Atazanavir is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection.[1] Once the establishment of infection, HIV cannot be eradicated from the body, although an undetectable viral load equates with the virus being untransmittable sexually, so long as antiviral therapy continues.[2] The goal of life-long drug treatment in HIV-infected patients is to suppress viral replication and sustain viral target CD4+ T lymphocyte counts to prevent the development of clinical conditions associated with acquired immunodeficiency syndrome (AIDS), as well as prevent viral transmission to others.[3]

Atazanavir therapy works in combination with other anti-HIV drugs.[4] The high error rate of HIV polymerase creates extensive mutations and promotes the development of antiretroviral drug-resistant strains. The administration of multiple drugs addresses this problem with at least two different modes of action. The combination of protease inhibitors, such as atazanavir, paired with two nucleoside analogs, can reduce the HIV viral load to undetectable levels in the blood.[5]

Because of cross-resistance among antiretroviral agents, information on the baseline mutations in the virus, as determined by genotype testing, should guide the drug regimen selection, especially in patients who have had prior treatment with protease inhibitors.[6]

Atazanavir is not recommended to children younger than three months of age, and the optimal dosage remains unestablished. Atazanavir may cause kernicterus in this group as it is a competitive inhibitor of an enzyme that catalyzes bilirubin glucuronidation.[7] Atazanavir is also not recommended for use during lactation.[8] Atazanavir may be given to HIV-infected pregnant patients, as it has not shown an increased risk of teratogenicity or genotoxicity in human and animal studies.[9] However, elevated bilirubin levels are observable in neonates whose mothers were taking atazanavir during pregnancy, and the selection of other available protease inhibitor combinations may reduce potential adverse effects to the infant.[10][11]

Human immunodeficiency virus is a lentivirus in the retrovirus family.[12] It is an enveloped RNA virus. The virus contains two identical linear positive-strand RNA molecules that form its genome, along with the enzymes reverse transcriptase (RNA-dependent DNA polymerase), integrase, protease, as well as structural proteins, envelope proteins, regulatory proteins, accessory proteins, and transfer RNAs needed for viral replication.

The life cycle of HIV provides several drug targets.[13] Viral entry to host cells is initiated by binding of the viral envelope glycoprotein to host cell surface receptor CD4 and chemokine co-receptors. Once the fusion of the viral membrane with the host cell membrane occurs, the contents of the HIV capsid get released into the host cytosol, and double-stranded DNA is produced by the HIV reverse transcriptase using the viral RNA genome as a template. Then, the viral DNA is transported into the nucleus and integrated into host chromosomes, using viral integrase enzymes. Using the host cellular transcription machinery leads to the synthesis of viral mRNAs and the production of proteins. Most viral proteins are made as a precursor protein and assembled with other components of the virus. After 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, a nucleoside analog of thymidine without 3’-hydroxyl group on the sugar.[1] Cellular tri-phosphorylation of the 5’-hydroxyl group of azidothymidine results in viral reverse transcriptase incorporation of this nucleotide during reverse transcription. However, due to the lack of the 3’-hydroxyl group, the DNA chain elongation is prematurely terminated. Other nucleoside reverse transcriptase inhibitors include dideoxycytidine, dideoxyinosine, idoxuridine, ribavirin, stavudine, trifluridine, and others. Lamivudine has a modified sugar, and idoxuridine, ribavirin, and trifluridine have modified bases.

Non-nucleoside reverse transcriptase inhibitors also bind to the enzyme, but not at the same sites where the nucleotide substrate binds. Non-nucleoside reverse transcriptase inhibitors are non-competitive inhibitors of reverse transcriptase. The six FDA approved non-nucleoside reverse transcriptase inhibitors are delavirdine, doravirine, efavirenz, etravirine, nevirapine, and rilpivirine.[14][15] These drugs only inhibit the reverse transcriptase of HIV-1 and not HIV-2, which is less common than HIV-1 in HIV infections worldwide.[16]

Viral integrase enzyme is essential for the integration of proviral DNA into the host chromosome. The four FDA approved viral integrase inhibitors are bictegravir, dolutegravir, elvitegravir, and raltegravir are integrase inhibitors.[17]

Due to the essential role of HIV protease in the production of the mature virus, HIV protease has been the target for anti-HIV drugs. The ten FDA approved protease inhibitors are 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), leading to the accumulation of bilirubin in the serum.[19] However, atazanavir use is associated with fewer cardiac and lipid profile adverse effects that other protease inhibitors.[20]

Additionally, enfuvirtide and maraviroc are viral entry inhibitors. Enfuvirtide is a peptide mimic to the region of the HIV-1 glycoprotein 41 that is essential for the entry of HIV-1 to the host cells. Maraviroc is a chemokine receptor CCR5 inhibitor. The CCR5 is a co-receptor that HIV uses 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 their drug resistance.[23] Atazanavir was the first protease inhibitor that received approval for once-daily dosing. Protease inhibitors have shown improved efficacy in reducing HIV viral load over other antiretroviral therapeutics alone but also contribute to the most serious antiretroviral adverse effects, impacting patient compliance.

Atazanavir administration is via the oral route. Administration with food has demonstrated enhanced bioavailability and reduce pharmacokinetic variability. Gastric acid is necessary for the dissolution of atazanavir. Therefore, co-administration of antacids, buffered medications, proton pump inhibitors, and histamine H2-receptor antagonists requires a careful plan for separated dosing time.[24]

Atazanavir is the first once-daily administered protease inhibitor; administration is with low dose ritonavir or cobicistat. Cobicistat and ritonavir are cytochrome P450 (CYP) 3A inhibitors. Because the same enzyme metabolizes atazanavir, co-administration with cobicistat or ritonavir will increase the bioavailability of atazanavir. Atazanavir without these pharmacokinetic boosts may be administered in patients with underlying hyperlipidemia as ritonavir-boosted therapy may enhance the risk of hyperlipidemia.[20]

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

Although immune reconstitution inflammatory syndrome (IRIS) is not a direct side effect of atazanavir, a pathological inflammatory response may occur after initiation of antiretroviral treatment for HIV infection. Up to a 75% mortality rate in IRIS with tuberculosis in the central nervous system has been reported.[26] There have been suggestions that successful treatment with antiretroviral drugs enables the recovery of the immune function, but may also exacerbate existing opportunistic infections (paradoxical IRIS) or unmasks opportunistic infections (unmasking IRIS).[27] Clinical symptoms may vary depending on the type of opportunistic infections, but a common feature includes acute generalized or local inflammation responses such as fever or localized tissue edema. The timing of initiating antiretroviral therapy, therefore, is crucial to prevent IRIS.

Hypersensitivity reaction to atazanavir in the form of mild skin rash, Stevens-Johnson syndrome, toxic skin eruptions, or erythema multiforme may occur. Atazanavir should be discontinued in patients who develop serious hypersensitivity reactions.[28]

 Atazanavir metabolism occurs via CYP3A and inhibits CYP3A, CYP1A2, and CYP2C9.[29] Patients who also take drugs that inhibit or are substrates of these enzymes with a narrow therapeutic index should not take atazanavir. For example, significant drug interactions may occur with warfarin, irinotecan, diltiazem, simvastatin, lovastatin, phosphodiesterase inhibitors, Saint John’s wort, and tenofovir.