Lamivudine + Zidovudine + Nevirapine

Approved Indications:

• HIV-1 Infection (Adults and Adolescents ≥35 kg):
  Indicated for use as part of combination antiretroviral therapy in the treatment of HIV-1 infection in patients who have previously tolerated nevirapine.

Clinically Accepted Off-label Uses:

• Prevention of Mother-to-Child Transmission (PMTCT):
  Utilized in select resource-limited settings to reduce vertical transmission of HIV.
• Post-Exposure Prophylaxis (PEP):
  Occasionally used as a component of PEP regimens in situations where preferred alternatives are unavailable.

Adults and Adolescents (≥35 kg):

• Dose: One tablet (Lamivudine 150 mg + Zidovudine 300 mg + Nevirapine 200 mg) orally twice daily.

Pediatrics (<35 kg):

• Not recommended due to fixed dosing; individual components should be dosed based on body weight.

Renal Impairment:

• CrCl <50 mL/min: Use of the fixed-dose combination is not recommended. Dose adjustment of Lamivudine and Zidovudine is required individually.

Hepatic Impairment:

• Contraindicated in moderate to severe hepatic impairment (Child-Pugh B or C) due to increased risk of hepatotoxicity.

Geriatric Patients:

• Use with caution. Monitor renal and hepatic function regularly.

Important Administration Note:

• Nevirapine requires a 14-day lead-in period (200 mg once daily) to reduce the risk of rash and hepatotoxicity. This fixed-dose combination should only be used in patients who have completed the lead-in period with nevirapine and demonstrated tolerance.

This combination includes two nucleoside reverse transcriptase inhibitors (NRTIs) — lamivudine and zidovudine — and one non-nucleoside reverse transcriptase inhibitor (NNRTI) — nevirapine. Lamivudine and zidovudine incorporate into viral DNA by competing with natural nucleoside triphosphates, leading to premature chain termination during reverse transcription. Nevirapine binds directly to HIV-1 reverse transcriptase at a distinct site, inducing a conformational change that inhibits the enzyme’s activity. The combination blocks HIV replication at multiple points, leading to a sustained reduction in viral load.

Lamivudine:

• Absorption: Rapid and extensive (bioavailability ~85%)
• Distribution: Widely distributed; crosses the placenta and blood-brain barrier
• Metabolism: Minimal hepatic metabolism
• Half-life: Plasma ~5–7 hours; intracellular ~10–15 hours
• Excretion: Primarily renal (unchanged)

Zidovudine:

• Absorption: Bioavailability ~60–70%
• Distribution: Crosses blood-brain barrier and placenta
• Metabolism: Hepatic glucuronidation
• Half-life: Plasma ~1 hour; intracellular 3–4 hours
• Excretion: Renal (mostly as glucuronide metabolite)

Nevirapine:

• Absorption: Bioavailability >90%
• Distribution: Extensive, including CSF
• Metabolism: Hepatic via CYP3A4 and CYP2B6 (autoinduction)
• Half-life: ~25–30 hours after autoinduction
• Excretion: Renal (as inactive metabolites)

Pregnancy:

• Category C (former FDA classification)
• Extensively used in pregnancy for HIV treatment and PMTCT. Benefits outweigh potential risks when appropriately monitored.

Lactation:

• Lamivudine, zidovudine, and nevirapine are excreted into breast milk.
• WHO recommends continued breastfeeding in HIV-positive mothers on effective ART in resource-limited settings.
• Infants should be monitored for signs of adverse effects, including rash or hepatotoxicity.

• Primary Class: Antiretroviral Combination
• Subclasses:
• Lamivudine & Zidovudine: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
• Nevirapine: Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)

• Hypersensitivity to any component of the combination
• Moderate to severe hepatic impairment (Child-Pugh Class B or C)
• Prior severe rash or hepatotoxicity due to nevirapine
• Severe anemia or neutropenia (associated with zidovudine)
• Concurrent use of drugs that are contraindicated with nevirapine (e.g., St. John’s Wort)

• Severe and Fatal Hepatotoxicity (Nevirapine):
  Risk is highest in the first 6 weeks; monitor liver enzymes regularly.
• Severe Skin Reactions:
  Including Stevens-Johnson syndrome and toxic epidermal necrolysis.
• Myelosuppression (Zidovudine):
  May cause anemia and neutropenia; monitor complete blood counts frequently.
• Lactic Acidosis with Hepatic Steatosis:
  Rare but potentially fatal; monitor for signs such as abdominal pain, fatigue, or elevated lactate.
• Immune Reconstitution Inflammatory Syndrome (IRIS):
  May occur as the immune system recovers.

Common Side Effects:

• Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain
• Central Nervous System: Headache, fatigue, dizziness
• Hematologic: Anemia, neutropenia
• Skin: Rash (especially within the first 6 weeks of nevirapine use)

Serious/Rare Side Effects:

• Hepatotoxicity (nevirapine)
• Stevens-Johnson syndrome
• Lactic acidosis
• Pancreatitis (lamivudine)
• Myopathy (zidovudine)

Timing:

• Rash and liver enzyme abnormalities typically occur within 2–8 weeks of nevirapine initiation.

Major Drug Interactions:

• Rifampin: Reduces nevirapine levels
• Fluconazole, Ketoconazole: Increase nevirapine levels and risk of toxicity
• Stavudine: Antagonistic interaction with zidovudine
• Ribavirin: Increases zidovudine toxicity

CYP450 Involvement:

• Nevirapine induces CYP3A4 and CYP2B6, potentially reducing levels of other drugs (e.g., oral contraceptives, antifungals, protease inhibitors)

Food Interaction:

• No significant food interactions

• WHO 2025 Update: Nevirapine-based regimens are no longer recommended as first-line due to toxicity concerns, but remain in use for PMTCT or when better options are unavailable.
• DHHS Guidelines (2025):
  Lamivudine + Zidovudine + Nevirapine is not preferred for initial ART; newer regimens with integrase inhibitors are favored.
• Monitoring Update:
  Increased frequency of liver function tests (weekly for first 6–8 weeks) is recommended after nevirapine initiation.

• Temperature: Store below 30°C (86°F)
• Humidity: Keep in a dry place
• Light Protection: Protect from light; store in original packaging
• Handling Instructions:
  – Do not initiate with fixed-dose combination until nevirapine tolerance is confirmed.
  – Keep container tightly closed.