(nucleo-side/tide reverse transcriptase inhibitors) -- st. zelda - stavudine - tenofovir - zidovudine - emtricitabine - lamivudine - didanosine - abacavir

L23- Antiretroviral Drugs, HIV Flashcards by Connor Patrick

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

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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

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(1) % chance of vertical transmission of HIV w/o Tx

(2) % with Tx

1- 20-30% (no Tx)

2- <0.5% (w/ Tx)

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describe HAART

highly active antiretroviral treatment:

-3 active drugs from at least 2 drug classes (of the 6 classes)

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anti-HIV therapy is usually initiated when…. (in uncomplicated cases)

CD4 T cell count <500 cells/mm^3

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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

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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

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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

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list the entry / fusion inhibitors, ARVs

Maraviroc- entry

Enfuvirtide- fusion

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(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)

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Maraviroc:

(1) metabolism
(2) route of administration
(3) AEs

1- CYP3A4
2- oral
3- well-tolerated, some risk for hepatotoxicity

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(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

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______ is the only ARV not given orally

enfuvirtide, fusion inhibitor / gp41 analog

-given SQ

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Enfuvirtide:

(1) AEs
(2) importantly absent AE

1- Injection related –> hypersensitivituy reactions and eosinophilia rarely occur

2- no drug interactions

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list the NRTIs

(nucleo-side/tide reverse transcriptase inhibitors) – st. zelda

stavudine
tenofovir
zidovudine
emtricitabine
lamivudine
didanosine
abacavir

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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

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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)

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______ NRTIs are associated with dyslipidemia and insulin resistance

zidovudine

- stavudine

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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

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______ is the only nucleotide analog (all others are nucleosides)

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tenofovir

NRTI, Tenofovir:

(1) analog
(use/avoid)
(3) common AEs
(4) is monitored

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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

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tenofovir (only nucleotide analog)

inc [didanosine] –> dec dosage
dec [atazanavir] –> inc dosage

NRTI, Zidovudine:

(1) analog
(use/avoid)
(3) AEs

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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

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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

L23- Antiretroviral Drugs, HIV Flashcards

(49 cards)