Therapeutics Slide Deck 2 Flashcards
Antiretroviral classes
Antiretroviral classes
NRTI, NNRTI, PI, INSTI, Attachment & Entry Inhbiitors, Capsid Inhibitor
What are the drugs for NRTI?
TDF, TAF, FTC, 3TC, ABC, ZDV
What drugs belong to NNRTI?
DOR, RPV, EFV, NVP, ETR
What drugs belong to PI?
DRV/r or DRV/c, ATV/r, LPV/r
What are the drugs for INSTI?
What are the drugs for INSTI?
CAB, BIC, DTG, EVG/c, RAL
Attachment and Entry Inhibitors?
T-20, MVC, FTR, IBA
Capsid Inhibitor ?
LEN
TDF stands for?
Tenofovir** d**isoproxil fumarate (TDF)
TAF stands for?
Tenofovir** alaf**enamide
FTC stands for?
Emtricitabine
3TC stands for?
Lami-vudine
ABC stands for?
ABA-cavir
ZDV stands for?
Zido-vudine
What does DOR stand for?
DORAVIRINE
What does RPV stand for?
Rilpivirine
What does EFV stand for?
Efavirenz
What does NVP stand for?
Nevirapine
What does ETR stand for?
Etravirine
PIs: DRV is what and given with what?
DRV: Darunavir
can be given with (r) or (c)
PIs: What is ATV and what is it given with?
Atazanavir and given with (r)
PIs: What does LPV stand for and what is it given with?
LPV= Lopinavir and given with r
CAB stands for what?
Cabotegravir
BIC stands for what?
Bictegravir
DTG stands for what?
Dolutegravir
EVG stands for what? anything unusual for this?
Elvitegravir and given with booster (c)
RAL stands for what?
Raltegravir
T-20 stands for what?
Enfuvirtide
MVC stands for what?
Maraviroc
FTR stands for what?
Fostemsavir
IBA stands for what?
Ibalizumab
LEN stands for what?
LENA-capavir
HIV Drug Therapy Key Points:
What are the possible combinations of typical ART regimens?
2 NRTIs + INSTI
2 NRTIs + PI+PK enhancer
2 NRTIs + NNRTI
When to take PK boosters ?
At the same time as ARV drug being boosted
Ritonavir:
Protease inhibitor, causes adverse GI evenrs, taste disturbances, hyperlipidemia, insulin resistance.
Cobicistat
only as part of combo, adverse GI events, inhibits CrCl via MATE1 inhibition, but eGFR is not affected/
The (5) 1st Line ARV regimens for most HIV Tx Naive Patients
1). BIC/FTC/TAF
2). DTG + FTC/TAF
3). DTIG+ FTC/TDF
4). DTG/ABC/3TC
5). DTG/3TC
Selecting Initial ART: Pt characteristics
Pre-Tx HIV-1 RNA
Pre-Tx CD4 count
HIV genotype results
HLA-B*5701 status
Individual preferences Anticipated adherence
ART timing post-diagnosis
Selecting Initial ART: Regimen-specific considerations
1) Barrier to resistance
2) Potential AEs and drug toxicities, including risk of development of comorbid diseases
3) Known/potential DDIs
4) Convenience
5) Cost and access
Selecting Initial ART: Presence of specific conditions/factors
1) Comorbid conditions
2) Pregnancy or wish to become pregnant
3) Coinfections: HVC, HCV, TB
Step #1 The _ _ _ _ backbone . Identify the drugs that belong to this class
The Nucleoside Reverse Transcriptase Inhbitors
- TDF (Tenofovir disoproxil fumarate)
**- TAF **(Tenofovir AlaFenamide)
- **ABC (Abacavir)
- FTC **(Emtricitabine)
- **3TC **( Lamivudine)
HSR is a reaction to what?
Abacavir Hypersensitivity Reaction (HSR)
AHS reactions can cause what symptoms and median onset? Aggrevating/Remitting factors?
- Non-specific symptoms:
fever, rash, GI, malaise, respiratory issues - median onset is 9 days
- sx worsen if continuation fo drug, will reverse if stopped
HLA-B*5701 test is what for?
If positive= Do not initiate abacavir.
* Very strong association between HLA-B5701 presence and abacavir HSR
If positive, 40-50% chance of abacavir HSR
* Should screen for HLA-B5701 before starting on abacavir- screen once in lifetime
* White pts have higher risk
* A negative HLA-B*5701 result doesn’t absolutely rule out the possibility of some form of ABC HSR
Is ABC still recommended as initial therapy in most people with HIV/ concerns?
NO! Hard to start ARVs w/in 7 days when it takes > 7days to get HLA*B5701 result back in developed world.
NO large advantage over DTG/3TC alone
TDF vs TAF
What are both their advantages compared to ABC?
- They are both active against HBV
- They both dont require HLAB5701 testing
- TDF is associated with favorable lipid effects
TDF vs TAF. What are each others advantages?
- TDF= better lipid profile
- TAF= better on renal markers and BMD
What is the advantage of ABC compared to TAF/TDF? What pts could we use it in?
No dose adjustment in Renal pts, no nephrotoxicity and less BMD effects than either of them
**Use in pts with renal dysfunction or BMD issues? **
Disadvantages of TDF?
- decline in kidney function
- proximal renal tubulopathy= proteinuria, phosphate wasting
- BMD reductions due to phosphate wasting
Disadvantages of TAF?
- bad bad for lipids
- more weight gain than TDF
Disadvantages of ABC?
- Requires HLA*B5701
- unsolved MI risk
What are the doses of TDF, TAF, and ABC?
TDF= 300 mg OD
TAF= 10 mg OD when given with boosted PI/Cobicistat boosted elvitegravir
or 25 mg OD when given with non boosted ARVs
ABC= 600 mg OD
Renal adjustment in HIV Tx for TDF and TAF
TDF= Recommended for CrCl < 50mL/min
TAF=Not required if CrCl > 15 mL/min
*Cavet: TAF is co-formulated with FTC when used to treat HIV infection; b/c FTC has renal dose adjustment recommendations for CrCl < 30mL/min, TAF containing regimens aren’t recommended if CrCl < 30mL/min and patient not on hemodialysis.
FTC (Emtrici-tabine). What is the dose, and active against what?
200 mg daily and active against HBV as well
3TC (Lamivudine)
Standard dose 300 mg daily , commonly used with ABC
Active against HBV as well
Product monograph will tell you to dose reduce if renal function is < 50 mL/min…… but in practice this varies due to available only in 300 mg or 150 mg tablets, as a study showed that pts with renal function issues can tolerate normal doses of lamivudine
All patients with coinfection of HIV & HBV should receive ARV regimen that……
Includes 2 drugs with activity against HBV:
TAF or TDF + FTC or 3TC
INSTI (integrase strand inhibitor). What are the two players and their doses?
Bictegravir (BIC) - 50 mg
Dolutegravir (DTG)- 50 mg OD (Tx/INSTI naive) or 50 mg BID (INSTI resistance or in Tx/INSTI naive when given with enzyme inducers)
Bictegravir side effects?
Diarrhea
Nausea
Headache
Weight gain
Dolutegravir side effects?
Insomnia
Headache
Depression and suicidal ideation
(rare; usually in patients with pre- existing psychiatric conditions)
Weight gain
What are the benefits of the INSTIs?
High efficacy, tolerability, safety, high barrier to resistance, few DI, low pill burden
Explain the SCr change we see with bictegravir and dolutegravir or elvitegravir/c ?
SCr INCREASES by approx. 8 to 13 umol/L occurs within the first 4 weeks of bictegravir and dolutegravir (and elvitegravir/c)- eGFR decreases (but does not mean kidneys are worsening). Tx due to inhibition of renal proximal tubule secretion of creatinine but remains stable thereafter.
THIRD STEP: add Step 1 & Step 2 together (2 NRTI + 1 INSTI approach)
BIC/FTC/TAF= Biktarvy
DTG+ FTC/TAF= Tivicay + Descovy
DTG+ FTC/TDF= Tivicay+ Truvada
DTG/ABC/3TC= Triumeq
What are the advantages of single tablet regimens?
Simplicity, convenience, fewer copays, reduces selective nonadherence to components of regimen
What are the disadvantages of single tablet regimens?
inability to adjust dosages of components if needed to drug-drug interactions or tolerability issues (renal insufficiency), not available for all ART regimens, and not available for all NRTI pairings
When can we use 2 ARV drug regimen? (i.e., Dovato (DTG+3TC) Dolutegravir/lamivudine
Tx-Naive PLWH, contains 50 mg DTG, 1 pill once a day. Who is this NOT for?
* HIV Viral Load > 500,000 copies/mL,
* HBV co-infection
* ART being started before the results of HIV genotype resistance testing or HBV testing are available
* MAYBE if CD4 count < 200 cells/mm3 ????????
What drug can we use in pregnancy and in situations where more long-term clinical experience is needed? (i.e., chemo or TB Tx)
Tenofovir prodrug (TDF or TAF) + emtricitabine + raltegravir
side effects of raltegravir ??
WEIGHT gain, insomnia, uncommon CK elevation, muscle weakness, and rhabdomyolysis, Rare (TEN or SJS, rashes)
Raltegravir (RAL) - old INSTI
either 400 mg BID or 1200 mg PO OD. Benefits: low resistance barrier, higher pill burden, less convenient BID dosing
Elvitegravir- old INSTI
low barrier to resistance, PK booster needed (cobicistat), required which means +++ drug interactions
When would we use Stribild, Genvoya (Tenofovir prodrug, emtricitabine, + elvitegravir/cobicistat)
This player isn’t going to get any field time anymore….
What if we can’t/don’t go with an INSTI containing regimen?
Could prop up the PI or revive the NNRTI as the 3rd wheel for the NRTI backbone
Protease Inhibitor (PI)s . What is a current drug example and a benched one?
Darunavir (DRV) Dosing: 1) 800 mg PO daily with Food for Tx/PI naive- boost with ritonavir 100 mg PO daily or Cobicistat 150 mg PO daily
2) 600 mg PO BID for Tx experienced with at least 1 of 11 darunavir reisstance assoicated mutations (RAMs) - boost with ritonavir 100 mg PO BID
Atazanavir (ATV) is a benched player
-Has moderate barrier to resistance, low gastric pH required for absorption so PPI contraindicated, bilirubin is a surrogate marker for checking adherence
- atazanavir inhibits UGT1A1 to cause unconjugated hyperbilirubinemia (benign), but unless jaundice or scleral icterus happens, we dont have to stop
What is the benfit of darunavir? In what patients would we use this?
Benefit is that darunavir (DRV) has a HIGH barrier to resistance so we can use it in people who have been HIV+ for a long time, since the 90’s, as they probably have complex resistance profiles
What are the common protease inhbiitor side effects?
1) Nausea
2) GI intolerance
3) Diarrhea
& can also have increase in lipids, triglycerides, can have some CVD risks
NNTRIs. What are these? Who could we use it for?
Non-nucleoside reverse transcriptase inhibitors (NNRTIs). Potential niche area for those experiencing s/e with INSTIs use like extreme weight gain
What are the two key players that are NNRTIs? Whats a retired player?
Dora-VIRINE (DOR)
Rilpi-VIRINE (RPV)
retired- Efavirenz (EFV)
DORAvirine
-Resistance to both DOR and NRTIs at virologic failure
-Combo product is with TDF rather than TAF (only tenofovir combo product with 3TC)
**TDF/DOR/3TC **
Rilpivirine (RPV)
- Higher rates of virologic failure in patients with HIV VL > 100,000 copies/mL, CD4 counts < 200 cells/mm³
- Requires an acidic environment for absorption
PPI contraindicated
Counselling for Doravirine?
100 mg PO once daily, with or without food
Counselling for rilpivirine?
25 mg PO once daily with a MEAL containing at least 390 calories
Efavirenz counselling and when would we see efavirenz?
600 mg PO HS
OR 400mg daily studied in ENCORE-1 and found to be non-inferior for viral suppression with fewer efavirenz related s/e vs. 600 mg daily.
A STR with efavirenz 400mg/ TDF/ lamivudine is available in some countries (400mg daily dose not studied in pregnant women or TB/HIV co-infx)
Empty stomach to reduce CNS s/e (high fat foods increases absorption by 50%)
