Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel.

IMPORTANCE: New data and antiretroviral regimens expand treatment choices in resource-rich settings and warrant an update of recommendations to treat adults infected with human immunodeficiency virus (HIV). OBJECTIVE: To provide updated treatment recommendations for adults with HIV, emphasizing when to start treatment; what treatment to start; the use of laboratory monitoring tools; and managing treatment failure, switches, and simplification. DATA SOURCES, STUDY SELECTION, AND DATA SYNTHESIS: An International Antiviral Society-USA panel of experts in HIV research and patient care considered previous data and reviewed new data since the 2012 update with literature searches in PubMed and EMBASE through June 2014. Recommendations and ratings were based on the quality of evidence and consensus. RESULTS: Antiretroviral therapy is recommended for all adults with HIV infection. Evidence for benefits of treatment and quality of available data increase at lower CD4 cell counts. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (NRTIs; abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine) and a third single or boosted drug, which should be an integrase strand transfer inhibitor (dolutegravir, elvitegravir, or raltegravir), a nonnucleoside reverse transcriptase inhibitor (efavirenz or rilpivirine) or a boosted protease inhibitor (darunavir or atazanavir). Alternative regimens are available. Boosted protease inhibitor monotherapy is generally not recommended, but NRTI-sparing approaches may be considered. New guidance for optimal timing of monitoring of laboratory parameters is provided. Suspected treatment failure warrants rapid confirmation, performance of resistance testing while the patient is receiving the failing regimen, and evaluation of reasons for failure before consideration of switching therapy. Regimen switches for adverse effects, convenience, or to reduce costs should not jeopardize antiretroviral potency. CONCLUSIONS AND RELEVANCE: After confirmed diagnosis of HIV infection, antiretroviral therapy should be initiated in all individuals who are willing and ready to start treatment. Regimens should be selected or changed based on resistance test results with consideration of dosing frequency, pill burden, adverse toxic effect profiles, comorbidities, and drug interactions.

Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study.

Extranodal NK/T-cell lymphoma, nasal type, is a rare and highly aggressive disease with a grim prognosis. No therapeutic strategy is currently identified in relapsing patients. We report the results of a French prospective phase II trial of an L-asparaginase-containing regimen in 19 patients with relapsed or refractory disease treated in 13 centers. Eleven patients were in relapse and 8 patients were refractory to their first line of treatment. L-Asparaginase-based treatment yielded objective responses in 14 of the 18 evaluable patients after 3 cycles. Eleven patients entered complete remission (61%), and only 4 of them relapsed. The median overall survival time was 1 year, with a median response duration of 12 months. The main adverse events were hepatitis, cytopenia, and allergy. The absence of antiasparaginase antibodies and the disappearance of Epstein-Barr virus serum DNA were significantly associated with a better outcome. These data confirm the excellent activity of L-asparaginase-containing regimens in extranodal NK/T-cell lymphoma. L-Asparaginase-based treatment should thus be considered for salvage therapy, especially in patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma warrants evaluation in prospective trials. This trial is registered at www.clinicaltrials.gov as #NCT00283985.

Enterobiasis and strongyloidiasis and associated co-infections and morbidity markers in infants, preschool- and school-aged children from rural coastal Tanzania: a cross-sectional study.

Background. There is a paucity of data pertaining to the epidemiology and public health impact of Enterobius vermicularis and Strongyloides stercoralis infections. We aimed to determine the extent of enterobiasis, strongyloidiasis, and other helminth infections and their association with asymptomatic Plasmodium parasitaemia, anaemia, nutritional status, and blood cell counts in infants, preschool-aged (PSAC), and school-aged children (SAC) from rural coastal Tanzania.MethodsA total of 1,033 children were included in a cross-sectional study implemented in the Bagamoyo district in 2011/2012. Faecal samples were examined for intestinal helminth infections using a broad set of quality controlled methods. Finger-prick blood samples were subjected to filariasis and Plasmodium parasitaemia testing and full blood cell count examination. Weight, length/height, and/or mid-upper arm circumference were measured and the nutritional status determined in accordance with age.Results E. vermicularis infections were found in 4.2% of infants, 16.7%, of PSAC, and 26.3% of SAC. S. stercoralis infections were detected in 5.8%, 7.5%, and 7.1% of infants, PSAC, and SAC, respectively. Multivariable regression analyses revealed higher odds of enterobiasis in children of all age-groups with a reported anthelminthic treatment history over the past six months (odds ratio (OR): 2.15; 95% confidence interval (CI): 1.22 - 3.79) and in SAC with a higher temperature (OR: 2.21; CI: 1.13 - 4.33). Strongyloidiasis was associated with eosinophilia (OR: 2.04; CI: 1.20-3.48) and with Trichuris trichiura infections (OR: 4.13; CI: 1.04-16.52) in children of all age-groups, and with asymptomatic Plasmodium parasitaemia (OR: 13.03; CI: 1.34 - 127.23) in infants. None of the investigated helminthiases impacted significantly on the nutritional status and anaemia, but moderate asymptomatic Plasmodium parasitaemia was a strong predictor for anaemia in children aged older than two years (OR: 2.69; 95% CI: 1.23 ¿ 5.86).Conclusions E. vermicularis and S. stercoralis infections were moderately prevalent in children from rural coastal Tanzania. Our data can contribute to inform yet missing global burden of disease and prevalence estimates for strongyloidiasis and enterobiasis. The association between S stercoralis and asymptomatic Plasmodium parasitaemia found here warrants further comprehensive investigations.

Risk of hepatitis C among brazilian ex-soccer players

In order to evaluate the significance of injecting vitamins complexes and stimulants minutes before soccer games and its role in spread of hepatitis C virus (HCV) we interviewed and tested 40 ex-soccer players, who played professionally in Mato Grosso, Brazil, between 1970 and 1989. Five players were found anti-HCV positive with enzyme-immunoassay. When re-tested by imunoblot (RIBA), three of these five were confirmed to be positive reacting. The anti-HCV positivity (7.5%) was higher than usually found among blood donors (0.9%) in this region (p < 0.01). None of the players had had prior history of any risk factor that might indicate HCV exposure. We suggest that the common practice of soccer players in the inner part of Brazil in the 70's and 80's, to receive fortifying injections, often with shared syringes, may place ex-soccer players in a potencial risk group for HCV infection and warrants further investigation and attention by public health workers.

Atherosclerotic renal artery stenosis: update on management strategies.

Purpose of reviewAtherosclerotic renal artery stenosis (ARAS) usually occurs in patients at high risk of vascular disease, and is associated with increased mortality. The primary goals of ARAS treatment include the control of blood pressure (BP), the improved renal function, and the benefit on cardiovascular events. Although medical therapy remains the standard approach to the management of ARAS, percutaneous transluminal renal angioplasty (PTRA) revascularization can be a therapeutic option under certain conditions.Recent findingsRecent evidence confirms that ARAS increases cardiovascular risk, independent of BP and renal function. This suggests that revascularization might potentially improve overall prognosis, but no data are available currently. In cases of significant ARAS, the accepted indications for PTRA are uncontrollable hypertension, gradual or acute renal function decline with the use of agents blocking the renin-angiotensin-aldosterone system, and recurrent flash pulmonary edema. The key point of treatment success remains in all cases a careful patient selection.SummaryAlthough the atherosclerotic lesions of the renal arteries tend to progress over time, the anatomical lesion progression is not always associated with changes in BP. Furthermore, a poor correlation was noted between the degree of anatomic stenosis and glomerular filtration rate. The high cardiovascular risk warrants aggressive pharmacological treatment to prevent progression of the generalized vascular disorder. Ongoing trials will show whether PTRA revascularization has added, long-term effects on BP, renal function, and cardiovascular prognosis. With or without PTRA revascularization, medical therapy using antihypertensive agents, statins, and aspirin is necessary in almost all cases.

In house reverse membrane hybridisation assay versus GenoType MTBDRplus and their performance to detect mutations in the genes rpoB, katG and inhA

Drug-resistant tuberculosis (TB) threatens global TB control and is a major public health concern in several countries. We therefore developed a multiplex assay (LINE-TB/MDR) that is able to identify the most frequent mutations related to rifampicin (RMP) and isoniazid (INH) resistance. The assay is based on multiplex polymerase chain reaction, membrane hybridisation and colorimetric detection targeting of rpoB and katG genes, as well as the inhA promoter, which are all known to carry specific mutations associated with multidrug-resistant TB (MDR-TB). The assay was validated on a reference panel of 108 M. tuberculosis isolates that were characterised by the proportion method and by DNA sequencing of the targets. When comparing the performance of LINE-TB/MDR with DNA sequencing, the sensitivity, specificity and agreement were 100%, 100% and 100%, respectively, for RMP and 77.6%, 90.6% and 88.9%, respectively, for INH. Using drug sensibility testing as a reference standard, the performance of LINE-TB/MDR regarding sensitivity, specificity and agreement was 100%, 100% and 100% (95%), respectively, for RMP and 77%, 100% and 88.7% (82.2-95.1), respectively, for INH. LINE-TB/MDR was compared with GenoType MTBDRplus for 65 isolates, resulting in an agreement of 93.6% (86.7-97.5) for RIF and 87.4% (84.3-96.2) for INH. LINE-TB/MDR warrants further clinical validation and may be an affordable alternative for MDR-TB diagnosis.

Molecular typing of mycobacteria isolated from extrapulmonary tuberculosis patients at Debre Birhan Referral Hospital, central Ethiopia.

Abstract Background: Extrapulmonary tuberculosis (EPTB) constitutes about 10% to 20% of all cases of tuberculosis in immunocompetent patients and more than 50% of the cases in HIV-positive individuals worldwide. Little information is available on the clonal diversity of Mycobacterium species in Ethiopia from EPTB. Methods: This study was carried out on smear-negative EPTB patients to molecularly characterize Mycobacterium tuberculosis complex strains. A questionnaire, smear staining, culture, deletion typing, and spoligotyping were employed. Results: The proportional distribution of EPTB and isolates did not vary substantially (p > 0.05) amongst the socio-demographic parameters considered in the current investigation. Out of 98 fine needle aspirates processed for culture, 36.7% (36/98) were positive for mycobacterial growth. Further speciation of those culture-positive isolates showed that 88.9% were M. tuberculosis and the remaining could be non-tuberculous mycobacterial species. Spoligotyping revealed 16 clusters out of which 2 were new to the SITVIT database. The most dominant spoligotypes were SIT54, SIT53, and SIT149 in decreasing order. SIT54, SIT134, SIT173, SIT345, SIT357, SIT926, SIT91088, and SIT1580 were reported for the first time in Ethiopia. The family with the highest frequency identified was M. tuberculosis family T1, followed by family 33. Most of the strains belonged to Euro-American (61.4%) and Indo-Oceanic (36.3%) lineages. Conclusions: The present study shows the importance of M. tuberculosis as a major cause of EPTB in the study area. Moreover, the majority of isolates of M. tuberculosis were found in clusters, suggesting the possibility of the existence of recent transmission. This warrants strengthening of the control programs for EPTB in the study area.

Frequency and effects of meeting health behaviour guidelines among adolescents.

Background: To assess the relationship between overweight status and the concomitant adherence to physical activity, daily screen time and nutritional guidelines. Methods: Data were derived from the Swiss Health Behaviour in School-aged Children Survey 2006. Participants (n = 8130, 48.7% girls) were divided into two groups: normal weight (n = 7215, 44.8% girls) and overweight (n = 915, 34.8% girls), using self-reported height and weight. Groups were compared on adherence to physical activity, screen time and nutritional guidelines. Bivariate analyses were carried out followed by multivariate analyses using normal-weight individuals as the reference category. Results: Regardless of gender, overweight individuals reported more screen time, less physical activity and less concomitant adherence to guidelines. For boys, the multivariate analysis showed that any amount exceeding screen time recommendations was associated with increased odds of being overweight [>2-4 h: adjusted odds ratio (AOR) = 1.40; >4-6 h: AOR = 1.48; >6 h: AOR = 1.83]. A similar relation was found for any amount below physical activity recommendations (4-6 times a week: AOR = 1.67; 2-3 times a week: AOR = 1.87; once a week or less: AOR = 2.1). For girls, not meeting nutritional guidelines was less likely among overweight individuals (0-2 recommendations: AOR = 0.54). Regardless of weight status, more than half of the adolescents did not comply with any guideline and <2% met all three at the same time. Conclusions: Meeting current nutritional, physical activity and screen time guidelines should be encouraged with respect to overweight. However, as extremely low rates of concomitant adherence were found regardless of weight status, their achievability is questionable (especially for nutrition), which warrants further research to better adapt them to adolescents.

Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease.

OBJECTIVE: Connective tissue diseases (CTDs) are associated with several interstitial lung diseases. The aim of this study was to describe the recently individualized syndrome of combined pulmonary fibrosis and emphysema (CPFE) in a population of patients with CTD. METHODS: In this multicenter study, we retrospectively investigated data from patients with CTD who also have CPFE. The demographic characteristics of the patients, the results of pulmonary function testing, high-resolution computed tomography, lung biopsy, and treatment, and the outcomes of the patients were analyzed. RESULTS: Data from 34 patients with CTD who were followed up for a mean±SD duration of 8.3±7.0 years were analyzed. Eighteen of the patients had rheumatoid arthritis (RA), 10 had systemic sclerosis (SSc), 4 had mixed or overlap CTD, and 2 had other CTDs. The mean±SD age of the patients was 57±11 years, 23 were men, and 30 were current or former smokers. High-resolution computed tomography revealed emphysema of the upper lung zones and pulmonary fibrosis of the lower zones in all patients, and all patients exhibited dyspnea during exercise. Moderately impaired pulmonary function test results and markedly reduced carbon monoxide transfer capacity were observed. Five patients with SSc exhibited pulmonary hypertension. Four patients died during followup. Patients with CTD and CPFE were significantly younger than an historical control group of patients with idiopathic CPFE and more frequently were female. In addition, patients with CTD and CPFE had higher lung volumes, lower diffusion capacity, higher pulmonary pressures, and more frequently were male than those with CTD and lung fibrosis without emphysema. CONCLUSION: CPFE warrants inclusion as a novel, distinct pulmonary manifestation within the spectrum of CTD-associated lung diseases in smokers or former smokers, especially in patients with RA or SSc.

Maladies infectieuses en pratique ambulatoire (sauf sida) [Infectious diseases (beside AIDS)]

A simplified version of the US guidelines for prophylaxis of infectious endocarditis was published in 2007. Changes are expected in Switzerland as well. Posaconsole is a new antifungal agent available mostly for prophylaxis in immunocompromised patients. Epidemiology of sexually transmitted infections warrants screening in young adults and after one episode. A meta-analysis clarified the impact of antibiotic therapy in patients with Campylobacter spp. infection. In the field of emerging diseases, we discuss Norovirus epidemics, community-acquired bacteria producing extended-spectrum betalactamases, extensively resistant tuberculosis, and new respiratory viruses. Finally, we address a basic research topic that may change practice in the future: the relationship between individual susceptibility to infection and innate immunity.

Frequency and effects of meeting health-behavior guidelines among adolescents

Objective: To assess the relationship between overweight status and the concomitant adherence to physical activity, daily screen time, and nutritional guidelines. Methods: Data were derived from the Swiss HBSC survey 2006. Participants (n=8130, 48.7% girls) were divided into two groups: normal-weight (n=7215, 44.8% girls), and overweight (n=915, 34.8% girls), using self-reported height and weight. Groups were compared on adherence to physical activity, screen time and nutritional guidelines. Bivariate analyses were carried out followed by multivariate analyses using normal-weight individuals as the reference category. Results: Regardless of gender, overweight individuals reported more screen time, less physical activity, and less concomitant adherence to guidelines. For boys, the multivariate analysis showed that any amount exceeding screen time recommendations was associated with increased odds of being overweight (>2-4h: adjusted odds ratio (AOR)=l .40; >4-6h: AOR=l .48; >6h: AOR=l .83). A similar relation was found for any amount below physical activity recommendations (4-6 times a week: AOR=1.67; 2-3 times a week: AOR=1.87; once a week or less: AOR=2.1). For girls, not meeting nutritional guidelines was less likely among overweight individuals (0-2 recommendations: AOR=0.54). Regardless of weight status, more than half of adolescents did not comply with any guideline and less than 2% met all 3 at the same time. Conclusions: Meeting current nutritional, physical activity and screen time guidelines should be encouraged with respect to overweight. However, as extremely low rates of concomitant adherence were found regardless of weight status, their achievability is questionable (especially for nutrition) which warrants further research to better adapt them to adolescents.

The chemokine receptor CXCR4 strongly promotes neuroblastoma primary tumour and metastatic growth, but not invasion.

Neuroblastoma (NB) is a heterogeneous, and particularly malignant childhood neoplasm in its higher stages, with a propensity to form metastasis in selected organs, in particular liver and bone marrow, and for which there is still no efficient treatment available beyond surgery. Recent evidence indicates that the CXCR4/CXCL12 chemokine/receptor axis may be involved in promoting NB invasion and metastasis. In this study, we explored the potential role of CXCR4 in the malignant behaviour of NB, using a combination of in vitro functional analyses and in vivo growth and metastasis assessment in an orthotopic NB mouse model. We show here that CXCR4 overexpression in non-metastatic CXCR4-negative NB cells IGR-NB8 and in moderately metastatic, CXCR4 expressing NB cells IGR-N91, strongly increased tumour growth of primary tumours and liver metastases, without altering the frequency or the pattern of metastasis. Moreover shRNA-mediated knock-down experiments confirmed our observations by showing that silencing CXCR4 in NB cells impairs in vitro and almost abrogates in vivo growth. High levels of CXCL12 were detected in the mouse adrenal gland (the primary tumour site), and in the liver suggesting a paracrine effect of host-derived CXCL12 on NB growth. In conclusion, this study reveals a yet unreported NB-specific predominant growth and survival-promoting role of CXCR4, which warrants a critical reconsideration of the role of CXCR4 in the malignant behaviour of NB and other cancers.

Breast cancer incidence in younger swiss women

Background Breast cancer in younger women has received increased attention in recent years. Although breast cancer is uncommon in young women, it is the most frequent cancer and the leading cause of cancer death for younger women in developed countries. For Switzerland, the United States and several European countries, declines in breast cancer incidence have been reported since around the year 2000, after decades of increase, among women aged 50 and older. On the other hand an increase in the incidence of breast cancer in younger women has been reported in recent years. Therefore, this study aims to evaluate time trends in breast cancer incidence in younger women in Switzerland. Methods Data on invasive breast cancer cases were obtained from the Swiss Cancer Registries of Basel, Fribourg, Geneva, Graubunden/Glarus, Jura, Neuchatel, St. Gallen-Appenzell, Ticino, Valais, Vaud and Zurich, covering the time period 1996 to 2009. Mid-year population estimates for the respective time period were supplied by the Swiss Federal Statistical Office. For females aged 20-49 years, annual age-standardized incidence rates (ASIRs) (European standard) per 100,000 person-years and corresponding 95%-confidence intervals (95% CI) were calculated. For females aged 20-39 and 40-49 years, ASIRs and incidence rate ratios (IRRs) were calculated by grouped time periods, consisting of 3-5 incidence years. IRRs and corresponding 95% CI were calculated using Poisson regression adjusting for age (reference period 1996-2000). Results ASIRs in females aged 20-49 increased gradually since 1996, being 57.36 per 100,000 person-years in 1996 (95% CI 52.54-62.51) and rising to 68.34 (95% CI 63.40-73.57) per 100,000 person-years in 2009. Comparing the time-period 2007-2009 and the reference period 1996-2000, IRRs show values of 1.17 (95% CI 1.04-1.31) for the age-group 20-39 years and 1.04 (95% CI 0.97-1.10) for the age-group 40-49 years. Conclusions Our findings confirm a slight increase in the incidence of invasive breast cancer in younger women in Switzerland during the period 1996-2009. An increase in breast cancer incidence in younger patients is an important public health problem. It warrants further investigations to identify specific risk factors of this population and to better understand the biology of this particular breast cancer.

Intralesional adenovirus-mediated interleukin-2 gene transfer for advanced solid cancers and melanoma.

Numerous preclinical and clinical studies have shown that interleukin-2 (IL-2) induces regression of metastatic tumors. We have conducted a phase I/II, multicenter, open-label, dose-escalating study to evaluate the safety, efficacy, and biological effects of repeated intratumoral injections of adenovirus-IL-2 (TG1024) in patients with advanced solid tumors and melanoma. Thirty five patients (twenty-five with metastatic melanoma and ten with other solid tumors) were treated in eight successive cohorts at dose levels ranging from 3 x 10(8) to 3 x 10(11) viral particles (vp). Intratumoral TG1024 injections in combination with dacarbazine (DTIC) were tested in metastatic melanoma in one cohort. No clinical responses were observed at doses below 3 x 10(11) vp. Six local objective responses were recorded in patients receiving 3 x 10(11) vp per treatment [five in metastatic melanoma and one in metastatic squamous cell carcinoma (SCC) of the skin], of which two were complete responses (CRs). Most of the common side effects were injection site reactions and flu-like syndrome. TG1024 dose intensification across cohorts resulted in increased serum IL-2 levels after the injection. Intratumoral TG1024 injection induced pronounced inflammation of the treated lesion, with predominant CD8(+), TIA+ lymphocytic infiltrate. Our results show that intratumoral injections of TG1024 are safe and well tolerated. The clinical activity of TG1024 observed in this study warrants further investigations.

Gross to Net Calculator, November 2009

Gross-to-Net is a payroll calculator modeled after the actual payroll calculation program used for state employees’ pay warrants. This calculator can be used to project changes in deduction amounts and net pay when there are changes in pay amounts, hours worked, mandatory and voluntary deductions, including all pre-tax deductions such as retirement, insurances, deferred compensation or flexible spending plans. Federal and state tax withholding, retirement rates, OASDI and Medicare (FICA), and insurance deductions are calculated using current rates on HRIS Production. The Gross-to-Net Calculator is accessed through the employee’s timesheet. For instructions on accessing the timesheet, please refer to the HRIS Time Reporting System Manual. When viewing the timesheet, enter “GN” in the header action field to go to the calculator.