ANTIRETROVIRALS (ANTI-HIV)

HIV

• human immunodeficiency virus

• infects CD4+ lymphocytes, leading to HIV infection

AIDS

• acquired immune deficiency syndrome

• advanced stage of HIV infection

• CD4 T-cell count < 200 cells/mm³ (<14% of total T-cell count)

• a diagnosis of and AIDS-defining condition

how does HIV cause disease

• depletes CD4+ T-lymphocytes and causes severe immunosuppression → puts patients at significant risk for infectious diseases and caused by opportunistic pathogens

opportunistic infections in setting without access to antiretroviral drugs are _____

chief cause of morbidity and mortality

HIV hijacking can result in ____

CD4+ cell death

mechanisms of CD4+ T cell depletion and immune dysfunction

• direct infection and destruction

• immune clearance of infected cells

• cell death

• immune exhaustion

resistance and adherence in HIV

• incomplete suppression of HIV allows resistant variants to emerge

• complete regimen are essential for viral suppression

• adherence is critical to prevent resistance

• partial regimens can lead to resistance: partial fills, drug interactions

missed doses =

replication and opportunity for resistance

why is HIV hard to cure

• latent reservoir formation

• longevity of latent cells

• barrier to cure

latent reservoir formation

a pool of infected cells enter latency early in HIV infection

longevity of latent cells

these cells can persist for years, with long half-lives, making them difficult to eliminate

barrier to cure

latent reservoir is the primary obstacle to completely eradicating HIV from the body

NNRTIs (non-nucleoside reverse transcriptase inhibitors)

• doravirine

• efavirenz

• etravirine

• nevirapine

• rilpivirine

NNRTI MOA

• bind to a hydrophobic pocket in the p66 subunit of the HIV-1 reverse transcriptase, in a site distant from the active site

• compound induces a conformational change in the 3-D structure of the enzyme that greatly reduces its activity, and thus act as noncompetitive inhibitors

NNRTI ADEs

• rash, stevens-johnson syndrome, toxic epidermal necrosis

• hepatotoxicity, increased LFTs

NNRTIs are eliminated by ____ and are substrate of ____

• CYPs

• 3A4

• run drug inte

NNRTI inducers

nevirapine and etravine

NNRTI mixed inducer > inhibitor

efavirenz

NNRTI resistance develops ____ with ____

• rapidly 

• poor adherence 

efavirenz

• take on empty stomach

• do not take in pregnancy

• mixed inducer/inhibitor (mostly induction

efavirenz ADEs

• CNS stimulation (nightmares, abnormal dreams, dizziness, depression, anxiety, insomnia, jitteriness, daytime somnolence, psychosis, problems with memory and concentration)

• rash

• hyperlipidemia

rilpivirine

• take with food (normal or high-calorie meal)

• substrate of 3A4

• do not take with acid reducing agents

rilpivirine ADEs

• CNS effects (depression, mood changes, suicidal ideation, insomnia)

• rash

• lipid abnormalities

• increased liver enzymes

doravirine

• substrate 3A4

• well-tolerated

which NNRTI causes sleep-related CNS side effects?

efavirenz

which NNRTI interacts with acid-reducing agents

rilpivirine

PIs (protease inhibitors)

• atazanavir

• darunavir

• ritonavir

PI MOA

• inhibits HIV protease from cleaving the post-translational viral poly protein into its functional subunits

• competitively inhibit the action of virus aspartyl protease

PI toxicities

• GI effects

• insulin resistance

• lipid metabolism changes

• morphological changes

PI GI effects

• nausea, vomiting, diarrhea

• resolve in ~4 weeks

PI insulin resistance

• new onset DM or worsening of current

• impairment of glucose tolerance

• hyperglycemia

PI lipid metabolism changes

increase in triglycerides and cholesterol

PI morphological changes

• abdominal obesity

• buffalo hump

• lipomatosis

• breast enlargement

PI kinetics

• eliminated by CYP 3A4

• strong inhibitors of 3A4

  • ritonavir is most potent

  • can be used for pharmacokinetic enhancement (boosting) of other PIs

ritonavir

• take with food

• ADEs: GI intolerance, PR prolongation, taste perversion, elevated transaminases, hypertriglyceridemia, hyperlipidemia

what does ritonavir do to other PIs

boosts

cobicistat

• selectively inhibits CYP3A4 with potency but without anti-HIV activity

  • not a PI, but used as a booster like ritonavir

• blocks tubular transport of creatine, resulting in a small but reversible increase in serum creatinine

• only available in coformulation with elvitegravir, atazanvir, or darunavir

atazanavir

• take with food

• ADEs: hyperbilirubinemia, jaundice, nephrolithiasis, PR interval prolongation

• do not take with acid reducing agents and tenofovir

darunavir

• take with food

• contains sulfonamide

• ADEs: N/V/D, rash, increased LFTs, fat redistribution, hyperlipidemia, T2DM possible

INSTIs (integrase inhibitors)

• bictegravir

• cabotegravir

• dolutegravir

• elvitegravir

• raltegravir

INSTI MOA

prevent formation of covalent bonds between host and viral DNA

INSTI considerations

• no renal elimination

• no major CYP interactions

• separate from polyvalent cations

what category of drug are used for treatment experienced patients

entry inhibitors and capsid inhibitors

entry inhibitors

• enfuvirtide

• maraviroc

• ibalizumab

capsid inhibitor

lenacapavir

enfuvirtide subcategory

fusion inhibition

enfuvirtide MOA

inhibits fusion of the viral and cell membranes mediated by gp41 and CD4

what is the dosage form of enfuvirtide

injection

enfuvirtide ADEs

• injection site reaction

• diarrhea

• nausea

• fatigue

• nerve pain

• decreased appetide

• pneumonia

when is enfuvirtide used

patients with multi-drug resistant HIV

maraviroc subcategory

CCR5 antagonist

maraviroc MOA

chemokine receptor antagonist and binds to the host cell CCR5 receptor to block binding of viral gp120

what determines maraviroc use

genetic pre-test

• only works against R5-tropic virus

• blocks the humans side of the gp120/CCR interaction

fostemavir blocks ____

viral side of the gp120/CCR5 interaction

fostemsavir MOA

pre-attachment inhibitor that binds to the gp120 subunit of HIV envelope proteins, inhibiting interaction between the virus and the host cell

ibalizumab subcategory

anti-CD4 antibody

ibalizumab MOA

monoclonal antibody post-attachment inhibitor that binds to CD4 receptors leading to a conformational change that blocks the interaction of viral gp120 and chemokine co-receptors; active against CCR5 and CXCR4 tropic viruses

what does ibalizumab do

blocks the CD4 receptor without causing immunosuppression or depleting CD4 cell counts

when is ibalizumab used

for patients failing other therapies

• high cost

lenacapavir MOA

interferes with multiple early- to late-stage processes of the viral life cycle: nuclear transport, virus assembly and release, and capsid assembly

lenacapavir

• oral and injectable

• do not take with strong CYP3A4 inducers

drug-drug interactions of antiretroviral agents

• intra-class interactions: lamivudine, emtricitabine

• inter-class interactions: efavirenz, PIs

NRTI summary

• eliminated renally

• can cause pancreatitis, lactic acidosis, and peripheral neuropathy

NNRTI summary

• eliminated by CYP450 (3A4)

• CYP450 induction

• can cause rash and hepatotoxicity

PI summary

• eliminated by CYP450 (3A4)

• CYP450 inhibition

• can cause endocrine, lipid, and fat effects; GI

INSTI summary

eliminated by glucuronidation and CYP450 (3A4)

bictegravir/emtricitabine/TAF

• Biktarvy

• for treatment-naive adults

dolutegravir/abacavir/lamivudine

• Triumeq

• for treatment-naive adults

dolutegravir/lamivudine

• Dovato

• for treatment-naive adults

dolutegravir + emtricitabine/TDF

• Tivicay

• Truvada

• for treatment-naive adults

dolutegravir + emtricitabine/TAF

• Tivicay

• Descovy

• for treatment-naive adults

major antiretroviral agent interactions

• PIs: inhibit and are substrates of 3A4

• NNRTIs: generally induced and are substrates of 3A4

• NRTIs: renally eliminated

PI clinical drug interactions

• fluticasone (inhaled)

• simvastatin

• lovastatin

rilpivirine clinical drug interactions

acid reducers

atazanavir clinical drug interactions

acid reducers

NRTIs (nucleoside reverse transcriptase inhibitors)

• abacavir

• emtricitabine

• lamivudine

• tenofovir alafenamide

• tenofovir disoproxil fumarate

• zidovudine

NRTI MOA

phosphorylated analogs block replications of the viral genome both by competitively inhibiting incorporation of native nucleotides and by terminating elongation of proviral DNA because they lack  a 3’-hydroxyl group

• competitive inhibition of reverse transcriptase

NRTI kinetics

• renally eliminated with exception of abacavir

• take without regard to meals

• check drug interactions

NRTI toxicity can be _____

attributed to an agent’s affinity for a human enzyme

NRTI toxicity

• depends on their ability to inhibit the HIV reverse transcriptase without inhibiting human mitochondrial DNA polymerase-gamma

NRTI ADEs

• anemia

• granulocytopenia

• myopathy

• peripheral

• neuropathy

• pancreatitis