Lamivudine + Nevirapine + Stavudine

Usage

• Medical Conditions: Lamivudine + Nevirapine + Stavudine is prescribed for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults and children. This fixed-dose combination is particularly relevant in resource-limited settings. It is not a cure for HIV/AIDS, but helps manage the infection by suppressing viral replication.
• Pharmacological Classification: This is a combination product containing three antiretroviral drugs:
  • Lamivudine and Stavudine: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
  • Nevirapine: Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)
• Mechanism of Action: Lamivudine and Stavudine are nucleoside analog reverse-transcriptase inhibitors (NRTIs) that, after intracellular phosphorylation to their active triphosphate metabolites, inhibit the HIV reverse transcriptase enzyme by competing with natural substrates and causing DNA chain termination. Nevirapine is an NNRTI that binds directly to reverse transcriptase, inhibiting both RNA- and DNA-dependent polymerase activity, thus blocking HIV replication.

Alternate Names

• This combination is often referred to as 3TC/NVP/d4T, representing the abbreviations of its components.
• Brand names include Triomune (and its pediatric formulation, Triomune Junior). Availability may vary regionally.

How It Works

• Pharmacodynamics: The combination exerts synergistic antiretroviral activity by targeting HIV reverse transcriptase through two distinct mechanisms (NRTI and NNRTI). This inhibits viral replication, reducing viral load and increasing CD4 cell counts.

• Pharmacokinetics:

  • Absorption: All three components are well-absorbed orally. Food does not significantly affect the absorption of Lamivudine/Nevirapine/Stavudine tablets.
  • Metabolism: Lamivudine is primarily excreted unchanged renally. Stavudine is minimally metabolized. Nevirapine is extensively metabolized by the liver via cytochrome P450 (CYP) enzymes, primarily CYP3A4 and CYP2B6.
  • Elimination: Lamivudine and stavudine are eliminated renally. Nevirapine’s metabolites are excreted in urine and feces.

• Mode of Action: Lamivudine and stavudine compete with natural substrates to inhibit HIV reverse transcriptase and terminate viral DNA chain synthesis. Nevirapine binds directly to a different site on reverse transcriptase, allosterically inhibiting enzyme function and causing a conformational change.

Dosage

Standard Dosage

Adults:

• One tablet containing 150 mg lamivudine, 30 mg/40 mg stavudine, and 200 mg nevirapine twice daily. For the initial 14 days of nevirapine therapy, nevirapine should be administered as a lead-in dose of 200 mg once daily to reduce the risk of rash.

Children:

• Triomune Junior, containing lower doses of each component, is available for children. The dose is determined by the weight band.
• Pediatric dosing is based on a complex formula and requires individualized adjustment. Specific preparations of lamivudine, nevirapine, and stavudine should be used if dose adjustment is needed in children under 12 years of age or in those with kidney problems.

Special Cases:

• Elderly Patients: No specific dose adjustments are needed for mild-to-moderate hepatic impairment.
• Patients with Renal Impairment: Dose reduction is required for lamivudine and stavudine. The combination tablet is not recommended for creatinine clearance <50 mL/min. Individual components should be dosed separately.
• Patients with Hepatic Dysfunction: This combination is contraindicated in patients with severe hepatic impairment (Child-Pugh C).
• Patients with Comorbid Conditions: Caution should be exercised in patients with liver disease (including hepatitis B or C), pancreatitis, peripheral neuropathy, or bone marrow suppression.

Clinical Use Cases

This drug combination is specific for HIV-1 infection and is not used in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations outside of HIV management.

Dosage Adjustments

Dose adjustments are necessary for renal impairment and hepatic dysfunction. Due to the fixed-dose nature, separate components should be administered in these cases.

Side Effects

Common Side Effects:

Headache, nausea, vomiting, diarrhea, fatigue, insomnia, peripheral neuropathy (tingling and numbness), rash, fever.

Rare but Serious Side Effects:

Lactic acidosis, severe hepatotoxicity (including liver failure), Stevens-Johnson syndrome, pancreatitis, bone marrow suppression, lipodystrophy.

Long-Term Effects:

Peripheral neuropathy, lipodystrophy, metabolic abnormalities, increased risk of cardiovascular disease.

Adverse Drug Reactions (ADR):

Severe rash, hepatotoxicity, lactic acidosis, pancreatitis, Stevens-Johnson syndrome.

Contraindications

• Hypersensitivity to any component of the drug.
• Severe hepatic impairment (Child-Pugh C).
• History of severe rash or hepatic reactions to nevirapine.
• Abnormally low neutrophil or hemoglobin levels.
• Concomitant use of rifampicin or St. John’s wort.

Drug Interactions

• St. John’s wort: Reduces nevirapine levels.
• Rifampicin: Reduces nevirapine levels.
• Other antiretrovirals: Potential for additive or synergistic effects and/or overlapping toxicities.
• Medications metabolized by CYP3A4: Nevirapine may affect their metabolism.

Pregnancy and Breastfeeding

• While not absolutely contraindicated, the safety of this combination during pregnancy has not been fully established. Data is limited. Use only if the potential benefit outweighs the potential risk to the fetus.
• All three drugs are present in breast milk. Women with HIV should not breastfeed due to the risk of transmitting the virus. If prescribed during breastfeeding, stopping breastfeeding is advised.

Drug Profile Summary

• Mechanism of Action: NRTIs (lamivudine and stavudine) inhibit reverse transcriptase by DNA chain termination; NNRTI (nevirapine) binds directly to reverse transcriptase.
• Side Effects: Rash, peripheral neuropathy, hepatotoxicity, lactic acidosis, pancreatitis, nausea, fatigue.
• Contraindications: Severe hepatic impairment, hypersensitivity, low neutrophil/hemoglobin, concomitant rifampicin or St. John’s wort use.
• Drug Interactions: St. John’s wort, rifampicin, other antiretrovirals.
• Pregnancy & Breastfeeding: Use with caution in pregnancy; contraindicated during breastfeeding due to the risk of HIV transmission.
• Dosage: Adults: one tablet twice daily after an initial nevirapine lead-in period. Children: Dose adjusted based on a weight band formula and given as Triomune Junior.
• Monitoring Parameters: CD4 cell count, viral load, liver function tests, complete blood counts, renal function.

Popular Combinations

This fixed-dose combination contains the three drugs commonly used together. If this combination is not suitable due to adverse effects or resistance, other antiretroviral combinations will be considered.

Precautions

• Monitor for hepatotoxicity, lactic acidosis, pancreatitis, rash, and bone marrow suppression.
• Perform regular CD4 counts and HIV RNA viral load testing.
• Avoid alcohol consumption.
• Caution should be exercised in patients with pre-existing liver disease, renal impairment, or peripheral neuropathy.
• Counsel patients regarding safe sex practices to prevent HIV transmission.

FAQs (Frequently Asked Questions)

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

A: Adults: One tablet twice daily after a 14-day nevirapine lead-in period of 200mg once daily. Dosage for children needs to be calculated according to weight.

Q2: What are the most common side effects?

A: Rash, nausea, vomiting, fatigue, headache, peripheral neuropathy.

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

A: Lactic acidosis, severe hepatotoxicity, pancreatitis, Stevens-Johnson syndrome.

Q4: Is this combination safe in pregnancy?

A: It is used in some pregnant individuals when the benefits outweigh the risks. The safest course is to avoid ARVs if possible in the first trimester.

Q5: Can HIV-positive mothers taking this combination breastfeed?

A: No. All three components are secreted into breast milk, posing a risk of HIV transmission to the infant. HIV positive mothers should not breastfeed.

Q6: What are the key drug interactions?

A: St. John’s wort and rifampicin significantly reduce nevirapine levels.

Q7: What should be monitored in patients taking this combination?

A: CD4 count, viral load, liver function tests, complete blood counts, renal function.

Q8: What are the contraindications to this combination?

A: Severe hepatic impairment, hypersensitivity to any component, history of severe rash or hepatic reactions to nevirapine, and concomitant use of rifampicin or St. John’s wort.

Q9: Can this combination be used in patients with renal impairment?

A: Dose adjustments are required for renal impairment. For creatinine clearance <50 mL/min, the individual components should be dosed separately.

Q10: What is the role of the nevirapine lead-in dose?

A: The initial 14-day lead-in dose of nevirapine (200 mg once daily) is used to reduce the incidence of rash.