant born to HIV infected mother
Zidovudine, immediately after birth for 6 weeks
Post-exposure prophylaxis for HIV
Raltegravir + Tenofovir + Emtricitabine; give for 28 days and stop if source is found to HIV negative
Prophylactic vaccines recommended for HIV patients
S. pneumoniae, HAV, HBV, Influenza
Contraindicated vaccines in patients with CD4 count < 200
MMR, Varicella, and Zoster
