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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Ther Drug Monit 2007 Oct
PMID:Monitoring atazanavir concentrations with boosted or unboosted regimens in HIV-infected patients in routine clinical practice. 1789 58

In the United States, more than 100,000 adults 50 years old and over are diagnosed with the Human Immunodeficiency Virus (HIV). The number of older adults living with HIV is increasing dramatically due primarily to Highly Active Antiretroviral Therapy (HAART) which is transforming this disease into a chronic condition for many who are responding well to treatment. This population is also growing due to later-life infections and reflects the overall aging of the larger population in general. Yet, despite the novelty of such developing demographic trends, the negative consequences of aging with HIV are largely unknown. Therefore, it is necessary to synthesize the gerontological and HIV/AIDS literatures to hypothesize possible areas that may be of concern to people as they age with this disease. One area of particular concern focuses on tell-tale signs of cognitive problems and the development of dementia. Separately, older adults and adults with HIV are more susceptible of experiencing cognitive declines and dementia. Thus, as people age with HIV, they may be particularly susceptible of such cognitive problems and therefore detecting such problems in the early stages may be vital in preventing further problems. Based on the literature, adults infected with HIV experience impairments in olfaction and psychomotor ability. Similar symptoms are exhibited in older adults with Parkinson's disease and other dementias. Thus, for older adults with HIV, declines in both olfaction and psychomotor skills may be early signs of a developing neurodegenerative disorder. Implications for those aging with HIV are posited.
Med Sci Monit 2007 Oct
PMID:Olfactory and psychomotor symptoms in HIV and aging: potential precursors to cognitive loss. 1790 63

Cytochrome P450 (CYP) 3A4 is the most abundant enzyme of CYPs in the liver and gut that metabolizes approximately 50% currently available drugs. A number of important drugs have been identified as substrates, inducers, and/or inhibitors of CYP3A4. The substrates of CYP3A4 considerably overlap with those of P-glycoprotein. Both CYP3A4 and P-glycoprotein are subject to inhibition and induction by a number of factors. Mechanism-based inhibition of CYP3A4 is characterized by NADPH-, time-, and concentration-dependent enzyme inactivation occurring when some xenobiotics or drugs are converted by CYPs to reactive metabolites. Such an inhibition of CYP3A4 is caused by chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. To date, the identified clinically important mechanism-based CYP3A4 inhibitors mainly include macrolide antibiotics (eg, clarithromycin and erythromycin), anti-HIV agents (eg, ritonavir and delavirdine), antidepressants (eg, fluoxetine and fluvoxamine), calcium channel blockers (eg, verapamil and diltiazem), steroids and their modulators (eg, gestodene and mifepristone), and several herbal and dietary components. The inactivation of CYP3A4 by drugs often causes unfavorable and long-lasting drug-drug interactions and probably fatal toxicity, depending on many factors associated with the enzyme, drugs, and the patients. Clinicians are encouraged to have a sound knowledge of drug-induced, mechanism-based CYP3A4 inhibition; take proper cautions, and perform close monitoring for possible drug interactions when using drugs that are mechanism-based CYP3A4 inhibitors. To minimize drug-drug interactions involving mechanism-based CYP3A4 inhibition, it is necessary to choose safe drug combination regimens, adjust drug dosages appropriately, and conduct therapeutic drug monitoring for drugs with narrow therapeutic indices.
Ther Drug Monit 2007 Dec
PMID:Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. 1804 68

This was an open-label, crossover study to investigate the pharmacokinetic interaction between darunavir (TMC114), coadministered with low-dose ritonavir (darunavir/ritonavir), and the protease inhibitor saquinavir in HIV-negative healthy volunteers. Thirty-two volunteers were randomized into two cohorts (panel 1 and panel 2). In two separate sessions, panel 1 received 400/100 mg darunavir/ritonavir twice a day and 400/1000/100 mg darunavir/saquinavir/ritonavir twice a day; panel 2 received 1000/100 mg saquinavir/ritonavir twice a day and 400/1000/100 mg darunavir/saquinavir/ritonavir twice a day. All treatments were administered orally under fed conditions for 13 days with an additional single morning dose on day 14. Treatment sessions were separated by a washout period of at least 14 days. Twenty-six volunteers completed the study (n=14, panel 1; n=12, panel 2), whereas six discontinued as a result of adverse events. Coadministration of saquinavir with darunavir/ritonavir resulted in decreases of darunavir area under the curve and maximum and minimum plasma concentrations of 26%, 17%, and 42%, respectively, compared with administration of darunavir/ritonavir alone. Relative to treatment with saquinavir/ritonavir alone, saquinavir exposure was not significantly different with the addition of darunavir. Ritonavir area under the curve12h increased by 34% when saquinavir was added to treatment with darunavir/ritonavir. The coadministration of darunavir/saquinavir/ritonavir was generally well tolerated. Similar findings are expected with the approved 600/100 mg darunavir/ritonavir twice-a-day dose. The combination of saquinavir and darunavir/ritonavir is currently not recommended.
Ther Drug Monit 2007 Dec
PMID:Pharmacokinetic interaction between darunavir and saquinavir in HIV-negative volunteers. 1804 78

The majority of those infected with HIV in sub-Saharan Africa do not have access to antiretroviral therapy, which is known to prolong the lives of HIV-positive persons in industrialized countries. Although the availability of antiretroviral therapy for those infected with HIV has increased worldwide, the infection rate out surpasses those started on such treatment. Without an AIDS vaccine or curative treatment, and given the difficulty in getting persons at risk to adopt healthy sexual behaviors, alternative approaches to decrease the spread of HIV infection are urgently needed. Three recent randomized controlled trials undertaken in Kisumu, Kenya, Raki District, Uganda and Orange Farm, South Africa have confirmed that male circumcision reduces the risk of heterosexually acquired HIV infection in men by approximately 51% to 60%. These three studies provide a solid evidence-base for future health policy. The procedure for adolescents and adults is expensive compared to abstinence, condoms or other methods; and the surgery is not without serious risks if performed by traditional healers using unsterilized blades as often happens in rural Africa. However, neonatally, the procedure is relatively inexpensive and the risks diminish considerably. Mandating neonatal male circumcision is an effective therapy that has minimal risks, is cost efficient and will save human lives. To deny individuals access to this effective therapy is to deny them the dignity and respect all persons deserve. Neonatal male circumcision is medically necessary and ethically imperative.
Med Sci Monit 2007 Dec
PMID:Mandatory neonatal male circumcision in Sub-Saharan Africa: medical and ethical analysis. 1866 4

Intrapatient variability in drug plasma concentrations is critical to the use of therapeutic drug monitoring with efavirenz, a non-nucleoside reverse-transcriptase inhibitor. Marked intrapatient variability, particularly for concentrations near the minimal therapeutic concentration, could be a predictor of virologic failure, meaning that a single concentration is of limited value. Previous reports on efavirenz intra-individual variability were obtained only in follow-up periods of 3 to 12 months and do not provide a rationale for the periodicity of sample measurements needed in long-term therapy to identify patients with a large variability and increased risk of therapeutic failure. The aim of this work was to investigate intra-individual variability in efavirenz plasma concentrations over a long-term follow-up period to support therapeutic drug monitoring. In a case series study, clinical and laboratory data were collected from all HIV-positive adults at the immunodeficiency outpatient clinic who were on regimens containing efavirenz in 2002 and who gave their informed consent (n = 31). Efavirenz plasma concentrations were measured throughout a 3 year period, without dose adjustments. For each patient, 6 to 12 samples were obtained over the follow-up period with an interval of at least 3 months between each sample. Mean plasma concentrations (mg/L) in the first, second, and third year of follow-up were 2.20 +/- 0.64, 2.17 +/- 0.68, and 2.31 +/- 0.57. Mean intra-individual variability throughout the first, second, and third year of study was 27%, 31%, and 25%, ranging from 12% to 63%. No differences in intrapatient variability in efavirenz plasma concentrations were found between females and males, HBV/HCV and HBV/HCV patients, or age above/below 40 years. Mean values (intra-individual variability) in plasma concentrations (mg/L) found in 3 of 31 patients who experienced virologic failure were 1.78 (42%), 1.52 (16%), and 1.68 (45%). The high interindividual variability and low maintained values of intrapatient variability in plasma concentrations support therapeutic drug monitoring, which could be based on measurements taken quarterly during the first year of therapeutics. In patients presenting high values of intra-individual variability (eg, >40%) associated with low plasma concentrations (eg, <2 mg/L), more frequent measurements over longer periods (more than 1 yr) of controlled concentrations might be recommended, but this requires further investigation.
Ther Drug Monit 2008 Feb
PMID:Intra-individual variability in efavirenz plasma concentrations supports therapeutic drug monitoring based on quarterly sampling in the first year of therapy. 1822 64

Liver disease may alter the pharmacokinetics of antiretrovirals and produce changes in plasma protein binding. The aim was to evaluate the pharmacokinetics of total and unbound lopinavir (LPV) in HIV-infected patients with and without hepatitis C virus (HCV) coinfection. Fifty-six HIV+ patients receiving lopinavir/ritonavir (LPV/r) (group I = 24 controls; II = 23 HIV/HCV-coinfected; III = 9 cirrhotic HIV/HCV-coinfected) were included. Total (n = 56) and unbound (n = 36) LPV pharmacokinetic parameters were determined at steady-state using validated high-performance liquid chromatography with ultraviolet detection and high-performance liquid chromatography-tandem mass spectrometry methods, respectively. Pharmacokinetic parameters (plasma concentration just before drug administration, peak concentrations in plasma, times to maximum plasma concentration, areas under the plasma concentration-time curve from 0 to 12 hours, and CL/F/kg) of both total and unbound LPV were calculated by standard noncompartmental methods and differences among groups evaluated (Kruskal-Wallis test).LPV apparent oral clearance normalized to body weight (median, interquartile range) was 55 (40-68), 59 (44-69), and 71 (53-78) mL/h/kg for groups I, II, and III, respectively (II vs. I, P = 0.52; III vs. I, P = 0.16). The areas under the plasma concentration-time curve from 0 to 12 hours were 110.4 (80.9-135.2), 103.4 (85.5-131.3), and 92.8 (87.4-116.3) microg h/mL for groups I, II, and III, respectively (II vs. I, P = 0.68; III vs. I, P = 0.71). Chronic liver impairment produced a slight, although not significant, decrease in plasma protein binding. The free-fraction of LPV increased ( approximately 21%) from 0.97% (0.80-1.06) in HIV+/HCV- patients to 1.18% (0.89-1.65) in HIV/HCV+ cirrhotic patients. The apparent oral clearance of unbound LPV (CLu/F/kg) in cirrhotic patients did not change significantly, supporting the concept that the clearance of unbound LPV in liver disease is not affected after being inhibited by low-dose ritonavir co-administration.LPV total and unbound pharmacokinetics were not affected by hepatic impairment, suggesting that no adjustment of LPV/r dose is required for HIV/HCV-coinfected patients with and without cirrhosis and moderate impairment of liver function.
Ther Drug Monit 2008 Jun
PMID:Lopinavir/ritonavir pharmacokinetics in HIV/HCV-coinfected patients with or without cirrhosis. 1852 Jun 2

Total plasma concentrations are used for therapeutic drug monitoring of antiretroviral drugs, whereas antiviral activity is expected to depend on unbound concentrations. The determination of free (unbound) concentrations by ultrafiltration may be flawed by the irreversible adsorption of many drugs onto the membrane filters and plastic components of the device. The authors describe a modified ultrafiltration method enabling the accurate measurement of unbound concentrations of 10 antiretroviral drugs by liquid chromatography-tandem mass spectroscopy, which circumvents the problem of loss by adsorption in the early ultrafiltration fractions. The method was applied to assess the variability of free fractions of antiretroviral drugs during routine therapeutic drug monitoring in 144 patients with HIV. In in vitro experiments, ultrafiltrate collected in four fractions (0-8, 8-16, 16-24, and 24-30 minutes) gave much lower and more variable free drug concentrations in the first ultrafiltrate fraction than in the last three fractions for lopinavir, nelfinavir, saquinavir, tipranavir, and efavirenz. In the last two fractions, free concentrations remained constant, indicating saturable adsorption. The adsorption was modest for indinavir, amprenavir, and ritonavir, and unnoticeable for atazanavir and nevirapine. Free fraction values obtained with this modified ultrafiltration method reveal substantial interindividual variability, suggesting that monitoring unbound antiretroviral drug concentrations may increase its clinical usefulness, especially for lopinavir, saquinavir, and efavirenz.
Ther Drug Monit 2008 Aug
PMID:Determination of unbound antiretroviral drug concentrations by a modified ultrafiltration method reveals high variability in the free fraction. 1864 38

Studying the pharmacokinetics of antiretroviral drugs in breast milk has important implications for the health of both the mother and the infant, particularly in resource-poor countries. Breast milk is a highly complex biological matrix, yet it is necessary to develop and validate methods in this matrix, which simultaneously measure multiple analytes, as women may be taking any number of drug combinations to combat human immunodeficiency virus infection. Here, we report a novel extraction method coupled to high-performance liquid chromatography and tandem mass spectrometry for the accurate, precise, and specific measurement of 7 antiretroviral drugs currently prescribed to infected mothers. Using 200 microL of human breast milk, simultaneous quantification of lamivudine (3TC), stavudine (d4T), zidovudine (ZDV), nevirapine (NVP), nelfinavir (NFV), ritonavir, and lopinavir was validated over the range of 10-10,000 ng/mL. Intraday accuracy and precision for all analytes were 99.3% and 5.0 %, respectively. Interday accuracy and precision were 99.4 % and 7.8%, respectively. Cross-assay validation with UV detection was performed using clinical breast milk samples, and the results of the 2 assays were in good agreement (P = 0.0001, r = 0.97). Breast milk to plasma concentration ratios for the different antiretroviral drugs were determined as follows: 3TC = 2.96, d4T = 1.73, ZDV = 1.17, NVP = 0.82, and NFV = 0.21.
Ther Drug Monit 2008 Oct
PMID:Studies on antiretroviral drug concentrations in breast milk: validation of a liquid chromatography-tandem mass spectrometric method for the determination of 7 anti-human immunodeficiency virus medications. 1875 93

The aim of this short communication is to assess colonization by MRSA, penicillin-resistant pneumococci (PRP), fluconazole-resistant (FLU-R) Candida albicans (CA) and non-albicans Candida (NAC), and ciprofloxacin-resistant E. coli with regard to immune recovery due to CD4 T-cell increase depending on the duration of highly active antiretroviral therapy (HAART). Prior exposure to oral cephalosporins (P<0.01) was significantly related to MRSA colonization. Penicillin-resistant pneumococci were more frequently (40% vs. 12.5%, NS) related to prior cephalosporins, but not to penicillins or macrolides use. However, this association was not statistically significant. Prior receiving of fluconazole was also not associated with increased colonization by FLU-R Candida spp. (30% vs. 16.7%, NS). Cotrimoxazole (P<0.01) and amoxicillin/amoxicillin clavulanate (P<0.01) were surprisingly protective against colonization by fluconazole-resistant Candida spp. Exposure to quinolones was not a risk factor for colonization by ciprofloxacin-resistant E. coli, but receiving of rifampin was (P<0.01). Colonization by cefotaxime-resistant Klebsiella spp. and Enterobacter spp. was not significantly associated with cephalosporins, but it was with cotrimoxazole use (P<0.05). In addition, HIV-infected children on HAART who received any antibiotic were significantly more colonized by cotrimoxazole-resistant E. coli (P<0.01) than those not receiving any antibiotic prior to colonization. Exposure to cephalosporins and macrolides was significantly related to cotrimoxazole-resistant E. coli (100% vs. 20%, 75% vs. 10%; P<0.01 for both), but exposure to cotrimoxazole itself was not.
Med Sci Monit 2008 Dec
PMID:Colonization of the respiratory tract by drug-resistant bacteria in HIV-infected children and prior exposure to antimicrobials. 1904 82


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