HIV drugs

zidovudine

NRTI (AZT), the first of its kind

interferes with thymidine incorporation and terminates elongation

may cause loss of limb fat, bone marrow suppression, skeletal muscle myopathy, or hepatic steatosis

often used in pregnant women or areas with limited resources

stavudine

NRTI (d4T)

interferes with thymidine and terminates elongation

may cause peripheral neuropathy, fat wasting/lipodystrophy, lactic acidosis

hepatic steatosis

emtricitabine

NRTI (FTC)

interferes with cytosine incorporation and terminates elongation

used for HIV-1 and HIV-2, low barrier to resistance if monotherapy.

shouldn’t be used for HBV unless TAF and TDF are also administered

used alongside tenofovir

has a long half- life and is excreted out unchanged

not very toxic, may cause hyperpigmentation with prolonged use

lamivudine

NRTI (3TC)

interferes with cytidine incorporation, terminates elongation

low barrier to resistance it monotherapy,

Dual combination with dolutegravir is appropriate for naïve patients

sorbitol interferes with this drug

no significant adverse effects

abacavir

NRTI (ABC)

only guanosine analog. terminates elongation

not for people with HLA-B 5701 genotype due to deadly toxicity. Not for HBV

potentially fatal if given to HLA-B 5701 genotype. generally avoided with people with coronary artery disease

Also may cause major cardiovascular adverse event

didanosine

he did not talk about this but…

tenofovir disoproxil fumarate

NRTI (TDF)

nucleoTIDE RT inhibitor. adenosine analog. parent compound has very poor bioavailability, which is why pro drug disoproxil fumarate prodrug given to increase bioavailability.

terminates elongation, has broad spectrum activity against viral DNA pol. and low affinity for human DNA pol.

resistance caused by K65R point mutation

can cause nephrotoxicity with acute tubular necrosis → fanconi syndrome. decreased bone mineral density

Reduced renal function

tenofovir alafenamide

NRTI (TAF)

nucleoTIDE RT inhibitor. adenosine analog, parent compound has poor bioavailability, so pro drug alafenamide given

resistance caused by K65R point mutation

well tolerated, less renal toxicity than TDF. can cause weight gain

raltegravir

INSTI - will block integrase

first in its class

generally well tolerated

dolutegravir

INSTI - so it blocks chromosomal integration of viral DNA by blocking integrase strand transfer

first choice for treatment naive patients, dual combination with lamivudine

14 hour half life

generally well tolerated, may cause weight gain

bictegravir

INSTI - so it blocks integrase, inhibiting the integration of viral DNA into the host

only available with TAF/FTC/BIC combo

glucuronidated by UGT1A1

generally well tolerated, may cause weight gain

cabotegravir

INSTI - so blocks integrase which normally incorporates viral DNA into host genome

combo with Rilpivirine

glucuronidated by UGT1A1

injected IM every 2 months

generally well tolerated, may experience weight gain

enfuvirtide

this is an entry inhibitor that works by blocking gp41, thus inhibiting fusion of HIV to the host cell

36aa peptide

only for patients that are treatment experienced

only drug administered parenterally, and is admin 2x/day

expensive, last resort

maraviroc

CCR5 blocker, thus blocking the binding of gp120 to this co-receptor

resistance develops when HIV tropism switches from CCR5 to CXCR4

more of a late stage therapy (which confuses me because doesn’t tropism switch later in HIV?)

well tolerated, but is a CYP3A4 substrate, so if you are taking other drugs that are metabolized by that then be cautious

saquinavir

PI, so it prevents the maturation of HIV particles and budding

no longer used, caused GI distress and lipodystrophy with long term use

lopinavir

PI hat prevents maturation of HIV particle

does not get used as much anymore, currently used if others fail

atazanavir

PI, prevents maturation of capsid and blocks HIV budding

used in both treatment naive and treatment experienced patients currently

current PI of choice if boosted

can cause jaundice but it generally well tolerated (he said not to worry about jaundice)

darunavir

PI, prevents maturation of capsid and blocks HIV budding

current PI DOC

is a sulfa drug so be cautious of allergies, otherwise pretty well tolerated

nevirapine

NNRTI (non-competitive antagonist of reverse transcriptase)

historically important, not a big deal now

unique in that it could be resisted after a single exposure in about 1/3 of the patients. Thus, it must be administered with other drugs

efavirenz

NNRTI (non-competitive antagonist for reverse transcriptase)

caused CNS toxicity including depression and suicidality (he emphasized this)

was considered teratogenic

late choice

what is the adverse effect associated with efavirenz

CNS toxicity, including depression and suicidality

etravirine

NNRTI (non-competitive antagonist for reverse transcriptase)

used in treatment experienced patients, worked after getting mutations that would often inactivate other NNRTIs

can cause fat redistribution and possibly stevens-johnson syndrome (though he didn’t talk about this)

rilpivirine

NNRTI (non-competitive antagonist for reverse transcriptase)

approved for naive patients

not susceptible to mutations of other NNRTIs, but still affected by some, so it is not as resistant as etravirine

must be taken with meal, don’t use it with a proton pump inhibitor

can also be in new combo with cabotegravir IM

causes side effects, but nothing remarkable

doravirine

NNRTI (non-competitive antagonist for reverse transcriptase) newest one, seems like DOC

approved for naive patients

has different resistance mutations

taken without food unlike rilpivirine

low incidence of side effects

lenacapavir

binds to capsid which leads to its dysfunction (normally it acts as a chaperone of DNA into the cell nucleus). Blocking this function will impair new virion formation/release

• interferes with gag and pol processing

first in its class, highly potent, used for MDR hiv

requires loading dose, is otherwise administered subQ but is released slowly (t1/2 of 8-12 weeks)

few toxicities (aside from some with loading dose)

ritonavir

this is a PI that is mainly used because it blocks CYP3A4, so it boosts the levels of other drugs

cobicistat

this is a PI that works as a CYP3A4 inhibitor that boosts the action of other drugs

list the different targets of HIV therapy

NRTI (nucleoside reverse transcriptase inhibitor)

PI (protease inhibitors)

NNRT (non-nucleoside reverse transcriptase inhibitor)

Entry inhibitor (HIV attachment and fusion inhibition)

Entry inhibitor (CCR5 blocker)

INSTI (integrase strand transfer inhibitors)

explain how NRTIs work

they bind to the DNA strand being created and terminate elongation

act as competitive antagonists of reverse transcriptase

can sometimes cause toxicity if they inhibit mitochondrial DNA polymerase (aka polymerase y)

the drugs with lower affinity for mitochondrial dna polymerase have less toxic effects

what are the most common NRTIs? what makes them commonly used?

lamivudine

emtricitabine

abacavir

tenofovir

they are common because they have less toxicity (they bind less to mitochondrial DNA)

toxicities associated with NRTI

lactic acidosis syndrome

peripheral neuropathy

pancreatitis

anemia

myopathy

which drugs cause lipodystrophy?

most strongly associated with stavudine

also in saquinavir

compare the adverse effects of TAF vs TDF

TAF causes weight gain more than TDF

(TAF is FAT backwards…)

TDF causes proximal tubule pathology and bone mineralization more so than TAF

what are the notable side effects from abacavir?

MACE (major cardiovascular adverse event) and toxic in patients with HLA-B 5701

explain how INSTIs work

they block integrase strand transfer which normally inserts viral DNA into the host genome

they do so by preventing covalent bonds to form between viral and host DNA

what is the major side effect from INSTIs?

generally well tolerated, though can cause weight gain due to adipose tissue fibrosis

how do protease inhibitors work?

basically they prevent HIV maturation, leading to its inability to bud off/spread.

works by inhibiting protease which normally causes cleavage of long polypeptides into functional proteins (cuts out the unnecessary parts so the good part is functional)

PIs make gag and pol unable to generate reverse transcriptase/protease/integrase

some can block CYP3A4 which is what metabolizes most other drugs. doing so will give other drugs a boost

they are also substrates for P-glycoprotein, so can influence drug transport

explain the effects of the protease inhibitors used to boost other drugs

the CYP3A4 is what metabolizes many other drugs

these PIs block this, and also use it to be metabolized themselves

because it takes up so much of CYP3A4’s attention, it keeps it from metabolizing other drugs which in turn leads to more of them present in the system

explain how NNRTIs work

they bind to a site (that is distinct from the active binding site) on the reverse transcriptase, and turn transcription off

they do not require phosphorylation for activation, and cannot be active against human DNA polymerase like NRTIs

function as non-competitive antagonists of reverse transcriptase in other words

when should you initiate ART therapy?

immediately after HIV diagnosis, unless patient has cryptococcal or TB meningitis

what is the general guideline for treating naive HIV patients?

start with an INSTI and 2 NRTIs (that target different nucleosides)

could also consider doing dolutegravir and lamivudine

how would you treat treatment-experienced HIV patients or those with resistance?

protease inhibitor (darunavir) + 2 NRTIs (TAD/TAF and one other)

common side effect of dolutegravir?

weight gain, especially in black women

what is a way to remember lenacapavir?

it has CAP in the middle of its name, and its a capsid inhibitor

how can I remember INSTIs?

they are integrase inhibitors which kinda sounds like “in the grave” and they all have “-gravir” at the end of their name

how can I remember NNRTIs?

they all have “…vir…” in the middle of their name

these are indirect antagonists, indirect makes me think that they veered off the mian path

how can I remember which NRTIs are for purines and pyrimidines?

all the ones for pyrimidines end in “-dine” except for emtricitabine, but that’s close enough

somehow need to remember that em and lam are associated with cytosine

what drug is administered IM? What is its MOA? What is it commonly given in combo with?

cabotegravir - an INSTI

commonly given in combo with rilpivirine - an NNRTI

how does P glycoprotein influence protease inhibitors