Atazanavir (DB01072): A Comprehensive Pharmacological and Clinical Monograph

Introduction: Atazanavir in the HIV Treatment Armamentarium

Atazanavir is an azapeptide antiretroviral agent belonging to the protease inhibitor (PI) class, developed by Bristol-Myers Squibb and licensed from Novartis.[1] It is indicated for the treatment of Human Immunodeficiency Virus Type 1 (HIV-1) infection, always as a component of combination antiretroviral therapy (cART) with other agents.[2]

Upon its initial approval by the U.S. Food and Drug Administration (FDA) in 2003, Atazanavir represented a significant advancement in the PI class.[2] It was distinguished from its predecessors by two clinically important features that addressed major challenges in long-term HIV management. First, its pharmacokinetic profile permitted a once-daily dosing schedule, a marked improvement over the multiple daily doses required for older PIs, which enhanced patient convenience and was expected to improve treatment adherence.[2] Second, and perhaps more importantly, it demonstrated a more favorable metabolic profile, particularly its lesser impact on serum lipids, including total cholesterol and triglycerides.[2] This characteristic made it a particularly attractive option for patients with, or at high risk for, cardiovascular disease and other metabolic complications, which were becoming increasingly prevalent as people with HIV lived longer.[7]

The clinical role of Atazanavir has evolved considerably since its introduction. It was initially utilized as an unboosted agent in treatment-naive individuals. However, its therapeutic application shifted predominantly toward co-administration with a pharmacokinetic (PK) enhancer, or "booster," such as a low dose of ritonavir or, later, cobicistat.[3] This boosting strategy became a cornerstone of its use, necessary to overcome inherent PK limitations and maintain therapeutic drug concentrations. These limitations include a pH-dependent absorption that is significantly reduced by common acid-suppressing medications and drug-drug interactions with other antiretrovirals, like tenofovir, that lower Atazanavir levels.[7] Boosting enhances its potency, particularly in treatment-experienced populations with pre-existing resistance mutations.[7] While boosted Atazanavir was once a preferred first-line PI regimen, its standing in treatment guidelines has been re-contextualized by the emergence of integrase strand transfer inhibitor (INSTI) regimens.[9] INSTIs generally offer a superior combination of high efficacy, a high barrier to resistance, fewer drug interactions, and a more benign side-effect profile, leading to their current status as the recommended first-line therapy for most patients.[9]

The clinical journey of Atazanavir effectively mirrors the broader evolution of HIV therapy. The field has progressed from an initial focus on achieving maximal viral suppression with the available tools, even at the cost of significant long-term toxicities, to a more nuanced approach that prioritizes not only virologic control but also long-term safety, regimen simplicity, and the minimization of metabolic complications. Atazanavir's initial success was a direct result of its improvements over the first generation of PIs, which were often burdened by complex dosing and severe dyslipidemia. However, its own pharmacological complexities, such as the need for food, acidic gastric pH, and PK boosting—which itself can negate some of the drug's metabolic advantages—highlighted the need for even better therapeutic options.[5] The subsequent rise of INSTIs, which largely circumvent these issues, demonstrates the high therapeutic bar set by modern antiretroviral agents. Atazanavir should not be viewed as a failure, but rather as a critical "bridge" therapy. It provided a safer and more convenient PI option that served patients effectively for over a decade before being largely superseded in first-line recommendations by a new, more advanced class of drugs. It continues to hold a valuable, albeit more specialized, role in the HIV treatment armamentarium.

Chemical Identity and Pharmaceutical Formulations

The precise identification of Atazanavir and its pharmaceutical salt form is fundamental to understanding its properties and clinical use. The drug is a small molecule azapeptide that is most commonly formulated and administered as a sulfate salt to improve its physicochemical properties for oral administration.

Table 1: Atazanavir Identification and Chemical Properties

Identifier/Property	Value (Atazanavir Free Base)	Value (Atazanavir Sulfate)	Source(s)
Drug Type	Small Molecule	Salt	2
DrugBank ID	DB01072	DBSALT000426	2
CAS Number	198904-31-3	229975-97-7	2
UNII	QZU4H47A3S	4MT4VIE29P	2
Chemical Class	Azapeptide, HIV Protease Inhibitor	Azapeptide, HIV Protease Inhibitor	3
Molecular Formula	C38​H52​N6​O7​	C38​H54​N6​O11​S	2
Molecular Weight	Average: 704.86 g/mol; Monoisotopic: 704.389748 Da	Average: 802.93 g/mol; Monoisotopic: 802.357127 Da	2
IUPAC Name	methyl N-amino]-4-phenylbutyl]-2-[(4-pyridin-2-ylphenyl)methyl]hydrazinyl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate	(2S)-2-{[hydroxy(methoxy)methylidene]amino}-N-amino}-3,3-dimethylbutylidene]amino}({[4-(pyridin-2-yl)phenyl]methyl})amino)-1-phenylbutan-2-yl]-3,3-dimethylbutanimidic acid; sulfuric acid	2
Synonyms	BMS-232632, CGP-73547, Latazanavir, Zrivada	BMS-232632-05	2
Brand Names	Reyataz®	Reyataz®	3
Fixed-Dose Combo	Evotaz® (with cobicistat)	N/A	3
Water Solubility	0.00396 mg/mL (predicted)	Soluble	2
pKa (Strongest Basic)	4.88 (predicted)	-	2
logP	4.36 - 5.86 (predicted)	-	2

Chemical Structure and Description

Atazanavir is classified as an azapeptide, a type of peptide mimetic where a nitrogen atom replaces one of the alpha-carbon atoms in the peptide backbone. This structural modification was a key part of its rational drug design, creating a molecule that acts as a structural analog of the peptide chain substrate targeted by the HIV protease enzyme.[5] Its systematic chemical name is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester.[12]

The molecule's structure contains several motifs that are critical to its function and properties. These include two bulky tert-butyl groups that interact with the hydrophobic pockets of the enzyme, a central hydroxyl group that is crucial for binding to the active site aspartic acid residues, a phenylmethyl (benzyl) group, and a distinctive 4-(pyridin-2-yl)phenylmethyl moiety that contributes to its binding affinity and specificity.[3] For pharmaceutical use, Atazanavir is formulated as Atazanavir sulfate (

C38​H52​N6​O7​⋅H2​SO4​), which presents as a white to pale yellow crystalline powder, enhancing its stability and handling properties.[14]

Pharmaceutical Formulations

Atazanavir is available in several formulations to accommodate different patient populations and clinical scenarios.

• Capsules (Reyataz®): The primary formulation for adults and older children is an oral capsule. These are available in strengths of 150 mg, 200 mg, and 300 mg of Atazanavir (as the sulfate salt).[3] The 100 mg and 150 mg strength capsules have been discontinued by the manufacturer in some markets.[20] The capsules contain inactive ingredients such as crospovidone, lactose monohydrate, and magnesium stearate.[14]
• Oral Powder (Reyataz®): To facilitate administration in pediatric patients, an oral powder formulation was developed and approved. It is supplied in individual packets containing the equivalent of 50 mg of Atazanavir base and is indicated for patients aged 3 months and older.[3] A critical feature of this formulation is its use of the artificial sweetener aspartame, which contains phenylalanine. This makes the powder unsuitable for patients with the metabolic disorder phenylketonuria (PKU), a warning that is highlighted in prescribing information.[4]
• Fixed-Dose Combination Tablets: To simplify treatment regimens and reduce pill burden, Atazanavir is also available in single-tablet, fixed-dose combinations (FDCs) with its pharmacokinetic enhancers.
• Evotaz®: This is a single tablet containing 300 mg of Atazanavir and 150 mg of the PK enhancer cobicistat.[3] It was approved by the FDA and EMA in 2015.[24]
• Atazanavir/Ritonavir Tablets: An FDC tablet containing 300 mg of Atazanavir and 100 mg of the PK enhancer ritonavir is also commercially available, providing the most commonly prescribed boosted regimen in a single pill.[28]

Core Pharmacology

The clinical utility and limitations of Atazanavir are directly derived from its core pharmacological properties, including its specific mechanism of action against HIV, its broader effects on human physiological systems (pharmacodynamics), and the way the body processes the drug (pharmacokinetics).

A. Mechanism of Action

Atazanavir is a highly potent and selective inhibitor of the HIV-1 protease enzyme.[3] This aspartic protease is an enzyme encoded by the virus that is absolutely essential for its replication and maturation. During the late stages of the viral life cycle, after a new virus particle has budded from the host cell membrane, the HIV-1 protease is responsible for cleaving large, non-functional viral polyprotein precursors, specifically the Gag and Gag-Pol polyproteins, into smaller, individual structural proteins and enzymes (such as reverse transcriptase, integrase, and protease itself).[5]

As an azapeptide, Atazanavir was rationally designed to mimic the three-dimensional structure of the transition state of the peptide bond between the amino acids phenylalanine and proline, which is a primary cleavage site for HIV protease.[5] By competitively and reversibly binding with high affinity to the active site of the protease, Atazanavir physically obstructs the enzyme, preventing it from binding to and cleaving the natural polyprotein substrates.[5] This inhibition is highly specific to the viral enzyme, as human proteases do not typically cleave this type of peptide bond, which contributes to the drug's targeted antiviral effect.[5]

The direct consequence of this enzymatic blockade is a complete halt in the processing of viral proteins. This results in the assembly and release of structurally disorganized, immature, and, most importantly, non-infectious viral particles. By preventing the formation of mature virions, Atazanavir effectively breaks the chain of infection, leading to a reduction in viral load in the patient's plasma and slowing the progressive destruction of the immune system.[5]

B. Pharmacodynamics

The pharmacodynamic profile of Atazanavir encompasses its direct antiviral effects, the development of viral resistance, and its significant off-target effects on human enzymes and physiological processes, which are responsible for its characteristic side effects and interactions.

Antiviral Activity and Resistance Profile

• In Vitro Activity: Atazanavir demonstrates potent activity against HIV-1 in laboratory settings, with a mean 50% effective concentration (EC50​) in the low nanomolar range (2-5 nM) across various susceptible cell lines and against a wide array of laboratory and clinical HIV-1 isolates.[12] Its activity extends across the major HIV-1 Group M subtypes, including A, B, C, D, and various circulating recombinant forms.[14] In contrast, its activity against HIV-2 is variable and generally weaker, making it a less reliable option for treating HIV-2 infection.[7]
• Resistance Pathway: Compared to some other antiretroviral classes like non-nucleoside reverse transcriptase inhibitors (NNRTIs), Atazanavir possesses a relatively high genetic barrier to resistance, meaning multiple mutations are often required to confer high-level clinical resistance.[9] In treatment-naive patients who experience virologic failure on an Atazanavir-containing regimen, the signature primary mutation that typically emerges in the viral protease gene is the substitution of isoleucine with leucine at codon 50 (I50L).[7] A clinically significant feature of the I50L mutation is that, while conferring resistance to Atazanavir, it often preserves or even increases the susceptibility of the virus to other protease inhibitors. This is a key distinction from other PI resistance pathways and can be advantageous when selecting subsequent therapies.[7] In heavily treatment-experienced patients, a much more complex pattern of multiple PI resistance-associated mutations (RAMs) tends to accumulate, leading to broad cross-resistance across the entire PI class.[3] The use of Atazanavir in these patients should be guided by genotypic resistance testing.[3]

Cardiovascular Effects (Electrocardiogram)

• PR Interval Prolongation: A well-characterized pharmacodynamic effect of Atazanavir is a concentration-dependent prolongation of the PR interval on the electrocardiogram (ECG).[32] Clinical studies have shown a mean maximum increase of approximately 24 milliseconds (msec) from baseline in patients receiving 400 mg of Atazanavir, compared to a 13 msec increase with placebo.[32] This effect is typically asymptomatic and manifests as a first-degree atrioventricular (AV) block.[32] While generally benign, there have been rare postmarketing reports of higher-grade heart block (second- or third-degree AV block).[28] Consequently, caution is advised when prescribing Atazanavir to patients with pre-existing conduction system disease (e.g., marked first-degree AV block) or when it is co-administered with other medications known to prolong the PR interval, such as diltiazem, verapamil, or certain beta-blockers.[4]
• QTc Interval: In contrast to its effect on the PR interval, Atazanavir does not cause clinically significant prolongation of the QTc interval.[32] This is an important safety feature, as it distinguishes Atazanavir from some other antiretroviral and non-antiretroviral drugs that carry a risk of inducing life-threatening arrhythmias like Torsades de Pointes.

Metabolic and Off-Target Effects

The pharmacodynamic profile of Atazanavir is fundamentally shaped by its off-target interactions with key human enzymes. While its primary mechanism is highly specific to the viral protease, its effects on UGT1A1 and CYP3A4 are what define its unique clinical character, creating both its most common side effect and its greatest clinical challenge.

• UGT1A1 Inhibition and Hyperbilirubinemia: Atazanavir is a potent inhibitor of the hepatic enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1).[5] This enzyme plays a critical role in the metabolism of bilirubin, a yellow pigment formed from the breakdown of red blood cells. UGT1A1 conjugates bilirubin with glucuronic acid, making it water-soluble for excretion into the bile. By inhibiting UGT1A1, Atazanavir blocks this conjugation step, leading to a predictable and dose-dependent accumulation of unconjugated (indirect) bilirubin in the bloodstream. This results in asymptomatic indirect hyperbilirubinemia in the vast majority of patients. In a substantial minority, with rates reported up to 45%, this elevated bilirubin manifests as clinical jaundice, a visible yellowing of the skin and sclera (whites of the eyes).[5] This effect is generally considered benign and is not indicative of liver injury, but it can be cosmetically distressing for patients and may be mistaken for hepatotoxicity, requiring careful patient counseling and clinical assessment.[7] Patients with congenital UGT1A1 deficiency, such as Gilbert's syndrome, are particularly susceptible to developing marked jaundice.[5]
• CYP450 and P-glycoprotein Inhibition: Atazanavir is both a substrate and a potent inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme, a major pathway for drug metabolism in the liver and gut wall. It is also an inhibitor of the P-glycoprotein (P-gp) drug efflux pump.[7] This dual inhibition is the fundamental mechanism responsible for its extensive and clinically significant drug-drug interaction profile. By inhibiting the clearance of other drugs that are metabolized by CYP3A4, Atazanavir can dangerously increase their plasma concentrations, leading to toxicity.

C. Pharmacokinetics

The pharmacokinetic (PK) profile of Atazanavir—encompassing its absorption, distribution, metabolism, and excretion (ADME)—is complex and is a primary determinant of its dosing requirements and interaction potential.

Table 2: Summary of Atazanavir Pharmacokinetic Parameters

Parameter	Unboosted ATV (400 mg QD)	Boosted ATV/r (300/100 mg QD)	Source(s)
Bioavailability	~60-68% (with food)	Enhanced by ritonavir	5
Tmax (Time to Peak)	~2.5 hours	~2.0-2.5 hours	9
Effect of Food	Required. Light meal: 70% ↑ AUC. High-fat meal: 35% ↑ AUC.	Required. Light meal: 33% ↑ AUC. Reduces PK variability by ~25%.	9
Cmax (Peak Conc.)	3152 ng/mL	4466 ng/mL	35
Cmin (Trough Conc.)	273 ng/mL	654 ng/mL	35
Elimination Half-life	~6.5-7 hours	~8.6 hours	17
Plasma Protein Binding	~86% (to AAG and albumin)	~86%	14
Metabolism	Extensive, primarily via CYP3A4/5	CYP3A4 metabolism inhibited by ritonavir	7
Excretion	~79% feces, ~13% urine	Similar	9
CSF:Plasma Ratio	0.0021 - 0.0226 (low penetration)	Not specified, likely similar	35

Absorption

Atazanavir is rapidly absorbed following oral administration, reaching peak plasma concentrations (Tmax​) in approximately 2.5 hours.[9] However, its absorption and overall bioavailability are critically dependent on two factors: an acidic gastric environment and the presence of food.[9] Atazanavir's solubility decreases as gastric pH increases. Therefore, administration with food, which stimulates gastric acid secretion, is mandatory. A light meal can increase the area under the concentration-time curve (AUC), a measure of total drug exposure, by up to 70% compared to the fasting state.[17] This pH-dependency is the basis for the clinically significant drug interaction with acid-reducing agents like proton pump inhibitors (PPIs) and H2-receptor antagonists.[11] Atazanavir also exhibits non-linear pharmacokinetics, meaning that increases in the administered dose result in greater-than-proportional increases in plasma concentrations and AUC.[17]

Distribution

Once absorbed, Atazanavir is highly bound (~86%) to plasma proteins, primarily to alpha-1-acid glycoprotein (AAG) and, to a lesser extent, albumin.[14] This high degree of protein binding limits the amount of free, active drug available to exert its effect. Its apparent volume of distribution is approximately 88.3 liters, indicating some distribution into tissues.[31] However, its penetration into sanctuary sites like the central nervous system is poor, as evidenced by a low cerebrospinal fluid (CSF) to plasma concentration ratio.[35] This is a potential limitation for the management of CNS-resident HIV reservoirs.

Metabolism

Atazanavir undergoes extensive metabolism in the liver. The primary metabolic pathway is mediated by the cytochrome P450 isoenzymes CYP3A4 and CYP3A5.[10] The major biotransformation reactions are mono- and dioxygenation. Minor metabolic pathways include N-dealkylation, hydrolysis, and oxygenation with dehydrogenation.[10] While the FDA-approved drug label also mentions glucuronidation as a minor pathway, some research has failed to detect glucuronidated metabolites in human plasma, suggesting this pathway is likely of minimal clinical relevance.[10] The metabolites of Atazanavir do not possess significant antiviral activity.[17]

Role of Pharmacokinetic Enhancers

Standard clinical practice involves the co-administration of Atazanavir with a low dose of a PK enhancer, either ritonavir (100 mg) or cobicistat (150 mg).[3] These agents are potent inhibitors of the CYP3A4 enzyme. By inhibiting the primary enzyme responsible for Atazanavir's metabolism, they significantly increase its plasma concentrations (both peak (

Cmax​) and trough (Cmin​)) and prolong its elimination half-life.[5] This "boosting" effect serves several crucial purposes: it increases overall drug exposure to enhance virologic efficacy, it raises the trough concentration to help overcome viral resistance, and it allows for once-daily dosing. Boosting is essential when Atazanavir is co-administered with drugs that are known to lower its levels, such as the NNRTI efavirenz or the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF).[4]

Elimination

The primary route of elimination for Atazanavir and its metabolites is through the biliary system into the feces, which accounts for approximately 79% of an administered dose. A smaller portion, around 13%, is recovered in the urine, with only about 7% of the dose being excreted as unchanged drug in the urine.[9] The mean elimination half-life of unboosted Atazanavir is approximately 7 hours, which is extended to about 8.6 hours when boosted with ritonavir, further supporting the once-daily dosing interval.[17]

Clinical Efficacy and Therapeutic Application

Atazanavir's clinical use is defined by its approved indications, complex dosing regimens tailored to specific patient populations and concomitant therapies, and important considerations for its use in special populations such as pregnant women and children.

A. Approved Indications and Off-Label Use

• Approved Indications: Atazanavir, as part of a combination antiretroviral regimen, is approved by major regulatory bodies, including the U.S. FDA and the European Medicines Agency (EMA), for the treatment of HIV-1 infection.[3] Its indication covers both adult and pediatric patients and includes individuals who are treatment-naive (have never taken HIV therapy) as well as those who are treatment-experienced.[5] The fixed-dose combination of Atazanavir with the pharmacokinetic enhancer cobicistat (Evotaz®) is also specifically approved for the treatment of HIV-1 infection.[3]
• Off-Label Use: Beyond its primary indication, Atazanavir is sometimes used off-label as a component of a post-exposure prophylaxis (PEP) regimen. This is for individuals who have had a potential exposure to HIV, such as through a needlestick injury in a healthcare setting or other high-risk contact.[5]

B. Dosage and Administration

The dosing of Atazanavir is highly nuanced and must be carefully tailored based on the patient's age, body weight, pregnancy status, prior treatment history, and, critically, any co-administered medications that may interact with it. The following table summarizes the recommended dosing regimens, but prescribers must always consult the most current full prescribing information.

Table 3: Recommended Dosing Regimens for Atazanavir

Patient Population	Regimen	Dose	Key Considerations/Source(s)
Adult, Treatment-Naive	Unboosted (Ritonavir intolerant)	400 mg once daily	Must be taken with food. Not recommended with tenofovir or efavirenz. 4
	Boosted (Preferred)	300 mg ATV + 100 mg ritonavir once daily	Must be taken with food. 4
	Boosted FDC	Evotaz® (300 mg ATV / 150 mg COBI) once daily	Must be taken with food. 3
Adult, Treatment-Experienced	Boosted Only	300 mg ATV + 100 mg ritonavir once daily	Unboosted ATV is not recommended due to risk of sub-therapeutic levels. 4
Pregnant Patients	Boosted Only	300 mg ATV + 100 mg ritonavir once daily	Dose must be increased to 400/100 mg if given with tenofovir or an H2RA. Monitor for 2 months postpartum for increased levels. 4
Pediatric (Capsules, ≥6 yrs)	Weight-based, Boosted	15 to <35 kg: 200 mg ATV + 100 mg ritonavir QD. ≥35 kg: 300 mg ATV + 100 mg ritonavir QD.	Dose determined by physician based on weight band. 3
Pediatric (Oral Powder, ≥3 mos)	Weight-based, Boosted	5 to <15 kg: 200 mg ATV + 80 mg ritonavir QD. 15 to <25 kg: 250 mg ATV + 80 mg ritonavir QD.	Must be mixed with food/liquid and taken immediately. Contains phenylalanine (contraindicated in PKU). 3

Administration Guidelines

Adherence to specific administration guidelines is critical for achieving therapeutic concentrations of Atazanavir.

• Administration with Food: Atazanavir must always be taken with food. Food enhances its bioavailability and reduces pharmacokinetic variability, ensuring more consistent drug exposure.[4]
• Capsule Integrity: The capsules should be swallowed whole and not opened, crushed, or chewed.[4]
• Interaction with Acid-Reducing Agents: Due to its pH-dependent absorption, strict timing is required when co-administering with acid-suppressing medications. For antacids or buffered medications like didanosine, Atazanavir should be taken at least 2 hours before or 1 hour after the antacid.[4] For more potent acid reducers like H2-receptor antagonists and proton pump inhibitors, more complex dose separation schedules are required, and their use is restricted or contraindicated in some patient populations.[11]

C. Use in Special Populations

• Pregnancy: Atazanavir is classified as Pregnancy Category B by the FDA, indicating that animal studies have not shown a risk but there are no adequate and well-controlled studies in pregnant women.[41] Data from the Antiretroviral Pregnancy Registry, which has tracked over 2,500 live births with Atazanavir exposure, has not found an increased risk of major birth defects.[5] It is considered a preferred PI for use in pregnant women who are treatment-naive.[5] A critical pharmacokinetic consideration is that Atazanavir concentrations are significantly reduced during the second and third trimesters of pregnancy. This physiological change necessitates that Atazanavir must be boosted with ritonavir during pregnancy. Unboosted Atazanavir or the cobicistat-boosted FDC (Evotaz®) are not recommended, as they can lead to sub-therapeutic drug levels and risk of virologic failure.[42] Furthermore, if Atazanavir/ritonavir is co-administered with TDF or an H2-receptor antagonist during pregnancy, the dose should be increased to 400/100 mg once daily to compensate for further reductions in exposure.[4]
• Pediatric Use: Atazanavir is approved for use in children, with specific formulations and dosing based on age and weight. Capsules are indicated for children 6 years of age and older who weigh at least 15 kg, while the oral powder formulation is available for infants from 3 months of age weighing at least 5 kg.[3] Atazanavir is strictly contraindicated in infants younger than 3 months of age. This is due to the risk of kernicterus, a rare but devastating form of brain damage caused by excessively high levels of unconjugated bilirubin crossing the immature blood-brain barrier. Given Atazanavir's potent inhibition of bilirubin metabolism, its use in neonates poses an unacceptable risk.[31]
• Hepatic Impairment: As Atazanavir is primarily metabolized and eliminated by the liver, its use must be modified in patients with hepatic impairment. For unboosted Atazanavir, a dose reduction may be considered in patients with mild-to-moderate hepatic impairment (Child-Pugh Class A or B).[14] However, the combination of Atazanavir with ritonavir is not recommended for patients with any degree of hepatic impairment due to the potential for increased toxicity from both drugs.[35] Boosted Atazanavir is contraindicated in patients with moderate to severe hepatic impairment, and unboosted Atazanavir is contraindicated in severe impairment.[34]
• Renal Impairment: Atazanavir itself undergoes minimal renal clearance, so no dose adjustment is required for patients with renal impairment, including those with end-stage renal disease (ESRD) not on dialysis.[14] For treatment-naive patients with ESRD who are on hemodialysis, a boosted regimen of 300/100 mg is recommended. However, for treatment-experienced patients on hemodialysis, the use of Atazanavir is not recommended due to a lack of sufficient data.[14]

Safety and Tolerability Profile

The safety profile of Atazanavir is complex, characterized by a unique and very common cosmetic side effect, several serious warnings that require diligent clinical monitoring, and a number of class-wide effects shared with other protease inhibitors.

A. Overview of Adverse Reactions

The most commonly reported side effects in clinical trials are generally of mild-to-moderate severity and include gastrointestinal complaints such as nausea and diarrhea, as well as headache, abdominal pain, insomnia, fever, and rash.[5] The most distinctive and frequent adverse event associated with Atazanavir is asymptomatic indirect hyperbilirubinemia, which often leads to cosmetic jaundice.[5] While this is not a sign of liver damage, it can be a significant concern for patients and may affect adherence if not properly explained.

B. Warnings, Precautions, and Management of Significant Adverse Events

While the provided research materials do not indicate that Atazanavir carries an FDA-issued Black Box Warning, its prescribing information contains numerous serious warnings, precautions, and contraindications that are critical for safe clinical use.[4]

• Severe Skin Reactions: Although a mild maculopapular rash is common, Atazanavir has been associated with rare but severe and potentially life-threatening cutaneous reactions. These include Stevens-Johnson syndrome (SJS), erythema multiforme, and toxic skin eruptions.[5] The drug must be discontinued immediately at the first sign of a severe rash, or a rash accompanied by systemic symptoms like fever, blistering, or mucosal lesions.[22]
• Cardiac Conduction Abnormalities: As detailed in the Pharmacodynamics section, Atazanavir is known to cause PR interval prolongation. While this is usually a benign first-degree AV block, caution and consideration of ECG monitoring are necessary in patients with pre-existing conduction system disease or when used with other PR-prolonging agents.[4]
• Hepatotoxicity: Atazanavir can cause elevations in liver transaminases (ALT, AST). This risk is substantially increased in patients with underlying chronic liver disease, particularly hepatitis B (HBV) or hepatitis C (HCV) co-infection. In these patients, Atazanavir use can lead to severe hepatic adverse reactions, including hepatic decompensation.[22] Baseline and periodic monitoring of liver function tests is mandatory for all patients, especially those with co-infections.[23] A key clinical challenge is distinguishing benign hyperbilirubinemia from true drug-induced liver injury. A patient presenting with jaundice requires immediate evaluation of liver function tests. If only indirect bilirubin is elevated while transaminases remain normal, this points to the expected benign effect of UGT1A1 inhibition, and the clinical response should be patient reassurance and continued monitoring. Conversely, if transaminases are also significantly elevated, this is a red flag for potential hepatotoxicity, requiring a full clinical workup and likely discontinuation of the drug. Failure to make this distinction can lead to either the unnecessary cessation of an effective therapy or the failure to manage a serious adverse event.
• Nephrolithiasis and Chronic Kidney Disease: Postmarketing reports have identified cases of kidney stones (nephrolithiasis) in patients taking Atazanavir, which can be severe enough to require hospitalization.[22] In addition, reports of chronic kidney disease have been associated with long-term use.[22] Patients should be counseled on the importance of maintaining adequate fluid intake to help reduce this risk.[23]
• Cholelithiasis: Similar to kidney stones, cases of gallbladder stones (cholelithiasis) have been reported, which may present with symptoms of right upper quadrant pain, nausea, and fever, and may also require hospitalization.[22]
• Metabolic Complications:
• Hyperglycemia: New-onset diabetes mellitus, worsening of pre-existing diabetes, and hyperglycemia have been reported with PI therapy, including Atazanavir.[5]
• Hyperlipidemia: While Atazanavir has a more favorable lipid profile than older PIs, it can still cause elevations in total cholesterol and triglycerides, particularly when boosted with ritonavir.[8] Lipid levels should be monitored periodically.
• Other Protease Inhibitor Class Effects: Atazanavir shares several adverse effects common to the PI class:
• Immune Reconstitution Inflammatory Syndrome (IRIS): As the immune system recovers after the initiation of cART, it can mount an exaggerated inflammatory response to previously undiagnosed, subclinical opportunistic infections. This can present as a paradoxical worsening of symptoms and requires clinical evaluation.[22]
• Fat Redistribution (Lipodystrophy): Changes in body fat distribution, including central fat accumulation (e.g., "buffalo hump," abdominal obesity) and peripheral fat loss (lipoatrophy), can occur with long-term antiretroviral therapy.[22]
• Increased Bleeding in Hemophiliacs: There have been reports of increased spontaneous bleeding episodes (e.g., skin hematomas, hemarthroses) in patients with hemophilia type A and B treated with PIs.[4]

C. Contraindications

The use of Atazanavir is absolutely contraindicated in several clinical situations due to the risk of severe or life-threatening adverse events.

• Hypersensitivity: It is contraindicated in any patient with a known prior severe hypersensitivity reaction to Atazanavir, such as Stevens-Johnson syndrome.[5]
• Hepatic Impairment: Unboosted Atazanavir is contraindicated in patients with severe hepatic impairment. Ritonavir-boosted Atazanavir is contraindicated in patients with moderate to severe hepatic impairment.[34]
• Co-administered Medications: Due to its potent inhibition of CYP3A4, Atazanavir is contraindicated with a number of medications. These contraindications are based on two primary mechanisms:
• Strong CYP3A4 Inducers: Drugs like rifampin, St. John's Wort, carbamazepine, and phenytoin are potent inducers of CYP3A4. They dramatically accelerate the metabolism of Atazanavir, leading to sub-therapeutic plasma concentrations, loss of virologic efficacy, and rapid development of drug resistance.[34]
• Sensitive CYP3A4 Substrates with Narrow Therapeutic Windows: Atazanavir can dangerously increase the plasma concentrations of drugs that are highly dependent on CYP3A4 for their clearance. If these drugs also have a narrow therapeutic index, the resulting toxicity can be life-threatening. This list includes agents like alfuzosin, cisapride, ergot derivatives, orally administered midazolam and triazolam, pimozide, lurasidone, sildenafil (when used for pulmonary arterial hypertension), and the statins lovastatin and simvastatin.[5]
• Other Antiretrovirals: Co-administration with indinavir is contraindicated due to the additive risk of severe hyperbilirubinemia. Co-administration with nevirapine is also contraindicated.[5]

Drug-Drug and Food Interactions

The clinical management of Atazanavir is dominated by its extensive potential for drug-drug interactions, which stem from its pharmacokinetic and pharmacodynamic properties. Safe use of this medication requires a thorough review of all concomitant medications.

A. Mechanisms of Interaction

The vast majority of Atazanavir's drug-drug interactions are driven by two key mechanisms:

1. Metabolic Inhibition: Atazanavir is a potent inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme and, to a lesser extent, an inhibitor of the UGT1A1 enzyme and the P-glycoprotein (P-gp) drug efflux pump.[7] When co-administered with drugs that are substrates of these pathways, Atazanavir can significantly decrease their clearance, leading to elevated plasma concentrations and an increased risk of toxicity. This effect is amplified when Atazanavir is boosted with ritonavir or cobicistat, which are themselves even more potent CYP3A4 inhibitors.
2. pH-Dependent Absorption: Atazanavir requires an acidic gastric environment for proper dissolution and absorption. Therefore, any medication that increases gastric pH (i.e., reduces stomach acid) can significantly impair its absorption, leading to sub-therapeutic Atazanavir levels, virologic failure, and the development of resistance.[11]

B. Clinically Significant Interactions

With over 570 documented drug interactions, a comprehensive list is beyond the scope of this report; however, a summary of the most clinically critical interactions is essential for safe prescribing.[49]

Table 4: Clinically Significant Drug-Drug Interactions with Atazanavir

Interacting Drug Class	Specific Drug(s)	Mechanism	Clinical Recommendation	Source(s)
Acid-Reducing Agents	Proton Pump Inhibitors (e.g., omeprazole)	↓ ATV absorption due to ↑ gastric pH	Contraindicated in treatment-experienced patients. In naive patients, give ATV ≥12 hrs after PPI and limit PPI dose.	11
	H2-Receptor Antagonists (e.g., famotidine)	↓ ATV absorption due to ↑ gastric pH	Dose separation required. Administer ATV simultaneously with or ≥10 hrs after H2RA.	11
	Antacids, Buffered Meds	↓ ATV absorption due to ↑ gastric pH	Administer ATV 2 hrs before or 1 hr after antacid.	4
Strong CYP3A4 Inducers	Rifampin, St. John's Wort, Phenytoin, Carbamazepine	↑ ATV metabolism, causing sub-therapeutic levels	CONTRAINDICATED	5
Statins	Simvastatin, Lovastatin	↓ Statin metabolism (CYP3A4), ↑ risk of myopathy	CONTRAINDICATED	11
	Atorvastatin, Rosuvastatin	↓ Statin metabolism (CYP3A4)	Use with caution at lowest possible dose.	57
Anticoagulants	Rivaroxaban, Apixaban	↓ Anticoagulant metabolism (CYP3A4), ↑ bleeding risk	Avoid or use with extreme caution. Rivaroxaban is contraindicated.	11
	Warfarin	Unpredictable effect on INR	Monitor INR frequently.	11
Antiarrhythmics	Amiodarone, Dronedarone, Quinidine	↓ Drug metabolism (CYP3A4), ↑ risk of arrhythmia	CONTRAINDICATED or avoid.	28
Other Antiretrovirals	Tenofovir DF	↓ ATV concentrations	Requires boosting with ritonavir.	4
	Efavirenz	Induces ATV metabolism	Requires boosting with ritonavir.	4
	Integrase Inhibitors (Raltegravir)	ATV inhibits UGT1A1, ↑ raltegravir levels	No dose adjustment needed for twice-daily raltegravir, but interaction exists.	58

C. Food and Lifestyle Interactions

• Food: The interaction with food is not only significant but also a mandatory part of administration. Taking Atazanavir with food is essential to ensure adequate bioavailability. Food enhances absorption and reduces the pharmacokinetic variability between patients, leading to more reliable and therapeutic drug levels.[17]
• Hyperlipidemia: While not a direct food interaction, treatment with protease inhibitors, including Atazanavir, is associated with a risk of causing or exacerbating hyperlipidemia. This is considered a disease-state interaction, where the drug can worsen an underlying metabolic condition. Regular monitoring of lipid panels is recommended, and management of dyslipidemia may be required.[48]

Regulatory History and Status

The regulatory journey of Atazanavir reflects its development, approval for various populations and formulations, and its eventual transition to a market with generic availability.

A. U.S. Food and Drug Administration (FDA)

• Initial Approval: Reyataz® (Atazanavir sulfate) capsules, sponsored by Bristol-Myers Squibb, received their initial approval from the FDA on June 20, 2003, under New Drug Application (NDA) 021567.[2]
• Key Labeling Updates and New Approvals:
• In 2009, the FDA approved a labeling update to include 96-week efficacy and safety data from the pivotal CASTLE Study, which compared boosted Atazanavir to boosted lopinavir in treatment-naive adults, reinforcing its role as a first-line agent at the time.[51]
• In 2011, a significant labeling update was approved to include specific dose recommendations for the use of boosted Atazanavir in HIV-infected pregnant women, based on pharmacokinetic data demonstrating safety and efficacy during pregnancy.[32]
• The oral powder formulation for pediatric use was approved on June 2, 2014, expanding its indication to younger children.[20]
• The fixed-dose combination tablet Evotaz®, containing Atazanavir and the booster cobicistat, was approved on January 29, 2015, offering a simplified single-tablet regimen.[24]
• Generic Availability: The patent exclusivity period for Reyataz® has expired, leading to the approval of multiple generic versions. The first generic Atazanavir capsules were approved by the FDA as early as 2014 (Teva) and 2018 (Aurobindo), increasing access and reducing costs.[20]

B. European Medicines Agency (EMA)

• Reyataz® Approval: The reference product, Reyataz®, was approved for use throughout the European Union following its U.S. approval. The indication was formally expanded to include pediatric patients between the ages of 6 and 18 in July 2010.[44]
• Evotaz® Approval: The Committee for Medicinal Products for Human Use (CHMP) of the EMA issued a positive opinion recommending approval for the fixed-dose combination Evotaz® in May 2015, which was followed by formal marketing authorization.[27]
• Generic Approvals: Similar to the U.S., numerous generic versions of Atazanavir have been authorized for use in the EU. These approvals, such as for Atazanavir Krka (March 2019) and Atazanavir Mylan/Viatris (August 2016), are typically granted based on studies demonstrating that the generic product is bioequivalent to the reference medicine, Reyataz®, ensuring comparable quality, safety, and efficacy.[39]

Conclusion: Expert Synthesis and Future Perspective

Atazanavir holds a significant place in the history of HIV therapy, defined by its substantial improvements over the first generation of protease inhibitors. Its introduction marked a pivotal step forward, offering a once-daily dosing regimen, a high genetic barrier to resistance, and, most notably, a more neutral lipid profile. These attributes were major advancements that improved patient adherence, simplified regimens, and mitigated some of the severe long-term metabolic toxicities associated with earlier PIs, thereby enhancing the quality of life for many individuals living with HIV.[2]

However, these clear benefits are intrinsically counterbalanced by a distinct and challenging set of pharmacological properties. The most common side effect, benign but often cosmetically distressing hyperbilirubinemia, can impact patient well-being and be easily mistaken for hepatotoxicity without careful clinical evaluation.[5] Its potent inhibition of the CYP3A4 enzyme results in a complex and extensive drug-drug interaction profile that requires vigilant management by clinicians and pharmacists.[11] Furthermore, its critical dependence on an acidic gastric environment and the presence of food for adequate absorption complicates its use with extremely common medications like proton pump inhibitors and necessitates strict patient counseling on administration.[11]

For over a decade, boosted Atazanavir was a cornerstone of recommended first-line therapy in major international guidelines.[7] The current era of HIV management, however, is now dominated by integrase strand transfer inhibitors (INSTIs). The INSTI class generally offers an even more favorable overall profile, characterized by comparable or superior efficacy, an excellent safety and tolerability profile with fewer metabolic disturbances, a simpler drug interaction profile, and a lack of food or pH restrictions.[9] As a result of this paradigm shift, major treatment guidelines have moved to universally favor INSTI-based regimens for the majority of treatment-naive patients.

In this modern context, Atazanavir is no longer a primary choice for initiating antiretroviral therapy in most patients in well-resourced settings. Its clinical utility has transitioned from a first-line workhorse to more specific, niche roles. It remains a valuable therapeutic option for certain treatment-experienced patients, particularly as part of a salvage regimen where its unique resistance profile—specifically, its retained activity against viruses with certain PI mutations that do not include the I50L substitution—may be advantageous. Furthermore, in the rare instance that a patient has contraindications to or has experienced intolerance with all available INSTI-based regimens, boosted Atazanavir can still serve as a viable and effective component of a fully suppressive cART regimen. Its favorable lipid profile continues to make it a consideration for patients with significant pre-existing dyslipidemia, provided that its other pharmacological challenges, particularly drug interactions and administration requirements, can be successfully navigated. In essence, Atazanavir has evolved into a crucial second-line or alternative agent, a status that is a testament to both its enduring virologic efficacy and the remarkable, ongoing progress in the field of antiretroviral therapy.

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