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
Bictegravir
prevents formation of covalent bonds between viral and host DNA, process known as strand transfer
- blocks chromosomal integration of viral DNA (i.e., blocks HIV integrase), which is 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 2018 for use in HIV-infectedadults, including treatment-naïve patients
- resistance can develop due to mutations in integrase, but has high genetic barrier to resistance similar to dolutegravir
- variable kinetics, but terminalelimination half-time is ~16-23 hrs… suitable for once daily dosing in some patients
- more soluble/readily absorbed than other INSTI
- glucuronidatedby UGT1A1 and metabolized by CYP3A4, but only affected by potent dual inhibitors of those enzymes or strong CYP3A4 inducers… so fewer drug-drug interactions
- normally ~1/3 eliminated in urine and 2/3 in feces
- only available as a fixed-dose single tablet regimen of bitegravir/emtricitabine/tenofovir alafenamide (Biktarvy®)
- generally very well tolerated individually… some reports of headaches, diarrhea, insomnia
- toxicities are those of the drugs in combination
what is the second line +1 active agent
Protease inhibitors
what are the functions of Protease inhibitors
peptide-like chemicals that competitively inhibit activity of virus aspartyl protease
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enzyme is a homodimerwith each Asp essential for catalysis
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cleaves N-terminal side of Pro residues
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human aspartyl proteases (renin, pepsin, cathepsin D, others) are monomers and not inhibited by viral protease inhibitors
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protease inhibitors prevent proteolytic cleavage of HIV gag and pol precursor peptides
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these are neededto generate reverse transcriptase, protease, integraseand various structural polypeptides of the capsid needed for the metamorphosis of HIV particles into their mature infectious form
how are protease Inhibitors cleared and how are they affected by p-Glycoprotein MDr1
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highly protein-bound, poor penetration into CSF (significance unknown)
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class cleared mainly by hepatic clearance (via oxidation) but wide variability
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metabolized primarily by CYP3A4, all inhibit metabolism of other drugs
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ritonaviris by far the most potent inhibitor, this is the reason a low dose of it is able to ”boost” other agents
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t1/2ranges from ~1.8 –10 hrs, sufficient for 1x-2x/day dosing
•
all are substrates for P-glycoprotein (MDR1), so can influence/be influenced by other drugs transported via this mechanism
Saquinavir
- first protease inhibitor
- prevents maturation of HIV particle that buds off
- inhibits both HIV-1 and HIV-2
- no longer widely used in developed world due to pill burden
- comparable to other agentswhen boosted
- poor bioavailability
- t1/2~ 1-2 hr
- GI distress, nausea, vomiting, diarrhea
- long-term leads to lipodystrophy
Indinavir
- early protease inhibitor
- as other protease inhibitors
- inhibits both HIV-1 and HIV-2
- see general
- short t1/2~ 1.8 hr 3x/day dosing
- others plus unique crystaluria/renalstones
Darunavir
a non-peptidicprotease inhibitor
- prevents maturation of capsid, other crucial proteins in HIV particle that buds off
- inhibits both HIV-1 and HIV-2, indicated for HIV-1 treatment
- used off-label for post-exposure prophylaxis
- a current first-choice PI when boosted
- t1/2~ 15 hrswhen boosted
- metabolized by CYP3A4
- ~80% excreted in feces, ~40% as unchanged drug
- a current PI of first choice
- GI distress, nausea, vomiting, diarrhea similar to other PI
- increases triglycerides and cholesterol
- fat redistribution syndrome
- immune reconstitution syndrome
- sulfa drug, so some rash, hypersensitivity above and beyond that already associated with PI drugs
atazanavir
•protease inhibitor, a current first-choice PI when boosted
•prevents maturation of capsid, other crucial proteins
in HIV particle that buds off
- inhibits both HIV-1 and HIV-2
- treatment-naïve patients
- use in treatment-experienced patients guided by protease inhibitor resistance substitutions
- t1/2~ 7 –9 hrs, doubled when boosted
- metabolized by CYP3A4
- mostly excreted in feces, ~20% of dose as unchanged drug
- a current PI of first choice when boosted with ritonavir or cobicistat
- GI distress, nausea, vomiting, diarrhea, cough, fever similar to other PI
- increases serum cholesterol
- elevated bilirubin, unconjugated hyperbilirubinemia not associated with hepatitis
- fat redistribution
- hypersensitivity reactions
- immune reconstitution syndrome
Lopinavir
- protease inhibitor, only availablein form boosted with ritonavir (i.e., “Lop/r”)
- prevents maturation of HIV particle that buds off
- inhibits both HIV-1 and HIV-2
- often works after failure of other PI-containing regimens
- treatment-naïve patient failing lopinavir is generally not resistant to Lop/r
- t1/2~ 5-6 hrs
- GI distress, nausea, vomiting, diarrhea
- increases triglycerides and cholesterol
Ritonavir
CYP3A4 inhibitor
- protease inhibitor, but used ~only to block CYP3A4
- “boosts” levels of other more potent protease inhibitors
- boost plasma levels of other drugs
- t1/2 ~ 3-5 hr, potent CYP3A4 inhibitor
- flushing, rash, GI upset + misc. due to effects on CYP3A4 and other drugs being used
Cobicistat
- CYP3A4 inhibitor
- used to “boost” levels of protease inhibitors
- used to boost plasma levels of azatanavirand darunavir
- not considered a replacement for ritonavir in instances where ritonavir is used (lack of data)
- t1/2 ~ 3-5 hr, potent CYP3A4 inhibitor
- primarily excreted in feces
- misc. due to effects on CYP3A4 and other drugs being used
what is the third line of +1 active agents?
NNRTI
Non-nucleoside Reverse transcriptase inhibitors
what is the function of the Non nucleoside reverse transcriptase inhibitors
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bind to hydrophobic pocket in p66 subunit of HIV reverse transcriptase
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site is removed from active site and not essential for function of enzyme
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binding in this pocket induces a conformational change in the enzyme that greatly reduces its activity… therefore NNRTI function as non-competitive antagonists
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do not require phosphorylation for activation
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only active against HIV-1
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HIV-2 is intrinsically resistant to NNRTI
how are NNRTI eliminated and can their be resistance to them?
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no activity against human DNA polymerases
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all are eliminated by hepatic metabolism
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single aa substitution in pocket can cause resistance
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single exposure to nevirapinein absenceof other drugs cause resistance in ~1/3 of HIV-infected people
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therefore, must be combined with other drugs to avoid rapid appearance of resistance, which typically extends to several other NNRTI
Nevirapine
- non-nucleoside reverse transcriptase inhibitor
- prevents generation of DNA from viral RNA in host cells
- approved for treatment of HIV-1 infection in adults and children in combination
- t1/2~ 25-30 hrs
- induces CYP3A4
- reduceslevel of oral contraceptives so alternative form of birth control is needed
- rash/itching are most common side effects
efavirenz
- non-nucleoside reverse transcriptase inhibitor
- prevents generation of DNA from viral RNA in host cells
- approved for treatment of HIV-1 infection in adults and children in combination
- co-formulated with emtricitabine and tenofovir… helps maintain this as early NNRTI selected in class
- should not be added to afailing regimen
- t1/2~ 40-50 hrs, first NNRTI approved for once daily dosing
- induces CYP3A4
- reduceslevel of oral contraceptives so alternative form of birth control is needed
- most significantadverse effect is CNS toxicity/ psychiatric side effects, but few discontinue because of this
- side effects include dizziness, impaired concentration, vivid dreams, etc., but typically resolve in a few week
- rash is also common, but resolves in a few weeks
- wasconsidered teratogenic, more recent data analysis significantly diminished that concern
etravirine
- non-nucleoside reverse transcriptase inhibitor
- prevents generation of DNA from viral RNA in host cells
- approved for treatment-experienced patients with HIV-1 infection
- unique in that it still works after mutations that disrupt activity of other NNRTI
- apparently possesses some molecular flexibility
- t1/2 ~ 41 hrs, longer than initially thought, so 1x/day rather than 2x/day dosing should be possible
- induces CYP3A4, also affects other proteins and has range of clinically significant drug interactions
- fat redistribution
- immune reconstitution syndrome
- rash is common… often resolves spontaneously but Stevens-Johnson syndrome, etc., are possible
rilpivirine
- non-nucleoside reverse transcriptase inhibitor
- prevents generation of DNA from viral RNA in host cells
- approved for treatment-naïve patients with HIV-1 infection
- not susceptible to common mutation that renders efavirenz and nevirapine ineffective (i.e., K103N)… but
- affected by multiple other mutations making it less resistant than etravirine
- t1/2~ 50 hrs
- metabolized by CYP3A4
- 85% excreted in feces, 25% as unchanged drug
- adverse effects are more common in children and adolescents
- CNS: depression, headache drowsiness
- Endo: decreased cortisol
- GI: nausea
- fat redistribution
- immune reconstitution syndrome
Doravirine
best in class
- newest non-nucleoside reverse transcriptase inhibitor
- prevents generation of DNA from viral RNA in host cells
- very effective agents
- approved for treatment-naïve patients with HIV-1 infection
- or for switching patients on a stable effective regimen to this drug
- differs from other NNRTI in that it has novel resistance mutations…
- so works when resistance to efavirenz of rilpivirine
- etravirine and rilpivirinework when resistance to it
- t1/2 ~15 hrs
- metabolized by CYP3A4, significant drug interactions but less than other NNRTI
- unlike others, not impacted by acid-reducing agents
- available individually and co-formulated with lamivudine and tenofovir
- relatively low incidence of typical CV, CNS, GI, skin adverse effects, better than other NNRTI
- potential for “immune reconstitution syndrome”
Enfuvirtide
aka T-20
- 36 aa peptide derived from viral gp41 part that fuses with cell membrane
- was initiallydeveloped as vaccine component
- inhibits formation of a 6-helix bundle critical for membranefusion
- inhibits infection CD4+by free virus particles
- also inhibits cell-to-cell transmission in vitro
- resistance develops by mutations in gp41
- approved for use only in treatment-experienced adults with viralreplication despite therapy
- not active against HIV-2, but range of potenciesagainst HIV-1
- unique mechanism of action, so retains its activity against viruses resistant to other drug classes
- very expensive because expensive to manufacture, a last resort drug due to its cost
- only HIVdrug that must be administered parenterally(2x/day SC) … a challenge to adherence
- (90 mg @ ~$72 ea2X/day)
- injectionsite reaction is the major toxicity
Maraviroc
- chemokine receptor antagonist, blocks binding of GP120 to CCR5 co-receptor
- blocks entry of CCR5-trophic HIV into cells
- resistance develops by:
- shift from CCR5 to CXCR4 tropism (or)
- mutation in V3 loop of GP120
- approved foruse in ART combinations for HIV caused by CCR5 (“R5”)trophic virus
- notactive against CXCR4 (“X4”)or mixedtrophic viruses
- essentialand expensivephenotypic test required to determine tropismbefore using
- retains activity against viruses that have become resistant to other classes because of its unique mechanism
- orally active
- t1/2~ 10.6 hrs
- a CYP3A4 substrate, so need to be wary of other CYP3A4 metabolized drugs (e.g., other antiretroviral drugs)
- also renal elimination, need to adjust dose of ClCR< 30 ml/min
- generally well tolerated, little toxicity… may see some
- cold-like symptoms
- dizziness
- GI upset
- rare systemic allergic reaction followed by hepatic toxicity
when to initiate ART
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The Panel on Antiretroviral Guidelines for Adults and Adolescents recommends initiating ART immediately (or as soon as possible) after HIV diagnosis in order to
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increase the uptake of ART and linkage to care
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decrease the time to viral suppression
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improve the rate of virologic suppression
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When initiating ART, it is important to educate patients regarding the benefits of ARTand to deploy strategies to optimize care engagement and treatment adherence.
when to prevent sexual transmission
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All persons with HIV should be informed that maintaining a plasma HIV RNA (viral load) of <200 copies/mL, including any measurable value below this threshold value, with antiretroviral therapy (ART) prevents sexual transmission of HIV to their partners.
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Persons with HIV who are starting ART should use another form of prevention with sexual partners (e.g., condoms, pre-exposure prophylaxis [PrEP] for the HIV-negative sexual partner, sexual abstinence) for ≥ first 6 months of treatment
still vulnerable to other STIs
What to do for Child bearing potential or pregnant
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ART is recommended for all persons living with HIV to improve their health and to reduce the risk of HIV transmissionto sexual partners without HIV.
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When prescribing antiretroviral drugs, recognize that some have significant pharmacokinetic interactions with hormonal contraceptives…
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an alternative or additional effective contraceptive method is recommended to prevent unplanned pregnancy
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switching to another antiretroviral drug may also be considered
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A pregnancy test should be performed for those of childbearing potential prior to initiation of ART.
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Data suggest there may be an increased risk of neural tube defects in infants born to women who were receiving dolutegravir (DTG) at the time of conception; providers need to discuss with patients.
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During pregnancy, an additional goal of ART is to maintain a viral load below the limit of detection throughout pregnancy to reduce the risk of transmission to the fetus and newborn .
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When selecting an ART regimen for a pregnant woman, clinicians should consult the most current Perinatal Guidelines and consider the available safety, efficacy, and pharmacokinetic data on use during pregnancy for each agent.
