HIV Medications Flashcards
HIV Antivirals
Drug Classes
- Fusion inhibitors
- Co-receptor Antagonists
-
Reverse Transcriptase Inhibitors
- Nucleoside analogues (NRTI)
- Nucleotide analogues (NRTI)
- Non-nucleoside (NNRTI)
- Integrase Inhibitor
- Protease Inhibitors
Fusion Inhibitors
Drugs & MOA
Enfuvirtide (Fuzeon/T-20)
Binds gp41 ⇒ ⊗ entry of HIV into host cell
Not yet part of a recommended regimen
Reserved for patients resistant to other drugs
Enfuvirtide (Fuzeon)
Adverse Effects
Subcutaneous injection BID
Side effects are local injection site reaction, increased rate of bacterial pneumonia, and hypersensitivity
Co-Receptor Blockers
Drugs & MOA
Maraviroc (Selzentry)
CCR5 Antagonist
- Maraviroc blocks CCR5 co-receptor ⇒ ⊗ viral entry
- Only effective for CCR5-tropic HIV ⇒ susceptibility tests
- Not yet part of a recommended regimen
- Reserved for pts resistant to other drugs
- ~ 55% of pts who fail two antiviral regimens infected w/ CCR5-tropic virus
Maraviroc (Selzentry)
Adverse Effects
- Cough, fever, rash, URI, MSK symptoms, abdominal pain, and postural dizziness
- Black box warning for hepatoxicity
- Cardiovascular events ⇒ poss. ↑ in MI
- Metabolized by cytochrome p450 ⇒ ∆ by enzyme inducers and inhibitors
Reverse Transcriptase (RT)
DNA Synthesis
Makes dsDNA from viral RNA
Nucleoside Analogues
(NRTI)
Part of the first line therapy for AIDS
- Zidovudine (AZT) ⇒ 1st drug in this class but now not as widely used
- Lamivudine (3TC)
- Emtricitabine (Emtriva)
- Abacavir (ABC)
Nucleoside Reverse Transcriptase Inhibitors (NRTI)
MOA
- 2’3’ dideoxyanalogues phosphorylated to triphosphates by host cellular kinases
- Integrated by RT in growing DNA chain
- Reverse transcriptase more susceptible vs mammalian DNA polymerase
- Causes chain termination of RNA → DNA
Nucleoside Analogues
Class Specific Adverse Effects
-
Mitochondrial toxicity
-
⊗ of mitochondrial DNA polymerase 𝛾
- ⊗ DNA replication
- Impaired synthesis of mitochondrial enzymes
- Abnormal oxidative phosphorylation
- Tissue sensitivity ∝ cellular mitochondrial content
- Rare especially w/ agents selected for current use
- Can lead to lactic acidosis, pancreatitis, peripheral neuropathy, myopathy, cardiomyopathy, hepatic steatosis, and lipid dystrophy
- Lactic acidemia ass. w/ common NRTI side effects
- N/V, headache, abd pain, fatigue, weight loss
-
⊗ of mitochondrial DNA polymerase 𝛾
Zidovudine (AZT)
Adverse Effects
frAnemia and neutropenia
May also be related to mitochondrial toxicity
Abacavir (ABC)
Adverse Effects
-
Causes a hypersensitivity reaction
- Not related to mitochondrial toxicity
- Can be fatal
- Occurs in 6% of the population
- Related to HLA-B*5701 variant
- Fever, rash, nausea, malaise, respiratory sx
Nucleoside Analogues
Pharmacokinetics
All of the NRTI’s are excreted in the kidney
Require dosage adjustment in renal insufficiency
Nucleoside Analogues
Drug Interactions
-
Inhibitors of cytochrome p450 (ex. Cimetidine) ⇒ ↑ level of some drugs in this class including AZT
- Probenecid can also increase the levels
- Inducers of cytochrome p450 (Ex. Rifampin) ⇒ ↓ levels
-
Overlapping toxicity
- Avoid drugs with similar adverse effects
-
Competition for activation
- Drugs should not be activated by the same kinase
Nucleotide Reverse Transcriptase Inhibitor (NRTI)
Drugs & MOA
Tenofovir (Vemlidy, Viread)
-
Same as nucleoside analogue but does not need to be phosphorylated
- Administered as a prodrug - Tenofovir alafenamide
- Causes DNA chain termination of RT
- Used in combo w/ a nucleoside analogue
- Used alone as pre-exposure prophylaxis and for Hep B treatment
Nucleotide Analogues
Adverse Effects
Weakness, headache, diarrhea
No reported mitochondrial toxicity
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
Drugs & MOA
Efavirenz (Sustiva) / Nevirapine
⊗ Reverse Transcriptase @ allosteric site
- Different mech. than nucleoside/nucleotide inhibitors
- Used in combo w/ them
- Do not require phosphorylation
NNRTI
Class Specific Side Effects
-
CNS adverse effects
- Dizziness: initially dose @ bedtime
- Vivid dreams
- Depression
- Rash
- Steven-Johnson syndrome
-
Hepatitis esp. w/ nevirapine
- Usually occur early in therapy
-
Teratogenic in animals
- Not used during pregnancy
NNRTI
Drug Interactions
Drugs in this class are substrates for cytochrome P450 system and inducers (cyp450 3A4)
Integrase Inhibitors
Drugs
- Dolutegravir
-
Elvitegravir
- CYP3A4 metabolized
- Ritonavir boosts bioavailability
-
Raltegravir
- Glucuronidated
- No ritonavir boosting
Integrase Inhibitors
MOA
Target the viral integrase
- Used in combo w/ two nucleoside/nucleotides as part of a standard regimen
- Dolutegravir/lamivudine recommended as initial treatment for pts w/ a viral load < 500k
- Integrase inhibitor-based combinations are the recommended initial treatment for HIV infection
Integrase Inhibitors
Adverse Effects
- Hypersensitivity reactions
- Serious dermatological reactions
- Rhabdomyolysis
- Diarrhea
- Nausea
- Headache
Integrase Inhibitors
Drug Interactions
- Rifampin ⇒ ↑ glucuronidation ⇒ ↑ elimination
- Divalent cations (ex. Antacids) may bind raltegravir ⇒ ⊗ action
- Elvitegravir is marketed w/ cobistat which ⊗ cytochrome P450 3A ⇒ prolonged action
Protease Inhibitors
Drugs & MOA
Darunavir (Prezista) & Ritonavir (Norvir)
- Viral proteases ⇒ cleave proteins used in viral assembly ⇒ vital for viral production
- HIV viral aspartate protease (pol gene encoded) that contains a dipeptide structure not seen in mammalian proteins
- Protease inhibitors target this dipeptide region
Protease Inhibitors (PI)
Class Specific Adverse Effects
- Most can cause nausea, vomiting and diarrhea
-
Hyperglycemia
- Insulin resistance
- ↓ glucose tolerance
- New-onset DM / DKA
-
Lipodystrophy ⇒ changes in body fat distribution
- Central obesity and peripheral fat wasting
- Pts may have Cushingoid appearance
- Fat atrophy may be due to mitochondrial toxicity of NRTI
- Fat accumulation may be due to HLD and insulin resistance caused by PIs
-
Hyperlipidemia ⇒ ↑ triglycerides and/or cholesterol
- Ritonavir has the largest effect
- Long- term effects are not clear but ↑ lipids could lead to cardiovascular events or pancreatitis
- Evaluate lipids and fhx of cardiac disease
-
Hepatotoxicity ⇒ ± ↑ transaminase levels w/ or w/o clinical hepatitis
- Most cases are asymptomatic
- Can occur at any point during therapy
PI Boosting
Ritonavir causes a profound ⊗ cytochrome p450
Low concentrations used to prolong actions of other HAARTs ⇒ “PI boosting”
Possible effects of PI boosting:
-
↑ Absorption & ↓ first-pass metabolism ⇒ ∆ Cmax
- ⊗ cyp450 in wall of GI tract that normally metabolizes drug
- ⊗ P-gp that normally transports drug out of endothelial cells
- More drug cross GI into blood
- ↓ Liver metabolism ⇒ ∆ T½
Long-term Antiretroviral Therapy
Metabolic Effects
HIV Lipodystrophy
Combination Therapy
Justification
- Greater efficacy & dec. toxicity
- Lower dosing of each drug in combo
- Mutation conferring resistance to one drug do not necessarily confer resistance to other drugs
- Integrase inhibitor-based combos are currently preferred
Integrase Inhibitor-Based Regimen
Recommended initial treatment for HIV infection
- Dolutegravir + abacavir/lamivudine (test for HLA-B*5701) ⇒ first choice
- Dolutegravir + tenofovir/emtricitabine
- Elvitegravir-combistat (booster) + tenofovir/emtricitabine
- Raltegravir + tenofovir/emtricitabine
PI-Based Regimen
Darunavir/ritonavir + tenofovir/emtricitabine
(PI + NRTI)
NNRTI based regimen
Efavirenz + tenofovir/emtricitabine marketed as Atripla
No longer recommended
CNS effects
Possible association w/ suicidality
Truvada
Tenofovir/emtricitabine marketed as Truvada
Taken prophylactically ↓ infection rate by almost 70%
HIV
Genotyping
Important in new pts or those who failed therapy d/t resistance
Post-Exposure Prophylaxis
Exposure to HIV ⇒ immediate tx w/ combo therapy used in pts w/ advanced disease
Raltegravir + Tenofovir/Emtricitabine
HIV Antivirals
Summary
-
Fusion inhibitors
- Enfuvirtide
- Nevirapine
-
Co-receptor Antagonists
- Maraviroc
-
Reverse Transcriptase Inhibitors
-
Nucleoside (NRTI)
- Zidovudine
- Lamivudine
- Emtricitabine
- Abacavir
-
Nucleotide (NRTI)
- Tenofovir
-
Non-Nucleoside (NNRTI)
- Efavirenz
-
Nucleoside (NRTI)
-
Integrase Inhibitor
- Raltegravir
- Dolutegravir
- Elvitegravir
-
Protease Inhibitors
- Darunavir
- Ritonavir
