pharm week 20

What are the non-nucleoside reverse transcriptase inhibitors? (NNRTIs)

“DREEN”

doravirine, rilpivirine, efavirenzy, nevirapine, and etravirine

Which NNRTI is well tolerated and is not associated with any specific adverse effects?

doravirine

Which NNRTI is associated with neuropsych side effects like dissziness, abnormal dreams, HA, drepression, insomnia, as well as skin rash and QTc prolongation?

efavirenz

Which NNRTI is generally well tolerated but is associated with depression, HA, and QTc prolongation?

rilpivirine

What drug is only used for treatment-naive adults with HIV RNA </= 100,000 copies/mL and CD4 count >/= 200c/mm³? Why?

rilpivirine; increased risk of virologic failure in pts with viral load less than 100,000

What drug’s MOA:

binds to allosteric site on reverse transcriptase and induces a confirmational change and decreases activity of the reverse transcriptase

NNRTIs

What is a key difference between NRTIs and NNRTIs?

NNRTIs do not need to be activated by cellular enzymes

What are two class adverse effects with all NNRTIs?

rashes and GI issues

Which drug’s interact with efavirenz-methadone and what is the interaction?

NNRTIs, the protease inhibitors,

they decrease methadone levels and can lead to opiod withdrawal symptoms

What drug’s MOR:

single amino acid changes, transmitted resistance, and high levels of cross-resistance

NNRTIs

Which NNRTI has a low barrier for resistance, not recommended for initial ART, and is mainly used as an option for presumptive therapy in neonates at high risk of HIV?

nevirapine

What drug should not be used in females with CD4 count >/= 250 or males >/=400? Why?

nevirapine

there is an association with severe life-threating and fatal hepatotoxicity

What are the HIV protease inhibitors?

atazanavir and darunavir

What drug needs boosted? how does this occur? why does it need boosted?

the protease inhibitors (atazanavir and darunavir) need to be boosted by ritonavir or cobicistat (potent CYP3A4 and Pgp inhibitors)

this will increase concentrations, increase duration of action, and have improved virologic activity of these protease inhibitors

What drug’s AE include: n/v/d, cardiac conduction abnormalities, glucose and lipid metabolism (cushingoid fat distribution)

the protease inhibitors; atazanavir and darunavir

Which drug’s AE include: class effects as well as jaudice/ increased bilirubin, cholelithiasis, nephrolithiasis, and kidney injury

atazanavir

Which drug’s AE include: class effects as well as skin rash (can be severe), caution in pts with a sulfonamide allergy, and liver toxicity (contraindicated in pts with severe liver disease

darunavir

What drug’s MOA:

prevent proteolytic cleavage of HIV gag and pol proteins into a number of essential enzymes leading to the release of immature, noninfectious viral particles

the protease inhibitors: atazanavor and darunavir

What drug’s MOR:

accumulation of multipl point mutations in the pol gene

the protease inhibitors: atazanavor and darunavir

What drug has high drug interactions with:

• statins and midazolam

• digoxin (p-gp)

• UGT induction → decrease hormonal contraceptive efficacy

the protease inhibitors: atazanavor and darunavir

What drugs MOA:

blocks the binding of the HIV outer envelope protein gp120 to the CCR5 chemokine receptor

maraviroc

What drug’s MOR:

shift in tropism to CXCR4 or dual tropism

maraviroc

What drug rpior to being started, a patient must get tropism testing for the presence of CCR5-tropic HIV-1 infection?

maraviroc

What is the main AE of maraviroc?

hepatotoxicity

What drug’s MOA:

binds HIV envelope protein gp41 inhibitors and inhibits the confirmational change in gp41 required for membrane fusion (inhibits fusion of virus)

enfuvirtide

What drug is a synthetic peptide derived from a part of the transmembrane gp41 protein of HIV-1 involved in fusion and is only give SubQ

enfuvirtide

What drug’s MOR: mutations in the codon of the binding domain of gp41

enfuvirtide

What drug is used only for treatment-experienced pts, is known to cause injection site reactions, and has no known metabolic reactions?

enfuvirtide

What drug’s MOA: binds HIV-1 gp120 envelope adjacent to the gp120-CD4 binding site → prevents the gp120 confirmational change → prevents attachment of CD4

fostemasavir

What drug’s AE include: nausea, elevations in hepatic enzymes especially in HBV or HCV (hepatitis B or C) infection, and QT interval prolongation

fostemasavir

What drug’s MOA:

blocks domain 2 and interferes with post attachment steps required for HIV-1 entry into host cells

ibalizumab

What drug is IV and only given to heavily treatment experienced adults?

Which one is given oral then subQ maintenance to heavily treatment experienced adults?

IV: ibalizumab

oral then subq maintenance: lenacapavir

What drug’s MOA:

directly binds the interface between capsid protein subunits and prevents viral uncoating

• blocks capsid-mediated nuclear uptake

• interferes with gag/gag-pol functioning

• and capsid core formation

lenacapavir

What is the treatment guildline for pre-exposure prophylaxis? (PrEP)

TDF-emtricitabine

TAF-emtricitabine

cabotegravir

What is the treatment guildline for post-exposure prophylaxis (PEP) for healthcare workers?

TDF-emtricitabine with dolutegravir or raltegravir

What is the treatment guildline for pregnent people wiht HIV?

2-NRTI backbone plus dolutegravir

What is the treatment guildline for prevention of mother-to-child transmission during/near delivery?

zidovudine IV if pt has >1,000 copies (no tx needed <1,000)

What is the treatment guildline for neonate prophylaxis?

low risk: zidovudine

high risk: zidovudine + nevirapine or zidovudine + raltegravir

What is the treatment guildline for breast-feeding mothers with HIV?

immediately d/c breastfeeding

What is the main adverse effect of antiretrovirals as a whole?

immune reconstitution inflammatory syndrome: when you increase the immune system then you get an inflammatory reaction to overt or subclinical opportunistic infections or malignancies

What are the NRTIs (nucleoside/nucleotide reverse transcriptace inhibitors)?

“ZALTE” (like salty but fancy)

zidovudine, abacavir, lamivudine, tenofovir, and emtricitabine

explain the activation of the NRTIs (zidovudine, abacavir, lamivudine, tenofovir, and emtricitabine)

they are activated by tri-phosphorylation by host kinases

What drug’s MOA:

competitively inhibit the orcorporation of native nucleotides in the RNA-DNA duplex and terminate elongation of the viral DNA chain due to the absence of the 3’ -OH group and block replication

NRTIs (zidovudine, abacavir, lamivudine, tenofovir, and emtricitabine)

MOR:

M184V/I confers high-level resistance to ______

lamivudine and emtricitabine

MOR:

M184V/I confers low-level resistance to ______

abacavir

MOR:

M184V/I restores susceptibility to ______

tenofovir and zidovudine

MOR: M184V/I (varies) and K65R and L74R

NRTIs (zidovudine, abacavir, lamivudine, tenofovir, and emtricitabine)

What is a major toxicity of the NRTIs (zidovudine, abacavir, lamivudine, tenofovir, and emtricitabine)?

mitochondrial toxicity: by inhibiting host DNA polymerase-gamma which is a mitochondrial enzyme (it does not get our other DNA polymerases)

Which NRTI has the highest mitochondrial toxicity?

zalcitabine

What drug’s AE?

hepatic steatosis and hepatic failure with lactic acidosis (rare but fatal), myopathy, peripheral neuropathy, lipoatrophy, etc.

NRTIs (zidovudine, abacavir, lamivudine, tenofovir, and emtricitabine)

Explain tenofovir’s two configurations: TDF and TAF in regards to metabolism

TDF is converted after absorption before it an be taken up, then gets metabolized again once it is in the cells

TAF is not cleaved in circulation, it gets taken into the cells and then is metabolized

Explain tenofovir’s two configurations: TDF and TAF in regards to intracellular concentrations and dosing

TAF is given as a lower dose so there is less drug in the plasma than TDF, but TAF gets higher concentrations intracellularly (due to its metabolism)

What drug’s therapeutic uses:

• pregnant pts in all trimesters

• pre-exposure and post-exposure prophylaxis

• chronic HBV treatment and prophylaxis

tenofovir (TDF and TAF)

What drug’s toxicities include:

renal impairment, kidney injury (including fanconi syndrome), and bone loss (decreased mineral density)

Tenofovir (TDF and TAF)

TAF has lower plasma concentrations so it has less toxicity than TDF

tenofovir + _____ leads to high rates of virologic failure

abacavir

What drug is contraindicated with P-gP inducers (rifampin, carbamazepine, oxcarbazepine, phenytoin, phenobarbital)?

TAF because they will decrease the levels and decrease the efficacy

what NRTI is the adenosine analog?

tenofovir

what NRTI is the cytidine analog?

lamivudine and emtricitabine

what drug may cause hyperpigmentation usually on the hands and/or soles of the feet?

emtricitabine

what NRTI is the guanosine analog?

abacavir

What drug undergoes hepatic metabolism by alcohol dehydrogenase and glucuronyl transferase?

abacavir

what NRTI is the thymidine analog?

zidovudine

What drug’s therapeutic uses include: perinatal IV infusion to prevent vertical transmission in mothers and ART for neonates?

zidovudine

Which of the second-generation NRTIs should not be combined and why?

Lamivudine and emtricitabine because emtricitabine is fluorinated lamivudine (they are too similar and will compete with eachother)

What screening test must be performed prior to administering abacavir and why?

HLA-B*5701 which is associated with severe multiorgan hypersensitivity reactions in patients positive for this allele

What drugs can cause reactivation of HBV and hepatitis when withdrawn in patients with HIV/HBV coinfection? (US boxed warning)

Lamivudine, emtricitabine, tenofovir DF, tenofovir AF

What drugs are the INSTIs (HIV integrase strand transfer inhibitors)?

the “tegravir”s: Bictegravir, dolutegravir, elvitegravir, raltegravir, and cabotegravir

What are the 2nd gen INSTIs?

bictegravir and dolutegravir

What are the 1st gen INSTIs?

elvitegravir and raltegravir

What drug can we use to treat elvitegravir or raltegravir (1st gens) resistant HIV?

dolutegravir (bictegravir was shown to work in vitro but no clinical data is available yet)

Which INSTIs are CYP3A4 substrates?

dolutegravir, bictegravir, and elvitegravir (not raltegravir)

What drug may have reduced oral absorption when taken with antacids?

the INSTIs (tegravir)

Bictegravir, dolutegravir, elvitegravir, raltegravir, and cabotegravir

What drug has a drug-drug interaction with UGT1A1 inducers/inhibitors?

Bictegravir, dolutegravir, elvitegravir, raltegravir

What drug’s AE: weight gain, diarrhea, HA, insomnia, depression and suicidality?

class effecs of the INSTIs (tegravirs)

What drug’s MOA:

block the catalytic activity of the HIV integrase and prevents integration of virus DNA into the host chromosome

the INSTIs (tegravir)

Bictegravir, dolutegravir, elvitegravir, raltegravir, and cabotegravir

explain the selectivity of the INSTIs (tegravir)

humans do not have integrase which is their mechanistic target

What drug’s MOR:

primary mutation in the integrase gene

the INSTIs (tegravir)

Bictegravir, dolutegravir, elvitegravir, raltegravir, and cabotegravir

Whcih INSTIs have a high barrier to resistance and a low barrier to resistance?

1st gens raltegravir and elvitegravir: lower barrier

2nd gens dolutegravir and bictegravir: high barrier

What are the most frequently reported side effects of the INSTIs?

HA and GI effects (an injection site reactions with cabotegravir)

What drug is only given IM into the gluteal muscles and may not be an option for pts with butt filler/implants?

cabotegravir (can be combined in suspension with rilpivirine)

What is the oral bridinging therapy for cabotegravir + rilpivirine?

they are given together as an IM injection, but if a pt is going to miss a scheduled injection then they can take the oral combo instead)

What drug has this required criteria before treatment?

no resistance, no prior virologic failures, no HBV infection (unless already being treated for it, not pregnant or planning to become pregnant

cabotegravir + rilpivirine

besides an active HIV infection, what is another therapeutic use of cabotegravir IM?

PrEP: pre-exposure therapy

Which two are the first-line INSTIs?

Dolutegravir and bictegravir are second-generation INSTs with a higher barrier to
resistance than the first-generation INSTIs and are available in fixed-dose combination allowing one pill once daily dosing for improved patient adhererence