L23- Antiretroviral Drugs, HIV Flashcards
describe the 4 F’s of HIV progression
Flu-like Sxs (acute HIV)
Feels fine (chronic latent HIV, asymptomatic)
Falling T cell count (<200 = AIDS)
Final crisis
HIV treatment goals:
- (1) generally for patient
- (2) in terms of function and lab values
- (3) in terms of prevention
1- reduce HIV related morbidity, prolong survival, improve quality of life
2- restore/preserve immune function, maximally suppress viral load (<50 copies/mL = undetectable)
3- prevent vertical transmission
(1) % chance of vertical transmission of HIV w/o Tx
(2) % with Tx
1- 20-30% (no Tx)
2- <0.5% (w/ Tx)
describe HAART
highly active antiretroviral treatment:
-3 active drugs from at least 2 drug classes (of the 6 classes)
anti-HIV therapy is usually initiated when…. (in uncomplicated cases)
CD4 T cell count <500 cells/mm^3
list the situations where there is urgency to initiate anti-HIV therapy
-Pregnancy- to avoid vertical transmission
- AIDS defining conditions
- acute opportunistic infections
- HIV-associated nephropathy (possible CKD)
- lower CD4 cell counts
- acute/early infection
- HepB or HepC co-infection
HAART:
- usually undetectable levels of viral load occurs w/in (1) timeframe
- (2) list the many predictors for successful Tx
1- 12-24 wks
2: -low baseline viral count ARV therapy: -high potency -tolerability -convenience and excellent adherence to Tx
list the ARV drug classes
- entry / fusion inhibitors
- NRTIs (nucleoside/tide reverse transcriptase inhibitors)
- NNRTIs (non-nucleoside/tide RTIs)
- integrase inhibitors
- protease inhibitors
- pharmacokinetic enhancers
list the entry / fusion inhibitors, ARVs
Maraviroc- entry
Enfuvirtide- fusion
(1) is the entry inhibitor of HIV by blocking (2) receptor, therefore is only effective in (3) situations.
1- maraviroc
2- CCR5 receptor (HIV co-receptor)
3- m-tropic phase // early infection (before transition to t-tropic / CXCR4)
Maraviroc:
- (1) metabolism
- (2) route of administration
- (3) AEs
1- CYP3A4
2- oral
3- well-tolerated, some risk for hepatotoxicity
(1) is the fusion inhibitor of HIV by (2) mechanism. It is approved for (3) uses.
1- enfuvirtide
2- resembles gp41 structure –> inhibits function
3- treatment experienced adults (previously on ARVs) with evidence of viral replication ++++ only for HIV-1 Tx
______ is the only ARV not given orally
enfuvirtide, fusion inhibitor / gp41 analog
-given SQ
Enfuvirtide:
- (1) AEs
- (2) importantly absent AE
1- Injection related –> hypersensitivituy reactions and eosinophilia rarely occur
2- no drug interactions
list the NRTIs
(nucleo-side/tide reverse transcriptase inhibitors) – st. zelda
- stavudine
- tenofovir
- zidovudine
- emtricitabine
- lamivudine
- didanosine
- abacavir
NRTIs:
- (1) key structural feature related to function
- (2) is the key risk with monotherapy (hint- kinda 2 things)
- (3) general metabolism feature
1- lacks 3’-OH –> stops transcription / chain termination
2- rapid resistance —> cross-resistance to other NRTIs
3- most are not metabolized by cytochrome enzymes => no drug interactions
NRTIs stop DNA transcription which importantly includes (1) and can lead to (2) AEs.
- (3) are the other common AEs
- (4) are the rare, but fatal AEs
1- inhibition of mitochondrial DNA polymerase
2- peripheral neuropathy, myopathy, lipoatrophy, lactic acidosis
3- pancreatitis, myelosuppression, cardiomyopathy
4- hepatotoxicity (lactic acidosis, hepatomegaly w/ steatosis)
______ NRTIs are associated with dyslipidemia and insulin resistance
- zidovudine
- stavudine
NRTI, Stavudine:
- (1) analog
- (use/avoid)
- (3) AEs
1- thymidine
2- avoid (‘stabs you in the back with AEs– high mitochondrial DNA polymerases)
3- peripheral neuropathy, lactici acidosis, hyperlipidemia, neuromuscular weakness
______ is the only nucleotide analog (all others are nucleosides)
tenofovir
NRTI, Tenofovir:
- (1) analog
- (use/avoid)
- (3) common AEs
- (4) is monitored
1- adenosine (only nucleotide analog)
2- use
3- upset GI (common in lactose intolerant patients)
4- serum creatinine for renal insufficiency
______ is the only NRTI with significant drug interactions, describe common interactions with other ARVs
tenofovir (only nucleotide analog)
- inc [didanosine] –> dec dosage
- dec [atazanavir] –> inc dosage
NRTI, Zidovudine:
- (1) analog
- (use/avoid)
- (3) AEs
1- thymidine
2- avoid — except 1st line for pregnant Pts (best at preventing vertical transmission
3- neutropenia, macrocytic anemia (bone marrow suppression), lipoatrophy —- avoid with Stavudine
NRTI, Lamivudine:
- (1) analog
- (use/avoid)
- (3) AEs
- (4) importantly absent mechanism
1- cytosine
2- avoid
3- HA, dry mouth, high level resistance
4- no effect on mitochondrial DNA polymerase or bone marrow precursor cells
NRTI, Emtricitabine:
- (1) analog
- (use/avoid)
- (3) AEs
1- cytosine
2- use
3- hyperpigmentation on palms/soles, 1-3% of Pts, more in darker skin
NRTI, Didanosine:
- (1) analog
- (use/avoid)
- (3) AEs
1- adenosine
2- avoid (high affinity mitochondrial DNA polymerase)
3- *pancreatitis (–> death), peripheral neuropathy, diarrhea, hepatic dysfunction, CNS effects
NRTI, Abacavir:
- (1) analog
- (use/avoid)
- (3) AEs
- (4) is necessary before use
1- guanosine
2- use, slow development of resistance — *avoid in cases with HLA-B57.01 => hypersensitivity rxns
3- *hypersensitivity rxns (if predisposed), GI upset, HA, dizziness
4- *genetic testing
list the NNRTIs
(non-nucleo-side/tide reverse transcriptase inhibitors)
- rilpivirine
- efavirenz
- nevirapine
NNRTIs:
- (1) discuss general usage
- (2) discuss general AEs
1- ONLY for HIV-1, largely avoided but still used b/c cheap
2- skin rash (SJS = steven-johnson syndrome, TEN = toxic epidermal necrolysis), GI intolerance
what are the main concerns and disadvantages with usage of NNRTIs
1) resistance + cross-resistance with other NNRTIs –> mutations in the NNRTI pocket that bids the drugs
2) drug interactions –> induction and inhibition of CYPs
3) high incidences of hypersensitivity rxns
what are the main advantages of with usage of NNRTIs
- lacks effects on blood forming elements (bone marrow precursors)
- lacks cross-resistance with NRTIs (different binding sites)
NNRTI, Nevirapine:
- (use/avoid)
- (2) AEs
- (3) metabolism
- (4) previous use, explain
1- avoid (all NNRTIs) – if used, titrate dose
2- severe hepatotoxicity (not for women T cell count >250, men >400)
3- urine metabolites via CYP3A4, CYP2B6
4- single does to prevent vertical transmission b/c most effective —- but pregnancy is predisposition for hepatotoxicity
NNRTI, Efavirenz:
- (use/avoid)
- (2) AEs
- (3) are monitored
1- avoid (all NNRTIs)
2:
- CNS toxicities (50%): dizziness, drowsiness, insomnia, nightmares / vivid dreams, HA
- Psychiatric disturbances: depression, mania, psychosis, *suicide
- Rash (25%)
3- TGs, HDL, LDL, total cholesterol
NNRTI, Rilpivirine:
- (use/avoid)
- (2) AEs
1- avoid in general — use in pregnancy
2- rash, depression, HA, insomnia, elevated LFTs + creatinine (reversible)
-QT prolongation at high doses
list the integrase inhibitors
bictegravir
raltegravir
elvitegravir
dolutegravir
describe the AEs of Integrase Inhibitors
For All: GI upset, rash
Raltegravir- slight inc in CK (creatinine phosphokinase)
Integrase Inhibitors:
- (1) are metabolized by CYP3A4
- (2) are metabolized by UGT1A1
1- bictegravir, elvitegravir, dolutegravir
2- bicetegravir, *raltegravir, dolutegravir
______ integrase inhibitor requires co-administration with PK enhancers
elvitegravir
(1) integrase inhibitor is recommended for pregnant Pts
(2) integrase inhibitor is contraindicated in pregnancy
1- raltegravir
2- dolutegravir (neural tube defects)
list protease inhibitors (indicate specific enzyme)
*inhibits HIV aspartyl protease
- lopinavir
- indinavir
- nelfinavir
- darunavir
- atazanavir
Protease Inhibitors:
- (good/poor) bioavailability
- high fat meals inc F for (2) and dec F for (3)
- (4) is a key associated risk
- (5) is also usually required
1- poor F 2- nelfinavir 3- indinavir 4- drug interactions - high potential 5- requires PK enhancers
list the AEs for protease inhibitors
- GI upset
- paresthesia
-*lipid metabolism disturbances: hypertriglyceridemia, hypercholesterolemia, DM –> contraindications
***Fat redistribution / accumulation – Cushing Syndrome: central obesity, buffalo hump, facial / peripheral wasting, breast enlargement, Cushingoid appearance
Protease Inhibitors:
- (1) is not associated with dyslipidemia and hyperglycemia, but may cause PR prolongation
- (2) should be avoid with EtOH as it can lead to disulfiram rxn
- (3) may precipitate a Sulfa allergy
- (4) can lead to unconjugated hyperbilirubinemia and or nephrolithiasis
1- atazanavir
2- lopinavir
3- darunavir
4- indinavir
list the pharmacokinetic enhancers
cobicistat
ritonavir
PK enhancers have (1) activity in order to improve (2) and (3) of other ARVs in order to change (4) in terms of ARV therapy
1- inhibits CYP3A4
2- inc ARV plasma concentration
3- inc tolerability
4- lower and less frequent dosing
PreP = (1):
-(2) effectiveness
Pre-Exposure Prophylaxis- combination NRTIs
- emtricitabine
- tenofovir
-99% effective via sex, 74% effective via IV drug use
Post-exposure prophylaxis = ______
1) emtricitabine + tenofovir + dolutegravir
2) emtricitabine + tenofovir + raltegravir
-given for 28 days or until source is shown to be HIV-negative
list the regimens usually used initially in HIV patients
[2 NRTIs + 1 integrase inhibitor]
1) emtricitabine + tenofovir + bicetegravir
2) emtricitabine + tenofovir + dolutegravir
3) emtricitabine + tenofovir + raltegravir
4) abacavir + lamivudine + dolutegravir
describe the HIV treatment for newborns
- 4-6 wk prophylaxis
- Nevirapine + Zidovudine
-nevirapine hepatotoxicity not as prevalent in infants
