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The Journal of Antimicrobial... Apr 2017Combination ART (cART)-related toxicities and costs have prompted the need for treatment simplification. The ATLAS-M trial explored 48 week non-inferior efficacy of... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Treatment simplification to atazanavir/ritonavir + lamivudine versus maintenance of atazanavir/ritonavir + two NRTIs in virologically suppressed HIV-1-infected patients: 48 week results from a randomized trial (ATLAS-M).
BACKGROUND
Combination ART (cART)-related toxicities and costs have prompted the need for treatment simplification. The ATLAS-M trial explored 48 week non-inferior efficacy of simplification to atazanavir/ritonavir + lamivudine versus maintaining three-drug atazanavir/ritonavir-based cART in virologically suppressed patients.
METHODS
We performed an open-label, multicentre, randomized, non-inferiority study, enrolling HIV-infected adults on atazanavir/ritonavir + two NRTIs, with stable HIV-RNA <50 copies/mL and CD4 + >200 cells/mm 3 . Main exclusion criteria were hepatitis B virus coinfection, past virological failure on or resistance to study drugs, recent AIDS and pregnancy. Patients were randomly assigned 1:1 to either switch to 300 mg of atazanavir/100 mg of ritonavir once daily and 300 mg of lamivudine once daily (atazanavir/ritonavir + lamivudine arm) or to continue the previous regimen (atazanavir/ritonavir + two NRTIs arm). The primary study outcome was the maintenance of HIV-RNA <50 copies/mL at week 48 of the ITT-exposed (ITT-e) analysis with switch = failure. The non-inferiority margin was 12%. This study is registered at ClinicalTrials.gov, number NCT01599364.
RESULTS
Between July 2011 and June 2014, 266 patients were randomized (133 to each arm). After 48 weeks, the primary study outcome was met by 119 of 133 patients (89.5%) in the atazanavir/ritonavir + lamivudine arm and 106 of 133 patients (79.7%) in the atazanavir/ritonavir + two NRTIs arm [difference atazanavir/ritonavir + lamivudine versus atazanavir/ritonavir + two NRTIs arm: +9.8% (95% CI + 1.2 to + 18.4)], demonstrating non-inferiority and superior efficacy of the atazanavir/ritonavir + lamivudine arm. Virological failure occurred in two (1.5%) patients in the atazanavir/ritonavir + lamivudine arm and six (4.5%) patients in the atazanavir/ritonavir + two NRTIs arm, without resistance selection. A similar proportion of adverse events occurred in both arms.
CONCLUSIONS
Treatment simplification to atazanavir/ritonavir + lamivudine showed non-inferior efficacy (superiority on post-hoc analysis) and a comparable safety profile over continuing atazanavir/ritonavir + two NRTIs in virologically suppressed patients.
Topics: Adult; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Coinfection; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; RNA, Viral; Ritonavir; Viral Load; Young Adult
PubMed: 28093483
DOI: 10.1093/jac/dkw557 -
African Health Sciences Mar 2020This systematic review and meta-analysis was conducted to evaluate the safety and effectiveness of Atazanavir/ritonavir over lopinavir/ritonavir in human... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This systematic review and meta-analysis was conducted to evaluate the safety and effectiveness of Atazanavir/ritonavir over lopinavir/ritonavir in human immunodeficiency virus-1 (HIV-1) infection.
METHODS
Clinical trials with a head-to-head comparison of atazanavir/ritonavir and lopinavir/ritonavir in HIV-1 were included. Electronic databases: PubMed/Medline CENTRAL, Embase, Scopus, and Web of Science were searched. Viral suppression below 50 copies/ml at the longest follow-up period was the primary outcome measure. Grade 2-4 treatment-related adverse drug events, lipid profile changes and grade 3-4 bilirubin elevations were used as secondary outcome measures.
RESULTS
A total of nine articles from seven trials with 1938 HIV-1 patients were included in the current study. Atazanavir/ritonavir has 13% lower overall risk of failure to suppress the virus level < 50 copies/ml than lopinavir/ritonavir in fixed effect model (pooled RR: 0.87; CI: 0.78, 0.96; P=0.006). The overall risk of hyperbilirubinemia is very high for atazanavir/ritonavir than lopinavir/ritonavir in the random effects model (pooled RR: 45.03; CI: 16.03, 126.47; P< 0.0001).
CONCLUSION
Atazanavir/ritonavir has a better viral suppression at lower risk of lipid abnormality than lopinavir/ritonavir. The risk and development of hyperbilirubinemia from atazanavir-based regimens should be taken into consideration both at the time of prescribing and patient follow-up.
Topics: Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hyperbilirubinemia; Lopinavir; Ritonavir; Treatment Outcome; Viral Load
PubMed: 33402897
DOI: 10.4314/ahs.v20i1.14 -
Biopharmaceutics & Drug Disposition Dec 2016Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice-daily (b.i.d.). Raltegravir 1200... (Randomized Controlled Trial)
Randomized Controlled Trial
Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice-daily (b.i.d.). Raltegravir 1200 mg once-daily (q.d.) (investigational q.d. formulation of 2 × 600 mg tablets; q.d. RAL) was found to be generally well tolerated and non-inferior to the marketed 400 mg b.i.d. dose at 48 weeks in a phase 3 trial. Since raltegravir is eliminated mainly by metabolism via a uridine diphosphate glucuronosyltransferase (UGT) 1A1-mediated glucuronidation pathway, co-administration of UGT1A1 inhibitors may increase the plasma levels of q.d. RAL. To assess this potential, the drug interaction of 1200 mg raltegravir using atazanavir, a known UGT1A1 inhibitor, was studied. An open-label, randomized, 2-period, fixed-sequence phase 1 study was performed in adult healthy male and female (non-childbearing potential) subjects ≥ 19 and ≤ 55 years of age, with a body mass index (BMI) ≥ 18.5 and ≤ 32.0 kg/m . Subjects (n = 14) received a single oral dose of 1200 mg raltegravir in period 1. After a washout period of at least 7 days, the subjects received oral doses of 400 mg atazanavir q.d. for 9 consecutive days, with a single oral dose of 1200 mg raltegravir co-administered on day 7 of period 2. Serial blood samples were collected for 72 h following raltegravir dosing and analysed using a validated bioanalytical method to quantify raltegravir plasma concentrations. Co-administration with atazanavir yielded GMRs (90% CIs) for raltegravir AUC , C and C of 1.67 (1.34, 2.10), 1.16 (1.01, 1.33) and 1.26 (1.08, 1.46), respectively. There was no effect of raltegravir on serum total bilirubin. In contrast, atazanavir increased the mean bilirubin by up to 200%, an effect that was preserved in the atazanavir/raltegravir treatment group. Administration of single q.d. RAL alone and co-administered with multiple oral doses of atazanavir were generally well tolerated in healthy subjects. The results show that atazanavir increased the PK exposure of raltegravir; therefore, co-administration of atazanavir with raltegravir q.d. is not recommended. Copyright © 2016 John Wiley & Sons, Ltd.
Topics: Administration, Oral; Adult; Atazanavir Sulfate; Drug Interactions; Female; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Male; Middle Aged; Raltegravir Potassium; Young Adult
PubMed: 27696440
DOI: 10.1002/bdd.2043 -
The Journal of Antimicrobial... Jun 2016To report the 96 week results on efficacy, safety and bone mineral density (BMD) in subjects with HIV-1 that were virologically suppressed and treated with... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To report the 96 week results on efficacy, safety and bone mineral density (BMD) in subjects with HIV-1 that were virologically suppressed and treated with atazanavir/ritonavir monotherapy versus atazanavir/ritonavir triple therapy.
METHODS
MODAt is a prospective, multicentre, open-label, non-inferiority, randomized, 96 week trial (NCT01511809) comparing efficacy of atazanavir/ritonavir monotherapy versus atazanavir/ritonavir triple therapy. Treatment success was defined as no occurrence of confirmed viral rebound (two consecutive HIV-RNA >50 copies/mL) or discontinuation for any cause of the ongoing regimen.
RESULTS
The 96 week treatment success was 64% in the atazanavir/ritonavir monotherapy arm and 63% in the triple-therapy arm (difference 1.3%, 95% CI: -17.5 to 20.1). In the atazanavir/ritonavir monotherapy arm, no PI- or NRTI-associated resistance mutations were observed at virological failure and all patients re-suppressed after re-intensification. In the monotherapy arm, treatment failure was more frequent in patients coinfected with hepatitis C virus [64% versus 28% (difference 35.4%, 95% CI: 3.7-67.2)]. Drug-related adverse events leading to discontinuation were 3 (6%) in the atazanavir/ritonavir monotherapy arm and 11 (21.5%) in the triple-therapy arm (P = 0.041). The 96 week adjusted mean percentage change in total proximal femur (not at lumbar spine) BMD was +1.16% and -1.64% in the atazanavir/ritonavir monotherapy arm and the triple-therapy arm, respectively (P = 0.012).
CONCLUSIONS
The 96 week analyses suggested that long-term efficacy of atazanavir/ritonavir monotherapy was inferior as compared with atazanavir/ritonavir triple therapy, particularly when administered in subjects coinfected with hepatitis C virus. In the atazanavir/ritonavir monotherapy arm, reintroduction of nucleosides, as needed, was always effective with no new resistance mutation; monotherapy was also associated with a lower incidence of adverse events and improvement in femur BMD.
Topics: Adult; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Bone Density; Coinfection; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Hepatitis C; Humans; Male; Middle Aged; Prospective Studies; RNA, Viral; Ritonavir; Treatment Failure; Treatment Outcome; Viral Load
PubMed: 26945711
DOI: 10.1093/jac/dkw031 -
Clinical Pharmacology and Therapeutics Feb 2020rs73208473 was recently associated with decreased atazanavir (ATV) concentration in the hair of women with seropositive HIV. Herein, we report on a pharmacogenetic... (Observational Study)
Observational Study
rs73208473 was recently associated with decreased atazanavir (ATV) concentration in the hair of women with seropositive HIV. Herein, we report on a pharmacogenetic study of women with seropositive HIV demonstrating a similar association between rs73208473 and dose-adjusted plasma ATV concentration in African Americans.
Topics: ATP Binding Cassette Transporter, Subfamily B; Area Under Curve; Atazanavir Sulfate; Chromatography, High Pressure Liquid; Citrus sinensis; Cytochrome P-450 CYP3A Inhibitors; Diarrhea; Dose-Response Relationship, Drug; Female; Genotype; HIV Infections; HIV Protease Inhibitors; Hair; Heroin Dependence; Humans; Hydrogen-Ion Concentration; Longitudinal Studies; MicroRNAs; Polymorphism, Single Nucleotide; Racial Groups; Receptors, Cell Surface; Tandem Mass Spectrometry
PubMed: 31562781
DOI: 10.1002/cpt.1605 -
Basic & Clinical Pharmacology &... Feb 2018Atazanavir sulphate, an antiretroviral protease inhibitor, has been used to treat HIV/AIDS, but its ability to serve as an antipulmonary fibrosis (PF) agent remains...
Atazanavir sulphate, an antiretroviral protease inhibitor, has been used to treat HIV/AIDS, but its ability to serve as an antipulmonary fibrosis (PF) agent remains unknown. In this study, the effects of atazanavir sulphate on various aspects of PF were examined and CoCl was used to induce the hypoxia-mimicking condition in vitro, including epithelial-mesenchymal transition (EMT) in A549 cells, endothelial-mesenchymal transition (EndMT) in human pulmonary microvascular endothelial cells (HPMECs), proliferation in human lung fibroblasts (HLF-1) and potential protective effects in human type I alveolar epithelial cells (AT I). Additionally, the effects of atazanavir sulphate were examined using a bleomycin (BLM)-induced pulmonary fibrosis model. After atazanavir sulphate treatment, in A549 cells and HPMECs, the expression of vimentin, HMGB1, Toll-like receptor 4 (TLR-4) and p-NF-κB decreased, while the expression of E-cadherin and VE-cadherin increased. In AT I cells, the expression of aquaporin 5 and RAGE were increased after atazanavir treatment. Proliferation of HLF-1 was reduced after atazanavir treatment, meanwhile the expression of hypoxia-inducible factor-1α (HIF-1α), prolyl hydroxylase domain protein 2 (PHD-2), HMGB1, TLR-9, p-NF-κB, collagen I and collagen III was decreased. In the BLM-induced pulmonary fibrosis rat model, atazanavir sulphate ameliorated PF by reducing pathological score, collagen deposition and the expression of α-SMA, HIF-1α, PHD-2, HMGB1, TLR-4, TLR-9 and p-NF-κB. In summary, our study supports the proposal that atazanavir sulphate may have a therapeutic potential in reducing the progression of pulmonary fibrosis by suppressing HMGB1/TLR signalling.
Topics: A549 Cells; Animals; Atazanavir Sulfate; Bleomycin; Cell Proliferation; Collagen; Cytoprotection; Disease Models, Animal; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibroblasts; HMGB1 Protein; Humans; Lung; Male; Pulmonary Fibrosis; Rats, Sprague-Dawley; Signal Transduction; Toll-Like Receptors
PubMed: 28816009
DOI: 10.1111/bcpt.12871 -
Clinical Pharmacokinetics Mar 2022The aim of this study was to simulate the drug-drug interaction (DDI) between ritonavir-boosted atazanavir (ATV/r) and rifampicin (RIF) using physiologically based...
OBJECTIVES
The aim of this study was to simulate the drug-drug interaction (DDI) between ritonavir-boosted atazanavir (ATV/r) and rifampicin (RIF) using physiologically based pharmacokinetic (PBPK) modelling, and to predict suitable dose adjustments for ATV/r for the treatment of people living with HIV (PLWH) co-infected with tuberculosis.
METHODS
A whole-body DDI PBPK model was designed using Simbiology 9.6.0 (MATLAB R2019a) and verified against reported clinical data for all drugs administered alone and concomitantly. The model contained the induction mechanisms of RIF and ritonavir (RTV), the inhibition effect of RTV for the enzymes involved in the DDI, and the induction and inhibition mechanisms of RIF and RTV on the uptake and efflux hepatic transporters. The model was considered verified if the observed versus predicted pharmacokinetic values were within twofold. Alternative ATV/r dosing regimens were simulated to achieve the trough concentration (C) clinical cut-off of 150 ng/mL.
RESULTS
The PBPK model was successfully verified according to the criteria. Simulation of different dose adjustments predicted that a change in regimen to twice-daily ATV/r (300/100 or 300/200 mg) may alleviate the induction effect of RIF on ATV C, with > 95% of individuals predicted to achieve C above the clinical cut-off.
CONCLUSIONS
The developed PBPK model characterized the induction-mediated DDI between RIF and ATV/r, accurately predicting the reduction of ATV plasma concentrations in line with observed clinical data. A change in the ATV/r dosing regimen from once-daily to twice-daily was predicted to mitigate the effect of the DDI on the C of ATV, maintaining plasma concentration levels above the therapeutic threshold for most patients.
Topics: Anti-HIV Agents; Atazanavir Sulfate; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Rifampin; Ritonavir
PubMed: 34635995
DOI: 10.1007/s40262-021-01067-1 -
Therapeutic Delivery Apr 2023The current research focused on formulation of spherical crystal agglomerates (SCA) of atazanavir sulphate for improving flow property and solubility. SCA were...
The current research focused on formulation of spherical crystal agglomerates (SCA) of atazanavir sulphate for improving flow property and solubility. SCA were formulated by quasi-emulsification solvent diffusion. Methanol, water and dichloromethane were employed as a good solvent, bad solvent and bridging liquid respectively. SCA with improved solubility and micromeritic properties were directly compressed into a tablet. The SCA tablets had higher dissolution rates compared with plain drug and marketed product. pharmacokinetic studies revealed higher C and AUC of the SCA than marketed product with relative bioavailability of 1.74. The formulation was stable for more than 3 months, with insignificant difference in % drug content and % drug dissolution.
Topics: Atazanavir Sulfate; Biological Availability; Solubility; Drug Liberation; Solvents; Tablets; Administration, Oral
PubMed: 37340886
DOI: 10.4155/tde-2022-0063 -
HIV Clinical Trials Aug 2018Limited studies have compared the impact of different antiretroviral regimens on soluble markers of inflammation with discordant results. (Comparative Study)
Comparative Study
BACKGROUND
Limited studies have compared the impact of different antiretroviral regimens on soluble markers of inflammation with discordant results.
METHODS
In this prospective study, treatment naïve HIV-1-infected patients were included if they started their current regimen with atazanavir/ritonavir (ATV/r) (N = 73, Group 1) or darunavir/ritonavir (DRV/r) (N = 85, Group 2) plus tenofovir/emtricitabine. The analysis of IL-6, MCP-1, sCD163, VCAM-1, ox-LDL, and adiponectine was performed on two stored plasma samples, the first prior to antiretroviral therapy initiation and the second one year after initiation.
RESULTS
The results of our analysis show a difference in ox-LDL between the two groups with higher mean (SD) values in ATV/r based group 608.5 ± 137.4 versus 519.1 ± 119.6 in DRV/r group, after controlling for baseline levels of ox-LDL as well as other potential confounding factors controlled by means of matching design or linear regression modelling.
CONCLUSIONS
Our analysis provides further data examining the association between the modulation of vascular inflammatory and of activation markers with specific protease inhibitors-based treatments over one year of exposure to these drugs. The data show little evidence for an association, supporting the notion that antiretroviral regimens has generally poor efficiency in downregulating these soluble markers.
Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Biomarkers; Darunavir; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Inflammation; Male; Middle Aged; Prospective Studies; Ritonavir
PubMed: 30422095
DOI: 10.1080/15284336.2018.1488453 -
Expert Opinion on Drug Safety Nov 2021: Cumulative use of some first-generation protease inhibitors has been associated with higher rates of dyslipidemia and increased risk of cardiovascular disease. The... (Review)
Review
: Cumulative use of some first-generation protease inhibitors has been associated with higher rates of dyslipidemia and increased risk of cardiovascular disease. The protease inhibitors most commonly in use are atazanavir and darunavir, which have fewer detrimental lipid effects and greater tolerability. This paper aims to review the evidence of a potential association of these contemporary protease inhibitors with the risk of ischemic CVD and atherosclerotic markers.: We searched for publications of randomized trials and observational studies on from 1 January 2000 onwards, using search terms including: protease inhibitors; darunavir; atazanavir; cardiovascular disease; cardiovascular events; dyslipidemia; mortality; carotid intima media thickness; arterial elasticity; arterial stiffness and drug discontinuation. Ongoing studies registered on as well as conference abstracts from major HIV conferences from 2015-2020 were also searched.: Atazanavir and darunavir are no longer part of first-line HIV treatment, but continue to be recommended as alternative first line, second- and third-line regimens, as part of two drug regimens, and darunavir is used as salvage therapy. Although these drugs will likely remain in use globally for several years to come, baseline CVD risk should be considered when considering their use, especially as the population with HIV ages.
Topics: Animals; Atazanavir Sulfate; Atherosclerosis; Cardiovascular Diseases; Darunavir; Dyslipidemias; HIV Infections; HIV Protease Inhibitors; Heart Disease Risk Factors; Humans; Randomized Controlled Trials as Topic
PubMed: 34047238
DOI: 10.1080/14740338.2021.1935863