Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review

The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin derivatives been used but mostly in south east Asia. Experience has shown that resistance eventually curtails the life-span of antimalarial drugs. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. Current efforts focus on research into new compounds with novel mechanisms of action, and on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and costly ventures. Antimalarial drug development has traditionally been slow but now various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial development pipeline is looking reasonably healthy. Most development relies on the quinoline, antifolate and artemisinin compounds.There is a pressing need to have effective, easy to use, affordable drugs that will last a long time. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focused on the use of artesunate combined with currently used standard drugs, namely, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and depend on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. This review will summarise current antimalarial drug developments and outline recent clinical research that aims to bring artemisinin based combinations to those that need them most

Geometric least squares means ratios for the analysis of Plasmodium falciparum in vitro susceptibility to antimalarial drugs

<p>Abstract</p> <p>Background</p> <p>The susceptibility of microbes such as <it>Plasmodium falciparum </it>to drugs is measured in vitro as the concentration of the drug achieving 50% of maximum effect (IC₅₀); values from a population are summarized as geometric means. For antimalarial drugs, as well as for antibiotics, assessing changes in microbe susceptibility over time under drug pressure would help inform treatment policy decisions, but no standard statistical method exists as yet.</p> <p>Methods</p> <p>A mixed model was generated on log_e-transformed IC₅₀values and calculated geometric least squares means (GLSM) with 90% confidence intervals (CIs). In order to compare IC₅₀s between years, GLSM ratios (GLSMR) with 90%CIs were calculated and, when both limits of the 90%CIs were below or above 100%, the difference was considered statistically significant. Results were compared to those obtained from ANOVA and a generalized linear model (GLM).</p> <p>Results</p> <p>GLSMRs were more conservative than ANOVA and resulted in lower levels of statistical significance. The GLSMRs approach allowed for random effect and adjustment for multiple comparisons. GLM was limited in the number of year-to-year comparisons by the need for a single reference year. The three analyses yielded generally consistent results.</p> <p>Conclusion</p> <p>A robust analytical method can palliate inherent limitations of in vitro sensitivity testing. The random effects GLSMRs with adjustment for multiple comparisons and 90%CIs require only assumptions on the mixed model to be applied. Results are easy to display graphically and to interpret. The GLMSRs should be considered as an option for monitoring changes in drug susceptibility of <it>P. falciparum </it>malaria and other microbes.</p

Ten months of temporal variation in the clinical journey of hospitalised patients with COVID-19: an observational cohort

Background: There is potentially considerable variation in the nature and duration of the care provided to hospitalised patients during an infectious disease epidemic or pandemic. Improvements in care and clinician confidence may shorten the time spent as an inpatient, or the need for admission to an intensive care unit (ICU) or high density unit (HDU). On the other hand, limited resources at times of high demand may lead to rationing. Nevertheless, these variables may be used as static proxies for disease severity, as outcome measures for trials, and to inform planning and logistics. Methods: We investigate these time trends in an extremely large international cohort of 142,540 patients hospitalised with COVID-19. Investigated are: time from symptom onset to hospital admission, probability of ICU/HDU admission, time from hospital admission to ICU/HDU admission, hospital case fatality ratio (hCFR) and total length of hospital stay. Results: Time from onset to admission showed a rapid decline during the first months of the pandemic followed by peaks during August/September and December 2020. ICU/HDU admission was more frequent from June to August. The hCFR was lowest from June to August. Raw numbers for overall hospital stay showed little variation, but there is clear decline in time to discharge for ICU/HDU survivors. Conclusions: Our results establish that variables of these kinds have limitations when used as outcome measures in a rapidly-evolving situation. Funding: This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [215091/Z/18/Z] and the Bill and Melinda Gates Foundation [OPP1209135]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Systematic review of studies generating individual participant data on the efficacy of drugs for treating soil-transmitted helminthiases and the case for data-sharing

Preventive chemotherapy and transmission control (PCT) by mass drug administration is the cornerstone of the World Health Organization (WHO)’s policy to control soil-transmitted helminthiases (STHs) caused by Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm) and hookworm species (Necator americanus and Ancylostama duodenale) which affect over 1 billion people globally. Despite consensus that drug efficacies should be monitored for signs of decline that could jeopardise the effectiveness of PCT, systematic monitoring and evaluation is seldom implemented. Drug trials mostly report aggregate efficacies in groups of participants, but heterogeneities in design complicate classical meta-analyses of these data. Individual participant data (IPD) permit more detailed analysis of drug efficacies, offering increased sensitivity to identify atypical responses potentially caused by emerging drug resistance

Ten months of temporal variation in the clinical journey of hospitalised patients with COVID-19: an observational cohort

Background: There is potentially considerable variation in the nature and duration of the care provided to hospitalised patients during an infectious disease epidemic or pandemic. Improvements in care and clinician confidence may shorten the time spent as an inpatient, or the need for admission to an intensive care unit (ICU) or high density unit (HDU). On the other hand, limited resources at times of high demand may lead to rationing. Nevertheless, these variables may be used as static proxies for disease severity, as outcome measures for trials, and to inform planning and logistics. Methods: We investigate these time trends in an extremely large international cohort of 142,540 patients hospitalised with COVID-19. Investigated are: time from symptom onset to hospital admission, probability of ICU/HDU admission, time from hospital admission to ICU/HDU admission, hospital case fatality ratio (hCFR) and total length of hospital stay. Results: Time from onset to admission showed a rapid decline during the first months of the pandemic followed by peaks during August/September and December 2020. ICU/HDU admission was more frequent from June to August. The hCFR was lowest from June to August. Raw numbers for overall hospital stay showed little variation, but there is clear decline in time to discharge for ICU/HDU survivors. Conclusions: Our results establish that variables of these kinds have limitations when used as outcome measures in a rapidly-evolving situation. Funding: This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [215091/Z/18/Z] and the Bill and Melinda Gates Foundation [OPP1209135]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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

Women's Experiences and Views about Costs of Seeking Malaria Chemoprevention and other Antenatal Services: A Qualitative Study from two Districts in Rural Tanzania.

The Tanzanian government recommends women who attend antenatal care (ANC) clinics to accept receiving intermittent preventive treatment against malaria during pregnancy (IPTp) and vouchers for insecticide-treated nets (ITNs) at subsidized prices. Little emphasis has been paid to investigate the ability of pregnant women to access and effectively utilize these services. To describe the experience and perceptions of pregnant women about costs and cost barriers for accessing ANC services with emphasis on IPTp in rural Tanzania. Qualitative data were collected in the districts of Mufindi in Iringa Region and Mkuranga in Coast Region through 1) focus group discussions (FGDs) with pregnant women and mothers to infants and 2) exit-interviews with pregnant women identified at ANC clinics. Data were analyzed manually using qualitative content analysis methodology. FGD participants and interview respondents identified the following key limiting factors for women's use of ANC services: 1) costs in terms of money and time associated with accessing ANC clinics, 2) the presence of more or less official user-fees for some services within the ANC package, and 3) service providers' application of fines, penalties and blame when failing to adhere to service schedules. Interestingly, the time associated with travelling long distances to ANC clinics and ITN retailers and with waiting for services at clinic-level was a major factor of discouragement in the health seeking behaviour of pregnant women because it seriously affected their domestic responsibilities. A variety of resource-related factors were shown to affect the health seeking behaviour of pregnant women in rural Tanzania. Thus, accessibility to ANC services was hampered by direct and indirect costs, travel distances and waiting time. Strengthening of user-fee exemption practices and bringing services closer to the users, for example by promoting community-directed control of selected public health services, including IPTp, are urgently needed measures for increasing equity in health services in Tanzania

In vitro and in vivo antileishmanial efficacy of a combination therapy of diminazene and artesunate against Leishmania donovani in BALB /c mice

The in vitro and in vivo activity of diminazene (Dim), artesunate (Art) and combination of Dim and Art (Dim-Art) against Leishmania donovani was compared to reference drug; amphotericin B. IC50 of Dim-Art was found to be $2.28 \pm 0.24 \mu$ g/mL while those of Dim and Art were $9.16 \pm 0.3 \mu$ g/mL and $4.64 \pm 0.48 \mu$ g/mL respectively. The IC50 for Amphot B was $0.16 \pm 0.32 \mu$ g/mL against stationary-phase promastigotes. In vivo evaluation in the L. donovani BALB/c mice model indicated that treatments with the combined drug therapy at doses of 12.5 mg/kg for 28 consecutive days significantly ($p < 0.001$) reduced parasite burden in the spleen as compared to the single drug treatments given at the same dosages. Although parasite burden was slightly lower ($p < 0.05$) in the Amphot B group than in the Dim-Art treatment group, the present study demonstrates the positive advantage and the potential use of the combined therapy of Dim-Art over the constituent drugs, Dim or Art when used alone. Further evaluation is recommended to determine the most efficacious combination ratio of the two compounds.Comment: 4 Pages, 3 Figure

Epidemiological Interactions between Urogenital and Intestinal Human Schistosomiasis in the Context of Praziquantel Treatment across Three West African Countries

© 2015 Knowles et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The attached file is the published version of the article

Prospective validation of the 4C prognostic models for adults hospitalised with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol

Purpose: To prospectively validate two risk scores to predict mortality (4C Mortality) and in-hospital deterioration (4C Deterioration) among adults hospitalised with COVID-19. // Methods: Prospective observational cohort study of adults (age ≥18 years) with confirmed or highly suspected COVID-19 recruited into the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study in 306 hospitals across England, Scotland and Wales. Patients were recruited between 27 August 2020 and 17 February 2021, with at least 4 weeks follow-up before final data extraction. The main outcome measures were discrimination and calibration of models for in-hospital deterioration (defined as any requirement of ventilatory support or critical care, or death) and mortality, incorporating predefined subgroups. // Results: 76 588 participants were included, of whom 27 352 (37.4%) deteriorated and 12 581 (17.4%) died. Both the 4C Mortality (0.78 (0.77 to 0.78)) and 4C Deterioration scores (pooled C-statistic 0.76 (95% CI 0.75 to 0.77)) demonstrated consistent discrimination across all nine National Health Service regions, with similar performance metrics to the original validation cohorts. Calibration remained stable (4C Mortality: pooled slope 1.09, pooled calibration-in-the-large 0.12; 4C Deterioration: 1.00, –0.04), with no need for temporal recalibration during the second UK pandemic wave of hospital admissions. // Conclusion: Both 4C risk stratification models demonstrate consistent performance to predict clinical deterioration and mortality in a large prospective second wave validation cohort of UK patients. Despite recent advances in the treatment and management of adults hospitalised with COVID-19, both scores can continue to inform clinical decision making