This class of drugs competes with endogenous deoxyribonucleotides for the catalytic site of reverse transcriptase and prematurely terminates DNA elongation as it lacks the requisite 3-OH for sugar phosphate linking. This results in potent antiviral activity against HIV-1 and HIV-2
reverse transcriptase inhibitors (NRTIs)
Thymidine analogs of NRTIs?
stavudine and zidovudine
Deoxycytidine analogs of NRTIs?
emtricitabine and lamivudine
Deoxyguanosine analogs of NRTIs?
didanosine and tenofovir (tenofovir diosproxil fumarate, a deoxyadenosine-monophosphate nucleotide analog) - a nucleotide is a nucleoside with one more phosphate
NRTIs require phosphorylation to the _______ moiety to become active.
NRTIs are mainly eliminated by the ____
kindey (Dosage adjustments)
chemically heterogenous group the bind noncompetitively to reverse transcriptase. Do not require activation and do not compete against endogenous deoxyribonucleotides. Do not have potent viral activity against HIV-2.
What are the 4 NNRTIs?
efavirenz, delavirudine, nevirapine, etravirine
side effects associated with NNRTIs?
rash, elevated liver fxn test (esp nevirapine)
efavirenz - CNS
NNRTIs have (long or short) t1/2s and are cleared by the ____ or _____ thru cyp450. NNRTIs are unique in the only a single ______ is needed to confer high-level cross resistance for the class
liver or gut
a single mutation
What NNRTI is an exception to the high level of cross resistance?
etravirine (low genetic barrier to resistance!)
This group of drugs completely inhibit the cleavage of the GAG-POL polyprotein, which is a cruicial step in the viral maturation process, resulting in the production of immature, noninfection virions
Protease inhibitiors (all end in -navir except for tripanavic)
Common side effects with PIs?
GI distress and metabolic changes (increased lipids, insulin insensitivity, changes in body fat distribution)
PIs are metabolized by the ___ and ___ (mainly cyp ___). They are almost always used with small doses of _____.
liver and gut (mainly by cyp 3A4)
ritonavir (a cyp 3A4 inhibitor that enhances plasma concentrations of the PI of interest)
_____ is a fusion inhibitor. It is a synthetic 36-AA peptide that binds to GP 41, which inhibits fusion of HIV with target cell.
enfuvirtide is preferably administered via ____.
Most common SE is _____.
It is cleared via _____.
It has a low/high genetic barrier to resistance.
Subq (but it can be given orally)
Injection site reactoin
protein catabolism and AA recycling
low genetic barrier to resistance
_____ blocks the CCR5 co-receptor
resistance to maraviroc may be more difficult to develop.
*ONLY affective against R5 virus! assay must be performed
Maraviroc increases susceptibility to ______.
It is metabolized by ____ and _____ so it is susceptible to drug-drug interactions.
flavivirus (west nile)
bind to HIV integrase while it is in a specific complex with viral DNA. As a result, the viral DNA cannot become incorporated in the human genome and cellular enzymes degrade unincorporated viral DNA
integrase strand inhibitor (InSTIs) - raltegravir, elvitegravir
raltegravir is metabolized by ___
elvitegravir is metabolized by ___
UGT1A1 (glucoronidaiton) - not highly susceptible to DIs
CYP 3A4, then glucoronidated - highly susceptible to DIs... sometimes given with with ritonavir for high concentrations
HIV drugs that are substrates of CYP3A4:
ALL PIs (except nelfinavir-cyp2C19)
NNRTIs: delzvirdine adn etravirine
CCR5 antagonist maraviroc
HIV drugs that are inducers of CYP3A4:
HIV drugs that inhibit CYP3A4:
All PIs and delavirudine (NNRTI)
What PI does not have to be used with ritonavir to increase concentrations?
nelfinavir, b/c it is metabolized by cyp2C19
Rifampin is a potent cyp3A4 ______ and is CI with use of most PIs, etravirine, and maraviroc
BUT, ritonavir given with PIs allows the use of Rifabutin (still have to give rifabutin at a higher dose)
What is the recommended first line tx for initial treatment of HIV?
tenofovir (NRTI) + emtricitabine(NRTI) + either PI (daranavir or atazanavir w/ ritonavir) or efavirenz (NNRTI) or raltegravir (InSTI)
What are noticable updates about initial tx in the WHO guidelines?
being tx at higher CD4 threshholds (350 cells/mm3) and do not include stavudine (NRTI) as initial therapy
Avoid ____ in pts with pre-existing renal dysfunction
tenofovir (use abacavir instead)
avoid ____ in fertile women not on stable birth control
efavirenz (PIs are alternatives)
If you want to use abacavir (NRTI) in your regimen, you must test for ______
human leukocyte antigen (HLA) B* 5701 - if the patient is postive it is strongly correlated to abacavir HS
you use a ____ test before initiating maraviroc to est if the virus uses the CCR5 co receptor
Do not use:
____ is also recommended:
Post exposure prophylaxis of HIV:
2 NRTIs w/ ritonavir boosted PI for atleast 4 weeks within 72 hours of exposure
(Two NRTIs can be offered to healthcare workers at lower risk - ie mucous membrane contact)
New drugs active against highly active HIV:q
newest PIs (darunavir and tipranavir) and newest NNRTI etravirine
____, ____, _____ are active against NRTI, NNRTI, and PI resistant viruses
raltegravir (integrase strand inh), maraviroc (co receptor inhibitor), and enfuvirtide (fusion inhibitor)
tenofovir disoproxil fumerate
DRV - must combine with ritonavir
TPV - must be combined with ritonavir
How is PCP treated?
trimethoprim-sulfamethoxazole, 15-20 mg/kg/day in 3-4 divided doses based on TMP component for 21 days. (patients with mod to sev should also be treated with corticosteroids).
What are some alternate regimens for PCP?
pentamadine (mod-sev) (pronounced SEs like hypotension, tachycardia, n/v, hypo/hyperglycemia, pancreatitis, irreversible DM, elevated transaminase levels, nephrotoxicity, leucopenia, and arrhythmias), dapsone + TMP (mild-mod), primaquine + clinda (mild-mod), and atovaquone (mild-mod)
tenofavir has been associated with:
renal proximal tubulopathy and osteoporosis
PIs and zimovudine-lamivudine has been associated with:
PIs, efavirenz, thymidine analogs have been associated with ______
increased TGs and LDL
abnormal glucose homeostasis
body fat abnormalities (central fat increases, peripheral fat decreases)
lactic acidosis (ALL NRTIS!!!)
What can reverse central fat accumulation?
Metformin (but it can lead to unwanted reductions in lead body mass and peripheral fat)
Hyperlipidemia can be controlled with statins, but ____ and ____ need to be avoided b/c of their potential drug interactions
lovastatin and simvastatin
What makes up Atripla?
efavirenz (600 mg) NNRTI
emtricitabine (200 mg) NRTI
tenofovir (300 mg) NRTI
BBW for Atripla?
Lactic acidosis and severe hepatomegaly with steatosis. Not approved for the treatment of chronic hep B infection and safety/efficacy have not been established in patients with both HIV and hep B. Severe exacerbations of hep b have been seen in patients who d/c emtricitabine or tenofovir, monitor liver upon d/c
how do you administer Atripla?
orally once daily on an empty stomach at bedtime (to help with nerves)
Atripla should not be used in patients with a creatinine clearance below
Atripla preg category ___
Atripla common AEs
rash, N/D, decreased bone mineral density, dizziness, HA, anxiety, depression, dream disorder, incr CrKinase, sinusitis, URTI, fatigue
Serious AEs associated with Atripla
prolonged QT interval, tosades de pointes, lactic acidosis, severe depression/suicidal thoughts, acute renal failure
Metabolism of Atripla:
main one is efavirenz (induces cyp3A4)
T1/2 of Atripla:
efavirenz: 40-55 hrs
emtricitabine: 10 hours
tenofovir: 17 hours
Do not give ___ vaccines to HIV patients
live (zoster, varicella, MMR)
_____ has a documented hx of causing oxidative stress, and this is compounded in people with glucose-6-phosphate-dehydrogenase deficiency
Dapsone -- G6PD causes Dapsone hemolytic anemia
Multi class drug combo's:
Atripla (efavirenzNNRTI + tenofovirNRTI + emtricitabineNRTI)
Complera (rilpivirineNNRTI + tenofovir + emtricitabine)
Combivir (zidovudine + lamivudine, AZT + 3TC)
Epzicom (Kivexa, abacavir + lamivudine, ABC + 3TC)
Trizivir (abacavir + zidovudine + lamivudine, ABC + AZT + 3TC)
Truvada (tenofovir DF + emtricitabine, TDF + FTC)