Aadyot Mitra

2014-15 Mitra FAMILY GRANT Recipient Using Antimalarial and Insecticide Resistance to Contextualize the Future of Malaria Control in Tanzania Aadyot Bhatnagar, Class of 2015

USING ANTIMALARIAL AND INSECTICIDE RESISTANCE TO CONTEXTUALIZE THE FUTURE OF MALARIA CONTROL IN TANZANIA

Aadyot Bhatnagar Mitra Family Scholar Mentors: Mr. Damon Halback and Ms. Susan Smith April 12, 2015

Bhatnagar 2 1. Introduction.

In Tanzania, malaria is the leading cause of child mortality, claiming the lives of 1 in every 12 children under five years old.1 Unfortunately, the country’s widespread poverty and slow economic growth have hindered the large-scale implementation of an effective national policy, placing much of the onus on international aid organizations.2 This problem is further compounded by local resistance to Western interventions, largely driven by historical economic and colonial tensions, including the World Bank’s recent attempts to force capitalist reforms onto the Tanzanian economy.3 Any effective health policy for the country must therefore take into account these underlying issues.

This paper examines the history of malaria control policies both around the world and in Tanzania in an attempt to formulate a comprehensive long-term plan for Tanzania that avoids the development of resistance to the insecticides and antimalarial drugs it relies upon. Such a policy must include three key technical elements. First, vector control prevents mosquitoes from transmitting the Plasmodium parasite to human hosts. Since these strategies rely on the efficacy of the insecticides they use, they must be managed carefully to prevent local mosquito populations from developing resistance. Second, case management, the treatment of individuals who have contracted the disease, is a necessary component of any malaria control policy.

Establishing an effective framework for the distribution of high-quality antimalarial drugs must be at the center of such measures. Third, with artemisinins as the last effective class of drugs, the current diagnostic paradigm, which, by equating a fever with malaria, has resulted in false positive rates as high as 87% and has contributed to the development of biological resistance to three different antimalarial drugs in the past decade, must be improved.4 When implementing these policies, important factors to be considered include the pre-existing health infrastructure, the incentives of and funding available to actors involved in aid disbursement, and the effective

Bhatnagar 3 social marketing of the interventions used. This paper uses these practical constraints to contextualize the more technical aspects of a comprehensive Tanzanian malaria control policy.

2. Vector Control Malaria develops when a human is infected by a protozoan of the genus Plasmodium (most commonly P. falciparum). The parasite’s life cycle has two distinct stages. In the human stage of the infection parasites, transferred from a mosquito’s bite, proliferate in the blood and other organs, causing the clinical symptoms associated with malaria. The parasite is then ingested by a mosquito during a blood meal, where it ultimately enters the insect’s salivary glands to allow itself to be transferred to future human hosts via a mosquito bite. Vector control measures attack Plasmodium during this second stage by preventing mosquitoes from biting humans. On a large scale, Tanzania’s current malaria control strategy relies predominantly on two strategies: insecticide-treated bednets (ITNs), which are used to protect potential victims of mosquito bites at night, and indoor residual spraying (IRS), whereby the walls of residences are sprayed with insecticides.

2.1. Insecticide-Treated Nets (ITNs).

Because of their ability to provide both a physical and a chemical barrier protecting against mosquito bites at an affordable cost, ITNs have become the most widely endorsed intervention against malaria. In 1999, the National Insecticide Treated Net Campaign (NATNETS) was launched in Tanzania under an enabling environment for multi-stakeholder investment including national textile manufacturers, private sector retailers, social marketing groups, non-governmental partners and the government sector.5 It was not until 2004, however, that the Tanzanian National ITN Voucher Scheme (TNVS) was established under the auspices of NATNETS with the funding of the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria (GFATM) to distribute highly subsidized and even free nets to families with pregnant women

Bhatnagar 4 and/or young children on a much larger scale.6 As the primary national framework for the distribution of ITNs, NATNETS and TNVS have been highly successful: between 2000 and 2012, they were responsible for the distribution of 27 million nets free of charge, as well as the sale of 7.8 million at highly subsidized rates.7 Consequently, as of 2013, ITN ownership rates in Tanzania stood between 85% and 96%.8 While the basic distribution framework for bednets is clearly effective, the primary challenge lies in maintaining current coverage levels. Doing so will require a three-pronged approach. First, speeding the large-scale adoption of long-lasting insecticidal bednets (LLINs) should be a priority. In much of Tanzania, “mosquito nets worn out are not replaced and retreatments are not done in time to provide a continuous protection against mosquito bites.”9 Currently, most ITNs are made of polyester and rarely last longer than 2-3 years after either tearing or losing the insecticides with which they were treated. LLINs, on the other hand, are made of more durable polyethylene and retain the insecticides in their fibers for the entirety of their 5-7 year lifespans.10 Due to the optimization of manufacturing and insecticide-treatment procedures, “in a recent analysis of the cost of five ITN and two IRS programmes, the costs per death averted with LLINs lasting 3 years were less than half the comparable costs incurred using conventional ITNs” despite higher initial costs.11 More specifically, assuming that 5.5 lives are saved per 1000 children sleeping under an LLIN and a distribution cost of US$ 2.50 per LLIN, the cost per death averted “is US$ 212 for an LLIN purchased for US$ 4.50 that lasts for 3 years, US$ 145 for an LLIN purchased for US$ 5.50 that lasts for 5 years, and US$ 104 for an LLIN purchased for US$ 5.50 that lasts for 7 years.”12 Indeed, due to these very factors, such a shift is already underway in malaria endemic countries throughout sub-Saharan Africa.13 Second, when bednets do wear out, an effective framework must be established to facilitate their replacement. The Tanzanian government’s National Malaria Control Programme

Bhatnagar 5 (NMCP) has already developed a highly effective policy of ITN replacement with the goal of maintaining coverage levels of at least 80%. This policy includes three key elements. First, a school based network that distributes free ITNs to children in the first, third, fifth, seventh, ninth, and eleventh grades is designed to cover about 30% of the Tanzanian population. Second, a mass replacement campaign is targeted to the 15 regions with the oldest nets, worst access to other means of ITN acquisition, and the highest malaria prevalence. Third, the TNVS works by using health facilities that offer antenatal and child health services to issue vouchers that can be redeemed for ITNs at a retail shop for a nominal fee.14 Because net manufacturers and distributors receive full funding from international donors like PMI and GFATM, as well as a network of domestic private sector textile- and insecticide-producing firms involved in the process, there is no cost passed on to the retailer; the fee simply provides the retailer an incentive to participate in the program. The TNVS currently operates through a network of more than 6000 retailers and has achieved near ubiquity throughout Tanzania.15, 16 Finally, to improve the longevity of existing ITNs, this paper recommends the adoption of community health education programs to address the widespread ITN misuse that occurs because locals are unaware of how to properly handle and maintain their bednets.17 There are a number of reasons to believe that such programs will prove effective. For instance, the recent increase in ITN usage from 16% for both children under five and pregnant women, the most susceptible groups, to over 70% for both groups between 2004 and 2012 can largely be attributed to the success of large-scale public health education initiatives, largely managed through ITN distribution chains, about ITNs’ ability to prevent malaria.18 Moreover, studies have shown that community-level health education programs can rectify misconceptions about proper ITN use even into the long term.19, 20 Further research is still required to determine the actor best suited to implementing such a policy at a national level, taking into account factors like the long distances

Bhatnagar 6 between villages and health centers, a poor transportation infrastructure, and an almost nonexistent referral system.21 2.2. Indoor Residual Spraying (IRS).

IRS is 4-5 times more expensive than LLIN use and can only feasibly be targeted towards residences with children.22 Prolonged usage is also correlated significantly with the emergence of insecticide resistance in local mosquito populations.23 Thus, it should only be used to supplement LLINs where malaria prevalence is especially high. In Tanzania, IRS is handled almost entirely by foreign actors, with the primary contributor being USAID’s President’s Malaria Initiative (PMI) and GFATM playing a smaller, secondary role.24 Until recently, there were only enough funds to use IRS in the Kagera region of Tanzania, long associated with the highest prevalence of malaria in the nation (over 40%). However, with the success of existing interventions (malaria prevalence in the province has now fallen to 8.3% as reported by PMI) and the fear of developing insecticide resistance, IRS was discontinued in Kagera in 2013 and is now used exclusively in the neighboring provinces of Mwanza (18.6% malaria prevalence), Mara (25.4%), Geita (31.8%), and Kigoma (26.0%).25 Once the malaria prevalence has declined substantially in these four provinces, PMI should next target it to the southeastern regions of Lindi (26.3%) and Mtwara (17.4%), the only other areas with malaria prevalence over 15%.26 2.3. Insecticide Resistance.

The 4 broad classes of insecticides currently in widespread use for malaria control are pyrethroids (PYR), DDT, carbamates (CX), and organophosphates (OP). Although resistance greatly reduces the efficacy of a certain insecticide against a mosquito, it comes with a set of evolutionary disadvantages, known as a fitness cost, to resistant individuals. For this reason, while an individual resistant to one particular insecticide would have a selective advantage over others in an environment exposed to that insecticide, in all other scenarios, that individual would

Bhatnagar 7 be less likely to survive. As such, replacing the current insecticide with one that has a different mode of action would reduce the likelihood that resistance alleles spread widely through the population. For this reason, frequent insecticide rotations informed by the specific forms of resistance observed in the field will prove central to insecticide resistance management efforts by reducing the frequency of a particular resistance allele in a given population of mosquitoes.

2.3.1. Target-Site Resistance.

“Target-site resistance occurs when the site of action of an insecticide (typically within the nervous system) is modified in resistant strains, such that the insecticide no longer binds effectively and the insect is therefore unaffected, or less affected, by the insecticide.”27 There are two types of target-site mutations: kdr and Ace-1R. The kdr mutation confers resistance to PYR and DDT by changing the structure of one of the voltage-gated sodium channels targeted by these insecticides in such a way that it retains most of its native functions but is no longer susceptible to a loss of function precipitated by the introduction of these insecticides.28 However, kdr strains of mosquitos have been found to be associated with fitness costs including longer larval development and lower female fertility and fecundity. When competing with wild-type mosquitoes in a controlled, insecticide-free environment, the frequency of the kdr mutation decreases significantly, suggesting that the removal of PYR and DDT stress would cause levels of kdr resistance to normalize to natural levels over time.29, 30 Moreover, “[i]n most vector species, kdr resistance to pyrethroids does not completely reduce the effect of the insecticide,” as PYRs continue to be an irritant even to kdrresistant mosquitoes. In practice, this phenomenon should reduce mosquito blood-feeding or encourage diversion to other hosts by vector species that do not feed exclusively on human hosts.31 As such, ITNs, which are exclusively PYR-treated at present time, would retain some efficacy as a vector control measure if IRS is not an option due to budgetary constraints.32

Bhatnagar 8 On the other hand, the Ace-1R mutation modifies the structure of a protein known as acetylcholinesterase in such a way that it can no longer bind CX and OP, which normally sabotage the enzyme’s ability to fulfill natural role in the coordination of the nervous system.33 Although the fitness costs of Ace-1R are, on their own, greater than those associated with kdr,34, 35 the fitness costs of harboring both forms of metabolic resistance are significantly lower than for harboring Ace-1R alone.36 It is notable that even if associated with significant fitness costs, a mosquito strain with both forms of target-site resistance is nearly impossible to eliminate, as it would exhibit resistance to all four classes of insecticides currently on the market. Such an outcome must be avoided if at all possible. To do so, the following measures must be taken to prevent any one form of resistance from becoming so widespread that the proliferation of mosquitoes with multiple target-site resistance alleles becomes as feasible an outcome as the emergence of a single resistance allele in a wild-type population. When kdr resistance is detected, ITN use should be continued but, when affordable, supplemented with the mosaic spraying (see section 2.3.3) of OP and CX to avoid allowing the development of either P450 or Est resistance (see section 2.3.2). In cases of Ace-1R resistance, IRS is to be suspended, allowing PYR-treated ITNs and the already high fitness costs of the mutation to reduce the numbers of resistant populations. DDT IRS is acceptable in especially severe scenarios. The continuation of frequent surveys of insecticide resistance (see section 2.3.4) is a crucial step in introducing these responsive interventions soon enough to prevent the emergence of multi-resistant populations.

2.3.2. Metabolic Resistance.

Metabolic resistance to an insecticide occurs when a mutation causes the overproduction of a protein associated with the detoxification of that insecticide.37 Although less common, metabolic pathways tend to confer significantly higher levels of resistance than their target-site counterparts while simultaneously being associated with a lower fitness cost.38 The three

Bhatnagar 9 mechanisms of metabolic insecticide resistance involve the elevated activity of P450 monooxygenases (P450), esterases (Est) and glutathione S-transferases (GST), respectively.

P450 resistance is most heavily associated with PYR resistance,39 but significant crossresistance with CX has also been observed. 40 Although individuals homozygous for P450mediated resistance were selected against in a standard lab environment, heterozygotes continued to persist.41 This trend is particularly worrisome, since heterozygotes were still found to harbor PYR resistance still 100 to 500 times stronger than that of the wild type.42 However, when treated with an OP, the populations of individuals both homozygous and heterozygous for P450mediated resistance declined precipitously, suggesting that this particular mechanism of resistance is associated with a heightened vulnerability to OPs.43 Est overproduction, on the other hand, have been found to confer “broad-spectrum organophosphate resistance,�44 while GST overproduction is responsible for metabolic resistance to DDT, while also playing a secondary role in OP resistance.45 In a sample of mosquitoes from France, fitness costs for the Ace-1R allele were found to be about twice as high as those for the Est allele. However, because Est fitness costs were only large enough to cause significant population shifts during the French winter, which bears little resemblance to any climate found in Tanzania, further scientific research must be conducted to assess the viability of Est as a mechanism of OP resistance in Tanzania.46 Trends outlined by the literature suggest that GST overproduction is similarly associated with a relatively low fitness cost.47, 48, 49 More disturbingly, both Est and GST mutations encompass broad classes of proteins that may be modified to alter the mosquito’s metabolic mechanisms of detoxifying OP and DDT, respectively.50 Because of this wide range of potential mutations (each associated with different fitness costs), over time, those mutations with the lowest fitness costs are selected for (after they manifest on a large scale). This hypothesis has been empirically confirmed for Est; given the similarity of the two

Bhatnagar 10 genes, it should also hold true for GST, though experimental data are required to test this prediction.51 Because metabolic resistance grants mosquitoes more virulent resistance against insecticides than a target-site mutation while simultaneously having substantially lower fitness costs, responses to them must necessarily be more forceful. Although P450 can be contained with the introduction of OP IRS, Est and GST are not associated with heightened vulnerability to any insecticide currently on the market. As such, the specific details of a policy response to their emergence remain unclear.

2.3.3. Guiding Principles of Insecticide Resistance Management.

Managing the recent development of insecticide resistance in Tanzania is of the highest priority, as no new class of insecticide for malaria control is anticipated until 2020 at the earliest.52 Globally, three broad strategies are used in such efforts. First, insecticides with different modes of action are rotated on a periodic basis.53 This technique is largely limited to IRS, since only PYR is currently approved for ITN usage.54 Second, two or more insecticidebased vector control interventions can be used in a single residence (e.g., PYR on ITNs and an insecticide of a different class for IRS on the walls), so that a mosquito is likely to come into contact with the second insecticide if it survives exposure to the first.�55 Finally, in mosaic spraying, “[o]ne compound is used in one geographic area and a different compound in neighboring areas, the two being in different insecticide classes.�56 In creating small pockets of alternating insecticides, resistance is more likely to be localized to one region and thus easier to combat. This strategy should be adopted in any areas where IRS is used to minimize the heightened risk of resistance developing.

More specifically, kdr resistance is to be met with rotations and/or mosaics of OP and CX IRS where it becomes especially detrimental to malaria control efforts. Introducing OP and CX

Bhatnagar 11 jointly in mosaic spraying would greatly reduce the probability of the simultaneous development of P450 and Est resistance by providing clear selective pressures against both mutations.

Frequent alternation of these two insecticides would help achieve the same objective, though further research is required to determine which intervention would be more effective. In less severe cases, OP alone is to be preferred because it is about half as expensive as CX.57 If resources cannot be spared, ITN usage should continue as before, as PYRs retain some of their efficacy even in the face of kdr resistance.58 However, since P450 provides much more virulent resistance to PYR than kdr and is associated with heightened OP vulnerability, any area with this form of resistance must be met with OP IRS as quickly as possible, even if the necessary resources are drawn from another component of the budget. On the other hand, an appropriate response to Ace-1R resistance is the suspension of OP and CX IRS and the introduction of DDT IRS in areas of especially severe resistance. Such a strategy is preferable to any combination of DDT and PYR IRS because the ubiquity of PYR-treated bednets renders PYR IRS redundant.

Finally, of the five pathways, Est and GST are by far the most devastating because their lower fitness costs make them difficult to manage with current strategies. While aggressive IRS with an insecticide unaffected by these pathways of resistance is recommended, every step should be taken to prevent their emergence on a large scale.

The timeframe over which these policies are updated is just important as the policies themselves, as insecticides must be cycled before a particular form of resistance comes to dominate the mosquito populations in an area for two reasons. First, it is much easier to eliminate resistance alleles from a population with a low frequency of that allele than one with a high frequency. But second, although multi-insecticide resistance is highly anomalous in nature because the frequency of even a single resistance mechanism is so rare, substantially increasing the frequency of one allele increases the probability of the development of multi-insecticide

Bhatnagar 12 resistance. Thus, biannual monitoring and evaluation efforts in the style of Tanzania’s 2013 review of its National Malaria Programme (see section 2.3.4) are recommended to gather the data necessary for a policy that can be updated to reflect present circumstances.59 2.3.4. Recommendations for Tanzania.

As of 2013, there is “evidence of a rapid spread of resistance amongst An. gambiae s.l. populations to pyrethroids, across the country. Reduced susceptibility to DDT was recorded in Bariadi and Geita, but the mosquitoes were still highly susceptible to Fenitrothion [an OP] and Bendiocarb [a CX] in all the sentinel sites/districts.”60 The PYR-DDT cross-resistance accompanied by the lack of CX (Bendiocarb) resistance suggests that the primary form of resistance currently developing across Tanzania is kdr, not P450. As such, in regions where malaria incidence is especially high, IRS efforts should reduce PYR and DDT usage to focus instead on OP (since CX is nearly twice as expensive per unit sprayed).61 However, Kagera, the province of Tanzania traditionally associated with the highest incidence of malaria, provides an important cautionary tale against over-reliance on a single form of IRS. Although malaria prevalence in the province has fallen from over 40% to just 8.3% in over the past decade,62 “tests in 2011 showed extremely low mortality rates to DDT, pyrethroids and even bendiocarb.”63 Further testing is warranted to determine if these resistance trends are a combination of kdr and P450 resistance, kdr and Ace-1R resistance, or another pairing. Either way, IRS, which has already been suspended in the region, should not be resumed unless the situation deteriorates significantly, in which case OP use is recommended. In the surrounding provinces, which are now the targets of IRS, mosaic spraying should be used to minimize the risk of multi-allele resistance traveling any further than Kagera.64 Currently, bednets are only treated with PYRs.65 Even so, LLIN usage should be continued because they still provide a physical barrier against mosquitoes and do not exert as

Bhatnagar 13 much of a selective pressure as IRS (because mosquitoes are less exposed to insecticides with ITNs, which are present in only one part of the household, than IRS, which, by its very nature, pervades the entire residence). Taken with PYRs’ continued irritability even to resistant mosquitoes, ITNs remain a viable defense against mosquitoes even in the face of insecticide resistance.66 That said, research has shown that durable polypropylene sheeting (much like a bednet) can maintain high levels of CX for 10 washes67 (more than the 3 washes of traditional ITNs, but less than the 20 of LLINs).68 This paper recommends that future research focus on developing durable, wash-resistant ITNs impregnated with OPs and DDT while maintaining low mammalian toxicity. Such developments would allow for effective cyclical insecticide rotations with both ITNs and IRS. The effective coordination of a vector control policy responsive to fluctuations in resistance patterns requires an infrastructure that not only communicates scientific research to groups like the NMCP, PMI, and GFATM, but also gives these organizations the ability to conduct and commission such research independently. While publications in open-access journals like Malaria Journal and PLoS can provide such organizations with a great deal of important information on the factors contributing to the successes and failures of certain policies, both in Tanzania and abroad, national-level evaluations of insecticide resistance are difficult to extrapolate from these highly specific papers. Instead, national reports on insecticide resistance are conducted by the Tanzanian government and have been issued in 1999, 2004, 2008, 2011, and 2013, with funding drawn from international agencies like the United Kingdom Department for International Development (2013), PMI and USAID (2011), and the Gates Foundation (2008). Such evaluations rely on data collected from over ten (11 in 2004, 14 in 2011, 12 in 2013) sites distributed around Tanzania in a manner that accurately represents the disaggregated national data on insecticide resistance.69, 70 The East African Network for Monitoring

Bhatnagar 14 Antimalarial Treatment (EANMAT) (see section 3) for monitoring antimalarial drug resistance works in a similar way. The current biannual frequency of these evaluations is ideal, as it allows for the creation of an adaptive policy that can squelch emerging resistance before it becomes widespread.

2.4. The Future of Tanzanian Vector Control.

In the past, the most common Tanzanian malaria vectors have been An. gambiae s.s. and An. funestus, species of mosquitoes that are primarily anthropophagic (human-biting) and endophilic (active indoors).71 Following the past decade’s scale-up of vector control policies, An. arabiensis, a species that exhibits exophilic (active outdoors) behavior, has replaced An. gambiae s.s. and An. funestus as the most prevalent vector because it has remained relatively unaffected by these predominantly indoor measures. This resilience can further be attributed to An. arabiensis’ ability to exploit cattle as a blood source in addition to humans.72 However, the rise of An. arabiensis does not necessarily bode a resurgence in malaria prevalence: given this species’ exophilic behavior, Plasmodium transmission can only occur when potential human hosts are active outdoors at the same hours as the mosquitoes.73 Moreover, their behavioral resilience would increase the likelihood that An. arabiensis specimens exhibiting kdr resistance would be deterred from entering households protected by PYRs, preferring instead to feed outdoors on cattle.74 Even so, for further reductions in vector prevalence to occur, future strategies must address the behavioral resistance of An. arabiensis to current measures. Potential solutions include insecticide-treated cattle, increased house screening, and larval source management (LSM).75 While the use of insecticide-treated cattle is highly experimental, and programs to scale up house screening require more funds than are currently available, recent research has increased the viability of LSM, where efforts are taken to introduce larvicides to mosquitoes’ nesting sites.

Bhatnagar 15 Traditionally, this technique was largely infeasible because of the difficulty in accessing and even finding all nearby nests.76 However, a recent field trial in rural Tanzania tested autodissemination, a new method for LSM whereby adult mosquitoes are baited into coating themselves with the larvicide Pyriproxyfen (PPF) (typically stored with the bait in a clay pot), and then disseminate that PPF into the bodies of water surrounding their nests.77 PPF has the unique benefit of being a compound that avoids killing adult mosquitoes outright (preventing the emergence of cross-resistance with insecticides currently in use) by instead targeting the larvae specifically.78 Moreover, in field trials, surviving larvae (21% during LSM as opposed to 95% in the control) exhibited no genetic resistance, instead surviving because their exposure to PPF was more limited.79 Because it not only uses a compound existing mosquito populations have not yet been exposed to, but can also be implemented entirely outdoors, LSM provides a potential solution to both insecticide resistance and the rise of An. arabiensis.80 3. Malaria Case Management.

Until the 1990s, the chief antimalarial drug used in Tanzania was CQ. In 1997, however, EANMAT was established to track the alarming rates of CQ resistance emerging at the time.81 As a result of the data generated by EANMAT, SP displaced CQ as the first-line drug in 2001, followed by artemether-lumefantrine (ALu), an artemisinin-based combination therapy (ACT), which includes both an artemisinin derivative (artemether) and a synergistic partner drug (lumefantrine), in 2006.82 Given that ACTs, the current first-line treatment option, are the final class of drugs against which resistance has not yet manifested (in the region), steps must be taken to ensure that they remain viable options in the future.83 It is important to realize that unlike insecticide resistance, antimalarial drug resistance develops incrementally. Typically, the therapeutic dosage of a given drug is potent enough to kill very nearly all parasites in an environment that has not previously been exposed to that drug.

Bhatnagar 16 However, when parasites are exposed to subtherapeutic dosages, selection in favor of those individuals that exhibit some resistance to the drug can occur. Eventually, multiple resistance alleles manifest, resulting in full resistance to the drug.84 This resistance can develop at three different steps of the case management process. First, if a fever patient is misdiagnosed as malaria-positive and receives treatment with an ACT, resistance to the partner drug can develop.

While artemisinins have a short half-life within the body, most partner drugs take a longer time to dissipate. As such, if a misdiagnosed patient is infected with malaria after completing a treatment regimen, parasites would be exposed to subtherapeutic concentrations of the partner drug, allowing for the selection of resistant specimens.85 If the patient is infected while the artemisinin is still present in the blood, however, selection for resistance is less likely to occur because multi-drug resistant specimens are relatively rare in nature.86 Second, when administered to patients who do have malaria, substandard drugs (which contain insufficient levels of the drug in question) expose the parasites in the patients’ blood to subtherapeutic drug concentrations, allowing for the stepwise selection of resistant phenotypes.87 Third, for many drugs with longer treatment regimens, patients often stop taking the drug before the regimen is complete because their symptoms have subsided, thus preventing the parasites in their blood from being exposed to fully therapeutic levels of the drug. Artemisinin-based monotherapies, with their 7-day regimens, are most susceptible to this trend.88 Empirically, across Tanzania, less than a third of malaria-positive patients received ACTs in 2014.89 Even more disturbingly, however, of the patients who were able to obtain ACTs, however, less than a quarter tested positive for malaria in a laboratory setting.90 To effectively address this tragic contradiction, both the public’s access to high-quality ACTs and the accuracy of current diagnostic paradigms must be improved. Doing so would likely play an additional role in reducing the net costs incurred by RDT and ACT procurement organizations.

Bhatnagar 17 3.1. Diagnostics.

“Microscopy is regarded as the ‘gold standard’ for malaria diagnosis. However, the lack of skilled technologists in medical facilities in affected areas often leads to poor interpretation of data. Furthermore, microscopy is time consuming and labor-intensive”91 and requires microscopes and a source of electricity, which are often lacking in point-of-care settings.92 As a result, the current diagnostic paradigm relies on the presentation of often-ambiguous clinical symptoms and equates fever with malaria.93 Unfortunately, this presumptive approach has led to false positive diagnosis rates between 53.9% in the northeastern provinces (areas with a malaria prevalence between 30% and 40%) and 87% at the Muhimbili National Hospital in Dar es Salaam (malaria prevalence of 3.6%).94 In the literature, antibody tests known as rapid diagnostic tests (RDTs) are often touted as a solution to these deficiencies because they are compact, available in easily transportable strips, inexpensive, easy to use, require little expertise to interpret, do not require a source of electricity, and can yield fairly accurate results in a matter of minutes.95 3.1.1. A Technical Evaluation of RDTs. RDTs are designed to detect the presence of one of two different Plasmodium proteins found in the blood of malaria-positive patients: HRP-2 and pLDH. Currently, HRP-2 tests are much more common.96 While different Plasmodium species have different HRP-2 and pLDH genes, all malaria in Tanzania can be attributed to P. falciparum. 97 Thus, this paper does not differentiate between RDTs that test specifically for P. falciparum and those that are not specific to any particular species of Plasmodium.

HRP-2 RDTs have sensitivities (the percentage of positive tests among the total number of positive samples, or a measure of false negatives) greater than 90%, but their specificities (the percentage of negative tests among the total number of negative samples, or a measure of false

Bhatnagar 18 positives) tend to be lower and more variable, ranging from 39% to 88%. The most comparable datapoint (considering the genetics of local Plasmodium populations), measured by Swarthout et al. in the nearby eastern Democratic Republic of the Congo, found a 100% sensitivity and 52% specificity for the Paracheck-P.f. HRP-2 test. These false positives can largely be attributed to “the persistence of HRP-2 in the blood for long periods after parasite clearance.” Inconsistencies between manufacturing processes are responsible for some variations in both metrics.98 Although pLDH RDTs are associated with a substantially higher specificity for malaria cases than HRP-2 (94.0% and 70.9%, respectively),99 their sensitivity generally decreases at lower levels of parasitemia.100 The magnitude of this decrease varies with the genetic composition of the region’s Plasmodium populations and the brand of RDT in question.

Specificity, however, remains unaffected.101 However, the lower sensitivity P.f.-pLDH-detecting RDTs was found to be highly product dependent.102 For instance, the SD BIOLINE Ag. P.f. pLDH RDT (SD90) was found to have an overall sensitivity of 99.5% (compared with 100% for the HRP-2 line of the same test), maintaining accuracy even at low levels of parasitemia: the only false negative in the study was from a sample with a parasite concentration of 62/μL (below the 100/μL threshold of detection by even microscopy).103 In the field, improvements in pLDH RDT sensitivity can largely be attributed to the more recent shift away from multi-step RDTs to more user-friendly single-step tests.104, 105 An additional advantage of pLDH RDTs is the fact that the HRP-2 gene experiences antigenic variations between Plasmodium populations, while the pLDH gene does not, simplifying the process of adapting to the evolution of local Plasmodium populations.106 From a purely technical standpoint, the newest wave of pLDH tests are far superior to any HRP-2 tests currently on the market. The consistently higher specificity values of these tests address the high incidence of false positive results seen with HRP-2 tests while simultaneously

Bhatnagar 19 achieving the high sensitivities that minimize the number of malaria patients who would not receive the drugs they need due to a false negative RDT result. The primary concern then becomes the financial feasibility of such a policy.

3.1.2. Reducing the Costs of an RDT Policy.

Financially, HRP-2 RDTs are less efficient than the current presumptive diagnostic paradigms, as determined by a cost-benefit analysis considering the prices of the RDTs purchased and the amount of antimalarial drugs saved per death averted. This trend can largely be attributed to the poor adherence to negative test results observed in point-of-care settings.107 Thus, before a financial comparison between HRP-2 and pLDH RDTs can occur, both clinician and patient behavior must change to better accommodate negative RDT results.

On the healthcare side, Tanzania’s Ministry of Health (MoH) currently provides a twoday, 16-hour RDT training program to provide health workers with the knowledge and skills to properly use RDTs in malaria treatment. In these sessions, trainers explicitly approved by the MoH create an engaging, interactive atmosphere to convey the content of a standardized learner manual to health workers. These programs are then followed up two weeks later with a threeday, six-hour session designed to reinforce proper laboratory techniques for RDT use.108 In order to maintain good clinical practices well after such training has been concluded, this paper looks to Kenya, where health workers are texted daily reminders of the necessity of RDT usage accompanied by motivational messages intended to reinforce the importance of following RDT test results in reducing the national prevalence of malaria.109 Taken together, these policies have reduced the overtreatment of malaria in the highly localized areas to which they have been targeted, at least in the short term. However, because these training programs are largely funded by independent researchers, long-term success will require the allocation of financial resources on a national scale.110

Bhatnagar 20 When examining the interactions between health workers and patients, however, any gains made entirely in the healthcare sector would evaporate without further action. Because locals associate a wide range of symptoms, from joint and back pain to headaches and fevers, with malaria, patients are often dissatisfied at being denied antimalarial drugs after a negative test result and lose faith in their local dispensaries’ ability to cure them, pressuring health workers into prescribing unnecessary antimalarials.111, 112 Both in Tanzania and elsewhere, a particularly effective way of reducing patients’ distrust of RDTs has been the provision of an alternative diagnosis or treatment, particularly antipyretics and/or anti-inflammatory drugs.113, 114 To make negative RDT results more palatable to locals, this paper recommends strengthening local supply chains for these drugs, ensuring that they be supplied directly to health centers as well as community drug outlets. In the longer term, more effectively treating malaria-negative cases requires expanding health worker education and training programs to also discuss symptoms for common viral and bacterial illnesses. Moving forward, the provision of additional tests and drugs to diagnose and treat these conditions will be equally important.115 Finally, to independently improve the community’s trust of RDT results, official patient leaflets, to be distributed by health centers among local populations, can help to disseminate reliable information about proper clinical practices. A field study in Tanzania, after creating such a leaflet that encouraged the public to trust negative diagnoses for malaria as determined by an RDT and was comprehensible to 97% of the rural population examined, helped reduce public backlash against the potential outcome of being denied antimalarials for a non-malarial febrile illness, in turn increasing health workers’ incentives not to prescribe antimalarials in such cases.116 Unfortunately, even at an ideal adherence of 90%, the low specificity of HRP-2 tests makes RDT use fiscally advisable for adults, but disadvantageous for children, the prime victims

Bhatnagar 21 of the disease. Even with realistic subsidies, the costs per death averted of RDT-based relative to presumptive diagnoses still vary substantially on a case-by-case basis for children.117 On the other hand, with the (now) comparable sensitivity of pLDH RDTs and their much higher specificities, RDTs now have the ability to actually reduce net case management expenditures by cutting spending on antimalarial drugs, provided that adherence to test results is improved by the measures outlined above.118 Such policies may also serve to decrease the likelihood of ACT stockouts and free up resources for additional programs.119 Further research is recommended to isolate additional pLDH tests of comparable sensitivity to the SD BIOLINE pLDH test cited in this paper, as introducing multiple competing brands into Tanzania will keep RDT prices low.120 3.1.3. RDT Procurement.

The procurement of RDTs and ACTs is managed almost entirely through GFATM, though PMI provides some support “to place emergency orders in case of delayed release of funds or late delivery of commodities.”121 In such a supply system centralized at the national and international levels, the first step is to accurately quantify demand for both RDTs and ACTs for the country as a whole.122 Ideally, RDT quantification should be based on the incidence of febrile illness throughout the nation, as every such case, at least while health workers continue to equate fever with malaria, merits an accurate diagnosis. For effective quantification, the hierarchical structure of Tanzania’s system of hospitals, health centers, and dispensaries (of which approximately 66% are government-owned) would allow for periodic reporting of the relevant medical data to central procurement authorities. 123, 124, 125 However, given the country’s deficient infrastructure, such efforts would need to be conducted in a largely top-down fashion, placing more of the burden on central data collecting authorities than on independent reporting by local health centers.126 The public’s reliance on the largely informal private sector for malaria treatment presents another obstacle that requires further research to adequately address.127

Bhatnagar 22 When addressing the actual purchase of RDTs, although current international funds are considered sufficient for establishing the necessary levels of RDT procurement, “continuing to scale up laboratory diagnosis of malaria with microscopy and RDTs will be a major challenge on the Mainland with the continuing problems related to supply chain management [and] the frequent stockouts of RDTs and ACTs at the health facility level.�128 Over time, a large-scale rise in effective RDT use would decrease the demand for ACTs as the incidence of false positive malaria diagnoses begins to decline. However, efforts to scale up RDT procurement and distribution would inevitably increase the financial burden on donor organizations in the short term. This paper recommends seeking support from private for-profit firms and faith-based organizations to expedite this interim period, as such partnerships have previously seen success in Tanzanian distribution networks for both ITNs and antimalarial drugs.129, 130 3.1.4. RDT Supply Chain Management.

For the public sector, this paper recommends sending RDTs to each of Tanzania’s 132 high-level district hospitals as intermediary suppliers. The RDT demand for each of these hospitals should be conveyed in a bottom-up manner to central distribution authorities, minimizing the risk of over- or under-stocking at this level.131 While RDT use is initially being scaled up, a top-down distribution strategy starting from each of these hospitals should be implemented to help ensure wide coverage of local dispensaries either equipped with poor communications and infrastructure or unaware of the importance or existence of nonpresumptive malaria diagnosis. There are two key advantages to using district-level hospitals in such a capacity. First, their better access to proper equipment would allow them to store RDTs in appropriately controlled conditions to prevent their premature expiry.132, 133 Second, using them as intermediaries allows RDT distribution to be controlled at a secondary level much closer to point-of-care settings than a system centralized at the national level.

Bhatnagar 23 However, given the fact that the vast majority of malaria and fever cases are treated outside of formal health facilities for reasons of convenience, accessibility, and price negotiability, a long-term solution requires the integration of RDTs into the private sector.134 In particular, this paper recommends exploiting the rise of accredited drug dispensing outlets (ADDOs), which are staffed by workers accredited through a dispensers’ course approved by the Tanzanian Food and Drugs Authority. Following their introduction, the sale of antimalarials by the untrained owners of general drugstores declined significantly. While this trend is partially attributable to the tighter regulations enacted around the same time, general shops were also simply competed out of the market by their licensed counterparts.135 For proper private-sector implementation of the program, three mechanisms must be established. First, ADDOs must receive a steady supply of RDTs. The mechanics of such a policy are discussed further in section 3.2.2. Second, drug store attendants must receive proper RDT training.136 Such programs could be labeled by central authorities as a necessary step in renewing ADDO status, while reinforcing messages could be sent to workers via text message.137 Third, procedures for addressing negative RDTs must also be created. In the short term, these steps could involve the prescription of antipyretics or anti-inflammatory drugs,138 but in the longer term, an effective referral system from local dispensaries to better-equipped regional hospitals must be introduced.139 3.2. Antimalarials.

Because drug resistance has rendered the vast majority of antimalarial drugs obsolete, artemisinins and their derivatives have become the world’s last-line drugs against Plasmodium and are available both as monotherapies (AMTs) and combination therapies (ACTs). This paper recommends investing entirely in ACTs to reduce the risk that artemisinin resistance develops.

Because AMTs require a seven-day course, patients often discontinue treatment too early

Bhatnagar 24 because their symptoms have subsided, even though the parasitemia has not been fully cleared.140 Unfortunately, such behavior encourages the development of drug resistance by exposing parasites to subtherapeutic artemisinin concentrations.141 Although the sale of AMTs in Tanzania is almost non-existent, large-scale global action is required by the governments of major international donors, such as the US and UK, and IGOs like the WHO and UN to prevent the transfer of artemisinin resistance from neighboring countries.142, 143 Such measures would entail blacklisting known AMT manufacturers, working with governments to create effective domestic frameworks to enforce anti-AMT regulations, and creating public health education programs to warn patients against the use of AMTs (as discussed in section 3.2.3 with respect to expired, counterfeit, and substandard drugs).144 On the other hand, widespread adoption of artemisinin-based combination therapies as a first-line drug would substantially reduce the biological risk of the development of antimalarial resistance to either artemisinin derivatives or their partner drugs for three reasons. First, considering the stepwise development of antimalarial resistance, it is highly unlikely that resistance to therapeutic concentrations of two drugs will be found in nature.145 Second, the two components of almost all ACTs are selected such that they operate in a synergistic manner that amplifies the metabolic efficacy of both drugs. In this way, a more potent treatment is created.146, 147

Third, while artemisinins, with their short biological half-lives, require a seven-day treatment

regimen in the form of an AMT, ACTs are prescribed for a course of only three days because in an ACT, an artemisinin derivative is paired with a partner drug that the body takes longer to fully metabolize. Consequently, patient adherence to ACT regimens is much higher, reducing the likelihood of exposing parasites to subtherapeutic drug concentrations.148 However, because combination therapies inherently involve multiple pills, there is still some risk that a patient will deviate from the prescribed regimen.149 Such confusion can be minimized by enacting centrally

Bhatnagar 25 enforced regulations requiring all components of a combination therapy to be co-packaged by drug manufacturers.150 Finally, the protection of the ACT’s status as an effective drug requires that intermittent preventative treatment (IPT) be discontinued. In IPT, infants and pregnant women are prescribed antimalarial drugs as a preventative measure against future malarial infections.151 Although IPT has been responsible for a reduction in the number of clinical episodes per patient, it has the key disadvantage of contributing to the development of drug resistance.152 Especially given the lower overall incidence of malaria following the success of vector control policies and the long-term risks to the efficacy of the world’s last line antimalarial drugs, the money currently allocated to IPT would be better spent elsewhere. Such a shift would have the added symbolic value of painting the presumptive use of antimalarial drugs in any context in a negative light.

3.2.1. ACT Procurement.

Like RDTs, ACT procurement is managed entirely through the GFATM and PMI.153 Similarly, ACT quantification efforts should also be coordinated through the country’s hierarchical healthcare system. However, while Tanzania’s highly decentralized, unregulated system of drug distribution hinders quantification efforts, ACT procurement is associated with a number of additional confounding factors.154 Most importantly, unlike RDTs, which can be produced in the lab with a relatively short turnaround time, artemisinin-based drugs are plantbased products. Thus, supply is much more inelastic, as a single production cycle takes about fourteen months. Although initiatives are underway to provide farmers and pharmaceutical firms with incentives to consistently produce at necessary levels, the supply of plant-based precursors remains unstable. For example, “in 2004, there was a scarcity and a rise in price due to a rapid increase in the demand for ACTs, and in 2008 and 2009 agricultural production was reduced in response to overproduction in 2006 and 2007 with a consequent fall in prices.”155

Bhatnagar 26 Accurately quantifying demand to suppliers is the best way to ensure a more predictable supply of ACTs, but doing so would require the creation of a more effective national health database. Securing such stability can also be further assisted by the “conclusion of long-term, extendable agreements” between donor organizations and suppliers that include provisions for advanced drug purchases within a certain tolerance range.156, 157 Finally, while the GFATM is expected to finance the procurement of the entirety of Tanzania’s projected ACT demand, on multiple occasions, PMI has needed to procure emergency stock due to the delayed disbursement of GFATM money. PMI is currently planning an emergency fund to minimize the chance of such stockouts occurring at a central level in the future.158 In doing so, PMI is also reducing the risk that suppliers are left with unsold product for an extended period of time, thus reducing the price of the final product paid by consumers.159 3.2.2. ACT Supply Chain Management.

One of the most significant issues with current ACT supply chains is the excessive risk placed on manufacturers compared to funding agencies.160 Most notably, the volatility of ACT demand in both the short and long term is a major source of risk for manufacturers, as firms suffer both from overproduction (unsold, perishable excesses) and underproduction (substantial negative publicity).161 While accurate quantification can mitigate immediate-term uncertainty, seasonal and annual fluctuations will continue to be sources of concern to manufacturers because of the inelasticity of their supply.162 Addressing this imbalance is central to decreasing ACT prices for Tanzanian consumers.

From 2010 to 2012, the Affordable Medicines Facility – malaria (AMFm), a GFATM-run mechanism for financing antimalarial drugs, succeeded in accomplishing these goals. Its operation was responsible for not only increasing the availability of ACTs from 25.5% of all Tanzanian outlets to 69.5% (with increases in the private sector from 10.8% to 66.4%)163 by

Bhatnagar 27 creating a global subsidy targeted towards ACT manufacturers and producers that “stabilize[d] demand and create[d] incentives for ACT production,”164 but also precipitating a fivefold decrease in ACT prices from $5.28 to $0.94 as pharmaceutical companies were able to enjoy greatly reduced short-term risks and reap the benefits of economies of scale.165 The simultaneous increases in availability and decreases in prices led to significant increases in ACT usage across all countries in which AMFm was implemented.166 These same trends were also responsible for increasing the market share (in Tanzania) of ACTs relative to other antimalarials from 6% to 47%, decreasing the risk of patients resorting to old, ineffective drugs.167 However, AMFm was discontinued after its pilot phase because it flooded the informal private sector with ACTs sold over the counter, often to malaria-negative fever patients, thus heightening the risk of artemisinin resistance developing.168 Just as importantly, the program acquired nearly five times more ACTs than were actually required, not only wasting hundreds of millions of dollars, but also throwing the entire international market into chaos.169 To address the shortcomings and market failures of AMFm while still maintaining the tremendous gains in coverage it secured, this paper recommends expanding AMFm to also cover the private-sector acquisition of RDTs for accurate diagnosis, as well as training that advises the prescription of anti-inflammatory drugs and antipyretics for patients who test malaria-negative. As suggested in section 3.1.4, such programs could be construed as a necessary step in renewing an ADDO’s accredited status, creating an incentive for drug shop employees to pursue this training. An appropriate balance between overproducing and achieving economies of scale remains to be found, especially given the reductions in ACT use expected to follow widespread RDT adoption.

3.2.3. Ensuring High Drug Quality. “‘Substandard drugs’ are medicines that do not meet the correct scientific specifications for composition and ingredients and are consequently ineffective and potentially dangerous for

Bhatnagar 28 the patient. ‘Counterfeit drugs’ are a category of substandard drugs that are deliberately and fraudulently mislabeled for profit-making purposes. Counterfeits may contain only traces of active ingredients or no active ingredient at all.”170 Although responsible for the development of drug resistance, counterfeit and substandard drugs also have the equally pernicious effect of compromising the perceived efficacy of ACTs and thus jeopardize the sustainability of ACT demand.171 Throughout the country, 13% to 32% of these drugs were found to be substandard, though few were counterfeit.172 Additionally, about 18% of the drugs being sold had already expired at the time of their sale.173 These issues can be addressed in three ways.

First, given the highly decentralized nature of Tanzania’s systems of drug retailers, the creation of district-level drug inspectors is highly infeasible.174 Instead, with the projected declines in ACT expenditures following the increased relevance of RDT-based diagnosis, this paper recommends redirecting GFATM and PMI money to establishing a policy of inspecting products both pre- and post-shipment at major transit hubs. Such inspections should include: a review of all documentation and certifications; “a visual inspection of the products, including labeling, dosage form and strength, and packaging” and seals; and laboratory testing of random product samples.175 On a larger scale, the coordination of international efforts by groups like Interpol and the WHO’s International Medical Products Anti-Counterfeiting Taskforce “to share data on sources of poor quality drugs in various countries in order to shut down illegal manufacturing facilities” responsible for the proliferation of substandard and counterfeit drugs will be equally important in establishing high drug quality standards throughout the market in the longer term.176, 177 Second, medicines produced at specific sites by a given pharmaceutical firm can be prequalified by the WHO as safe, effective, and high-quality products. The prequalification process entails 5 steps: an invitation to a firm to have its product evaluated; the submission of a

Bhatnagar 29 dossier on the quality, safety, and efficacy of the product to be evaluated; an assessment of the data presented; a WHO-conducted inspection of the manufacturing sites in question; and a decision of whether the product meets the specified requirements.178 This paper recommends that the Tanzanian government only allow medicines prequalified by the WHO to enter its healthcare system and ensure that such medicines are clearly labeled in a way that distinguishes them from unverified products.179, 180, 181 Similar labeling strategies are advised for expiration dates.

Empirically, countries that use the WHO Prequalification of Medicines Program (PQP) have seen drug failure rates drop to below 4% from their previous levels, which often stood above 30%.182 Considering that one of the most significant challenges of regulating Tanzanian drug quality is the presence of over 1000 different brands of antimalarial drugs with little to distinguish each one in the eyes of local retailers, such a policy, which would give prequalified firms a competitive advantage over their unapproved counterparts, would create a much more manageable nexus of firms selling products of verified quality.183 Third, public health education programs would help legitimate pharmaceutical firms outcompete producers of substandard and counterfeit drugs by painting their products as inferior goods, thus decreasing demand for them. In a notable global example of one such program, the WHO PQP advocates in favor of medicines of assured quality in the countries of their sale after prequalifying them. Such programs already have been successful at giving prequalified medicines a competitive advantage over unverified products in the eyes of both patients and health workers in other countries.184 This paper recommends supplementing such efforts with further action by local health dispensaries to distribute leaflets and conduct public education programs on the importance of not only using prequalified medicines, but also checking their expiration dates. Such programs should operate in much the same way as those outlined for promoting adherence to RDT results.

Bhatnagar 30 Although these three policies would have the cumulative effect of removing a large quantity of inferior but previously undifferentiable products from the Tanzanian market, further investigation is required to determine the magnitude of the effect on drug prices resulting from the decrease in the number of competing firms, as well as the impact on drug availability.

4. Conclusions.

Because malaria is a vector-borne disease, infection can either be prevented by killing mosquitoes before they transfer the parasite to human hosts, or can be treated by antimalarial drugs during the blood-borne stage of Plasmodium’s life cycle. At both steps of the process, however, biological resistance threatens to eradicate any of the gains made by existing programs.

Although current vector control measures have been responsible for reducing Tanzania’s national malaria prevalence by almost 50%, pyrethroid resistance is beginning to manifest throughout the country, accompanied by cross-resistance to other insecticides in the northeastern province of Kagera. Future research should be directed towards developing affordable larval source management and bednets that can be treated with non-pyrethroid insecticides to create an economically feasible method of insecticide alternation in provinces not afflicted with an especially high malaria prevalence. At present time, however, the majority of Tanzania should continue ITN use as is, simply ensuring that a long-term plan for the replacement of worn out ITNs with LLINs is in place to maintain current coverage rates of over 80%. That said, to prevent the spread of more virulent non-kdr resistance from Kagera, the neighboring provinces should be targeted with annually rotating patterns of mosaic IRS to limit the further spread of insecticide resistance.

Should a Plasmodium-infected mosquito still manage to bite a human, however, the focus then turns to improving the national framework for case management. One of the most significant deficiencies of the existing system is that it provides antimalarial drugs to only a third

Bhatnagar 31 of the patients who need them, while of the patients who receive these drugs, only a quarter are actually malaria positive. In so doing, it not only misallocates valuable resources, but also heightens the risk that ACT resistance develops, a risk compounded by the widespread presence of substandard drugs in the country. While substandard pharmaceutical practices can be curtailed through national and international regulation, ACTs must penetrate the private sector to increase general availability, accompanied by pLDH RDTs to improve poor diagnostic practices.

Supplemented with mandatory drug shop attendant and health worker training programs (as a necessary condition to re-accreditation), an expanded AMFm that covers RDTs as well as ACTs could meet both goals simultaneously, considering the pilot program’s success in increasing the private sector availability of ACTs from 10.8% to 66.4%. Further research is required to determine whether the resultant treatment prices would actually be affordable.

Bhatnagar 32

Notes 1

United Kingdom Department for International Development, An Epidemiological Profile of Malaria and Its Control in Mainland Tanzania, by Prosper Chaki, et al. (Dar es Salaam: 2013), 9, accessed July 24, 2014.

2

Maxon, Robert M, “Independent East Africa, 1960s to 1990s,” in East Africa: An Introductory History, 3rd ed. (Morgantown, WV: West Virginia University Press, 2009), 280.

3

Elizabeth Heath, "Tanzania," in Africana: The Encyclopedia of the African and African American Experience, ed. Henry Louis Gates and Kwame Anthony Appiah, 2nd ed. (Oxford University Press, 2005), 5:18.

Leonard E.G. Mboera, Emmanuel A. Makundi, and Andrew Y. Kitua, "Uncertainty in Malaria Control in Tanzania: Crossroads and Challenges for Future Interventions," American Journal of Tropical Medicine and Hygiene 77, no. 6 (December 2007): 114, accessed July 24, 2014.

4

5

UK Department for International Development, An Epidemiological Profile of Malaria, 35.

6

Ibid., 36.

7

Ralph Fuller, “35 Million Nets Distributed, NATNETS Continues Its War on Mosquitoes -UPDATE,” Case Studies for Global Health, last modified May 27, 2012, accessed December 2, 2014.

8

United States Agency for International Development President's Malaria Initiative, Malaria Operational Plan FY2014 (Washington, D.C.: 2013), 24, accessed August 28, 2014.

9

Mboera, Makundi, and Kitua, “Uncertainty in Malaria Control,” 114.

10

World Health Organization Global Malaria Programme, Insecticide-Treated Mosquito Nets: A WHO Position Statement (Geneva: WHO Press, 2008), 2, accessed August 1, 2014.

11

Ibid., 3.

12

Ibid., 3-4.

13

World Health Organization Global Malaria Programme, World Malaria Report 2014 (Geneva: WHO Press, 2014), 12, accessed December 26, 2014.

14

USAID President's Malaria Initiative, Malaria Operational Plan FY2014, 23-24.

15

UK Department for International Development, An Epidemiological Profile of Malaria, 34-36.

16

The United Republic of Tanzania Ministry of Health, National Health Policy (Dar es Salaam: 2003), 27-28, accessed July 21, 2014.

Bhatnagar 33

17

Maria Widmar et al., “Determining and addressing obstacles to the effective use of longlasting insecticide-impregnated nets in rural Tanzania,” Malaria Journal 8, no. 315 (December 31, 2009): 3-4, accessed December 23, 2014, doi:10.1186/1475-2875-8-315.

18

USAID President's Malaria Initiative, Malaria Operational Plan FY2014, 25.

19

Ibid., 4-5.

20

Francis Mkutu et al., “Physical condition and maintenance of mosquito bed nets in Kwale County, coastal Kenya,” Malaria Journal 12, no. 46 (February 1, 2013): 11-13, accessed December 24, 2014, doi:10.1186/1475-2875-12-46.

21

Mboera, Makundi, and Kitua, “Uncertainty in Malaria Control,” 115-16.

22

WHO Global Malaria Programme, Insecticide-Treated Mosquito Nets, 3.

23

UK Department for International Development, An Epidemiological Profile of Malaria, 91-92.

24

USAID President's Malaria Initiative, Malaria Operational Plan FY2014, 16-17.

25

Ibid., 12.

26

Ibid., 12.

27

World Health Organization Global Malaria Programme, Global Plan for Insecticide Resistance Management in Malaria Vectors (Geneva: WHO Press, 2012), 27, accessed July 31, 2014.

28

Ibid., 32.

29

Luiz Paulo Brito et al., “Assessing the Effects of Aedes aegypti kdr Mutations on Pyrethroid Resistance and Its Fitness Cost,” PLoS ONE 8, no. 4 (April 8, 2013): 1, accessed August 1, 2014.

30

Claire Berticat et al., “Costs and benefits of multiple resistance to insecticides for Culex quinquefasciatus mosquitoes,” BMC Evolutionary Biology 8, no. 104 (April 8, 2008): 6, accessed November 29, 2014.

31

WHO Global Malaria Programme, Global Plan for Insecticide Resistance Management, 4445.

32

Ibid., 17.

33

Ibid., 32.

34

Denis Bourget et al., “Fitness Costs of Insecticide Resistance in Natural Breeding Sites of the Mosquito Culex pipens,” Evolution 58, no. 1 (2004): 132, accessed August 4, 2014.

35

Berticat et al., “Costs and benefits of multiple,” 5.

Bhatnagar 34

36

Ibid., 1.

37

WHO Global Malaria Programme, Global Plan for Insecticide Resistance Management, 27.

38

Janet Hemingway and Hilary Ranson, “Insecticide Resistance in Insect Vectors of Human Disease,” Annual Review of Entomology 45 (2000): 377, accessed July 24, 2014.

39

Ibid., 375.

40

WHO Global Malaria Programme, Global Plan for Insecticide Resistance Management, 32.

41

Melissa C. Hardstone, Brian P. Larazzo, and Jeffrey G. Scott, “The effect of three environmental conditions on the fitness of cytochrome P450 monooxygenase-mediated permethrin resistance in Culex pipiens quinquefasciatus,” BMC Evolutionary Biology 9, no. 42 (February 19, 2009): 4, accessed August 1, 2014.

42

Melissa C. Hardstone et al., “Cytochrome P450 monooxygenase-mediated permethrin resistance confers limited and larval specific cross-resistance in the southern house mosquito, Culex pipiens quinquefasciatus,” Pesticide Biochemistry and Physiology 89 (June 2007): 179, accessed August 3, 2014.

43

Hardstone, Larazzo, and Scott, “The effect of three,” 6.

44

Hemingway and Ranson, “Insecticide Resistance in Insect Vectors,” 374.

45

Ibid., 379.

46

Bourget et al., “Fitness costs of Insecticide,” 133.

47

Hemingway and Ranson, “Insecticide Resistance in Insect Vectors,” 377.

48

Bourget et al., “Fitness costs of Insecticide,” 133.

49

Hardstone, Larazzo, and Scott, “The effect of three,” 4.

50

Hemingway and Ranson, “Insecticide Resistance in Insect Vectors,” 374-75.

51

Michel Raymond et al., “An overview of the evolution of overproduced esterases in the mosquito Culex pipiens,” Philosophical Transactions of the Royal Society B 353 (October 29, 1998): 1710, accessed August 4, 2014.

52

Benjamin G. Koudou et al., “Multiple-Insecticide Resistance in Anopheles gambiae Mosquitoes, Southern Côte d’Ivoire,” Emerging Infectious Diseases 18, no. 9 (September 2012): 1509, accessed July 31, 2014.

53

WHO Global Malaria Programme, Global Plan for Insecticide Resistance Management, 44.

54

Ibid., 17.

Bhatnagar 35

55

Ibid., 44.

56

Ibid., 44.

57

USAID President's Malaria Initiative, Malaria Operational Plan FY2014, 33.

58

WHO Global Malaria Programme, Global Plan for Insecticide Resistance Management, 4445.

59

Yeya Touré, "New methods and strategies," Special Programme for Research and Training in Tropical Diseases, last modified 2015, accessed February 18, 2015.

60

UK Department for International Development, An Epidemiological Profile of Malaria, 90-91.

61

USAID President's Malaria Initiative, Malaria Operational Plan FY2014, 33.

62

Ibid., 12.

63

UK Department for International Development, An Epidemiological Profile of Malaria, 91-92.

64

USAID President's Malaria Initiative, Malaria Operational Plan FY2014, 30.

65

WHO Global Malaria Programme, Global Plan for Insecticide Resistance Management, 17.

66

Ibid., 44-45.

67

Armel Djènontin et al., “Managing insecticide resistance in malaria vectors by combining carbamate-treated plastic wall sheeting and pyrethroid-treated bed nets,” Malaria Journal 8, no.

233 (October 20, 2009): 5-7, accessed August 5, 2014, doi:10.1186/1475-2875-8-233.

68

WHO Global Malaria Programme, Insecticide-Treated Mosquito Nets, 2.

69

United Republic of Tanzania National Institute for Medical Research, Detection and Monitoring of Insecticide Resistance in Malaria Vectors in Tanzania Mainland, by W. Kisinza, et al. (Muheza, Tanzania: NIMR, 2011), 9-10, accessed November 4, 2014.

70

UK Department for International Development, An Epidemiological Profile of Malaria, 90-91.

71

Ibid., 92-93.

72

Ibid., 87-88.

73

Jovin Kitau et al., “Species Shifts in the Anopheles gambiae Complex: Do LLINs Successfully Control Anopheles arabiensis?,” PLoS ONE 7, no. 3 (March 16, 2012): 7, accessed August 5, 2014, doi:10.1186/1475-2875-8-233.

74

WHO Global Malaria Programme, Global Plan for Insecticide Resistance Management, 4445.

Bhatnagar 36

75

Ibid., 8.

76

Gregor J. Devine and Gerry F. Killeen, “The potential of a new larviciding method for the control of malaria vectors,” Malaria Journal 9, no. 142 (May 25, 2010): 1, accessed August 6, 2014, doi:10.1186/1475-2875-9-142.

77

Dickson Lwetoijera et al., “Effective autodissemination of pyriproxyfen to breeding sites by the exophilic malaria vector Anopheles arabiensis in semi-field settings in Tanzania,” Malaria Journal 13, no. 161: 8-9, accessed August 6, 2014, doi:10.1186/1475-2875-13-161.

78

Devine and Killeen, “The potential of a new larviciding strategy,” 2-3.

79

Lwetoijera et al., “Effective autodissemination of pyriproxyfen,” 1.

80

Devine and Killeen, “The potential of a new larviciding strategy,” 1-2.

81

UK Department for International Development, An Epidemiological Profile of Malaria, 33.

82

Ibid., 34.

83

Ibid., 32.

84

Wendy Prudhomme O'Meara, David L. Smith, and F. Ellis McKenzie, “Potential Impact of Intermittent Preventive Treatment (IPT) on Spread of Drug-Resistant Malaria,” PLoS Medicine 3, no. 5 (May 2006): 634, accessed January 9, 2015, doi:10.1371/journal.pmed.0030141.

85

WHO Global Malaria Programme, Global Plan for Artemisinin Resistance Containment (Geneva: WHO Press, 2011), 43, accessed August 14, 2014.

86

Ibid., 43.

87

Ibid., 21.

88

Ibid., 47.

89

Melissa A. Briggs et al., "Prevalence of Malaria Parasitemia and Purchase of ArtemisininBased Combination Therapies (ACTs) among Drug Shop Clients in Two Regions in Tanzania with ACT Subsidies," PLoS ONE 9, no. 4 (April 14, 2014): 8, accessed December 31, 2014, doi:10.1371/journal.pone.0094074.

90

Ibid., 10.

91

Joel C. Moutacho and J.P. Dean Goldberg, “Malaria rapid diagnostic tests: challenges and prospects,” Journal of Medical Microbiology 62, no. 10 (October 2013): 1491, accessed January 2, 2015, doi:10.1099/jmm.0.052506-0.

92

Ibid., 1499.

Bhatnagar 37

93

UK Department for International Development, An Epidemiological Profile of Malaria, 41-42.

94

Mboera, Makundi, and Kitua, “Uncertainty in Malaria Control,” 114.

95

Moutacho and Goldberg, “Malaria rapid diagnostic tests,” 1492.

96

Jessica Maltha et al., “Accuracy of HRP-2 versus Pf-pLDH antigen detection by malaria rapid diagnostic tests in hospitalized children in a seasonal hyperendemic malaria transmission area in Burkina Faso,” Malaria Journal 13, no. 20 (January 13, 2014): 1, accessed January 3, 2015, doi:10.1186/1475-2875-13-20.

97

WHO Global Malaria Programme, World Malaria Report 2014, 158.

98

Moutacho and Goldberg, “Malaria rapid diagnostic tests,” 1493-94.

99

Maltha et al., “Accuracy of PfHRP2 versus Pf-pLDH antigen detection,” 1.

100

Moutacho and Goldberg, “Malaria rapid diagnostic tests,” 1496.

101

Ibid., 1495-96.

102

Maltha et al., “Accuracy of PfHRP2 versus Pf-pLDH antigen detection,” 6.

103

Maltha et al., “Accuracy of PfHRP2 versus Pf-pLDH antigen detection,” 6-7.

104

Ibid., 7.

105

Philippe Gillet et al., “External quality assessment on the use of malaria rapid diagnostic tests in a non-endemic setting,” Malaria Journal 9, no. 359 (December 13, 2010): 9, accessed January 3, 2015, doi:10.1186/1475-2875-9-359.

106

Moutacho and Goldberg, “Malaria rapid diagnostic tests,” 1499.

107

Zeno Biffosi et al., “Strict adherence to malaria rapid test results might lead to a neglect of other dangerous diseases: a cost benefit analysis from Burkina Faso,” Malaria Journal 10, no.

226 (August 4, 2011): 11, accessed January 3, 2015, doi:10.1186/1475-2875-10-226.

108

Clare I.R. Chandler et al., "The development of effective behaviour change interventions to support the use of malaria rapid diagnostic tests by Tanzanian clinicians," Implementation Science 9, no. 83 (June 26, 2014): 8-9, accessed January 7, 2015, doi:10.1186/1748-5908-9-83.

109

Ibid., 9.

110

Ibid., 10.

111

Marycelina Mubi et al., "Malaria diagnosis and treatment practices following introduction of rapid diagnostic tests in Kibaha District, Coast Region, Tanzania," Malaria Journal 12, no. 293 (August 26, 2013): 4-5, accessed January 6, 2015, doi:10.1186/1475-2875-12-293.

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112

Chandler et al., "The development of effective behaviour change," 5.

113

Ibid., 6.

114

M. Irene Masanja et al., "Health Workers' Use of Malaria Rapid Diagnostic Tests (RDTs) to Guide Clinical Decision Making in Rural Dispensaries, Tanzania," American Journal of Tropical Medicine and Hygeine 83, no. 6 (December 6, 2010): 1239-40, accessed January 6, 2015, doi:10.4269/ajtmh.2010.10-0194.

115

Kimberly Baltzell et al., "Febrile illness management in children under five years of age: a qualitative pilot study on primary health care workers’ practices in Zanzibar," Malaria Journal 12, no. 37 (January 28, 2013): 6, accessed January 4, 2015, doi:10.1186/1475-2875-12-37.

116

Chandler et al., “The development of effective behaviour change,” 9-10.

117

Biffosi et al., “Strict adherence to malaria rapid test results,” 6-7.

118

Maltha et al., “Accuracy of PfHRP2 versus Pf-pLDH antigen detection,” 8.

119

Masanja et al., "Health Workers' Use of Malaria Rapid Diagnostic Tests," 1240.

120

United States Agency for International Development DELIVER Project, Price Analysis of Malaria Rapid Diagnostic Test Kits, 5-7, accessed January 1, 2015.

121

USAID President's Malaria Initiative, Malaria Operational Plan FY2014, 16.

122

Paul Chinnock, Tony Murdoch, and Beatrice Gordis, Malaria Rapid Diagnostic Tests: An Implementation Guide (Geneva: Foundation for Innovative New Diagnostics, 2013), 30, accessed January 19, 2015.

123

Amani Thomas Mori and Eliangiringa Amos Kaale, "Priority setting for the implementation of artemisinin-based combination therapy policy in Tanzania: evaluation against the accountability for reasonableness framework," Implementation Science 7, no. 18 (March 18, 2012): 2, accessed February 1, 2015, doi:10.1186/1748-5908-7-18.

124

The United Republic of Tanzania Ministry of Health, National Health Policy, 19-20.

125

Gideon Kwesigabo et al., "Tanzania's health system and workforce crisis," Journal of Public Health Policy 33 (2012): S36-S38, accessed November 5, 2014, doi:10.1057/jphp.2012.55.

126

Ibid., S41-S42.

127

Briggs et al., “Prevalence of Malaria Parasitemia and Purchase,” 2.

128

USAID President's Malaria Initiative, Malaria Operational Plan FY2014, 21.

129

Fuller, "35 Million Nets Distributed," Case Studies for Global Health.

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130

UK Department for International Development, An Epidemiological Profile of Malaria, 42.

131

Kwesigabo et al., “Tanzania’s health system,” S37.

132

Ibid., S41.

133

Chinnock, Murdoch, and Gordis, Malaria RDTs: An Implementation Guide, 16.

134

Briggs et al., “Prevalence of Malaria Parasitemia and Purchase,” 2.

135

Sandra Alba et al., "Improvements in access to malaria treatment in Tanzania after switch to artemisinin combination therapy and the introduction of accredited drug dispensing outlets - a provider perspective," Malaria Journal 9, no. 164 (June 15, 2010): 13, accessed February 12, 2015, doi:10.1186/1475-2875-9-164.

136

Anthony K. Mbonye et al., "The feasibility of introducing rapid diagnostic tests for malaria in drug shops in Uganda," Malaria Journal 9, no. 367 (December 21, 2010): 6, accessed February 12, 2015, doi:10.1186/1475-2875-9-367.

137

Chandler et al., “The development of effective behaviour change,” 9.

138

Masanja et al., "Health Workers' Use of Malaria Rapid Diagnostic Tests," 1239-40.

139

Mbonye et al., “The feasibility of introducing,” 5.

140

World Health Organization Global Malaria Programme, Emergence and spread of artemisinin resistance calls for intensified efforts to withdraw oral artemisinin-based monotherapy from the market (Geneva: WHO Press, 2014), 13, accessed January 4, 2015.

141

Ibid., 4.

142

Briggs et al., “Prevalence of Malaria Parasitemia and Purchase,” 6.

143

WHO Global Malaria Programme, Global Plan for Artemisinin Resistance Containment, 86.

144

WHO Global Malaria Programme, Emergence and Spread of Artemisinin Resistance, 7.

145

WHO Global Malaria Programme, Global Plan for Artemisinin Resistance Containment, 43.

146

Ibid., 47.

147

Gau Majori, "Antimalarial combination therapy using artemisinin," Parassitologia 46, no. 2 (June 2004): 85-86, accessed January 28, 2015.

148

WHO Global Malaria Programme, Global Plan for Artemisinin Resistance Containment, 47.

149

Ibid., 45.

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150

Roger Bate et al., "Antimalarial Drug Quality in the Most Severely Malarious Parts of Africa – A Six Country Study," PLoS ONE 3, no. 5 (May 7, 2008): 1-2, accessed January 5, 2015, doi:10.1371/journal.pone.0002132.

151

UK Department for International Development, An Epidemiological Profile of Malaria, 39.

152

Wendy Prudhomme O'Meara, David L. Smith, and F. Ellis McKenzie, "Potential Impact of Intermittent Preventive Treatment (IPT) on Spread of Drug-Resistant Malaria," PLoS Medicine 3, no. 5 (May 2006): 640, accessed January 9, 2015, doi:10.1371/journal.pmed.0030141.

153

USAID President's Malaria Initiative, Malaria Operational Plan FY2014, 16.

154

Harprakash Kaur et al., "A Nationwide Survey of the Quality of Antimalarials in Retail Outlets in Tanzania," PLoS ONE 3, no. 10 (October 15, 2008): 2, accessed January 22, 2015, doi:10.1371/journal.pone.0003403.

155

World Health Organization Global Malaria Programme, Good procurement practices for artemisinin-based antimalarial medicines (Geneva: WHO Press, 2010), 12-13, accessed February 11, 2015.

156

Ibid., 12.

157

"Expert Consultation on the Procurement and Financing of Antimalarial Drugs" (paper presented at World Bank, Institute of Medicine, and Roll Back Malaria Partnership Meeting, Washington, D.C., September 16, 2003), 9-10, accessed February 11, 2015.

158

USAID President's Malaria Initiative, Malaria Operational Plan FY2014, 48.

159

Prashant Yadev, Kristen Curtis, and Neelam Sekhri, "Mapping and Realigning Incentives in the Global Health Supply Chain" (unpublished manuscript, December 2006), 18, accessed February 12, 2015.

160

Ibid., 27.

161

Ibid., 22-23.

162

WHO Global Malaria Programme, Good procurement practices, 12.

163

Sarah Tougher et al., “Effect of the Affordable Medicines Facility—malaria (AMFm) on the availability, price, and market share of quality-assured artemisinin-based combination therapies in seven countries: a before-and-after analysis of outlet survey data,” Lancet 380, no. 9857 (October 31, 2012): 1920, accessed February 13, 2015., doi:10.1016/S0140-6736(12)61732-2.

164

Anya Levy Guyer, "From Idea to Initiative: Comparing the Development of the Affordable Medicines Facility - Malaria and the Advance Purchase Commitment for Pneumococcal Vaccine" (master's thesis, Harvard University, 2009), 6, accessed February 13, 2015.

165

Tougher et al., “Effect of the Affordable Medicines Facility—malaria (AMFm),” 1921.

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166

Alexandra Morris et al., Price Subsidies Increase the Use of Private Sector ACTs: Evidence from a Systematic Review (Boston: Clinton Health Access Initiative, 2012), 7, accessed February 13, 2015.

167

Tougher et al., “Effect of the Affordable Medicines Facility—malaria (AMFm),” 1923.

168

Mohga M. Kamal-Yanni, Salt, Sugar, and Malaria Pills: How the Affordable Medicine Facility–malaria endangers public health (Oxford.: Oxfam International, 2012), 3, accessed February 13, 2015.

169

Ibid., 14.

170

WHO Global Malaria Programme, Global Plan for Artemisinin Resistance Containment, 54.

171

Yadev, Curtis, and Sekhri, "Mapping and Realigning Incentives," 15.

172

World Health Organization, Survey of the Quality of Selected Antimalarial Medicines Circulating in Six Countries of Sub-Saharan Africa (Geneva: WHO Press, 2011), 13-14, accessed January 9, 2015.

173

Kaur et al., “A Nationwide Survey of the Quality,” 3.

174

Ibid., 2.

175

United States Pharmacopeia Drug Quality and Information Program, Ensuring the Quality of Medicines in Resource-Limited Countries: An Operational Guide (Rockville, MD: U.S. Pharmacopeial Convention, 2007), 71-73, accessed January 9, 2015.

176

WHO Global Malaria Programme, Global Plan for Artemisinin Resistance Containment, 50.

177

U.S. Pharmacopeia Drug Quality and Information Program, Ensuring the Quality of Medicines, 69.

178

"Prequalification of medicines by WHO," WHO Media Centre, last modified January 2013, accessed January 17, 2015.

179

U.S. Pharmacopeia Drug Quality and Information Program, Ensuring the Quality of Medicines, 62.

180

Ibid., 69-70.

181

WHO Global Malaria Programme, Global Plan for Artemisinin Resistance Containment, 50.

182

"WHO: Low quality drugs continue to afflict Africa," Medicines for Malaria Venture, last modified February 25, 2011, accessed January 2, 2015.

183

Kaur et al., “A Nationwide Survey of the Quality,” 2-3.

184

"Prequalification of medicines by WHO," WHO Media Centre.

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Bibliography Alba, Sandra, Manuel W. Hetzel, Catherine Goodman, Angel Dillip, Jafari Liana, Hassan Mshinda, and Christian Lengeler. "Improvements in access to malaria treatment in Tanzania after switch to artemisinin combination therapy and the introduction of accredited drug dispensing outlets - a provider perspective." Malaria Journal 9, no. 164 (June 15, 2010). Accessed February 12, 2015. doi:10.1186/1475-2875-9-164.

This article discusses the rise of accredited drug dispensing outlets (ADDOs) as a tool to better improve the regulation of antimalarial drug distribution throughout Tanzania. Given the importance of the private sector in drug acquisition for the majority of Tanzanian citizens, official accreditation provides an assurance of quality for the medical services provided by these shops.

Baltzell, Kimberly, Kristina Elfving, Deler Shakely, Abdullah S. Ali, Mwinyi Msellem, Shilpa Gulati, and Andreas Mårtensson. "Febrile illness management in children under five years of age: a qualitative pilot study on primary health care workers’ practices in Zanzibar." Malaria Journal 12, no. 37 (January 28, 2013). Accessed January 4, 2015. doi:10.1186/1475-2875-12-37.

The examination of Zanzibari health workers' practices, particularly those concerning diagnostics, reveals general deficiencies in training programs. In particular, this pilot study identified a need for better education on the symptoms of malaria, especially in how they compare with bacterial and viral infections.

Bate, Roger, Philip Coticelli, Richard Tren, and Amir Attaran. "Antimalarial Drug Quality in the Most Severely Malarious Parts of Africa – A Six Country Study." PLoS ONE 3, no. 5 (May 7, 2008). Accessed January 5, 2015. doi:10.1371/journal.pone.0002132.

This paper conducts a survey of antimalarial drug quality in some of the most malariaendemic African countries, including Taznania. The authors report a high prevalence of substandard drug quality based on laboratory testing of large samples of different classes of antimalarial drugs collected in each country, identifying a major problem with unregulated private sector pharmaceuticals in these areas.

Berticat, Claire, Julien Bonnet, Stéphane Duchon, Philip Agnew, Mylène Weill, and Vincent Corbel. "Costs and benefits of multiple resistance to insecticides for Culex quinquefasciatus mosquitoes." BMC Evolutionary Biology 8, no. 104 (April 8, 2008).

Accessed November 29, 2014. doi:10.1186/1471-2148-8-104.

One of the most worrying trends in insecticide resistance is that of resistance to multiple insecticides. This peer-reviewed journal article examines the fitness costs associated with variants of mosquitoes harboring both forms of target-site resistance. The results obtained demonstrate that such a form of multi-insecticide resistance becomes particularly difficult to combat should it ever manifest in the field.

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Biffosi, Zeno, Sodiomon B. Sirima, Filip Meheus, Claudia Lodesani, Federico Gobbi, Andrea Angheben, Halidou Tinto, Bouma Neya, Clara Van den Ende, Annalisa Romeo, and Jef Van den Ende. "Strict adherence to malaria rapid test results might lead to a neglect of other dangerous diseases: a cost benefit analysis from Burkina Faso." Malaria Journal 10, no. 226 (August 4, 2011). Accessed January 3, 2015. doi:10.1186/1475-2875-10-226.

At the time of publication, PfHRP2-based tests were the primary form of RDTs used to diagnose malaria caused by Plasmodium falciparum. This article conducts a cost-benefit analysis comparing the monetary cost per life saved of RDT-based diagnostics to the presumptive approach currently used in most malaria-endemic countries. Such analysis is central to informing a fiscally feasible RDT policy in malaria-endemic countries, as such an approach is currently the only way reduce the role of presumptive diagnostics in creating antimalarial drug resistance.

Bourget, Denis, Thomas Guillemand, Christine Chevillon, and Michel Raymond. "Fitness Costs of Insecticide Resistance in Natural Breeding Sites of the Mosquito Culex pipens."

Evolution 58, no. 1 (2004): 128-35. Accessed August 4, 2014. http://www.evolutionhumaine.fr/michel/publis/pdf/bourguet_2004_Evolution.pdf.

There are two biological mechanisms of resistance to organophosphates, one of the primary types of insecticides currently being employed: the overproduction of esterases (metabolic) and a mutation in the gene that produces acetylcholinesterase (target-site). This peerreviewed article finds that in an environment lacking the selective pressure of organophsphate usage, these resistant phenotypes are less viable than their susceptible counterparts. However, the extent of the fitness cost determined must be taken with a grain of salt: the study points to variations with seasons and was conducted with a different species of mosquito in France -- thus, it only serves as a guideline for this paper.

Briggs, Melissa A., Admirabilis Kalolella, Katia Bruxvoort, Ryan Wiegand, Gerard Lopez, Charles Festo, Pierre Lyaruu, Mitya Kenani, Salim Abdulla, Catherine Goodman, and S. Patrick Kachur. "Prevalence of Malaria Parasitemia and Purchase of Artemisinin-Based Combination Therapies (ACTs) among Drug Shop Clients in Two Regions in Tanzania with ACT Subsidies." PLoS ONE 9, no. 4 (April 14, 2014). Accessed December 31, 2014. doi:10.1371/journal.pone.0094074.

This article examines 773 clients seeking antimalarial drugs at 73 different Tanzanian drug-shops. They not only find that the vast majority of malaria-positive patients are unable to obtain ACTs, the country's first-line drug at the time of publication, but also report that of the patients who do receive these drugs, more than three-quarters are malaria negative.

Brito, Luiz Paulo, Jutta G.B. Linss, Tamara N. Lima-Camara, Thiago A. Belinato, Alexandre A. Peixoto, JosĂŠ Bento P. Lima, Denise Valle, and Ademir J. Martins. "Assessing the Effects of Aedes aegypti kdr Mutations on Pyrethroid Resistance and Its Fitness Cost." PLoS ONE 8, no. 4 (April 8, 2013). Accessed August 1, 2014. doi:10.1371/journal.pone.0060878.

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In order for insecticide rotation programs to successfully reduce the frequency of an allele resistant to a particular type of insecticide, there must be a fitness cost associated with that resistance mechanism. This peer-reviewed journal article finds that there is such a cost associated with the kdr allele for pyrethroid and DDT resistance.

Chandler, Clare I.R., Judith Meta, Célia Ponzo, Fortunata Nasuwa, John Kessy, Hilda Mbakilwa, Ane Haaland, and Hugh Reyburn. "The development of effective behaviour change interventions to support the use of malaria rapid diagnostic tests by Tanzanian clinicians."

Implementation Science 9, no. 83 (June 26, 2014). Accessed January 7, 2015. doi:10.1186/1748-5908-9-83.

Throughout Tanzania and other African nations, one of the biggest problems hindering the efficacy of RDT policies is the lack of adherence to negative test results. By evaluating effective existing practices and contrasting them with the more common behaviors surrounding diagnostics in the country, this paper outlines strategies to spur longer-term behavioral changes that address deficiencies in current paradigms.

Chinnock, Paul, Tony Murdoch, and Beatrice Gordis. Malaria Rapid Diagnostic Tests: An Implementation Guide. Geneva: Foundation for Innovative New Diagnostics, 2013.

Accessed January 19, 2015. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/243817/m alaria_rdt_implementation_guide2013.pdf.

This report details a step-by-step implementation plan for an effective RDT policy at all both the central and community levels. In this way, this source contextualizes the specific measures examined in journal articles cited for the community level challenges of proper implementation with the broader trends surrounding the distribution and adoption of RDTs. Devine, Gregor J., and Gerry F. Killeen. "The potential of a new larviciding method for the control of malaria vectors." Malaria Journal 9, no. 142 (May 25, 2010). Accessed August 6, 2014. doi:10.1186/1475-2875-9-142.

Larval source management is an important supplement to existing vector control strategies (namely insecticide-treated bednets and indoor residual spraying) for two reasons: first, it can use different classes of chemicals that do not interact with resistance mechanisms to the four primary classes of insecticides; second, these methods are not very effective at dealing with the growing exophagic (mosquitoes that bite outdoors) populations of mosquitoes in Tanzania and other countries. However, until recently, the primary problem with the use of larvicides was that it required a great deal of human capital to dispense them to the appropriate mosquito colonies, especially in rural settings. This peer-reviewed article discusses the development of a promising new strategy for the dispersal of these larvicides to mosquito colonies that requires minimal human resources (outside of delivery mechanisms) because it uses adult mosquitoes as the vectors that carry the larvicides back to their colonies.

Djènontin, Armel, Joseph Chabi, Thierry Baldet, Seth Irish, Cédric Pennetier, Jean-Marc Hougard, Vincent Corbel, Martin Akogbéto, and Fabrice Chandre. "Managing insecticide

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resistance in malaria vectors by combining carbamate-treated plastic wall sheeting and pyrethroid-treated bed nets." Malaria Journal 8, no. 233 (October 20, 2009). Accessed August 5, 2014. doi:10.1186/1475-2875-8-233.

Currently, the only class of insecticides that is viable for use in bednets is pyrethroids, to which resistance is rapidly emerging. Although the net itself provides a physical barrier against mosquitoes, the resistance to pyrethroids limits their effectiveness. This study, which is the culmination of research into a carbamate-based sheeting that can be used either in conjunction or in rotations with classic pyrethroid-treated bednets, shows that the effects of pyrethroid resistance can be mitigated by the use of this new technology, which is in the final stages of testing and approval.

"Expert Consultation on the Procurement and Financing of Antimalarial Drugs." Paper presented at World Bank, Institute of Medicine, and Roll Back Malaria Partnership Meeting, Washington, D.C., September 15, 2003. Accessed February 11, 2015. http://www.who.int/medicines/technical_briefing/tbs/AntimalarialDrugProcurementFinan cing_Draft.pdf.

By compiling data from past attempts at financing the procurement and distribution of antimalarial drugs, this report details the components of an effective global policy to stimulate private sector ACT production, procedures for the pooled procurement of ACTs (later realized in the collaboration between PMI and the Global Fund), potential sources of funding, and potential strategies for increasing access to malaria treatment in affected countries.

Fuller, Ralph. "35 Million Nets Distributed, NATNETS Continues Its War on Mosquitoes -UPDATE." Case Studies for Global Health. Last modified May 27, 2012. Accessed December 2, 2014. http://www.casestudiesforglobalhealth.org/post.cfm/35-million-netsdistributed-natnets-continues-its-war-on-mosquitoes-update.

Although bednets are, in theory, a highly effective intervention, for them to make any real impact, they must be properly distributed to their targets. This article reviews the efficacy of NATNETS, the largest Tanzanian public-private partnership for bednet distribution, and finds that in the (then) twelve years it has been active, it has successfully distributed nearly 35 million ITNs and LLINs, many of them free of charge.

Gillet, Philippe, Pierre Mukadi, Kris Vernelen, Marjan Van Esbroeck, Jean-Jaques Muyembe, Cathrien Bruggeman, and Jan Jacobs. "External quality assessment on the use of malaria rapid diagnostic tests in a non-endemic setting." Malaria Journal 9, no. 359 (December 13, 2010). Accessed January 3, 2015. doi:10.1186/1475-2875-9-359.

While point-of-care studies are important in assessing the viability of RDTs for widespread use, such papers often use highly trained practitioners to test the sensitivity and specificity of the various RDTs. This article provides a more accurate view on the ease of use of RDTs currently on the market.

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Guyer, Anya Levy. "From Idea to Initiative: Comparing the Development of the Affordable Medicines Facility - Malaria and the Advance Purchase Commitment for Pneumococcal Vaccine." Master's thesis, Harvard University, 2009. Accessed February 13, 2015. http://siteresources.worldbank.org/INTMALARIA/Resources/AMFmProcessEvaluation. pdf.

From 2009 to 2012, the Affordable Medicines Facility-malaria (AMFm) provided a highly effective mechanism for purchasing ACTs and making them accessible in malariaendemic countries across the developing world. This paper evaluates the benefits of the risksharing framework used by the AMFm with advanced market commitments (AMCs) and finds that the AMFm is the best framework to date for improving ACT accessibility to the date of publication.

Hardstone, Melissa C., Brian P. Larazzo, and Jeffrey G. Scott. "The effect of three environmental conditions on the fitness of cytochrome P450 monooxygenase-mediated permethrin resistance in Culex pipiens quinquefasciatus." BMC Evolutionary Biology 9, no. 42 (February 19, 2009). Accessed August 2, 2014. doi:10.1186/1471-2148-9-4.

The ISOP450 strain of mosquitoes is highly resistant to two major classes of pesticides: pyrethroids and carbamates. In determining the feasibility of insecticide resistance management, it is important to determine whether or not certain resistance mutations are associated with a decreased overall organismal viability. This peer-reviewed article concludes that such is indeed the case with the ISOP450 mechanism of resistance, as these mosquitoes are far less likely to outcompete their non-resistant counterparts in the absence of pyrethroid usage, lending credence to the idea of insecticide rotations as a method to manage one of the two mechanisms of resistance to the most commonly used class of pesticide.

Hardstone, Melissa C., Cheryl Leichter, Laura C. Harrington, Shinji Kasai, Takashi Tomita, and Jeffrey G. Scott. "Cytochrome P450 monooxygenase-mediated permethrin resistance confers limited and larval specific cross-resistance in the southern house mosquito, Culex pipiens quinquefasciatus." Pesticide Biochemistry and Physiology 89 (June 2007): 17584. Accessed August 2, 2014. doi:10.1016/j.pestbp.2007.06.006.

Although insecticide resistance management can reduce the prevalence of homozygous ISOP450 resistance to pyrethroid and carbamate pesticides, studies have shown that the heterozygous individuals, which exhibit a lesser degree of pesticide resistance, continue to persist. This study examines the viability of different mosquito genotypes (with respect to ISOP450) when exposed to permethrin, one of the most commonly used pyrethroids.

Hemingway, Janet, and Hilary Ranson. "Insecticide Resistance in Insect Vectors of Human Disease." Annual Review of Entomology 45 (2000): 371-91. Accessed July 24, 2014. http://pcwww.liv.ac.uk/~hranson/Hemingway%20a.pdf.

This peer-reviewed journal article provides an overview of the five major biochemical avenues of insecticide resistance employed by mosquitoes. It proved a good starting point to use

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in aiding research into each specific mechanism as I examined feasible methods of insecticide resistance management.

Kamal-Yanni, Mohga M. Salt, Sugar, and Malaria Pills: How the Affordable Medicine Facility– malaria endangers public health. Oxford: Oxfam International, 2012. Accessed February 13, 2015. http://www.oxfam.org/sites/www.oxfam.org/files/bp163-affordable-medicinefacility-malaria-241012-en.pdf.

Although the AMFm was hugely successful in improving the availability of ACTs, it was dubious whether these drugs were actually going to malaria patients. This Oxfam report explains a number of the public health risks of AMFm's approach of distributing ACTs to the largely unregulated private sectors of the countries in which it was implemented.

Kaur, Harprakash, Catherine Goodman, Eloise Thompson, Katy-Anne Thompson, Irene Masanja, S. Patrick Kachur, and Salim Abdulla. "A Nationwide Survey of the Quality of Antimalarials in Retail Outlets in Tanzania." PLoS ONE 3, no. 10 (October 15, 2008).

Accessed January 22, 2015. doi:10.1371/journal.pone.0003403.

This authors of this paper tested in the laboratory 1080 of the different antimalarial formulations available in Tanzania, acquired from all three different classes of drugstores across the country. They found that while counterfeit drugs are not a significant problem in the country, substandard drugs are rampant.

Kitau, Jovin, Richard M. Oxborough, Patrick K. Tungu, Johnson Matowo, Robert C. Malima, Stephen M. Magesa, Jane Bruce, Franklin W. Mosha, and Mark W. Rowland. "Species Shifts in the Anopheles gambiae Complex: Do LLINs Successfully Control Anopheles arabiensis?" PLoS ONE 7, no. 3 (March 16, 2012). Accessed September 4, 2014. doi:10.1371/journal.pone.0031481.

One of the most significant trends in Tanzanian malaria transmission is the species shift in the populations of mosquitoes towards Anopheles arabiensis. Due to distinct behavioral patterns, this mosquito comes into less contact with indoor vector control measures like bednets and indoor residual spraying, and as a result, is thriving as its sibling species An. gambiae and An. funestus are on the decline. This journal article discusses the impacts that this trend could have on the efficacy of existing measures and provides a brief outline for the future of vector control.

Koudou, Benjamin G., Christopher M. Jones, Hilary Ranson, and David Weetman. "MultipleInsecticide Resistance in Anopheles gambiae Mosquitoes, Southern Côte d’Ivoire."

Emerging Infectious Diseases 18, no. 9 (September 2012): 1508-11. Accessed July 31, 2014. doi:10.3201/eid1809.120262.

Anopheles gambiae is one of the four major malaria vectors in Africa (including Tanzania). This article from a journal run by the CDC discusses the rise of multi-insecticide resistant strains of An. gambiae in a part of Côte d’Ivoire with populations of mosquitoes with high frequencies of resistance to every major class of existing insecticide. Although the cause for

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such intense resistance in the region is unclear, the study concludes that current patterns of insecticide-based treatment could very well facilitate the rise of similar resistance throughout the continent of Africa in all major vector species, making the need for insecticide resistance management very clear.

Kwesigabo, Gideon, Mughwira A. Mwangu, Deodatus C. Kakoko, Ina Warriner, Charles A. Mkony, Japhet Killewo, Sarah B. MacFarlane, Ephata E. Kaaya, and Phyllis Freeman.

"Tanzania's health system and workforce crisis." Journal of Public Health Policy 33 (2012): S35-S44. Accessed November 5, 2014. doi:10.1057/jphp.2012.55.

This article provides an insight into the organization and infrastructure underlying Tanzania's largely hierarchical system of hospitals and dispensaries. At local levels, trained personnel, proper equipment, and effective infrastructure are highly lacking, but most district hospitals are furnished with functioning laboratories for diagnostic services, as well as trained medical professionals. Thus, in Tanzania, an effective health policy must be coordinated from the top down.

Lwetoijera, Dickson, Caroline Harris, Samson Kiware, Stefan Dongus, Gregor J. Devine, Philip J. McCall, and Silas Majambere. "Effective autodissemination of pyriproxyfen to breeding sites by the exophilic malaria vector Anopheles arabiensis in semi-field settings in Tanzania." Malaria Journal 13, no. 161. Accessed August 6, 2014. doi:10.1186/14752875-13-161.

The larviciding technique of auto-dissemination had previously been tested in two places: Italy and Peru. Although these initial studies were important in shedding light on the feasibility of the new strategy, their results varied because of differences between the local climates and mosquitoes being studied. This peer-reviewed article, in an attempt to address these shortcomings, conducts a similar field study on the efficacy of auto-dissemination in a setting that is highly characteristic of rural Tanzania, providing results that can be directly translated into a policy recommendation.

Majori, Gau. "Antimalarial combination therapy using artemisinin." Parassitologia 46, no. 2 (June 2004): 85-87. Accessed January 28, 2015. http://www.ncbi.nlm.nih.gov/pubmed/15305693.

This article discusses the role of drug synergy in the success of an effective artemisininbased combination therapy. While the use of two drugs with a distinct mechanism of action is useful in preventing the emergence of antimalarial drug resistance, these two drugs must be selected in such a way that avoids conflict between their modes of action. Instead, a combination therapy often magnifies the metabolic efficacy of each individual partner drug beyond its ordinary levels.

Maltha, Jessica, Issa Guiraud, Palpouguini Lompo, BĂŠrenger KaborĂŠ, Philippe Gillet, Chris Van Geet, Halidou Tinto, and Jan Jacobs. "Accuracy of PfHRP2 versus Pf-pLDH antigen detection by malaria rapid diagnostic tests in hospitalized children in a seasonal

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hyperendemic malaria transmission area in Burkina Faso." Malaria Journal 13, no. 20 (January 13, 2014). Accessed January 3, 2015. doi:10.1186/1475-2875-13-20.

The two major types of RDTs currently in use are PfHRP2 and pLDH. This 2014 paper presents a comparative analysis of sensitivity, specificity, positive predictive value, and negative predictive value of the two classes of tests. Such a study, which controls for the same variables for both tests, can prove helpful in formulating a more technical policy proposal.

Masanja, M. Irene, Meredith McMorrow, Elizeus Kahigwa, S. Patrick Kachur, and Peter D. McElroy. "Health Workers' Use of Malaria Rapid Diagnostic Tests (RDTs) to Guide Clinical Decision Making in Rural Dispensaries, Tanzania." American Journal of Tropical Medicine and Hygeine 83, no. 6 (December 6, 2010): 1238-41. Accessed January 6, 2015. doi:10.4269/ajtmh.2010.10-0194.

After distributing RDTs to and training health workers in 12 Tanzanian dispensaries, this study recorded a 98.6% adherence to positive test results and a 96.0% adherence to negative results by health workers. When compared with the literature suggesting a low adherence to negative test results, the primary difference between this study and others is the provision of an alternative treatment (often in the form of antipyretics, anti-inflammatory drugs, and/or antibiotics) by health workers, suggesting that such an approach is effective at building confidence in RDT test results.

Maxon, Robert M. East Africa: An Introductory History. 3rd ed. Morgantown, WV: West Virginia University Press, 2009.

Robert Maxon is a professor of East African history at West Virginia University. His book discusses the history of Tanzania, Uganda, and Kenya from prehistoric times to the 2000s.

For the purposes of this paper, the sections on the past century of Tanzania's history were examined to help understand the cultural, economic, and political trends that have shaped the country's recent history. Evaluating these patterns is important in determining the type of external health aid that the Tanzanian government and people will be most receptive to, given the country's legacy of colonialism, socialism, and poverty.

Mboera, Leonard E.G., Emmanuel A. Makundi, and Andrew Y. Kitua. "Uncertainty in Malaria Control in Tanzania: Crossroads and Challenges for Future Interventions." American Journal of Tropical Medicine and Hygiene 77, no. 6 (December 2007): 112-18. Accessed July 24, 2014. http://www.ncbi.nlm.nih.gov/books/NBK1714/.

This peer-reviewed article examines all of the major malaria control stragegies in case management, vector control, and epidemic prevention that were in place by 2007 and addresses challenges these tactics were facing at the time. Consequently, it provides an outline to direct future research for this paper as far as developing policies that work to address each of these challenges individually.

Mbonye, Anthony K., Richard Ndyomugyenyi, Asaph Turinde, Pascal Magnussen, Si창n Clarke, and Clare I.R. Chandler. "The feasibility of introducing rapid diagnostic tests for malaria

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in drug shops in Uganda." Malaria Journal 9, no. 367 (December 21, 2010). Accessed February 12, 2015. doi:10.1186/1475-2875-9-367.

One of the ancillary benefits of requiring training programs to accredit the owners and attendants of drug outlets is the potential to provide proper medical services from the much more easily accessible private sector. This article discusses the feasibility of establishing a framework to give these shops the equipment and ability to diagnose malaria using RDTs before selling antimalarial drugs to potential patients.

Mkutu, Francis, Maureen Khambira, Donal Bisanzio, Peter Mungai, Isaac Mwanzo, Eric M. Muchiri, Charles H. King, and Uriel Kitron. "Physical condition and maintenance of mosquito bed nets in Kwale County, coastal Kenya." Malaria Journal 12, no. 46 (February 1, 2013). Accessed December 24, 2014. doi:10.1186/1475-2875-12-46.

Although this article examines a community in Kenya with respect to bednet maintenance, it confirms the trend observed in Widmar et al. (that community education about ITN maintenance is deficient but can be addressed feasibly) in both an alternative setting and a more recent timeframe. Other articles also corroborate the conclusions of these two publications.

Mori, Amani Thomas, and Eliangiringa Amos Kaale. "Priority setting for the implementation of artemisinin-based combination therapy policy in Tanzania: evaluation against the accountability for reasonableness framework." Implementation Science 7, no. 18 (March 18, 2012). Accessed February 1, 2015. doi:10.1186/1748-5908-7-18.

This article discusses many of the shortcomings in effective communications that have limited the adoption of ACTs over older antimalarials by Tanzanian health workers. As such, it provides valuable insight into the way an effective top-down health policy should be implemented in Tanzana.

Morris, Alexandra, Justin M. Cohen, Abigail Ward, Bruno Moonen, and Oliver Sabot. Price Subsidies Increase the Use of Private Sector ACTs: Evidence from a Systematic Review.

Boston: Clinton Health Access Initiative, 2012. Accessed February 13, 2015. http://www.clintonhealthaccess.org/files/ACT_Usage_1.1.pdf.

While the initial evaluation of the AMFm by the Global Fund lacked the resources and equipment to accurately measure any changes in ACT usage rates on the ground, this report evaluates secondary evidence of ACT usage rates in the literature and determines that the program was responsible for an increase in usage rates across all 7 countries in which it was implemented.

Moutacho, Joel C., and J.P. Dean Goldberg. "Malaria rapid diagnostic tests: challenges and prospects." Journal of Medical Microbiology 62, no. 10 (October 2013): 1491-505.

Accessed January 2, 2015. doi:10.1099/jmm.0.052506-0.

This 2013 literature review discusses a number of different antigens associated with malaria that can be detected by rapid diagnostic tests. Most notably, it provides data on the

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sensitivity (false negatives) and specificity (false positives) of RDTs currently on the market, as well as factors in local Plasmodium populations that might affect these parameters.

Mubi, Marycelina, Deodatus Kakoko, Billy Ngasala, Stefan Peterson, Anders Björkman, and Andreas Mårtensson. "Malaria diagnosis and treatment practices following introduction of rapid diagnostic tests in Kibaha District, Coast Region, Tanzania." Malaria Journal 12, no. 293 (August 26, 2013). Accessed January 6, 2015. doi:10.1186/1475-2875-12293.

This article surveys real-world diagnostic practices for malaria at 10 different government health facilities. The interviews with health workers and patients that were conducted by the researchers reveal important insights into local perceptions of RDTs, as well as ways to improve their perceived legitimacy among local populations.

O'Meara, Wendy Prudhomme, David L. Smith, and F. Ellis McKenzie. "Potential Impact of Intermittent Preventive Treatment (IPT) on Spread of Drug-Resistant Malaria." PLoS Medicine 3, no. 5 (May 2006): 633-42. Accessed January 9, 2015. doi:10.1371/journal.pmed.0030141.

In intermittent preventive treatment, a pregnant woman or child is given an antimalarial drug during malaria season to reduce the risk that the patient ever contract malaria. However, because this sort of treatment ultimately results in low concentrations of the drug being present in the patient's blood post-treatment, IPT can cause selection for resistant parasites. This journal article empirically confirms these suspicions, making IPT seem less viable as a long-term solution to the malaria problem.

Osta, Mike A., Zeinab J. Rizk, Perrick Labbé, Mylène Weill, and Khouzama Knio. "Insecticide resistance to organophosphates in Culex pipiens complex from Lebanon." Parasites and Vectors 5, no. 132 (July 3, 2012). Accessed August 4, 2014. doi:10.1186/1756-3305-5132.

This peer-reviewed journal article uses a long-term field study in Lebanon to determine the feasibility of using insecticide rotations to combat the Ace-1R mechanism of resistance to organophosphates. The authors conclude that the fitness cost associated with the Ace-1R mutation are high enough that temporarily discontinuing the use of organophosphates returns the frequency of the allele within mosquito populations to manageable levels.

Raymond, Michel, Christine Chevillon, Thomas Guillemand, and Thomas Lenormand. "An overview of the evolution of overproduced esterases in the mosquito Culex pipiens."

Philosophical Transactions of the Royal Society B 353 (October 29, 1998): 1707-11.

Accessed August 4, 2014. doi:10.1098/rstb.1998.0322.

The metabolic pathway of resistance to organophosphates via esterase overproduction is the most complex of the 5 main resistance mechanisms because it involves eight different alleles instead of the usual two. As such, understanding its evolution over the past few decades is important in understanding how resistance will manifest in the future. This peer-reviewed journal

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article projects that in the future, while esterase overproduction will likely only confer a low to intermediate resistance to organophosphates, the fitness cost associated with it will continue to decrease over time. These considerations are important in developing a detailed insecticide rotation plan.

Tougher, Sarah, the ACTwatch Group, Yazoume He, John H Amuasi, Idrissa A Kourgueni, Rebecca Thomson, Catherine Goodman, Andrea G Mann, Ruilin Ren, Barbara A Willey, Catherine A Adegoke, Abdinasir Amin, Daniel Ansong, Katia Bruxvoort, Diadier A Diallo, Graciela Diap, Charles Festo, Boniface Johanes, Elizabeth Juma, Admirabilis Kalolella, Oumarou Malam, Blessing Mberu, Salif Ndiaye, Samuel B Nguah, Moctar Seydou, Mark Taylor, Sergio Torres Rueda, Marilyn Wamukoya, Fred Arnold, and Kara Hanson. "Effect of the Affordable Medicines Facility—malaria (AMFm) on the availability, price, and market share of quality-assured artemisinin-based combination therapies in seven countries: a before-and-after analysis of outlet survey data." Lancet 380, no. 9857 (October 31, 2012): 1916-26. Accessed February 13, 2015. doi:10.1016/S0140-6736(12)61732-2.

The success of the AMFm mechanism's pilot phase (in terms of increased market share, decreased price, and increased availability of ACTs) was evaluated in this report. Particularly in Tanzania, this program saw great success across these parameters.

TourĂŠ, Yeya. "New methods and strategies." Special Programme for Research and Training in Tropical Diseases. Last modified 2015. Accessed February 18, 2015. http://www.who.int/tdr/research/vectors/methods_strategies/en/.

Examining the strategies used to control other major African diseases is a helpful step in understanding some of the deficiencies in Tanzania's framework for malaria control. This compilation of current research is a useful source of information on the broad measures that prove useful for the purposes of this paper.

United Kingdom Department for International Development. An Epidemiological Profile of Malaria and Its Control in Mainland Tanzania. By Prosper Chaki, Renata Mandike, Ally Mohammed, Fabrizio Molenti, Clara Mundia, Ritha Njau, Abdisalan Mohamed Noor, Fredros Okumu, and Bob Snow. Dar es Salaam: 2013. Accessed July 24, 2014. http://www.natnets.org/attachments/article/65/Tanzania%20Malaria%20Epi%20Report% 202013%20%28230713%29.pdf.

This report was jointly commissioned by Tanzania's National Malaria Control Programme, the Ifakara Health Institute (a prominent Tanzanian health research organization), and the Tanzanian office of the WHO, underwritten by the UK government. It reviews the history of malaria control policies in the country, focusing particularly on the Roll Back Malaria program in place since 2000 and then proceeds to examine the effectiveness of these policies by modeling changes in the transmission rate of the P. falciparum parasite over the years. The conclusions and future policy recommendations are largely based on the challenges the existing policies have faced (from the perspective of the native government) and are thus a good starting point for examining further policy actions.

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United Republic of Tanzania Ministry of Health. National Health Policy. Dar es Salaam: 2003.

Accessed July 21, 2014. http://apps.who.int/medicinedocs/documents/s18419en/s18419en.pdf.

This document issued by the Tanzanian Ministry of Health details the national health policies currently being implemented in the country. It describes the administrative structure of Tanzania's health facilities and also includes a number of specific policy initiatives to help reduce the spread of diseases, such as public health education, expanding the existing medical infrastructure, improving the availability of drugs and supplies, better training health workers, and increasing the role of public-private partnerships. While other, more malaria-specific policy solutions will be investigated, improving the native government's ability to combat malaria with its pre-existing faculties would likely be advisable because it obviates the need to build a completely new infrastructure. Working to simply improve the efficacy of these existing initiatives would also mitigate the culture clash inherent to solutions conceived entirely by Western NGOs, IGOs, or governments.

United Republic of Tanzania National Institute for Medical Research. Detection and Monitoring of Insecticide Resistance in Malaria Vectors in Tanzania Mainland. By W. Kisinza, B. Kabula,P. Tungu, C. Sindato, C. Mweya, D. Massue, B. Emidi, J. Kitai, M. Chacha, B. Batengana, J. Matowo, S. Msangi, R. Malima, and S. Magesa. Muheza, Tanzania: NIMR, 2011. Accessed November 4, 2014. http://ihi.eprints.org/779/1/INSECTICIDE_RESISTANCE_TECHNICAL_REPORT_NI MR_DEC_2011.pdf.

This report is one of the Tanzanian government's evaluations of the state of insecticide resistance within its borders. It provides both important data on the status of insecticide resistance in Tanzania and a history contextualizing the details of the commission of similar reports.

United States Agency for International Development DELIVER Project. Price Analysis of Malaria Rapid Diagnostic Test Kits. Accessed January 1, 2015. http://deliver.jsi.com/dlvr_content/resources/allpubs/logisticsbriefs/RDTPricAnal.pdf.

This USAID publication discusses the prices of different brands of RDTs in different countries, comparing the prices both of different manufacturers in a vacuum and and of the same products in single-source and competitive markets. Because the success of any large-scale RDT policy relies on the accuracy, as well as the prices of the tests it endorses, exploiting current market trends will help maximize the efficacy of such a policy, given the budgets allocated to it.

United States Agency for International Development President's Malaria Initiative. Malaria Operational Plan FY2014. Washington, D.C.: 2013. Accessed July 28, 2014. http://www.pmi.gov/docs/default-source/default-document-library/malaria-operationalplans/fy14/tanzania_mop_fy14.pdf?sfvrsn=12.

The President's Malaria Initiative is one of the primary sources of funding for Tanzania's malaria control policies, currently accounting for almost half of mainland Tanzania's malaria funding. PMI has been in place since 2005; the revised plan for FY2014 takes into account

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challenges the initiative has faced in the past and outlines vector control, treatment, surveillance, and other policies that will be continued into the future. It also details the amount of money that will be allocated to specific policies, providing a baseline for budgetary considerations in malaria policies.

United States Pharmacopeia Drug Quality and Information Program. Ensuring the Quality of Medicines in Resource-Limited Countries: An Operational Guide. Rockville, MD: U.S. Pharmacopeial Convention, 2007. Accessed January 9, 2015. http://www.usp.org/sites/default/files/usp_pdf/EN/dqi/ensuringQualityOperationalGuide. pdf.

With the prevalence of substandard drugs across Africa, this more general publication describes the steps necessary to combat their production, particularly at a national level. The report effectively describes the logistics of domestic measures aimed at ensuring high drug quality from prequalified manufacturers and cracking down on actors responsible for putting low-quality drugs on the retail market.

"WHO: Low quality drugs continue to afflict Africa." Medicines for Malaria Venture. Last modified February 25, 2011. Accessed January 2, 2015. http://www.mmv.org/newsroom/news/who-low-quality-drugs-continue-afflict-africa.

The statistics cited by this article provide a comparative picture of countries with and without programs to assure the quality of antimalarial medicines. In particular, the author points to the WHO's widely successful prequalified medicines program, which has reduced drug failure rates to below 4% in its countries of operation.

Widmar, Maria, Courtney J. Nagel, Deborah Y. Ho, Peter W. Benziger, and Nils Hennig.

"Determining and addressing obstacles to the effective use of long-lasting insecticideimpregnated nets in rural Tanzania." Malaria Journal 8, no. 315 (December 31, 2009).

Accessed December 23, 2014. doi:10.1186/1475-2875-8-315.

This peer-reviewed journal article discusses one of the most significant challenges facing malaria control in Tanzania after the establishment of a highly effective bednet distribution framework: maintenance. Although the authors find that existing views about proper ITN usage are often misinformed, a relatively short community education program can rectify these misconceptions even in the long-term.

World Health Organization. "Prequalification of medicines by WHO." WHO Media Centre. Last modified January 2013. Accessed January 17, 2015. http://www.who.int/mediacentre/factsheets/fs278/en/.

This page details the process by which the WHO conducts its Prequalification of Medicines Programme (PQP) to designate a particular drug producer as a source of qualityassured medicines. Such programs are crucial in reducing the prevalence of counterfeit and substandard drugs.

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———. Survey of the Quality of Selected Antimalarial Medicines Circulating in Six Countries of Sub-Saharan Africa. Geneva: WHO Press, 2011. Accessed January 9, 2015. http://www.who.int/medicines/publications/WHO_QAMSA_report.pdf.

This WHO report conducted both a literature review and independent study to determine the quality of antimalarial drugs found in some of the most severely malarious African countries.

All metrics used in the study reported a significant presence of substandard and/or counterfeit drugs in all countries examined, including Tanzania. The end of the report also provided valuable insight into large-scale international strategies that could address the problem at a global level.

World Health Organization Global Malaria Programme. Emergence and spread of artemisinin resistance calls for intensified efforts to withdraw oral artemisinin-based monotherapy from the market. Geneva: WHO Press, 2014. Accessed January 4, 2015. http://www.who.int/malaria/publications/atoz/oral-artemisinin-based-monotherapies1may2014.pdf.

Although not a major problem in Tanzania, one of the most significant threats to the efficacy of artemisinins is the use of artemisinin-based monotherapies (AMTs). This WHO paper explains the risks posed specifically by AMTs in precipitating the development of drug resistance and outlines potential steps to remove them from the international market altogether.

———. Global Plan for Artemisinin Resistance Containment. Geneva: WHO Press, 2011.

Accessed August 14, 2014. http://www.who.int/malaria/publications/atoz/artemisinin_resistance_containment_2011. pdf.

When vector control measures fail to prevent the transmission of malaria, the efficacy of antimalarial drugs is essential in combating the disease. However, Plasmodium in Tanzania has quickly developed resistance to two distinct classes of antimalarials: CQ and SP. Malaria treatment is now becoming increasingly reliant on artemisinin-based combination therapies, or ACTs, because these drugs have the advantage of using two distinct but synergistic classes of drugs in conjunction, minimizing the odds of resistance developing to either one. However, for this for this final treatment option to remain efficacious, resistance to neither artemisinin nor its partner drugs can be allowed to develop. This WHO paper gives a series of policy recommendations that will help prevent or at least delay this disastrous scenario from becoming a reality.

———. Global Plan for Insecticide Resistance Management in Malaria Vectors. Geneva: WHO Press, 2012. Accessed July 31, 2014. http://apps.who.int/iris/bitstream/10665/44846/1/9789241564472_eng.pdf.

One of the most significant emerging challenges to Tanzanian malaria policy is that of insecticide, larvicide, and antimalarial drug resistance. This WHO publication discusses certain strategies that the international organization recommends as a means to manage this trend of resistance, outlining different initiatives for different regions based on the predominant policies (the source of the resistance, typically either insecticidal nets or indoor residual spraying) already

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in place. While the report discusses the plan for insecticide resistance management in a global context, much of its content is directly applicable to the policy environments and climates present throughout Tanzania.

———. Good procurement practices for artemisinin-based antimalarial medicines. Geneva: WHO Press, 2010. Accessed February 11, 2015. http://whqlibdoc.who.int/publications/2010/9789241598927_eng.pdf.

This publication details the process by which the WHO recommends both international donors providing support to malaria-endemic countries and the governments of those countries themselves procure artemisinin-based drugs for that country's domestic malaria programme.

Understanding the components of the ideal procurement policy, outlined here, is a crucial step in identifying the obstacles hindering the implementation of such a policy in a country like Tanzania, where ACT access is deficient.

———. Insecticide-Treated Mosquito Nets: A WHO Position Statement. Geneva: WHO Press, 2008. Accessed August 1, 2014. http://www.who.int/malaria/publications/atoz/itnspospaperfinal.pdf.

This WHO report discusses the advantages of replacing standard insecticide-treated bednets (ITNs) with long lasting insecticidal bednets (LLINs) as malaria control polices go forward. Notably, it outlines potential strategies that can be adopted to facilitate LLIN delivery to their target households and the replacement of damaged nets to ensure continuous coverage. The paper demonstrates how a relatively old idea can practically be adapted to become more useful while considering practical constraints in the modern world.

———. World Malaria Report 2014. Geneva: WHO Press, 2014. Accessed December 26, 2014. http://www.who.int/malaria/publications/world_malaria_report_2014/en/.

This WHO report on the global status of malaria provides important context for the efficacy of malaria control policies in a wide range of circumstances, both similar to and different from Tanzania's. Most importantly, it collates information from numerous policies in differing states of implementation, providing valuable indicators for the future success of the policies recommended by this paper for Tanzania.

Yadev, Prashant, Kristen Curtis, and Neelam Sekhri. "Mapping and Realigning Incentives in the Global Health Supply Chain." Unpublished manuscript, December 2006. Accessed February 12, 2015. http://www.zlc.edu.es/content/files/RealigningIncentives.pdf.

In the framework for ACT acquisition and distribution, there are a number of areas where the incentives of different actors (manufacturers, demand forecasters, etc.) are misaligned. As a result, the actions dictated by different actors (based on their power in the framework) can often cause an unequal balancing of risk, increasing the final price of the drug. This paper provides an overview of these misalignments and suggests policies to help share the risk more equitably.

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