Efavirenz + Lamivudine + Tenofovir disoproxil fumarate

Usage

• This fixed-dose combination is prescribed for the treatment of HIV-1 infection in adults and children.
• Pharmacological Classification: Antiretroviral (specifically a combination of a non-nucleoside reverse transcriptase inhibitor (NNRTI) - efavirenz, and two nucleoside reverse transcriptase inhibitors (NRTIs) - lamivudine and tenofovir disoproxil fumarate).
• Mechanism of Action: This combination targets multiple stages of the HIV-1 replication cycle. Efavirenz inhibits the reverse transcriptase enzyme, preventing the conversion of viral RNA to DNA. Lamivudine and tenofovir disoproxil fumarate (which is metabolized to tenofovir) are nucleoside analogs that, once phosphorylated to their active forms, get incorporated into the growing viral DNA chain, causing chain termination.

Alternate Names

• This combination is commonly referred to as the “Atripla” (brand name). It’s specifically efavirenz, emtricitabine, and tenofovir disoproxil fumarate in a single tablet though sometimes confused with the combination in the prompt question.
• Other than Atripla, there isn’t a widely recognized international nonproprietary name for this specific three-drug combination. Many countries have their own fixed-dose combinations with different brand names. However, each component has its own alternate names: efavirenz (EFV, EFZ, Sustiva), lamivudine (3TC, Epivir), and tenofovir disoproxil fumarate (TDF, Viread).

How It Works

• Pharmacodynamics: Efavirenz, lamivudine, and tenofovir work synergistically to suppress HIV-1 replication by inhibiting key viral enzymes. This leads to a decrease in viral load and an increase in CD4+ T-cell counts, improving immune function.

• Pharmacokinetics:

  • Absorption: All three drugs are orally absorbed. Efavirenz absorption is enhanced by food, but a high-fat meal increases side effects. Tenofovir disoproxil fumarate is a prodrug that is rapidly converted to tenofovir.
  • Metabolism: Efavirenz is primarily metabolized in the liver by CYP450 enzymes, specifically CYP2B6, CYP3A4, and CYP2A6. Lamivudine and tenofovir are minimally metabolized.
  • Elimination: Efavirenz metabolites are primarily excreted in the feces, with a small amount in the urine. Lamivudine and tenofovir are primarily renally excreted.

• Mode of Action:

  • Efavirenz: Non-competitive inhibitor of HIV-1 reverse transcriptase.
  • Lamivudine and Tenofovir: Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) that compete with natural substrates and cause DNA chain termination.

• Receptor Binding/Enzyme Inhibition:

  • Efavirenz binds to the reverse transcriptase enzyme’s non-nucleoside binding site.
  • Lamivudine and Tenofovir, in their triphosphate forms, bind to the reverse transcriptase enzyme’s active site, competing with natural nucleotides.

• Elimination Pathways:

  • Efavirenz: Hepatic metabolism (CYP450 enzymes), primarily fecal excretion.
  • Lamivudine: Renal excretion.
  • Tenofovir: Renal excretion.

Dosage

Standard Dosage

Adults:

Efavirenz 600 mg + Lamivudine 300 mg + Tenofovir disoproxil fumarate 300 mg orally once daily, preferably at bedtime.

Children:

Dosing for children is complex and based on weight; consult pediatric HIV treatment guidelines. Simplified pediatric dosage information is available, but it is not the current recommendation and should be verified with up-to-date guidelines.

Special Cases:

• Elderly Patients: No specific dose adjustments are typically needed unless there is renal impairment.

• Patients with Renal Impairment: Dose adjustments for tenofovir disoproxil fumarate and lamivudine are required based on creatinine clearance. Efavirenz dosage may not need adjustment.

• Patients with Hepatic Dysfunction: Caution is advised with efavirenz in moderate to severe hepatic impairment. Dosage adjustments might be necessary. No adjustments are usually needed for lamivudine and tenofovir.

• Patients with Comorbid Conditions: Consider individual patient factors, particularly drug interactions.

Clinical Use Cases The combination therapy itself doesn’t have specific dosage variations for procedures like intubation, surgery, mechanical ventilation, or ICU use. Dosage depends on the HIV infection status and overall patient health. Drug interactions are very important to consider for all concomitant medications.

Dosage Adjustments Adjustments are based on renal and hepatic function and potential drug interactions, and possibly genetic polymorphisms affecting efavirenz metabolism.

Side Effects

Common Side Effects

Rash, nausea, vomiting, diarrhea, headache, dizziness, fatigue, insomnia, abnormal dreams, and psychiatric symptoms (e.g., depression, anxiety).

Rare but Serious Side Effects

Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), liver damage, lactic acidosis, pancreatitis, seizures, suicidal ideation.

Long-Term Effects

Dyslipidemia, insulin resistance, lipodystrophy, renal impairment, osteoporosis.

Adverse Drug Reactions (ADR)

Hepatotoxicity, severe psychiatric symptoms, hypersensitivity reactions.

Contraindications

• Hypersensitivity to any of the components.
• Coadministration with drugs that significantly prolong the QT interval.
• Severe hepatic impairment (for efavirenz).

Drug Interactions

• Numerous drug interactions exist. Some notable ones include:
  • CYP450 interactions: Efavirenz is both an inducer and substrate of CYP450 enzymes.
  • Drugs metabolized by CYP2B6, CYP3A4, and CYP2A6: Efavirenz may alter their concentrations.
  • Anticonvulsants, rifampin, St. John’s wort, and other CYP450 inducers: May decrease efavirenz levels.
  • Azole antifungals, macrolide antibiotics, and other CYP450 inhibitors: May increase efavirenz levels.
  • Drugs that are substrates or inhibitors of P-glycoprotein transporter (e.g., tipranavir, digoxin, atazanavir): potential for drug interactions.
  • Didanosine: avoid concomitant use with tenofovir disoproxil fumarate.

Pregnancy and Breastfeeding

• Efavirenz is contraindicated in the first trimester of pregnancy due to teratogenic effects. Use with caution in later trimesters.
• Lamivudine and tenofovir are considered relatively safe during pregnancy, but individual risk-benefit assessments are crucial.
• All three drugs are present in breast milk. While lamivudine and tenofovir are generally considered safe during breastfeeding, the decision of whether to breastfeed should be made in consultation with a healthcare provider, balancing the benefits of breastfeeding with the potential risks of drug exposure to the infant. Efavirenz levels are lower in breastmilk than in maternal plasma, but potential risk to the infant is unknown.

Drug Profile Summary (See above details)

Popular Combinations

• This specific three-drug combination itself is not typically used as a standard of care anymore. Current first-line regimens usually involve two NRTIs plus an integrase inhibitor or other antiretroviral classes. Each individual drug may be combined with other antiretrovirals depending on resistance patterns and other considerations.

Precautions (See side effects and contraindications)

FAQs (Frequently Asked Questions)

(Refer to the details given above for answers)

Q1: What is the recommended dosage for Efavirenz + Lamivudine + Tenofovir disoproxil fumarate?

A: (Refer to the dosage section)

Q2: What are the most common side effects?

Q3: What are the serious side effects I need to watch out for?

Q4: Are there any specific contraindications to this medication?

Q5: What are the key drug interactions I should be aware of?

Q6: Can this combination be used during pregnancy or breastfeeding?

Q7: How do these medications affect the liver and kidneys?

Q8: What should I do if a patient misses a dose?

Q9: Are there alternative medications available if this combination is not suitable?