Abacavir + Dolutegravir + Lamivudine

Usage

• Abacavir + Dolutegravir + Lamivudine is prescribed for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults, adolescents, and children. It is a complete regimen and should not be administered with other antiretroviral products. This combination therapy helps to lower the amount of HIV in the blood, supporting the immune system’s ability to fight infections, which can delay the progression to Acquired Immunodeficiency Syndrome (AIDS) and other HIV-related illnesses.

• Pharmacological Classification: Antiretroviral, specifically a combination of:

  • Nucleoside Reverse Transcriptase Inhibitor (NRTI) - Abacavir and Lamivudine
  • Integrase Strand Transfer Inhibitor (INSTI) - Dolutegravir

• Mechanism of Action:

  • Abacavir and Lamivudine: These NRTIs interfere with the reverse transcription process of HIV, preventing the viral RNA from being converted into DNA, thus inhibiting viral replication.
  • Dolutegravir: This INSTI blocks the integration of viral DNA into the host cell’s DNA, a crucial step in the HIV replication cycle. The combined action of these drugs targets multiple stages of the HIV life cycle.

Alternate Names

• International Nonproprietary Name (INN): Dolutegravir, Abacavir and Lamivudine fixed dose combination.
• Brand Name: Triumeq (tablets), Triumeq PD (tablets for oral suspension)

How It Works

• Pharmacodynamics: The combination acts synergistically to suppress HIV replication by inhibiting reverse transcription and integration of viral DNA. This leads to a reduction in the viral load and an increase in CD4 cell counts, improving immune function.

• Pharmacokinetics:

  • Absorption: All three drugs are orally absorbed. Food does not significantly affect the absorption of Triumeq.
  • Metabolism: Abacavir is primarily metabolized by the liver through alcohol dehydrogenase and glucuronyl transferase. Dolutegravir is mainly metabolized by uridine diphosphate glucuronosyl transferase (UGT) 1A1, with minor contributions from UGT1A3, UGT1A9, and CYP3A4. Lamivudine is not extensively metabolized and is primarily excreted unchanged renally.
  • Elimination: Abacavir and Dolutegravir metabolites are primarily eliminated in the urine, while Lamivudine is eliminated unchanged by the kidneys.

• Mode of Action:

  • Abacavir and Lamivudine are phosphorylated intracellularly to their active forms, which compete with natural nucleosides for incorporation into the viral DNA chain, causing chain termination.
  • Dolutegravir inhibits the HIV integrase enzyme by binding to the integrase active site and blocking the strand transfer step, preventing the integration of viral DNA.

• Receptor binding, enzyme inhibition, or neurotransmitter modulation:

  • Abacavir and Lamivudine: Inhibition of HIV reverse transcriptase enzyme.
  • Dolutegravir: Inhibition of HIV integrase enzyme.

• Elimination pathways:

  • Abacavir: Primarily renal excretion of metabolites.
  • Dolutegravir: Primarily renal excretion of metabolites.
  • Lamivudine: Primarily renal excretion of unchanged drug.

Dosage

Standard Dosage

Adults and Adolescents (≥12 years and ≥40 kg):

• One Triumeq tablet (600 mg abacavir / 50 mg dolutegravir / 300 mg lamivudine) once daily orally, with or without food. Do not use Triumeq PD for adults.

Children (3 months to <12 years or <40 kg):

• Triumeq PD tablets for oral suspension should be used. The dose is based on body weight and should be determined by the doctor. Dissolve the tablets in 20 mL of drinking water before administrating.
• 6 kg to <10 kg: 3 tablets (180 mg abacavir / 15 mg dolutegravir / 90 mg lamivudine) once daily.
• 10 kg to <14 kg: 4 tablets (240 mg abacavir / 20 mg dolutegravir / 120 mg lamivudine) once daily.
• 14 kg to <20 kg: 5 tablets (300 mg abacavir / 25 mg dolutegravir / 150 mg lamivudine) once daily.
• 20 kg to <25 kg: 6 tablets (360 mg abacavir / 30 mg dolutegravir / 180 mg lamivudine) once daily.
• ≥ 25 kg: Triumeq tablets are recommended (see adult dose).

Special Cases:

• Elderly Patients: No dose adjustment is generally necessary, but close monitoring is recommended due to age-related changes in renal function and other physiological parameters.
• Patients with Renal Impairment:
  • CrCl 30-49 mL/min: Monitor for lamivudine-related adverse events, especially hematologic toxicities. Dose adjustment may be required, and if so, use individual components as the fixed dose combination can’t be adjusted.
  • CrCl <30 mL/min: Not recommended.
• Patients with Hepatic Dysfunction:
  • Mild Impairment: Not recommended using the fixed-dose combination; close monitoring required, possibly including abacavir plasma levels if feasible.
  • Moderate to Severe Impairment: Contraindicated.
• Patients with Comorbid Conditions: Careful consideration is required for patients with diabetes, cardiovascular disease, or other relevant conditions, as they might increase the risk of certain side effects.

Clinical Use Cases

Abacavir + Dolutegravir + Lamivudine is specifically indicated for chronic HIV-1 infection and does not have specific dosage adjustments for procedures like intubation, surgical procedures, mechanical ventilation, ICU use, or acute emergency situations.

Dosage Adjustments

• Coadministration with efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin requires an additional dolutegravir dose (as a single entity) 12 hours after the standard Triumeq dose. The additional dolutegravir dose is dependent on weight for children using Triumeq PD. Adults should take an additional 50 mg dolutegravir tablet.

Side Effects

Common Side Effects:

• Insomnia
• Headache
• Fatigue
• Diarrhea
• Nausea
• Vomiting
• Fever

Rare but Serious Side Effects:

• Hypersensitivity reactions (potentially fatal)
• Lactic acidosis
• Hepatotoxicity (liver inflammation)
• Severe skin reactions
• Myopathy (muscle weakness)
• New or worsening renal impairment
• Depressed mood or suicidal ideation
• Pancreatitis

Long-Term Effects:

• Changes in body fat distribution
• Increased risk of cardiovascular disease
• Osteoporosis (bone loss)
• Immune reconstitution inflammatory syndrome (IRIS)

Adverse Drug Reactions (ADR):

• Hypersensitivity reactions to abacavir (requiring immediate discontinuation)
• Lactic acidosis
• Hepatotoxicity
• Stevens-Johnson syndrome

Contraindications

• Hypersensitivity to any of the components (abacavir, dolutegravir, or lamivudine)
• Presence of HLA-B*5701 allele (genetic marker associated with increased risk of hypersensitivity to abacavir)
• Coadministration with dofetilide
• Moderate or severe hepatic impairment (liver dysfunction)

Drug Interactions

• Dolutegravir is primarily metabolized by UGT1A1 and is also a substrate of UGT1A3, UGT1A9, CYP3A4, and P-glycoprotein (P-gp). Abacavir and lamivudine have limited drug interactions. However, the combination should not be taken with other medicines containing dolutegravir or lamivudine, except where a dose adjustment of dolutegravir is indicated.
• Drugs that induce UGT1A1 (such as rifampin) can decrease dolutegravir concentrations.
• Drugs that inhibit UGT1A1 or P-gp may increase dolutegravir concentrations.
• Coadministration with metformin can increase metformin levels.
• Consult drug interaction resources for a comprehensive list of interactions.

Pregnancy and Breastfeeding

• Pregnancy: Not recommended during the first trimester due to potential fetal harm. Dolutegravir may pose a risk of neural tube defects. If pregnancy occurs, consult with a healthcare professional immediately. Effective contraception should be used during treatment.
• Breastfeeding: Not recommended. HIV can be transmitted through breast milk. The drug components can also be excreted in breast milk and may have adverse effects on the infant.

Drug Profile Summary

• Mechanism of Action: Combined NRTI (abacavir and lamivudine) and INSTI (dolutegravir) action inhibits HIV replication.
• Side Effects: Common: Insomnia, headache, fatigue, diarrhea, nausea. Serious: Hypersensitivity reactions, lactic acidosis, hepatotoxicity.
• Contraindications: Hypersensitivity, HLA-B*5701 allele, coadministration with dofetilide, moderate-severe hepatic impairment.
• Drug Interactions: Multiple drug interactions, especially with UGT1A1 inducers and inhibitors.
• Pregnancy & Breastfeeding: Not recommended.
• Dosage: Adults: One tablet once daily. Pediatric: Weight-based dosing using the PD formulation.
• Monitoring Parameters: HIV viral load, CD4 cell count, liver function tests, renal function tests, signs of hypersensitivity.

Popular Combinations

Abacavir + Dolutegravir + Lamivudine is a fixed-dose combination and should generally not be used in combination with other antiretrovirals except for a dose adjustment of dolutegravir.

Precautions

• Pre-screening for HLA-B*5701 is mandatory before starting abacavir.
• Monitor for hypersensitivity reactions, especially during the first few weeks of treatment.
• Regular monitoring of liver and renal function, CD4 cell count, and viral load is crucial.
• Assess cardiovascular risk factors and manage appropriately.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Abacavir + Dolutegravir + Lamivudine?

A: Adults and adolescents ≥12 years and ≥40 kg: One Triumeq tablet once daily. Children: Weight-based dosing using Triumeq PD. See detailed pediatric dosing information in the Dosage section above.

Q2: What are the most serious side effects?

A: The most serious side effects include hypersensitivity reactions (potentially fatal), lactic acidosis, and liver toxicity.

Q3: What should I do if a patient develops a hypersensitivity reaction?

A: Discontinue the medication immediately and permanently. Do not rechallenge the patient with abacavir.

Q4: Can this medication be used during pregnancy?

A: It is generally not recommended, especially during the first trimester, due to potential harm to the fetus, including neural tube defects with Dolutegravir. Effective contraception should be used. Consult a doctor immediately if pregnancy occurs during treatment.

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

A: Drugs that affect UGT1A1 (such as rifampin) can alter dolutegravir levels. Consult a comprehensive drug interaction resource or checker before co-prescribing.

Q6: Is there a specific diet or lifestyle advice for patients on this medication?

A: Patients should maintain a healthy lifestyle, including a balanced diet and regular exercise. Alcohol consumption should be moderate. Smoking cessation is strongly encouraged.

Q7: How should I monitor patients on this medication?

A: Monitor HIV viral load, CD4 cell count, liver and renal function, and any signs of hypersensitivity reactions.

Q8: What is the role of HLA-B*5701 testing?

A: HLA-B*5701 testing is essential before starting abacavir-containing regimens to identify individuals at high risk of developing hypersensitivity reactions. Patients who test positive should not receive abacavir.

Q9: Can patients with renal or hepatic impairment take this drug?

A: Patients with moderate to severe hepatic impairment should not take this drug. Dose adjustments and close monitoring are necessary for patients with renal impairment. Consult the Dosage section above.