8 research outputs found
Prophylaxis in children with haemophilia in an evolving treatment landscape
Introduction For children with haemophilia, early initiation of prophylaxis is crucial to prevent life-threatening bleeds and maintain joint health throughout life. Options for prophylaxis have recently increased from replacement therapy with standard or extended half-life coagulation factor products to include other haemostasis products, such as the non-replacement therapy emicizumab. Aim To review key factors that determine the choice of prophylaxis in young children. Methods Key clinical questions on the implementation of prophylaxis for haemophilia in children were identified and PubMed was searched for evidence supporting guidance on the implementation of prophylaxis. Results The results of the literature search and the practical experience of the authors were used to build consensus on when to start prophylaxis, the pros and cons of the products available to guide the choice of product, and practical aspects of starting prophylaxis to guide the choice of regimen. Conclusions In this era of increasing therapeutic choices, available information about the range of treatment options must be considered when initiating prophylaxis in young children. Parents or care givers must be sufficiently informed to allow informed shared decision making. Although plentiful data and clinical experience have been gathered on prophylaxis with clotting factor replacement therapy, its use in young children brings practical challenges, such as the need for intravenous administration. In contrast, our relatively brief experience and limited data with subcutaneously administered non-replacement therapy (i.e., emicizumab) in this patient group imply that starting emicizumab prophylaxis in young children requires careful consideration, despite the more convenient route of administration.TakedaThis article was written on behalf the European Collaborative Haemophilia Network (ECHN). ECHN is supported by an Independent Educational Grant from Takeda. Medical writing assistance was provided by Janet R. Davies, PhD, ELS, and Kim Grootscholten, MSc, of COR2ED, Basel, Switzerland
Altered DNA Methylation Profiles in SF3B1 Mutated CLL Patients
Mutations in splicing factor genes have a severe impact on the survival of cancer patients. Splicing factor 3b subunit 1 (SF3B1) is one of the most frequently mutated genes in chronic lymphocytic leukemia (CLL); patients carrying these mutations have a poor prognosis. Since the splicing machinery and the epigenome are closely interconnected, we investigated whether these alterations may affect the epigenomes of CLL patients. While an overall hypomethylation during CLL carcinogenesis has been observed, the interplay between the epigenetic stage of the originating B cells and SF3B1 mutations, and the subsequent effect of the mutations on methylation alterations in CLL, have not been investigated. We profiled the genome-wide DNA methylation patterns of 27 CLL patients with and without SF3B1 mutations and identified local decreases in methylation levels in SF3B1(mut) CLL patients at 67 genomic regions, mostly in proximity to telomeric regions. These differentially methylated regions (DMRs) were enriched in gene bodies of cancer-related signaling genes, e.g., NOTCH1, HTRA3, and BCL9L. In our study, SF3B1 mutations exclusively emerged in two out of three epigenetic stages of the originating B cells. However, not all the DMRs could be associated with the methylation programming of B cells during development, suggesting that mutations in SF3B1 cause additional epigenetic aberrations during carcinogenesis
Long-term trends in mortality and AIDS-defining events after combination ART initiation among children and adolescents with perinatal HIV infection in 17 middle- and high-income countries in Europe and Thailand: A cohort study
Background
Published estimates of mortality and progression to AIDS as children
with HIV approach adulthood are limited. We describe rates and risk
factors for death and AIDS-defining events in children and adolescents
after initiation of combination antiretroviral therapy (cART) in 17
middle-and high-income countries, including some in Western and Central
Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand.
Methods and findings
Children with perinatal HIV aged < 18 years initiating cART were
followed until their 21st birthday, transfer to adult care, death, loss
to follow-up, or last visit up until 31 December 2013. Rates of death
and first AIDS-defining events were calculated. Baseline and
time-updated risk factors for early/late (<=/> 6 months of cART) death
and progression to AIDS were assessed. Of 3,526 children included, 32%
were from the United Kingdom or Ireland, 30% from elsewhere in W&CE,
18% from Russia or Ukraine, and 20% from Thailand. At cART initiation,
median age was 5.2 (IQR 1.4-9.3) years; 35% of children aged < 5 years
had a CD4 lymphocyte percentage < 15% in 1997-2003, which fell to 15%
of children in 2011 onwards (p < 0.001). Similarly, 53% and 18% of
children >= 5 years had a CD4 count < 200 cells/mm(3) in 1997-2003 and
in 2011 onwards, respectively (p < 0.001). Median follow-up was 5.6
(2.9-8.7) years. Of 94 deaths and 237 first AIDS-defining events, 43
(46%) and 100 (42%) were within 6 months of initiating cART,
respectively. Multivariable predictors of early death were: being in the
first year of life; residence in Russia, Ukraine, or Thailand; AIDS at
cART start; initiating cART on a nonnucleoside reverse transcriptase
inhibitor (NNRTI)-based regimen; severe immune suppression; and low
BMI-for-age z-score. Current severe immune suppression, low current
BMI-for-age z-score, and current viral load > 400 c/mL predicted late
death. Predictors of early and late progression to AIDS were similar.
Study limitations include incomplete recording of US Centers for Disease
Control (CDC) disease stage B events and serious adverse events in some
countries; events that were distributed over a long time period, and
that we lacked power to analyse trends in patterns and causes of death
over time.
Conclusions
In our study, 3,526 children and adolescents with perinatal HIV
infection initiated antiretroviral therapy (ART) in countries in Europe
and Thailand. We observed that over 40% of deaths occurred <= 6 months
after cART initiation. Greater early mortality risk in infants, as
compared to older children, and in Russia, Ukraine, or Thailand as
compared to W&CE, raises concern. Current severe immune suppression,
being underweight, and unsuppressed viral load were associated with a
higher risk of death at > 6 months after initiation of cART
Von Willebrand Factor antigen and age explain variation in baseline FVIII:C among nonsevere hemophilia A patients with the same F8 genotype (Arg593Cys and Asn618Ser)
Von Willebrand Factor antigen and age explain variation in baseline FVIII:C among nonsevere hemophilia A patients with the same F8 genotype (Arg593Cys and Asn618Ser)
Predictors of faster virological suppression in early treated infants with perinatal HIV from Europe and Thailand The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) and Early-treated Perinatally HIV-infected Individuals: Improving Children's Actual Life with Novel Immunotherapeutic Strategies (EPIICAL) study groups
Objective: To identify predictors of faster time to virological
suppression among infants starting combination antiretroviral therapy
(cART) early in infancy.
Design: Cohort study of infants from Europe and Thailand included in
studies participating in the European Pregnancy and Paediatric HIV
Cohort Collaboration.
Methods: Infants with perinatal HIV starting cART aged less than 6
months with at least 1 viral load measurement within 15 months of cART
initiation were included. Multi-variable interval-censored flexible
parametric proportional hazards models were used to assess predictors of
faster virological suppression, with timing of suppression assumed to
lie in the interval between last viral load at least 400 and first viral
load less than 400 copies/ml.
Results: Of 420 infants, 59% were female and 56% from Central/Western
Europe, 26% United Kingdom/Ireland, 15% Eastern Europe and 3%
Thailand; 46 and 54% started a boosted protease inhibitor-based or
nonnucleoside reverse transcriptase inhibitor-based regimen,
respectively. At cART initiation, the median age, CD4(+) % and viral
load were 2.9 [interquartile range (IQR): 1.4-4.1] months, 34 (IQR:
24-45)% and 5.5 (IQR: 4.5-6.0) log(10) copies/ml, respectively.
Overall, an estimated 89% (95% confidence interval: 86-92%) achieved
virological suppression within 12 months of cART start. In multivariable
analysis, younger age [adjusted hazard ratio (aHR): 0.84 per month
older; P < 0.001], higher CD4(+) % (aHR: 1.11 per 10% higher; P=0.010)
and lower log(10) viral load (aHR: 0.85 per log(10) higher; P < 0.001)
at cART initiation independently predicted faster virological
suppression.
Conclusion: We observed a significant independent effect of age at cART
initiation, even within a narrow 6 months window from birth. These
findings support the earliest feasible cART initiation in infants and
suggest that early therapy influences key virological and immunological
parameters that could have important consequences for long-term health.
Copyright (C) 2019 The Author(s). Published by Wolters Kluwer Health,
Inc