Estudo duplo-cego, randômico comparando indinavir, zidovudina e indinavir mais zidovudina na terapia anti-retroviral de indivíduos HIV+ sem tratamento anterior, com contagem de células CD4 entre 50 e 250/mm3

Treatment with indinavir has been shown to result in marked decreases in viral load and increases in CD4 cell counts in HIV-infected individuals. A randomized double-blind study to evaluate the efficacy of indinavir alone (800 mg q8h), zidovidine alone (200 mg q8h) or the combination was performed to evaluate progression to AIDS. 996 antiretroviral therapy-naive patients with CD4 cell counts of 50-250/mm3 were allocated to treatment. During the trial the protocol was amended to add lamivudine to the zidovudine-containing arms. The primary endpoint was time to development of an AIDS-defining illness or death. The study was terminated after a protocol-defined interim analysis demonstrated highly significant reductions in progression to a clinical event in the indinavir-containing arms, compared to the zidovudine arm (p<0.0001). Over a median follow-up of 52 weeks (up to 99 weeks), percent reductions in hazards for the indinavir plus zidovudine and indinavir groups compared to the zidovudine group were 70% and 61%, respectively. Significant reductions in HIV RNA and increases in CD4 cell counts were also seen in the indinavir-containing groups compared to the zidovudine group. Improvement in both CD4 cell count and HIV RNA were associated with reduced risk of disease progression. All three regimens were generally well tolerated.Foi demonstrado que o tratamento com indinavir resulta em importante redução da carga viral e aumentos das células CD4 em pacientes infectados pelo HIV. Foi realizado um estudo duplo-cego, randômico para avaliar a eficácia do indinavir isoladamente (800 mg cada 8h), zidovudina isoladamente (200 mg cada 8h) ou a combinação, para avaliar a progressão para AIDS. Foram distribuidos para tratamento 996 pacientes virgens de tratamento antiretroviral, com contagens de CD4 entre 50 e 250 células/mm3. Durante o estudo, o protocolo foi modificado para adicionar lamivudina aos braços contendo zidovudina. O "endpoint" primário foi o tempo para o desenvolvimento de uma doença-definidora de AIDS ou morte. O estudo foi interrompido após uma análise preliminar definida no protocolo ter demonstrado reduções significativas na progressão para um evento clínico nos grupos contendo indinavir, comparado ao grupo da zidovudina (p< 0,0001). Após uma mediana de seguimento de 52 semanas (chegando a 99 semanas), as reduções percentuais nas ocorrências para indinavir+zidovudina e indinavir, comparado com zidovudina foram de 70% e 61%, respectivamente. Reduções significativas na medida do RNA viral e aumentos nas contagens de CD4 também foram observadas nos grupos contendo indinavir, em relação ao da zidovudina. A melhora nas células CD4 e RNA viral foram ambas associadas a risco reduzido de progressão da doença. Os três tratamentos foram geralmente bem tolerados

A Generalized Linear Model for Estimating Spectrotemporal Receptive Fields from Responses to Natural Sounds

In the auditory system, the stimulus-response properties of single neurons are often described in terms of the spectrotemporal receptive field (STRF), a linear kernel relating the spectrogram of the sound stimulus to the instantaneous firing rate of the neuron. Several algorithms have been used to estimate STRFs from responses to natural stimuli; these algorithms differ in their functional models, cost functions, and regularization methods. Here, we characterize the stimulus-response function of auditory neurons using a generalized linear model (GLM). In this model, each cell's input is described by: 1) a stimulus filter (STRF); and 2) a post-spike filter, which captures dependencies on the neuron's spiking history. The output of the model is given by a series of spike trains rather than instantaneous firing rate, allowing the prediction of spike train responses to novel stimuli. We fit the model by maximum penalized likelihood to the spiking activity of zebra finch auditory midbrain neurons in response to conspecific vocalizations (songs) and modulation limited (ml) noise. We compare this model to normalized reverse correlation (NRC), the traditional method for STRF estimation, in terms of predictive power and the basic tuning properties of the estimated STRFs. We find that a GLM with a sparse prior predicts novel responses to both stimulus classes significantly better than NRC. Importantly, we find that STRFs from the two models derived from the same responses can differ substantially and that GLM STRFs are more consistent between stimulus classes than NRC STRFs. These results suggest that a GLM with a sparse prior provides a more accurate characterization of spectrotemporal tuning than does the NRC method when responses to complex sounds are studied in these neurons

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Primary Antiretroviral Drug Resistance among HIV Type 1-Infected Individuals in Brazil

Infection with drug-resistant human immunodeficiency virus type 1 (HIV-1) has been documented in all countries that have surveyed for it and may result in an unfavorable response to therapy. the prevalence and characteristics of individuals with transmitted resistance to antiretroviral drugs have been scarcely described in Brazil. We performed antiretroviral resistance testing prior to initiation of therapy in 400 subjects enrolled from 20 centers in 13 Brazilian cities between March and September 2007. Genotyping was conducted using PCR-amplified HIV pol products by automated sequencing, and genotype interpretation was done according to the IAS-USA consensus. of 400 eligible participants, 387 (95.8%) were successfully tested. Seven percent of antiretroviral-naive patients carried viruses with one or more major mutation associated with drug resistance. the prevalence of these mutations was 1.0% for protease inhibitors, 4.4% for nonnucleoside reverse transcriptase inhibitors, and 1.3% for nucleoside reverse transcriptase inhibitors. the frequency of multidrug resistance among the resistant strains was 13.6%. Among subjects infected with drug-resistant virus, the majority were infected with subtype B viruses (91%). Subjects from the city of São Paulo had higher transmitted resistance mutations compared to the rest of the country. Reporting a partner taking antiretroviral medications was associated with a higher chance of harboring HIV variants with major drug resistance mutations [odds ratio = 2.57 (95% confidence interval, 1.07-6.16); p = 0.014].Resistance testing in drug-naive individuals identified 7% of subjects with mutations associated with reduced susceptibility to antiretroviral drugs. Continued surveillance of drug-resistant HIV-1 in Brazil is warranted when guidelines for HIV prophylaxis and treatment are updated. Resistance testing among drug-naive patients prior to treatment initiation should be considered, mainly directed at subjects whose partners are already on antiretroviral therapy.Laboratorio Pfizer do BrasilUniv Fed Rio Grande do Sul, Hosp Clin, Porto Alegre, RS, BrazilHosp Univ Prof Edgard Santos, Salvador, BA, BrazilPontificia Univ Catolica, Hosp & Maternidade Celso Pierro, Campinas, SP, BrazilHosp Heliopolis, São Paulo, BrazilInst Infectol Emilio Ribas, São Paulo, BrazilProjeto Praca Onze, Rio de Janeiro, BrazilCRT AIDS, São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilUniv Estadual Campinas, Campinas, SP, BrazilUniv Fed Rio de Janeiro, Rio de Janeiro, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc

Patient empowerment improves follow-up data collection after fetal surgery for spina bifida: institutional audit

OBJECTIVES: To define and grade fetal and maternal adverse events following fetal surgery for spina bifida and to report on the impact of engaging patients in collecting follow-up data. METHODS: This prospective single-center audit included one hundred consecutive patients undergoing fetal surgery for spina bifida from the first onwards. In our setting, patients return to their referring unit for further pregnancy care and delivery. On discharge, referring hospitals were requested to return outcome data. For this audit, we prompted patients and referring hospitals for missing outcomes. Outcomes were categorized as missing, returned spontaneously or following additional request, and as either provided by the patients or referring center. Postoperative maternal and fetal complications until delivery were defined and graded according to the Maternal and Fetal Adverse Event Terminology (MFAET) and the Clavien-Dindo classification. RESULTS: There were no maternal deaths and seven (7%) severe maternal complications (anemia in pregnancy, postpartum hemorrhage, pulmonary edema, lung atelectasis, urinary tract obstruction, and placental abruption). No uterine ruptures were reported. Perinatal death occurred in 3% and other severe fetal complications in 15% (perioperative fetal bradycardia/cardiac dysfunction, fistula-related oligohydramnios, and preterm rupture of membranes <32 weeks). Preterm rupture of membranes occurred in 42% and overall, delivery took place at a median gestational age of 35.3 weeks [IQR 34.0-36.6]. Information following additional request, both from centers, but mainly through patients reduced missing data by 21% for the gestational age at delivery, by 56% for the uterine scar status at birth, and by 67% for the shunt insertion at 12 months. Compared to the generic Clavien-Dindo classification, the Maternal and Fetal Adverse Event Terminology ranked complications in a clinically more relevant way. CONCLUSIONS: The nature and rate of severe complications were similar to those reported in other larger series. Spontaneous return of outcome data by referring centers was low, yet patient empowerment improved data collection. This article is protected by copyright. All rights reserved

Patient empowerment improves follow‐up data collection after fetal surgery for spina bifida: institutional audit

Objectives To define and grade fetal and maternal adverse events following fetal surgery for spina bifida and to report on the impact of engaging patients in collecting follow-up data. Methods This prospective single-center audit included one hundred consecutive patients undergoing fetal surgery for spina bifida from the first onwards. In our setting, patients return to their referring unit for further pregnancy care and delivery. On discharge, referring hospitals were requested to return outcome data. For this audit, we prompted patients and referring hospitals for missing outcomes. Outcomes were categorized as missing, returned spontaneously or following additional request, and as either provided by the patients or referring center. Postoperative maternal and fetal complications until delivery were defined and graded according to the Maternal and Fetal Adverse Event Terminology (MFAET) and the Clavien-Dindo classification. Results There were no maternal deaths and seven (7%) severe maternal complications (anemia in pregnancy, postpartum hemorrhage, pulmonary edema, lung atelectasis, urinary tract obstruction, and placental abruption). No uterine ruptures were reported. Perinatal death occurred in 3% and other severe fetal complications in 15% (perioperative fetal bradycardia/cardiac dysfunction, fistula-related oligohydramnios, and preterm rupture of membranes <32 weeks). Preterm rupture of membranes occurred in 42% and overall, delivery took place at a median gestational age of 35.3 weeks [IQR 34.0-36.6]. Information following additional request, both from centers, but mainly through patients reduced missing data by 21% for the gestational age at delivery, by 56% for the uterine scar status at birth, and by 67% for the shunt insertion at 12 months. Compared to the generic Clavien-Dindo classification, the Maternal and Fetal Adverse Event Terminology ranked complications in a clinically more relevant way. Conclusions The nature and rate of severe complications were similar to those reported in other larger series. Spontaneous return of outcome data by referring centers was low, yet patient empowerment improved data collection

Estudo duplo-cego, randômico comparando indinavir, zidovudina e indinavir mais zidovudina na terapia anti-retroviral de indivíduos HIV+ sem tratamento anterior, com contagem de células CD4 entre 50 e 250/mm3

Treatment with indinavir has been shown to result in marked decreases in viral load and increases in CD4 cell counts in HIV-infected individuals. A randomized double-blind study to evaluate the efficacy of indinavir alone (800 mg q8h), zidovidine alone (200 mg q8h) or the combination was performed to evaluate progression to AIDS. 996 antiretroviral therapy-naive patients with CD4 cell counts of 50-250/mm3 were allocated to treatment. During the trial the protocol was amended to add lamivudine to the zidovudine-containing arms. The primary endpoint was time to development of an AIDS-defining illness or death. The study was terminated after a protocol-defined interim analysis demonstrated highly significant reductions in progression to a clinical event in the indinavir-containing arms, compared to the zidovudine arm (p&lt;0.0001). Over a median follow-up of 52 weeks (up to 99 weeks), percent reductions in hazards for the indinavir plus zidovudine and indinavir groups compared to the zidovudine group were 70% and 61%, respectively. Significant reductions in HIV RNA and increases in CD4 cell counts were also seen in the indinavir-containing groups compared to the zidovudine group. Improvement in both CD4 cell count and HIV RNA were associated with reduced risk of disease progression. All three regimens were generally well tolerated.Foi demonstrado que o tratamento com indinavir resulta em importante redução da carga viral e aumentos das células CD4 em pacientes infectados pelo HIV. Foi realizado um estudo duplo-cego, randômico para avaliar a eficácia do indinavir isoladamente (800 mg cada 8h), zidovudina isoladamente (200 mg cada 8h) ou a combinação, para avaliar a progressão para AIDS. Foram distribuidos para tratamento 996 pacientes virgens de tratamento antiretroviral, com contagens de CD4 entre 50 e 250 células/mm3. Durante o estudo, o protocolo foi modificado para adicionar lamivudina aos braços contendo zidovudina. O endpoint primário foi o tempo para o desenvolvimento de uma doença-definidora de AIDS ou morte. O estudo foi interrompido após uma análise preliminar definida no protocolo ter demonstrado reduções significativas na progressão para um evento clínico nos grupos contendo indinavir, comparado ao grupo da zidovudina (p&lt; 0,0001). Após uma mediana de seguimento de 52 semanas (chegando a 99 semanas), as reduções percentuais nas ocorrências para indinavir+zidovudina e indinavir, comparado com zidovudina foram de 70% e 61%, respectivamente. Reduções significativas na medida do RNA viral e aumentos nas contagens de CD4 também foram observadas nos grupos contendo indinavir, em relação ao da zidovudina. A melhora nas células CD4 e RNA viral foram ambas associadas a risco reduzido de progressão da doença. Os três tratamentos foram geralmente bem tolerados.273