Search

Tetrabromobisphenol A (TBBPA) is the most widely used brominated flame retardant worldwide. A detailed examination of the degradation products emitted during thermal decomposition of TBBPA is presented in the study. Runs were performed in a laboratory furnace at different temperatures (650 and 800 °C) and in different atmospheres (nitrogen and air). More than one hundred semivolatile compounds have been identified by GC/MS, with special interest in brominated ones. Presence of HBr and brominated light hydrocarbons increased with temperature and in the presence of oxygen. Maximum formation of PAHs is observed at pyrolytic condition at the higher temperature. High levels of 2,4-, 2,6- and 2,4,6- bromophenols were found. The levels of polybrominated dibenzo-p-dioxins and furans have been detected in the ppm range. The most abundant isomers are 2,4,6,8-TeBDF in pyrolysis and 1,2,3,7,8-PeBDF in combustion. These results should be considered in the assessment of thermal treatment of materials containing brominated flame retardants., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

On the basis of laboratory experiments with model mixtures (active carbon+CuBr2 at different loads), this work studies the formation of polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) by de novo synthesis. For the different samples, the temperature of the maximum carbon oxidation rate was determined by thermogravimetric analysis, and a kinetic model was proposed for the degradation of the materials in an oxidizing atmosphere (synthetic air). The effect of the addition of different amounts of CuBr2 was studied, finding that its presence accelerates the degradation of the carbonaceous structure in the presence of oxygen. The thermal degradation of the samples in air is satisfactorily described by a first-order single-reaction model. In addition, combustion runs of one of the mixtures (consisting of activated carbon+50 wt % CuBr2, pyrolyzed at 700 °C) were performed in a quartz horizontal laboratory furnace. The analysis of the emissions and the solid residue proved the formation of brominated dioxins and furans at 300, 400, and 500 °C, with a maximum yield at 300 °C (91.7 ng/g of total PBDD/Fs) and a higher bromination degree with increasing temperature.

This study examined differential associations between phenotypic domains of the triarchic conceptualization of psychopathy (boldness, meanness, and disinhibition; Patrick, Fowles, & Krueger, 2009), as assessed by the Triarchic Psychopathy Measure (Patrick, 2010b), and the five-factor model (FFM) of normal personality, as indexed by the Revised NEO Personality Inventory (Costa & McCrae, 1992; Spanish version, Costa & McCrae, 1999), in 349 undergraduates (96 men). Distinctive patterns of correlations for psychopathy components did not differ significantly across gender, although relations between Meanness and Agreeableness were stronger for men than for women. Our findings are largely consistent with the conceptualization of psychopathy in terms of FFM constructs and provide discriminant evidence in support of all 3 triarchic domains. Thus, meanness is marked by low Agreeableness and some degree of low Conscientiousness, whereas disinhibition is characterized both by low Conscientiousness and low Agreeableness along with high Neuroticism and Extraversion. Notably, the constellation of low Neuroticism, high Extraversion, and high Openness, with facets of low Agreeableness, supports the idea that boldness encompasses some adaptive features of psychological adjustment while depicting the interpersonal features of psychopathy., (2014 APA)

Background: Etravirine (ETR) was approved for patients with virological failure and antiretroviral resistance mutations. It has also shown antiviral efficacy in antiretroviral-naïve patients. However, data on the switching from protease inhibitors (PI) to ETR are lacking., Methods: HIV-1-infected patients with suppressed viral load (VL) during a PI-containing regimen (>12 months) and no previous virological failure were randomized to switch from the PI to ETR (400 mg/day, dissolved in water) (ETR group, n = 22) or to continue with the same regimen (control group, n = 21). Percentage of patients with VL ≤ 50 copies/mL were assessed at week 48, as well as changes in CD4 T-cell counts and metabolic profile., Results: We included 43 patients [72.9% male, 46.3 (42.2; 50.6) years]. Two patients receiving ETR (grade-1 diarrhea and voluntary discontinuation) and another in the control group (simplification) discontinued therapy early. No patients presented virological failure (two consecutive VL>50 copies/mL); treatment was successful in 95.2% of the control group and 90.9% of the ETR group (intention-to-treat analysis, missing = failure) (p = 0.58). CD4+ T-cell counts did not significantly vary [+49 cells/µL in the ETR group (p = 0.25) and -4 cells/µL in the control group (p = 0.71)]. The ETR group showed significant reductions in cholesterol (p<0.001), triglycerides (p = <0.001), and glycemia (p = 0.03) and higher satisfaction (0-10 scale) (p = 0.04). Trough plasma concentrations of ETR were similar to observed in studies using ETR twice daily., Conclusion: Switch from a PI-based regimen to a once-daily combination based on ETR maintained undetectable VL during 48 weeks in virologically suppressed HIV-infected patients while lipid profile and patient satisfaction improved significantly., Trial Registration: ClinicalTrials.gov NCT01034917.

Objectives: To describe raltegravir pharmacokinetics at steady-state in HIV/hepatitis C virus (HCV)-coinfected patients under antiretroviral (ARV) treatment with (n = 5) and without (n = 5) advanced liver cirrhosis (Child-Pugh C)., Methods: This was a non-randomized, Phase I, parallel-assignment, open-label pharmacokinetic study in HIV/HCV-coinfected patients with Child-Pugh grade C hepatic cirrhosis. We recruited clinically stable HIV/HCV-coinfected adult patients with controlled HIV viraemia (<50 copies/mL) for at least 6 months. Raltegravir (400 mg twice daily) was added under fasting conditions for 5 days to the successful ritonavir-boosted protease inhibitor-based ARV regimen. The trial was registered in the ClinicalTrials.gov database (NCT01289951) (LIVERAL)., Results: Raltegravir AUC0-12 and C12 were increased 1.72-fold (90% CI, 1.02 to 2.92) and 6.58-fold (90% CI, 2.92 to14.85), respectively, in patients with advanced liver cirrhosis. No safety issues were identified and raltegravir was well tolerated by all patients., Conclusions: Raltegravir plasma levels are increased in HIV/HCV-coinfected patients with advanced liver cirrhosis (Child-Pugh C). Despite the higher exposure, raltegravir was safe and well tolerated.

Background: Chronic HIV infection leads to premature atherosclerosis. Arterial stiffness is considered a subclinical marker of cardiovascular disease., Methods: Pulse wave velocity (PWV) was determined in 254 individuals (174 HIV-infected patients and 80 healthy controls, 2:1 matched by age and gender) to compare the prevalence of arterial stiffness and to identify associated factors. PWV was determined using noninvasive automated device (Complior). Factors associated with impaired PWV were assessed among cardiovascular risk factors, HIV infection parameters, and laboratory data. Logistic regression analyses were performed to determine differences between groups and factors associated to arterial stiffness., Results: Overall, 81.4% of participants were male, median age was 46.54 [interquartile range (IQR): 41-52] years. Higher percentages of HIV-infected subjects showed dyslipemia (P = 0.012) and smoking habit (P = 0.002). The median time from HIV diagnosis was 13 (IQR: 6-18) years and the median time on antiretroviral therapy was 11 (IQR: 5-15) years. Nearly, all patients were virologically suppressed (89.7%) at the time of PWV. Arterial stiffness in the global population was 20.5%, 18.9% in HIV-infected group, and 23.8% in controls (P = 0.405). High diastolic blood pressure and high levels of triglycerides at time of PWV were associated with increased PWV (P = 0.009 and P = 0.023, respectively)., Conclusions: Virologically suppressed HIV-infected patients showed similar arterial elasticity to non-HIV-infected patients. HIV-related conditions were not associated with arterial stiffness, probably because of the good immunologic and virological status of this group. However, high diastolic pressure at the time of PWV and high levels of triglycerides were associated risk factors.

Background: Immune hyperactivation in immunodiscordant patients can induce residual HIV replication and limit CD4 T cell recovery. We assessed the impact of raltegravir intensification on CD4 T cell recovery and viral persistence., Methods: We performed a randomized, controlled, pilot trial. Patients with CD4 T cell counts <350 cells/mm(3) despite suppressive antiretroviral therapy were randomized (2 : 1) to intensify with raltegravir (intensified arm, n = 30) or to continue with the same regimen (control arm, n = 14) for 48 weeks. Then, the control individuals intensified their treatment for 24 weeks (delayed-intensification arm). We analysed changes in CD4 T cell counts, total and episomal HIV DNA in peripheral blood mononuclear cells and predictive factors for response., Results: Raltegravir intensification induced a rapid increase in CD4 T cell counts (week 12) (P = 0.007), although this was not sustained over time. Control patients maintained constant but slow increases in CD4 T cell counts (present in the pre-study period), reaching CD4 T cell counts similar to those of patients in the intensification arm at week 48. This effect was confirmed by the analysis of the delayed-intensification arm. Proviral DNA levels remained stable in both arms over time; episomal DNA forms and ultrasensitive plasma viral load were barely detected during the study. Increases in CD4 T cell counts were associated with low baseline CD95 expression in CD4 and CD8 T cells (P = 0.020)., Conclusions: Raltegravir intensification modestly impacts viral dynamics and induces a rapid but limited gain in CD4 T cell counts in immunodiscordant patients. Residual viral replication does not seem to be the main cause of unsatisfactory CD4 T cell recovery in these patients.

Background: Data on suppression of HIV replication in the CNS and on the subsequent risk of neurocognitive impairment using monotherapy with boosted protease inhibitors are limited., Methods: Ours was an exploratory cross-sectional study in patients on lopinavir/ritonavir-based monotherapy (LPV/r-MT) or standard triple therapy (LPV/r-ART) for at least 96 weeks who maintained a plasma viral load <50 copies/mL. HIV-1 RNA in CSF was determined by HIV-1 SuperLow assay (lower limit of detection, 1 copy/mL). Neurocognitive functioning was assessed using a recommended battery of neuropsychological tests covering 7 areas. Neurocognitive impairment (NCI) was determined and also a global deficit score (GDS) for study comparisons., Results: Seventeen patients on LPV/r-MT and 17 on LPV/r-ART were included. Fourteen (82.4%) patients on LPV/r-MT and 16 (94.1%) on LPV/r-ART had HIV-1 RNA <1 copy/mL in CSF (p = 0.601). NCI was observed in 7 patients on LPV/r-MT and in 10 on LPV/r-ART (41% vs 59%; p = 0.494). Mean (SD) GDS was 0.22 (0.20) in patients on LPV/r-MT and 0.47 (0.34) in those on LPV/r-ART (p = 0.012)., Conclusions: Suppression of HIV in CSF is similar in individuals with durable plasma HIV-1 RNA suppression who are receiving LPV/r-MT or LPV/r-ART for at least 96 weeks. Findings for HIV-1 replication in CSF and neurocognitive status indicate that this strategy seems to be safe for CNS functioning.

Background: Darunavir is a potent protease inhibitor of HIV. To enhance its pharmacokinetic profile, darunavir must be co-administered with ritonavir. There is wide inter-patient variability in darunavir pharmacokinetics among HIV-infected individuals, however. Darunavir is a known substrate for influx transporters, such as the 1A2 and the 1B1 members of the solute carrier organic anion transporter family (SLCO1A2, SLCO1B1), as well as for efflux transporters such as the multi-drug resistance protein 1 (MRP1)., Objective: The aim of this study was to develop a semi-mechanistic population pharmacokinetic model for darunavir and ritonavir administered in HIV-infected adults. The desired model would incorporate patient characteristics and pharmacogenetic data contributing to variability in drug concentrations and also take into account the interaction between the two compounds., Methods: A population pharmacokinetic analysis was performed with 705 plasma samples from 75 Caucasian individuals receiving darunavir/ritonavir (600/100 mg twice daily) for at least 4 weeks. At least one full pharmacokinetic profile was obtained for each participant, and darunavir and ritonavir concentrations in plasma were determined by high performance liquid chromatography. Genotyping for 148 polymorphisms in genes coding for transporters or metabolizing enzymes was conducted by two methods: MALDI-TOF mass spectrometry and real-time polymerase chain reaction-based allelic discrimination. A population pharmacokinetic model was developed for darunavir and for ritonavir. The effect of single nucleotide polymorphisms on the post hoc individual pharmacokinetic parameters was first explored using graphic methods and regression analysis. Those covariates related to changes in darunavir or ritonavir pharmacokinetic parameters were then further evaluated using non-linear mixed effects modeling (NONMEM version VII)., Results: Darunavir and ritonavir pharmacokinetics were best described by a two- and one-compartment model, respectively, both with first-order absorption and elimination. The darunavir peripheral volume of distribution decreased as α1-acid glycoprotein concentrations increased. Darunavir clearance was 12 % lower in patients with SLCO3A1 rs8027174 GT/TT genotypes, while homozygosity for the rs4294800 A allele was associated with 2.5-fold higher central volume of distribution. Body weight influenced ritonavir clearance. Ritonavir inhibited darunavir clearance following a maximum-effect model., Conclusion: A population pharmacokinetic model to simultaneously describe the pharmacokinetics of darunavir and ritonavir was developed in HIV-infected patients. The model provides better understanding of the interaction between darunavir and ritonavir and suggests an association between SLCO3A1 polymorphisms and darunavir pharmacokinetics. Bayesian estimates of individual darunavir parameters and ritonavir may be useful to predict darunavir exposure.

This study investigated the degradation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in contaminated soil using low temperature treatment (200-280°C) both alone and in combination with nanosized zerovalent iron (nZVI) particles or CaO. Control soil samples and soil fortified with nZVI particles or CaO were treated at 200 and 250°C in sealed glass ampoules. Treatment of the ampouled samples at 250°C was more effective than treatment at 200°C and the reduction in PCDD/F concentration was greatest when soil was treated at 250°C with nZVI addition (indeed, treatment at 200°C in the absence of nZVI resulted in increases in total PCDD and PCDD/F concentrations). In larger-scale experiments based on the obtained results, using a rotary furnace, the greatest reduction in total PCDD/F concentration was achieved by treating soil at 280°C, and adding nZVI to the soil resulted in almost no detectable PCDD/F in the gas phase., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Combustion runs at 700 °C in a horizontal laboratory furnace were carried out on two different electric wires (PVC and halogen-free wire). Tests were performed in the presence and in the absence of the metal conductor of the wires. The analyses of the polycyclic aromatic hydrocarbons (PAHs), chlorobenzenes (CBzs), chlorophenols (CPhs), mono- to octa-chlorodibenzo-p-dioxin and dibenzofurans (PCDD/Fs), and dioxin-like PCBs are shown. Regarding semivolatile compounds, PAHs production decreases in the presence of metal, while a higher amount of chlorinated compounds are emitted. Respect to the PCDD/Fs, the PVC wire in the presence of metal presents the highest emission, with a much more emission of furans than dioxins. The maximum emission is with 2 or 3 chlorine atom PCDD/Fs. PCBs emission correlates with PCDD/F production and represents 3-4% of total toxicity, determined by using WHO2005 factors., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The role of the two dimensions of psychopathy-dispositional fearlessness (theorized to reflect variations in reactivity of the brain's defensive system) and externalizing proneness (presumed to reflect variations in function of anterior regulatory systems)-in fear learning was examined in a sample of undergraduates assessed using the Psychopathic Personality Inventory-Revised (PPI-R) who participated in a differential aversive conditioning task. Only scores on self-reported "fearless dominance," irrespective of scores on "impulsive antisociality," were related to diminished acquisition of physiological fear. Consistent with dual-process accounts of psychopathy proposing divergent etiological pathways for the interpersonal/affective and the social deviance features of the disorder, our results lend support to the existence of a deficit in reactivity of the brain's defensive system underlying the fearlessness dimension of psychopathy., (Copyright © 2012 Society for Psychophysiological Research.)

The aim of this open-label, fixed-sequence study was to investigate the potential of the botanical supplement Echinacea purpurea to interact with etravirine, a nonnucleoside reverse transcriptase inhibitor of HIV. Fifteen HIV-infected patients receiving antiretroviral therapy with etravirine (400 mg once daily) for at least 4 weeks were included. E. purpurea root/extract-containing capsules were added to the antiretroviral treatment (500 mg every 8 h) for 14 days. Etravirine concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, 12, and 24 h after a morning dose of etravirine on day 0 and etravirine plus E. purpurea on day 14. Individual etravirine pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 by means of the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 46 years (interquartile range, 41 to 50), and the median body weight was 76 kg (interquartile range, 68 to 92). Echinacea was well tolerated, and all participants completed the study. The GMR for etravirine coadministered with E. purpurea relative to etravirine alone was 1.07 (90% CI, 0.81 to 1.42) for the maximum concentration, 1.04 (90% CI, 0.79 to 1.38) for the area under the concentration-time curve from 0 to 24 h, and 1.04 (90% CI, 0.74 to 1.44) for the concentration at the end of the dosing interval. In conclusion, the coadministration of E. purpurea with etravirine was safe and well tolerated in HIV-infected patients; our data suggest that no dose adjustment for etravirine is necessary.

The aim of this open-label, fixed-sequence study was to investigate the potential of the botanical supplement milk thistle (silymarin) to interact with the boosted protease inhibitor combination darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy with darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included. Silymarin (150 mg every 8 h) was added to the antiretroviral treatment from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on day 0 and darunavir-ritonavir plus silymarin on day 14. Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 by means of the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 48 years (interquartile range, 44 to 50 years), and the median body weight was 70 kg (interquartile range, 65 to 84 kg). Silymarin was well tolerated, and all participants completed the study. The GMRs for darunavir coadministered with silymarin relative to darunavir alone were 0.86 (90% CI, 0.70 to 1.05) for the area under the concentration-time curve from 0 to 12 h, 0.83 (90% CI, 0.80 to 0.98) for the maximum concentration, and 0.94 (90% CI, 0.73 to 1.19) for the concentration at the end of the dosing interval. In summary, coadministration of silymarin with darunavir-ritonavir seems to be safe in HIV-infected patients; no dose adjustment for darunavir-ritonavir seems to be necessary.

Background and Objective: To evaluate the prevalence and patterns of use of herbal remedies among HIV-infected patients, and to identify potential health risks and correlates associated with the use of these products., Patients and Methods: Cross-sectional survey including 1000 HIV-infected outpatients in Barcelona. Participants completed a questionnaire on the use of herbal remedies and other types of complementary treatments within the previous year as well as on sociodemographic and clinical characteristics. Herbal users' questionnaires were scrutinized for potential adverse effects and drug interactions with antiretroviral treatment. Correlates of use of herbal remedies were evaluated through logistic regression analyses., Results: One third of patients (n=355) had used herbal remedies, but doctors were informed about such a use by only 69 (19.4%) herbal users. Potential health problems were identified in 193 (54.4%) cases. Herbal remedy use was related to a history of ever discussing complementary and alternative medicine use with the physician (OR: 3.12; 95% CI: 2.30-4.23), having a secondary-school or higher education (OR: 2.63; 95% CI: 1.78-3.88), and perception of complementary therapies as effective (OR: 2.28; 95% CI: 1.18-4.41). Other factors were non-Caucasian ethnicity (OR: 1.65; 95% CI: 1.07-2.56) and the presence of non-HIV-related symptoms (OR: 1.68; 95% CI: 1.24-2.28)., Conclusions: Herbal remedy use is common among HIV-infected patients. HIV caregivers and patients should be sensitized to potential risks and the use of these remedies should be routinely monitored in clinical practice., (Copyright © 2011 Elsevier España, S.L. All rights reserved.)

Background: Simplification of antiretroviral treatment (ART) with darunavir/ritonavir (DRV/r) monotherapy has achieved sustained suppression of plasma viral load (pVL) in clinical trials; however, its effectiveness and safety profile has not been evaluated in routine clinical practice., Methodology/principal Findings: We performed a retrospective cohort analysis of HIV-1-infected patients who initiated DRV/r monotherapy once daily with a pVL <50 copies/mL under ART and at least 1 subsequent follow-up visit in our clinic. The primary study endpoints were the percentage of patients with virological failure (VF, defined as 2 consecutive pVL>50 copies/mL) at week 48, and time to VF. Other causes of treatment discontinuation and changes in lipid profile were evaluated up to week 48. Ninety-two patients were followed for a median (IQR) of 73 (57-92) weeks. The median baseline and nadir CD4+ T-cell counts were 604 (433-837) and 238 (150-376) cells/mm3, respectively. Patients had previously received a median of 5 (3-9) ART lines and maintained a pVL<50 copies/mL for a median of 76 (32-176) weeks before initiating DRV/r monotherapy. Nine (9.8%) patients developed VF at week 48; time to VF was 47.1 (IQR: 36.1-47.8) weeks among patients with VF. Other reasons for changing ART were gastrointestinal disturbances (n = 3), rash (n = 1), and impaired CD4 recovery (n = 2). Median low-density lipoprotein cholesterol levels increased from 116.1 mg/dL at baseline to 137.3 mg/dL at 48 weeks (p = 0.001)., Conclusions/significance: Treatment simplification with DRV/r monotherapy seems safe and effective in routine clinical practice. Further research is needed to elucidate the effect of DRV/r monotherapy on cholesterol levels.

Pyrolysis and combustion runs at 850°C in a horizontal laboratory furnace were carried out on different parts of a mobile phone (printed circuit board, mobile case and a mixture of both materials). The analyses of the carbon oxides, light hydrocarbons, polycyclic aromatic hydrocarbons (PAHs), polychlorodibenzo-p-dioxin, polychlorodibenzofurans (PCDD/Fs), and dioxin-like PCBs are shown. Regarding semivolatile compounds, phenol, styrene, and its derivatives had the highest yields. In nearly all the runs the same PAHs were identified, naphthalene being the most common component obtained. Combustion of the printed circuit board produced the highest emission factor of PCDD/Fs, possibly due to the high copper content., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Particle-bound PAHs were measured at three sites in southeastern Spain (an urban background location, a suburban-industrial site in the vicinity of two cement plants and a rural area) in order to investigate the influence of the type of location on PAH concentrations. A clear influence of cement production on particulate PAH levels could not be established since for the urban background and suburban-industrial sites the average concentrations of total PAHs in the PM2.5 fraction were very similar (1.085 and 1.151 ng m(-3), respectively), with benzo[b+k]fluoranthene and chrysene as the predominant compounds. Diagnostic ratios, used to identify PAH emission sources, pointed to traffic as the main source of particulate PAH at both locations. As expected, PAH levels at the rural site were significantly lower (0.408 ng m(-3) in the PM10 fraction) due to increasing distance from the emission sources. PAH seasonal variations at the urban background and suburban-industrial sites were the same as reported in many previous studies. Average winter to summer ratios for total PAHs were 4.4 and 4.9 for the urban background and industrial sites, in that order. This seasonal cycle could be partially explained by the higher temperature and solar radiation during summer enhancing PAH evaporation from the particulate phase and PAH photochemical degradation, respectively. The study of PAH distribution between the fine and coarse fraction at the urban site revealed that on average around 80% of total PAHs were associated with fine particles.

The aim of this open-label, fixed-sequence study was to investigate the potential of Echinacea purpurea, a commonly used botanical supplement, to interact with the boosted protease inhibitor darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy including darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included. E. purpurea root extract capsules were added to the antiretroviral treatment (500 mg every 6 h) from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on days 0 (darunavir-ritonavir) and 14 (darunavir-ritonavir plus echinacea). Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 with the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 49 (range, 43 to 67) years, and the body mass index was 24.2 (range, 18.7 to 27.5) kg/m(2). Echinacea was well tolerated, and all participants completed the study. The GMR for darunavir coadministered with echinacea relative to that for darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time curve from 0 to 12 h, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration. In summary, coadministration of E. purpurea with darunavir-ritonavir was safe and well tolerated. Individual patients did show a decrease in darunavir concentrations, although this did not affect the overall darunavir or ritonavir pharmacokinetics. Although no dose adjustment is required, monitoring darunavir concentrations on an individual basis may give reassurance in this setting.

Maraviroc belongs to the family of chemokine (C-C motif) receptor 5 (CCR5) antagonists that prevent the entry of human immunodeficiency virus (HIV) into host CD4+ T cells by blocking the CCR5 co-receptor R5. Maraviroc is currently the only CC5R co-receptor inhibitor that has been approved for clinical use in HIV-1-infected patients carrying the CCR5 tropism who are antiretroviral-naïve or have experienced therapeutic failure following traditional antiretroviral therapies. This article is a review of the main characteristics of maraviroc and the latest data regarding its clinical application. Maraviroc is effective and well tolerated in pre-treated and antiretroviral-naïve patients with HIV-1 infections carrying the CCR5 tropism. Data from the phase III programme of maraviroc, which includes the MOTIVATE 1 and 2 studies and the MERIT study, indicate that maraviroc significantly (p < 0.001) increases CD4+ cell counts compared with placebo in pre-treated patients and to a similar extent as efavirenz in antiretroviral-naïve patients. Even in cases where viral load is not completely suppressed, maraviroc improves immunological response compared with placebo. In addition, promising research suggests that maraviroc has favourable pharmacokinetic and safety profiles in patients with high cardiovascular risk or those co-infected with tuberculosis or hepatitis and could be considered an option for treatment of HIV-infected patients with these co-morbidities. Resistance to maraviroc is low and mainly related to the presence of chemokine (C-X-C motif) receptor 4 (CXCR4) tropism HIV-1-infections or to mutations in the V3 region of glycoprotein (gp) 120; however, the exact mechanisms by which resistance is acquired and their genotypic and phenotypic pattern have not yet been established. It is recommended that a tropism test should be performed when considering maraviroc as an alternate drug in HIV-1-infected patients. Current tropism assays have increased sensitivity to reliably detect CXCR4 HIV with rapid turn-around and at a low cost. Improved detection together with positive data on the drug's efficacy and safety profiles should help physicians to identify more accurately the appropriate candidates for commencement of treatment with maraviroc. In summary, maraviroc improves immunological response and has shown favourable pharmacokinetic and safety profiles in patients with high cardiovascular risk or in those co-infected with tuberculosis or hepatitis. Long-term studies are needed to confirm whether therapeutic expectations resulting from clinical trials with maraviroc translate into a real benefit for HIV-1-infected patients for whom traditional antiretroviral therapies have failed or are not suitable.

The aim of this study was to evaluate the plasma and intracellular pharmacokinetics of raltegravir in HIV-infected patients receiving once-daily raltegravir. Five HIV-infected patients on stable therapy with lopinavir-ritonavir monotherapy whose HIV-1 RNA load was <50 copies/ml were included in this open-label, pilot study. Raltegravir was added to the antiretroviral regimen at a dose of 800 mg once daily from days 0 to 10. On day 10, a full pharmacokinetic profile was obtained for each participant. Raltegravir concentrations in plasma and peripheral blood mononuclear cells (PBMCs) were determined by high-performance liquid chromatography with a fluorescence detector and by liquid chromatography-tandem mass spectrometry (LC-MS/MS), respectively. The values of the raltegravir pharmacokinetic parameters in plasma and PBMCs were calculated by noncompartmental analysis. Raltegravir was well tolerated, and all participants completed the study. No differences in the times to the maximum concentration of raltegravir in plasma or the raltegravir half-lives were observed between plasma and PBMCs. The geometric mean raltegravir maximum concentration, the concentration at the end of the dosing interval, and the area under the concentration-time curve during the dose interval in plasma versus PBMCs were 2,640 ng/ml (range, 887 to 10,605 ng/ml) versus 199 ng/ml (range, 82 to 857 ng/ml) (geometric mean ratio [GMR], 13.30; 95% confidence interval [CI], 3.11 to 56.89; P = 0.003); 89 ng/ml (range, 51 to 200 ng/ml) versus 7 ng/ml (range, 2 to 15 ng/ml) (GMR, 13.21; 95% CI, 3.94 to 44.26; P = 0.001); and 12,200 ng·h/ml (range, 5,152 to 30,130 ng·h/ml) versus 909 ng·h/ml (range, 499 to 2,189 ng·h/ml) (GMR, 13.43; 95% CI, 5.13 to 35.16; P < 0.001), respectively. Raltegravir does not accumulate in PBMCs, with intracellular concentrations being about 1/10 of the concentrations in plasma. Despite once-daily dosing, mean raltegravir concentrations at the end of the dosing interval in plasma and PBMCs exceeded the reported protein-binding-adjusted 95% inhibitory concentration (IC(95)) and IC(50) for wild-type viral strains, respectively.

Background: It is uncertain whether a 4-week induction period of pegylated interferon and ribavirin increases early virological response (EVR) in HIV-HCV-coinfected patients., Methods: HIV and HCV genotype 1- and 4-coinfected subjects were randomized to receive pegylated interferon-α2a 270 μg/week plus ribavirin 1,600 mg daily and epoetin-β for 4 weeks, followed by pegylated interferon-α2a at standard dosages plus weight-based ribavirin (WBR) dosage for 8 weeks (induction arm [IA]), or pegylated interferon-α2a plus WBR for 12 weeks (standard therapy arm [SA]). HCV RNA was determined at weeks 0, 1, 2, 3, 4, 8 and 12. Ribavirin plasma trough concentrations were determined at weeks 4 (RBV-C(4)) and 12 (RBV-C(12))., Results: A total of 67 patients were included; 33 in the SA and 34 in the IA. Overall, 25% received nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens. More patients achieved an HCV RNA decrease ≥1 log(10) at week 4 in the IA than in the SA (62% versus 38%; P=0.017), but EVR rates were similar in the two groups (74% versus 59% in the IA and SA, respectively; P=0.15). Independent predictors of faster HCV RNA decrease at 12 weeks were higher RBV-C(4) and younger age. RBV-C(4) were higher in patients allocated in the IA and in those receiving NRTIs (P=0.039)., Conclusions: A 4-week induction with pegylated interferon-α2a plus ribavirin was associated with a greater decrease in HCV RNA at week 4; however, this did not translate into higher EVR rates. Higher RBV doses and avoidance of NRTI-sparing antiretroviral regimens might improve HCV treatment efficacy., (© 2011 International Medical Press)

The launch of generic forms of some of the drugs included in fixed-dose combinations of antiretrovirals (FDCA) raises the potential risk of breaking these combinations in order to allow the administration of the new cheaper generic drug. This could result in a step back in some major advances achieved in simplicity and treatment adherence, resulting in an increased risk of selective treatment withdrawal of some of the drugs administered separately. Due to the mechanism of action of the currently available antiretroviral treatment administration must be life-long in infected individuals, both children and adults. FDCA are a significant advance in antiretroviral treatment simplification, contributing to increase compliance of complex chronic therapies, thus increasing the patient's quality of life. They reduce the risk of treatment errors and can also reduce the possibility of unprescribed monotherapy with selective non-compliance. Hence, they contribute to reduce the risk of selection of HIV-1 clones with antiretroviral resistance, a situation that not only compromises future treatment options of the infected individual, but can also be transmitted and are a situation of Public Health concern. Excluding those cases that require a particular dose adjustment, FDCA are a preferred treatment option and their use must be strongly recommended in all scenarios where the components included in the combination are preferred drugs., (Copyright © 2010 Elsevier España, S.L. All rights reserved.)

Ritonavir-related adverse events have been reported in patients taking tipranavir/ritonavir at the licensed dosage of 500/200 mg twice daily (bid). The aim of this open-label, prospective, single-arm pilot study was to evaluate the efficacy and safety of a ritonavir dose reduction to 100 mg bid guided by the tipranavir virtual inhibitory quotient (vIQ) in HIV-infected patients receiving tipranavir/ritonavir 500/200 mg bid whose viral load was <50 copies/ml and whose tipranavir vIQ was >60. Viral load, blood chemistry, and tipranavir and ritonavir trough concentrations (C(trough)) in plasma were determined at baseline and up to 48 weeks. If the tipranavir vIQ fell to <40, the ritonavir dose was increased to 200 mg bid. The primary endpoint was the percentage of treatment failure after 48 weeks. Eleven patients were enrolled. At baseline, the median (IQR) CD4+ T-cell count and vIQ were 380 (231-520) cells/mm(3) and 233.4 (73.8-584.8), respectively. Ten patients (90.9%) maintained a viral load <50 copies/ml at week 48. Geometric mean (95% confidence interval) tipranavir C(trough) decreased from 24.7 (12.9-47.5) mg/l at baseline to 13.6 (7.1-26.2) mg/l at week 48 (p = 0.194), but the ritonavir dose had to be raised in only one patient. Median triglycerides and ALT concentrations decreased from 177.2 (132.9-292.4) mg/dl and 59 (23-128) IU/l at baseline to 158.0 (131.0-186.0) mg/dl and 28 (20-71) IU/l at week 48 (p = 0.047, p = 0.041), respectively. As a conclusion, ritonavir-dose reduction to 100 mg bid as a treatment-simplification strategy guided by the tipranavir vIQ in patients receiving salvage therapy with tipranavir/ritonavir 500/200 mg bid seems to be safe enough to be tested in adequately powered clinical trials.

Little is known about raltegravir removal by hemodialysis in patients with end-stage renal disease (ESRD). We therefore measured raltegravir concentrations in plasma in pre- and postdialyzer blood samples from 2 ESRD HIV-infected patients. The hemodialysis extraction ratio and raltegravir hemodialysis clearance were 5.5% and 9.1 ml/min in patient 1 and 9.5% and 19.1 ml/min in patient 2, respectively. Our results suggest minimal raltegravir removal by hemodialysis with no specific raltegravir dosage adjustments required in HIV-infected patients undergoing hemodialysis.

Background: Although antiretroviral therapy improves immune response, some human immunodeficiency virus-infected patients present unsatisfactory CD4 T cell recovery despite achieving viral suppression, resulting in increased morbidity and mortality., Methods: Cross-sectional, case-control study to characterize the mechanism and to identify predictive factors of poor immune response. We included 230 patients who were receiving highly active antiretroviral therapy and who had a viral load <50 copies/mL for >2 years; 95 were "discordant" (case patients; CD4 T cell count always <350 cells/microL), and 135 were "concordant" (control subjects). Activation markers, CD4 T cell death (necrosis, intrinsic apoptosis, and extrinsic apoptosis), and caspase-3 were measured. Clinical parameters, particularly antiretroviral combinations, were correlated with immune recovery., Results: Discordant patients showed higher levels of activation markers, mainly in CD4 T cells (p < .001), and higher rates of spontaneous cell death (P < .001). Rates of activation and rates of CD4 T cell death (mainly by intrinsic apoptosis) were the best predictive factors for immune recovery, along with nadir CD4 T cell count. Patients who were receiving a protease inhibitor-based regimen were more likely to be discordant and showed higher rates of activation (P= .011), higher rates of CD4 T cell death (P = .033), and a lower nadir CD4 T cell count (P < .001). Multivariate analysis, however, ruled out any effect of protease inhibitors on immune recovery. No differences were observed between the use of tenofovir-emtricitabine (Truvada) and the use of abacavir-lamivudine (Kivexa)., Conclusions: CD4 T cell apoptosis by the intrinsic pathway represents the determinant mechanism of the unsatisfactory immune recovery and should be targeted to manage therapy for discordant patients. The predictive value of low nadir CD4 T cell count for a poor immune recovery led us to consider starting antiretroviral therapy earlier. No differences were observed among antiretrovirals in terms of immune recovery.

Because interruptions of antiretroviral treatment may entail clinical risks for human immunodeficiency virus (HIV)-infected individuals, we investigated their impact on neurocognitive functioning. Cross-sectional study was carried out, comparing HIV-infected persons who had interrupted antiretroviral therapy in the past (interruption group, IG) with persons who had never discontinued therapy (noninterruption group, NIG). Interruption was defined as the discontinuation of highly active antiretroviral therapy (HAART) for more than 15 days after previous treatment of at least 15 days. All the participants were on therapy. Demographic, clinical, and neurocognitive variables were assessed. The primary end point was the percentage of people with neurocognitive impairment. The score in different neurocognitive domains was a secondary end point. A total of 83 subjects participated in the study (IG: n = 27; NIG: n = 56). Demographic and clinical characteristics were balanced between the groups, except for years since HIV diagnosis (IG, 13.8; NIG, 10.2 [P = .003]). The percentage of people with neurocognitive impairment was significantly higher in the IG group (IG, 59.25%; NIG, 33.92% [P = 0.02]). As for scores in neurocognitive domains, individuals in the IG showed worse neurocognitive functioning, and significant differences in attention/working memory and information processing speed were found. The adjusted analysis supported the unadjusted analysis. In this study, a higher prevalence of neurocognitive impairment was detected in HIV-infected persons who had interrupted antiretroviral therapy in the past. Additionally, neurocognitive functioning was observed to be more impaired in the same individuals. Further studies should examine the potential negative effects of antiretroviral therapy interruptions on neurocognitive functioning.

Material and Methods: To evaluate the influence of nevirapine on atazanavir trough concentrations (Ctrough) in a group of HIV-infected patients, we performed an open-label pilot study enrolling patients receiving 300/100 mg atazanavir/ritonavir once daily for 2 weeks or longer. Nevirapine was added at a dose of 200 mg once daily from Days 0 to 14 and 200 mg twice daily from Days 14 to 28. Atazanavir and nevirapine plasma Ctroughs were determined at Days 0 and 28. Atazanavir Ctroughs were compared between Days 0 and 28. Atazanavir and nevirapine Ctroughs at Day 28 were compared with historical controls receiving either 400 mg atazanavir once daily or 200 mg nevirapine twice daily., Results: Fourteen patients were enrolled and 11 completed the study. The geometric mean (range) atazanavir Ctrough decreased from 0.631 mg/L (range, 0.235-1.87 mg/L) at Day 0 to 0.316 mg/L (range, 0.142-1.109 mg/L) at Day 28 to give a geometric mean ratio of 0.59 (95% confidence interval, 0.38-0.80; P = 0.026); nonetheless, the atazanavir Ctrough remained higher than the minimum effective concentration in 80% of the participants and higher than the median concentration in the control subjects receiving 400 mg atazanavir once daily without ritonavir (geometric mean ratio, 3.20; 95% confidence interval, 1.65-6.22; P = 0.001). The nevirapine Ctrough at Day 28 was slightly higher than in the historical controls on 200 mg nevirapine twice daily without atazanavir (geometric mean ratio, 1.46; 95% confidence interval, 1.04-2.06; P = 0.030)., Conclusion: We conclude that coadministration of 300/100 mg atazanavir/ritonavir once daily plus 200 mg nevirapine twice daily was safe and well tolerated but resulted in a decrease of atazanavir Ctrough by nearly half. Therefore, monitoring atazanavir Ctrough is recommended in patients treated with this drug combination, and increasing the atazanavir dose might be necessary.

In an initial effort to minimize some of the uncertainty regarding the open burning of biomass, emission factors of carbon oxides, light hydrocarbons, PAHs, PCDD/Fs and dioxin-like PCBs were determined in the combustion of tomato plant in a residential stove and in two runs at 500 degrees C and 850 degrees C in a laboratory scale reactor. In all the runs nearly the same PAHs were identified, being naphthalene the main obtained. Combustion of tomato plant at 500 degrees C in the laboratory scale reactor produced the highest emission factors for all compounds analyzed. Tomato plant was analyzed for PCDD/F and dioxin-like PCB content in order to establish the level of pollutants in the sample itself. Ash obtained in the combustion carried out in the residential stove was analyzed for the dioxin-like compound content and compared with a sample of ash collected from the open burning of tomato plant.

The influence of iron nanoparticles in the fuel-rich combustion of PVC has been studied in this work. Dynamic runs for PVC and the mixture PVC and iron nanoparticles were firstly carried out by TGA-MS in order to study the influence of iron on the compounds evolved in the thermal degradation of PVC. To complete the study both PVC and a mixture of PVC and iron nanoparticles were burnt in a laboratory reactor under two different operating conditions: at 850 degrees C and in two stages, the first one at 375 degrees C and the resulting char cooled and subsequently burnt at 850 degrees C. Carbon oxides, light hydrocarbons, PAHs, chlorophenols, chlorobenzenes and PCDD/Fs were analyzed. It was observed that the mixture of PVC with iron nanoparticles at 375 degrees C greatly enhances the formation of light hydrocarbons and polychlorinated compounds, probably indicating that the presence of iron during the thermal decomposition of PVC causes the formation of iron chloride which may have a high catalytic effect.

Background: We explored a treatment simplification strategy to darunavir/ritonavir 900/100 mg once daily guided by the darunavir virtual inhibitory quotient (vIQ) in patients receiving salvage therapy with darunavir/ritonavir 600/100 mg twice daily., Methods: Open-label, randomized pilot study in HIV-infected patients on darunavir/ritonavir 600/100 mg twice daily (viral load <50 copies/ml; darunavir vIQ >2). Thirty patients were randomized to darunavir/ritonavir 900/100 mg once daily (once-daily group, n=15) or 600/100 mg twice daily (twice-daily group, n=15). Viral load, blood chemistry, and darunavir and ritonavir trough plasma concentrations (C(trough)) were determined up to 48 weeks. If the darunavir vIQ fell to <1.5, the dosage was switched to 600/100 mg twice daily. The primary end point was the percentage of 48-week treatment failure., Results: Patients had taken a mean 11.6 (sd +/-3.9) antiretroviral regimens before darunavir/ritonavir administration. The proportion of patients without 48-week treatment failure was 86.7% in both groups. The median (interquartile range [IQR]) darunavir C(trough) decreased from 3.09 mg/l (IQR 2.43-3.93) at baseline to 1.60 mg/l (IQR 1.25-2.04) at week 48 (P=0.001) in the once-daily group. Three once-daily group patients switched to darunavir/ritonavir 600/100 mg twice daily. Fewer patients had triglyceride levels >200 mg/dl at week 48 in the once-daily group (20.0%) than in the twice-daily group (20.0% versus 57.1%; P=0.046)., Conclusions: Treatment simplification to darunavir/-ritonavir 900/100 mg once daily guided by the darunavir vIQ in treatment-experienced HIV-infected patients receiving darunavir/ritonavir 600/100 mg twice-daily seems to be safe enough to be tested in adequately powered clinical trials.

Prior studies have demonstrated that differences in activation of the defensive motivational system - as indexed by cardiac responses to the CS+ during aversive conditioning - are related to differences in the acquisition of two-levels-of-learning: cognitive (contingency learning) and emotional (fear learning). Here we further explored these differences using an independent psychophysiological test to assess cardiac reactivity - Cardiac Defense Response (CDR) - prior to the aversive conditioning task. Participants were then classified as accelerators or decelerators based on the CDR second accelerative component. Both groups showed contingency learning, as indexed by greater skin conductance changes to CS+ than to CS- during acquisition and by consistent contingency awareness ratings after the conditioning task. However, only accelerators showed affective fear learning, as indexed by greater blinks to CS+ than to CS- during (acquisition) and after (extinction) aversive conditioning. These results extend evidence about differences in the two-levels-of-learning in aversive conditioning as a function of defensive reactivity, and suggest that the CDR second accelerative component could be a reliable predictor of fear learning.

Objective: To assess the Efficacy and safety of switching from HAART containing enfuvirtide to raltegravir as a simplification strategy in patients with viral suppression and intolerance to enfuvirtide., Methods: Thirty-six patients with sustained plasma HIV RNA levels <50 copies/mL for at least 3 months with injection site reactions and/or injection fatigue while receiving an enfuvirtide-containing optimized background regimen switched from enfuvirtide to raltegravir (400 mg bid)., Results: Patientshad received enfuvirtide for a median of 96 weeks and had sustained HIV RNA <50 copies/ mL for a median of 95 weeks. One patient discontinued raltegravir due to the appearance of cutaneous rash (grade 2) unresponsive to antihistamines after 19 days of starting raltegravir. The remaining 35 patients were followed for 24 weeks and 18 of them for 48 weeks. All patients maintained virological suppression <50 copies/mL at Weeks 24 and 48. No patient had blips in their viral load after switching to raltegravir. There were no grade 3 or 4 adverse events related to raltegravir., Conclusions: A switch from enfuvirtide to raltegravir in virologically suppressed patients who are highly treatment-experienced maintained both virologic and immunologic efficacy up to 48 weeks.

We designed a multicenter cross-sectional study to describe the epidemiological characteristics of the HIV-1-infected population aged 70 years or more in our setting. 179 individuals from eight university hospitals in Barcelona, Spain, were included, representing 1.5% of HIV-1 infected subjects followed during 2008. Most subjects were male (76%) and had acquired HIV infection through sexual intercourse (87%); 69% had been diagnosed with HIV-1 after their sixties. The CD4 cell counts at HIV-1 diagnosis were < 200 cells/mm(3) in 52% of individuals, whereas this was only seen in 34% of subjects from a published cohort including younger HIV- infected adults from the same setting [1]. Most of our patients were on HAART, had undetectable HIV-1 viremia and the most recent median CD4 cell counts were >or= 350 cells/mm(3). 154 subjects had at least one comorbid condition, including dyslipidemia (54%), hypertension (36%), hyperglycemia or diabetes (30%), cardiovascular disease (23%), chronic renal failure (18%), history of neoplasia (17%) and cognitive impairment (11%). Lipodystrophy was reported in 58% of individuals. Rates of hypercholesterolemia, diabetes and cancer were higher than those reported in unselected local population (28%, 17% and 7%, respectively). The study participants were taking an average of 2.97 drugs (range 1-10) other than antiretrovirals. In conclusion, the elder population infected with HIV-1 is likely being diagnosed late and at lower CD4+ counts and is frequently affected by comorbidities and co-medication. Based on our findings, we suggest some recommendations regarding the management of this growing population.

Objective: To assess the effectiveness and safety of antiretroviral therapy with unboosted atazanavir (400 mg once daily) plus co-formulated abacavir/lamivudine as a treatment simplification strategy in HIV-infected patients with sustained viral suppression in routine clinical practice., Methods: We performed a retrospective study including patients who were switched to unboosted atazanavir plus abacavir/lamivudine and whose HIV-1 RNA was <50 copies/mL. The primary endpoint was the percentage of subjects who maintained viral suppression after 48 weeks of follow-up. Secondary endpoints included the percentage of subjects who maintained viral suppression after 96 weeks of follow-up, the incidence of adverse events, changes in CD4+ T-cell count and in lipid profile, and the percentage of patients with subtherapeutic atazanavir trough concentrations during follow-up., Results: Forty-six patients were included. None had a prior history of resistance to protease inhibitors or to lamivudine or abacavir. The percentage of patients with viral suppression at Week 48 was 73.9% when all the included patients were considered (full dataset analysis) and 85.0% when only subjects on treatment were considered. There was a continuous immune recovery and an improvement in lipid profile during follow-up. Two thirds of the patients had subtherapeutic atazanavir trough concentrations in plasma in at least one determination during follow-up., Conclusion: Antiretroviral therapy with unboosted atazanavir plus abacavir/lamivudine is safe and effective in the long term as a treatment simplification strategy in HIV-infected patients with sustained virological suppression in routine clinical practice.

The non-nucleoside analog reverse transcriptase inhibitor efavirenz is one of the most common components of HAART. Neuropsychiatric symptoms are frequently reported in patients taking efavirenz-based regimens. These symptoms are usually transient, although they can sometimes persist for up to two years after initiation of treatment. This review describes in detail the most common neuropsychiatric symptoms related to efavirenz, outlines relevant and recent findings on this agent, and suggests possible interventions based on neurobehavioral results. Different recommendations on the assessment of efavirenz-related adverse events are also provided.

Although guidelines for the treatment of HIV-infected patients recommend triple drug antiretroviral therapy, because of the toxicity of these regimens, the complexity of treatment and its costs, other therapeutic options are desirable. Several clinical trials have shown that lopinavir/ritonavir (LPV/r) as a simplification strategy in antiretroviral therapy in HIV-infected patients who maintain suppression of viral replication while receiving conventional treatment regimens is safe and is associated with less toxicity than that due to prolonged exposure to protease inhibitors and nucleoside analogs. The present review summarizes the main results of the various retrospective studies on LPV/r as a simplification strategy of antiretroviral therapy in daily clinical practice.

Objectives: To evaluate the expected activity of etravirine in clinical samples, according to mutational patterns associated with decreased virological response (VR)., Methods: We identified 1586 routine clinical samples with resistance-associated mutations (RAMs) to nevirapine and efavirenz (K103N 60%, Y181C 37%, G190A 27%, V108I 13%). Concerning in vitro identified etravirine mutations, samples with F227C, Y181I, M230L or L100I plus K103N plus Y181C were considered highly resistant. Samples with two RAMs plus Y181C or V179D or K101E or Y188L were considered intermediate. The prevalence of 13 RAMs recently associated with decreased VR to etravirine in the DUET clinical trials was also investigated., Results: Most samples (69%) harboured more than one IAS-USA RAM to first-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs): 42% harboured two RAMs, 21% three RAMs and 6% four or more RAMs. The prevalence of 13 specific etravirine RAMs was V179F 0.12%, G190S 3.9%, Y181V 0.1%, V106I 2.6%, V179D 1.6%, K101P 2.0%, K101E 10.1%, Y181C 36.9%, A98G 5.9%, V90I 6.9%, Y181I 3.6%, G190A 27% and L100I 9.1%. The five RAMs with the most impact on VR (V179F/D, G190S, Y181V and V106I) occurred less often. Overall, 8.2% of the samples had three or more etravirine RAMs and only 1.1% had four or more. In addition, patterns of RAMs previously associated with intermediate etravirine resistance were present in 26.2% of the samples, whereas 4.85% displayed patterns of high-degree resistance., Conclusions: For RAMs associated with decreased VR, etravirine resistance in routine clinical samples was lower than previously reported. High-degree resistance was uncommon, even in patients with resistance to first-generation NNRTIs, whereas low-to-intermediate etravirine resistance was more common.

The aim of this study was to evaluate the relationship between the virological response to darunavir-based salvage antiretroviral therapy and the darunavir genotypic and virtual inhibitory quotients (gIQ and vIQ, respectively). Thirty-seven HIV-infected patients failing protease inhibitor-based antiretroviral regimens who started salvage therapy containing darunavir-ritonavir were prospectively studied. The primary outcome of the study was a viral load (VL) of <50 copies/ml at week 48. The trough concentrations of darunavir in plasma, the number of darunavir resistance mutations, the change in the 50% inhibitory concentration (IC(50)) of darunavir in the virtual phenotype, and the darunavir gIQ and vIQ were correlated with the virological outcome in regression analyses adjusted by the number of active drugs in the background regimen. The VL was <50 copies/ml in 56.8% of patients at week 48. Changes in the VL were not significantly associated with the darunavir concentration (P = 0.304), the number of darunavir resistance mutations (P = 0.695), or the change in the IC(50) (P = 0.750). However, patients with darunavir vIQs of >or=1.5 had a 12-fold greater chance of achieving a >or=1 log(10) reduction in the VL (odds ratio [OR], 12.7; 95% confidence interval [95% CI], 1.9 to 81.6; P = 0.007), and a 5-fold greater chance of achieving a VL of <50 copies/ml (OR, 5.4; 95% CI, 1.2 to 24.5; P = 0.028), at week 48 than patients with darunavir vIQs of <1.5. The positive and negative predictive values of this darunavir vIQ cutoff for achieving a VL of <50 copies/ml at week 48 were 70% and 69%, respectively. The darunavir vIQ predicts virological response to darunavir-based salvage therapy better than the darunavir trough concentration or resistance mutations alone. We suggest targeting a darunavir vIQ of 1.5 for achieving long-term viral suppression.

Ochratoxigenic fungi are natural contaminants of cereal and the produced toxins are harmful to humans and animals. Ochratoxin A (OTA) is among the most important mycotoxins, and the International Agency for Research on Cancer (IARC) classifies it as possibly carcinogenic to humans (group 2B). A total of 61 samples of bread from the central zone of Portugal were analysed for OTA by liquid chromatography (LC) with fluorescence detection (FD). For confirmation two procedures were applied, methyl ester derivatization with boron trifluoride-methanol and liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI/MS/MS). As far as we know, this is the first report where on-line LC/electrospray ionization (ESI) tandem mass spectrometry (MS/MS) was used for OTA analysis in bread. Limits of detection (LOD) and quantification (LOQ) were 0.015 and 0.03 ng/g, using LC-FD, and 0.03 and 0.09 ng/g by LC-MS/MS. The incidence of OTA was 12.9% and 70.0% for wheat and maize bread, respectively. The highest OTA levels were obtained for maize bread, having one sample exceeded the European maximum limit established for OTA in cereal products. The estimate daily intake (EDI) was below the tolerable daily intake.

Objectives: The aim of this study was to develop and validate a population pharmacokinetic model for nevirapine in a population of HIV-infected adults and to evaluate the influence of nevirapine dosing regimen and patient characteristics on nevirapine trough concentration., Methods: HIV-infected adults receiving oral nevirapine for at least 4 weeks were included. A concentration-time profile was obtained for each patient, and nevirapine concentrations in plasma were determined by HPLC. Pharmacokinetic parameters, inter-individual variability and residual error were estimated using non-linear mixed effects modelling. The influence of patient characteristics on the pharmacokinetics of nevirapine was explored, and the predictive performance of the final model was evaluated in an external data set of observations., Results: Totals of 40 and 18 Caucasian patients were included in two data sets for model building and model validation, respectively. A mono-compartmental model with first-order absorption and elimination best described the pharmacokinetics of nevirapine. Body weight influenced oral clearance (CL/F) and volume of distribution (V/F). The estimated population pharmacokinetic parameters (inter-individual variability) for an individual weighing 70 kg were CL/F 2.95 L/h (24%), V/F 95.2 L (30%) and k(a) 1.8 h(-1) (96%). The final model predicted nevirapine concentrations in the external model-validation data set with no systematic bias and adequate precision. Bayesian estimates of nevirapine trough concentrations were lower when nevirapine was administered once instead of twice daily, and nearly half of the patients weighing 90 kg had drug concentrations <3.0 mg/L when nevirapine was dosed once daily., Conclusions: A population model to describe the pharmacokinetics of nevirapine was developed and validated in HIV-infected patients. Body weight influenced CL/F and V/F. Based on Bayesian estimates of individual nevirapine concentrations, twice- instead of once-daily administration of nevirapine would be more optimal in patients weighing >70 kg.

Though antiretroviral therapy attenuates neurocognitive disruption, impairment is still observed. We studied the nadir CD4 cell count as a predictor of neurocognitive changes. This cross-sectional study assessed 64 HIV-infected patients in two groups: G1 (n = 26, nadir CD4 < or =200 cells/ml) and G2 (n = 38, nadir CD4 >200 cells/ml). Percentages of patients showing neurocognitive impairment were compared according to different nadir CD4 cutoffs (200, 250, 300, and 350 cells/ml). From G2, we also took the subgroup of patients receiving treatment (G3) and compared this group with G1, in which all patients were being treated. Demographic and clinical variables were evaluated, as were differences in neurocognitive function. Neurocognitive impairment tended to be more prevalent in G1 [19 patients (73.1%)] than in G2 [20 (52.6%), p = 0.123]. When nadir CD4 cutoffs were compared, there was a trend toward more impaired subjects as the CD4 nadir decreased. Significantly different functioning was found in attention/working memory (digit span backward, p = 0.032) and executive functions (trail making test, part B, p = 0.020), with better performance in G2. Comparison between G1 and G3 confirmed those findings. We found differences in neurocognitive functioning in relation to nadir CD4 count in HIV-infected patients. Attention should be given to this value in the management of neurocognitive protection in HIV infection.

Darunavir is a new HIV protease inhibitor that has been shown to be highly useful in HIV-infected patients. This drug is primarily metabolized by the liver through the cytochrome P450 3A4 (CYP3A4) isozyme and consequently coadministration with low doses of ritonavir markedly increases exposure and allows both daily doses and pill burden to be reduced. Both darunavir and ritonavir act as inhibitors and substrates of CYP3A4 and may therefore present pharmacological interactions with a large number of drugs commonly used in HIV-infected patients. The present review aims to summarize the main studies that have evaluated drug interactions and to provide recommendations on treatment with darunavir/ritonavir in clinical practice.

The objective of this study was to assess adherence of HIV-1-infected patients who started treatment in the pre-HAART era and to determine variables associated with better adherence, including relevant attitudes and beliefs. This is a cross-sectional study enrolling patients who had received antiretroviral therapy for >or=10 years. Adherence was evaluated through self-reporting and plasma drug concentrations. Treatment variables, attitudes and beliefs were collected during structured interviews. The results show that for 87 patients the median (interquartile range) time on therapy was 13 (10-19) years; 80 were on therapy at the time of analysis. Adherence was >or=95% in 54 patients (67.5%), 90-94% in 22 (27.5%) and <90% in 4 (5%). Drug concentrations were below the lower limit of detection in five patients. Younger age (p=0.014), female gender (p=0.005), current substance abuse (p=0.004) and hepatitis C virus co-infection (p<0.001) were related to lower adherence. Adherence did not differ in relation to different drug families or once- or twice-daily regimens. Patients with adherence <95% were more likely to have interrupted treatment without doctor's recommendation (p=0.009). Adherent patients exhibited a higher perception of risk of developing the illness and of benefits of therapy, higher self-efficacy and intention to adhere and were more influenced by events that motivate medication intake. To conclude, adherence was >90% in most patients on antiretroviral therapy for >or=10 years. Adherence was more related to beliefs about health and illness than to the characteristics of medication or level of knowledge about treatment. Care adherence interventions should include assessment of health beliefs.

The widespread contamination of foodstuffs and beverages by mycotoxins, such as ochratoxin A (OTA), has made the monitoring of human contamination levels essential. By using a sensitive, accurate and speedy method that combines extraction with 5% NaHCO(3), immunoaffinity column clean-up and HPLC with fluorescence detection, the human exposure to OTA through urine analysis can be monitored. This method is less invasive than blood monitoring and has the potential to be a good marker of human exposure. The limit of quantification of the method was 0.007 ng/mL of urine, with recoveries of OTA, from urine samples spiked at levels between 0.02 and 0.1 ng/mL, higher than 91% with RSD lower than 15.5%. This study evaluated OTA contamination levels in human urine sample fractions, collected in the morning and afternoon, in two populations, one from Coimbra city, in Portugal, and another from the Valencian community, in Spain. In the Coimbra population, 60 samples from 30 healthy individuals were analyzed, levels of OTA in 13 morning samples and 14 afternoon samples having been detected, with concentrations ranging from 0.011 to 0.208 and 0.008 to 0.11 ng/mL respectively. In the Valencia population, 62 samples from 31 healthy individuals were analyzed, with OTA being detected in 25 morning samples and 26 afternoon samples. The concentrations varied between 0.007 and 0.124 ng/mL in the morning samples, and 0.008 and 0.089 ng/mL in the afternoon samples. Significant differences were found between the morning levels of OTA from both populations (P=0.033). For afternoon samples, significant differences were not found, P value=0.163.

Event-related potentials (ERP) were measured when pleasant, neutral or unpleasant pictures were presented in the context of similarly valenced stimuli, and compared to ERPs elicited when the same pictures were viewed in an intermixed context. An early ERP component (150-300 ms) measured over occipital and fronto-central sensors was specific to viewing pleasant pictures and was not affected by presentation context. Replicating previous studies, emotional pictures prompted a larger late positive potential (LPP, 400-700 ms) and a larger positive slow wave (1-6 s) over centro-parietal sensors that also did not differ by presentation context. On the other hand, ERPs elicited when viewing neutral pictures varied as a function of context, eliciting somewhat larger LPPs when presented in blocks, and prompting smaller slow waves over occipital sensors. Taken together, the data indicate that emotional pictures prompt increased attention and orienting that is unaffected by its context of presentation, whereas neutral pictures are more vulnerable to context manipulations.

Background: Lopinavir is a protease inhibitor indicated for the treatment of HIV infection. It is coformulated with low doses of ritonavir in order to enhance its pharmacokinetic profile. After oral administration, plasma concentrations of lopinavir can vary widely between different HIV-infected patients., Objective: To develop and validate a population pharmacokinetic model for lopinavir and ritonavir administered simultaneously in a population of HIV-infected adults. The model sought was to incorporate patient characteristics influencing variability in the drug concentration and the interaction between the two compounds., Methods: HIV-infected adults on stable therapy with oral lopinavir/ritonavir in routine clinical practice for at least 4 weeks were included. A concentration-time profile was obtained for each patient, and blood samples were collected immediately before and 1, 2, 4, 6, 8, 10 and 12 hours after a morning lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. First, a population pharmacokinetic model was developed for lopinavir and for ritonavir separately. The pharmacokinetic parameters, interindividual variability and residual error were estimated, and the influence of different patient characteristics on the pharmacokinetics of lopinavir and ritonavir was explored. Then, a simultaneous model estimating the pharmacokinetics of both drugs together and incorporating the influence of ritonavir exposure on oral clearance (CL/F) of lopinavir was developed. Population analysis was performed using nonlinear mixed-effects modelling (NONMEM version V software). The bias and precision of the final model were assessed through Monte Carlo simulations and data-splitting techniques., Results: A total of 53 and 25 Caucasian patients were included in two datasets for model building and model validation, respectively. Lopinavir and ritonavir pharmacokinetics were described by one-compartment models with first-order absorption and elimination. The presence of advanced liver fibrosis decreased CL/F of ritonavir by nearly half. The volume of distribution after oral administration (Vd/F) and CL/F of lopinavir were reduced as alpha1-acid glycoprotein (AAG) concentrations increased. CL/F of lopinavir was inhibited by ritonavir concentrations following a maximum-effect model (maximum inhibition [Imax] = 1, concentration producing 50% of the I(max) [IC50] = 0.36 mg/L). The final model appropriately predicted plasma concentrations in the model-validation dataset with no systematic bias and adequate precision., Conclusion: A population model to simultaneously describe the pharmacokinetics of lopinavir and ritonavir was developed and validated in HIV-infected patients. Bayesian estimates of the individual parameters of ritonavir and lopinavir could be useful to predict lopinavir exposure based on the presence of advanced liver fibrosis and the AAG concentration in an individual manner, with the aim of maximizing the chances of treatment success.

Patulin is a mycotoxin produced by species of Penicillium, Aspergillus and Byssochylamys. Several Scientific Committees classify patulin as mutagenic, embryotoxic and immunotoxic. It has been found as a natural contaminant of processed apple products and its presence may be indicative of the quality of fruit used in production. In this work, a method for the analysis of patulin is described, based on a simple liquid-liquid extraction with acetonitrile; patulin is analyzed using liquid chromatography with UV detection. Patulin identity was confirmed by GC-MS after its reaction with N-methyl-N-(trimethylsilyl)trifluoroacetamide. Fifty-three apple-containing products were analyzed and patulin was detected in 14 samples in a range 1.5-50.9 microg l(-1); six of which were above the maximum permitted level of the European Union. Based on these results and juice consumption by the Spanish adult population, patulin estimated intake was 0.42 ng kg(-1) body weight per day.

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.

Ochratoxin A (OTA) is a secondary fungal metabolite produced by several moulds, mainly by Aspergillus ochraceus, A. carbonarius, A. niger and by Penicillium verrucosum. The present work shows the results of comparative studies using different procedures for the analysis of OTA in maize bread samples. The studied analytical methods involved extraction with different volumes of PBS/methanol, different extraction apparatus, and clean-up through immunoaffinity columns. The separation and identification were carried out by high-performance liquid chromatography with fluorescence detection. The optimized method for analysis of OTA in maize bread involved extraction with PBS:methanol (50:50), and clean-up with IAC column. The limit of quantification was 0.033ngg(-1). Recoveries ranged from 87% to 102% for fortifications at 2.000 and 0.500ngg(-1), respectively, within-day R.S.D. of 1.4% and 4.7%. The proposed method was applied to 15 samples and the presence of OTA was found in nine samples at concentrations ranging from nd to 2.650ngg(-1).