Atazanavir

Usage

• Atazanavir is an antiviral medication specifically prescribed for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection. It’s always used in combination with other antiretroviral medications as part of antiretroviral therapy (ART). It does not cure HIV, but it helps manage the infection and slows the progression to Acquired Immunodeficiency Syndrome (AIDS).
• Pharmacological Classification: Antiretroviral, Protease Inhibitor.
• Mechanism of Action: Atazanavir inhibits the HIV-1 protease enzyme. This enzyme is essential for the virus to replicate by cleaving viral polyproteins into functional proteins. By blocking this action, atazanavir prevents the formation of mature infectious viral particles.

Alternate Names

• International Nonproprietary Name (INN): Atazanavir sulfate
• Brand Names: Reyataz, Evotaz (combined with cobicistat)

How It Works

• Pharmacodynamics: Atazanavir works by selectively inhibiting the HIV-1 protease, preventing viral replication. It doesn’t eliminate the virus, but it reduces the viral load, thus boosting the immune system.

• Pharmacokinetics:

  • Absorption: Atazanavir’s absorption is significantly enhanced when taken with food. Co-administration with ritonavir further increases atazanavir plasma concentrations by inhibiting its metabolism.
  • Metabolism: Primarily metabolized by the liver via CYP3A4 enzyme. Ritonavir boosting inhibits this metabolism, leading to higher and more sustained atazanavir levels.
  • Elimination: Excreted primarily in feces, with a small amount in urine.

• Mode of Action: Atazanavir binds to the active site of the HIV-1 protease enzyme, preventing it from cleaving viral polyproteins. This leads to the production of immature, non-infectious viral particles.

• Receptor binding, enzyme inhibition, or neurotransmitter modulation: Atazanavir exerts its effect through enzyme inhibition (HIV-1 protease).

• Elimination pathways: Primarily hepatic metabolism (CYP3A4), followed by fecal excretion.

Dosage

Standard Dosage

Adults:

• Treatment-naive: Atazanavir 300 mg + ritonavir 100 mg orally once daily with food. If ritonavir is not tolerated, Atazanavir 400 mg orally once daily with food. If used with efavirenz: 400mg Atazanavir + 100mg ritonavir.

• Treatment-experienced: Atazanavir 300 mg + ritonavir 100 mg orally once daily with food. If used with both an H2-receptor antagonist and tenofovir disoproxil fumarate: Atazanavir 400 mg + ritonavir 100 mg orally once daily with food.

Children (6 to <18 years):

• Weight 15 kg to <35 kg: Atazanavir 200 mg + ritonavir 100 mg orally once daily with food.
• Weight ≥35 kg: Atazanavir 300 mg + ritonavir 100 mg orally once daily with food.

Children (3 months to <6 years and ≥5 kg):

Consult specific product information for other formulations for children (oral powder is usually used).

Special Cases:

• Elderly Patients: No specific dose adjustments, but caution and close monitoring are advised due to potential age-related organ function decline.
• Patients with Renal Impairment: No dose adjustment necessary. Not recommended for treatment-experienced patients with ESRD on hemodialysis.
• Patients with Hepatic Dysfunction:
  • Mild impairment: Use with caution.
  • Moderate to severe impairment: Contraindicated with ritonavir boosting. Unboosted atazanavir might be considered with dose adjustments (consult specialist guidelines).
• Patients with Comorbid Conditions: Dosage adjustments may be needed based on specific conditions and concomitant medications.

Clinical Use Cases Atazanavir is exclusively indicated for chronic HIV-1 infection management. Its use in acute settings like intubation, surgical procedures, mechanical ventilation, ICU, or emergencies is not applicable.

Dosage Adjustments

• Pregnancy: Atazanavir MUST be used with ritonavir during pregnancy. No dose adjustment is generally needed, except in treatment-experienced pregnant patients during the second or third trimester when co-administered with an H2-receptor antagonist OR tenofovir, in which case Atazanavir 400mg + ritonavir 100mg is used. Do not use with both at the same time.
• Postpartum: No dose adjustment.

Side Effects

Common Side Effects

• Nausea, vomiting, diarrhea, abdominal pain
• Headache, fatigue
• Insomnia
• Peripheral neuropathy (numbness, tingling)
• Rash
• Changes in body fat distribution

Rare but Serious Side Effects

• Hepatotoxicity (jaundice, liver failure)
• Stevens-Johnson syndrome, toxic epidermal necrolysis
• Cardiac conduction abnormalities (QT prolongation)
• Hyperbilirubinemia (especially in neonates)
• Nephrolithiasis (kidney stones)
• Pancreatitis
• Diabetes

Long-Term Effects

• Dyslipidemia (changes in cholesterol and triglyceride levels)
• Insulin resistance, type 2 diabetes
• Lipodystrophy (changes in body fat distribution)
• Increased risk of cardiovascular disease

Adverse Drug Reactions (ADR)

• Any signs of hypersensitivity reactions (rash, itching, swelling, difficulty breathing)
• Signs of hepatotoxicity or pancreatitis
• Cardiac arrhythmias
• New or worsening kidney problems

Contraindications

• Hypersensitivity to atazanavir
• Severe hepatic impairment (Child-Pugh Class C)
• Co-administration with certain medications (see Drug Interactions)

Drug Interactions

Atazanavir is primarily metabolized by CYP3A4 and is both a substrate and an inhibitor of this enzyme. It also interacts with UGT1A1. Many clinically significant drug interactions exist. Always consult a drug interaction checker before prescribing or dispensing atazanavir. Some notable interactions include:

• CYP3A4 inducers: Rifampin, St. John’s wort (reduce atazanavir levels)
• CYP3A4 substrates: Midazolam, simvastatin (atazanavir can increase levels of these drugs)
• PPIs and H2-receptor antagonists: Reduce atazanavir absorption
• Indinavir: Contraindicated due to risk of indirect hyperbilirubinemia
• Efavirenz: Dose adjustments are needed when combined.
• Tenofovir + H2-receptor blocker: Dose adjustments of Atazanavir may be necessary.
• Alfuzosin: Contraindicated.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: While generally considered safe, there is a potential risk of lower drug levels in pregnant women, especially in the 2nd and 3rd trimesters, especially when also taking tenofovir or H2-receptor antagonists. Use must be with ritonavir. Therapeutic drug monitoring (TDM) is sometimes used to ensure adequate concentrations.

• Fetal risks: No consistent evidence of increased risk of major birth defects.

• Breastfeeding: Contraindicated. Atazanavir is excreted in breast milk, and there’s a risk of HIV transmission. Replacement feeding is recommended.

Drug Profile Summary

• Mechanism of Action: HIV-1 protease inhibitor
• Side Effects: Nausea, vomiting, diarrhea, headache, rash, peripheral neuropathy, changes in body fat, hyperbilirubinemia, hepatotoxicity, cardiac conduction abnormalities
• Contraindications: Hypersensitivity, severe hepatic impairment, concomitant use of specific drugs (e.g., rifampin, indinavir, alfuzosin)
• Drug Interactions: Numerous; consult a drug interaction checker before prescribing. Major interactions with CYP3A4 inducers/substrates, PPIs, H2 blockers.
• Pregnancy & Breastfeeding: Generally safe during pregnancy (use with ritonavir), contraindicated during breastfeeding.
• Dosage: Adults: 300 mg + ritonavir 100 mg once daily with food; adjustments required in specific situations. Pediatric: Weight-based dosing.
• Monitoring Parameters: HIV viral load, CD4 count, liver function tests, lipid profile, blood glucose, bilirubin (especially in neonates), electrocardiogram (ECG)

Popular Combinations

Atazanavir is always used in combination with other antiretroviral drugs. Common combinations include:

• Atazanavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine
• Atazanavir/ritonavir + abacavir/lamivudine
• Other combinations depending on individual patient characteristics and resistance patterns

Precautions

• General Precautions: Assess liver and kidney function, screen for hepatitis B and C, monitor for hyperbilirubinemia, dyslipidemia, and other metabolic abnormalities.
• Specific Populations: Use with caution in elderly patients. Not recommended for patients with moderate to severe hepatic impairment.
• Pregnant Women: Use MUST be with ritonavir; dose adjustment in specific situations; monitor bilirubin levels in neonates.
• Breastfeeding Mothers: Contraindicated.
• Children & Elderly: Weight-based dosing in children. Caution in elderly due to potential for organ dysfunction.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Atazanavir?

A: Adults: 300 mg + ritonavir 100 mg once daily with food. Pediatric: Weight-based dosing (see Dosage section).

Q2: What are the most common side effects?

A: Nausea, vomiting, diarrhea, headache, rash, and peripheral neuropathy.

Q3: Can Atazanavir be used in pregnancy?

A: Yes, but only if clearly needed. It must be used in combination with ritonavir. Careful monitoring is essential.

Q4: Is it safe to breastfeed while taking Atazanavir?

A: No, it is contraindicated. Atazanavir is present in breast milk and may cause harm to the infant.

Q5: What are the serious side effects to watch out for?

A: Hepatotoxicity, Stevens-Johnson syndrome, cardiac conduction abnormalities, hyperbilirubinemia, pancreatitis.

Q6: What are the major drug interactions with Atazanavir?

A: Many drugs interact with atazanavir, notably CYP3A4 inducers and substrates, PPIs, H2 blockers, and certain antiretrovirals. Always check for interactions.

Q7: How does ritonavir affect Atazanavir?

A: Ritonavir “boosts” Atazanavir levels by inhibiting its metabolism via CYP3A4.

Q8: What should be monitored in patients taking Atazanavir?

A: HIV viral load, CD4 count, liver function tests, lipid profile, blood glucose, bilirubin (especially in neonates), and ECG.

Q9: Can Atazanavir cure HIV infection?

A: No, Atazanavir is not a cure. It helps manage the infection and slows down the progression to AIDS.

Q10: How should Atazanavir be taken?

A: Orally with food, once daily, always in combination with other antiretroviral medications.