New approaches to measuring anthelminthic drug efficacy: parasitological responses of childhood schistosome infections to treatment with praziquantel

By 2020, the global health community aims to control and eliminate human helminthiases, including schistosomiasis in selected African countries, principally by preventive chemotherapy (PCT) through mass drug administration (MDA) of anthelminthics. Quantitative monitoring of anthelminthic responses is crucial for promptly detecting changes in efficacy, potentially indicative of emerging drug resistance. Statistical models offer a powerful means to delineate and compare efficacy among individuals, among groups of individuals and among populations.; We illustrate a variety of statistical frameworks that offer different levels of inference by analysing data from nine previous studies on egg counts collected from African children before and after administration of praziquantel.; We quantify responses to praziquantel as egg reduction rates (ERRs), using different frameworks to estimate ERRs among population strata, as average responses, and within strata, as individual responses. We compare our model-based average ERRs to corresponding model-free estimates, using as reference the World Health Organization (WHO) 90 % threshold of optimal efficacy. We estimate distributions of individual responses and summarize the variation among these responses as the fraction of ERRs falling below the WHO threshold.; Generic models for evaluating responses to anthelminthics deepen our understanding of variation among populations, sub-populations and individuals. We discuss the future application of statistical modelling approaches for monitoring and evaluation of PCT programmes targeting human helminthiases in the context of the WHO 2020 control and elimination goals

Response to ‘Re: Kakkos et al. Efficacy and Safety of the New Oral Anticoagulants Dabigatran, Rivaroxaban, Apixaban, and Edoxaban in the Treatment and Secondary Prevention of Venous Thromboembolism: A Systematic Review and Meta-analysis of Phase III Trials’

We estimated and compared the risk of clinically identified acquired drug resistance under immediate initiation [the currently recommended antiretroviral therapy (ART) initiation strategy], initiation with CD4 cell count less than 500 cells/μl and initiation with CD4 cell count less than 350 cells/μl. Cohort study based on routinely collected data from the HIV-CAUSAL collaboration. For each individual, baseline was the earliest time when all eligibility criteria (ART-naive, AIDS free, and others) were met after 1999. Acquired drug resistance was defined using the Stanford classification as resistance to any antiretroviral drug that was clinically identified at least 6 months after ART initiation. We used the parametric g-formula to adjust for time-varying (CD4 cell count, HIV RNA, AIDS, ART regimen, and drug resistance testing) and baseline (calendar period, mode of acquisition, sex, age, geographical origin, ethnicity and cohort) characteristics. In 50 981 eligible individuals, 10% had CD4 cell count more than 500 cells/μl at baseline, and 63% initiated ART during follow-up. Of 2672 tests for acquired drug resistance, 794 found resistance. The estimated 7-year risk (95% confidence interval) of acquired drug resistance was 3.2% (2.8,3.5) for immediate initiation, 3.1% (2.7,3.3) for initiation with CD4 cell count less than 500 cells/μl, and 2.8% (2.5,3.0) for initiation with CD4 cell count less than 350 cells/μl. In analyses restricted to individuals with baseline in 2005-2015, the corresponding estimates were 1.9% (1.8, 2.5), 1.9% (1.7, 2.4), and 1.8% (1.7, 2.2). Our findings suggest that the risk of acquired drug resistance is very low, especially in recent calendar periods, and that immediate ART initiation only slightly increases the risk. It is unlikely that drug resistance will jeopardize the proven benefits of immediate ART initiation

Transmitted Drug Resistance in Persons with Acute/Early HIV-1 in San Francisco, 2002-2009

Transmitted HIV-1 drug resistance (TDR) is an ongoing public health problem, representing 10-20% of new HIV infections in many geographic areas. TDR usually arises from two main sources: individuals on antiretroviral therapy (ART) who are failing to achieve virologic suppression, and individuals who acquired TDR and transmit it while still ART-naïve. TDR rates can be impacted when novel antiretroviral medications are introduced that allow for greater virologic suppression of source patients. Although several new HIV medications were introduced starting in late 2007, including raltegravir, maraviroc, and etravirine, it is not known whether the prevalence of TDR was subsequently affected in 2008-2009.We performed population sequence genotyping on individuals who were diagnosed with acute or early HIV (<6 months duration) and who enrolled in the Options Project, a prospective cohort, between 2002 and 2009. We used logistic regression to compare the odds of acquiring drug-resistant HIV before versus after the arrival of new ART (2005-2007 vs. 2008-2009). From 2003-2007, TDR rose from 7% to 24%. Prevalence of TDR was then 15% in 2008 and in 2009. While the odds of acquiring TDR were lower in 2008-2009 compared to 2005-2007, this was not statistically significant (odds ratio 0.65, 95% CI 0.31-1.38; p = 0.27).Our study suggests that transmitted drug resistance rose from 2003-2007, but this upward trend did not continue in 2008 and 2009. Nevertheless, the TDR prevalence in 2008-2009 remained substantial, emphasizing that improved management strategies for drug-resistant HIV are needed if TDR is to be further reduced. Continued surveillance for TDR will be important in understanding the full impact of new antiretroviral medications

Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand.

OBJECTIVE: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV. DESIGN: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. METHODS: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters. RESULTS: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean. CONCLUSION: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age

Cardiovascular and hormonal responses to static handgrip in young and older healthy men

The purpose of this study was to investigate the effect of age on cardiovascular changes and plasma concentrations of adrenomedullin (ADM), catecholamines, endothelin-1 (ET-1) and plasma renin activity (PRA) in healthy men. A total of 15 young (21 ± 0.3 years) and 15 older (64 ± 0.7 years) healthy men performed two 3-min bouts of static handgrip at 30% of maximal voluntary contraction, alternately with each hand without any break between the bouts. During exercise heart rate (HR), blood pressure (BP), stroke volume (SV) and pre-ejection period (PEP) and left ventricle ejection time (LVET) were measured. Blood samples were taken before exercise, at the end of both exercise bouts and in the fifth minute of the recovery period. The handgrip-induced increases in HR and cardiac output were significantly smaller in older than in young men (p < 0.01). SV decreased only in older men (p < 0.001). There were no differences between groups in BP increases. The baseline plasma ADM and catecholamines were higher in older man compared to young subjects. Handgrip caused increases in plasma ADM, ET-1 and PRA only in older men (p < 0.05). The increases in plasma ADM correlated positively with those of noradrenaline (NA), PRA, ET-1 and LVET and negatively with changes in total peripheral resistance (TPR), SV, PEP and PEP/LVET ratio. The increases in plasma ET-1 correlated positively with those of NA, PRA, TPR, mean BP and SV. These results revealed that ADM, ET-1 and angiotensin II can contribute to maintain vascular tone during static exercise in older but not in younger men

Effect of Schistosomiasis and Soil-Transmitted Helminth Infections on Physical Fitness of School Children in Côte d'Ivoire

The burden of parasitic worm infections is considerable, particularly in developing countries. It is acknowledged that parasitic worm infections negatively impact on children's school performance and physical development. A deeper understanding of these linkages is important for updating burden of disease measures. We investigated the relationship between worm infection status and physical fitness of 156 school children from Côte d'Ivoire and controlled for potential confounding of Plasmodium infection (the causative agent of malaria) and environmental parameters (temperature and humidity). Children were diagnosed for parasitic worm and Plasmodium infections, examined by a physician, and participated in a 20 m shuttle run test to assess their maximal oxygen uptake (VO2 max) as a proxy for physical fitness. Most of the children had parasitic worms and a Plasmodium infection. Nevertheless, their physical fitness was excellent (average VO2 max: 52.7 ml kg−1 min−1). The level of VO2 max was only influenced by sex and age, but not by parasitic worms and Plasmodium infections. In future studies, the dynamics of children's physical performance should be assessed before and after control interventions, including the assessment of blood hemoglobin, hematocrit, and nutritional indicators to determine whether physical fitness in worm- and Plasmodium-infected individuals can be further improved

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

Peer reviewe

Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch