HIV Pharm Flashcards
what are the treatment goals of ART
–maximally and durably suppress plasma HIV RNA
–restore and preserve immunologic function
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⇓HIV-associated morbidity and ⇑duration and quality of survival
–prevent HIV transmission
predictors of virologic success
–Low baseline viremia –High potency of the ARV regimen –Tolerabilityof the regimen –Convenience of the regimen –Excellent adherence to the regimen
NRTI target?
Nucleoside reverse transcriptase inhibitors
ART typically begins with 2 NRTIs as the back bone of the therapy
Binds to the DNA chain and terminates its production
good for preventing spread but does not eradicate already infected cells
must enter the cell and become phosphorylated
inhibit incorporation of native nucleotides and by terminating elongation (lack 3’OH group)
Toxicity of NRTI
depends on their abillity to affect host cell DNA polymerase
some mitochondrial DNA polymerases are inhibited (gamma)
emtricitabine, lamivudine, abacavirand tenofovirhave lower affinity for DNA polymerase γin various assays
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all have “black box” warnings due to possibility of lactic acidosis syndrome due to mitochondrial toxicity
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peripheral neuropathy due to mitochondrial toxicity
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pancreatitis due to mitochondrial toxicity
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anemia, granulocytopenia
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myopathy
… risks are much lower now with commonly used agents
Zidovudine
Mechanism of Action Effects Clinical Applications Pharmacokinetics Toxicities •nucleosidereverse transcriptase inhibitor, interferes with thymidineincorporation
•first antiretroviral drug discovered, found by screening nucleicacid analogs that had been generated as potential anticancer drugs
- inhibits incorporation of native nucleotides and also terminates elongation of nascent proviral DNA
- most potent in active cells since thymidine kinase is anS-phase specific enzyme
•inhibits HIV-1, HIV-2, HTLV-1 and HTLV-2
- FDA approved for:
- treatment of adults and children with HIV
- preventing mother-to-child transmissionduring childbirth
- post-exposure prophylaxis in HIV-exposed health care workers (large volume of data supporting efficacy)
- oldest drug but still in widespread use, especially in resource-poor settings, due to broad experience with drug and its well-known tolerability, toxicity and efficacy profiles
- well absorbed, extensive first-pass effect
- t1/2~ 3-4 hrs
- undergoes hepatic glucuronidation, excreted in urine as metabolites and someunchangeddrug
- only NRTI available IV
- common complaints are fatigue,malaise, myalgia, nausea, anorexia, headache, insomnia and loss of limb fat
- bone marrow suppression occurs primarily in those with advanced disease
- skeletal muscle myopathy occurs in association with mitochondrial DNA polymerase inhibition
- hepatic steatosis due to mitochondrial toxicity, potentially fatal
Stavudine
- nucleosidereverse transcriptase inhibitor, interferes with thymidineincorporation
- like AZT
- inhibits HIV-1, HIV-2
- t1/2 ~ 3.5 hrs
- absorbed well and penetrates well (e.g., CSF conc. ~40%)
•excreted in urine primarily as unchanged drug
- most common serious toxicity is peripheral neuropathy
- NRTI associated most strongly with lipodystrophy/fat wasting
- unsure if due to effects on mitochondria orsomething else
- reason stavudine has fallen out of favor
•lactic acidosis and hepatic steatosis have also been associated with its use
Emtricitabine
- nucleosidereverse transcriptase inhibitor, interferes with cytosineincorporation
- inhibits incorporation of native nucleotides and also terminates elongation of nascent proviral DNA
- FDA-approved fortreating HIV-1 and HIV-2 infected adults in combination
- low barrier to resistance if monotherapy (e.g., M184V)
- also active against HBV; discontinuation can cause rebound exacerbation of HBV
- co-formulatedwith tenofovir, NRTI combination that seems superior to others
- rapid, extensive absorption
- long intracellular half-life (~39 hrs) makes it a current NRTI of choice
- excreted primarily as unchanged drug in the urine
- one of theleast toxic antiretroviral agents, but >10%…
- headache
- nausea/diarrhea
- rash
- cough, nasal symptoms
- infection
- fever
•prolonged use leads to hyperpigmentationof skin, especially in palms and soles… more common in African Americans
Lamivudine
nucleosidereverse transcriptase inhibitor, interferes with cytidineincorporation
- inhibits incorporation of native nucleotides and also terminates elongation of nascent proviral DNA
- FDA-approved fortreating HIV-1 and HIV-2 infected adults in combination
- low barrier to resistance if monotherapy (e.g., M184V)
- also active against HBV; resistance develops if monotherapy, discontinuation can cause rebound exacerbation of HBV
- co-formulatedwith tenofovir
- of note, use of the dualagent combination (i.e., not triple) of lamivudineand doltegraviris approved for treatment naïve patients with low HIV copy numbers in plasma
- rapid, extensive absorption
- long intracellular half-life (~12-18 hrs) makes it a current NRTI of choice
- excreted primarily as unchanged drug in the urine
- one of theleast toxic antiretroviral agents, but… >10%
- headache, fatigue
- nausea, diarrhea
- rash
- neutropenia
- nasal symptoms, infections of ears, nose, throat
- musculoskeletal pain
- fever
Abacavir (ABC)
nucleosidereverse transcriptase inhibitor, only guanosine analog
- inhibits incorporation of native nucleotides and also terminates elongation of nascent proviral DNA
- FDA-approved fortreating HIV infection in combination with other drugs
- should notbe given to patient with HLA-B*5701 genotype due to toxicity, a potentially fatal hypersensitivity syndrome
- also note that abacavir is noteffective against HBV
- rapid and extensive absorption
- has intracellular half-life ~21 hrs, now approved for 1x/day dosing
- not a CYP substrate, but metabolized by dehydrog-enasesand conjugated with glucuronide for renal elimination
- has a unique/ potentially fatal hypersensitivity syndrome
•see fever, abdominal pain/GI
distress, mild maculopapular rash, malaise, fatigue.. typically at 6 d-6 wks
- unlike for other drugs, does not resolve and instead worsens…
- must discontinue drug and never restarted since death
- due HLA-B*5701 locus leading to aberrant TNF release
- one of strongest pharmacogenomic associations identified to date
- ~ 0 risk in all others
•generally to be avoidedin patients with coronary artery disease since some evidence of association with hyperlipidemiaand cardiovascularevents
tenofovir disoproxil fumarate (TDF)
- nucleotidereverse transcriptase inhibitor, adenosine analog
- only nucleotide used, parent compound has very poor bioavailability; reason for disoproxil fumarate prodrug formulation
- inhibits incorporation of native nucleotides and also terminates elongation of nascent proviral DNA
- has broad spectrum activity against viral DNA polymerases, but low affinityfor human DNA polymerases, so selectively toxic
- FDA-approved fortreating HIV infection in combination with other drugs
- also approved for HBV
- often co-formulated with emtricitabine; combination seems superior to those of other NRTIs
- resistance is due to a single substitution in reverse transcriptase (K65R), but this mutation is seldom cause of treatment failure in tenofovir-containing regimens
- has intracellular half-life 10-50 hrs
- approved for 1x/day dosing, contributes to this being a current combination drug of choice
- excreted primarily unchanged in the urine
- generally very well tolerated with few adverse effects other than GI upset
- but, can see nephrotoxicity with acute tubular necrosis leading to Fanconi syndrome, so good practice to avoid if eGFR < 60 ml/min/1.75 m2
- also see decreased bone mineral density, but stabilizeswith
didanosine:
adenosine analog active against HIV-1, HIV-2 and HTLV-1, supplanted by less toxic drugs … causes peripheral neuropathy, pancreatitis and/or hepatic steatosis thought to be due to mitochondrial toxicity
tenofovir alafenamide (TAF)
nucleotidereverse transcriptase inhibitor, adenosine analog
- only nucleotide used, parent compound has very poor bioavailability; reason for alafenamide prodrug formulation
- inhibits incorporation of native nucleotides and also terminates elongation of nascent proviral DNA
- has broad spectrum activity against viral DNA polymerases, but low affinityfor all human DNA polymerases, so selectively toxic
- FDA-approved fortreating HIV infection in combination with other drugs
- also approved for HBV
- often co-formulated with emtricitabine; combination seems superior to those of other NRTIs
- resistance is due to a single substitution in reverse transcriptase (K65R), but this mutation is seldom cause of treatment failure in tenofovir-containing regimens
- has intracellular half-life 10-50 hrs
- approved for 1x/day dosing, contributes to this being a current combination drug of choice
- TAF is transported differently than TDF… lower doses administered meaning lower plasma concentrations but higher intracellular concentrations of tenofovir-diphosphate
- excreted primarily unchanged in the urine
- generally very well tolerated with few adverse effects other than bloating, diarrhea, flatulence
- less renal and bone toxicity than TDF because plasma concentration is lower
what combinations does ART usually have?
typically means that 2 NRTI targeting a different base and then another active agent from another class
one exception is lamivudine (by itself) in combination with INSTI dolutegravir is however now recommended for use in treatment naïve patients unless HIV load is high (e.g., > 500,000 copies per ml)
what is the primary +1 class of active agents now recommended for naive HIV treatment
Integrase strand Transfer inhibitors (INSTI)
Raltegravir
prevents formation of covalent bonds between viral and host DNA, process known as strand transfer
- blocks strand transfer, the defining characteristic of retrovirus life cycles that allows viral DNA to remainin host for prolonged periods of inactivity
- lowers plasma viral RNA faster than NNRTI efavirenz
- approved for ART combinations used in HIV-infectedadults, class now preferred for treatment-naïve patients
- unique mechanism of action retains its activity against viruses resistant to other drug classes…
- resistance develops due to mutations in integrase
- highly variable kinetics, but terminalelimination half-time is ~9 hrs
- eliminated in urine and feces as unchanged drug, also undergoes glucuronidation
- generally well tolerated, has “remarkably little” clinical toxicity… but
- rare potentially severe skin and hypersensitivity reactions
- can see “immune reconstitution syndrome”
- some incidence of myopathy / rhadomyolysis
- excellent target since human DNA is not known to undergo excision/
Dolutegravir
prevents formation of covalent bonds between viral and host DNA, process known as strand transfer
- blocks chromosomal integration of viral DNA, defining characteristic of retrovirus life cycles that allows viral DNA to remainin host for prolonged periods of inactivity
- lowers plasma viral RNA faster than NNRTI efavirenz
- approved for first-line use in HIV-infectedadults, including treatment-naïve patients
- retains its activity against viruses resistant to other drug classes
- resistance can develop due to mutations in integrase, but has high genetic barrier to resistance
- variable kinetics, but terminalelimination half-time is ~14 hrs… suitable for once daily dosing in some patients
- primarily metabolized by UGR1A1 glucuronidation before renal excretion
- available in fixed dose combinations with abacavir and lamivudine (Triumeq®) and rilpivirine(Juluca®), respectively, 2X/day
- generally well tolerated, similar to raltegravir
- rare potentially severe skin and hypersensitivity reactions
- can see “immune reconstitution syndrome”
- can see increase in liver enzymes
- avoid in pregnancy since evidence of increased neural
