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Nephrology, Dialysis, Transplantation :... Mar 2017Chronic kidney disease (CKD) is a critical comorbidity for patients living with HIV, with an estimated prevalence between 2.4 and 17%. Such patients are increasingly... (Review)
Review
Chronic kidney disease (CKD) is a critical comorbidity for patients living with HIV, with an estimated prevalence between 2.4 and 17%. Such patients are increasingly affected by diseases associated with ageing, including cardiovascular disease and CKD, and the prevalence of risk factors such as smoking and dyslipidaemia is increased in this population. Proteinuria is also now recognized as a common finding in individuals living with HIV. While combination antiretroviral (ARV) treatments reduce CKD in the HIV-infected population overall, some ARV drugs have been shown to be nephrotoxic and associated with worsening renal function. Over the last few years, several highly efficacious new ARV agents have been introduced. This brief review will look at the novel agents dolutegravir, raltegravir, elvitegravir, cobicistat, tenofovir alafenamide fumarate and atazanavir, all of which have been licensed relatively recently, and describe issues relevant to renal function, creatinine handling and potential nephrotoxicity. Given the prevalence of CKD, the wide range of possible interactions between HIV, ARV therapy, CKD and its treatments, nephrologists need to be aware of these newer agents and their possible effect on kidneys.
Topics: Adenine; Alanine; Anti-HIV Agents; Atazanavir Sulfate; Cobicistat; Creatinine; Disease Progression; HIV Infections; Heterocyclic Compounds, 3-Ring; Humans; Oxazines; Piperazines; Proteinuria; Pyridones; Quinolones; Raltegravir Potassium; Renal Insufficiency, Chronic; Tenofovir
PubMed: 27190354
DOI: 10.1093/ndt/gfw064 -
AIDS (London, England) Sep 2007
Topics: Alkynes; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Male; Middle Aged; Oligopeptides; Pyridines; Reverse Transcriptase Inhibitors; Ritonavir; Urolithiasis
PubMed: 17721118
DOI: 10.1097/QAD.0b013e3282ef792f -
AIDS Research and Therapy Feb 2023Chronic inflammation has been described in people living with HIV (PLHIV) receiving antiretroviral therapy (ART) despite viral suppression. Inflammation associated... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of pitavastatin on atherosclerotic-associated inflammatory biomarkers in people living with HIV with dyslipidemia and receiving ritonavir-boosted atazanavir: a randomized, double-blind, crossover study.
BACKGROUND
Chronic inflammation has been described in people living with HIV (PLHIV) receiving antiretroviral therapy (ART) despite viral suppression. Inflammation associated non-communicable diseases, including atherosclerosis, are becoming recognized complication of HIV infection. We studied the effect of pitavastatin on atherosclerotic-associated inflammatory biomarkers in PLHIV receiving ART.
METHODS
A randomized, double-blind, crossover study was conducted in HIV-infected persons with dyslipidemia and receiving atazanavir/ritonavir (ATV/r) to evaluate the effect of 2 mg/day pitavastatin treatment versus placebo. High-sensitivity CRP (hs-CRP), cytokines, and cellular markers in PLHIV receiving 12 weeks of pitavastatin or placebo were investigated.
RESULTS
A total of 24 HIV-infected individuals with a median (interquartile range) age of 46 (41-54) years were recruited, and the median CD4 T cell count was 662 (559-827) cells/mm. The median duration of ATV/r use was 36 (24-48) months. Significant change in levels of basic fibroblast growth factor (FGF) between pitavastatin treatment and placebo at week 12 from baseline was observed (27.1 vs. 20.5 pg/mL; p=0.023). However, there were no significant changes from baseline of hs-CRP and other plasma cytokine levels at week 12 of pitavastatin or placebo. Regarding cellular markers, percentages of HLA-DRCD38CD4 T cells and PD1CD4 T cells significantly decreased from baseline in PLHIV receiving pitavastatin for 12 weeks, as compared to placebo (- 0.27 vs. 0.02%; p=0.049 and - 0.23 vs. 0.23%; p=0.022, respectively).
CONCLUSIONS
Pitavastatin treatment increases basic FGF levels, and lowers HLA-DRCD38CD4 T cells, and PD1CD4 T cells. Further study on the effects of pitavastatin on preventing cardiovascular diseases in PLHIV should be pursued.
Topics: Humans; Middle Aged; Cross-Over Studies; Atazanavir Sulfate; C-Reactive Protein; HIV Infections; Ritonavir; Dyslipidemias; Atherosclerosis; Biomarkers; Cytokines; Inflammation
PubMed: 36849967
DOI: 10.1186/s12981-023-00506-2 -
Journal of the American Heart... Oct 2020Serum bilirubin is inversely associated with cardiovascular risk. Atazanavir, an HIV protease inhibitor that competitively inhibits bilirubin conjugation, provides a...
BACKGROUND
Serum bilirubin is inversely associated with cardiovascular risk. Atazanavir, an HIV protease inhibitor that competitively inhibits bilirubin conjugation, provides a unique opportunity to examine whether selectively increasing bilirubin is cardioprotective. We sought to determine whether patients receiving atazanavir manifest a reduced risk of cardiovascular disease compared with those receiving darunavir, an HIV protease inhibitor that does not increase serum bilirubin.
METHODS AND RESULTS
This was a retrospective cohort study of 1020 patients with HIV. The main outcome was time to myocardial infarction or ischemic stroke. Mean follow-up was 6.6±3.4 years, with 516 receiving atazanavir and 504 darunavir. Atazanavir patients exhibited significantly higher serum total bilirubin (1.7 versus 0.4 mg/dL; <0.001) and longer mean time to ischemic event (10.2 versus 9.4 years; <0.001). On Cox regression, atazanavir treatment (hazard ratio [HR], 0.38; 95% CI, 0.21-0.71; =0.002) and serum bilirubin (HR, 0.60; 95% CI, 0.41-0.89; =0.011) were independently associated with a lower risk of an ischemic event. Notably, when atazanavir and bilirubin were included together in the Cox regression model, atazanavir lost significance (HR, 0.55; 95% CI, 0.24-1.29; =0.169) consistent with bilirubin being an intermediate variable on the causal pathway between atazanavir and its effect on cardiovascular disease. Patients on atazanavir also had a significantly lower risk of developing new cardiovascular disease (HR, 0.53; 95% CI, 0.33-0.86; =0.010) and longer mean time to death (12.2 versus 10.8 years; <0.001).
CONCLUSIONS
Patients with HIV on atazanavir manifest a decreased risk of cardiovascular disease when compared with those on darunavir, an effect that appears to be mediated by serum bilirubin.
Topics: Atazanavir Sulfate; Bilirubin; Cardiovascular Diseases; Darunavir; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperbilirubinemia; Ischemic Stroke; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Retrospective Studies; Time Factors
PubMed: 32930032
DOI: 10.1161/JAHA.120.016310 -
AAPS PharmSciTech Sep 2022This study investigates the development of atazanavir-concentrate loaded soft gelatin capsule for achieving enhanced atazanavir (ATV) concentration in plasma, brain,...
This study investigates the development of atazanavir-concentrate loaded soft gelatin capsule for achieving enhanced atazanavir (ATV) concentration in plasma, brain, spleen, and lymphatics beneficial in the significant reduction of viral load in HIV infection. For this purpose, ATV-concentrate in the presence and absence of Soluplus with corn oil, oleic acid, tween 80, and propylene glycol was developed. The developed ATV-concentrate was found to have enhanced dispersibility with no signs of precipitation after dilution with simulated G.I fluid as evident from particle size (16.49±0.32 nm) and PDI (0.217±0.02) analysis. The rheological and molecular docking studies explainedthe reduction of viscosity of SuATV-C due to the intermolecular H-bond between ATV and Soluplus that helps to retard crystallization. The shell of the soft gelatin capsule retains its integrity when subjected to a folding endurance test on a texture analyzer depicting that the concentrate did not affect the integrity of the soft gelatin capsule shell. An ex vivo and in vivo pharmacokinetic study in rats revealed that the SuATV-C soft gelatin capsule (SuATV-C SGC) indicated 2.9 fold improvement in rate and extent of permeation and absorption than that of ATV-suspension. The tissue distribution study also exhibited higher drug concentration in the brain (2.5 fold), lymph nodes (2.7 fold), and spleen (1.2 fold) administered with SuATV-C SGC, revealing the overwhelming influence of Soluplus and corn oil. In a nutshell, these studies demonstrated that SuATV-C SGC seems to have the potential to deliver an anti-retroviral drug to the viral sanctuaries for the better management of HIV.
Topics: Animals; Anti-HIV Agents; Atazanavir Sulfate; Brain; Corn Oil; Gelatin; HIV Infections; Molecular Docking Simulation; Oleic Acid; Polyethylene Glycols; Polysorbates; Polyvinyls; Propylene Glycols; Rats; Spleen
PubMed: 36171353
DOI: 10.1208/s12249-022-02428-0 -
Antiviral Therapy 2015We studied the effect of pregnancy on atazanavir pharmacokinetics in the presence and absence of tenofovir.
BACKGROUND
We studied the effect of pregnancy on atazanavir pharmacokinetics in the presence and absence of tenofovir.
METHODS
This was a non-randomized, open-label, multicentre Phase IV study in HIV-infected pregnant women recruited from European HIV treatment centres. HIV-infected pregnant women treated with boosted atazanavir (300/100 mg or 400/100 mg atazanavir/ritonavir) as part of their combination antiretroviral therapy (cART) were included in the study. 24 h pharmacokinetic curves were recorded in the third trimester and postpartum. Collection of a cord blood and maternal sample at delivery was optional.
RESULTS
31 patients were included in the analysis, 21/31 patients used tenofovir as part of cART. Median (range) gestational age at delivery was 39 weeks (36-42). Approaching delivery 81% (25 patients) had an HIV viral load <50 copies/ml, all <1,000 copies/ml. Least squares means ratios (90% CI) of atazanavir pharmacokinetic parameters third trimester/postpartum were: 0.66 (0.57, 0.75) for AUC0-24h, 0.70 (0.61, 0.80) for Cmax and 0.59 (0.48, 0.72) for C24h. No statistical difference in pharmacokinetic parameters was found between patients using tenofovir versus no tenofovir. None of the patients showed atazanavir concentrations <0.15 mg/l (target for treatment-naive patients). One baby had a congenital abnormality, which was not likely to be related to atazanavir/ritonavir use. None of the children were HIV-infected.
CONCLUSIONS
Despite 34% lower atazanavir exposure during pregnancy, atazanavir/ritonavir 300/100 mg once daily generates effective concentrations for protease inhibitor (PI)-naive patients, even if co-administered with tenofovir. For treatment-experienced patients (with relevant PI resistance mutations) therapeutic drug monitoring of atazanavir should be considered to adapt the atazanavir/ritonavir dose on an individual basis. ClinicalTrials.gov number NCT00825929.
Topics: Adolescent; Adult; Area Under Curve; Atazanavir Sulfate; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Female; Gestational Age; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Pregnancy; Pregnancy Trimester, Third; RNA, Viral; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Treatment Outcome; Viral Load
PubMed: 24992294
DOI: 10.3851/IMP2820 -
Journal of Pharmaceutical and... Apr 2011This paper proposes a simple and selective RP-HPLC method for the determination of process impurities and degradation products (degradants) of atazanavir sulfate (ATV)...
This paper proposes a simple and selective RP-HPLC method for the determination of process impurities and degradation products (degradants) of atazanavir sulfate (ATV) drug substance. Chromatographic separation was achieved on Ascentis(®) Express C8, (150mm×4.6mm, 2.7μm) column thermostated at 30°C under gradient elution by a binary mixture of potassium dihydrogen phosphate (pH 3.5, 0.02M) and ACN at a flow rate of 1.0ml/min. A photodiode array (PDA) detector set at 250nm was used for detection. Stress testing (forced degradation) of ATV was carried out under acidic, alkaline, oxidative, photolytic, thermal and humidity conditions. In presence of alkali, ATV transformed into cyclized products and the order of degradation reaction is determined by the method of initial rates. The unknown process impurities and alkaline degradants are isolated by preparative LC and characterized by ESI-MS/MS, (1)H NMR, and FT-IR spectral data. The developed method is validated with respect to sensitivity (lod and loq), linearity, precision, accuracy and robustness and can be implemented for routine quality control analysis and stability testing of ATV.
Topics: Atazanavir Sulfate; Chromatography, High Pressure Liquid; Drug Contamination; Drug Stability; HIV Protease Inhibitors; Hydrogen-Ion Concentration; Kinetics; Limit of Detection; Magnetic Resonance Spectroscopy; Molecular Structure; Oligopeptides; Pyridines; Quality Control; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Spectroscopy, Fourier Transform Infrared; Tandem Mass Spectrometry; Technology, Pharmaceutical
PubMed: 21316175
DOI: 10.1016/j.jpba.2011.01.002 -
AIDS (London, England) May 2016To evaluate the safety of in-utero exposure to atazanavir and neurodevelopment in perinatally HIV-exposed but uninfected (PHEU) infants. (Comparative Study)
Comparative Study
OBJECTIVE
To evaluate the safety of in-utero exposure to atazanavir and neurodevelopment in perinatally HIV-exposed but uninfected (PHEU) infants.
DESIGN
Prospective cohort study of mother-PHEU infant pairs in the Surveillance Monitoring for ART Toxicities protocol of the Pediatric HIV/AIDS Cohort Study.
METHODS
Pregnant women living with HIV who initiated an antiretroviral regimen during pregnancy were followed from the date of antiretroviral initiation. Women were classified according to whether the antiretroviral regimen contained atazanavir and the trimester of antiretroviral initiation. Neurodevelopment at 9-15 months was evaluated using the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). We estimated mean differences for the five Bayley-III domains for atazanavir-containing regimens versus all other regimens. Models included baseline covariates and adjustment for failure to complete the Bayley-III using inverse probability weighting.
RESULTS
PHEU infants were exposed in utero to atazanavir-containing (n = 167) and nonatazanavir-containing (n = 750) antiretroviral regimens. The adjusted mean differences (95% confidence interval) in Bayley-III domain scores for initiating an atazanavir-containing regimen in the first trimester were: cognitive, -1.5 (-6.2, 3.2); language, -3.3 (-7.6, 1.0); motor, -2.9 (-7.7, 1.9); social-emotional, 0.1 (-6.2, 6.4); and adaptive behavior, -0.1 (-4.3, 4.0). The mean differences for the second or third trimester were: cognitive, 0.4 (-3.2, 4.0); language, -3.4 (-6.2, -0.5); motor, 0.3 (-2.9, 3.4); social-emotional, -5.9 (-9.4, -2.3); and adaptive behavior, -2.5 (-5.9, 0.8).
CONCLUSION
In-utero exposure to atazanavir-containing regimens compared with non-atazanavir-containing regimens may adversely affect language and social-emotional development in PHEU infants during the first year of life, but the absolute difference is small.
Topics: Adult; Atazanavir Sulfate; Female; Fetal Development; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Infant, Newborn; Male; Nervous System; Pregnancy; Pregnancy Complications, Infectious; Prenatal Exposure Delayed Effects; Prospective Studies; Young Adult
PubMed: 26867136
DOI: 10.1097/QAD.0000000000001052 -
Archives of Virology Aug 2017Atazanavir (ATZ) is a well-tolerated protease inhibitor that can be boosted with ritonavir (r) to treat infection with resistant strains of human immunodeficiency virus... (Meta-Analysis)
Meta-Analysis Review
Atazanavir (ATZ) is a well-tolerated protease inhibitor that can be boosted with ritonavir (r) to treat infection with resistant strains of human immunodeficiency virus 1 (HIV-1). The aim of this meta-analysis was to compare the efficacy, safety, and metabolic effects of ATZ/r regimen versus commonly used antiretroviral drugs such as lopinavir (LPV) and darunavir (DRV) in HIV-1-infected patients. We searched PubMed, Scopus, Embase and Cochrane CENTRAL, using relevant keywords. Data were extracted from eligible randomized trials and pooled as risk ratios (RR) or standardized mean differences (SMD) in a meta-analysis model using RevMan software. Nine randomized controlled trials (RCTs) (3292 patients) were eligible for the final analysis. After 96 weeks of treatment, the pooled effect estimate did not favor either ATZ/r or LPV/r in terms of virological failure rate (RR 1.11, 95% CI [0.74, 1.66]). However, ATZ/r was marginally superior to LPV/r in terms of increasing the proportion of patients with HIV RNA <50 copies/ml (RR 1.09, 95% CI [1.01, 1.17]). The pooled effect estimate did not favor ATZ/r over DRV/r regarding the change in plasma levels of total cholesterol, triglycerides, or high-density lipoprotein at 24, 48, and 96 weeks. Moreover, no significant difference was found between the two regimens (ATZ/r and DRV/r) in terms of change in visceral (SMD -0.06, 95%CI [-0.33, 0.21]) or subcutaneous adipose tissue (SMD 0.12, 95% CI [-0.15, 0.39]). The ATZ/r regimen was generally as effective and well-tolerated as the LPV/r regimen for the treatment of HIV-1 patients. Compared to the DRV/r regimen, ATZ/r has no favorable effect on the plasma lipid profile or adipose tissue distribution.
Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; CD4 Lymphocyte Count; Darunavir; HIV Infections; HIV-1; Humans; Lopinavir; RNA, Viral; Randomized Controlled Trials as Topic; Ritonavir; Treatment Outcome; Viral Load
PubMed: 28361290
DOI: 10.1007/s00705-017-3346-9 -
BMC Pharmacology & Toxicology May 2021Drug potency is a pharmacological parameter defining dose or concentration of drug required to obtain 50% of the drug's maximal effect. Pharmacokinetic-pharmacodynamic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Drug potency is a pharmacological parameter defining dose or concentration of drug required to obtain 50% of the drug's maximal effect. Pharmacokinetic-pharmacodynamic modelling and simulation allows estimation of potency and evaluate strategies improving treatment outcome. The objective of our study is to determine potency of atazanavir in hair, defined as atazanavir level in hair associated with 50% probability of failing to achieve viral load below 1000 copies/ml among adolescents, and explore the effect of participant specific variables on potency.
METHODS
A secondary analysis was performed on data from a previous study conducted in HIV-infected adolescents failing 2nd line ART from Harare central hospital, Zimbabwe, between 2015 and 2016. We simulated atazanavir concentrations in hair using NONMEM (version 7.3) ADVAN 13, based on a previously established pharmacokinetic model. Logistic regression methods were used for PKPD analysis. Simulations utilising PKPD model focused on estimation of potency and exploring the effect of covariates.
RESULTS
The potency of atazanavir in hair was found to be 4.5 ng/mg hair before adjusting for covariate effects. Participants at three months follow-up, reporting adequate adherence, having normal BMI-for-age, and cared for by mature guardians had increased potency of atazanavir in hair of 2.6 ng/mg, however the follow-up event was the only statistically significant factor at 5% level.
CONCLUSION
Atazanavir in hair in the range 2.6 to 4.5 ng/mg is associated with above 50% probability of early viral load suppression. Adherence monitoring to adolescents with lower potency of atazanavir is recommended. The effect self-reported adherence level, BMI-for-age, and caregiver status require further evaluation.
Topics: Adolescent; Anti-Retroviral Agents; Atazanavir Sulfate; Caregivers; Female; HIV Infections; Hair; Humans; Lamivudine; Male; Medication Adherence; Models, Biological; Overweight; Ritonavir; Tenofovir; Thinness; Viral Load; Zimbabwe
PubMed: 34030726
DOI: 10.1186/s40360-021-00497-8