Pharmacology of Efavirenz

Introduction/Overview

Efavirenz represents a cornerstone non-nucleoside reverse transcriptase inhibitor (NNRTI) in the historical and contemporary management of human immunodeficiency virus type 1 (HIV-1) infection. Its development marked a significant advancement in antiretroviral therapy, contributing to the establishment of highly active antiretroviral therapy (HAART) regimens that transformed HIV from a fatal diagnosis to a manageable chronic condition. The drug’s unique pharmacokinetic and pharmacodynamic profile, characterized by a long half-life permitting once-daily dosing and a distinct adverse effect spectrum, has cemented its role in treatment guidelines for many years. Understanding the pharmacology of efavirenz is essential for clinicians to optimize therapeutic outcomes, manage its characteristic toxicities, and navigate its complex drug interaction profile.

Learning Objectives

• Describe the molecular mechanism of action of efavirenz as a non-nucleoside reverse transcriptase inhibitor and its specific binding site on the HIV-1 reverse transcriptase enzyme.
• Outline the key pharmacokinetic properties of efavirenz, including its absorption, distribution, metabolism by cytochrome P450 enzymes, and long elimination half-life, and relate these to dosing recommendations.
• Identify the common and serious adverse effects associated with efavirenz therapy, with particular emphasis on central nervous system (CNS) disturbances and their management.
• Analyze major drug-drug interactions involving efavirenz, based on its role as both a substrate and an inducer of CYP450 enzymes, and apply this knowledge to clinical contraindications and dose adjustments.
• Evaluate the use of efavirenz in special populations, including pregnant individuals, pediatric patients, and those with hepatic impairment, recognizing the associated risks and necessary monitoring.

Classification

Efavirenz is classified within two primary frameworks: therapeutic and chemical. Therapeutically, it belongs to the class of antiretroviral agents known as non-nucleoside reverse transcriptase inhibitors. This classification distinguishes it from nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), which act as competitive substrate analogs, and from other classes such as protease inhibitors, integrase strand transfer inhibitors, and entry inhibitors. NNRTIs bind allosterically to a hydrophobic pocket distal to the active site of the HIV-1 reverse transcriptase enzyme, inducing a conformational change that inhibits its polymerase function.

Chemically, efavirenz is a benzoxazin-2-one derivative. Its systematic name is (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one. The molecular structure features a cyclopropylacetylene side chain and a trifluoromethyl group, which are critical for its high binding affinity and specificity for the HIV-1 reverse transcriptase. This specific structure confers its activity against HIV-1 but not against HIV-2 or other retroviruses, as the binding pocket in HIV-2 reverse transcriptase has a different conformation. The drug is formulated for oral administration and is marketed under the brand name Sustiva, as well as in fixed-dose combinations such as Atripla (efavirenz/tenofovir disoproxil fumarate/emtricitabine).

Mechanism of Action

Pharmacodynamic Target

The primary pharmacodynamic target of efavirenz is the HIV-1 reverse transcriptase (RT) enzyme. Reverse transcriptase is a virally encoded RNA-dependent DNA polymerase that is essential for viral replication. It catalyzes the conversion of single-stranded viral RNA into double-stranded proviral DNA, which is then integrated into the host genome. Inhibition of this enzyme halts the early stage of the viral life cycle, preventing the establishment of productive infection in new host cells.

Molecular and Cellular Mechanism

Efavirenz exerts its antiviral effect through a non-competitive, allosteric inhibition mechanism. Unlike NRTIs, which mimic natural nucleosides and incorporate into the growing DNA chain to cause termination, NNRTIs like efavirenz bind to a specific, hydrophobic pocket in the p66 subunit of the HIV-1 RT heterodimer. This binding site, often termed the NNRTI-binding pocket (NNIBP), is located approximately 10 Å from the enzyme’s catalytic site. The binding of efavirenz induces a conformational change in the thumb and palm subdomains of the RT enzyme. This alteration repositions the catalytic aspartate residues (Asp110, Asp185, and Asp186) and distorts the geometry of the polymerase active site, dramatically reducing its catalytic efficiency. The result is a blockade of DNA polymerase activity without affecting the enzyme’s RNAse H function.

The inhibition is considered non-competitive because efavirenz does not compete with the natural substrates (dNTPs) or the template-primer for binding at the active site. Instead, it modulates enzyme function through binding at a distinct allosteric site. The binding of efavirenz is highly specific to HIV-1 RT; it does not inhibit cellular DNA polymerases (α, β, γ, or δ) at therapeutic concentrations, which contributes to its selective toxicity and relatively favorable cellular safety profile compared to some earlier antiretrovirals. The antiviral activity is quantified by the concentration needed to inhibit 50% or 90% of viral replication in vitro (IC₅₀ or IC₉₀), which for efavirenz is in the low nanomolar range against wild-type HIV-1.

Pharmacodynamic Effects and Resistance

The primary pharmacodynamic effect is a potent suppression of HIV-1 replication, leading to a decrease in plasma viral load and an increase in CD4⁺ T-lymphocyte counts. The relationship between efavirenz concentration and antiviral effect is best described by an inhibitory sigmoid E_max model. A key pharmacodynamic parameter is the trough concentration (C_trough), which should be maintained above the protein-binding-adjusted IC₉₀ to prevent the emergence of resistance. Subtherapeutic concentrations provide selective pressure for the emergence of resistant viral strains.

Resistance to efavirenz emerges rapidly when the drug is used as monotherapy, underscoring the necessity for combination antiretroviral therapy. The most common resistance mutation is K103N in the RT gene, which results in a substitution of asparagine for lysine at codon 103. This mutation increases the rigidity of the NNIBP, reducing the binding affinity of efavirenz and other first-generation NNRTIs by over 20-fold. Other notable mutations include Y181C and G190S/A/E. These mutations often confer high-level cross-resistance within the first-generation NNRTI class (nevirapine, delavirdine), though the patterns can be complex. The presence of certain baseline resistance mutations is a contraindication to efavirenz use.

Pharmacokinetics

Absorption

Efavirenz is administered orally and is subject to significant inter- and intra-individual variability in absorption. Its bioavailability in the fasting state is estimated to be approximately 40-45%, which increases substantially when taken with a high-fat meal. A meal containing 50 grams of fat can increase the area under the concentration-time curve (AUC) by up to 50% and the peak plasma concentration (C_max) by up to 80%. However, due to the increased risk of central nervous system side effects associated with higher plasma levels, standard clinical guidance recommends administration on an empty stomach, preferably at bedtime, to improve tolerability. The time to reach C_max (T_max) is typically 3 to 5 hours post-dose. The absorption process is not well characterized but is presumed to occur via passive diffusion across the gastrointestinal mucosa.

Distribution

Following absorption, efavirenz is extensively distributed throughout the body. It is highly protein-bound, primarily to albumin (>99.5%). This extensive binding limits the free, pharmacologically active fraction of the drug in plasma to less than 1%. The apparent volume of distribution is large, ranging from 200 to 400 L, indicating significant tissue penetration. Efavirenz readily crosses the blood-brain barrier, achieving cerebrospinal fluid (CSF) concentrations that are approximately 0.5% to 1.2% of corresponding plasma concentrations. This penetration is therapeutically beneficial for targeting HIV reservoirs in the CNS but is also implicated in the drug’s characteristic neuropsychiatric adverse effects. The drug also crosses the placenta and is found in breast milk.

Metabolism

Efavirenz undergoes extensive hepatic metabolism, which is the primary route of its elimination. The major pathways involve cytochrome P450 (CYP) enzymes, predominantly CYP2B6 and, to a lesser extent, CYP3A4 and CYP1A2. The principal metabolites are hydroxylated derivatives, which undergo further glucuronidation via UDP-glucuronosyltransferases (UGTs) to form water-soluble glucuronide conjugates. The 8-hydroxyefavirenz and 7-hydroxyefavirenz metabolites are considered inactive or possess minimal antiviral activity. A minor pathway involves N-glucuronidation of the parent drug. The metabolism of efavirenz exhibits significant genetic polymorphism, particularly related to CYP2B6. Individuals homozygous for the CYP2B6*6 allele (common in certain ethnic populations) are slow metabolizers, leading to significantly higher plasma exposure (AUC) and prolonged elimination half-life, which increases the risk of toxicity.

Excretion

Renal excretion of unchanged efavirenz is negligible, accounting for less than 1% of the administered dose. The majority of the drug and its metabolites are excreted in the feces, primarily as metabolites, with a small fraction of unchanged drug. Biliary excretion of glucuronide conjugates occurs, with possible hydrolysis in the gut and some reabsorption (enterohepatic recirculation), which may contribute to the drug’s long half-life. The total body clearance of efavirenz is relatively low and is dependent on hepatic metabolic capacity.

Half-life and Dosing Considerations

The elimination half-life (t_1/2) of efavirenz after single doses is 40 to 55 hours. With multiple dosing, the half-life increases to 52 to 76 hours due to autoinduction of its own metabolism, a process that reaches steady-state after approximately 2 to 4 weeks of therapy. This prolonged half-life is the pharmacokinetic basis for once-daily dosing. The recommended adult dose is 600 mg orally once daily. The long half-life also has implications for both the time to reach steady-state (approximately 6 to 10 days) and for the management of treatment interruptions or discontinuation, as drug levels persist for an extended period. In slow metabolizers (e.g., those with CYP2B6*6/*6 genotype), the half-life can extend beyond 100 hours, necessitating careful monitoring for adverse effects. Dose reduction to 400 mg daily may be considered in certain combination regimens based on clinical trial data, though the standard 600 mg dose remains widely used.

Therapeutic Uses/Clinical Applications

Approved Indications

Efavirenz is approved for the treatment of HIV-1 infection in combination with other antiretroviral agents. It has been a preferred or alternative component of initial combination regimens in various international treatment guidelines for many years. Its efficacy is well-established in treatment-naïve patients, where regimens containing efavirenz have demonstrated durable virologic suppression and immunologic recovery in numerous clinical trials. It is typically co-administered with two nucleoside reverse transcriptase inhibitors, such as tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), in a single-tablet regimen (Atripla). Efavirenz is also indicated for use in pediatric patients older than 3 months of age and weighing at least 3.5 kg.

Off-Label Uses and Considerations

While the primary indication is for treatment-naïve HIV-1 infection, efavirenz has been used in other contexts, though these are less common and often superseded by newer agents. Historical off-label use included post-exposure prophylaxis (PEP) regimens, though its CNS side effect profile made it less ideal for short-term use in this setting. Its use in treatment-experienced patients is generally not recommended unless guided by genotypic resistance testing confirming susceptibility, due to the high likelihood of NNRTI cross-resistance. There is no role for efavirenz in the treatment of HIV-2 infection, as this virus is intrinsically resistant. Its use in HIV prevention as pre-exposure prophylaxis (PrEP) has been explored but is not an approved or recommended strategy, with tenofovir-based regimens being the standard.

Adverse Effects

Common Side Effects

The adverse effect profile of efavirenz is characterized by a high incidence of central nervous system (CNS) and psychiatric symptoms, especially during the initial weeks of therapy. Up to 50% of patients experience some form of neuropsychiatric disturbance. These commonly include dizziness, insomnia, abnormal dreams, somnolence, impaired concentration, and headache. A sensation of euphoria or agitation may also occur. These symptoms are often dose-related and typically diminish in frequency and severity after 2 to 4 weeks of continued therapy. Administration at bedtime is a standard strategy to improve tolerability of these transient effects. Other common side effects include maculopapular rash, which occurs in approximately 10-20% of patients, usually within the first two weeks, and typically resolves without intervention. Mild to moderate elevations in serum total cholesterol and triglycerides are also frequently observed.

Serious and Rare Adverse Reactions

More serious adverse effects necessitate careful monitoring and, in some cases, drug discontinuation. Severe psychiatric experiences, including severe depression, suicidal ideation, paranoid reactions, and aggressive behavior, have been reported. Although rare, these events can be life-threatening and require immediate medical evaluation. Severe cutaneous reactions, such as Stevens-Johnson syndrome, are rare but serious. Hepatotoxicity, including hepatic enzyme elevations and clinical hepatitis, can occur. False-positive cannabinoid test results have been reported with some screening assays. Long-term use has been associated with potential neurotoxicity, though the clinical significance of this is an area of ongoing research. Lipodystrophy, a redistribution of body fat, has been observed in patients on long-term antiretroviral therapy, though its association specifically with efavirenz is less clear than with some other drug classes.

Black Box Warnings

The United States Food and Drug Administration (FDA) prescribing information for efavirenz carries several boxed warnings, the most prominent being the risk of severe psychiatric experiences. Patients with a history of psychiatric illness may be at increased risk. Another boxed warning concerns fetal harm when used during the first trimester of pregnancy. Efavirenz is classified as Pregnancy Category D (under the old FDA classification system) due to reports of neural tube defects in primates and retrospective human data. Consequently, pregnancy should be avoided in women receiving efavirenz, and effective contraception is mandatory. A third warning highlights the potential for lactic acidosis and severe hepatomegaly with steatosis, which is a class effect of nucleoside analogs but is included due to efavirenz’s use in combination regimens containing these drugs.

Drug Interactions

Major Drug-Drug Interactions

Efavirenz is a substrate, an inducer, and a mixed inducer/inhibitor of various cytochrome P450 enzymes, leading to a complex and extensive drug interaction profile. As a moderate inducer of CYP3A4 and a potent inducer of CYP2B6, efavirenz can significantly decrease the plasma concentrations of drugs metabolized by these pathways. This is a major mechanism for many clinically significant interactions.

• Anticonvulsants: Carbamazepine, phenytoin, and phenobarbital induce CYP enzymes and can reduce efavirenz concentrations. Conversely, efavirenz can reduce concentrations of these anticonvulsants, potentially leading to loss of seizure control. Concurrent use requires careful therapeutic drug monitoring.
• Antimycobacterials: Rifampin, a potent CYP3A4 inducer, decreases efavirenz AUC by approximately 25%. When co-administered, an increase in the efavirenz dose to 800 mg daily is recommended, though this may exacerbate CNS side effects. Rifabutin levels are decreased by efavirenz, necessitating a rifabutin dose increase.
• Azole Antifungals: Efavirenz reduces the concentrations of voriconazole and itraconazole. Concurrent use of efavirenz and voriconazole is contraindicated unless the voriconazole dose is significantly increased and efavirenz dose is decreased, which is complex and not recommended. Fluconazole, a CYP2C9/C19 inhibitor, can increase efavirenz levels.
• Other Antiretrovirals: Efavirenz reduces the AUC of protease inhibitors like atazanavir, indinavir, saquinavir, and lopinavir. Boosting with ritonavir or cobicistat is required to counteract this induction. It also reduces concentrations of the integrase inhibitor raltegravir. Co-administration with other NNRTIs is not recommended due to lack of additive benefit and potential for additive toxicity.
• Immunosuppressants: Concentrations of cyclosporine, tacrolimus, and sirolimus may be decreased by efavirenz, requiring close monitoring of drug levels in transplant patients.
• Direct-Acting Oral Anticoagulants (DOACs): Efavirenz may decrease concentrations of apixaban and rivaroxaban, potentially reducing anticoagulant efficacy.
• Hormonal Contraceptives: Efavirenz may decrease plasma levels of ethinyl estradiol and other contraceptive steroids, potentially compromising efficacy. Use of alternative or additional contraceptive methods is advised.

Contraindications

Absolute contraindications to efavirenz therapy include:

1. Concomitant administration with drugs with narrow therapeutic indices that are highly dependent on CYP3A4 for clearance and for which elevated levels are associated with serious events, such as cisapride, midazolam, triazolam, pimozide, and ergot alkaloids.
2. Concomitant use with voriconazole or elbasvir/grazoprevir, due to complex bidirectional interactions that lead to subtherapeutic levels of one or both agents.
3. Known hypersensitivity to efavirenz or any component of the formulation.
4. Confirmed virologic failure on a prior NNRTI-based regimen with evidence of NNRTI resistance mutations (e.g., K103N).

Relative contraindications, requiring extreme caution and often favoring alternative agents, include a history of severe psychiatric illness, uncontrolled seizure disorder, and severe hepatic impairment (Child-Pugh Class C).

Special Considerations

Use in Pregnancy and Lactation

The use of efavirenz during pregnancy, particularly the first trimester, is a major concern due to teratogenic risk. Based on retrospective data and the known mechanism of neural tube defects in animal models, efavirenz is not recommended during the first trimester of pregnancy. Alternative antiretroviral regimens are preferred for individuals who are pregnant or planning pregnancy. If a patient becomes pregnant while on an efavirenz-based regimen, the benefits of continued viral suppression must be weighed against the potential fetal risk; a switch to an alternative regimen is often undertaken, but discontinuation of all antiretrovirals is not recommended due to the risk of increased viral load and maternal disease progression. Efavirenz is excreted in human breast milk. The World Health Organization recommends that HIV-infected mothers not breastfeed in resource-rich settings to avoid postnatal transmission, regardless of maternal antiretroviral therapy.

Pediatric and Geriatric Considerations

In pediatric patients, efavirenz is approved for use in children over 3 months of age. Dosing is based on body weight and body surface area, using specific pediatric formulations. The adverse effect profile in children is similar to that in adults, with CNS symptoms and rash being common. Monitoring of growth and development is advised. In geriatric patients, no specific dose adjustment is recommended based on age alone. However, age-related declines in hepatic or renal function, a higher likelihood of concomitant medications, and increased susceptibility to CNS effects may necessitate increased vigilance and potentially favor the selection of alternative agents with fewer neuropsychiatric effects.

Renal and Hepatic Impairment

No dose adjustment is required for efavirenz in patients with renal impairment, including those undergoing hemodialysis or peritoneal dialysis, as renal clearance is negligible. The drug is not significantly removed by hemodialysis. In contrast, hepatic impairment significantly affects efavirenz pharmacokinetics due to its extensive hepatic metabolism. In patients with mild hepatic impairment (Child-Pugh Class A), no dose adjustment is needed. In patients with moderate hepatic impairment (Child-Pugh Class B), caution is advised, and a dose reduction to 200 mg once daily has been suggested, though clinical data are limited. Efavirenz is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) due to the lack of safety and pharmacokinetic data and the potential for drug accumulation and toxicity. Liver function tests should be monitored prior to and during therapy, especially in patients with pre-existing liver disease or co-infection with hepatitis B or C viruses.

Summary/Key Points

• Efavirenz is a first-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that acts through allosteric, non-competitive inhibition of the HIV-1 reverse transcriptase enzyme, specifically binding to a hydrophobic pocket distinct from the active site.
• Its pharmacokinetics are defined by variable absorption improved by fat, extensive tissue distribution including CNS penetration, and predominant hepatic metabolism by CYP2B6 (subject to genetic polymorphism), resulting in a long elimination half-life (52-76 hours) that supports once-daily dosing.
• The drug has been a cornerstone of initial combination antiretroviral therapy for HIV-1, offering potent virologic suppression, but its use has been tempered by the availability of newer agents with improved tolerability profiles.
• The most distinctive adverse effects are central nervous system disturbances (dizziness, abnormal dreams, insomnia), which are often transient, and serious psychiatric reactions, which require monitoring. A boxed warning exists for fetal harm if used in the first trimester of pregnancy.
• Efavirenz is a potent inducer of CYP3A4 and CYP2B6, leading to numerous clinically significant drug interactions that can reduce the efficacy of co-administered medications, including other antiretrovirals, anticonvulsants, and antifungals.
• Use requires special caution in patients with psychiatric history, hepatic impairment, and in women of childbearing potential not using effective contraception. Dose adjustments may be necessary in slow metabolizers (CYP2B6*6/*6 genotype) and in moderate hepatic impairment.

Clinical Pearls

• Administration at bedtime on an empty stomach can mitigate the initial CNS side effects and improve patient adherence and tolerability during the first month of therapy.
• Resistance to efavirenz emerges quickly with monotherapy or suboptimal adherence; it is almost always used in combination with at least two other active antiretroviral agents.
• The K103N mutation confers high-level resistance to efavirenz and nevirapine, making genotypic resistance testing critical prior to using efavirenz in treatment-experienced patients.
• When managing drug interactions, particularly with rifampin or anticonvulsants, therapeutic drug monitoring of efavirenz levels, if available, can guide dose adjustments to ensure therapeutic exposure while minimizing toxicity.
• Although its role as a first-line agent has diminished in many guidelines in favor of integrase inhibitors, understanding efavirenz pharmacology remains vital for managing patients on long-term stable regimens and for resource-limited settings where it may still be widely used.

References

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