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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

Kabanywanyi, A. M. (2012) 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. Doctoral thesis, University of Basel.

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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% efficacious after controlling for re-infection by Polymerase 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% using a complex six-dose regimen 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% increases in ITN coverage, there was a 48% reduction in the annual community parasitaemia [IRR=0.52; 95% CI=0.38 to 0.73]. It also showed that, compared to a period when anti-malaria first line was SP, ACT was responsible for nearly 11% annual decreases in under five mortality when adjusted for other key factors [IRR= 0.89; 95% CI=0.79 to 1.0]. 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% reduction in annual mortality [IRR=0.64; 95% 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% in the 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% der 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 die

Item Type: Thesis (Doctoral)
Keywords: Malaria Control,Plasmodium Falciparum, Anti-Malaria Drug, Artemisinin-Based Combination Therapy, Vaccine, Vector Control, Management, Mosquito,Morbidity and Mortality, Kilombero, Tanzania, Africa
Subjects: Malaria > Surveillance, monitoring, evaluation
Malaria > Vector control
Malaria > Diagnosis & treatment
Divisions: Other
Depositing User: Mr Joseph Madata
Date Deposited: 12 Feb 2013 13:44
Last Modified: 12 Feb 2013 13:44

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