Hubert Barennes

Efficacy of artesunate-amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis.

BackgroundArtesunate and amodiaquine (AS&AQ) is at present the worlds second most widely used artemisinin-based combination therapy (ACT). It was necessary to evaluate the efficacy of ACT, recently adopted by the World Health Organization (WHO) and deployed over 80 countries, in order to make an evidence-based drug policy.MethodsAn individual patient data (IPD) analysis was conducted on efficacy outcomes in 26 clinical studies in sub-Saharan Africa using the WHO protocol with similar primary and secondary endpoints.ResultsA total of 11,700 patients (75% under 5 years old), from 33 different sites in 16 countries were followed for 28 days. Loss to follow-up was 4.9% (575/11,700). AS&AQ was given to 5,897 patients. Of these, 82% (4,826/5,897) were included in randomized comparative trials with polymerase chain reaction (PCR) genotyping results and compared to 5,413 patients (half receiving an ACT).AS&AQ and other ACT comparators resulted in rapid clearance of fever and parasitaemia, superior to non-ACT. Using survival analysis on a modified intent-to-treat population, the Day 28 PCR-adjusted efficacy of AS&AQ was greater than 90% (the WHO cut-off) in 11/16 countries. In randomized comparative trials (n = 22), the crude efficacy of AS&AQ was 75.9% (95% CI 74.6–77.1) and the PCR-adjusted efficacy was 93.9% (95% CI 93.2–94.5). The risk (weighted by site) of failure PCR-adjusted of AS&AQ was significantly inferior to non-ACT, superior to dihydroartemisinin-piperaquine (DP, in one Ugandan site), and not different from AS+SP or AL (artemether-lumefantrine). The risk of gametocyte appearance and the carriage rate of AS&AQ was only greater in one Ugandan site compared to AL and DP, and lower compared to non-ACT (p = 0.001, for all comparisons). Anaemia recovery was not different than comparator groups, except in one site in Rwanda where the patients in the DP group had a slower recovery.ConclusionAS&AQ compares well to other treatments and meets the WHO efficacy criteria for use against falciparum malaria in many, but not all, the sub-Saharan African countries where it was studied. Efficacy varies between and within countries. An IPD analysis can inform general and local treatment policies. Ongoing monitoring evaluation is required.

A randomized trial of amodiaquine and artesunate alone and in combination for the treatment of uncomplicated falciparum malaria in children from Burkina Faso.

Combining artesunate (AR) with existing antimalarial drugs may improve cure rates, delay emergence of resistance and reduce parasite clearance time. In order to investigate the latter, we conducted a randomized clinical trial testing the AR plus amodiaquine (AQ) combination for the treatment of uncomplicated Plasmodium falciparum malaria in Burkina Faso. Children aged 1–15u2003years were randomly assigned to either AQ (10u2003mg/kg) or AR (4u2003mg/kg first day then half dose) or AQu2003+u2003AR (AQAR) as a single daily dose under supervision for three consecutive days for all groups. Follow‐up lasted 28u2003days. Primary endpoints were parasite and fever clearance time. Eighty‐seven children were evaluated: 27 received AQ, 27 AR and 33 AQAR. Using an intention to treat analysis, fever clearance time was similar in the three groups. However, it was significantly faster in the AR (1.21u2003days; Pu2003=u20030.02) and AQAR groups (1.19u2003days; Pu2003<u20030.01) than in the AQ group (1.46u2003days) when excluding other concomitant causes of fever. Parasite clearance time was faster in AR (1.13u2003days; Pu2003=u20030.008) and AQAR groups (1.13u2003days; Pu2003<u20030.01) than in the AQ group (1.6u2003days). All children cleared their parasites by day 14, including the child with Late Parasitological Failure (LPF) at day 7 after rescue treatment. Only one child (4%) from the AR group and one (4%) from the AQ group presented with asymptomatic parasitaemia at day 7 and day 21, respectively (LPF). Gametocyte carriage was not detectable in any group during follow‐up nor was any adverse reaction observed. While resistance to first‐line treatment (chloroquine) is already established in the country, AQ and AR used alone or in combination therapy proved highly efficacious in our study. Burkina Faso stands in a very good situation for an internationally recommended switch to AR‐containing combination as first‐line treatment for uncomplicated malaria. Including AQ in this regimen seems the best option.

Sublingual sugar for hypoglycaemia in children with severe malaria: A pilot clinical study

BackgroundHypoglycaemia is a poor prognostic indicator in severe malaria. Intravenous infusions are rarely feasible in rural areas. The efficacy of sublingual sugar (SLS) was assessed in a pilot randomized controlled trial among hypoglycaemic children with severe malaria in Mali.MethodsOf 151 patients with presumed severe malaria, 23 children with blood glucose concentrations < 60 mg/dl (< 3.3 mmol/l) were assigned randomly to receive either intravenous 10% glucose (IVG; n = 9) or sublingual sugar (SLS; n = 14). In SLS, a teaspoon of sugar, moistened with a few drops of water, was gently placed under the tongue every 20 minutes. The child was put in the recovery position. Blood glucose concentration (BGC) was measured every 5–10 minutes for the first hour. All children were treated for malaria with intramuscular artemether. The primary outcome measure was treatment response, defined as reaching a BGC of >= 3.3 mmol/l (60 mg/dl) within 40 minutes after admission. Secondary outcome measures were early treatment response at 20 minutes, relapse (early and late), maximal BGC gain (CGmax), and treatment delay.ResultsThere was no significant difference between the groups in the primary outcome measure. Treatment response occurred in 71% and 67% for SLS and IVG, respectively. Among the responders, relapses occurred in 30% on SLS at 40 minutes and in 17% on IVG at 20 minutes. There was one fatality in each group. Treatment failures in the SLS group were related to children with clenched teeth or swallowing the sugar, whereas in the IVG group, they were due to unavoidable delays in beginning an infusion (median time 17.5 min (range 3–40).Among SLS, the BGC increase was rapid among the nine patients who really kept the sugar sublingually. All but one increased their BGC by 10 minutes with a mean gain of 44 mg/dl (95%CI: 20.5–63.4).ConclusionSublingual sugar appears to be a child-friendly, well-tolerated and effective promising method of raising blood glucose in severely ill children. More frequent repeated doses are needed to prevent relapse. Children should be monitored for early swallowing which leads to delayed absorption, and in this case another dose of sugar should be given. Sublingual sugar could be proposed as an immediate first aid measure while awaiting intravenous glucose. In many cases it may avert the need for intravenous glucose.

Blood glucose and prognosis in children with presumed severe malaria: is there a threshold for 'hypoglycaemia'?

Objectivesu2002 Hypoglycaemia (glucose <2.2u2003mmol/l) is a defining feature of severe malaria, but the significance of other levels of blood glucose has not previously been studied in children with severe malaria.

Gaps between research and public health priorities in low income countries: evidence from a systematic literature review focused on Cambodia

BackgroundEvidence-based public health requires that research provides policymakers with reliable and accessible information reflecting the disease threats. We described the scientific production of research in Cambodia and assessed to what extent it provides appropriate insights and implications for practice to guide health policymakers and managers and knowledge relevant for translation.MethodsWe conducted a systematic review of scientific articles published on biomedical research in Cambodia. Regression analysis assessed the trends over time and factors associated with actionable messages in the articles’ abstracts.ResultsFrom 2000 to 2012, 628 articles were published in 237 journals with a significant increase over time (from 0.6/million population to 5.9/million population, slope coefficient 7.6, 95% CI 6.5–8.7, pu2009<u20090.001). Most publications on diseases addressed communicable diseases (nu2009=u2009410, 65.3%). Non-communicable diseases (NCD) were under-addressed (7.7% of all publications) considering their burden (34.5% of the disease burden). Of all articles, 67.8% reported descriptive studies and 4.3% reported studies with a high level of evidence; 27.4% of studies were led by an institution based in Cambodia. Factors associated with an actionable message (nu2009=u200973, 26.6%) were maternal health (OR 3.08, 95% CI 1.55–6.13, pu2009=u20090.001), the first author’s institution being Cambodian (OR 1.78, 95% CI 1.06–2.98, pu2009=u20090.02) and a free access to full article (OR 3.07, 95% CI 1.08–8.70, pu2009=u20090.03). Of all articles, 87% (nu2009=u2009546) were accessible in full text from Cambodia.ConclusionsScientific publications do not fully match with health priorities. Gaps remain regarding NCD, implementation studies, and health system research. A health research agenda would help align research with health priorities. We recommend 1) that the health authorities create an online repository of research findings with abstracts in the local language; 2) that academics emphasize the importance of research in their university teaching; and 3) that the researcher teams involve local researchers and that they systematically provide a translation of their abstracts upon submission to a journal. We conclude that building the bridge between research and public health requires a willful, comprehensive strategy rather than relying solely only publications.

An assessment of early diagnosis and treatment of malaria by village health volunteers in the Lao PDR

BackgroundEarly diagnosis and treatment (EDAT) is crucial to reducing the burden of malaria in low-income countries. In the Lao PDR, this strategy was introduced in 2004-2005 and an assessment was performed at the community level in January 2007.MethodsEDAT with malaria rapid diagnostic test (MRDT) and artemisinin combination therapy (ACT) was prospectively assessed among 36 randomized village health volunteers (VHVs) and 720 patients in six malaria-endemic provinces of Laos (three pilot provinces (PP), and three non-pilots provinces (NPP)). ACT was also retrospectively assessed among 2188 patients within the same areas from June to November 2006. Two checklists were used and scores were calculated.ResultsEDAT performance of the VHVs was rated better in PP than in NPP (16.67% versus 38.89%, respectively, p = 0.004). Nearly all VHVs could diagnose malaria but only 16 (44%) could describe the symptoms of severe malaria. In January 2007, 31/720 (4%) patients tested positive using the Paracheck® test, 35 (5%) with microscopy (sensibility: 74.3%, specificity 99.3%, positive and negative predictive values: 83.9% and 98.7%, respectively). Patients from June to November were at higher risk of malaria: 35.19% of 2,188 febrile patients were positive (OR: 10.6, 95%CI: 7.4-15.5, p < 0.000). VHVs reported the MRDT easy to use, and yielded a satisfactory performance score. EDAT performance was rated as poor despite satisfactory results regarding ACT treatment, duration and dosages. Pre-referral treatment of severe malaria was infrequent and often inadequate, with 20% of these patients dying. Results suggest a higher mortality from severe malaria than officially reported. Shortage of ACT was frequent.Discussion and conclusionMRDT and ACT are useful and efficient and can be used by VHVs. VHVs global EDAT performance is enhanced through training and monitoring. Persistent gaps in knowledge, care of patients and wrong treatment have to be addressed.

Dose-Dependent Resorption of Quinine after Intrarectal Administration to Children with Moderate Plasmodium falciparum Malaria

ABSTRACT The pharmacokinetics of increasing doses of an intrarectal Cinchona alkaloid combination containing 96.1% quinine, 2.5% quinidine, 0.68% cinchonine, and 0.67% cinchonidine (Quinimax) was compared to that of parenteral regimens in 60 children with moderate malaria. Quinine exhibited a nonlinear pharmacokinetics, suggesting a saturation of rectal resorption. When early rejections appeared, blood quinine concentrations decreased by 30 to 50% and were restored by an immediate half-dose administration of the drug. Rectal administration of doses of 16 or 20 mg/kg of body weight led to concentration-time profiles in blood similar to those of parenteral regimens and could be an early treatment of childhood malaria.

Reasons for routine episiotomy: A mixed-methods study in a large maternity hospital in Phnom Penh, Cambodia

Abstract First documented in 1741, the practice of episiotomy substantially increased worldwide during the 20th century. However, research shows that episiotomy is not effective in reducing severe perineal trauma and may be harmful. Using a mixed-methods approach, we conducted a study in 2013–14 on why obstetricians and midwives in a large maternity hospital in Phnom Penh, Cambodia, still do routine episiotomies. The study included the extent of the practice, based on medical records; a retrospective analysis of the delivery notes of a random sample of 365 patients; and 22 in-depth interviews with obstetricians, midwives and recently delivered women. Of the 365 women, 345 (94.5%, 95% CI: 91.7–96.6) had had an episiotomy. Univariate analysis showed that nulliparous women underwent episiotomy more frequently than multiparous women (OR 7.1, 95% CI 2.0–24.7). The reasons given for this practice by midwives and obstetricians were: fear of perineal tears, the strong belief that Asian women have a shorter and harder perineum than others, lack of time in overcrowded delivery rooms, and the belief that Cambodian women would be able to have a tighter and prettier vagina through this practice. A restrictive episiotomy policy and information for pregnant women about birthing practices through antenatal classes should be implemented as soon as possible. Résumé Documentée pour la première fois en 1741, la pratique de l’épisiotomie s’est nettement développée dans le monde au XXe siècle. Néanmoins, il a été démontré que l’épisiotomie n’était pas efficace pour réduire les traumatismes périnéaux graves et pouvait être dommageable. Moyennant une méthode « mixte », nous avons réalisé une étude en 2013–2014 sur les raisons incitant les obstétriciens et les sages-femmes d’une grande maternité de Phnom Penh, Cambodge, à pratiquer encore des épisiotomies systématiques. L’étude incluait une évaluation de l’ampleur de la pratique, sur la base des dossiers médicaux ; une analyse rétrospective des comptes rendus d’accouchements d’un échantillon aléatoire de 365 patientes ; et 22 entretiens approfondis avec des obstétriciens, des sages-femmes et de jeunes accouchées. Sur les 365 femmes, 345 (94,5%, 95% IC : 91,7–96,6) avaient eu une épisiotomie. Une analyse univariée a montré que les nullipares subissaient plus fréquemment une épisiotomie que les multipares (RC 7,1, 95% IC 2,0–24,7). Pour expliquer cette pratique, les sages-femmes et les obstétriciens ont cité : la peur de déchirures périnéales, la conviction que le périnée des asiatiques était plus court et plus rigide que les autres, le manque de temps dans des salles de travail surchargées, et le sentiment que les Cambodgiennes pourraient avoir un vagin plus étroit et « plus joli » à travers cette pratique. Nous recommandons la mise en łuvre dès que possible d’une politique restrictive de recours à l’épisiotomie et une information pour les femmes enceintes des pratiques d’accouchement lors de séances de préparation prénatales. Resumen Documentada por primera vez en 1741, la práctica de episiotomía aumentó considerablemente a nivel mundial durante el siglo XX. Sin embargo, las investigaciones muestran que la episiotomía no es eficaz para disminuir el trauma perineal grave y puede ser dañina. Utilizando una estrategia de métodos combinados, realizamos un estudio en 2013–14 sobre por qué los obstetras y parteras en una importante maternidad en Phnom Penh, Camboya, aún efectúan episiotomías de rutina. El estudio incluyó la frecuencia de la práctica, basada en expedientes médicos, un análisis retrospectivo de las notas sobre el parto de una muestra aleatoria de 365 pacientes, y 22 entrevistas a profundidad con obstetras, parteras y mujeres que dieron a luz recientemente. De las 365 mujeres, 345 (94.5%, 95% IC: 91.7–96.6) habían tenido una episiotomía. El análisis univariado mostró que a las mujeres nulíparas les practicó una episiotomía con más frecuencia que a las multíparas (OR 7.1, 95% CI 2.0–24.7). Las razones dadas para esta práctica por parteras y obstetras fueron: temor de desgarros perineales, la convicción de que las mujeres asiáticas tienen un perineo más corto y más duro que otras, la falta de tiempo en salas de parto abarrotadas, y la creencia de que las mujeres camboyana podrían tener una “vagina más estrecha y más bonita” por medio de esta práctica. Se debe aplicar lo antes posible una política restrictiva referente a la episiotomía y proporcionar información a mujeres embarazadas sobre las prácticas relacionadas con el parto por medio de clases prenatales.

Caring for patients with rabies in developing countries – the neglected importance of palliative care

Although limited publications address clinical management of symptomatic patients with rabies in intensive care units, the overwhelming majority of human rabies cases occur in the rural setting of developing countries where healthcare workers are few, lack training and drugs. Based on our experience, we suggest how clinicians in resource‐limited settings can make best use of essential drugs to provide assistance to patients with rabies and their families, at no risk to themselves. Comprehensive and compassionate patient management of furious rabies should aim to alleviate thirst, anxiety and epileptic fits using infusions, diazepam or midazolam and antipyretic drugs via intravenous or intrarectal routes. Although the patient is dying, respiratory failure must be avoided especially if the family, after being informed, wish to take the patient home alive for funereal rites to be observed. Healthcare staff should be trained and clinical guidelines should be updated to include palliative care for rabies in endemic countries.

Enforcing the International Code of Marketing of Breast-milk Substitutes for Better Promotion of Exclusive Breastfeeding Can Lessons Be Learned?

Exclusive breastfeeding, one of the best natural resources, needs protection and promotion. The International Code of Marketing of Breast-milk Substitutes (the Code), which aims to prevent the undermining of breastfeeding by formula advertising, faces implementation challenges. We reviewed frequently overlooked challenges and obstacles that the Code is facing worldwide, but particularly in Southeast Asia. Drawing lessons from various countries where we work, and following the example of successful public health interventions, we discussed legislation, enforcement, and experiences that are needed to successfully implement the Code. Successful holistic approaches that have strengthened the Code need to be scaled up. Community-based actions and peer-to-peer promotions have proved successful. Legislation without stringent enforcement and sufficient penalties is ineffective. The public needs education about the benefits and ways and means to support breastfeeding. It is crucial to combine strong political commitment and leadership with strict national regulations, definitions, and enforcement. National breastfeeding committees, with the authority to improve regulations, investigate violations, and enforce the laws, must be established. Systematic monitoring and reporting are needed to identify companies, individuals, intermediaries, and practices that infringe on the Code. Penalizing violators is crucial. Managers of multinational companies must be held accountable for international violations, and international legislative enforcement needs to be established. Further measures should include improved regulations to protect the breastfeeding mother: large-scale education campaigns; strong penalties for Code violators; exclusion of the formula industry from nutrition, education, and policy roles; supportive legal networks; and independent research of interventions supporting breastfeeding.