Atazanavir: its role in HIV treatment

Wood, Robin

doi:10.1586/14787210.6.6.785

Cited by 42 publications

(30 citation statements)

References 84 publications

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“…Atazanavir, a protease inhibitor used to treat patients with human immunodeficiency virus (HIV), is known to block UDP glucuronosyltransferase 1A1 (UGT1A1) activity, leading to the accumulation of unconjugated bilirubin [20]. We tested the hypothesis that accumulation of bilirubin via UGT1A1 inhibition would reduce oxidative stress and result in improved endothelial function in patients with T1DM.…”

Section: Introductionmentioning

confidence: 99%

Atazanavir improves cardiometabolic measures but not vascular function in patients with long-standing type 1 diabetes mellitus

et al. 2015

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Aims Vascular disease is the leading cause of morbidity and mortality in type 1 diabetes mellitus (T1DM). We previously demonstrated that patients with T1DM have impaired endothelial function, a forme fruste of atherosclerosis, as a result of increased oxidative stress. Bilirubin has emerged as a potent endogenous antioxidant with higher concentrations associated with lower rates of myocardial infarction and stroke. Methods We tested the hypothesis that increasing endogenous bilirubin using atazanavir would improve cardiometabolic risk factors and vascular function in patients with T1DM to determine whether targeting bilirubin may be a novel therapeutic approach to reduce cardiovascular disease risk in this population. In this single-arm, open-label study, we evaluated blood pressure, lipid profile, and conduit artery function in fifteen subjects (mean age 45 ± 9 years) with T1DM following a 4-day treatment with atazanavir. Results As anticipated, atazanavir significantly increased both serum total bilirubin levels (p < 0.0001) and plasma total antioxidant capacity (p < 0.0001). Reductions in total cholesterol (p = 0.04), LDL cholesterol (p = 0.04), and mean arterial pressure (p = 0.04) were also observed following atazanavir treatment. No changes were seen in either flow-mediated endothelium-dependent (p = 0.92) or nitroglycerine-mediated endothelium-independent (p = 0.68) vasodilation, measured by high-resolution B-mode ultrasonography at baseline and post-treatment. Conclusion Increasing serum bilirubin levels with atazanavir in subjects with T1DM over 4 days favorably reduces LDL and blood pressure but is not associated with improvements in endothelial function of conduit arteries.

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Section: Introductionmentioning

confidence: 99%

Atazanavir improves cardiometabolic measures but not vascular function in patients with long-standing type 1 diabetes mellitus

et al. 2015

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“…PI are substrate analogs for the HIV aspartyl protease enzyme involved in processing viral proteins by cleaving precursor proteins into smaller fragments and enabling the release of mature viral particles from infected cells. Once bound to the active site, they block the viral protease and in turn inhibit viral maturation, which blocks the formation of replication-competent virions (12,13). Atazanavir (ATV), a U.S. Food and Drug Administration-approved PI for the treatment of HIV-1 infection, can selectively inhibit virus-specific processing of gag-pol polyproteins.…”

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confidence: 99%

Endosomal Trafficking of Nanoformulated Antiretroviral Therapy Facilitates Drug Particle Carriage and HIV Clearance

Guo

Zhang

Wysocki

et al. 2014

J Virol

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Limitations of antiretroviral therapy (ART) include poor patient adherence, drug toxicities, viral resistance, and failure to penetrate viral reservoirs. Recent developments in nanoformulated ART (nanoART) could overcome such limitations. To this end, we now report a novel effect of nanoART that facilitates drug depots within intracellular compartments at or adjacent to the sites of the viral replication cycle. Poloxamer 407-coated nanocrystals containing the protease inhibitor atazanavir (ATV) were prepared by high-pressure homogenization. These drug particles readily accumulated in human monocyte-derived macrophages (MDM). NanoATV concentrations were ϳ1,000 times higher in cells than those that could be achieved by the native drug. ATV particles in late and recycling endosome compartments were seen following pulldown by immunoaffinity chromatography with Rab-specific antibodies conjugated to magnetic beads. Confocal microscopy provided cross validation by immunofluorescent staining of the compartments. Mathematical modeling validated drug-endosomal interactions. Measures of reverse transcriptase activity and HIV-1 p24 levels in culture media and cells showed that such endosomal drug concentrations enhanced antiviral responses up to 1,000-fold. We conclude that late and recycling endosomes can serve as depots for nanoATV. The colocalization of nano-ATV at endosomal sites of viral assembly and its slow release sped antiretroviral activities. Long-acting nanoART can serve as a drug carrier in both cells and subcellular compartments and, as such, can facilitate viral clearance. IMPORTANCEThe need for long-acting ART is significant and highlighted by limitations in drug access, toxicity, adherence, and reservoir penetrance. We propose that targeting nanoformulated drugs to infected tissues, cells, and subcellular sites of viral replication may improve clinical outcomes. Endosomes are sites for human immunodeficiency virus assembly, and increasing ART concentrations in such sites enhances viral clearance. The current work uncovers a new mechanism by which nanoART can enhance viral clearance over native drug formulations.

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“…However, approximately 7% of atazanavir is excreted unchanged in urine and due to its poor solubility, has the potential for crystalline precipitation at physiologic urine pH: the frequency of lithiasis ranges from 7.3 to 23.7 per 1000 person-years [73, 77]. Ritonavir-boosted atazanavir exposure has also the potential to cause crystalluria and urolithiasis, and acute, chronic or granulomatous interstitial nephritis [32, 73, 74].…”

Section: Introductionmentioning

confidence: 99%

HIV and kidney diseases: 35 years of history and consequences

2016

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Kidney diseases in human immunodeficiency virus (HIV)-infected patients are often misdiagnosed. Despite reductions in morbidity and mortality owing to widespread use of highly effective combination antiretroviral therapy (cART), acute kidney injury (AKI) and chronic kidney disease (CKD) are still more common in these patients than in the general population, and are associated with poor health outcomes. HIV-associated nephropathy and HIV immune complex kidney diseases are the more recognizable HIV-related kidney diseases. However, a broad spectrum of kidney disorders related or not directly related with HIV infection can be observed, including cART-induced AKI, CKD, proximal tubular dysfunction, crystalluria and urolithiasis, among others. This review summarizes the major epidemiologic studies of kidney diseases in HIV-infected patients, discusses novel approaches that may potentially limit nephrotoxicity such as the use of tenofovir alafenamide, and outlines current screening measures for early diagnosis of kidney dysfunction or tubular damage, and for accurate detection of increased risk for acute or chronic kidney diseases.

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Atazanavir: its role in HIV treatment

Cited by 42 publications

References 84 publications

Atazanavir improves cardiometabolic measures but not vascular function in patients with long-standing type 1 diabetes mellitus

Atazanavir improves cardiometabolic measures but not vascular function in patients with long-standing type 1 diabetes mellitus

Endosomal Trafficking of Nanoformulated Antiretroviral Therapy Facilitates Drug Particle Carriage and HIV Clearance

HIV and kidney diseases: 35 years of history and consequences

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