Atazanavir

Mechanism of Action

HIV is a lentivirus belonging to the retrovirus family.[12] HIV is characterized as an enveloped RNA virus with a genome comprising 2 identical linear positive-strand RNA molecules. The virus carries enzymes such as reverse transcriptase (RNA-dependent DNA polymerase), integrase, and protease, as well as structural proteins, envelope proteins, regulatory proteins, accessory proteins, and transfer RNAs necessary for viral replication.

The life cycle of HIV provides several drug targets.[13] Initiation of viral entry into host cells involves binding the viral envelope glycoprotein to the host cell surface receptor CD4 and chemokine co-receptors. Following the fusion of the viral membrane with the host cell membrane, the contents of the HIV capsid are released into the host cytosol, and the HIV generates double-stranded DNA reverse transcriptase, utilizing the viral RNA genome as a template. Subsequently, the viral DNA is transported into the nucleus and integrated into host chromosomes through the action of viral integrase enzymes. The utilization of the host cellular transcription machinery results in the synthesis of viral mRNAs and the subsequent production of proteins. Most viral proteins are synthesized as precursor proteins and assembled with other viral components. Following the budding of the newly formed virions, HIV protease cleaves the precursor proteins into individual functional proteins. The newly synthesized viral particles are then capable of infecting subsequent host cells.

The first drug approved as an anti-HIV agent was azidothymidine (zidovudine)—a nucleoside analog of thymidine without a 3’-hydroxyl group on the sugar.[1] Cellular triphosphorylation of the 5’-hydroxyl group of azidothymidine leads to incorporating this nucleotide by viral reverse transcriptase during reverse transcription. However, the elongation of the DNA chain is prematurely terminated because of the absence of the 3’-hydroxyl group. Additional nucleoside reverse transcriptase inhibitors comprise dideoxycytidine, dideoxyinosine, idoxuridine, ribavirin, stavudine, and trifluridine. Lamivudine features a modified sugar, whereas idoxuridine, ribavirin, and trifluridine have modified bases.

Non-nucleoside reverse transcriptase inhibitors also bind to the enzyme but not at the same binding sites as the nucleotide substrate. Non-nucleoside reverse transcriptase inhibitors function as non-competitive inhibitors of reverse transcriptase. FDA-approved non-nucleoside reverse transcriptase inhibitors include delavirdine, doravirine, efavirenz, etravirine, nevirapine, and rilpivirine.[14][15] These drugs specifically inhibit the reverse transcriptase of HIV-1, but not HIV-2, the latter being less common than HIV-1 in global HIV infections worldwide.[16]

The viral integrase enzyme is essential for integrating proviral DNA into the host chromosome. FDA-approved viral integrase inhibitors include bictegravir, dolutegravir, elvitegravir, and raltegravir.[17] Owing to the essential role of HIV protease in producing the mature virus, HIV protease has been the target of anti-HIV drugs. FDA-approved protease inhibitors include amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. These drugs are peptide mimetics that compete with the Gag and Gag-Pol proteins, which are natural substrates of HIV protease.[18]

Inhibition of the protease cleavage of these precursor proteins results in incomplete packaging of the virus. Protease inhibitors also have various off-target interactions, such as atazanavir's inhibition of the UGT1A1 enzyme responsible for bilirubin glucuronidation. This inhibition can result in the accumulation of bilirubin in the serum.[19] However, atazanavir use is associated with fewer cardiac and lipid profile adverse effects than other protease inhibitors.[20] Furthermore, enfuvirtide and maraviroc are known as viral entry inhibitors. Enfuvirtide acts as a peptide mimic to a crucial region of the HIV-1 glycoprotein-41 necessary for HIV-1 entry into host cells. Conversely, maraviroc functions as a chemokine receptor CCR5 inhibitor, targeting the co-receptor that HIV utilizes for host cell entry.[21]

These therapeutics are used in various combinations, called antiretroviral treatment (ART), to combat the rapid mutation rate that leads to the evolution of drug resistance seen in HIV.[22] HIV protease inhibitors are a key component of highly active antiretroviral combination therapy (HAART) for patients infected with HIV. Mutations in HIV protease lead to drug resistance.[23] Atazanavir was the pioneer protease inhibitor to receive approval for once-daily dosing. Although protease inhibitors exhibit enhanced efficacy in reducing HIV viral load compared to other antiretroviral therapeutics alone, they also contribute to some of the most severe antiretroviral adverse effects, which can impact patient adherence to pharmacotherapy.

Pharmacokinetics

Absorption: Atazanavir is rapidly absorbed after oral ingestion and has a Tmax of approximately 2.5 hours. The oral bioavailability ranges from 60% to 68%. Administering atazanavir with food enhances the drug's bioavailability and reduces pharmacokinetic variability. 

Distribution: Atazanavir pharmacokinetics follows a one-compartment model with first-order absorption and elimination.[24] The drug's volume of distribution is 88.3 L.[25]

Metabolism: Atazanavir undergoes extensive metabolism in humans, primarily in the liver. The drug acts as a substrate for CYP3A4 and undergoes biotransformation primarily through monooxygenation and dioxygenation. In addition, glucuronidation, N-dealkylation, hydrolysis, and oxygenation or dehydrogenation contribute to its metabolic pathways to a lesser extent.

Elimination: Atazanavir is primarily excreted through feces (79%) and urine (13%). About 20% and 7% are unchanged in feces and urine, respectively. The drug exhibits a half-life of approximately 7 hours.

Administration

Available Dosage Forms and Strengths

Atazanavir is available in capsule form in strengths of 150 mg, 200 mg, and 300 mg for oral administration. In addition, there is an oral powder formulation, but it is not interchangeable with the capsules.

Administration with food has shown improved bioavailability and decreased pharmacokinetic variability for atazanavir. As the dissolution of atazanavir depends on gastric acid, careful planning is necessary when coadministering antacids, buffered medications, proton pump inhibitors, and histamine H2-receptor antagonists to ensure separated dosing times.[26]

Atazanavir is the first once-daily administered protease inhibitor, typically in conjunction with low-dose ritonavir or cobicistat. Both cobicistat and ritonavir function as cytochrome P450 (CYP3A4) inhibitors. As the same enzyme metabolizes atazanavir, coadministration with cobicistat or ritonavir increases the bioavailability of atazanavir. Atazanavir without these pharmacokinetic boosts may be prescribed for patients with underlying hyperlipidemia, as ritonavir-boosted therapy may heighten the risk of hyperlipidemia.[20]

Adult Dosage

Treatment-naive HIV infection: A boosted regimen is recommended for treatment-naive HIV infection, which involves administering 300 mg of atazanavir orally with 100 mg of ritonavir or 150 mg of cobicistat daily. Alternatively, an unboosted regimen requires a daily oral dosage of 400 mg of atazanavir.

Treatment-experienced HIV infection: The recommended dosage for treatment-experienced HIV infection involves administering 300 mg of atazanavir orally with 100 mg of ritonavir or 150 mg of cobicistat daily.

Pediatric Dosage

HIV infection: The recommended dosages of atazanavir for oral powder and capsule formulations for HIV infection are listed below.

• Oral powder formulation:
  • For individuals aged 3 months and older, with a body weight between 5 and 14.9 kg, the recommended daily dosage of atazanavir is 200 mg powder orally with 80 mg of ritonavir orally.
  • For individuals aged 3 months and older, with a body weight between 15 and 24.9 kg, the recommended daily dosage of atazanavir is 250 mg powder orally with 80 mg of ritonavir orally.
  • For individuals aged 3 months and older, with a body weight of more than 25 kg, the recommended daily dosage of atazanavir is 300 mg powder orally with 100 mg of ritonavir orally.

• Capsule formulation:
  • For individuals aged 6 to 17, with a body weight between 15 and 34.9 kg, the recommended daily dosage of atazanavir is 200 mg powder orally with 100 mg of ritonavir orally.
  • For individuals aged 6 to 17, with a body weight of more than 35 kg, the recommended daily dosage of atazanavir is 300 mg powder orally with 100 mg of ritonavir or 150 mg of cobicistat orally.

Specific Patient Populations

Hepatic impairment: In patients classified as Child-Pugh Class B, the recommended daily dosage of atazanavir is 300 mg. Atazanavir should be avoided in those in Child-Pugh Class C. Furthermore, the use of atazanavir with ritonavir is not recommended in patients with hepatic impairment.

Renal impairment: The recommended dosages of atazanavir for treatment-naive and treatment-experienced patients are mentioned below.

• Treatment-naive patients: No dosage adjustment is necessary for treatment-naive patients. For individuals undergoing hemodialysis, the recommended dosage is 300 mg with 100 mg of ritonavir orally daily, and no supplementation is required after dialysis. Peritoneal dialysis is currently undefined.

• Treatment-experienced patients: No dosage adjustment is necessary for treatment-experienced patients. For individuals undergoing hemodialysis, the use of atazanavir is to be avoided. The suitability of atazanavir in peritoneal dialysis remains undefined at present.

Pregnancy considerations: As the benefits of atazanavir outweigh the risks, it is recommended to administer it with ritonavir. However, cobicistat should be avoided during pregnancy due to the potential risk of maternal virologic failure resulting from lower systemic cobicistat exposure in the last 2 trimesters. Based on recent data, no known risk of fetal harm has been identified with atazanavir doses exceeding the recommended therapeutic dose.

Breastfeeding considerations: Healthcare providers advise patients to refrain from breastfeeding due to the potential risk of HIV transmission despite maternal HIV treatment.

Pediatric patients: Patients should refer to the Pediatric Dosage section provided above for more information on pediatric dosing.

Older patients: Research has not revealed specific issues that would restrict the effectiveness of atazanavir in older patients. However, these patients are more likely to have age-related renal, hepatic, or cardiovascular concerns, potentially requiring additional caution and vigilance when using atazanavir. 

Adverse Effects

Common adverse effects of atazanavir include hyperbilirubinemia (35% to 49% in adults and 16% in children), rash (up to 21%), hypercholesterolemia (6% to 25%), hyperamylasemia (14% to 33%), jaundice (5% to 9% in adults and 13% to 15% in children), nausea (3% to 14%), cough (21% in children), and fever (2% in adults and 18% to 19% in children). Severe adverse effects include Stevens-Johnson syndrome, toxic skin eruptions, erythema multiforme, angioedema, cholecystitis, pancreatitis, interstitial nephritis, diabetic ketoacidosis, and AV block. Additional potential adverse effects include nephrolithiasis, cholelithiasis, hyperlipidemia, hypertriglyceridemia, bleeding, pancreatitis, exacerbation of diabetes mellitus or hyperglycemia, and lactic acidosis when used in combination with nucleoside analogs.[27]

Although immune reconstitution inflammatory syndrome (IRIS) is not a direct adverse effect of atazanavir, it is noteworthy that a pathological inflammatory response may occur after initiating antiretroviral treatment for HIV infection. There have been reports of up to a 75% mortality rate in IRIS cases associated with tuberculosis in the central nervous system.[28] Although there have been suggestions that successful treatment with antiretroviral drugs enables the recovery of immune function, it may also exacerbate existing opportunistic infections (paradoxical IRIS) or reveal previously undetected opportunistic infections (unmasking IRIS).[29]

Clinical symptoms may vary based on the type of opportunistic infections, but a common feature includes acute generalized or local inflammatory responses, such as fever or localized tissue edema. Therefore, the timing of initiating antiretroviral therapy is crucial to prevent IRIS.

Drug-Drug Interactions

Atazanavir is metabolized through the CYP3A4 pathway and has inhibitory effects on CYP3A4, CYP1A2, and CYP2C9 enzymes.[30] Therefore, patients taking medications that inhibit or are substrates of these enzymes, especially those with a narrow therapeutic index, should avoid atazanavir. Significant drug interactions may arise with warfarin, irinotecan, diltiazem, simvastatin, lovastatin, phosphodiesterase inhibitors, St John's wort, and tenofovir.[31]

Contraindications

Hypersensitivity reactions to atazanavir may manifest as a mild rash, Stevens-Johnson syndrome, toxic skin eruptions, or erythema multiforme. Patients who experience severe hypersensitivity reactions should discontinue the use of atazanavir.[32]

Other contraindications include pregnancy when atazanavir is combined with cobicistat, patients younger than 3 months, and hemodialysis in treatment-experienced patients.

Monitoring

HIV is highly mutable due to the absence of proofreading capability in viral reverse transcriptase, resulting in an elevated risk of drug resistance development. Regular viral genetic testing is recommended to monitor potential drug resistance, particularly when the viral titer increases.

Research has reported first-degree AV block in patients treated with ritonavir and atazanavir coadministration. An electrocardiogram is necessary for patients with pre-existing conduction diseases or those simultaneously taking medications that may cause PR prolongation.[33] Patients should be vigilant for potential cardiac complications and report dizziness or lightheadedness.[34]

Delayed hypersensitivity to atazanavir or any of its components may occur, often manifesting as a mild rash that typically resolves within 1 to 2 weeks and does not necessitate discontinuation of atazanavir. However, monitoring is essential for severe drug reactions, particularly the development of severe rash, flu-like symptoms, fever, muscle or joint aches, conjunctivitis, blisters, mouth sores, facial swelling, and painful or inflamed skin lesions.

Clinicians should monitor the development of acute IRIS following the initiation of antiretroviral therapy.[29] Monitoring should also extend to potential drug interactions with coadministered medications and hepatic and renal function. Signs of hepatic impairment include hyperbilirubinemia, elevated liver enzymes in the serum, jaundice, dark-colored urine, light-colored bowel movements, nausea, itching, and abdominal pain.[35] Signs of renal impairment include back pain (due to kidney stones), crystalluria, or bloody urine. These symptoms may occur within weeks (acute kidney injury) or years (chronic kidney disease) after the initiation of atazanavir therapy.[23]

When starting treatment with atazanavir, patients are advised to perform the following tests:

• Measure creatinine level at the beginning of treatment and then regularly monitor it afterward.

• Perform liver function tests at baseline, 2 to 8 weeks after treatment initiation or changes, and then every 3 to 6 months for adults and every 3 to 4 months for pediatric patients.

• Conduct a lipid profile and urinalysis examination at baseline and repeat it every 6 to 12 months.

• Measure fasting glucose at baseline, 3 to 6 months after treatment initiation, and then every 12 months.

• Conduct electrocardiography or ECG—a valuable diagnostic test for patients experiencing cardiac disturbances.

Toxicity

Currently, no specific antidote exists for atazanavir toxicity. Patients should receive symptomatic and supportive care from healthcare staff while regularly monitoring their vital signs and looking for signs of respiratory distress. Electrocardiogram monitoring of the patient is recommended, as atazanavir may exacerbate AV block due to PR interval prolongation. In cases where a simultaneous overdose with nucleoside reverse transcriptase inhibitors is suspected, clinicians should carefully monitor patients for symptoms of lactic acidosis.[36]

Enhancing Healthcare Team Outcomes

Estimates indicate that more than a million people in the United States are living with HIV infection. Upon diagnosis of HIV infection, the recommended course is the prompt initiation of antiretroviral treatment to delay disease progression from HIV infection to AIDS. This approach necessitates a collaborative effort from an interprofessional healthcare team, including physicians or specialists, advanced practice practitioners, nursing staff, and pharmacists.

Adherence to the treatment plan is equally crucial to prevent HIV transmission to others by reducing viral load.[37] Moreover, studies have indicated that the stigma associated with HIV infection negatively influences treatment adherence.[26] This factor poses a non-trivial challenge to the entire healthcare team, encompassing the need to monitor patients for adverse drug events to enhance adherence to drug therapy, conduct tests for the occurrence of drug resistance, and deliver effective counseling on the significance of therapy adherence and behavioral modifications. The overarching goal is to mitigate patients' risk for opportunistic infections and minimize the public risk of HIV spread. Treatment adherence is improved by the healthcare team when they address patient concerns about adverse events, offer strategies to mitigate dosing forgetfulness, and promote disease and health literacy.

Recent research has demonstrated that a single-tablet regimen enhances pharmaceutical adherence compared to multiple-tablet regimens.[38] Nursing staff are crucial in conducting patient counseling to underscore the importance of strict regimen adherence. A lapse in this aspect can potentially render entire classes of antiretroviral drugs ineffective. Pharmacists with specialized expertise, preferably holding infectious disease board certification and additional specialization in HIV regimens, should verify the chosen agents and dosages, thoroughly assess potential drug interactions that may result in adverse effects or compromise therapeutic effectiveness, and promptly communicate any identified issues to the prescriber.

In summary, interprofessional healthcare teams can enhance HIV treatment outcomes by improving drug therapy adherence by educating patients, carefully monitoring their symptoms, and considering patients' requirements and lifestyles.