Pharmacology of AntiRETROvirals Dr. Lewis EXAM 4 Flashcards
What is PEPFAR?
Presidents Emergency Plan for AIDS Relief
What is the CD4 cell count associated with AIDS?
< 200 cells/mm3
What does the CD4 count and the viral load imply?
CD4 count: how close to the end
Viral load: how fast does the disease progress (you may have a decent amount of CD4 cells, but it can decrease rapidly with a high viral load)
-> The viral load is the best marker for treatment response
What are the steps during the infection of HIV?
Free virus
1. Attachment
2. Fusion
3. Reverse Transcription
4. Integration
5. Assembly
6. Maturation
What are the proteins on the surface of an HIV cell that bind to CD4 cells?
-Glycoprotein 120 (outside) and 41(integrated part)
-binding to CD4 receptor and CCR5 and CXCR4 Co-receptor on CD4 cells
-patients infected with CCR5-HIV receiving a bone marrow transplant with CXCR4 CD4 cells may be cured
What are the NRTIs used to treat HIV?
Abacavir (ABC), Ziagen®
Didanosine (ddI), Videx ®
Emtricitabine (FTC), Emtriva®
Lamivudine (3TC), Epivir ®
Tenofovir disoproxil fumarate (TDF), Viread®
Tenofovir alefenadamide Vemlidy® (TAF)
Zidovudine (AZT, ZDV), Retrovir (not used in practice; NAPLEX)
Class Side Effects of NRTIs
-Lactic acidosis, Hepatic steatosis (fatty liver)
-Pancreatitis and peripheral neuropathy with the “D” drugs: Didanosine (ddI), stavudine [d4T], and zalcitabine [ddC]
How are the NRTIs eliminated?
-All renally -> needs renal adjustment
-EXCEPT Abacavir !!!!
-Didanosine needs to be taken 30 min before or 2h after a meal (NOT on Exam but NAPLEX)
What are the cytosine analogs used to treat HIV?
Emtricitabine (FTC), Emtriva® (has a Flourid atom)
-> associated with skin hyperpigmentation
Lamivudine (3TC), Epivir ® (no Flourid atom)
-similar in structure -> interchangeable
both work for HBV
-these are newer agents and well-tolerated
Which side effect is associated with Emtricitabine (FTC), Emtriva®?
Skin hyperpigmentation
Which NRTI is a Guanine analog?
Abacavir
-check for HLA-B5701 -> allergic reaction (fatal rash) !!!
Which antiviral drug is the only nucleotide?
Tenofovir
-adenosine analog
-2 formulations (TAF, TDF)
-works for HBV
How is TAF different from TDF?
Tenofovir (TFV) by itself will not get absorbed (acidic GI?)
->TDF is the TFV salt and is protected from the acid but releases the active drug TFV in the plasma (too early) and causes TOXICITY
->TAF is a prodrug with a longer half-life allowing the drug to stay stable until it reaches the HIV target cell
DDIs and side effects of TDF
-it lowers the concentration of atazanavir, so atazanavir has to be boosted
ADE: renal insufficiency, proximal tubulopathy, Fanconi syndrome, bone toxicity
DDIs and side effects of TAF
DDI: rifampin/rifabutin (CYP inducer), St. Johns Wort, tipranavir
ADE: the toxicity caused by TDF was decreased, and higher lipid levels than TDF during the study
Which side effect is associated with Zidovudine?
NAPLEX
-bone marrow suppression
-need to monitor complete blood count (CBC)
What are the NNRTIs used to treat HIV?
Efavirenz (EFV), Sustiva® (lot of toxicity)
Nevirapine (NVP), Viramune® -> Hepatoxicity
(suggested by the mother-to-baby-transmission guidelines)
Newer agents:
Etravirine, Intelence®
Rilpivirine, Edurant® -> needs an acidic environment, low efficacy at high viral dose
Doravirine, Pifeltro®
How are NNRTIs different from NRTIs?
-No activation (phosphorylation) required
-they bind allosterically
-they don’t compete with other nucleosides or nucleotides (cross-reactivity only between NNRTIs)
Class ADE for NNRTIs
-Rash
-GI
-Hepatoxicity:
CD4 count-dependent hepatoxicity (fatal) for nevirapine
What are the side effects associated with Efavirenz (Sustiva)?
-has the lowest rash incidence
-but causes confusion, impaired concentration, and vivid dreams, can’t give it to pt with a psychiatric history -> concentration goes up with food -> issues with abuse bc of the hallucinogenic property
-CYP3A4 inducer and inhibitor, CYP2C19 inhibitor
Which patient population should Efavirenz be avoided?
Women in the first trimester of pregnancy
Which patient population is appropriate for using
Etravirine (Intelence®)?
for treatment-experienced patients
What to look out for when administering Rilpivirine, Edurant®?
-must be given with a high-fat meal
-low oral bioavailability with antiacids (need acidic environment)
-less effective with high viral load
DDIs of Doravirine (Pifeltro®)?
-Contraindicated with strong 3A4 inducers
-Carbamazepine, phenobarbital, phenytoin, Rifampin and rifapentine, St. John’s Wort
Important Protease Inhibitor
Often used:
Darunavir, Prezista®
Atazanavir, Reyataz®
Pregnancy:
Lopinavir/Ritonavir, Kaletra®
Fosamprenavir, Lexiva®
Indinavir, Crixivan® - drink with plenty of water (NAPLEX)
What are the Classe ADEs of Protease Inhibitors?
-Lipodystrophy
-Hyperlipidemia
-Hyperglycemia
-Bleeding in hemophiliacs (genetic bleeding disorder) -> NAPLEX
What to look out for in Protease Inhibitors?
-all should be taken with food bc N/V: EXCEPT Indinavir !!!
-monitor LFT and CBC
-monitor blood glucose and lipids (bc of hyperglycemia and hyperlipidemia)
-DDI with CYP3A4 drugs
In which patient population is Darunavir used?
-mostly treatment-experienced patients and pt infected with a virus carrying a PI mutation
-> Give BID instead of once a day
->BOOST with Ritonavir
-can cause a rash (higher with sulfa allergy)
-take with food, and avoid statins
What is important when administering Protease inhibitors?
They have to be boosted with Ritonavir or Cobicistat
Which Protease Inhibitor is different from the other and WHY?
Atazanavir
ADE different:
less hyperlipidemia, less metabolic ADEs
cause prolonged PR intervals, hyperbilirubinemia (fake sign of liver dysfunction, ATZ replaces bilirubin from the binding site causing accumulation -> yellowing, but the liver is OK)
A patient is treated with TDF and atazanavir,
what has te taken care of?
TDF decreases ATZ -> so ATZ needs to be boosted
Considerations about Raltegravir
-Integrase inhibitor
-when given with rifampin (CYP inducer) -> higher dose
-don’t give with Al-Mg hydroxide antacids, carbamazepine, phenobarbital, phenytoin
-a low barrier for resistance
Considerations for Elvitegravir
ELIVS needs a friend
-taken with Cobicistat
-Limited to CrCl > 70
-Cobicistat may inhibit SCr secretion
-take with food
-Do not give with inhaled steroids (except
beclomethasone)
-Low drug levels during pregnancy
Considerations for Dolutegravir
-can be used for RAL and ELV-resistant strains
-potent at any CD4 count or viral load
-no food requirement
-Absorption reduced by polycovalent cations
-dont give with dofetilide (antiarrhythmic)
-pregnancy test before starting
Considerations for Bictegravir
-Coformulated with emtricitabine/TAF
-May be useful in a majority of INSTI-mutations
-not used when CrCl is <30 ml/min
-give 2hr before antacids
-don’t use it with dofetilide (similar to dolutegravir)
How is Cabotegravir used?
Cabotegravir Apretude®
-used with Rilpivirine (NNRTI) for HIV treatment
-used for PrEP w/o Rilpivirine
-IM injection once monthly or once every other month !!!
1st Entry Inhibitor
-Maraviroc, Selzentry®
-only works with CCR5-tropic virus -> Trofile assay
-ORAL
How is the MOA of Entry inhibitors different from Fusion inhibitors?
-Entry inhibitor blocks the CCR5 Co-receptor on the target CD4 cell
-Fusion inhibitor blocks the Glycoprotein gp41 on the virus’s outer membrane
Considerations for Enfuvirtide, Fuzeon®
-Fusion inhibitor
-Reserve for last salvage therapy
-injection site reaction (injection site can be only used once)
How does Ibalizumab (Trogarzo) work?
-an antibody blocking the CD4 receptor
-for heavily treatment-experienced patient
-IV every 14 days
Fostemsavir (Rukobia)
-Film-coated, extended-release tablet, Oral
-used for treatment-experienced patients infected with MDR-virus
-MOA: binds to gp120 and prevents attachment
-ADEs: QTc prolongation, acute liver injury
What is the function of Metabolism inhibitors?
Ritonavir and Cobisistat
-used to BOOST antiviral agents
-Ritonavir with antiviral activity -> could contribute to resistance
Combiproduct: Genvoya
Elvitegravir / Cobicistat / Emtricitabine / TAF
Which product contains:
Elvitegravir / Cobicistat / Emtricitabine / TDF
Stribild
Which product contains:
Abacavir / Dolutegravir / Lamivudine
Triumeq
Combiporduct: Descovy
– Emtricitabine / TAF
Which product contains:
Emtricitabine / TDF
Truvada
What does Cabenuva contain?
Cabotegravir / rilpivirine
How is chronic Hepatitis B defined?
- defined as persistence of HBsAg > 6
months
-further: Further classified by “e” antigen (HBeAg) status AND by whether there is liver necroinflammation
How is hepatitis B treated?
-used to be treated with Interferons and Pegylated interferons
-then NRTIs
-now combination therapies
MOA of Interferons
Activates the Janus Kinase-Signal Transducer and the JAK-STAT pathway (inhibited in auto-immune diseases)
What is the purpose of Pegylated Interferons?
prolongs the half-life -> so it can be given less frequently
What are the side effects of Interferons?
-Flu-like symptoms:
N/V, chills, headaches, Malaise
-Bone marrow suppression
-Neuropsychiatric disturbance
Which drug is active against Hep B and HIV
and should not be co-administered?
Entecavir (Baraclude)
-not for treatment of HIV unless other HIV drugs are on board -> bc if treated for HepB alone HIV can develop resistance
-more potent than lamivudine
-take on an empty stomach (2hr space before or after food), avoid fatty meals
Entecavir is considered an alternative to which drug and to treat which disease?
-lamivudine (3TC) and tenofovir to treat only HepB
Which drug can be used in lamivudine and entecavir-resistant strains?
-Adefovir (HEPSERA)
-Less potent than lamivudine
-ADEs at higher doses: Nephrotoxicity, Falconi syndrome !!!
Which step of the infection is blocked by Neuraminidase?
The releasing step
-Neuraminidase cleaves off the sialic acid residue on the host cell -> the newly formed virus can be released
-Blocking neuraminidase will result in failed budding of the virus
Which steps are blocked by amantadine and rimantadine?
The viral uncoating step
What are the side effects of Oseltamivir?
-rare cases of SJS and neuropsychiatric effects (personality change)
-requires renal adjustment
Formulation of Anti-Influenza drugs
Osletamvir: Oral
Zanamivir: Inhaled
Peramivir: IV
ADE of Zanamivir
Bronchospasm
works against mild Influenza A and B, and some avian influenza
Peramivir
-given IV
-only FDA-approved for uncomplicated Influenza A/B
-20h half-life, single dose
-ADEs: Seizures, anticholinergic
What is Amantadine actually approved for
Anticholinergic
Class side effects: Seizueres, CNS, edema, anticholinergic (can’t see, can’t pee, can’t spit, can’t swallow)
Amantadine (SYMMETREL)
Rimantadine (FLUMADINE)
prevent uncoating of the virus
Baloxavir (Xofluza)
First-in-class polymerase acidic (PA) endonuclease inhibitor
-viral RNA polymerase complex for viral transcription
-may have activity against oseltamivir-resistant strains
