Atazanavir: Uses, Dosage, Side Effects and Interactions

Atazanavir, a once-daily oral protease inhibitor, has become a foundational medication in the treatment of HIV-1 infection. Known for its potent antiviral activity, favorable metabolic profile, and convenient dosing, atazanavir continues to play a key role in antiretroviral therapy (ART). However, as with all potent medications, it comes with considerations regarding dosing, possible side effects, and drug interactions. This comprehensive guide synthesizes current research to help patients and clinicians understand atazanavir’s clinical profile.

Uses of Atazanavir

Atazanavir is primarily designed for the treatment of HIV-1 infection and is a component of highly active antiretroviral therapy (HAART). Its use is guided by its efficacy, tolerability, and compatibility with other antiretrovirals, making it a versatile option for both new and treatment-experienced patients.

Use	Patient Group	Key Points	Source(s)
HIV-1 Treatment	Adults & Children	Core component of ART; sometimes used unboosted or with ritonavir	5, 12
First-Line ART	Treatment-Naive	Effective, but not always preferred as initial PI	6, 7, 12
Salvage Therapy	PI-Experienced	Boosting with ritonavir recommended	5, 12
COVID-19 (Investigational)	All groups	Inhibits SARS-CoV-2 replication in vitro, under investigation	3

Table 1: Key Clinical Uses of Atazanavir

Antiretroviral Therapy for HIV-1

Atazanavir is primarily indicated for use in combination with other antiretroviral agents for HIV-1 infection. It is effective in both adults and children, though pediatric use varies by country approval. Its once-daily dosing and lower pill burden make it user-friendly, which can improve adherence 5.

First-Line and Salvage Therapy

For patients who have not received prior antiretroviral therapy (treatment-naive), atazanavir—either alone or boosted with ritonavir—has demonstrated virological efficacy comparable to other standard regimens such as those containing efavirenz or lopinavir/ritonavir 6, 7. However, current guidelines may not always list it as the preferred initial protease inhibitor due to evolving resistance patterns and drug interaction profiles 12.

For treatment-experienced patients, especially those with previous protease inhibitor (PI) exposure or resistance, atazanavir is typically used with ritonavir boosting to enhance drug levels and overcome resistance 5, 12.

Investigational and Other Potential Uses

Recent in vitro studies suggest that atazanavir can inhibit SARS-CoV-2 replication, especially when combined with ritonavir, and may reduce the production of proinflammatory cytokines. However, clinical use for COVID-19 remains investigational and is not standard practice 3.

Dosage of Atazanavir

Personalized dosing is crucial for maximizing efficacy and minimizing toxicity. Atazanavir’s pharmacokinetics and interactions with food and other drugs guide its administration.

Dosage	Patient Group	Details & Considerations	Source(s)
400 mg once daily	Treatment-naive (Adults)	Standard monotherapy dose, with food	5, 6, 9, 12
300 mg + 100 mg ritonavir once daily	Experienced or with certain co-administered drugs	Boosting increases concentrations; with food	5, 8, 9, 12
Pediatric	Children	Dose varies by weight/age	5
Monitoring	All	Therapeutic drug monitoring may benefit select patients	4, 8

Table 2: Atazanavir Dosing Overview

Standard Adult Dosing

For most treatment-naive adults, the typical atazanavir dose is 400 mg once daily, taken with food. Food significantly increases absorption—by up to 70%—so it is crucial to take atazanavir with meals for optimal effectiveness 9.

Ritonavir Boosting

In treatment-experienced patients or those taking certain interacting medications (like efavirenz or tenofovir), atazanavir is used at 300 mg once daily, boosted with 100 mg of ritonavir, also once daily and with food. Ritonavir increases atazanavir concentrations by 3–4 times, prolonging the elimination half-life and ensuring therapeutic levels even in the presence of resistance or drug interactions 5, 8, 9, 12.

Pediatric Dosing

Atazanavir is approved for pediatric use in some countries, but dosing depends on the child’s weight and age. It is critical to adhere to country-specific guidelines and consult with a specialist 5.

Therapeutic Drug Monitoring (TDM)

Due to interpatient variability in atazanavir levels, TDM can be especially useful in patients with resistance mutations or those experiencing side effects such as hyperbilirubinemia. TDM helps tailor dosing for maximal efficacy and minimal toxicity 4, 8.

Side Effects of Atazanavir

While generally well-tolerated, atazanavir is associated with some side effects, some of which are unique among protease inhibitors. Most are mild and manageable, but awareness is crucial for early detection and intervention.

Side Effect	Frequency/Severity	Notes	Source(s)
Hyperbilirubinemia	Common (22–47%), often asymptomatic	Jaundice; rarely leads to discontinuation	1, 7, 10, 12
Gastrointestinal (GI)	Nausea, vomiting, diarrhea	Diarrhea less frequent than with nelfinavir	1, 6, 7, 12
Rash	Occasional, usually mild		12
Nephrolithiasis	Rare but serious	Kidney stones; may require intervention	11
Acute Interstitial Nephritis	Rare	Acute renal failure; case reports	13
Lipid Changes	Minimal effect	Fewer metabolic disturbances than other PIs	1, 5, 6, 7, 12

Table 3: Common and Notable Adverse Effects of Atazanavir

Hyperbilirubinemia and Jaundice

Perhaps the most distinctive side effect of atazanavir is benign, reversible hyperbilirubinemia. This occurs due to competitive inhibition of the enzyme UGT1A1, leading to elevated unconjugated (indirect) bilirubin. While up to 47% of patients may develop elevated bilirubin, clinical jaundice is less common and usually not dangerous. Fewer than 2% discontinue therapy because of this side effect. Grade IV (severe) hyperbilirubinemia is rare 1, 7, 10, 12.

Gastrointestinal Effects

GI symptoms such as nausea, vomiting, and diarrhea are possible, but diarrhea is less frequent than with other protease inhibitors like nelfinavir. These effects are usually mild to moderate and manageable 1, 6, 7, 12.

Renal Effects

Though rare, nephrolithiasis (kidney stones) has been reported and may require medical intervention. Acute interstitial nephritis leading to acute renal failure is extremely rare but has been documented 11, 13.

Metabolic Profile

One advantage of atazanavir is its minimal impact on lipid levels and absence of significant dyslipidemia, making it a preferred option for patients at risk of cardiovascular disease. Increases in total cholesterol, LDL, and triglycerides are significantly less pronounced compared to other PIs 1, 5, 6, 7, 12.

Other Adverse Effects

• Rash (typically mild)
• Headache
• Peripheral neuropathy (uncommon)

Interactions of Atazanavir

Atazanavir’s metabolism and transport are influenced by a number of enzymes and pathways, making drug-drug interactions a critical consideration in clinical practice.

Interaction Partner	Effect on Atazanavir or Partner	Clinical Implication	Source(s)
Ritonavir	Increases atazanavir levels	Used for boosting	5, 8, 9, 12
Tenofovir	Decreases atazanavir levels	May require ritonavir boosting	9, 14, 17
Efavirenz	Decreases atazanavir levels	Boosting required	9, 12, 15
Antacids/PPIs/H2 blockers	Decreases absorption	Space doses or avoid	12
Statins (simvastatin, lovastatin)	Increased statin levels; risk of toxicity	Avoid combination	12
Warfarin, diltiazem, irinotecan	Alters drug metabolism	Monitor/adjust dose	12
Buprenorphine	Increases buprenorphine/metabolite levels	May require lower buprenorphine dose	16
Daclatasvir (HCV therapy)	Requires daclatasvir dose adjustment	Adjust daclatasvir dose	15
St. John's Wort	Decreases atazanavir levels	Avoid combination	12

Table 4: Notable Atazanavir Drug Interactions

Mechanisms of Interaction

Atazanavir is both a substrate and moderate inhibitor of the cytochrome P450 system, particularly CYP3A4 and CYP2C9. It also interacts with drug transporters such as P-glycoprotein and organic anion transporting polypeptides (OATPs) 2, 12, 17.

Boosting and Inhibition

• Ritonavir is used intentionally to boost atazanavir levels by inhibiting CYP3A4 metabolism.
• Tenofovir and efavirenz both reduce atazanavir plasma concentrations, necessitating ritonavir boosting to maintain efficacy 9, 14, 15, 17.

Interactions with Acid-Reducing Agents

Atazanavir’s absorption is pH-dependent; antacids, proton pump inhibitors (PPIs), and H2-receptor antagonists can reduce its absorption. Doses should be spaced apart, or alternative therapies considered 12.

Other Drug Interactions

• Statins: Atazanavir can dramatically increase simvastatin or lovastatin levels, risking myopathy or rhabdomyolysis. Use alternative statins or avoid these combinations 12.
• Warfarin, diltiazem, irinotecan: Atazanavir can alter the metabolism of these drugs, requiring careful dose adjustments and monitoring 12.
• Buprenorphine: Atazanavir increases buprenorphine and metabolite levels, potentially causing sedation; dose adjustments may be needed 16.
• Daclatasvir: Dose modifications are required when co-administered with atazanavir/ritonavir due to increased daclatasvir exposure 15.
• St. John’s Wort: Induces CYP3A4, decreasing atazanavir concentrations and efficacy; avoid concurrent use 12.

Transporter-Based Interactions

Atazanavir’s absorption and elimination are regulated by P-glycoprotein and OATPs, contributing to its interaction profile with other drugs that inhibit or induce these transporters 2, 17.

Conclusion

Atazanavir remains a valuable option in HIV-1 treatment, offering potent antiviral effects and a favorable metabolic profile. However, its use requires careful attention to dosing, monitoring for side effects, and management of drug-drug interactions.

Key Takeaways:

• Primary Use: Core component of ART for HIV-1, suitable for both treatment-naive and experienced patients, with ongoing investigation for other viral infections such as COVID-19 3 5 12.
• Dosing: Typically 400 mg once daily (monotherapy) or 300 mg plus 100 mg ritonavir in special circumstances; always taken with food. Therapeutic drug monitoring can be beneficial for some patients 4 5 8 9 12.
• Side Effects: Hyperbilirubinemia is common but usually benign; GI symptoms and rare renal complications can occur. Less impact on lipids than other PIs 1 6 7 10 11 12 13.
• Drug Interactions: Multiple, involving CYP enzymes, drug transporters, and acid-reducing agents. Ritonavir is often needed for boosting; some drugs require dose adjustment or avoidance 2 9 12 14 15 16 17.
• Patient Considerations: Individualization of therapy, awareness of potential interactions, and monitoring for side effects are essential for optimal outcomes.

By understanding these aspects, clinicians and patients can ensure that atazanavir is used safely and effectively as part of comprehensive HIV care.