Antiretrovirals Flashcards
Course of HIV infection
Goal of pharmacotherapy is to extend clinical latency
HIV treatment
Therapy is usually initiated when CD4+ cells ≤500 cellsmm3
Regardless of CD4 count, initiation of therapy is strongly recommended for individuals with the following conditions:
• Pregnancy
- History of an AIDS-defining illness
- HIV-associated nephropathy (HIVAN)
- HIV/hepatitis B virus (HBV) co-infection
Current Rx recommendation for HIV: PI + 2 NRTI
Current HIV drugs
**Nucleoside/-tide Reverse Transcriptase Inhibitors (NRTIs): **Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine,Tenofovir, Zidovudine
- Zidovudine (ZDV): T analog; formerly AZT
- Stavudine (d4T): T analog
- avoid Zidovudine and Stavudine combinations
- avoid didanosine and Stavudine combinations: additive neuropathy and potentially fatal pancreatitis
- Emtricitabine (FTC): C analog
- Lamivudine (3TC): C analog
- avoid FTC and 3TC combinations
- Abacavir (ABC): G analog
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs): Delavirdine, Efavirenz, Etravirine, Nevirapine
Protease Inhibitors: Atazanavir, Darunavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Tipranavir
Entry Inhibitors: Enfuvirtide, Maraviroc
**Integrase Inhibitor: **Raltegravir
NRTI
- Analogs of native ribosides (lack 3’OH)
- includes Didanosine, Tenofovir, Abacavir
- Require intracytoplasmic activation via phosphorylation by cell enzymes and incorporated into viral DNA by reverse transcriptase
- Lack of 3’OH terminates DNA elongation, ie. they are competitive inhibitors of reverse transcriptase
- Most have activity against HIV-2 as well as HIV-1
Resistance/PK
- Emerges rapidly if used alone
- Most common mutation at viral codon 184: lamivudine (restores sensitivity to zidovudine & tenofovir)
- Cross-resistance between agents of same analog class can occur
- PK: Dosage adjustments required with renal insufficiency
- Note: require oral drugs since HIV + Pt take drugs the rest of the life (IV is impractical)
NRTI - Adverse & interactions
- inhibit mitochondrial DNA polymerase γ (didanosine & stavudine highest affinity)
- AE mainly due to inhibition of mitochondrial DNA polymerase: peripheral neuropathy, myopathy, lipoatrophy & lactic acidosis
- Pancreatitis, myelosuppression & cardiomyopathy can also occur
- Liver toxicity is rare but fatal (lactic acidosis, hepatomegaly with steatosis).
- Zidovudine & stavudine may be particularly associated with dyslipidemia & insulin resistance.
Drug interactions
- Didanosine & tenofovir: Tenofovir increases plasma didanosine levels ~60%.
- Doses of didanosine have to be reduced.
- NRTIs are not generally metabolized by cytochrome enzymes
Zidovudine (ZDV, AZT)
Nucleoside Analog: Thymidine
Pharmacokinetics
- Oral
- Penetrates well across BBB
- Dosage adjustments required in patients with cirrhosis
Zidovudine - Adverse effects
- Bone marrow suppression (neutropenia, anemia)
- Concurrent administration with ganciclovir can result in additive neutropenia.
- GI intolerance, headaches, insomnia
Contraindications
- Toxicity potentiated by coadmin. of probenecid, acetaminophen, lorazepam, indomethacin & cimetidine.
- Stavudine & ribavirin activated by same pathways (might reduce active levels of zidovudine)
Stavudine (d4T)
- Strong inhibitor of beta and gamma DNA polymerases (high affinity for mitochondrial DNA polymerase, which can lead to toxicity)
- Nucleoside Analog: Thymidine
Pharmacokinetics
- Oral
- Dosage adjustment required in renal insufficiency
Stavudine (d4T) - Adverse
- Peripheral neuropathy, lactic acidosis
- Hyperlipidemia, neuromuscular weakness
Didanosine (DDL)
Nucleoside Analog: Adenosine
Pharmacokinetics
- Absorption best if taken in fasting state (acid labile) or combined with antacid
- Penetrates into CSF
- Dosage adjustment required in renal insufficiency
Didanosine - Adverse
High affinity for mitochondrial DNA polymerase
- Pancreatitis (esp. alcoholics and patients with hypertriglyceridemia)
- Peripheral neuropathy, diarrhea, hepatic dysfunction
- CNS effects
Tenofovir (TDF)
- One of preferred NRTIs in currently recommended regimens
- Nucleotide Analog: Adenosine
Fixed-Dose Combinations Available
- Tenofovir + emtricitabine
- Tenofovir + emtricitabine + efavirenz
PK
- Should be taken with food to increase bioavailability
- Long t1/2 (can dose once daily)
Tenofovir - Adverse & contraindications
Adverse Effects: GI (nausea, diarrhea, vomiting, flatulence)
Contraindications
- Serum creatinine monitored with renal insufficiency
- Only NRTI with sig. drug interactions (increases didanosine concentrations and dosage reductions are usually required)
- Decreases concentrations of atazanavir. Atazanavir can be ‘boosted’ with ritonavir
Lamviduine (3TC) including adverse
- DOES NOT affect mitochondrial DNA synthesis or bone marrow precursor cells
- Nucleoside Analog: Cytosine
- Resistance: High level resistance occurs with single amino acid substitutions
PK: Dosage adjustment required with renal insufficiency
Adverse: Few significant (headache, dry mouth)
Emtricitabine (FTC) including Adverse
- Structural relative of lamivudine
- One of preferred NRTIs in currently recommended regimens
- Nucleoside Analog: Cytosine
- Pharmacokinetics: Once-a-day administration
- Adverse: Hyperpigmentation of palms and soles (occurs most frequently in dark-skinned people)
Abacavir (ABC) including Adverse
- Nucleotide Analog: Guanosine
- Resistance: HIV resistance requires several mutations and tends to develop slowly.
Adverse
- GI, headache, dizziness
- 5% - ‘hypersensitivity’ reaction (one or more of rash, GI, malaise, respiratory distress).
- Sensitized individuals should NEVER be rechallenged (can be genetically screened)
NNRTIs
- includes Nevirapine, Efavirenz, Delaviridine, Etravirine, Rilpivirine
MOA
- Highly selective, noncompetitive inhibitors of HIV-1 RT
- Bind at a distinct site away from active site (NNRTI pocket)
- All NNRTI’s bind within the same pocket
- All result in inhibition of RNA- and DNA-dependent DNA polymerase
- DO NOT REQUIRE PHOSPHORYLATION BY CELLULAR ENZYMES
- Lack in vitro activity against HIV-2
Advantages
- Lack of effect on host blood-forming elements
- Lack of cross resistance with NRTIs (binding sites are distinct)
Disadvantages
- Cross-resistance with NNRTIs
- Drug interactions
- High incidence of hypersensitivity reactions (eg, SJS rash)
NNRTI Adverse
- Skin rash (including Stevens-Johnson syndrome)
- GI intolerance
- All are CYP3A4 substrates and can act as inducers, inhibitors or both of CYPs
- inducers (nevirapine)
- inhibitors (delavirdine)
- mixed inducers and inhibitors (efavirenz, etravirine).
Nevirapine (NVP) including contraindications
Pharmacokinetics: Excreted mainly in urine as metabolites (CYP 3A4 & CYP 2B6)
Adverse Effects
- Potential severe hepatotoxicity (don’t use in women with CD4+ counts >250 cells/mm3 & men >400 cells/mm3)
- Rash (16%), dermatologic effects (Stevens-Johnson syndrome & toxic epidermal necrolysis)
- 14 day titration period at 1⁄2 dose is mandatory to reduce risk of serious epidermal reactions
Resistance: Target site of nevirapine is HIV-1 specific & not essential to enzyme (reverse transcriptase), thus mutations and resistance can develop rapidly
Contraindications
- Inducer of CYP 3A4
- Increases metabolism of PI’s (no dosage adjustment necessary), oral contraceptives, ketoconazole, methadone, metronidazole, quinidine, theophylline & warfarin
Delaviridine (DLV)
Clinical Applications: Not as widely used as other NNRTIs due to short t1/2 Pharmacokinetics
- Well absorbed orally (especially at pH <2; antacids, H2 blockers etc may decrease absorption)
- Excreted mainly in urine as metabolites (CYP 3A4 & 2D6)
- Non-linear PK (t1/2 increases with increasing doses)
Delaviridine - Adverse
Adverse Effects
- Rash (18-36%), Stevens-Johnson syndrome & toxic epidermal necrolysis
- Fever, headache & depression also common
- Teratogenic
Contraindications
- Inhibitor of and substrate of CYP3A4
- CYP 3A4 inducers (eg, rifampin, phenytoin) may decrease delavirdine concentrations
- Pregnancy (Cat C)
Resistance: Target site of delavirdine is HIV-1 specific & not essential to enzyme (reverse transcriptase) therefore resistance develops rapidly
Etravirine (ETV)
Clinical Applications
- Approved for use in treatment-experienced patients
- May be effective against HIV strains resistant to first-generation NNRTIs
Pharmacokinetics
- Metabolized by CYP 3A4, 2C9 and 2C19
- Metabolites have ~10% HIV activity of parent compound
Etravirine - Adverse
- Rash (normally resolves within 1-2 weeks), nausea, diarrhea
- Transaminase elevations (esp. in patients co-infected with hepatitis)
Contraindications
- CYP 3A4 inducer
- CYP 2C9 and 2C19 inhibitor
- Some interactions are difficult to predict
Efavirenz (EFV)
Clinical Applications
- Preferred NNRTI on DHHS guidelines
- Results in increased CD4+ counts & decreased viral load
Pharmacokinetics
- Oral
- t1/2 >40h (once-a-day dosing)
- Extensively metabolized to inactive products
Efavirenz - Adverse
Adverse Effects
- Mostly CNS (50%) (dizziness, headache, vivid dreams, loss of concentration) – resolve after few weeks.
- Rash (25%)
- Increased triglycerides, HDL and total cholesterol (lipid levels must be monitored at beginning of and during therapy)
- also teratogenic
Contraindications
- Potent inducer of CYP P450 enzymes.
- Pregnancy (D) (can be used after 1st trimester if considered best choice)
Protease inhibitors (PI)
MOA
- Reversible inhibitors of HIV aspartyl protease (enzyme responsible for cleavage of viral polyprotein into RT, protease & integrase)
- Protease inhibition prevents virus maturation & results in production of non-infectious virions
- DO NOT REQUIRE INTRACELLULAR ACTIVATION
- Active against both HIV-1 and HIV-2
PK
- includes ritonavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, tipranavir
- Poor oral bioavailability
- High-fat meals can increase (nelfinavir) or decrease (indinavir) bioavailability
- Substrates for CYP 3A4
- Substrates for P-glycoprotein pump
- Bound to plasma proteins (alpha1-acid glycoprotein which can increase in response to trauma & surgery)
Resistance: Accumulation of stepwise mutations of protease gene. Can lead to high levels of resistance.
Protease Inhibitors - Adverse & Interactions
- Parathesias, nausea, vomiting, diarrhea
- Disturbances in carb & lipid metabolism (diabetes, hypertriglyceridemia, hypercholesterolemia); all PI cause diabetes
- Chronic admin -> similar to cushingnoid appearance; fat redistribution & accumulation resulting in central obesity, dorsocervical fat enlargement (buffalo hump), peripheral & facial wasting, breast enlargement and a cushingoid appearance
- Atazanavir has less side effects than other PI’s
Drug interactions
- Potent inhibitors and substrates of CYP isoforms including 3A4 eg, rhabdomyolysis (simvastatin or lovastatin), excessive sedation (midazolam or triazolam), respiratory depression (fentanyl)
- Warfarin, sildenafil & phenytoin require dosage adjustments
- Rifampin & St.Johns Wort are contraindicated
Atazanavir (ATV)
Clinical application: ATV + RTV are only once-daily preferred PIs
PK:
- Structurally unrelated to other PIs
- Well absorbed with food
- Highly protein bound
**Contraindications: Less incidence of side-effects than other PIs **
- Metabolized by & inhibits CYP3A4
- PPI
- Admin. must be > 12h apart from H2- blockers & antacids
Ritonavir
- PI
- Clinical application: PK enhancer/ booster of other PI’s
- PK: Potent inhibitor of CYP3A4
- Contraindications: Numerous (due to inhibition of CYP)
Darunavir (DRV)
- PI
- Clinical application: Inhibits HIV protease resistant to other PIs
- PK: Well absorbed with food
- Contraindications: Metabolized & inhibits CYP3A4
Indinavir (IDV)
- PI
- Clinical application: Given with RTV
PK:
- Least protein bound (60%)
- Absorption
- decreased when taken with meals
Contraindications: Dosage should be reduced with hepatic insufficiency
- Special adverse effects: Well-tolerated, Nephrolithiasis & hyperbilirubinemia (adequate hydration important)
Lopinavir (LPVr)
PI
Clinical application:
- One of preferred PIs.
- Given with RTV
PK: Poor intrinsic bioavailability
Contraindications:
- Enzyme inducers (St Johns Wort) should be avoided.
- Oral solution contains EtOH (avoid disulfiram or metronidazole)
Nelfinavir (NFV)
PI
**Clinical application: **Cannot be boosted by RTV
**PK: **
- Metabolized by several CYPs
- Major metabolite (CYP2C19) has antiviral activity equal to parent compound
**Contraindications: **Numerous (due to inhibition of CYP)
**Specific adverse effects: **Diarrhea (controlled by loperamide), nausea, flatulence
Tipranavir (TPV)
PI
**Clinical application: **
- Inhibits HIV protease resistant to other PIs
- Twice-daily with RTV
**PK: **Well absorbed with food
**Contraindications: **Inducer of CYP P450
**Specific Adverse Effects: **Severe and fatal hepatitis; fatal & nonfatal intracranial hemorrhages
Entry/Fusion inhibitors
- Fusion Inhibitor: Enfuvirtide
- Entry Inhibitor: Maraviroc
Enfuvirtide (T-20)
- First approved drug that inhibits viral fusion
- Approved for use in treatment-experienced adults with evidence of HIV replication
- No activity against HIV-2
MOA
- Structurally similar to gp41 (HIV protein mediates membrane fusion)
- Binds to gp41 subunit of the viral envelope glycoprotein, preventing ability of virion to fuse cell membrane
PK: Parenteral admin. only
Enfuvirtide (T-20) - Adverse
- Injection-related (3% discontinue)
- Hypersensitivity reactions & eosinophilia rarely
- No drug interactions with other antiretrovirals have been noted
Maraviroc including Adverse
MOA
- Binds specifically and selectively to CCR5 (one of two coreceptors necessary for entrance of HIV into CD4+ cells)
- Result in blocking HIV entry (only CCR5-tropic virus can be treated with maraviroc)
**PK: **Metabolized by CYP 3A4 (reduce dose when given with PIs)
**Adverse: **Well tolerated, risk of hepatotoxicity
Integrase Strand Transfer Inhibitor (INSTI) - Raltegravir (RAL)
Clinical applications: In combination with other antiretrovirals, raltegravir is approved for treatment-experienced and treatment- naive patients with evidence of viral replication
Raltegravir (RAL)
INSTI
MOA
- Binds integrase (enzyme essential to the replication of both HIV-1 and HIV-2)
- Leads to specific inhibition of the final step in integration of viral DNA into host cell DNA
PK: Metabolism via UGT1A1-mediated glucuronidation
Raltegravir (RAL)
Adverse Effects
- Well tolerated (nausea, headache, diarrhea)
- Can cause increases in creatine phosphokinase
Drug Interactions
- Rifampin, tipranavir & efavirenz may decrease [raltegravir]
- PPI’s may increase [raltegraivr]
Current recommendations for treatment-naive Pt
Start with one of the following regimens:
(1) NNRTI & 2 x NRTI
(2) PI (preferably boosted with ritonavir) & 2 x NRTI (3) INSTI & 2 x NRTI
Selection is based on:
- Avoiding the use of 2 agents of the same nucleotide analog
- Avoiding overlapping toxicities and genotypic and phenotypic characteristics of the virus
- Patient factors such as disease symptoms and concurrent illnesses
- Impact of drug interactions; and
- Ease of adherence to a frequently complex administration regimen
Preferred regimens
- **NNRTI-based regimen: **Efavirenz + tenofovir + emtricitabine
- PI-based regimen
- (1) Ritonavir-boosted atazanavir + tenofovir + emtricitabine
- (2) Ritonavir-boosted darunavir + tenofovir + emtricitabine
- INSTI-based regimen: Raltegravir + tenofovir + emtricitabine
- For pregnant Pt: Ritonavir-boosted lopinavir (twice daily zidovudine/lamivudine)
- HIV infected mother: Zidovudine (start immediately after birth, 6 wk admin)
HIV prophylaxis following needle stick
- Postexposure prophylaxis regimen containing at least 3 antiretroviral drugs.
- Preferred regimen (09/2013): Raltegravir + tenofovir + emtricitabine; given for 28 days and can be stopped if source is shown to be HIV-negative.
- no longer require assessing the severity of exposure.
HIV Prophylactic Vaccines
- Streptococcus pneumoniae
- Hepatitis A
- Hepatitis B and
- Influenza
- are generally recommended for all HIV-infected patients
Vaccines contraindicated in HIV+ Pt w CD4+ < 200 cells/mm3
Live vaccines eg,
- MMR
- Varicella and
- Zoster
Other vaccines may be administered without regard to the patient’s CD4+
