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8. Malaria: Introducing ACT from Asia to Africa

Jean-Hervé Bradol
Jean-Hervé
Bradol

Medical doctor, specialized in tropical medicine, emergency medicine and epidemiology. In 1989 he went on mission with Médecins sans Frontières for the first time, and undertook long-term missions in Uganda, Somalia and Thailand. He returned to the Paris headquarters in 1994 as a programs director. Between 1996 and 1998, he served as the director of communications, and later as director of operations until May 2000 when he was elected president of the French section of Médecins sans Frontières. He was re-elected in May 2003 and in May 2006. From 2000 to 2008, he was a member of the International Council of MSF and a member of the Board of MSF USA. He is the co-editor of "Medical innovations in humanitarian situations" (MSF, 2009) and Humanitarian Aid, Genocide and Mass Killings: Médecins Sans Frontiéres, The Rwandan Experience, 1982–97 (Manchester University Press, 2017).

Claudine
Vidal

Claudine Vidal is a sociologist whose research has mainly centred on Rwanda (from its pre-colonial history to the genocide of Tutsi Rwandans in 1994) and Côte d'Ivoire (history and sociology of urbanisation in Abidjan). This research has been carried out in the framework of the Centre d'Études africaines de l'Ecole des Hautes Etudes en Sciences Sociales. Since 1995 she has collaborated with MSF on various publications and regularly participates in the reflection and work of the CRASH.

Suna Balkan and Jean-François Corty

Nearly one million deaths are attributed to malaria each year (World Health Organization (WHO), 2008), 91% in Africa and 85% in children less than five years of age. Although these figures are biased by inadequate national statistics, they do give some idea of the effect of parasitic infections due to plasmodiae species (falciparum, malariae, ovale, and vivax) (Snow, 2004). Malaria is common throughout the inter-tropical zone, and in reality may infect five hundred million people, and kill between two and three million people a year. Over one hundred countries and half of the world’s population live under threat of this febrile illness, of which some forms (principally Plasmodium falciparum) can lead to death, and is a major cause of infectious disease mortality. Current recommendations to reduce morbidity and mortality are based on the use of insecticides (house spraying and mosquito net impregnation), intermittent prophylaxis for pregnant women, biological confirmation of disease diagnosis, and treatment with Artemisinin-based Combination Therapy (ACT). The disease’s effect on health and survival rates in African children is proof that these recommendations are not properly implemented on the continent. At the end of the 1990s there were neither biological tests nor effective treatment in public health structures in many sub-Saharan African countries, leading to the development of resistance to standard therapies.

The efficacy of quinine, an alkaloid extracted from the bark of the quinquina tree, has been known since 1630. In 1944 Robert Woodward and William Doering from Harvard University published an article describing its complete chemical synthesis— then relatively laborious and costly compared to the technique of purifying natural quinine in use at the time. The technique proved useful during the Second World War when allied troops experienced quinine shortages. Later, in the 1950s and 1960s, the fight against malaria concentrated on vector reduction. The strategy was based on the eradication of the anopheles mosquito vector for interhuman transmission in defined areas, notably in Africa, using an insecticide, DDT. Despite initial successes, the use of DDT declined following the appearance of resistance, information on DDT toxicity, and campaigns by environmental groups.Although WHO recommendations since 2007 have reintroduced the use of DDT for spraying inside houses.In parallel, chloroquine (1947) and sulfadoxine-pyrimethamine (SP) (1969) were introduced for the treatment of simple forms of malaria. During the period of decolonization, antimalarial development was more a military than a public health concern for ex-colonial powers. The later wars in Asia were the starting point of intense military medical research.

During the 1960s and 1970s American medical research, stimulated by the large numbers of soldiers affected in Vietnam as well as the increasing resistance to available anti-malarials, led to the development of new molecules including halofantrine and mefloquine (MFQ). The North Vietnamese, trying to solve similar problems, turned to their Chinese allies, who proposed a family of molecules derived from artemisinin (artesunate and artemether, for example) extracted from a plant used in traditional Chinese medicine (a sagewort or wormwood, Artemisia annua L.). The American and Chinese discoveries came too late to influence the outcome of the conflict, but opened possibilities for the treatment of malaria strains resistant to the preceding generation of treatments (chloroquine and SP) in Asia, Latin America, and, later, in Africa (1979). Localized resistance to MFQ and halofantrine and their side effects ended the competition between the Walter Reed Army Institute of Research and traditional Chinese medicine used by the Maoist regime. The efficacy of artemisinin derivatives and their lesser toxicity mean they were top of the list of candidates to replace older treatments that had become, or were becoming, obsolete.Rapid and frequent resistance development is highly probable when monotherapies are used. It should be noted that Plasmodium falciparum becomes sensitive to chloroquine again after it is not used for a period of time in a given region. The adoption of ACTs by national and international health authorities met with three obstacles, however: political, economic, and scientific. ACTs were the symbols of political and military defeat, and, furthermore, were developed in a scientific context outside of evidence-based medicine. Randomized clinical trials, comparing the candidate to a reference product in double-blind conditions where neither the patient nor the investigator knows which product is administered—obligatory for international recognition—had not been performed. From an economic point of view, the fact that they originated in China complicated patent applications that would have guaranteed twenty years of commercial monopoly and attracted investors. It was essential to prove that compounds including artemisinin derivatives were superior to other medications in order to change treatment protocols in response to increasing drug resistance. Scientific studies conforming to international standards were required. Furthermore, it was also necessary to find an economic model allowing African countries to guarantee supply. The introduction of rapid tests and ACTs in MSF missions, along with the plea for their accessibility in public structures in African countries, opened the way for accurate diagnosis and effective treatment. MSF’s participation in their introduction through work in humanitarian circumstances (war refugees, neglected epidemics) and the long mediation process (from Asia to Africa, from Chinese science to international norms, from one economic model to another, etc.) remind us that medical progress arises not only from the most sophisticated research laboratories but also from the porosity of borders and from improbable meetings between refugees, researchers, and clinicians.

 

The 1980s and 1990s: The Asian Experience

Refugees and Scientific Research

MSF assisted hundreds of thousands of Khmer refugees on the Thai–Cambodian border during the 1980s. On the opposing Thai–Burmese border, MSF was also caring for tens of thousands of Burmese refugees in makeshift camps in Thailand. In both cases, the inhabitants, particularly the men, regularly crossed the border into Burma or Cambodia, through malaria-infested forest zones. Population movements in militarily unstable, unhealthy frontier zones, home to informal economic activity (particularly the trade of precious stones and tropical wood), smuggling, and uncontrolled medication use, seem to have played a role in the development of poly-resistant malaria and its geographical expansion.

In these zones, MSF was confronted by a particular kind of malaria often affecting young adults in good health, and it engendered a feeling of increasing impotence. The children were protected as long as they stayed in the camps that were less infested than border forest regions. At the end of the 1980s, refugee camp doctors became worried, seeing patients returning shortly after malaria treatment with recurrent symptoms. It was these clinicians who initially suspected the development of resistance to MFQ treatment.MFQ was being prescribed as a single dose of fifteen mg/kg/day. Doubts led to several resistance studies evaluating an MFQ-Fansidar combination (called Fansimef) and different MFQ dosages as a monotherapy.

Suspicions of treatment failure based on clinical observations triggered scientific works carried out by the Shoklo Malaria Research Unit (SMRU). The SMRU, a Tropical Medicine Department field unit of Mahidol University in Bangkok, was created in 1986 in the Shoklo Burmese refugee camp (Tak province, Thailand) and led by a doctor who had previously worked on site with MSF (Nosten, 2000). It was part of the partnership between the Tropical Medicine school of Mahidol University, Bangkok, and the Oxford University Research Unit.Its principal donor is the Welcome Trust (United Kingdom). The team was mostly made up of refugees, who also occupied senior posts, and its research aimed to “benefit populations along the border, including refugees and other migrants.” Relations between the SMRU and MSF were based on complementarity. The research team could not perform its work if it had to confront the refugee population’s health needs single-handedly, and MSF could not adequately treat poly-resistant malaria, a major cause of camp mortality, without scientific research support. The two teams were united by a common desire to help the refugees and the shared fear of the development of untreatable malaria. Relations were dynamic despite the potential for medical, scientific, ethical, and political tensions, and for institutional rivalries. SMRU partnerships in countries influenced by China (Vietnam, Cambodia, and Burma) led to English translations of Chinese medical literature, and the consideration of the role of artemisinin derivatives in the therapeutic arsenal.

Most of the clinical studies evaluating artemisinin-derivative bi-therapy (combined with other anti-malarials) at the beginning of the 1990s were performed in the camps on the Burmese border. These products were not recommended in Thai national protocols, but were available on the market. The high number of severe malaria cases in the camps meant quality scientific research had to be carried out to identify new treatments, and the camps’ context made this research feasible. Patient follow-up was made easier by the confines of refugee camps: the number of patients lost to follow-up in studies was limited, and the medical personnel lived on site.

The first results benefited MSF patients as early as 1994. Uncomplicated malaria was treated with MFQ and artesunate, with one treatment per day for three days (Luxemburger et al., 1994). Three years later, MSF introduced artemether, an injectable artemisinin derivative, once the advantages of this treatment compared with quinine had been proven (quicker reduction in parasite load and fever and simplified administration). The Thai Health Ministry recognized the public health risk of resistance development in the refugee camps. Although the new treatment protocols had not yet been adopted nationally, their use was tolerated under certain conditions (biological confirmation of the diagnosis and regular detailed reports to provincial and national authorities).

Available classical treatments were ineffective and the last option, the treatment of uncomplicated malaria using quinine and tetracycline, was limited by adherence issues due to the need to take numerous tablets three times a day for seven days. Furthermore, quinine’s side effects also caused patients to abandon treatment, and tetracycline use is not usually recommended for young children and pregnant women. The generalization of quinine for uncomplicated cases and the frequent nonadherence to a seven-day treatment protocol which also presented side effects increased the risk of quinine resistance—and quinine was the only readily available treatment for severe malaria. Other therapeutic options were urgently needed. In 1996–97, artemisinin derivative combinations were routinely prescribed as firstline therapy for uncomplicated malaria in Thai camps. Some MSF staff soon saw the potential for ACT use in sub-Saharan Africa for patients, health workers, and general public health. The question of biological confirmation of malaria diagnosis nevertheless remained a problem. According to opinions at the time, resistance development was not only due to the administration of monotherapies, but also partially due to unjustified anti-malarial prescriptions without biological confirmation of the disease.

The Need for Biological Confirmation of the Diagnosis

In Thailand in the 1990s, ACT treatment was preceded by dyed-blood microscopy (thick and thin films) to confirm diagnosis and specify the Plasmodium sub-species, as only Plasmodium falciparum malaria was associated with resistance and mortality. This prerequisite was not particularly problematic in standard local contexts involving low numbers of cases. Transmission rates were generally low, and health structures adequately supplied with staff and material. Biological confirmation could, however, be compromised by more difficult conditions such as epidemic peaks, population isolation, and population displacements. It was not always possible to perform numerous malaria smears and qualified personnel were often absent during crises. Such was the case across the border in Burma, where MSF was trying to develop activities to aid populations in significantly more resource limited settings than those in the Thai camps. A high number of malaria cases were reported; these were diagnosed too late, and were often fatal. If it were possible to confirm the diagnosis of malaria with rapid tests, artemisinin derivative therapies could be used in isolated areas as an alternative to failing MFQ monotherapy. Health authorities again tolerated the prescription of these new molecules on the condition of biological confirmation of the disease so as to avoid excessive use.

In 1996 MSF succeeded in sending mobile teams to diagnose and treat malaria cases among isolated populations in Burma that were frequently being forced to move by the army and guerrilla groups. They were also able to evaluate rapid test use in field conditions.The Parasight rapid test was used to study an epidemic in the Hmong population in April 1997 (Bee Ree village).

Initial results were promising. The test was easy to use, but deteriorating security conditions and the interruption of its manufacture brought an end to the evaluation. It would be attempted once again, a few years later, in Africa.

Malaria in Africa: A Disturbing Situation

Malaria treatments varied across African countries in the 1990s, and MSF generally applied national protocols based on WHO recommendations. Chloroquine, introduced at the end of the Second World War, contained malaria transmission and reduced morbidity and mortality until the end of the 1960s. Chloroquine resistance appeared in the 1970s, however, and grew progressively, justifying a shift to SP in a few East African countries. The parasite quickly developed worrying levels of resistance to this second drug. At the beginning of the 1990s, both treatments failed regularly in children, who are at the highest risk of death from malaria. Both drugs nonetheless remained in WHO recommendations and African national protocols, as national and international authorities considered proof of their inefficacy insufficient to justify the serious consequences of change. These consequences included significant budget increases, administrative authorizations, international supply, universal distribution, and prescription training for personnel.

Also, according to opinions at the time, malaria was deemed less severe in Africa than in Asia or in South America, where resistance had developed more rapidly. Constant high transmission rates in many African countries were thought to lead to better population immunity and lower incidences of severe malaria in adults. It is undeniably simplistic, however, to ascribe a uniform epidemiological profile to all African countries. Malaria transmission is highly unstable in some regions, reducing population immunity and leading to severe malaria in adults, particularly pregnant women. Moreover, despite the lag in the frequency and severity of resistance development, it was above all in Africa that malaria was killing patients.An estimated 80% to 90% of the million malaria deaths reported annually in the 1980s were among children in Africa.

The WHO was reticent about artemisinin derivative use for several reasons: political (influence of the United States),MSF doctors, attending the International Tropical Medicine Conference (Thailand, 1992), recall American military doctors promoting MFQ and halofantrine at the same venue. economic (increased cost), and scientific (medical research not corresponding to international standards). At the time, no pharmaceutical company was ready to invest in long, costly clinical trials, without hope of returns in the absence of official recommendations for use. At the end of 1993, the WHO organized its first informal consultation on “the role of artemisinin and its derivatives in malaria treatment.” The recommendations were reminders that “artemisinin derivatives should only be prescribed in countries where poly-resistant Plasmodium falciparum was present; should not be commercialized in countries without polypharmacoresistance such as in Africa; should be administered in combination with another efficacious anti-malarial treatment; and should be followed up by a surveillance system to detect possible side effects, treatment efficacy, and maximize quality” (WHO, 1994: 1). The meeting targeted Asian countries, not Africa. The WHO stressed the shortcomings of scientific data on the inefficacy of standard treatments and avoided mentioning the political and economic pressures to which it was being subjected, particularly by the US government, which had little desire to leave the way open for a Chinese breakthrough.WHO director Gro Harlem Brundtland acknowledged these pressures in 2002, at a meeting with MSF senior staff and in the presence of WHO infectious diseases department directors, some of whom were American.

A second meeting was held in 1995 to “revise the group’s recommendations and directives.” The conclusions were limited to “the treatment of uncomplicated malaria and the use of antimalarials to protect travelers.” While the WHO declared its concern about recent data showing reduced efficacy of standard treatments—particularly SP in Kenya, Tanzania, and Malawi— the use of artemisinin remained restricted to South East Asia: “At this time nothing justifies the use of oral or injectable forms of artemisinin in Africa as other efficacious treatments are available” (WHO, 1996, p. 57). The WHO also argued the need to avoid the “anarchistic” and “uncontrolled” arrival of artemisinin derivatives in Africa, citing the risk of a rapid decline in efficacy. In reality, artemisinin derivatives were already arriving in private pharmacies without any control of their usage, and they were being administered as monotherapies, favoring the rapid development of resistance.The WHO only requested pharmaceutical companies to stop producing artemisinin derivate monotherapies a further ten years later, emphasising the role of governments in this domain. Of the twenty-three companies contacted, thirteen agreed to the request.

Quality documentation on malaria resistance in Africa was rare at the beginning of the 1990s. This was a direct consequence of low interest among scientific institutions, health ministries, and international organizations—including MSF. MSF and Epicentre had only conducted three resistance studies on the African continent from 1984 to 1997.Moyo (Uganda) 1993, Tabou (Ivory Coast) 1995, and Benguela (Angola) in 1996. Some doctors had indeed observed resistances to treatment,In 1989, in Moyo, Uganda, the doctor and MSF–team leader wrote a report signalling malaria parasite resistance to chloroquine in the region, and the resulting difficulties in the treatment of uncomplicated malaria with available drugs. but found themselves out of their depth and without detailed knowledge about the state of scientific research at the time. Their worries were reinforced by particularly deadly epidemics in Kenya at the end of the 1990s.

Between January and May 1998, MSF intervened in response to a malaria epidemic that killed almost 4,000 people in the town of Wajir, Northeast Kenya (population 60,000). The epidemic probably caused 10,000 deaths in all at a district level (population 160,000) in association with malnutrition (Brown, 1998). At the same time, another epidemic started elsewhere in Kenya, in the Marsabit and Samburu districts. Standard malaria treatments were not brought into question, despite a Glaxo Wellcome study demonstrating a 60% treatment failure with chloroquine and complete efficacy for SP on the third day of treatment. It should be noted that the WHO recommends at least two weeks’ follow-up to detect late treatment failures, and, as such, the study did not correspond to norms, and could not detect late failures (between four and fourteen days). That same year, Kenyan health authorities published a malaria treatment guide. It recommended SP as first-line treatment for uncomplicated malaria, except in areas where the parasite was still sensitive to chloroquine. Second-line treatment was either oral amodiaquine or oral quinine, and intravenous quinine was the reference for severe malaria.Ministry of Health, National Guidelines for Diagnosis, Treatment and Prevention of Malaria for Health Workers, Republic of Kenya, Nairobi, January 1998.

A worrying rise in the number of cases of malaria had been observed in the Kenyan high plateaus since 1990 (Mlakooti, 1998; Snow, 1999). MSF intervened late in the Kisii and Gucha districts (Nyanza province) from June to August 1999, after being asked for help by Merlin,Merlin is an international medical NGO. which was overwhelmed by the number of cases. The scale of the epidemic was such that the Kenyan army was called in to help medical relief in mid-July.

At the epidemic’s peak, 600 patients were hospitalized at Kisii district hospital, 500 of whom were diagnosed with malaria. The hospital had a capacity of 250 beds, including 65 pediatric beds. Two hundred fifty of the 600 inpatients were children. The number of blood transfusions increased from 80 to 340 per week. Similarly, at Ogembo hospital, which had 25 beds, 130 patients were hospitalized. At the same time, three mobile clinics treated 30,000 patients between July 19 and August 19 (Bracknell, 1999).

MSF developed its malaria epidemic response strategy during these interventions. First, MSF brought support to the two district hospitals (Kisii and Ogembo) and one health centre (Kembu Health Center), strengthening their inpatient capacities, recruiting personnel, performing training in severe malaria treatment, increasing transfusion capacities, and supplying anti-malarials, including notably artemether for severe cases. The Kenyan authorities had already accepted the use of artemether, and it was already present in hospitals and available to those who could pay for it. MSF realized that this level of intervention was not enough; action was needed earlier, before cases became severe and flooded hospitals and health centers. This led to the organization of mobile clinics, allowing rapid diagnosis and treatment for populations often living too far from health centers. This type of strategy corresponded to that used in the small epidemics on the Thai border, which aimed quickly to diagnose and treat a maximum number of cases in the hope of slowing or stopping transmission. The scale of the Kenyan epidemic meant that this hope was illusory— particularly so given that artemisinin derivatives were not being used as first-line treatment (one of the characteristics of artemisinin derivatives is to destroy sexual forms—gametocytes—of the parasite which are necessary for transmission of the disease by mosquitoes).

The Kenyan guide (1998) recommended changing to SP, but this had not occurred; information had been poorly transmitted and health personnel inadequately trained. Furthermore, there was a will to use up existing stocks of chloroquine in national pharmacies before the switch to SP, despite chloroquine resistance rates of up to 85%.

Artemisinin derivatives had not been completely forgotten, however. On the contrary, they were officially adopted by Kenyan health authorities on July 21, 1999, at a Malaria Task Force meeting presided by the director of Medical Services,The protocol associated AS and SP for one day. and this information was quickly transmitted to provincial authorities. The 1999 epidemic was nearing its end, and this decision may have been taken for political reasons, aiming to reduce the epidemic’s political repercussions on central authorities. That said, at the end of July, for the last three weeks of the MSF’s malaria intervention, a dose of artesunate was added to ambulatory SP treatment in mobile clinics. This led to the successful treatment of some patients, but was too late to affect the course of the epidemic.

The precedent for ACT use had been established. The Kenyan epidemic experience would become a reference point for strategies in the epidemics that followed: Burundi (2001), Sudan (2002), and Ethiopia (2004) (Checchi, 2006).

Bringing ACT to Africa

ACT was prescribed in MSF missions in Thailand beginning in 1994. The plan to use them in Africa was only formulated in 1999, however, and only started to become reality the following year. This time lag can be explained primarily by the obligation to respect national protocols. Any exceptions implied obtaining agreement from national health authorities. These decisions were difficult to influence in Africa, where there was much scientific uncertainty, and where ACT use had strong political and economic implications. The problem of drug supply also slowed the introduction of ACTs, very sparsely available in Africa in the 1990s. Effort was required to ensure their production in sufficient quantities, their distribution, and to secure the corresponding national health ministry budget increases given their high relative cost compared to previous treatments. Scientifically, it could be comfortably argued that the continued use of monotherapies to which the parasite was significantly resistant would lead to a dead end in the short term (WHO, 2001). Chloroquine and SP treatment failure had not been clearly demonstrated by adequate studies, however, and immediate ACT use in Africa was controversial, even within MSF itself.From 2003, the international MSF movement was federated around the same strategy, and disagreements between operational sections were resolved through a malaria working group.Finally, there were other, internal, reasons why MSF was unable to introduce ACTs, namely the need to prepare for the change through training and protocol changes.

Clinical Operational Research and Humanitarian Action

The pilot projects

From 1999 onwards, MSF aimed to introduce ACTs in all health centers where the association was operating, in collaboration with local health authorities. A number of steps needed to be taken: evaluation of the efficacy of existing treatments (data often lacking or impossible to interpret), material support (drug and diagnostic test supply), organization of prescriptive matters (diagnostic and therapeutic protocols, training), epidemiological data collection and analysis, and assessment of the new treatment in terms of efficacy and efficiency. These steps brought MSF practice into line with project follow-up and evaluation as required by evidence-based medicine, and reinforced MSF’s arguments in discussions with ministries and international organizations, particularly the WHO.

An MSF doctor familiar with ACT use from his experience on the Thai border was given the role of lobbying for changes to national protocols. Right from the beginning it was a difficult process, particularly with the WHO. The institution is not, however, a monolith, and opinions differ according to departments. Although the Tropical Diseases Research program (TDR)Founded by the WHO in 1975.seemed to favor change, such was not the case at Roll Back Malaria (RBM).The Roll Back Malaria network was created in 1998 as a WHO initiative in association with United Nations Children’s Fund, the United Nations Development Programme, the World Bank, and other public and private partners.Nevertheless, MSF began using artemisinin derivatives for the treatment of severe malaria in therapeutic feeding centers in Brazzaville, the Republic of Congo, in 2000. In 2001 MSF then introduced them for the treatment of uncomplicated malaria in Zambia, Liberia, and the Republic of Congo, followed by Sierra Leone, Burundi, and Kenya in 2002. There were difficulties though, as in October 2000, during a large-scale epidemic in the Burundian high plateaus, where MSF was quick to measure the failure of available treatment through resistance studies, hoping to convince national and international health authorities of the necessity of using ACTs. Unfortunately, MSF did not manage to convince either the Burundian authorities or the WHO.See the chapter by M. Le Pape and I. Defourny in this book.

The opposition, skepticism, disorganization, and inertia often displayed by national and international authorities led MSF to increase the number of studies proving the inefficacy of national protocols in Africa. Studies to identify the best anti-malarial to combine with ACTs were also organized between 2000 and 2004. They took place in pilot projects involving training in the use of rapid tests, data collection and analysis, and resistance studies comparing various ACT combinations.

Resistance studies

MSF and Epicentre launched a series of efficacy studies in collaboration with health ministries in the early 2000s to evaluate national protocols and support alternative propositions. A total of forty-three clinical studies in eighteen different countries were conducted by MSF and Epicentre between 2000 and 2004: eight in Asia and thirty-five in Africa, representing 25% of all field clinical studies conducted during this period (Guthmann, 2008 and 2009).

By setting up these efficacy studies, Epicentre and MSF highlighted WHO resistance-study protocols that in many circumstances underestimated treatment failure. MSF and Epicentre and the WHO and TDR subsequently worked together to improve assessment methodology (Guthmann et al., 2006).

In an orientation document for field teams (MSF, 2001) drawn up by an MSF doctor in charge of malaria, the arguments justifying ACT use in health centers supported by MSF in Africa were the following: the morbidity and mortality due to malaria; the emergence of resistance to the most commonly used anti-malarials (chloroquine and SP) and subsequent treatment inefficacy; the potential public health effect of ACTs given their good results in treatment of the disease; the fight against resistance development and control of transmission.Artemisinin derivatives have a specific action against gametocytes. To transmit the disease, the anopheles mosquito feeds on infected blood containing gametocytes, which then evolve to an infectious form in its salivary glands and are injected at the next feed.

The introduction of rapid tests

In Thailand any suspicion of malaria was confirmed by biological examinations. In Africa, given the high number of cases and limited diagnostic means, treatment was often administered on clinical grounds. Laboratory confirmation is often impractical in isolated areas lacking staff and equipment, but it was the sheer number of malaria cases that often made laboratory testing difficult in health centers. The use of rapid tests needed to be validated, so Epicentre began a study in Mbarara, Uganda, in 2001. The objective was to compare various tests’ performances in terms of sensitivity and specificity, feasibility (ease of use in typical field conditions), and cost-efficacy. The rapid test in use at the time, specific for Plasmodium falciparum, was found to be very sensitive (96%), easy to use, and reasonably priced. It became MSF’s standard.

Political Efforts

In the early 2000s, numerous studies were published showing the level of resistance to standard anti-malarial treatments in Africa. Furthermore, knowledge about the mechanisms and causes of resistance development increased, refuting the idea of continuing to treat malaria with single-drug therapies. This opened the way for MSF to intensify its plea in favor of ACTs. Health authorities nevertheless freely proposed combinations of older molecules (notably amodiaquine and SP)—“poor people’s ACTs,” as some described them—as a last effort against ACT introduction. MSF increased the number of scientific studies in response, which had the added advantage of obtaining initial authorizations to bring ACTs into different countries. MSF’s insistence on ethical and scientific reasons (a doctor’s duty to prescribe the best available treatment) forced economic and political issues to the background. MSF’s inability to comprehend and master these factors severely hampered progress on the issue of ACT.

Plasmodium falciparum malaria cases increased markedly in KwaZulu-Natal province, South Africa, between 1995 and 2000, linked with development of resistance to insecticides and to SP (which had replaced chloroquine in 1998). In 2001, a year after the reintroduction of DDT spraying of houses, large-scale insecticide-impregnated mosquito net distribution, and the introduction of ACTs, hospitalizations and deaths due to malaria dropped by 89%. Malaria incidence also dropped by 85% in sentinel sites. These reductions were confirmed in the years that followed. The presentation of these results at an internal MSF conference in October 2002 (Barnes et al., 2005) had a considerable effect in removing resistance to ACT use within the association. The meeting report concluded “we have a tendency to concentrate on external obstacles, but there is also significant resistance to the use of ACTs within the association” (MSF, 2002).

During the Third Multilateral Initiative on Malaria–Pan African Malaria Conference in Arusha, Tanzania, in November 2002, a debate was held on the subject “How can expensive but essential drugs be made accessible to those in need ?” The Zambian health ministry representative asked the assembly if the question was whether an African child’s life was worth 2.4 dollars.The lowest-priced ACT at the time was $1.50, whereas chloroquine or SP cost around $0.10.Because the time for cheap (i.e., ineffective) drugs for poor people was a thing of the past, what were we waiting for to make effective treatments accessible in Africa? “The World Bank is here, at this table, and seems to be saying that the money is there!” Furthermore, several attendees were surprised that multinational drug companies had discouraged artesunate production in Tanzania, where the Artemisia plantations growing not far from Arusha were of high quality, and contained more artemisinin than Chinese productions. The crop was being exported to the USA (where they were trying to synthesize the drug) and Europe. Naturally, the cost of the drug would have been much lower if produced in Tanzania.

In 2002, several East African states thought about changing national malaria treatment protocols and introducing transition strategies. The choices generally were not made based on efficacy, but on financial criteria, negotiated between governments and donors. MSF and the Campaign for Access to Essential Medicines wrote a report on the costs of ACT introduction.

According to the report, “it is governments’ responsibility to modify malaria treatment protocols so as to offer efficacious treatment to patients in need. If we examine existing national health budgets and available international aid, it is financially possible to rapidly introduce ACTs where medically indicated” (Kindermans, 2002).

The report was a reference point at a press conference held in Nairobi on February 13, 2002. The idea was to show the real costs of ACT-based protocols and thereby motivate national program directors and international donors to adopt the approach. The additional cost of ACT introduction for the five East African countries with the highest levels of resistance (Burundi, Kenya, Rwanda, Tanzania, and Uganda) was estimated at $19 million a year. According to MSF representatives, this was not insurmountable once donors recognized the importance of introducing efficacious combinations. The need to expand the ACT market to reduce the cost of the drugs was also stressed.

At the same time, American researchers were attempting chemically to synthesize artemisinin, aiming to increase production independently of the constraints of wormwood cultivation. The economic return was to be reaped through patent applications.

The situation changed when the Global Fund to Fight AIDS, Tuberculosis and MalariaThe Global Fund was created in 2002.declared in 2004 that it would only finance projects using ACTs from that point onwards. The WHO followed in 2006 with a new guide on malaria treatment. New funds appeared from donor countries keen to protect themselves against the potential menace, ending a scientifi debate that had become obsolete. Public health institutions’ access to a new and essential effective treatment does not automatically mean ACT administration to patients at high risk of death, however.

Several Epicentre and MSF studies have shown that despite the introduction of ACTs into national protocols, patients still had little access to them. Aware of the limits, MSF worked on simplifying the prescription and reducing the costs of ACT through the Drugs for Neglected Diseases Initiative. Working in collaboration with Sanofi-Aventis, a combination (ASAQ) was commercialized in 2007: for the first time a child could be treated with a single tablet once a dayThe tablet’s dosage form permits easy dissolution in water and administration with a spoon, often indispensible for correct ingestion by small children.for three days for less than half a dollar.

Even when recommended by the WHO and integrated into national treatment protocols, effective treatments, once in national central stocks, are not readily available to small children. Public health strategies are needed to produce consensus, transmit national recommendations to all levels of health systems, and ensure continual long-lasting implementation. Should a medical humanitarian organization such as MSF engage in the processes of negotiations, persuasion, standardization, and economic planning? Are such procedures not outside the organization’s scope? Success in persuasion means having knowledge of local structures and traditions, along with social and political willpower, and the ability to galvanize national institutions. To make treatments accessible to those most in need—those who do not necessarily seek help from healthcare structures—pressure must continue to be placed on international donors and the pharmaceutical industry.

 

Bibliography

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