Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antiretroviral regimens based on human immunodeficiency virus-1 (HIV-1) protease inhibitors (PIs) are hampered by a number of side effects, mainly diarrhea, dyslipidemia, an increased risk of cardiovascular events and diabetes, and lipoaccumulation in the neck and abdomen. Although challenged by these potential untoward effects, PIs are still the cornerstone of highly active antiretroviral therapy (HAART) because of their potency and high genetic barrier. Atazanavir (ATV) is the first once-daily azapeptide HIV-1 PI and can be boosted by ritonavir. The efficacy of ritonavir-boosted ATV (ATV/r)-containing regimens in patients harboring drug-resistant variants is not statistically different from that of the reference PI lopinavir/ritonavir. In Italy, ATV, either boosted or unboosted, is licensed only for drug-experienced patients. However, in clinical trials ATV/r has proved to be effective in treatment-naive HIV-1-infected individuals. There is no evidence that ATV/r-based regimens lead to the selection of mutations conferring cross-resistance to other PIs, and this drug combination has now been included among those recommended by the International AIDS Society-USA Panel and the Department of Health and Human Services (DHHS) Panel as initial treatment when a boosted-PI-based regimen is preferred to a NNRTI-based regimen.
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PMID:Antiviral activity and clinical efficacy of atazanavir in HIV-1-infected patients: a review. 1761 50

Opioid addiction and HIV disease frequently co-occur. Adverse drug interactions have been reported between methadone and some HIV medications, but less is known about interactions between buprenorphine, an opioid partial agonist used to treat opioid dependence, and HIV therapeutics. This study examined drug interactions between buprenorphine and the protease inhibitors atazanavir and atazanavir/ritonavir. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n=10 per protease inhibitor) participated in two 24-h sessions to determine pharmacokinetics of (1) buprenorphine and (2) buprenorphine and atazanavir (400mg daily) or atazanavir/ritonavir (300/100mg daily) following administration for 5 days. Objective opiate withdrawal scale scores and mini-mental state examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls (n=10 per protease inhibitor) to determine effects of buprenorphine. With atazanavir and atazanavir/ritonavir, respectively concentrations of buprenorphine (p<0.001, p<0.001), norbuprenorphine (p=0.026, p=0.006), buprenorphine glucuronide (p=0.002, p<0.001), and norbuprenorphine glucuronide (NS, p=0.037) increased. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxone-maintained participants reported increased sedation with atazanavir/ritonavir. Atazanavir or atazanavir/ritonavir may increase buprenorphine and buprenorphine metabolite concentrations and might require a decreased buprenorphine dose.
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PMID:Interaction between buprenorphine and atazanavir or atazanavir/ritonavir. 1764 69

The molecular mechanisms of action of a HIV protease inhibitor, ritonavir, on hepatic function were explored on a genomic scale using microarrays comprising genes expressed in the liver of Sprague-Dawley rats (Rattus norvegicus). Analyses of hepatic transcriptional fingerprints led to the identification of several key cellular pathways affected by ritonavir treatment. These effects were compared to a compendium of gene expression responses for 52 unrelated compounds and to other protease inhibitors, including atazanavir and two experimental compounds. We identified genes involved in cholesterol and fatty acid biosynthesis, as well as genes involved in fatty acid and cholesterol breakdown, whose expressions were regulated in opposite manners by ritonavir and bezafibrate, a hypolipidemic agonist of the peroxisome proliferator-activated receptor alpha. Ritonavir also upregulated multiple proteasomal subunit transcripts as well as genes involved in ubiquitination, consistent with its known inhibitory effect on proteasomal activity. We also tested three other protease inhibitors in addition to ritonavir. Atazanavir did not impact ubiquitin or proteasomal gene expression, although the two other experimental protease inhibitors impacted both proteasomal gene expression and sterol regulatory element-binding protein-activated genes, similar to ritonavir. Identification of key metabolic pathways that are affected by ritonavir and other protease inhibitors will enable us to understand better the downstream effects of protease inhibitors, thus leading to better drug design and an effective method to mitigate the side effects of this important class of HIV therapeutics.
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PMID:Gene expression profiling of rat liver reveals a mechanistic basis for ritonavir-induced hyperlipidemia. 1771

Atazanavir (ATV) and lopinavir (LPV) are widely used HIV-1 protease inhibitors. Like with other protease inhibitors, careful monitoring of potential drug-drug and drug-disease interactions in clinical practice is necessary. The aim of this study was to assess the impact of substance use and hepatitis virus coinfection on plasma ATV and LPV trough concentrations in HIV-positive substance users and nonusers. Individuals established on ATV (300 mg and 100 mg ritonavir daily) or LPV (400 mg and 100 mg ritonavir twice daily)-containing regimens completed two clinical visits (trough and directly observed therapy) during which dosing characteristics, concomitant medication, and substance use were recorded. Trough plasma concentrations (22-26 hours for ATV and 10-14 hours for LPV) were measured using LCMSMS. The influence of substance use was evaluated by Kruskal-Wallis test. Substance use was associated with a marked decrease in trough LPV concentrations during the trough visit (median, 5.536 and 3.791 microg/mL for nonsubstance users and substance users, respectively, P = 0.029). Significantly lower LPV trough levels were also noted among patients with active hepatitis C virus coinfection evaluated as an independent variable (median, 2.253 and 5.927 microg/mL for active and inactive/no hepatitis C virus infection, respectively, P = 0.032). Substance use and hepatitis virus coinfection had limited effects on ATV trough levels. In this cohort, despite the wide interindividual variability of ATV and LPV trough concentrations, significant associations between substance use and active hepatitis C virus infection and low LPV trough concentrations were observed. Further work is needed to assess the optimal dosing regimen when using LPV in HIV-infected substance users.
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PMID:Assessing the impact of substance use and hepatitis coinfection on atazanavir and lopinavir trough concentrations in HIV-infected patients during therapeutic drug monitoring. 1789 44

Although atazanavir pharmacokinetics and pharmacodynamics are related, the atazanavir plasma trough concentrations of patients on regimens that are not boosted by low doses of ritonavir may not be high enough to maintain viral suppression. In this cross-sectional study, the percentage of patients with atazanavir trough concentrations lower than the proposed minimum effective concentration was compared between HIV-infected patients receiving antiretroviral therapy with ritonavir-boosted (ATV/r, n = 31) or unboosted (ATV, n = 54) atazanavir in clinical practice. Blood samples were drawn 21 to 25 hours after the last atazanavir dose. Drug concentrations in plasma were determined by high-performance liquid chromatography and considered suboptimal if they were lower than 0.15 mg/L or potentially toxic if higher than 0.85 mg/L. The median (interquartile range) atazanavir concentration was 0.711 (0.394-0.914) mg/L in patients receiving ATV/r and 0.121 (0.052-0.209) mg/L in patients receiving ATV (P < 0.001). None of the patients receiving ATV/r and 62.9% of the subjects receiving ATV showed drug concentrations below 0.15 mg/L (odds ratio, 2.7; 95% confidence interval, 1.9-3.8; P < 0.001). In contrast, atazanavir concentrations were higher than 0.85 mg/L in 32.2% of the patients receiving ATV/r compared with 3.7% of the subjects receiving ATV (odds ratio, 8.7; 95% confidence interval, 2.0-37.2; P = 0.001). Atazanavir and total bilirubin concentrations in plasma were correlated. In conclusion, atazanavir trough concentrations may be lower than the proposed minimum effective concentration in a considerable percentage of HIV-infected patients receiving antiretroviral therapy with unboosted atazanavir. Therapeutic drug monitoring may be useful in this setting.
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PMID:Monitoring atazanavir concentrations with boosted or unboosted regimens in HIV-infected patients in routine clinical practice. 1789 58

12B75, 274150; Abacavir sulfate/lamivudine, Abatacept, Ad2/HIF-1alpha, Adalimumab, Adefovir, Adefovir dipivoxil, AGN-201904-Z, AIDSVAX, Albinterferon alfa-2b, Alemtuzumab, Aliskiren fumarate, Alvimopan hydrate, Amlodipine besylate/atorvastatin calcium, Amlodipine besylate/Olmesartan medoxomil, Ammonium tetrathiomolybdate, Amodiaquine, Apaziquone, Aprepitant, Arsenic trioxide, Artesunate/Amodiaquine, Ascorbic acid, Atazanavir sulfate, Atazanavir/ritonavir, Atomoxetine hydrochloride, Atrigel-Leuprolide, Axitinib; Bevacizumab, Binodenoson, Bortezomib, Bovine lactoferrin; Calcipotriol/betamethasone dipropionate, Carisbamate, Certolizumab pegol, Ciclesonide, Conivaptan hydrochloride, CP-690550, CP-751871, Cypher; Dapivirine, Darbepoetin alfa, Darunavir, Dasatinib, del-1 Genemedicine, Denosumab, Desloratadine, Dexlansoprazole, DiabeCell, Drospirenone/ethinylestradiol, DTaP-HepB-IPV, Duloxetine hydrochloride, Dutasteride; Eculizumab, Eldecalcitol, Eletriptan, Emtricitabine, Entecavir, Eritoran tetrasodium, Ertapenem sodium, Escitalopram oxalate, Eslicarbazepine acetate, Esomeprazole magnesium, Estradiol acetate, Eszopiclone, ETEC vaccine, Etoricoxib, Exenatide, Ezetimibe; Fluticasone furoate, Fosmidomycin, Fosmidomycin/clindamycin; Glutamine; Heat Shock Protein 10, Hepatitis B hyperimmunoglobulin, HIV vaccine, Hochuekki-to, Human Albumin, Human papillomavirus vaccine; Immune globulin subcutaneous [human], IMP-321, Interferon omega, ISIS-301012, Istaroxime; Japanese encephalitis virus vaccine; Latanoprost/timolol maleate, Lenalidomide, Linaclotide acetate, Lumiracoxib, LY-517717; Malaria vaccine, MAS-063D, Meningitis B vaccine, Mepolizumab, Methylnaltrexone bromide, Micafungin sodium, MK-0822A, Morphine glucuronide, Morphine hydrochloride, Mycophenolic acid sodium salt; Natalizumab, Nesiritide, Norelgestromin/ethinyl estradiol, NT-201; Oblimersen sodium, Olmesartan medoxomil, Olmesartan medoxomil/hydrochlorothiazide, Omalizumab, Otamixaban; Paclitaxel nanoparticles, Panitumumab, Panobinostat, Parathyroid hormone (human recombinant), Parecoxib sodium, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pegvisomant, PI-88, Pimecrolimus, Pneumococcal 7-valent conjugate vaccine, Pneumococcal 9-valent conjugate vaccine, Pneumococcal conjugate vaccine, Poloxamer-188, Prasugrel, Pregabalin, Prulifloxacin; R-109339, Ramipril/amlodipine, Ranolazine, Rasburicase, rHA influenza vaccine, Ro-50-3821, Rosuvastatin calcium, Rotavirus vaccine, Rotigotine, Ruboxistaurin mesilate hydrate; Satavaptan, SC-75416, Solifenacin succinate, Sorafenib, Sugammadex sodium, Sunitinib malate, Synthetic conjugated estrogens B; Tadalafil, Talnetant, Taxus, Tegaserod maleate, Telbivudine, Temsirolimus, Tenofovir disoproxil fumarate, Tetomilast, Tiotropium bromide, Tipifarnib, Tofimilast, Tremelimumab, Trimethoprim; Udenafil, Urocortin 2; Valdecoxib, Vernakalant hydrochloride; XP-828L.
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PMID:Gateways to clinical trials. 1798 11

Recommendations for a highly active antiretroviral therapy (HAART) in either pretreated patients or symptomatic patients with an AIDS-defining event are based on a combination of three or more agents from different antiretroviral classes including two nucleoside reverse transcriptase inhibitors with at least one protease inhibitor. The majority of currently available protease inhibitors are coadministered with low-dose ritonavir as a pharmacoenhancer that significantly increases protease inhibitor plasma concentrations. Atazanavir is a highly active azapeptide inhibitor of the HIV protease. It was the first, and to date the only, protease inhibitor designed to be applied once daily (q.d.) and is expected to overcome the problems of earlier agents of this class of drugs, such as unfavorable adverse events like hyperlipidemia, diarrhea and lipodystrophy. Atazanavir, formerly known as BMS-232632, can be dosed either at 400 mg q.d. without a pharmacoenhancer as first-line HIV therapy or combined with ritonavir as atazanavir/ritonavir 300/100 mg q.d. for therapy-experienced patients. The pharmacoenhancing effect of ritonavir on atazanavir resulted in a potent, clinically effective and well-tolerated antiretroviral drug with high plasma concentrations and a sufficient genetic barrier to viral resistance. Nevertheless, noninferiority to lopinavir/ritonavir-containing HAART could not be shown when atazanavir was given unboosted in pretreated patients in the AI424-043 study. When atazanavir was boosted with low-dose ritonavir its efficacy was comparable to that of lopinavir/ritonavir in non-naive patients (AI424-045 study). Additionally, specific side effects were identified during clinical practice, such as an increased rate of patients with jaundice, and, more recently, genetic risk factors causing hyperbilirubinemia. Atazanavir inhibits glucuronyltransferase, an enzyme responsible for the metabolism of bilirubin in liver, thus increasing unconjugated bilirubin levels in blood. However, atazanavir itself also enhances plasma concentrations of other coadministered HIV-1 protease inhibitors, so that its use as a combination partner in boosted double protease inhibitor combinations, with or without the addition of nucleoside reverse transcriptase inhibitors, is being evaluated. Unboosted atazanavir is approved for first-line HIV therapy in adults in the United States, and atazanavir/ritonavir is recommended for the second-line therapy of HIV-1 infection in adult HIV-1-infected patients in the United States and the European Union. More recently, data from the CASTLE study (AI424-138) have been reported at the 15th Conference on Retroviruses and Opportunistic Infections by Molina et al., where boosted atazanavir-containing HAART was compared to a regimen with lopinavir/ritonavir in therapy-naive patients.
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PMID:Atazanavir/ritonavir: a review of its use in HIV therapy. 1838 89

Raltegravir is an HIV integrase inhibitor that is metabolized through glucuronidation by uridine diphosphate glucuronosyltransferase 1A1, and its use is anticipated in combination with atazanavir (a uridine diphosphate glucuronosyltransferase 1A1 inhibitor). Two pharmacokinetic studies of healthy subjects assessed the effect of multiple-dose atazanavir or ritonavir-boosted atazanavir on raltegravir levels in plasma. Atazanavir and atazanavir plus ritonavir modestly increase plasma levels of raltegravir.
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PMID:Atazanavir modestly increases plasma levels of raltegravir in healthy subjects. 1851 46

Efflux pumps, P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP) have been shown to extrude HIV protease inhibitors from cells. These transporters are present on many barrier sites such as the blood-brain barrier (BBB) and on many circulating cells such as lymphocytes, and could reduce protease inhibitor concentration in sanctuary or HIV-1 target sites. This study compares the potential of the antiretroviral drug atazanavir to modulate P-gp and MRP expression and function in total lymphocytes and in human fetal brain endothelial cells (HBMECs). We address the question of atazanavir transport across the human BBB. Following incubation with atazanavir, P-gp and MRP1 expression was determined by direct immunofluorescence. Transporter function was assessed by measuring fluorescent dye efflux, either with or without specific inhibitors. Atazanavir substrate properties were determined by transport quantification through a validated in vitro human BBB model. Our results show that in contrast to HBMECs, in lymphocytes, atazanavir has no effect on MRP1 and P-gp expression. However, there were overall changes in P-gp function increasing its activity in lymphocytes and HBMECs. Using the in vitro human BBB model, we confirm the interaction of atazanavir with P-gp, MRPs, and BCRP in preventing its passage across this barrier and thus its entry into the central nervous system.
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PMID:Comparison of ABC transporter modulation by atazanavir in lymphocytes and human brain endothelial cells: ABC transporters are involved in the atazanavir-limited passage across an in vitro human model of the blood-brain barrier. 1872 74

Atazanavir use is associated with increases in serum bilirubin. Ribavirin, used to treat hepatitis-C infection, cause hemolysis and may worsen hyperbilirubinemia. We studied HIV/hepatitis-C virus-coinfected patients who initiated hepatitis-C therapy. Hyperbilirubinemia grade 3-4 increased from 9% to 45% after the start of hepatitis-C treatment in patients who used atazanavir concomitantly. Atazanavir use and hemoglobin (Hb) drops were predictors of increases in bilirubin. A substantial proportion of patients under atazanavir-therapy experienced significant hyperbilirubinemia and jaundice following initiation of hepatitis-C therapy.
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PMID:Increase in serum bilirubin in HIV/hepatitis-C virus-coinfected patients on atazanavir therapy following initiation of pegylated-interferon and ribavirin. 1900 77


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