Efavirenz: Indications, Mechanism of Action and Side Effects

Indications

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) approved by the FDA for the treatment and prevention of HIV infection in adults and children 3 years of age and older. In addition, the combination of Efavirenz, Emtricitabine, and Tenofovir may be used alone or with other medications to treat human immunodeficiency virus (HIV) infection in adults and children weighing more than 40 kilograms (88 pounds), but not for the treatment of hepatitis B virus infection (HBV).

Patients previously needed three 200 mg efavirenz capsules daily, but this was changed to a single 600 mg tablet per day (Children's dosage is based on body weight and is to be used as directed by a doctor). However, the 600 mg daily dose was associated with poor HIV suppression and toxicity. Clinical data indicated that a lower dose of efavirenz could be as effective with fewer side effects and at a lower cost. The ENCORE1 study compared a 400 mg dose of efavirenz to the standard 600 mg dose combined with two NRTIs in HIV-infected individuals new to antiretroviral treatment. With the advent of integrase strand transfer inhibitors (INSTIs), some argue that efavirenz should no longer be a first-line global treatment option, where possible. Although efavirenz has been a primary first-line antiviral for over 15 years, its optimal use may now be for pre-exposure prophylaxis (PrEP) and other medical repurposing.

Mechanism of Action

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds to a specific site on the HIV reverse transcriptase enzyme, different from the enzyme's active site, thereby inhibiting the enzyme's activity and causing termination of the DNA chain. This mechanism prevents HIV replication by blocking the DNA polymerase activities. Efavirenz's antiviral effect depends on its intracellular conversion to an active triphosphorylated form, which interferes with the creation of viral DNA copies from RNA templates, essential for producing new virus particles. Although it does not eliminate HIV from the body, it helps control the virus by stopping its spread. Efavirenz is typically taken once daily, reaches peak concentrations within 5 hours, and has a half-life of approximately 45 hours. It is highly protein-bound, mainly to albumin, and is metabolized by the CYP3A4 enzyme into inactive metabolites. It is important to avoid taking efavirenz with food, as this can increase serum concentrations and the risk of adverse effects, such as sleep disorders. The drug is often combined with other antiviral medications to enhance its therapeutic effect.

Side Effects

Efavirenz, like other NNRTIs, is commonly linked to central nervous system (CNS) effects such as impaired concentration, abnormal dreams, insomnia, and suicidal ideation. Gastrointestinal issues like nausea and vomiting may also occur. These adverse effects can lead to non-adherence and treatment failure. Symptoms typically appear early in treatment but often lessen over time. Lipodystrophy is another common issue with NNRTIs. Additionally, efavirenz can cause skin rash, elevated liver enzymes, low neutrophil counts, high blood sugar, and high lipid levels. Resistance can emerge rapidly if efavirenz is used as a single therapy, especially in patients with previous NRTI resistance. Other side effects include nervous system symptoms like dizziness, insomnia, and lack of coordination, seizures, immune reconstitution inflammatory syndrome (IRIS), and changes in body fat and blood lipid levels. It's important to report bothersome or persistent side effects to your healthcare provider.

References:

[1] BÁRBARA COSTA; Nuno V. Efavirenz: History, Development and Future.[J]. Biomolecules, 2022. DOI:10.3390/biom13010088.

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