Antiretroviral Flashcards
HIV life cycle?
- binding
- fusion
- uncoating
- RT
- integration (integrase) – in to host cell DNA
- transcription
- translation
- virion assembly and budding
- maturation (proteases)
Course of HIV infection?
0-3 weeks - primary infections 3-6 weeks - possible acute HIV infection 9 weeks -8 years - clinical latency [no progression in clinical symptoms - no delcine or health] 8 years -constitutional symptoms 9 years - opportunistic disease 11 years - death
When is HIV treatment usually initiated?
When CD4+ count falls under 500 cells/mm^3
**pt needs to be motivated to get treatment
5 classes of drugs used to treat HIV?
- NRTIs
- NNRTIs
- Protease inhibitors
- Entry inhibitors
- Integrase inhibitor
NRTIs?
Nucleoside/tide reverse transcriptase inhibitors
These are analogs of native ribosides lacking 3-OH. Once inside the cell they are phosphorylated by cellular enzymes and then incorporated into viral DNA by RNA. Due to lack of 3’OH DNA elongation is terminated. Most activity against HIV-2 as well as HIV-1.
Resistance develops quickly if used alone. The most common mutation is at viral codon 184 when using Lamivudine, which actually restores sensitivity to zidovudine and tenofovir. Cross-resistance is possible.
AE - inhibition of mitochondrial DNA polymerase (peripheral neuropathy, myopathy, lipoatrophy, lactic acidosis), liver toxicity is rare but fatal [dyslipidemia and insulin resistance esp with Zidovudine and stavudine]
Drug interactions: Didanosine + Tenofovir = tenofovir increases plasma levels therefore didanosine dose needs to be reduced. NRTIs are not usually metabolized by cytochrome enzymes.
Zidovudine (ZDV, AZT)?
Nucleoside analog = thymidine
Administered orally, penetrates BBB well and dose needs to be adjusted in pts with cirrhosis
AE - bone marrow suppression (neutropenia and anemia), GI intolerance, headaches, insomnia [ Toxicity potentiated by coadmin. of probenecid, acetaminophen, lorazepam, indomethacin and cimetidine]
Stavudine (d4T)?
Nucleoside analog = thymidine
NRTI
Strong inhibitor of B and gamma DNA polymerase - high affinity for mitochondrial DNA polymerase leading to toxicity
Administered orally and dose needs to be adjusted in pt with renal insufficiency
AE - peripheral neuropathy, lactic acidosis, hyperlipidemia, neuromuscular weakness
Didanosine (DDL)?
Nucleoside analog = adenosine
NRTI
Absorption is best if taken in fasting state (acid labile) or combined with antacid. There is CSF penetration and dose needs to be adjusted in cases of renal insufficiency.
AE - high affinity for mitochondrial DNA polymerase, pancreatitis (esp in alcoholics and pts with hypertriglyceridemia), peripheral neuropathy, diarrhea, hepatic dysfunction, CNS effects
Tenofovir (TDF)?
Nucleotide analog = adenosine
Preferred NRTIs
Fixed dose combinations available…
Tenofovir + emtricitabine
Tenofovir + emtricitabine +efavirenz
[combination and fixed doses are better for compliance and for the pt – can only be give once original patent for drug runs out]
Take with food to increase bioavailability, long half life so dose needs to only be given once daily
AE - GI disturbance
Contraindications - renal insufficiency, drug interaction with didanosine, also decreases concentration of atazanavir [which can be overcome by boosting with Ritonavir]
Lamivudine (3TC)
Nucleoside analog = cytosine
Does not affect mitochondrial DNA synthesis or bone marrow rpecurosr cells
Resistance - high as it occurs with single AA substitution
AE - few as it does not affect mitochondrial polymerase
Emtricitabine (FTC)?
Nucleoside analog = cytosine
Preferred NRTI and is structurally related to lamivudine, given once daily
AE - Hypopigmentation of palms and soles – more commonly seen with darker skin patients compared to lighter skinned ptients
Abacavir (ABC)?
nucleoside analog = guanosine
HLA-B5701 association - DO NOT GIVE MEDICATION TO PTS WITH THIS HLA MARKER
Resistance = HIV virus requires several mutations so develops slowly
AE - GI, headache, dizziness, possible HSN reaction, sensitized individuals should NEVER be rechallenged (?)
NNRTIs?
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
MOA - selective, noncompetitive inhibitors of HIV-1 [not HIV-2]. They bind distinct site away form active site and result in inhibition of RNA and DNA-dependent DNA polymerase. Does not require phosphorylation by cellular enzymes.
Resistance - easy to develop b/c all drugs in this class bind to the same site away from RT, so even if mutations occur they cannot bind anymore, but the enzyme can still function and work for the virus. There is also cross-resistance as they all bind in the same location - they are not used in combination with each other
Advantage - lack effect of host blood-forming elements, lack cross resistance with NRTIs
Disadvantages - cross resistance with NNRTIs, drug interactions, high incidence of HSN reactions
AE - skin rash (including stevens-johnson syndrome), GI intolerance, all are CYP3A4 substrates acting as inducers and inhibitors
Nevirapine (NVP)?
NNRTIs
Excreted in urine as metabolites converted via CYP3A4, CYP2B6
AE…
- potential severe hepatotoxicity - do not sue in women with CD4 over 250 and men with CD4 over 400 [Once CD4 count drops, benefits outweight risks]
- Rash - dermatologic effects including up to Stevens-Johnson syndrome and toxic epidermal necrolysis
- 14 day titration pd at 1/2 dose required to reduce risk of serious epidermal reactions
Contraindications - induces CYP3A4 thereby increase metabolism of other drugs
Efavirenz (EFV)?
NNRTIs
Clinical Applications
• Results in increased CD4+ counts and decreased viral load
• No longer a first-line agent in new guidelines (2015)
Pharmacokinetics
• Oral
• t1/2 over 40h (once-a-day dosing)
• Extensively metabolized to inactive products
AE - high rate of CNS toxicity, rash, increased triglycerides, HDL and total cholesterol
Contraindications - potent inducer of CYP450, category D for pregnancy (don’t use within 1st week due to increased neural tube defects)
Rilpivirine?
NNRTI
Given orally and extensively metabolized to inactive products.
AE - rash, insomnia, depression, increased liver enzymes
Protease inhibitors (PIs)?
MOA
• Reversible inhibitors of HIV aspartyl protease (enzyme
responsibe for cleavage of viral polyprotein into RT, protease and integrase)
• Protease inhibition prevents virus maturation and results in production of non-infectious virions
• DO NOT REQUIRE INTRACELLULAR ACTIVATION
• Active against both HIV Active against both HIV-1 and HIV 1 and HIV-2
- poor oral bioavailability
- high fat meals increase BA with nelfinavir
- high fat meals decrease BA with Indinavir
- reduce metabolism as they are substrates of CYP3A4 [inhibitors]
- substrates for P-glycoprotein pump so kicked out of cells as soon as they are added in
- bound to plasma proteins [a1-acid glycoprotein which can increase in response to trauma and surgery]
AE - parathesias, nausea, vomiting, diarrhea, disturbance in lipid metabolism (diabetes, hypertriglyceridemia, hypercholesterolemia), chronic admin leads to a cushing-like appearance with fat redistribution and accumulation
**cannot stop drug and come back on
Drug interactions - potent inhibitors and substrates of CYP isoforms leading to many drug interactions
Resistance - accumulation of stepwise mutations of protease gene leading to high levels of resistance
Atazanavir (ATV)?
Protease Inhibitor
- administered with RTV
- structurally unrelated to other protease inhibitors
- well absorbed with food
- highly protein bound
- CYP3A4 metabolizer and inhibitor
- administration must be over 12 hrs apart from any H2-blockers and antacids
AE…
- PR interval prolongation
- Benign hyperbilirubinemia
- Rash
- Nephrolithiasis
Darunavir (DRV)?
Protease Inhibitor - inhibits HIV protease resistant to other protease inhibitors
- well absorbed with food
- metabolized and inhibits CYP3A4
AE - rash, avoid in pts with sulfur allergy
Indinavir (IDV)?
Protease Inhibitor
- administered with RTV
- least protein bound out of all protease inhibitors
- absorption is increased when taken with meals
- dosage should be reduced with hepatic insufficiency
AE – rash, blurred vision, nephrolithiasis, hyperbilirubinemia (adequate hydration is important)
Lopinavir (LPVr)?
Protease Inhibitor – one of the preferred Protease inhibitors and administered with RTV
-poor intrinsic bioavailability
Contraindicated for peole using St. Johns Wort as enzymes may be induced as well as pts on disulfiram or metronidazole as it is an oral solution containing EtOH
AE - generally well tolerated, diarrhea, nausea, flatulence
*give to pregnant pts
Nilfinavir (NFV)?
Protease Inhibitor – NOT boosted by RTV, only protease inhibitor give solo
-metabolized by several CYPs (esp CYP2C19) – it’s major metabolite has antiviral activity equal to parent compound
Contraindicated - many due to inhibition of CYP enzymes
AE - diarrhea which is controlled by loperamide, nausea, flatulence
Enfuvirtide (T-20)?
Fusion inhibitor
1st approved drug that inhibited viral fusion and were given to pts with tx-experience. It only has activity against HIV-1, there is no activity against HIV-2.
Similar in structure to gp41 which is a HIV protein that mediates membrane fusion. By binding gp41 subunit of the viral envelop glycoprotein preventing ability of virion to fuse cell membrane.
Parenteral administration only
AE - injection related problems, HSN rxn, eosinophilia, no drug interactions have been noted
Maraviroc?
Entry inhibitor
MOA - binds specifically and selectively to CCR5 thereby blocking HIV entry into cells
-metabolized by CYP3A4 and dose needs to be reduced when administered with protease inhibitors
AE - well tolerated with slight risk of hepatotoxicity
INSTIs?
Integrase strand transfer inhibitors
These medications are used in combination with other antiretrovirals. They are approved for treatment of experience and naive treatment patients with evidence of viral replication. This is the most popular antiretroviral class due to good side-effect profile and favorable effects on lipid metabolism.
MOA - bind integrase (enzyme used in replication of HIV-1 and HIV-2) leading to specific inhibition of final step of integration of viral DNA into host cell DNA
AE - well tolerated (rash, nausea, headache, diarrhea, insomnia), rhabdomyolysis is rare
Dolutegravir?
INSTI - Integrase strand transfer inhibitors
Primarily eliminated by glucoronidation via UGT1A1 enzyme but there is some contribution of metabolism from CYP3A4.
AE - well tolerated (nausea, headache, diarrhea), rare organ dysfunction
Drug interactions - occurs due to CYP3A4 interaction
Elvitegravir?
INSTI - Integrase strand transfer inhibitors
Primarily metabolized by CYP3A4 and may require pharmacokinetic enhancer (Cobicistat) to boost its effects [increasing bioavailability].
AE - well tolerated (nausea, headache, diarrhea)
Raltegravir?
INSTI - Integrase strand transfer inhibitors
Primarily eliminated by glucoronidation via UGT1A1 enzyme.
AE - well tolerated (nausea, headache, diarrhea) and possible increase in creatine phosphokinase
Drug interactions - with Rifampin, Tipranavir, efavirenz all may decreased Raltegravir concentration - PPIs may increase raltegravir concentration
What two medications are used as HIV drug enhancers for pharmacokinetics?
- Ritonavir (protease inhibitor)
2. Cobicistat
What is the role of the pharmacokinetic enhancer?
MOA
- potent inhibitor of CYP3A4 decreasing drug metabolism
- increase plasma concentration of anti-retroviral allowing for lower and/or less frequent dosing
- improve tolerability of ARV (side effects)
Ritonavir?
Used in combination with most protease inhibitors (except nelfinavir - all others are given with it). It is never used alone.
**some side effects of ritonivir alone
Cobicistat?
Used in combination with INSTI elvitegravir. It is also found in combination with darunavir and atazanavir.
**newest enhancer that is never used alone
What are the current medication regimes and recommendations for treatment-naive patients?
- 2x NRTI + INSTI
- 2x NRTI+PI
Preferred…
INSTI-based —
(1) Raltegravir (INSTI) + tenofovir(NRTI) + emtricitabine (NRTI)
(2) Dolutegravir (INSTI)+ tenofovir (NRTI) + emtricitabine (NRTI)
PI-based —
(1) Ritonavir-boosted darunavir (PI) + tenofovir (NRTI)+ emtricitabine (NRTI)
Recommendations:
- avoid using 2 agents of same nucleotide analog
- avoid overlapping toxicities
- pts symptoms and concurrent illness
- impact of drug interaction
- ease of adherence to a frequently complex administration regimen
What medication is recommended for infant born to HIV infected mother?
Zidovudine [start immediately after birth and administer for 6 weeks] – decreases risk of transmission
**maybe not the best drug due to AE, but is the oldest drug that we know works well
HIV prophylaxis post needle stick?
Raltegravi (INSTI)r+ tenofovir (NRTI) + emtricitabine (NRTI)
**regimen is given for 28 days and can be stopped if source is shown to be HIV negative
What prophylactic vaccines should be given to all-HIV infected pts?
- Streptococcus pneumonia
- Hepatitis A
- Hepatitis B
- Influenza
What vaccines are contraindicated in HIV positive patients with CD4+ count less than 200 cells/mm^3?
Live vaccines - MMR, varicella, zoster, etc
Do not give immunocompromised individual a live vaccine unless the benefits outweigh the risk [not under 200, but over 200 these live vaccines should be okay to administer]
