Opportunistic Disease Therapies Flashcards
HIV therapy is a ___________ therapy.
life-long
Goals of Antiretroviral Therapy (2)
- decrease viral load over time
2. restore and preserve immunological function
Treatment w/ ART promotes? (3)
- enhanced survival
- decreased morbidity
- reduced risk of transmission
What is essential to the effectiveness of treatment with ART?
patient adherence
What are the five classes of antiretroviral drugs?
- NRTIs: Nucleoside/tide reverse transcriptase inhibitors
- NNRTIs: Nonnucleoside reverse transcriptase inhibitors
- PIs: Protease inhibitors
- FIs: Fusion/Entry inhibitors
- INSTIs: Integrase inhibitors
Which CYP protein is taken advantage of by pharmacokinetic boosters to increase protease inhibitor levels? What drugs are used to do this?
- CYP450
2. ritonavir and cobicistat
Initial Therapy for HIV
2 NRTIs w/ one of the following:
- integrase inhibitors
- NNRTIs
- PI boosted w/ CYP450 inhibitor ritonavir/cobicistat
Common Regimens are formulated into __________
single tablet, fixed-dose
*not all cases of HIV can be treated as a coformulation
What are the three main initial regimens used in HIV patients?
- bictegravir/tenofovir alafenamide/emitricitabine
- Raltegravir plus tenofovir/emtricitabine
- Dolutegravir plus tenofovir/emtricitabine
What is the primary initial treatment given to a pt w/ HIV that is HLA-B*5701 negative?
dolutegravir/abacavir/lamivudine
Conditions when you should proceed with caution (5)
- low CD4 cell count
- high HIV RNA load
- positive for 5701 allele of human leukocyte antigen
4, the presence of other medical condition/coinfection - pregnancy (NOT contraindication)
Choice of second-line therapy depends on reason that first-line therapy failed (3)
- poor pt adherence
- drug-resistant strain
- suboptimal drug factors
What are fixes that can be made if first-line therapy is ineffective?
- boosted PI
- add/change INTSI and/or NRIs
- refer to current guidelines
How often should you dose with oral formulation?
once a day
Common ADRs of MOST antiretrovirals (6)
- headaches
- nausea
- vomiting
- diarrhea
- hepatotoxicity
- myelosuppression
Most antiretrovirals are metabolized/inhibited by _______
CYP enzymes
What are NRTIs?
nucleotide analogs
What are the prodrugs of tenofovir? (2)
- tenofovir alafenamide
2. tenofovir disoproxill fumarate
Because all NRTIs competitively inhibit reverse transcriptase, they are effective against HIV-
1 and 2
What are the thymine analogs? (2)
zidovudine and stavudine
What are the cytosine analogs? (2)
emtricitabine and lamivudine
What are the adenosine analogs? (2)
didanosine and tenofovir
What is the guanosine analog? (1)
abacavir
NRTIs are not activated until ________________?
they are phosphorylated by cellular machinery–> become the activated triphosphate form
Activated NRTIs lead to … (2)
- inhibition of binding w/ incoming nucleotide
2. Premature chain termination
Because NRTIs accumulate in all dividing cells in the body, _________ events can occur.
toxic; they inhibit reverse transcriptase more potently than human DNA polymerases
NRTI ADRs
- mitochondrial toxicity risk: peripheral neuropathy, pancreatitis, lipoatrophy, hepatic steatosis
- lactic acidosis: look for high aminotransferase, progressive hepatomegaly, metabolic acidosis of unknown cause
Lipoatrophy and insulin resistance occur most frequently in what two NRTIs?
stavudine and zidovudine
How are NRTIs excreted?
renal excretion of parent or conjugated compound
Inihibit reverse transcriptase but are NOT structurally related to nucleosides/tides
NNRTIs: non-nucleoside reverse transcriptase inhibitors
Are NNRTIs strain specific?
yes
What is the main limitation of NNRTIs?
resistance develops rapidly–> NEVER use as a single agent in monotherapy or as an add on to failing therapy
*cross-resistance w/ other NNRTIs occurs
NNRTI MOA
binds to a non-active site on reverse transcriptase–> drug-induced conformational change–> reduced activity of reverse transcriptase (negative allosteric modulation)
*no activity against host DNA polymerases
NNRTI ADRs
- hypersensitivity reactions (includes rash)
- dizziness
- neuropsychiatric effects(efavirenz)
What are the NNRTIs? (5)
- efavirenz
- nevirapine
- delavirdine
- etravirine
- rilpivirine
What is one easy way to increase absorption of NNRTIs?
take with food
Plasma protein binding for NNRTIs is ____
moderate to high
How are NNRTIs metabolized
hepatically–> many induce CYPs, the potential for DDI is high
What are the 2 fusion inhibitors?
maraviroc and enfuvirtide
*created due to some individuals exposed to HIV that didn’t get AIDS–> DELETION of CCR5 gene
Maraviroc (oral): CYP? Eliminated? ADRs?
- CYP3A4
- feces; 20% renally
- hepatotoxicity sometimes preceded by fever/rash, URI
Enfuvirtide(subQ): MOA? When is it used? Metabolized? ADRs?
- Binds HIV-1 protein gp41 = prevents conformational change needed for HIV to gain entrance into cell
- Indicated: treatment-experienced pts w/ evidence of viral replication despite ongoing therapy
- metabolized: proteolytic hydrolysis
- pain, erythema, induration, nodules(all pts)
Protease Inhibitors MOA
reversible inhibitors of HIV aspartyl protease = prevents cleaving of HIV proteins necessary for replication, maturity, and release
PI Indication
pts w/ uncertainties
PIs:
- atazanavir and darunavir most commonly prescribed
- all others end in -avir
PIs ADRs
- nausea
- diarrhea
- abdominal discomfort
- vomiting
- glucose/lipid metabolism issues = insuline resistance
- fat redistribution = buffalo hump
Food _______ absorption of PI
increases
PI Elimination?
CYPs
DDIs are ____________ for pts taking PIs
a significant concern
PI DDIs
inhibitors of CYP450
PI DDIs: simvastatin and lovastatin
rhabdo
PI DDIs: midazolam and triazolam
excessive sedation
PI DDIs: fentanyl
respiratory depression
PI DDIs: rifampin, St. John’s Wort
treatment failure due to induction of the CYPs
PI DDI Cautions
warfarin, sildenafil, phenytoin
Ritonavir Pharmacokinetics
- CYP3A4 inhibitor, CYP2D6
- low dose of ritonavir can be used to elevate levels of second PI
Cobicistat Pharmacokinetics
- inhibits CYP3A4, CYP3A isozymes, CYP2D6, and P-gp
- used to increase the bioavailability of atazanavir and darunavir
- increases serum creatinine
Integrase strand transfer inhibitors/INSTIs: what do they do?
- prevent the incorporation of HIV DNA into host genome
- first-line agents for newly diagnosed
- change to prevent infection after exposure if given immediately
What should be avoided while taking INSTIs?
antacids and other polyvalent cations (dairy)
INSTI: Raltegravir ADR?
rare but life-threatening rhabdo
INSTI: Bictegravir only available as coformulation tablet: dosing? Elimination? ADRs?
- daily dosing w/ food
- eliminated through glucuronidation and CYP
- nausea and diarrhea
INSTI class-wide ADR:
teratogenic: neural tube defects
In 2015 _____% of people were UNAWARE OF THEIR INFECTION
15
First indication of HIV?
opportunistic infections
In 2015 _____% of newly diagnosed hadn’t been linked to care w/n 3 mo
16
only about 49% of pts were effectively linked to care AND had durable viral suppression
likely due to poor adherence, unfavorable pharmacokinetics, or unexplained biologic factors
untreated pts survive ________ after initial manifestation of AIDS
1-2 yrs
What is the main principle of OI management?
treatment of HIV to restore fxnal immune system
6 Things to prevent OIs
- prevent exposure
- vaccinate
- use chemoprophylaxis to prevent first-episode disease
- treat emergent OI
- secondary chemoprophylaxis to prevent disease recurrence
- Discontinue prophylaxes w/ sustained ART
Immune Reconstitution Inflammatory Syndrome
inflammatory rxns that appear associate w/ immune reconstitution
- may be due to rapid increase in CD4 count
- fever, sweats, chills, malaise
- TB: paradoxical symptoms
- Mycobacterium Avium Complex: suppurative lymphadenitis
- Meningitis: increased intracranial pressure
- keep using ARTs, if severe enough may need to use corticosteroids
