Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing.

The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin-related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www.pharmgkb.org).

The diverse environmental burden of city-scale urban water systems.

Recent years have seen an increase in the use of Life Cycle Assessment (LCA) to inform urban water systems research. The attraction of LCA is its capacity to identify trade-offs across a broad range of environmental issues and a broad range of technologies. However, without some additional perspective on the scale of the results, prioritisation of these concerns will remain difficult. LCA studies at the whole-of-system level are required to identify the diversity of life cycle environmental burdens associated with urban water systems, and the main contributors to these impacts. In this study, environmental impact profiles were generated for two city-scale urban water systems: one typical of many urban centres, with a high reliance on freshwater extraction and the majority of treated wastewater being discharged to the sea; and one that adopts a more diverse range of water supply and wastewater recycling technologies. The profiles were based on measured data for most system components, otherwise best available empirical data from the literature. Impact models were chosen considering the substantial methodological developments that have occurred in recent years. System operations, directly within the sphere of influence of water system managers, play the dominant role in all but one of the 14 life cycle impact categories considered. While energy use is the main cause of changes in the impact profiles when the alternative water supply technologies are included, it is not the only important driver of impacts associated with city-scale urban water systems. Also extremely important are process emissions related to wastewater treatment and dams (notably fugitive gases, wastewater discharges, and biosolids disposal). The results clearly indicate a diverse range of environmental impacts of relevance, extending beyond the traditional concerns of water use and nutrient discharge. Neither energy use, nor greenhouse gas footprints, are likely to be an adequate proxy for representing these additional concerns. However, methodological improvements will be required for certain LCA impact models to support future case study analysis, as will a comprehensive critique of the implications from selecting different impact models.

Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing: 2014 update.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B Genotype and Abacavir Dosing were originally published in April 2012. We reviewed recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplementary Material online and included additional resources for applying CPIC guidelines to the electronic health record. Up-to-date information can be found at PharmGKB (http://www.pharmgkb.org).

Perspectives on greenhouse gas emission estimates based on Australian wastewater treatment plant operating data.

Primary operating data were collected from forty-six wastewater treatment plants (WWTPs) located across three states within Australia. The size range of plants was indicatively from 500 to 900,000 person equivalents. Direct and indirect greenhouse gas emissions were calculated using a mass balance approach and default emission factors, based on Australia's National Greenhouse Energy Reporting (NGER) scheme and IPCC guidelines. A Monte Carlo-type combined uncertainty analysis was applied to the some of the key emission factors in order to study sensitivity. The results suggest that Scope 2 (indirect emissions due to electrical power purchased from the grid) dominate the emissions profile for most of the plants (indicatively half to three quarters of the average estimated total emissions). This is only offset for the relatively small number of plants (in this study) that have significant on-site power generation from biogas, or where the water utility purchases grid electricity generated from renewable sources. For plants with anaerobic digestion, inventory data issues around theoretical biogas generation, capture and measurement were sometimes encountered that can skew reportable emissions using the NGER methodology. Typically, nitrous oxide (N(2)O) emissions dominated the Scope 1 (direct) emissions. However, N(2)O still only accounted for approximately 10 to 37% of total emissions. This conservative estimate is based on the 'default' NGER steady-state emission factor, which amounts to 1% of nitrogen removed through biological nitrification-denitrification processing in the plant (or indicatively 0.7 to 0.8% of plant influent total nitrogen). Current research suggests that true N(2)O emissions may be much lower and certainly not steady-state. The results of this study help to place in context research work that is focused on direct emissions from WWTPs (including N(2)O, methane and carbon dioxide of non-biogenic origin). For example, whereas non-biogenic CO(2) contributions are relatively minor, it appears that opportunities to reduce indirect emissions as a result of modest savings in power consumption are at least in the same order as those from reducing N(2)O emissions. To avoid potentially high reportable emissions under NGER guidelines, particularly for methane, the onus is placed on WWTP managers to ensure that accurate plant monitoring operating records are kept.

Measures of small-fiber neuropathy in HIV infection.

INTRODUCTION: Noninvasive methods are needed to detect distal sensory polyneuropathy in HIV-infected persons on antiretroviral therapy (ART). METHODS: Quantitative sudomotor axon reflex test (QSART) and Utah Early Neuropathy Scale (UENS), small-fiber sensitive measures, were assessed in subjects with and without clinical neuropathy. Pain was assessed by visual analog scale (VAS). RESULTS: Twenty-two subjects had symptoms and signs of neuropathy, 19 had neither, and all were receiving ART. Median sweat volume (µL) was lower at all testing sites in those with neuropathy compared to those without (p<0.01 for all). UENS and VAS (mm) were higher in neuropathy subjects (p<0.05 for each). Lower sweat volume at all sites correlated with higher pin UENS subscore, total UENS, and VAS (p<0.05 for all). In multivariable analyses adjusting for age, CD4⁺ T cells, sex, and use of "d-drug" ART, QSART and UENS remained associated (p=0.003). CONCLUSION: QSART and UENS have not been previously studied in this patient population and may identify small-fiber neuropathy in HIV-infected, ART-treated persons.

Clinical pharmacogenetics implementation consortium guidelines for HLA-B genotype and abacavir dosing.

Human leukocyte antigen B (HLA-B) is responsible for presenting peptides to immune cells and plays a critical role in normal immune recognition of pathogens. A variant allele, HLA-B*57:01, is associated with increased risk of a hypersensitivity reaction to the anti-HIV drug abacavir. In the absence of genetic prescreening, hypersensitivity affects ~6% of patients and can be life-threatening with repeated dosing. We provide recommendations (updated periodically at http://www.pharmkgb.org) for the use of abacavir based on HLA-B genotype.

Pulmonary cryptococcosis in patients without HIV infection: factors associated with disseminated disease.

Cryptococcus neoformans is an uncommonly recognized cause of pneumonia in HIV-negative patients. Because of its propensity to disseminate to the meninges and other sites, a lumbar puncture is recommended for patients with pulmonary cryptococcosis, regardless of other risk factors. This study explored clinical and laboratory features to help predict which patients had pulmonary disease alone versus those who had pulmonary plus extrapulmonary disease. A retrospective chart review at 15 medical centers was performed from 1990 to 2000 of all HIV-negative patients who had pulmonary cryptococcosis. Demographic, clinical, radiographic, and laboratory features were evaluated to determine factors that differentiated those patients who had extrapulmonary disease. Among 166 patients who had pulmonary cryptococcosis, 122 had pulmonary infection only and 44 had pulmonary plus extrapulmonary (disseminated) disease. A negative serum cryptococcal antigen titer was more common in patients with pulmonary disease alone (p < 0.01). Multivariate analysis demonstrated that patients who had disseminated disease were more likely than those who only had pulmonary disease to have cirrhosis (p = 0.049), headache (p < 0.001), weight loss (p = 0.003), fever (p = 0.035), altered mental status (p < 0.001), and to be receiving high-dose corticosteroids (p = 0.008). In this large cohort of HIV-negative patients with pulmonary cryptococcosis, there were easily distinguished clinical and laboratory features among patients with pulmonary disease alone versus those with pulmonary plus extrapulmonary disease. These findings may be helpful in the evaluation of HIV-negative patients with pulmonary cryptococcosis with regard to the need for lumbar puncture or to search for disseminated disease.

Normal chest radiography in pulmonary tuberculosis: implications for obtaining respiratory specimen cultures.

SETTING: Urban tuberculosis (TB) clinic, Nashville, Tennessee, USA. OBJECTIVE: Chest radiographs (CXRs) help in the diagnosis of pulmonary TB, but may be normal. Mycobacterium tuberculosis in culture is diagnostic of TB, but cultures are not routinely obtained in resource-poor settings. We examined rates and risk factors for pulmonary TB associated with normal CXR. DESIGN: An observational cohort study was performed among all respiratory culture-positive TB cases referred to the Nashville Health Department from October 1992 to July 2003. Clinical factors, demographics and underlying medical conditions were assessed. RESULTS: Of 601 study patients, 53 (9%) had normal CXRs: 31/138 (22%) were human immunodeficiency virus (HIV) infected and 22/463 (5%) were non-HIV-infected/unknown (P<0.001). Among HIV-infected patients, normal CXR was more likely in persons with renal failure (13% vs. 3%, P=0.048). Among non-HIV-infected/unknown patients, normal CXR was more likely in those who were asymptomatic at presentation (32% vs. 13%, P=0.022). In multivariable logistic regression analysis, HIV infection was associated with an increased risk of normal CXR (odds ratio [OR] 6.61, P<0.0001); factors associated with reduced risk were dyspnea (OR 0.24, P=0.026), positive sputum smear (OR 0.45, P=0.028) and cough (OR 0.48, P=0.038). CONCLUSIONS: The rate of normal CXR among persons with culture-confirmed pulmonary TB was high. Respiratory specimen cultures should be obtained in TB suspects with a normal CXR, particularly HIV-infected persons.

The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy.

Peripheral neuropathy (PN) due to mitochondrial injury complicates HIV therapy with some nucleoside reverse transcriptase inhibitors (NRTIs). Variation in the mitochondrial genome may influence susceptibility to NRTI toxicities. Two non-synonymous mitochondrial DNA polymorphisms, MTND1*LHON4216C (4216C) and MTND2*LHON4917G (4917G) were characterized in HIV-infected participants exposed to NRTIs in a randomized clinical trial. Among 250 self-identified white, non-Hispanic participants, symptomatic PN (> or = grade 1) developed in 70 (28%). Both 4216C (odds ratio (OR)=1.98 (95% confidence interval (CI) 1.05-3.75); P=0.04) and 4917G (OR=2.93 (95% CI 1.25-6.89); P=0.01) were more frequent in PN cases. These two polymorphisms remained independently associated with PN after adjusting for age, baseline CD4 count, plasma HIV RNA level, and NRTI randomization arm; 4216C (OR=2.0 (95% CI 1.1-4.0) P=0.04) and 4917G (OR=5.5 (95% CI 1.6-18.7) P<0.01). When 4917G individuals were excluded from the analysis, the association with 4216C was no longer seen. The mitochondrial 4917G polymorphism may increase susceptibility to NRTI-associated PN.

Two phases of HIV RNA decay in CSF during initial days of multidrug therapy.

BACKGROUND: Defining cellular and tissue sources of HIV-1 in CSF is important for understanding disease pathogenesis and optimal therapies for HIV infection in the brain. OBJECTIVE: To identify the time of maximal viral decay in CSF during the initial days of antiretroviral therapy. METHODS: Serial CSF and plasma data were available from four adults who underwent ultraintensive CSF sampling for 48 hours at baseline and again beginning 72 hours after starting antiretroviral therapy. Regression lines were generated using HIV-1 RNA data from 17 on-treatment serial CSF samples obtained at 3-hour intervals. Viral RNA was quantified by Nuclisens and Amplicor HIV-1 Monitor assays. RESULTS: Extrapolation of regression lines intersected baseline below actual baseline CSF HIV-1 RNA concentrations, indicating that virus decayed most rapidly on days 1 through 3 with half-lives of no more than 0.9 to 2.8 days. Half-lives on days 4 and 5 ranged from 1.3 to 4.9 days. Plasma data also showed early rapid decay. CONCLUSIONS: Multiple phases of viral decay suggest that virus in CSF originates from at least two sources during untreated, asymptomatic HIV-1 infection. The short half-life indicates that the primary source is CD4+ T cells. Sampling during days 1 through 3 and different stages of disease will better define sources of virus.

Antiretroviral activity and safety of abacavir in combination with selected HIV-1 protease inhibitors in therapy-naive HIV-1-infected adults.

OBJECTIVE: To assess antiretroviral efficacy and safety of abacavir in combination with selected HIV-1 protease inhibitors. DESIGN: A 48-week, open-label study. MATERIALS AND METHODS: Eighty-two antiretroviral naive HIV-1-infected adults (CD4 cell count > or = 100 cells/mm3, plasma HIV-1 RNA > or = 5,000 copies/ml) were randomly assigned to receive abacavir (300 mg twice daily) in combination with standard doses of one of five protease inhibitors: indinavir, saquinavir soft-gel, ritonavir, nelfinavir or amprenavir. Adults who met protocol-defined switch criteria at or after week 8 could modify their randomized therapy. Antiretroviral activity was assessed by the proportion of subjects with plasma HIV-1 RNA < or = 400 and < or = 50 copies/ml, and by changes in plasma HIV-1 RNA levels and CD4 cell counts. Safety was assessed by monitoring clinical adverse events and laboratory abnormalities. RESULTS: At week 48, the proportion of subjects in the indinavir, saquinavir, ritonavir, nelfinavir and amprenavir groups with plasma HIV-1 RNA < or = 400 copies/ml was 53, 50, 50, 41 and 56%, respectively, and the proportion with HIV-1 RNA < or = 50 copies/ml was 47, 56, 50, 47, and 44%, respectively (by intent-to-treat analysis). Median reductions from baseline in plasma HIV-1 RNA for each group ranged from 1.7 to 2.4 log10 copies/ml. The median CD4 cell count increase from baseline was 195, 131, 116, 136 and 259 cells/mm3 in the indinavir, saquinavir, ritonavir, nelfinavir, and amprenavir groups, respectively. Overall, the most common adverse events attributed to study drugs were diarrhoea, nausea, malaise/fatigue, headache and perioral paresthesia. The frequency of treatment-limiting adverse events did not differ between groups. CONCLUSIONS: Abacavir is safe and effective when used in combination with a protease inhibitor.

Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy.

We conducted a case study of human immunodeficiency virus (HIV)-negative patients with cryptococcosis at 15 United States medical centers from 1990 through 1996 to understand the demographics, therapeutic approach, and factors associated with poor prognosis in this population. Of 306 patients with cryptococcosis, there were 109 with pulmonary involvement, 157 with central nervous system (CNS) involvement, and 40 with involvement at other sites. Seventy-nine percent had a significant underlying condition. Patients with pulmonary disease were usually treated initially with fluconazole (63%); patients with CNS disease generally received amphotericin B (92%). Fluconazole was administered to approximately two-thirds of patients with CNS disease for consolidation therapy. Therapy was successful for 74% of patients. Significant predictors of mortality in multivariate analysis included age > or =60 years, hematologic malignancy, and organ failure. Overall mortality was 30%, and mortality attributable to cryptococcosis was 12%. Cryptococcosis continues to be an important infection in HIV-negative patients and is associated with substantial overall and cause-specific mortality.

Measurements of mandibular length: a comparison of articulare vs condylion.

This study examines the validity of articulare for mandibular length measurements by exposing 3 lateral cephalograms on each of 60 consecutive patients. The radiographs were exposed with the patient in a closed-mouth position in habitual occlusion, a closed-mouth position with the patient in centric relation, and in an open-mouth position. The linear distances (mm) of articulare (Ar) to pogonion (Pog), Ar to gonion (Go), and Go to Pog were measured on the 2 closed-mouth cephalograms and compared with each other as well as the linear distances of condyle (Co) to Pog, Co to Go, and Go to Pog measured from the open-mouth cephalogram on each individual. Product-moment correlation coefficients were used to measure the linear associations among the mandibular measurements from the 3 techniques. Repeated measures analyses of variance were also fit to estimate the correlations between the 3 measurements adjusted for age and sex. The results of this study show that measurements taken from both closed-mouthed techniques agreed extremely well (intraclass correlation coefficient = 0.99). In addition, measurements from both closed-mouth techniques highly agreed with the corresponding measurements taken with the open-mouth technique (intraclass correlation coefficient = 0.94). This data suggests that measurements taken from Ar correlate very well with measurements taken from Co and that this correlation is not dependent on whether the patient is positioned in habitual occlusion or centric relation.

Comparison of Roche MONITOR and Organon Teknika NucliSens assays to quantify human immunodeficiency virus type 1 RNA in cerebrospinal fluid.

We compared Roche MONITOR and Organon Teknika NucliSens assays for human immunodeficiency virus type 1 (HIV-1) RNA in cerebrospinal fluid (CSF). Results of 282 assays were highly correlated (r = 0.826), with MONITOR values being 0.29 +/- 0.4 log(10) copies/ml (mean +/- standard deviation) values. Both assays can reliably quantify HIV-1 RNA in CSF.

Therapy with efavirenz plus indinavir in patients with extensive prior nucleoside reverse-transcriptase inhibitor experience: a randomized, double-blind, placebo-controlled trial.

A randomized, double-blind, placebo-controlled trial compared efavirenz (600 mg every 24 h) plus indinavir (1000 mg every 8 h) with placebo (every 24 h) plus indinavir (800 mg every 8 h) among 327 nucleoside analogue reverse-transcriptase inhibitor (NRTI)-experienced human immunodeficiency virus (HIV)-infected adults. Patients received 50 cells/mm(3), >10,000 plasma HIV-1 RNA copies/mL, and no prior protease inhibitor or non-NRTI therapy. Patients had a mean of 2.8 years of prior NRTI therapy. At 24 weeks, plasma HIV-1 RNA level was <400 copies/mL in 68.2% of efavirenz versus 52.4% of placebo recipients (P=.004). CD4 cell count increases were 104+/-9 cells/mm(3) and 77+/-10 cells/mm(3) in efavirenz and placebo recipients, respectively (P=.023). Responses in efavirenz recipients were sustained at 48 weeks. Thus, efavirenz plus indinavir with concomitant NRTIs is effective therapy for NRTI-experienced patients.

Cellular restoration in HIV infected persons treated with abacavir and a protease inhibitor: age inversely predicts naive CD4 cell count increase.

OBJECTIVE: To characterize early and later indices of cellular restoration among HIV-1 infected persons treated with abacavir and one protease inhibitor and to identify predictors of CD4 cell increases. METHODS: Flow-cytometric analyses of lymphocyte phenotypes among 71 antiretroviral treatment naive adults in a 48 week treatment trial. RESULTS: During the first 4 weeks of therapy, increases in naive and memory CD4 cells and in B cells were seen; naive CD8 cells increased while CD8 cells remained stable as memory CD8 cells decreased. During the second phase total CD4 and naive CD4 and CD8 cells increased while total CD8 and memory CD8 cells decreased. The numbers of CD4 cells that expressed CD28 increased from a median of 308 x 10(6)/l at baseline to 477 x 10(6)/l at week 48. Higher baseline plasma HIV-1 RNA levels predicted the magnitude of early CD4 (r = 0.35; P = 0.01), memory CD4 (r = 0.38; P = 0.001) and CD28 CD4 cell (r = 0.29; P = 0.01) restoration but was not related to second phase changes. Younger age predicted a greater second phase (but not first phase) increase in naive CD4 cells (r = -0.31; P = 0.03). CONCLUSIONS: Higher baseline levels of HIV-1 replication determine the magnitude of first phase CD4 cell increases after suppression of HIV-1 replication. Second phase (primarily naive) CD4 cell increases are not related to HIV-1 replication but are inversely relate to age suggesting that thymic potential is a major determinant of long term cellular restoration in HIV-1 infected persons receiving antiretroviral therapy.

Comparison of human immunodeficiency virus type 1 RNA sequence heterogeneity in cerebrospinal fluid and plasma.

The source of human immunodeficiency virus type 1 (HIV-1) RNA in cerebrospinal fluid (CSF) during HIV-1 infection is uncertain. The sequence heterogeneity of HIV-1 RNA in simultaneous CSF and plasma samples was characterized for five patients at the baseline and during the first week of antiretroviral therapy by two commercial genotyping methodologies. In individual subjects, the sequences in CSF samples differed significantly from those in plasma. In contrast, the viral sequences in CSF at the baseline did not differ from the sequences in CSF during treatment. Similarly, viral sequences in plasma did not vary over this interval. This study provides evidence that HIV-1 RNA in CSF and plasma arise from distinct compartments.

Steady-state pharmacokinetics of indinavir in cerebrospinal fluid and plasma among adults with human immunodeficiency virus type 1 infection.

To characterize steady-state indinavir pharmacokinetics in cerebrospinal fluid and plasma, 8 adults infected with human immunodeficiency virus underwent intensive cerebrospinal fluid sampling while receiving indinavir (800 mg every 8 hours) plus nucleoside reverse transcriptase inhibitors. Nine and 11 serial cerebrospinal fluid and plasma samples, respectively, were obtained from each subject. Free indinavir accounted for 94.3% of the drug in cerebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid peak concentration, concentration at 8 hours, and area under the concentration-time profile calculated over the interval 0 to 8 hours [AUC(0-8)] for free indinavir were 294 nmol/L, 122 nmol/L, and 1616 nmol/L x h, respectively. The cerebrospinal fluid-to-plasma AUC(0-8) ratio for free indinavir was 14.7% +/- 2.6% and did not correlate with indexes of blood-brain barrier integrity or intrathecal immune activation. Indinavir achieves levels in cerebrospinal fluid that should contribute to control of human immunodeficiency virus type 1 replication in this compartment. The cerebrospinal fluid-to-plasma AUC(0-8) ratio suggests clearance mechanisms in addition to passive diffusion across the blood-cerebrospinal fluid barrier, perhaps by P-glycoprotein-mediated efflux.

Recurrent Achromobacter xylosoxidans bacteremia associated with persistent lymph node infection in a patient with hyper-immunoglobulin M syndrome.

Achromobacter xylosoxidans (formerly Alcaligenes xylosoxidans) is a rare but important cause of bacteremia in immunocompromised patients, and strains are usually multiply resistant to antimicrobial therapy. We report an immunocompromised patient with hyper-immunoglobulin M syndrome who suffered from 14 documented episodes of A. xylosoxidans bacteremia. Each episode was treated and resulted in rapid clinical improvement, with blood cultures testing negative for bacteria. Between episodes, A. xylosoxidans was isolated from an excised right axillary lymph node, whereas the culture of the central venous catheter, removed at the same time, was negative. Multiple cultures from sputum, stool, and urine samples, as well as from gastrointestinal biopsies or environmental sources, were negative. Results from antibiotic sensitivity testing and pulsed-field gel electrophoresis suggested that a single strain of A. xylosoxidans caused the recurrent bacteremias in this patient; this strain originated from persistently infected lymph nodes. Lymphoid hyperplasia is a prominent characteristic of hyper-IgM syndrome and may serve as a source of bacteremia with low-pathogenicity organisms.