How does Efavirenz (non-nucleoside reverse transcriptase inhibitor) cause skin rash, hepatitis, or central nervous system (CNS) manifestations?

Mechanisms of Efavirenz-Induced Skin Rash, Hepatitis, and CNS Manifestations

Efavirenz causes skin rash through immune-mediated hypersensitivity reactions, hepatitis through direct hepatotoxicity and immune-mediated mechanisms, and CNS manifestations through disruption of brain mitochondrial function and neurotransmitter pathways. 1, 2, 3

Skin Rash Mechanism

• Efavirenz hypersensitivity commonly manifests as mild to moderate skin rash, with severe eruptions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and erythema multiforme occurring in approximately 0.1% of patients 1
• The rash typically appears within the first 1-3 weeks of therapy initiation, suggesting an immune-mediated hypersensitivity reaction rather than direct toxicity 4
• Skin manifestations are typically erythematous and maculopapular in nature, similar to other drug hypersensitivity reactions 2
• The incidence of efavirenz-induced hypersensitivity ranges between 10% and 34%, making it one of the most common adverse effects of the medication 4

Hepatitis Mechanism

• Hepatotoxicity occurs less frequently with efavirenz compared to other NNRTIs like nevirapine, with grade 2-3 hepatic events seen in approximately 4% of patients 1
• The mechanism appears to be multifactorial, involving:
  • Direct antiretroviral toxicity to hepatocytes 1
  • Immune-mediated reactions, particularly in patients who develop concurrent skin rash 5
  • Potential genetic factors affecting drug metabolism through CYP2B6, which is responsible for almost 90% of efavirenz clearance 5
• High plasma concentrations of efavirenz (Cmin above 2.18 mg/L) have been associated with a 4.4-fold increased risk of elevated liver enzymes during the first 6 weeks of treatment 6
• Risk factors for efavirenz hepatotoxicity include alcohol abuse, hepatitis B or C co-infection, and concomitant use of other hepatotoxic drugs 1

CNS Manifestations Mechanism

• Efavirenz is associated with a wide range of neurological and neuropsychiatric reactions, including dizziness, insomnia, abnormal dreams, impaired concentration, and in more severe cases, depression and psychosis 2, 3
• CNS symptoms occur in approximately 52.7% of patients taking efavirenz, with 17.4% experiencing moderate symptoms and 2% experiencing severe symptoms 2
• The mechanisms responsible for efavirenz-induced neurotoxicity involve:
  • Disturbances in brain mitochondrial function and bioenergetics 3
  • High penetration of efavirenz into the CNS, allowing the drug to reach concentrations that can affect neuronal function 3
  • Possible interference with neurotransmitter systems, particularly those involved in sleep regulation and mood 1, 3
• Dosing at bedtime may minimize some CNS side effects, suggesting a relationship between peak plasma concentrations and symptom severity 1

Clinical Implications and Management

• For skin rash:

  • Most mild to moderate rashes can be managed symptomatically without discontinuation of therapy 4
  • Severe rashes (SJS/TEN) require immediate discontinuation of efavirenz 2
  • Desensitization protocols may be considered in patients with limited antiretroviral options 4

• For hepatotoxicity:

  • Regular monitoring of liver enzymes is recommended before and during treatment 2
  • Consider discontinuing efavirenz if transaminases exceed five times the upper limit of normal or if clinical signs of hepatitis develop 2, 5

• For CNS manifestations:

  • Symptoms often improve or resolve within 2-4 weeks of continued therapy 3
  • Bedtime dosing may reduce the impact of CNS symptoms 1
  • Patients with severe psychiatric symptoms may require discontinuation of efavirenz 2

Special Considerations

• Genetic factors may influence the risk of adverse reactions, with certain populations (Black and Latino patients) showing higher efavirenz concentrations and potentially increased risk of adverse effects 5
• Rechallenge with efavirenz after a hypersensitivity reaction can lead to more severe reactions and should generally be avoided 7
• Therapeutic drug monitoring may be valuable in managing patients with CNS symptoms or hepatotoxicity, particularly during the first 6 weeks of therapy 6