HIV Therapeutics

Question 1

principles of ART

Answer 1

minimum of 3 drugs
use phamacokinetic interactions to boost plasma levels
use drugs that interfere with HIV at different life cycle stages
consider adherence
consider resistance
choose drugs to delay toxicities

Question 2

mechanism of action of nucleoside RT inhibitors

Answer 2

the nucleoside RT inhibitor gets converted intracellularly to triPO4. it has an azide group instead of a 3’OH so when it gets incorporated into growing chain of DNA, it causes chain termination

Question 3

NRTI toxicities

Answer 3

Lactic acidosis- mainly with DDI and D4T due to mitochondrial damage that increases lactate conc. and decreases pH, causes nausea, vomitting etc.
Renal failure- tenofovir
anemia- AZT
hypersensitivity- Abacavir (you can send people for HLA B5701 testing to see if they’re going to react)

Question 4

what is another major problem with nucleoside analogs

Answer 4

resistance- there is no proofreading with RT therefore there are mutations a lot. Mutations can occur 10^4 times per day at each nucleotide position so you could have a patient that was resistant to a treatment even before you start them

Question 5

mechanism of NNRTI

Answer 5

bind to active site of reverse transcriptase and prevent DNA chain from elongating

Question 6

why are there 2 generations of NNRTI?

Answer 6

mostly because of resistance- and here there is cross class resistance

Question 7

NNRTI generation 1 toxicities

Answer 7

liver failure- nevirapine

CNS toxicity- efavirenz

Question 8

NNRTI generation2 toxicities

Answer 8

etravirine and rilpiverine- caused rashes, hepatic issues, and headaches

major takeaway with these is that you have them because of resistance

Question 9

what is the exception to the fact that mutations that confer resistance to one NNRTI confer cross-resistance to other NNRTIs

Answer 9

the second generation NNRTIs because they have a different mutation profile

Question 10

mechanism of action of protease inhibitors

Answer 10

they bind to the protease and prevent it from cleaning the gag/pol polyproteins to form a mature virion, keeping them in an immature and non-infectious state

Question 11

toxicities of protease inhibitors

Answer 11

hyperlipidemia (high LDL, high triglycerides)
insulin resistance, hyperglycemia, diabetes
lipodystrophy- excess fat in abdomen, lack of fate in facial area
hepatic- hyperbilirubinemia and elevated liver enzymes
BIG ONE = osteonecrosis, osteoporosis, and osteopenia (aseptic necrosis of the hips)

Question 12

resistance to protease inhibitors

Answer 12

very complex- at first it may be to a specific drug but with time you get more mutations, which confer more resistance and eventually you have a highly resistant virus that has cross -class resistance to the entire class

Question 13

2 antiretrovirals that inhibit hiv binding

Answer 13

enfuvirtide and maraviroc

Question 14

mechanism of enfuvirtide

Answer 14

bind to gp41 blocking the conformational change necessary for the viral and cell membrane to fuse

Question 15

downside to enfuvirtide

Answer 15

it must be administered subcutaneously and patients dont like it

Question 16

mechanism of chemokine receptor antagonist maraviroc

Answer 16

this blocks the ccr5 receptor; hiv must be ccr5-tropic in oder for this to work

Question 17

ADR for maraviroc

Answer 17

liver toxicity, cardiac events, and because it is metabolized by CYP3A4, there is a large potential for drug-drug interactions

Question 18

mechanism of integrase inhibitors

Answer 18

prevent the viral dna from integrating

Question 19

toxicity of integrase inhibitors

Answer 19

rhabdomyolysis (leading to kidney failure)

resistance can develop in the HIV integrase

Question 20

ritonavir

Answer 20

is used to boost the action of a primary protease inhibitor (usually lopinavir). ritonavir is not serving any other purpose than to increase the serum level and time over the curve of the primary protease

Question 21

number of virions produced daily in HIV

Answer 21

~10 billion

Question 22

incomplete suppression/drug resistance

Answer 22

when we kill the wt but we have residual live virus left over (mutant virus); this is either from using the wrong drug or from noncompliance

Question 23

durable suppression

Answer 23

we kill off the viral load from giving the right drug and the patient being compliant

Question 24

viral load

Answer 24

=SPEED; it is the plasma levels of HIV RNA and it is related to the rate of disease progression and the time to death

Question 25

CD4 count

Answer 25

= DISTANCE; it is the rate of immune damage that correlates with the risk for opportunistic infections and time to death

Question 26

delayed ART factors

Answer 26

risk of resistance and transmission of a resistant virus
drug toxicity
preservation of limited treatment options

Question 27

early ART factors

Answer 27

increase in potency, durability, safety, and simplicity of the regimens 
decrease in resistance
increase in treatment options
decrease in toxicity
decrease transmission
risk of uncontrolled viremia

Question 28

people now start ART with CD4 counts

Answer 28

500….but really it is up to provider discretion

Question 29

patients initiating ART must be willing to

Answer 29

commit to life-long tx, understand benefits, risks, and importance of adherence

Question 30

defer therapy

Answer 30

elite controllers
when there are no comorbities
when there is a concern for adherence
clinical/personal factors

Question 31

initial therapy recommended

Answer 31

integrase inhibitors with 2 other drugs
or protease inhibitors (boosted) with 2 other drugs
NNRTI now the alternative because of the CNS side effects

Question 32

change therapy when…

Answer 32

clinical failure (opportunistic infection)
virologic failure (failure to suppress viral load)
immunologic failure (failure to reconsitute CD4 cells)
toxicity/ intolerance
noncompliance

Question 33

bottom line

Answer 33

potency, simplicity, tolerance, and adherence –> prevent resistance and if viral failure occurs, evaluate resistance before going to salvage options

Question 34

factors that increase risk of HIV transmission

Answer 34

large, hollow-bore needle, deep injury, visible blood on the device, procedure with blood vessel, terminal AIDS in source patient

Question 35

PEP what do you do?

Answer 35

baseline HIV, HEP B/C test and start treatment as soon as possible with this 2 pill regimen (usually they use the old fashioned AZT); treatment depends on risk and source and may be stopped shortly after negative result

Question 36

Risk in occupational settings vs. nonoccupational settings

Answer 36

1-30% risk depends on the sexual behavior- ulcers, trauma

The needle risk is about .67% per contact but the sexual risk is much harder to quantify

Question 37

nPEP is controversial but it mentions

Answer 37

starting within 72 hours, sexual assault victims are covered, other people might not be covered and might have OOP expenses

Question 38

Use of PrEP with daily use of tenofovir-emtricidabine

Answer 38

decrease the risk of transmission between MSM or heterosexuals with an HIV-infected partner anywhere from 44-90%

Question 39

who gets PrEP?

Answer 39

adults at high risk of HIV infection- men who have unprotected anal sex with men and have multiple or anonymous partners, heterosexuals with multiple partners in areas of high HIV prevalence, partners of HIV-positive people who have no achieved viral suppression, injection drug users in treatment

Question 40

prior to PrEP what must be done?

Answer 40

HIV testing (because they must be negative prior to use), baseline labs of serum creatinine and urinalysis (because of the kidney toxicity of the medication), hep B serology, and pregnancy test

Question 41

PrEP is part of a…

Answer 41

a comprehensive prevention program involving counseling, acccess to condoms, and management of other sexually transmitted infections