Prophylactic and therapeutic recombinant factor VIIa administration to patients with Glanzmann's thrombasthenia: results of an international survey

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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

Comparison of smoothing techniques for CD4 data in a Markov model with states defined by CD4: an example on the estimation of the HIV incubation time distribution.

Multi-state models defined in terms of CD4 counts are useful for modelling HIV disease progression. A Markov model with six progressive CD4-based states and an absorbing state (AIDS) was used to estimate the cumulative probability of progressing to AIDS in 158 HIV-1 infected haemophiliacs with known seroconversion (SC) dates. A problem arising in such analysis is how to define CD4-based states, since this marker is subject to measurement error and short timescale variability. Four approaches were used: no smoothing, ad hoc smoothing (to move to a later/previous state two consecutive measurements to later/previous states are needed), kernel smoothing and random effects (RE) models. The estimates were compared with the Kaplan-Meier estimate based solely on data concerning time to AIDS. There was an apparent lack of agreement between the Kaplan-Meier and the "no smoothing" estimate. With the exception of the "no smoothing" method, "ad hoc", kernel and RE estimates fell within the range of the 95 per cent CIs of the Kaplan-Meier curve. Simulations demonstrated that the use of raw CD4 counts provides overestimated transition intensities. Compared to the kernel method, ad hoc is easier to implement and overcomes the problem of the choice of bandwidth. The RE approach leads to simple models, since it usually results in very few transitions to previous states, and can handle individuals with sparse data by smoothing their predictions towards the population mean. Ad hoc was the method that performed better, in terms of bias, than the other smoothing approaches

Extracorporeal lithotripsy in patients with hemophilia

Two hemophiliac patients with nephrolithiasis were treated with extracorporeal lithotripsy. Both patients were followed up by the 2nd Hemophilia Center of Athens. One is registered as severe hemophilia A and the other one suffers from hemophilia B. With the cooperation of the specialized center they were prepared as for a major operation by administration of substitution therapy. The least possible number of shock waves at low voltage was administered in order to minimize renal damage. Both patients had an uneventful postoperative course

Safety and efficacy of sequential combined bypass therapy of bleeds unresponsive to a single bypassing agent

Background: Replacement therapy is ineffective in high-responders and bypassing agents are required. Unfortunately, whatever by-passing agent is initially used, some bleeds (10%\u201320%) cannot be controlled. A synergistic effect of sequential combination of bypass therapy (SCBT) has been recently reported. The European Haemophilia Treatment Standardization Board conducted a survey of patients who underwent SCBT in Europe. Methods: A web-based database was prepared in order to collect data on each courses of SCBT in a anonymous manner. SCBT was defined as administration of recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) within a 12-h period. Results: SCBT was used in two children (8 & 14 year-old) and 4 adults (mean age:34,range:24\u201345) with haemophilia A (six patients) and B (one patient) and high-responding inhibitors, unresponsive to APCC or rFVIIa. The children had joint bleeds refractory to high doses of rFVIIa (up to 270 \ub5g/Kg/2 h) and/or to high doses of APCC (up to 80 U/Kg/8 h). Three adults had undergone major surgery (knee prosthesis removal, knee arthrodesis, laparotomy for kidney rupture), initially treated with rFVIIa 120\u2013270 \ub5g/Kg/2 h, followed by significant bleed. One of these patients was switched to APCC 80 U/Kg/8 h without success. The fourth adult was suffering from lower limb compartmental syndrome and had no response after five times 180 \ub5g/Kg/3 h and twice FEIBA 75 U/Kg. SCBT in children and adults included alternating one APCC dose (range 50\u201380 U/Kg) to one or two rFVIIa doses (range 90\u2013270 \ub5g/Kg) every 3\u201312 h. Complete bleeding control was achieved within 24 h in all patients. SCT was discontinued after 2\u201315 days and patients underwent prophylaxis with FEIBA or rFVIIa. No clinical adverse event was observed, but a rise of D-dimer levels occurred in three of six patients, without platelet and/or fibrinogen consumption. Conclusion: SCBT can represent a valid salvage treatment of unresponsive bleeds. A larger cohort or a prospective clinical trial are needed to confirm these finding

Comparison of smoothing techniques for CD4 data in a Markov model with states defined by CD4: an example on the estimation of the HIV incubation time distribution

Multi-state models defined in terms of CD4 counts are useful for modelling HIV disease progression. A Markov model with six progressive CD4-based states and an absorbing state (AIDS) was used to estimate the cumulative probability of progressing to AIDS in 158 HIV-1 infected haemophiliacs with known seroconversion (SC) dates. A problem arising in such analysis is how to define CD4-based states, since this marker is subject to measurement error and short timescale variability. Four approaches were used: no smoothing, ad hoc smoothing (to move to a later/previous state two consecutive measurements to later/previous states are needed), kernel smoothing and random effects (RE) models. The estimates were compared with the Kaplan-Meier estimate based solely on data concerning time to AIDS. There was an apparent lack of agreement between the Kaplan-Meier and the ‘no smoothing’ estimate. With the exception of the ‘no smoothing’ method, ‘ad hoc’, kernel and FLE estimates fell within the range of the 95 per cent Cls of the Kaplan-Meier curve. Simulations demonstrated that the use of raw CD4 counts provides overestimated transition intensities. Compared to the kernel method, ad hoc is easier to implement and overcomes the problem of the choice of bandwidth. The RE approach leads to simple models, since it usually results in very few transitions to previous states, and can handle individuals with sparse data by smoothing their predictions towards the population mean. Ad hoc was the method that performed better, in terms of bias, than the other smoothing approaches. Copyright (C) 2001 John Wiley & Sons, Ltd