Pharmaco-epidemiology of artemisinin-based combination therapy in the context of impact evaluation of artemether-lumefantrine on malaria morbidity and mortality during programmatic implementation in rural Tanzania

In sub-Saharan Africa previous efforts to control malaria have proved less successful mostly due to prolonged use of less efficacious mono-therapy drugs to which Plasmodium falciparum has developed drug resistance. In most parts of malaria endemic regions chloroquine (CQ) was found to be poorly effective for several decades but it was still being prescribed until recently. In Tanzania, for instance, P.falciparum was already resistant to CQ in more than 60% of all P. falciparum positive patients back in the late 80’s but was still used until when it was possible to replace it by sulfadoxine-pyrimethamine (SP) in 2001. SP is anti-folate sulfa based anti-malaria drug that was adopted as an interim first line drug by many malaria endemic countries as there was no affordable immediate alternative to CQ. Elsewhere in sub- Saharan Africa Zambia was the first African country to embrace policy change with efficacious anti-malaria combination therapy using Artemisinin-based Combination Therapy (ACT) back in 2004 after support from global funds. Until 1990, the past three decades have had a sustained global focus on malaria control strategy with the aim of intensifying developing intervention tools. This was preceded by specific eradication efforts of the 1940s, which were intensified in most parts of Southern Europe and America. It was during this period that the global focus on malaria sustained a great deal of change. In that same period therefore, the main focus was on technical issues as well as research and development for new tools, that could lead to advances in drug and vaccine development alongside vector control strategies. There were medium term gains during this period but at the same time some challenges were recorded. Key among these challenges was the fragmented global efforts, whereby there was total loss of a broad based global focus to a joint strategy on the fight against malaria. This resulted in little global support with no clear roadmap for developing states, mostly in Sub Saharan Africa, to establish adequate health systems and primary health care for comprehensive malaria management. These challenges resulted in to overuse of ant-malaria mono-therapies that were cheaply available in most of these countries and led to development of parasite resistance to drugs with far reaching consequences. Towards the mid of 1990s, the combination of a worsening malaria situation and emerging positive technical developments led to renewed global focus on malaria control. It is for the same reason that in 2000 the global head of states developed a joint position to address the global disease burden most affecting developing countries as part of the Millennium Development Goals (MDG) of global programme on development to be achieved by 2015. Two goals were developed to improved health for the Under Five (U5e.i, MDG4 and MGD6. MGD4 sets target to reduce child mortality by two third by 2015 while MGD6 aims at combating malaria and other major infectious diseases (HIV and TB) by year 2015 as compared to baseline 1990. As the results of the launch of these global initiatives, a number of new strategies and tools against malaria have been developed and existing ones sharpened to better address the problem. Not later than beginning of last decade, Artemisinin-based Combination Therapy (ACT) emerged as potential therapeutically efficacious proven tool to combat malaria. In the face of growing anti-malarial drug resistance due to the use of mono-therapies, ACT has placed itself as a novel treatment for malaria treatment. Use of insecticide Treated Mosquito bed-Nets (ITN) has also been advocated. With the support of Global Health Partners, ITN have been made available to the vulnerable persons within endemic communities. Support to control malaria has exceeded $1000 million a year but malaria still exerts a threat to the U5 and expectant mothers. In Tanzania ACT as the first line anti-malaria drug was introduced in late 2006, scaled for country wide use in 2007. The ACT implementations in Tanzania bear some similarities with approaches in other African countries but there are still major differences. Tanzania has a homogenous health system that facilitated the rolled out of the malaria control programme as part of the primary Health Care (PHC) system. This was also supported by the evidence generated from the North-South research collaborations that informed policy makers. Government and non-state collaboration within Tanzania was key in informing the above process. In some cases cross boarder collaboration among economic blocks of East Africa and Southern African Development Community (SADC) have provided insights into the control of malaria in the continent. Some of the novel implementation tools developed and tested in Tanzania have been applied in the rest of Sub-Saharan malaria endemic states and often supported the global campaign against malaria. In Tanzania, political stability and peace for over four decades has also made it easy for quick policy change and scale up of control interventions using ACT this could have been different in neighboring nations like Uganda, Sudan, Mozambique and Democratic republic of Congo which have experienced civil strife during this period. Tanzania has emerged as one of the few African countries that provided the ground to test some of the most successful malaria control interventions for the rest of the world to up-scale. The Kilombero River basin in Ifakara Tanzania is a known cradle for malaria endemicity. Several novel interventions have been tested for efficacy and then evaluated for impact during roll out as programmes. Most findings presented in this thesis have been largely derived from the Ifakara Demographic surveillance system among other study sites in Tanzania. This work has provided major insights into the policy change for ACT and its implementation at the national scale. The aim of the PhD work presented here was to contribute to a better understanding of the impact of the ACT introduction on malaria morbidity and mortality in rural Tanzania and to monitor its long-term safety when used at country wide. Availability of baseline efficacy profile, mobilization of stakeholders including participating communities and preparedness among researchers accelerated policy implementation in most part of Tanzania right from the on-set of policy inception. Findings from the Interdisciplinary Monitoring Project of Anti-malaria Combination Therapy (IMPACT) and East African Network for Monitoring Anti-malaria Treatment (EANMAT) programmes as described in this thesis have provided evidence that informed policy. The invivo studies have shown that artemetherlumefantrine (AL) was nearly 100 Chain Reaction (PCR) in children U5 years in the years prior policy change. We have also shown that in real life situation it is possible to build comprehensive researchers-policy makers-pharmaceutical industry partnership to implement strategies for monitoring safety and proper use of anti-malaria drugs as reported in the programme Artemether-Lumefantrine In Vulnerable patients: Exploring health Impact (ALIVE). We were able, for the first time in the ALIVE project to describe a compliance of more than 95 for AL in a randomized study conducted at community level. We have report the establishment of a pharmacovigilance system in a rural community that also tested for the first time the use of mobile phone technology with SMS to report anti-malarial serious adverse events (SAE). The ALIVE project provided an assessment of the impact of ACT and other malarial interventions on child mortality as well as on malaria transmission. It demonstrated that for every 10 parasitaemia [IRR=0.52; 95 under five mortality when adjusted for other key factors [IRR= 0.89; 95 ALIVE also showed the relationship of key contextual factors with malaria interventions and U5 child mortality. Food security was major determinant of under five child mortality; notably the rice yields was responsible for nearly 36 CI=0.54 to 0.75]. As far as malaria transmission is concerned, we observed parallel a 65 reduction of parasite prevalence in asymptomatic community members of study area as compared to baseline in 2006 before ACT was introduced in the study population. Lastly, these effects are likely to be sustainable since the efficacy of AL, as evaluated with an invivo study conducted one year after implementation has remained above 96 Kilombero valley in spite of its wide scale use. The findings of this thesis attest the importance of policy change in malaria control supported by evidence gathered from operational researches. The lessons learned from this work will be relevant to similar interventions locally and on a global scale in most malaria affected communities. We have also learnt that safety and compliance issues of medicinal products that are deployed at large scale such as ACT should be monitored and managed by strong partnership involving the Ministry of Health and it allied departments, the pharmaceutical industries when possible, the researchers and most importantly with full participation and support of local leadership and communities. We, recommend that this partnership gain support from other global health partners to ensure safety of drugs through rigorous monitoring of its use and long life span. Capacity building of market and policy implementers is another critical aspect that should be given priority. We also recommend that resources be made available to strengthen the health system (human resource, Health Information System and Infrastructure) in order to gain sustained results in malaria control. This will further create enabling environment and a critical mass of scientists and public health experts to spearhead anti-malaria policy implementations properly and monitor it on timely basis. As outlined in this work, a successful campaign against malaria can be realized through combining efforts of researchers, policy makers, global health development partners and communities. This partnership has lead to real life time achievements related programmes, such as the 1940s malaria elimination campaign in Sardinia Island of Italy. ---------- Zusammenfassung: In Subsahara-Afrika haben sich die bisherigen Bemühungen zur Bekämpfung von Malaria als wenig erfolgreich erwiesen, da vor allem auf eine Mono-Medikamente-Therapie gesetzt wurde, gegen welche Plasmodium falciparum inzwischen Resistenzen entwickelt hat. Obwohl sich Chloroquin (CQ) in den letzten Jahrzehnten in den meisten Malariagebieten als nur teilweise wirksam erwies, wurde es noch bis vor kurzem eingesetzt. Bereits in den späten 1980er Jahren wurden beispielsweise in Tansania in über 60 P.falciparum-positiven Patienten Resistenzen gegenüber CQ festgestellt. Trotzdem wurde CQ erst im Jahre 2001 durch Sulfadoxin-Pyrimethamin (SP) ersetzt. SP ist ein Malaria- Medikament, das in vielen Malaria-endemischen Ländern als Zwischenlösung eingeführt wurde, da noch keine erschwingliche Alternative zu CQ zur Verfügung stand. Etwa zur selben Zeit erlebte Sambia als erstes afrikanisches Land einen Politikwandel und führte 2004 mithilfe globaler Fördermittel die effizientere Artemisinin-based Combination Therapy (ACT) ein. Zwischen 1960 und 1990 wurde der Fokus auf eine nachhaltige Malaria-Kontroll-Strategie gelegt, die zum Ziel hatte, die Interventionsstrategien der Entwicklungsländer zu fördern. Vorangegangen sind in den 1940er Jahren spezifische Maßnahmen zur Ausrottung, wobei der Schwerpunkt auf technische Fragen sowie auf die Forschung und Entwicklung von neuen Werkzeugen gelegt wurde, die zu Fortschritten in der Medikamenten- und Impfstoffentwicklung, sowie in der Vektorkontrollstrategie hätten führen sollen. Es gab mittelfristig einige Errungenschaften, gleichzeitig entstanden aber in diesem Zeitraum auch neue Herausforderungen. Eine Hauptherausforderung lag in den globalen Bemühungen, die eine fokussierte, breit angelegte Strategie zur Bekämpfung von Malaria erschwerte. Dies war auch der Grund, weshalb es den Ländern südlich der Sahara nicht gelang, eine angemessene Gesundheitsversorgung aufzubauen. Sie waren deshalb immer noch von veralteten Mono- Therapien abhängig, die zwar in den meisten Ländern zu günstigen Preisen zur Verfügung standen, aber wegen deren chronischen Überbeanspruchung zur Entwicklung von Resistenzen beitrugen. Mitte der 1990er Jahre führte die verschlechterte Situation bezüglich Malaria zusammen mit den sich abzeichnenden positiven technischen Entwicklungen dazu, dass die Kontrolle von Malaria wieder in den globalen Fokus rückte. Aus dem gleichen Grund versuchten im Jahr 2000 verschiedene Staatschefs eine gemeinsame Position bezüglich der Strategie zur Bekämpfung der wichtigsten Krankheiten zu finden. Zwei Ziele wurden in Form der Millennium Development Goals (MDG) konkret formuliert und sollten bis 2015 erreicht werden. Das MGD 4 bestand darin die Kindersterblichkeit bezogen auf das Jahr 1990 um zwei Drittel zu senken, während MGD 6 darauf abzielte die Bekämpfung von Malaria und anderen schweren Infektionskrankheiten (z.B. HIV und TB) bezüglich der Situation in 1990 deutlich zu verbessern. Diese globalen Initiativen vermochten einige bereits bestehenden Interventionsstrategien gegen Malaria zu verbessern und halfen zur Entwicklung einer Reihe neuer Instrumente und Strategien bei. Erst zu Beginn des letzten Jahrzehnts kam die „Artemisinin-based Combination Therapy“ (ACT) als eine Alternative zu den Mono-Therapien auf, welche wegen der wachsenden Resistenz immer mehr an Wirksamkeit einbüsste. Des Weiteren wurde auch für den Einsatz von „insecticide treated mosquito bed-nets“ (ITNs) plädiert. Dank der Unterstützung von Global Health Partnern, konnten die ITNs nun für viele in Malariaendemischen Gebieten lebende Personen zugänglich gemacht werden. Obwohl bisher jährlich über 1000 Millionen US$ für die Bekämpfung von Malaria ausgegeben wurden, stellt Malaria weiterhin eine grosse Bedrohung vor allem für Kinder unter 5 Jahren und für schwangere Frauen dar. ACT wurde als Haupt-Malaria-Medikament in Tansania gegen Ende 2006 eingeführt und 2007 auf das ganze Land ausgeweitet. Die Realisierung dieses Projekts hatte einige Ähnlichkeiten mit Ansätzen in anderen afrikanischen Ländern, jedoch gibt es nach wie vor grosse Unterschiede. Das homogene Gesundheitssystem in Tansania im Allgemeinen und das „Primary Health Care“ (PHC) System im Speziellen erleichterten die Realisierung dieser Malaria-Programme erheblich. Auch die Erkenntnisse, die im Rahmen der Nord-Süd- Forschungskooperationen gewonnen wurden, die Kollaborationen zwischen NGOs und der Regierung, sowie die Bereitstellung der erforderlichen Nachweise durch die politischen Entscheidungsträger, führten schliesslich zu einer erfolgreichen Umsetzung. Zusätzlich ermöglichte die Zusammenarbeit zwischen den wirtschaftlichen Blöcken Ostafrikas und der „Southern African Development Community“ (SADC) neue Einblicke in die grenzüberschreitende Kontrolle von Malaria. Einige dieser in Tansania neu entwickelten und praxis-erprobten Instrumente wurden auch in anderen Staaten südlich der Sahara angewandt und dabei oft von globalen anti-Malaria Kampagnen unterstützt. Die politische Stabilität und der Frieden in Tansania während mehr als vier Jahrzehnten haben ein schnelles Umdenken in der Politik und die landesweite Ausdehnung der ACTKontrollstrategie überhaupt erst ermöglicht. Viele benachbarte Länder wie Uganda, Sudan, Mozambique und die Demokratische Republik Kongo erlebten im gleichen Zeitraum viele Unruhen. Tansania hat sich als eines der wenigen afrikanischen Länder nicht gescheut sich dem Rest der Welt für Grossversuche der heute erfolgreichsten Interventionen gegen Malaria zur Verfügung zu stellen. Der Kilombero River Basin in Ifakara Tansania wird als Wiege von Malaria bezeichnet. Etliche neue Interventionen wurden auf ihre Wirksamkeit getestet und evaluiert. Die in dieser Arbeit präsentierten Ergebnisse wurden hauptsächlich aus verschiedenen Studienzentren in Tansania zusammengetragen, wobei der grösste Teil aus dem „Ifakara Demographic Surveillance System“ stammt. Die vorliegende Arbeit gewährt Einblicke in das von Tansania verfolgte Programm zur landesweiten Umsetzung der ACT. Das Ziel der Doktorarbeit ist es, einen Beitrag zum besseren Verständnis der Auswirkungen, welche die Einführung der ACT auf die Malaria Morbidität und Mortalität hatte, beizutragen und die langfristige Sicherheit im landesweiten Einsatz zu überwachen. Die erfolgreiche Einbindung der Akteure, insbesondere der teilnehmenden Communities, sowie die grosse Bereitschaft unter den Forschern beschleunigten die Umsetzung der neuen Richtlinien von Beginn an. Die auf Beweisen basierten Erkenntnisse, die aus dem “Interdisciplinary Monitoring Project of anti-malaria Combination Therapy” (IMPACT) und dem “East African Network for Monitoring anti-malaria Treatment” (EANMAT) gewonnen wurden, werden in die Entwicklung von neuen Richtlinien einfliessen. Die in vivo Studien haben gezeigt, dass Artemether-Lumefantrin (AL) nach Kontrolle der Reinfektion durch Polymase Chain Reaction (PCR) bei Kindern unter fünf Jahren nahezu 100% wirksam war. Wir haben ebenfalls bewiesen, dass es durch eine intensive Zusammenarbeit zwischen Forschung, Politik und der pharmazeutischen Industrie möglich ist, auch unter Realbedingungen Strategien für die Überwachung der Sicherheit und dem sachgemäßen Gebrauch von Antixviii Malaria-Medikamenten umzusetzen. Das „Exploring Health Impact“ Programm (ALIVE) war als erstes Programm überhaupt in der Lage, in einem randomisierten Beurteilungsdesign auf Community-Level eine Compliance von mehr als 95% zu einer komplexen 6 Dosen Therapie von Artemether-Lumefantrin (AL) aufzuzeigen. In Kapitel 5 wird berichtet, dass „ALIVEpharmacovigilance“ afrikaweit die erste community-based Pharmakovigilanz-Studie ist, welche auch die Verwendung von SMS als Überbringer von schweren Nebenwirkungen untersucht. Das Projekt ALIVE gewährt sowohl einen Einblick in die Auswirkungen von ACT und anderen Interventionen auf die Kindersterblichkeit und die Prävalenz. ALIVE hat gezeigt, dass eine Erhöhung der ITN Abdeckung um 10% eine Verringerung von 48% jährlicher Malariabedingten Parasitämie auf kommunaler Ebene erzielt [IRR=0.52; 95% CI=0.38 to 0.73]. Es wurde ebenfalls gezeigt, dass im Vergleich zu der Zeit, als in erster Linie noch SP verwendet wurde, ACT für ungefähr 11% der jährlichen Reduktion der Mortalität verantwortlich war, wenn man für andere wichtige Faktoren stratifiziert [IRR = 0,89, 95% CI = 0,79 bis 1,0]. Des Weiteren wurde beobachtet, dass die Erhöhung der Ernährungssicherheit, insbesondere der Reiserträge, für fast 36% der Reduktion der jährlichen Mortalität von Kindern unter 5 Jahren verantwortlich war [IRR = 0,64, 95% CI = 0,54 - 0,75]. Hinsichtlich der Übertragung von Malaria wurde parallel eine Parasiten-Prävalenz Reduktion von 65% bei asymptomatischen Community-Mitgliedern im DSS in Ifakara aufgezeichnet, im Vergleich zum Ausgangswert im Jahr 2006 als ACT eingeführt wurde. Darüber hinaus wurden diese Auswirkungen als nachhaltig beurteilt, da die Wirksamkeit von AL, wie anhand einer in vivo Studie ein Jahr nach Umsetzung gezeigt, im Kilombero-Tal bei über 96% liegt. Die Ergebnisse dieser Arbeit unterstreichen die Bedeutung des politischen Wandels in der Malariabekämpfung. Dazu gehört die Forschung als systematischer Weg, um das Gesundheitssystem zu stärken und sich in der Malaria Bekämpfung innerhalb eines endemischen Entwicklungslands zu engagieren. Die Erfahrungen aus dieser Arbeit werden relevant sein für Malaria-betroffene Gebiete vor Ort und auf globaler Ebene. Wir haben auch gelernt, dass die Sicherheit und Compliance von Arzneimitteln, die, wie ACT, im großen Maßstab eingesetzt werden überwacht und verwaltet werden muss. Dabei sollten das Gesundheitsministerium und verwandte Fachbereiche sowie die pharmazeutische Industrie und Forschungspartner, als auch die örtliche Führung miteinbezogen werden. Wir empfehlen, dass diese Partnerschaft von globalen Gesundheitsorganisationen unterstützt wird. Die rigorose Überwachung der ordnungsgemässen Verwendung von Medikamenten würde zu einem besseren Verständnis betreffend der Fragen der Sicherheit von Arzneimitteln führen, sowie deren Lebensdauer verlängern. Ein weiterer kritischer Aspekt, welcher den Vorrang eingeräumt werden sollte, ist der Aufbau von Kapazitäten. Wir empfehlen, dass Ressourcen zur Verfügung gestellt werden um das Gesundheitssystem in Malaria-endemischen Gebieten zu stärken (human resources, Health Information und Infrastruktur), um nachhaltige Ergebnisse in der Malariabekämpfung zu erreichen. Damit werden günstige Rahmenbedingungen geschaffen um eine wirksame, regelmässig überwachte, Anti-Malaria- Politik zu implementieren. Wie in dieser Arbeit erläutert, kann eine erfolgreiche Kampagne gegen Malaria durch die Bemühungen der Forscher, politischer Entscheidungsträger, globaler Entwicklungs-Partnern und der lokalen Gemeinden realisiert werden. Eine solche Partnerschaft hat bereits Erfolge erzielt, wie das Beispiel in den 1940er Jahren der Malari

Infection Surveillance by Telephone, Early Postpartum (I-STEP)

Maternal and newborn infections are important causes of mortality but morbidity data from low- and middle-income countries is limited. We used telephone surveillance to estimate infection incidence and risk factors in women and newborns following hospital childbirth in Dar es Salaam We recruited postnatal women from two tertiary hospitals and conducted telephone interviews 7 and 28 days after delivery. Maternal infection (endometritis, caesarean or perineal wound, or urinary tract infection) and newborn infection (umbilical cord or possible severe bacterial infection) were identified using hospital case-notes at the time of birth and self-reported symptoms. Adjusted Cox regression models were used to assess the association between potential risk-factors and infection. We recruited 879 women and interviewed 791 (90%). From day 0-7, 6.7% (49/791) women and 6.2% (51/762) newborns developed infection. Using full follow-up data, the infection rate was higher in women with caesarean childbirth versus women with a vaginal delivery (aHR 1.93, 95%CI 1.11-3.36). Only 24% of women received pre-operative antibiotic prophylaxis before caesarean section. Infection was higher in newborns resuscitated at birth versus newborns who were not resuscitated (aHR 4.45, 95%CI 2.10-9.44). At interview, 66% (37/56) of women and 88% (72/82) of newborns with possible infection had sought health-facility care. Telephone surveillance identified a substantial risk of postnatal infection, including cases likely to have been missed by hospital-based data-collection alone. Risk of maternal endometritis and newborn possible severe bacterial infection were consistent with other studies. Caesarean section was the most important risk-factor for maternal infection. Improved implementation of pre-operative antibiotic prophylaxis is urgently required to mitigate this risk

Intermittent preventive therapy for malaria during pregnancy using 2 vs 3 or more doses of sulfadoxine-pyrimethamine and risk of low birth weight in Africa: systematic review and meta-analysis.

IMPORTANCE: Intermittent preventive therapy with sulfadoxine-pyrimethamine to control malaria during pregnancy is used in 37 countries in sub-Saharan Africa, and 31 of those countries use the standard 2-dose regimen. However, 2 doses may not provide protection during the last 4 to 10 weeks of pregnancy, a pivotal period for fetal weight gain. OBJECTIVE: To perform a systematic review and meta-analysis of trials to determine whether regimens containing 3 or more doses of sulfadoxine-pyrimethamine for intermittent preventive therapy during pregnancy are associated with a higher birth weight or lower risk of low birth weight (LBW) (<2500 g) than standard 2-dose regimens. DATA SOURCES AND STUDY SELECTION: ISI Web of Knowledge, EMBASE, SCOPUS, PubMed, LILACS, the Malaria in Pregnancy Library, Cochrane CENTRAL, and trial registries from their inception to December 2012, without language restriction. Eligible studies included randomized and quasi-randomized trials of intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine monotherapy. DATA EXTRACTION: Data were independently abstracted by 2 investigators. Relative risk (RR), mean differences, and 95% CIs were calculated with random-effects models. RESULTS: Of 241 screened studies, 7 trials of 6281 pregnancies were included. The median birth weight in the 2-dose group was 2870 g (range, 2722-3239 g) and on average 56 g higher (95% CI, 29-83 g; I2 = 0%) in the ≥3-dose group. Three or more doses were associated with fewer LBW births (RR, 0.80; 95% CI, 0.69-0.94; I 2 = 0%), with a median LBW risk per 1000 women in the 2-dose group (assumed control group risk) of 167 per 1000 vs 134 per 1000 in the ≥3-dose group (absolute risk reduction, 33 per 1000 [95% CI, 10-52]; number needed to treat = 31). The association was consistent across a wide range of sulfadoxine-pyrimethamine resistance (0% to 96% dihydropteroate-synthase K540E mutations). There was no evidence of small-study bias. The ≥3-dose group had less placental malaria (RR, 0.51; 95% CI, 0.38-0.68; I 2 = 0%, in 6 trials, 63 vs 32 per 1000; absolute risk reduction, 31 per 1000 [95% CI, 20-39]). In primigravid plus secundigravid women, the risk of moderate to severe maternal anemia was lower in the ≥3-dose group (RR, 0.60; 95% CI, 0.36-0.99; I2 = 20%; in 6 trials, 36 vs 22 per 1000; absolute risk reduction, 14 per 1000 [95% CI, 0.4-23]). There were no differences in rates of serious adverse events. CONCLUSIONS AND RELEVANCE: Among pregnant women in sub-Saharan Africa, intermittent preventive therapy with 3 or more doses of sulfadoxine-pyrimethamine was associated with a higher birth weight and lower risk of LBW than the standard 2-dose regimens. These data provide support for the new WHO recommendations to provide at least 3 doses of intermittent preventive therapy during pregnancy at each scheduled antenatal care visit in the second and third trimester

Prospective observational study to evaluate the clinical safety of the fixed-dose artemisinin-based combination Eurartesim® (dihydroartemisinin/piperaquine), in public health facilities in Burkina Faso, Mozambique, Ghana, and Tanzania.

BACKGROUND: The World Health Organization recommends artemisinin-based combination (ACT) for the treatment of uncomplicated malaria. Post-licensure safety data on newly registered ACT is critical for evaluating their risk/benefit profile in malaria endemic countries. The clinical safety of the newly registered combination, Eurartesim®, following its introduction into the public health system in four African countries was assessed. METHODS: This was a prospective, observational, open-label, non-comparative, longitudinal, multi-centre study using cohort event monitoring. Patients with confirmed malaria had their first dose observed and instructed on how to take the second and the third doses at home. Patients were contacted on day 5 ± 2 to assess adherence and adverse events (AEs). Spontaneous reporting of AEs was continued till day 28. A nested cohort who completed full treatment course had repeated electrocardiogram (ECG) measurements to assess effect on QTc interval. RESULTS: A total of 10,925 uncomplicated malaria patients were treated with Eurartesim®. Most patients,95% (10,359/10,925), did not report any adverse event following at least one dose of Eurartesim®. A total of 797 adverse events were reported. The most frequently reported, by system organ classification, were infections and infestations (3. 24%) and gastrointestinal disorders (1. 37%). In the nested cohort, no patient had QTcF > 500 ms prior to day 3 pre-dose 3. Three patients had QTcF > 500 ms (509 ms, 501 ms, 538 ms) three to four hours after intake of the last dose. All the QTcF values in the three patients had returned to <500 ms at the next scheduled ECG on day 7 (470 ms, 442 ms, 411 ms). On day 3 pre- and post-dose 3, 70 and 89 patients, respectively, had a QTcF increase of ≥ 60 ms compared to their baseline, but returned to nearly baseline values on day 7. CONCLUSION: Eurartesim® single course treatment for uncomplicated falciparum malaria is well-tolerated. QT interval prolongation above 500 ms may occur at a rate of three per 1,002 patients after the third dose with no association of any clinical symptoms. QT interval prolongation above 60 ms was detected in less than 10% of the patients without any clinical abnormalities

Residual antimalarials in malaria patients from Tanzania--implications on drug efficacy assessment and spread of parasite resistance.

BACKGROUND\ud \ud Repeated antimalarial treatment for febrile episodes and self-treatment are common in malaria-endemic areas. The intake of antimalarials prior to participating in an in vivo study may alter treatment outcome and affect the interpretation of both efficacy and safety outcomes. We report the findings from baseline plasma sampling of malaria patients prior to inclusion into an in vivo study in Tanzania and discuss the implications of residual concentrations of antimalarials in this setting.\ud \ud METHODS AND FINDINGS\ud \ud In an in vivo study conducted in a rural area of Tanzania in 2008, baseline plasma samples from patients reporting no antimalarial intake within the last 28 days were screened for the presence of 14 antimalarials (parent drugs or metabolites) using liquid chromatography-tandem mass spectrometry. Among the 148 patients enrolled, 110 (74.3%) had at least one antimalarial in their plasma: 80 (54.1%) had lumefantrine above the lower limit of calibration (LLC = 4 ng/mL), 7 (4.7%) desbutyl-lumefantrine (4 ng/mL), 77 (52.0%) sulfadoxine (0.5 ng/mL), 15 (10.1%) pyrimethamine (0.5 ng/mL), 16 (10.8%) quinine (2.5 ng/mL) and none chloroquine (2.5 ng/mL).\ud \ud CONCLUSIONS\ud \ud The proportion of patients with detectable antimalarial drug levels prior to enrollment into the study is worrying. Indeed artemether-lumefantrine was supposed to be available only at government health facilities. Although sulfadoxine-pyrimethamine is only recommended for intermittent preventive treatment in pregnancy (IPTp), it was still widely used in public and private health facilities and sold in drug shops. Self-reporting of previous drug intake is unreliable and thus screening for the presence of antimalarial drug levels should be considered in future in vivo studies to allow for accurate assessment of treatment outcome. Furthermore, persisting sub-therapeutic drug levels of antimalarials in a population could promote the spread of drug resistance. The knowledge on drug pressure in a given population is important to monitor standard treatment policy implementation

The Effect of Single Nucleotide Polymorphisms in Cytochrome P450 Isoenzyme and N-acetyltransferase-2 Genes on the Metabolism of Artemisinin-Based Combination Therapies in Malaria Patients from Cambodia and Tanzania.

The pharmacogenetics of antimalarials is poorly known, although its application might be critical to optimize treatment. This population pharmacokinetic-pharmacogenetic study aimed at assessing the effect of single nucleotide polymorphisms (SNPs) in cytochrome P450 isoenzyme (CYP, namely CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5) and N-acetyltransferase-2 (NAT2) genes on the pharmacokinetics of artemisinin-based combination therapies (ACT) in 150 Tanzanian patients treated with artemether-lumefantrine, 64 Cambodian patients treated with artesunate-mefloquine, and 61 Cambodian patients treated with dihydroartemisinin-piperaquine. The frequency of SNPs varied with the enzyme and the population. Higher frequencies of mutant alleles were found in Cambodians than Tanzanians for CYP2C9*3, CYP2D6*10 (100C>T), CYP3A5*3, NAT2*6, and NAT2*7. In contrast, higher frequencies of mutant alleles were found in Tanzanians for CYP2D6*17 (1023C>T and 2850C>T), CYP3A4*1B, NAT2*5, and NAT2*14. In 8 SNPs no significant differences in frequencies were observed. In the genetic-based population pharmacokinetic analyses, none of the SNPs improved model fit. This suggests that pharmacogenetic data need not be included in appropriate first-line treatments with the current artemisinin derivatives and quinolines for uncomplicated malaria in specific populations. However, it cannot be ruled out that our results represent isolated findings, and therefore more studies, ideally with the same artemisinin-based combination therapies, in different populations are needed to evaluate the influence of pharmacogenetic factors on the clearance of antimalarials

Laborativ matematik : en möjlighet eller en belastning

The past years there has been a big media circus, that states that the Swedish schoolsystem is broken and with dropping results in PISA as a proof of this statement. Voices have been heard that teachers rely on textbooks in a voluminous way and some suggest that this is the main problem as Swedish students dropping in mathematics results. This study shows how teachers perceive their use of laboratory mathematics and is therefore based on a teacher perspective. What I want with this study is to show how teachers looks at the correlation between benefits and disadvantages in using laboratory mathematics, but also to create an awareness for understanding the difficulties that you may face as teacher if you want to use laboratory mathematics as a tool when teaching. In this study, the main focus is on how teachers use laboratory mathematics as an option when teaching. Nine teachers participated in an online survey and answered questions about how they use laboratory mathematics and what benefits or disadvantages it may comprehend. To add, two teachers also attended to a private interview and another two were observed. The result that was found is that teachers can see big advantages in using laboratory mathematics especially when teaching geometry. The teachers pinpoint how using laboratory mathematics supports students deeper understanding for the mathematic contents. Though, teachers also highlight that there is a urgent need for the teacher to have the knowledge to comprehend meaningful and aimful lessons. Apart from knowledge teachers points to the lack of time to plan and execute as a disadvantage. The lack of time combined with insufficient knowledge in how to use laboratory mathematics is the determiner if laboratory mathematics is seen as a possibility or an affliction

Residual plasma concentrations of antimalarials found prior to treatment in 148 malaria patients [ng/mL].

<p>No artemether, artesunate, dihydroartemisinin, amodiaquine, <i>N</i>-desethyl-amodiaquine, piperaquine, pyronaridine, mefloquine, or chloroquine was found.</p

Review of pharmacokinetic studies of sulfadoxine (continued).

a<p>Derived from clearance and plasma half-life (<i>t_½</i>).</p>b<p>Derived from clearance and elimination rate constant (<i>λ</i>).</p>c<p>Derived from <i>V</i>/<i>CL</i> × ln(2).</p>d<p>Corrected by a factor of (<i>BW</i>/11 kg)^0.72 for other body weight (<i>BW</i>) values.</p>e<p>Corrected by a factor of (<i>BW</i>/11 kg)^0..64 for other body weight (<i>BW</i>) values.</p