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).
