Mechanism of Action of Efavirenz
Efavirenz acts primarily through noncompetitive inhibition of HIV-1 reverse transcriptase, preventing the conversion of viral RNA into DNA, thereby blocking viral replication. 1
Primary Mechanism
Efavirenz belongs to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of antiretroviral medications. Its mechanism of action involves:
- Noncompetitive inhibition: Unlike nucleoside reverse transcriptase inhibitors (NRTIs) that require phosphorylation for activation, efavirenz directly binds to and inhibits HIV-1 reverse transcriptase without requiring cellular activation 1, 2
- Selective inhibition: Efavirenz specifically inhibits HIV-1 reverse transcriptase but does not inhibit HIV-2 reverse transcriptase or human cellular DNA polymerases α, β, γ, and δ 1
- Binding site: Efavirenz binds to a hydrophobic pocket near the catalytic site of the reverse transcriptase enzyme
Secondary Effects on RNase H Activity
Recent research has revealed additional mechanisms that contribute to efavirenz's antiviral activity:
- RNase H stimulation: Efavirenz actually stimulates the RNase H activity of reverse transcriptase, which is responsible for degrading the RNA portion of RNA-DNA hybrids during reverse transcription 3
- Enhanced substrate binding: The drug promotes binding of reverse transcriptase to RNase H substrates 3
- Secondary cleavage acceleration: Efavirenz particularly accelerates secondary cuts made by RNase H, which occur approximately 9 nucleotides from the DNA 3'-end 3
Antiviral Activity
Efavirenz demonstrates potent antiviral activity:
- Effective concentration: The concentration inhibiting viral replication by 90-95% (EC90-95) ranges from 1.7 to 25 nM in various cell types 1
- Broad activity: Effective against HIV-1 clade B and most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, N), though it has reduced activity against group O viruses 1
- CNS penetration: Efavirenz penetrates the blood-brain barrier, reaching cerebrospinal fluid (CSF) concentrations above the IC95 for wild-type HIV-1, with a mean CSF-to-plasma ratio of 0.61% 4
Resistance Development
Resistance to efavirenz can develop through:
- Single mutations: Particularly K103N (most common), which occurs in 54% of virologic failures 1
- Additional mutations: L100I, K101E/Q/R, V108I, G190S/T/A, P225H, and M230I/L can also contribute to resistance 1
- Cross-resistance: HIV strains resistant to efavirenz typically show cross-resistance to other NNRTIs like nevirapine and delavirdine 1, 5
Clinical Implications
Understanding efavirenz's mechanism of action helps explain:
- Once-daily dosing: The drug's pharmacokinetic profile allows for convenient once-daily administration 2
- CNS side effects: Efavirenz's ability to cross the blood-brain barrier explains its neuropsychiatric side effects, including dizziness, insomnia, and abnormal dreams 6, 2
- Drug interactions: Efavirenz is both a substrate and inducer of CYP450 enzymes, leading to significant drug interactions, particularly with protease inhibitors and other medications metabolized by this pathway 6
The unique mechanism of action of efavirenz has made it an important component of antiretroviral therapy for HIV infection, contributing significantly to the evolution of highly active antiretroviral therapy (HAART) over the past decades.