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 clinical relevance of efavirenz persists, particularly in resource-limited settings, due to its potent antiviral activity, once-daily dosing, and extensive experience with its long-term use. Understanding its pharmacology remains essential for clinicians and pharmacists involved in HIV care, as its unique pharmacokinetic and adverse effect profile necessitates careful patient selection and monitoring.

Learning Objectives

• Describe the molecular mechanism by which efavirenz inhibits HIV-1 reverse transcriptase and its specificity for HIV-1.
• Outline the key pharmacokinetic properties of efavirenz, including its absorption, metabolism, and elimination pathways.
• Identify the approved clinical indications for efavirenz and its role within combination antiretroviral regimens.
• Analyze the spectrum of adverse effects associated with efavirenz, with particular emphasis on central nervous system manifestations and their management.
• Evaluate significant drug-drug interactions involving efavirenz, recognizing its dual role as both a substrate and an inducer of cytochrome P450 enzymes.

Classification

Efavirenz is classified within the broader therapeutic category of antiretroviral agents. Its primary classification is as a non-nucleoside reverse transcriptase inhibitor. This classification is based on its mechanism of action, which involves allosteric inhibition of the viral reverse transcriptase enzyme, distinct from the competitive inhibition exerted by nucleoside/nucleotide analogues.

Chemical Classification

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 chiral center, and the drug is administered as the active (S)-enantiomer. The presence of the cyclopropylethynyl and trifluoromethyl groups is critical for its high binding affinity to the NNRTI-binding pocket of HIV-1 reverse transcriptase and for conferring metabolic stability. This specific chemical architecture underpins its potent antiviral activity and its characteristic pharmacokinetic profile, including extensive protein binding and hepatic metabolism.

Mechanism of Action

The antiviral activity of efavirenz is mediated through highly specific inhibition of HIV-1 reverse transcriptase. This enzyme is essential for viral replication, catalyzing the transcription of single-stranded viral RNA into double-stranded DNA, which is subsequently integrated into the host genome.

Molecular and Cellular Mechanisms

Efavirenz exerts its effect via a non-competitive, allosteric mechanism. Unlike nucleoside reverse transcriptase inhibitors (NRTIs), which act as chain-terminating analogues of native nucleotides, efavirenz binds to a hydrophobic pocket located approximately 10 Å away from the enzyme’s active site. This binding pocket is distinct and is formed only in the presence of the inhibitor. The interaction between efavirenz and this allosteric site induces a conformational change in the three-dimensional structure of the reverse transcriptase enzyme. This structural alteration disrupts the catalytic function of the enzyme, primarily by affecting the mobility of the p66 thumb subdomain and the positioning of the DNA polymerase active site, thereby blocking the chemical step of DNA polymerization. The inhibition is often described as “datalike,” as it prevents the translocation of the enzyme along the template-primer complex.

The binding is highly specific for the HIV-1 reverse transcriptase. A critical consequence of this mechanism is the lack of activity against HIV-2 and other retroviruses, as the amino acid sequence in the NNRTI-binding pocket of HIV-2 reverse transcriptase differs significantly, preventing effective binding of efavirenz. Furthermore, this specific binding site is a locus for the development of resistance; single amino acid substitutions, such as K103N or Y181C, can markedly reduce the binding affinity of efavirenz, leading to virologic failure.

At the cellular level, efavirenz inhibits the replication of HIV-1 in activated T-lymphocytes and monocyte-derived macrophages. It is active against both laboratory strains and clinical isolates of HIV-1. The drug is classified as a virustatic agent; it suppresses viral replication but does not eliminate latent viral reservoirs or cure the infection. Its pharmacodynamic effect is concentration-dependent, with the area under the inhibitory curve (AUIC) being a predictor of virologic response.

Pharmacokinetics

The pharmacokinetic profile of efavirenz is characterized by high inter-individual variability, extensive metabolism, and a long terminal half-life, which supports once-daily dosing. Its properties are influenced by genetic polymorphisms, concomitant food intake, and drug interactions.

Absorption

Following oral administration, efavirenz is absorbed with a time to peak plasma concentration (t_max) of approximately 3 to 5 hours. Its oral bioavailability in the fasted state is estimated to be in the range of 40% to 45%. Absorption is significantly enhanced by a high-fat meal; administration with food can increase the area under the plasma concentration-time curve (AUC) by up to 50% and double the peak plasma concentration (C_max). However, to minimize central nervous system side effects and standardize absorption, current guidelines recommend administration on an empty stomach, preferably at bedtime. The lipophilic nature of the compound facilitates its absorption.

Distribution

Efavirenz is extensively distributed throughout the body. Its apparent volume of distribution is large, exceeding total body water, indicating significant tissue penetration. The drug is highly bound (>99.5%) to plasma proteins, primarily albumin. This extensive protein binding limits its dialyzability and can influence the free fraction of drug available for pharmacological activity and metabolism. Efavirenz achieves concentrations in the cerebrospinal fluid (CSF) that are approximately 0.5% to 1.2% of corresponding plasma concentrations, a level that exceeds the in vitro inhibitory concentration for wild-type virus. This penetration into the central nervous system is pharmacologically relevant but is also implicated in the genesis of its neuropsychiatric adverse effects.

Metabolism

Efavirenz undergoes extensive hepatic metabolism, primarily via the cytochrome P450 system. The major isoenzymes involved are CYP2B6 and, to a lesser extent, CYP3A4. The primary metabolic pathways are hydroxylation followed by subsequent glucuronidation. The metabolites, chiefly 8-hydroxy-efavirenz and 7-hydroxy-efavirenz, are considered to have minimal antiviral activity. The metabolism of efavirenz exhibits significant genetic polymorphism, particularly concerning CYP2B6. Individuals homozygous for the CYP2B6*6 allele (common in certain ethnic populations, including those of African descent) are slow metabolizers, resulting in significantly higher plasma efavirenz exposure (AUC) and prolonged elimination half-life. This polymorphism is a major contributor to the wide inter-patient variability observed in efavirenz pharmacokinetics and is associated with an increased risk of neurotoxicity.

Notably, efavirenz is also a moderate inducer of CYP3A4 and, to a lesser degree, CYP2B6. This auto-induction process typically reaches steady-state within 2 to 4 weeks of initiating therapy, leading to a decrease in efavirenz plasma concentrations by 20% to 40% from initial levels. This inductive property is a key driver of its numerous drug-drug interactions.

Excretion

Following metabolism, efavirenz is eliminated predominantly in the feces, with renal excretion playing a minor role. Approximately 14% to 34% of an administered dose is recovered in the urine, almost exclusively as glucuronidated metabolites, with less than 1% excreted as unchanged parent drug. The terminal elimination half-life (t_1/2) is long and variable, ranging from 40 to 55 hours after single doses and increasing to 52 to 76 hours after multiple doses, partly due to auto-induction resolving and the saturable nature of its metabolism. This prolonged half-life is a critical factor supporting once-daily dosing and contributes to a low genetic barrier to resistance if monotherapy or functional monotherapy occurs.

Therapeutic Uses/Clinical Applications

Efavirenz is indicated for the treatment of HIV-1 infection in adults and pediatric patients aged 3 months and older, weighing at least 3.5 kg. It must always be used in combination with other antiretroviral agents as part of a complete suppressive regimen to prevent the emergence of resistance.

Approved Indications

The primary indication is in combination antiretroviral therapy (cART) for treatment-naïve patients. For many years, efavirenz combined with tenofovir disoproxil fumarate and emtricitabine was considered a preferred or alternative first-line regimen in major international guidelines. Its use has declined in high-resource settings with the advent of better-tolerated integrase strand transfer inhibitors (INSTIs), but it remains a component of preferred or alternative regimens in certain global and resource-limited contexts due to its potency, durability, and cost-effectiveness. It is also indicated for use in treatment-experienced patients as part of a regimen constructed based on resistance testing, provided there is no documented resistance to efavirenz.

An additional approved use is for HIV post-exposure prophylaxis (PEP) as part of a combination regimen, although its CNS side-effect profile makes it less favored for this indication compared to other agents.

Off-Label Uses

Common off-label uses are limited, given its specific antiviral spectrum. Historically, it has been studied and occasionally used in combination regimens for the prevention of mother-to-child transmission (PMTCT) when other first-line options are not available or contraindicated, though its teratogenic potential requires stringent risk-benefit analysis. Its use in HIV-2 infection is not effective and is contraindicated.

Adverse Effects

The adverse effect profile of efavirenz is a major determinant of its tolerability and clinical utility. Adverse reactions can be broadly categorized into central nervous system effects, dermatological reactions, metabolic disturbances, and other organ system toxicities.

Common Side Effects

The most frequently reported adverse effects are neuropsychiatric. Up to 50% of patients experience some form of central nervous system symptom, particularly during the initial weeks of therapy. These include dizziness, insomnia, abnormal dreams, impaired concentration, somnolence, and headache. A characteristic symptom complex often referred to as “efavirenz fog” or “CNS toxicity” may occur. These symptoms are often transient, resolving within 2 to 4 weeks as tolerance develops. Administration at bedtime is a standard strategy to mitigate the impact of these effects. Rash is another common side effect, occurring in approximately 10% to 20% of patients, typically within the first two weeks of therapy. These rashes are usually mild to moderate, maculopapular, and self-limiting.

Serious and Rare Adverse Reactions

More serious neuropsychiatric effects occur in a smaller subset of patients. Severe depression, suicidal ideation, suicidal behavior, aggressive behavior, paranoid reactions, and severe psychosis have been reported. Patients with a pre-existing psychiatric history may be at increased risk. Hepatotoxicity, including hepatic enzyme elevations and cases of hepatic failure, has been observed. Severe skin reactions, such as Stevens-Johnson syndrome and erythema multiforme, are rare but potentially life-threatening. Other notable effects include gynecomastia, lipid abnormalities (increases in total cholesterol and triglycerides), and false-positive cannabinoid tests in some urine assays.

Black Box Warnings

Efavirenz carries several boxed warnings, the most stringent safety labeling issued by regulatory authorities. These warnings highlight:

• Psychiatric Symptoms: Serious psychiatric adverse experiences, including severe depression, suicidal ideation, non-fatal suicidal attempts, aggressive behavior, and paranoid reactions, have been reported in patients treated with efavirenz.
• Fetal Toxicity: Administration to pregnant women may cause fetal harm based on animal data and retrospective human reports. Major congenital malformations, particularly neural tube defects, have been reported with first-trimester exposure. Pregnancy should be avoided in women receiving efavirenz, and effective contraception is mandatory.
• Potential for Resistance: As a single agent, efavirenz has a low genetic barrier to resistance. It must not be used as monotherapy and must only be administered as part of a combination antiretroviral regimen.

Drug Interactions

Efavirenz is involved in numerous and clinically significant drug-drug interactions, primarily due to its metabolism by and induction of hepatic cytochrome P450 enzymes. These interactions can lead to subtherapeutic antiretroviral levels (risk of virologic failure and resistance) or toxic levels of concomitant medications.

Major Drug-Drug Interactions

As a moderate inducer of CYP3A4, efavirenz decreases the plasma concentrations of drugs that are substrates of this enzyme. This effect is of paramount clinical importance. Key interactions include:

• Protease Inhibitors (PIs): Most PIs are metabolized by CYP3A4. Coadministration with efavirenz significantly reduces PI concentrations (e.g., atazanavir, lopinavir, indinavir). Dose adjustments or additional ritonavir boosting are often required, and some combinations are not recommended.
• Other Antiretrovirals: Concentrations of maraviroc (a CCR5 antagonist) are reduced, necessitating a dose increase. The interaction with rilpivirine (another NNRTI) is contraindicated due to profound reduction in rilpivirine levels.
• Anticonvulsants: Carbamazepine, phenobarbital, and phenytoin induce CYP enzymes and can reduce efavirenz levels, while efavirenz can reduce levels of these anticonvulsants, creating a complex bidirectional interaction. Valproic acid may increase efavirenz levels.
• Antimycobacterials: Rifampin, a potent CYP inducer, decreases efavirenz exposure. A dose increase of efavirenz to 800 mg daily is often recommended when co-administered with rifampin in patients weighing ≥50 kg. Rifabutin levels are decreased by efavirenz.
• Azole Antifungals: Efavirenz reduces concentrations of itraconazole, ketoconazole, and posaconazole. Voriconazole concentrations are drastically reduced by efavirenz, while efavirenz levels are increased by voriconazole; coadministration is contraindicated unless the voriconazole dose is significantly increased and efavirenz is discontinued.
• Immunosuppressants: Levels of cyclosporine, tacrolimus, and sirolimus may be decreased, requiring therapeutic drug monitoring.
• Hormonal Contraceptives: Efavirenz may reduce plasma concentrations of ethinyl estradiol and other hormonal contraceptives, potentially compromising efficacy. Use of alternative or additional contraceptive methods is advised.
• Direct-Acting Oral Anticoagulants (DOACs): Efavirenz may reduce exposure to apixaban and rivaroxaban, potentially requiring avoidance or dose adjustment.

Conversely, efavirenz levels can be increased by strong CYP2B6 inhibitors (e.g., sertraline, bupropion) and decreased by strong inducers. Coadministration with other drugs that have similar CNS side-effect profiles (e.g., psychiatric medications) may have additive toxicities.

Contraindications

Absolute contraindications to efavirenz use include:

• Hypersensitivity to efavirenz or any component of the formulation.
• Coadministration with drugs that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., astemizole, terfenadine, cisapride, pimozide, midazolam, triazolam, ergot alkaloids, voriconazole [without dose adjustment], and St. John’s wort).
• Coadministration with other NNRTIs used for HIV treatment (e.g., rilpivirine, etravirine, nevirapine) due to potential antagonism and complex interactions, unless specifically recommended in guidelines.
• Use in patients with severe hepatic impairment (Child-Pugh Class C) due to lack of safety data and potential for accumulation.

Special Considerations

Use in Pregnancy and Lactation

Efavirenz is classified as Pregnancy Category D (US FDA) or its equivalent in other systems, indicating positive evidence of human fetal risk. Retrospective data from surveillance registries initially suggested a potential increased risk of neural tube defects with first-trimester exposure. Subsequent meta-analyses have found the absolute risk to be lower than initially feared, but a small increased risk cannot be excluded. Consequently, efavirenz is not recommended for use in the first trimester of pregnancy or in women who are trying to conceive. For women already stable on an efavirenz-based regimen who become pregnant, the decision to continue or switch therapy must be individualized, weighing the risk of virologic rebound against the potential fetal risk. Efavirenz is excreted in human milk. Because of the potential for HIV transmission and serious adverse reactions in nursing infants, breastfeeding is not recommended for HIV-infected mothers in settings where safe alternatives are available.

Pediatric and Geriatric Considerations

Efavirenz is approved for pediatric patients ≥3 months of age. Dosing is based on body weight and body surface area, using specific pediatric formulations. Pharmacokinetic variability can be pronounced in children. Neuropsychiatric side effects should be monitored closely, as they may be difficult for young children to articulate. In geriatric patients, no specific dose adjustment is recommended based on age alone. However, age-related decreases in hepatic or renal function, a higher likelihood of concomitant diseases, and polypharmacy increase the potential for adverse reactions and drug interactions. Careful monitoring is warranted.

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 a minor elimination pathway. The drug is not significantly removed by hemodialysis due to extensive protein binding. In patients with mild to moderate hepatic impairment (Child-Pugh Class A or B), caution is advised, and monitoring of liver function is recommended. A dose reduction may be considered in patients with moderate hepatic impairment, though specific guidelines vary. Efavirenz is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) due to the lack of pharmacokinetic and safety data and the potential for drug accumulation and exacerbated hepatotoxicity.

Summary/Key Points

• Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with potent activity against HIV-1, but not HIV-2. Its mechanism involves allosteric inhibition of the viral reverse transcriptase enzyme.
• Pharmacokinetically, it is characterized by variable absorption (enhanced by food), extensive protein binding, predominant hepatic metabolism via CYP2B6 (subject to genetic polymorphism), a long half-life enabling once-daily dosing, and significant CNS penetration.
• It is indicated for combination antiretroviral therapy in treatment-naïve and treatment-experienced patients without resistance, though its use as a first-line agent has diminished in favor of better-tolerated options in many settings.
• The adverse effect profile is dominated by CNS symptoms (dizziness, insomnia, abnormal dreams), which are often transient, and by rash. Serious psychiatric effects, hepatotoxicity, and severe skin reactions necessitate vigilant monitoring.
• Efavirenz is a moderate inducer of CYP3A4 and a substrate of CYP2B6, resulting in a wide array of clinically significant drug-drug interactions that require careful review of concomitant medications.
• Special considerations include its teratogenic potential (contraindicated in first-trimester pregnancy), the need for caution in hepatic impairment, and its viability in pediatric populations with weight-based dosing.

Clinical Pearls

• Administration at bedtime on an empty stomach can improve tolerability of initial CNS side effects.
• The auto-induction of its own metabolism means steady-state plasma levels are reached after 2-4 weeks; early side effects may attenuate over this period.
• Genetic testing for CYP2B6 polymorphisms, while not routine in all settings, can identify slow metabolizers at higher risk for neurotoxicity and may guide therapeutic decisions.
• When discontinuing an efavirenz-based regimen as part of a switch strategy, its long half-life necessitates overlapping or “bridging” therapy with other antiretrovirals to prevent functional monotherapy and the emergence of resistance.
• Patients should be counseled on the possibility of vivid dreams and dizziness, reassured about their typically transient nature, and instructed to report any severe mood changes or suicidal thoughts immediately.

References

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