Didanosine + Efavirenz + Lamivudine

This combination, while theoretically possible, is not recommended in clinical practice. The recommended combination for HIV treatment includes Efavirenz + Lamivudine + Tenofovir Disoproxil Fumarate. Co-administration of this combination with Didanosine is not recommended due to significant increase in Didanosine exposure when combined with Tenofovir, leading to a higher risk of pancreatitis and lactic acidosis. This document will therefore focus on the recommended combination of Efavirenz + Lamivudine + Tenofovir.

Usage

• Medical Conditions: This fixed-dose combination (FDC) medication is prescribed for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults and children (weight dependent). It is used as a complete antiretroviral therapy (ART) regimen. Note that this medication does not cure HIV, nor does it prevent transmission.

• Pharmacological Classification: Antiretroviral (includes nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs)).

• Mechanism of Action: This FDC combines three antiretrovirals that work together to inhibit HIV replication. Tenofovir disoproxil fumarate and Lamivudine are NRTIs that interfere with the reverse transcription of viral RNA into DNA. Efavirenz is an NNRTI that directly inhibits the reverse transcriptase enzyme. This multifaceted approach targets multiple steps in the viral life cycle.

Alternate Names

This combination is available under the brand names Symfi (600 mg/300 mg/300 mg) and Symfi Lo (400 mg/300 mg/300 mg), with variations in the Efavirenz component.

How It Works

• Pharmacodynamics: The combination suppresses HIV replication by inhibiting reverse transcriptase, preventing the formation of proviral DNA.

• Pharmacokinetics:

  • Absorption: Administered orally, ideally on an empty stomach and at bedtime to mitigate side effects.
  • Metabolism: Efavirenz is primarily metabolized by the CYP450 system, specifically CYP2B6, with minor contributions from CYP3A4 and CYP2A6. Lamivudine and Tenofovir are minimally metabolized.
  • Elimination: Lamivudine and Tenofovir are primarily renally excreted. Efavirenz metabolites are primarily excreted in feces, with a small amount in urine.

• Mode of Action: Tenofovir and Lamivudine, after intracellular phosphorylation, compete with natural nucleosides, incorporating into the viral DNA chain, causing chain termination. Efavirenz directly binds to reverse transcriptase at a site distinct from NRTIs, causing allosteric inhibition.

Dosage

Standard Dosage

Adults: Symfi Lo: For patients weighing 35 kg or more, one tablet (400 mg efavirenz/300 mg lamivudine/300 mg tenofovir disoproxil fumarate) orally once daily at bedtime. Symfi: For patients weighing 40 kg or more, one tablet (600 mg efavirenz/300 mg lamivudine/300 mg tenofovir disoproxil fumarate) orally once daily at bedtime.

Children: Symfi and Symfi Lo are not indicated for children weighing less than 35kg and 40kg respectively. Dosing adjustments may be required in children weighing 35kg/40kg and above based on weight bands. Efavirenz dosing may also be based on CYP2B6 genotype in children over 3 months old.

Special Cases:

• Elderly Patients: Exercise caution due to potential age-related decreases in hepatic, renal, or cardiac function.
• Patients with Renal Impairment: Not recommended for patients with creatinine clearance (CrCl) < 50 mL/min or end-stage renal disease.
• Patients with Hepatic Dysfunction: Not recommended for moderate to severe hepatic impairment. Use with caution in mild hepatic impairment.
• Patients with Comorbid Conditions: Close monitoring is necessary.

Clinical Use Cases

The dosage remains consistent across various clinical settings, as described in the standard adult dosage.

Dosage Adjustments

Adjustments are primarily based on renal and hepatic function as outlined above.

Side Effects

Common Side Effects: Rash, dizziness, nausea, vomiting, diarrhea, headache, fatigue, insomnia, abnormal dreams, depression, anxiety.

Rare but Serious Side Effects: Lactic acidosis, severe hepatomegaly with steatosis, Stevens-Johnson syndrome, pancreatitis, renal impairment including Fanconi syndrome, severe skin reactions, suicidal ideation.

Long-Term Effects: Changes in bone mineral density, kidney problems, fat redistribution.

Contraindications

• Hypersensitivity to any component of the medication.
• Coadministration with drugs that significantly interact with efavirenz, lamivudine, or tenofovir, such as elbasvir/grazoprevir and voriconazole.
• Severe hepatic impairment.

Drug Interactions

Numerous drug interactions exist. Refer to a comprehensive drug interaction resource for a complete list. Significant interactions can occur with certain anticonvulsants, antifungals, antimycobacterials, and some herbal supplements. CYP450 enzyme inducers or inhibitors may affect Efavirenz metabolism.

Pregnancy and Breastfeeding

Breastfeeding is not recommended while on this medication due to the potential for infant exposure and unknown effects. Use during pregnancy requires careful consideration of the risks and benefits, as efavirenz has been associated with birth defects in animal studies. Close monitoring is necessary.

Drug Profile Summary

Refer to the sections above for detailed explanations of the mechanism of action, side effects, contraindications, drug interactions, pregnancy/breastfeeding considerations, and dosage.

• Monitoring Parameters: Renal function (creatinine, phosphorus, urine glucose, urine protein), liver function tests, HIV viral load, CD4 count, bone mineral density.

Popular Combinations

This FDC is intended as a complete regimen and should not be combined with other antiretrovirals without specialist consultation.

Precautions

• Pre-screening for HBV is essential.
• Monitor renal and hepatic function closely.
• Assess for mental health issues.
• Counsel patients about potential side effects, including neuropsychiatric symptoms.
• Advise patients about drug interactions and the importance of adherence.

FAQs (Frequently Asked Questions)

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

A: Symfi Lo: One tablet (400 mg/300 mg/300 mg) orally once daily at bedtime for patients weighing 35 kg or more. Symfi: One tablet (600 mg/300 mg/300 mg) orally once daily at bedtime for patients weighing 40 kg or more.

Q2: What are the common side effects?

A: Common side effects include rash, dizziness, nausea, vomiting, diarrhea, headache, fatigue, insomnia, abnormal dreams, depression, and anxiety.

Q3: What are the serious side effects?

A: Serious side effects include lactic acidosis, severe hepatomegaly with steatosis, Stevens-Johnson syndrome, pancreatitis, renal impairment, and psychiatric symptoms.

Q4: What are the contraindications?

A: Contraindications include hypersensitivity to any component and coadministration with certain interacting medications.

Q5: Can this combination be used during pregnancy?

A: Use during pregnancy requires careful consideration of the risks and benefits. Efavirenz has shown to cause birth defects in animal studies, and its safety in human pregnancy isn’t fully established.

Q6: Can this combination be used during breastfeeding?

A: Breastfeeding is generally not recommended due to the potential for infant exposure and adverse effects.

Q7: What monitoring is required for patients on this medication?

A: Monitor renal function, liver function, HIV viral load, CD4 count, and bone mineral density.

Q8: What are the key drug interactions?

A: Many drug interactions exist. Consult a drug interaction checker or database for the most up-to-date and complete list.

Q9: What patient counseling points are important?

A: Counsel patients on the importance of adherence, potential side effects (including neuropsychiatric symptoms), drug interactions, and the need for regular monitoring. Emphasize that this drug doesn’t cure HIV or prevent transmission.