Efavirenz + Lamivudine + Stavudine

Usage

• Efavirenz + Lamivudine + Stavudine is prescribed for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults and children (weight dependent). This combination is typically not a first-line treatment anymore due to the toxicity profile of Stavudine. It is reserved for cases where other options are not feasible due to resistance or intolerance.
• Pharmacological Classification: Antiretroviral agent, specifically a combination of a non-nucleoside reverse transcriptase inhibitor (NNRTI, Efavirenz) and two nucleoside reverse transcriptase inhibitors (NRTIs, Lamivudine and Stavudine).
• Mechanism of Action: This combination targets and inhibits the reverse transcriptase enzyme, essential for HIV-1 replication. Efavirenz directly binds to the enzyme, while Lamivudine and Stavudine act as competitive substrates and chain terminators, disrupting viral DNA synthesis.

Alternate Names

• No internationally recognized non-proprietary name exists for this specific combination.
• This combination is often prescribed by its component names rather than under a single brand name. Generic versions are often available. Several sources refer to Symfi (Efavirenz 600mg/Lamivudine 300mg/Tenofovir DF 300mg) or Symfi Lo (Efavirenz 400mg/Lamivudine 300mg/Tenofovir DF 300mg) as similar combinations.

How It Works

• Pharmacodynamics: Efavirenz, Lamivudine, and Stavudine suppress HIV-1 replication by inhibiting reverse transcriptase, leading to a decrease in viral load and an increase in CD4+ T-cell counts.

• Pharmacokinetics:

  • Absorption: All three drugs are orally absorbed. Food can increase Efavirenz absorption, potentially increasing side effects.
  • Metabolism: Efavirenz is extensively metabolized by the CYP450 system, specifically CYP2B6. Lamivudine and Stavudine are primarily eliminated unchanged.
  • Elimination: Efavirenz is primarily eliminated by hepatic metabolism, while Lamivudine and Stavudine are predominantly excreted renally.

• Mode of Action: Efavirenz binds directly to reverse transcriptase, causing non-competitive allosteric inhibition. Lamivudine and Stavudine are phosphorylated intracellularly to their active triphosphate forms. These triphosphates compete with natural nucleotides and get incorporated into viral DNA, halting further chain elongation due to the lack of a 3’-hydroxyl group.

• Receptor Binding/Enzyme Inhibition: The primary mechanism is reverse transcriptase enzyme inhibition. Efavirenz binds directly to the enzyme while the NRTIs (Lamivudine and Stavudine) compete with the natural substrates in the catalytic site of the enzyme.

Dosage

Standard Dosage

Adults:

• Efavirenz 600 mg + Lamivudine 300 mg + Stavudine (d4T) based on weight and CD4 count.
• Administered orally, once daily, preferably at bedtime on an empty stomach.

Children:

• The combination is generally not recommended for children weighing less than 40kg due to the difficult in adjusting individual components and due to the Stavudine toxicity profile. If used, the dosage of each component needs careful weight-based adjustment.

Special Cases:

• Elderly Patients: Exercise caution due to the increased likelihood of renal or hepatic impairment.
• Patients with Renal Impairment: Dose adjustments are crucial for Stavudine and Lamivudine. Efavirenz may not require adjustment.
• Patients with Hepatic Dysfunction: Dose adjustment may be needed. Closely monitor liver function tests.
• Patients with Comorbid Conditions: Careful consideration is required, particularly with co-existing liver disease (including hepatitis B or C), mental illness, or pancreatitis.

Clinical Use Cases

• The use of this combination in specialized clinical settings like intubation, surgical procedures, mechanical ventilation, ICU, or emergency situations is not standard practice and would be determined by the specific patient’s HIV management needs in consultation with infectious disease specialists.

Dosage Adjustments

• Renal or hepatic impairment necessitates individual component dose adjustments.
• Concurrent medications metabolized by CYP450, especially CYP2B6, can affect Efavirenz levels and may require dosage modification.

Side Effects

Common Side Effects:

• Nausea, vomiting, diarrhea
• Headache, dizziness, insomnia, abnormal dreams
• Rash, itching
• Fatigue

Rare but Serious Side Effects:

• Lactic acidosis (especially with Stavudine use)
• Severe hepatotoxicity
• Pancreatitis
• Peripheral neuropathy
• Stevens-Johnson syndrome
• Depression and other neuropsychiatric effects

Long-Term Effects:

• Lipodystrophy
• Dyslipidemia
• Renal dysfunction
• Osteopenia/osteoporosis
• Increased risk of cardiovascular disease

Adverse Drug Reactions (ADR):

• Hypersensitivity reactions (rash, Stevens-Johnson Syndrome)
• Psychiatric adverse events (depression, suicidal ideation)
• Hepatotoxicity

Contraindications

• Hypersensitivity to any component of the combination
• Co-administration with drugs significantly metabolized by CYP3A4 (e.g., astemizole, cisapride, midazolam, triazolam) or CYP2B6 which can significantly raise efavirenz levels (e.g. voriconazole).
• Severe hepatic impairment
• History of pancreatitis (especially for Stavudine)

Drug Interactions

• Numerous drug interactions exist. Refer to detailed drug interaction resources.
• CYP450 inducers (e.g., rifampin) and inhibitors (e.g., ketoconazole) can alter Efavirenz levels.
• Interactions with other antiretrovirals, certain antibiotics, antifungals, anticonvulsants, and some herbal supplements are common.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Efavirenz is associated with potential fetal harm, especially in the first trimester. Lamivudine and Stavudine have also been shown to be excreted in breast milk, and their use during pregnancy or breastfeeding should be decided on a case by case basis where the benefits outweigh the risks.
• Not recommended during pregnancy or breastfeeding if safer alternatives are available. If used, close monitoring of mother and child is required.

Drug Profile Summary (See individual sections above for expanded details)

Popular Combinations

• This combination is not a common/popular regimen used. Previously combinations like zidovudine/lamivudine/efavirenz were more frequent, but now Tenofovir is generally preferred to Stavudine and many other combinations are also available.

Precautions (See individual sections above for expanded details)

FAQs (Frequently Asked Questions)

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

A: Efavirenz 600 mg + Lamivudine 300 mg + Stavudine (dose based on weight, generally 30mg or 40 mg twice a day for adults) once daily is the typical adult dosage. However, due to risk of Stavudine toxicity, other antiretroviral regimens are typically preferred, and this combination would not be recommended unless there are resistance or tolerability issues that prevent using alternative options.

Q2: What are the most common side effects?

A: Nausea, vomiting, diarrhea, headache, dizziness, insomnia, rash, itching, and fatigue are commonly reported.

Q3: Are there any serious side effects to watch for?

A: Yes, lactic acidosis (particularly with Stavudine), severe hepatotoxicity, pancreatitis, peripheral neuropathy, Stevens-Johnson syndrome, and neuropsychiatric events require immediate attention.

Q4: What are the contraindications for this drug combination?

A: Hypersensitivity to any component, co-administration with drugs that interact significantly through CYP3A4 or significantly raise Efavirenz levels through CYP2B6 inhibition (like Voriconazole), severe hepatic impairment, and history of pancreatitis (particularly with Stavudine) are major contraindications.

Q5: What are the key drug interactions?

A: Numerous interactions exist, especially with drugs metabolized by the CYP450 system. Always consult a comprehensive drug interaction resource before co-prescribing.

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

A: It is generally not recommended unless the benefits outweigh the risks and no safer alternatives are available. Efavirenz carries a risk of fetal harm. If used, close monitoring is mandatory. The CDC and other guidelines recommend against breastfeeding while using antiretroviral therapy to prevent HIV transmission.

Q7: What monitoring parameters are important for patients on this drug combination?

A: HIV-1 RNA viral load, CD4+ T-cell count, liver function tests, renal function tests, fasting lipid profile, and regular assessment for signs of lactic acidosis, pancreatitis, or peripheral neuropathy are essential.

Q8: What patient education is crucial for this combination?

A: Counsel patients on adherence to the prescribed regimen, potential side effects, drug interactions, the importance of safer sex practices, and the need for regular monitoring. Encourage reporting any new or worsening symptoms. Bedtime dosing is generally preferred to reduce side effects. Avoid drinking alcohol during treatment with this combination.

Q9: Is this fixed-dose combination still a recommended first line treatment for HIV?

A: No. This fixed-dose combination of Efavirenz, Lamivudine, and Stavudine is no longer a recommended first line treatment for HIV. Stavudine (d4T) has significant potential for mitochondrial toxicity which can cause a number of serious side effects such as peripheral neuropathy, lactic acidosis, lipoatrophy, and pancreatitis. As safer and better tolerated options are available, d4T is no longer recommended as part of a first line antiretroviral treatment regimen. Tenofovir-based regimens are currently preferred when using this type of drug combination.