Therapeutic Efficacy of Sulfadoxine-Pyrimethamine and Prevalence of Resistance Markers in Tanzania Prior to Revision of Malaria Treatment Policy: Plasmodium Falciparum Dihydrofolate Reductase and Dihydropteroate Synthase Mutations in Monitoring in Vivo Resistance.

Prior to the 2001 malarial treatment policy change in Tanzania, we conducted trials to assess the efficacy of sulfadoxine-pyrimethamine (SP) and the usefulness of molecular markers in monitoring resistance. A total of 383 uncomplicated Plasmodium falciparum malaria patients (between 6 and 59 months old) were treated with SP and their responses were assessed. Mutations in the P. falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) genes in admission day blood samples were analyzed. Results indicated that 85.6% of the patients showed an adequate clinical response, 9.7% an early treatment failure, and 4.7% a late treatment failure. The quintuple mutant genotype (pfdhfr 51 Ile, 59 Arg, and 108 Asn and pfdhps 437 Gly and 540 Glu) showed an association with treatment outcome (odds ratio = 2.1; 95% confidence interval = 0.94-4.48, P = 0.045). The prevalence of the triple pfdhfr mutant genotype (51 Ile, 59 Arg, and 108 Asn) at a site of high SP resistance (23.6%) was four times higher compared with that observed at sites of moderate SP resistance (6.8-14.4%) (P = 0.000001). The genotype failure index calculated by using this marker was invariable (1.96-2.1) at sites with moderate SP resistance, but varied (3.4) at a site of high SP resistance. In conclusion, our clinical and molecular findings suggest that SP may have a short useful therapeutic life in Tanzania; thus, its adoption as an interim first-line antimalarial drug. The findings also point to the potential of the triple pfdhfr mutant genotype as an early warning tool for increasing SP resistance. These data form the baseline SP efficacy and molecular markers profile in Tanzania prior to the policy change

Intermittent preventive treatment for malaria and anaemia control in Tanzanian infants; the development and implementation of a public health strategy.

Minimizing the time between efficacy studies and public health action is important to maximize health gains. We report the rationale, development and implementation of a district-based strategy for the implementation of intermittent preventive treatment in infants (IPTi) for malaria and anaemia control in Tanzania. From the outset, a research team worked with staff from all levels of the health system to develop a public-health strategy that could continue to function once the research team withdrew. The IPTi strategy was then implemented by routine health services to ensure that IPTi behaviour-change communication materials were available in health facilities, that health workers were trained to administer and to document doses of IPTi, that the necessary drugs were available in facilities and that systems were in place for stock management and supervision. The strategy was integrated into existing systems as far as possible and well accepted by health staff. Time-and-motion studies documented that IPTi implementation took a median of 12.4 min (range 1.6-28.9) per nurse per vaccination clinic. The collaborative approach between researchers and health staff effectively translated research findings into a strategy fit for public health implementation

Creating an "enabling environment" for taking insecticide treated nets to national scale: the Tanzanian experience

INTRODUCTION: Malaria is the largest cause of health services attendance, hospital admissions and child deaths in Tanzania. At the Abuja Summit in April 2000 Tanzania committed itself to protect 60% of its population at high risk of malaria by 2005. The country is, therefore, determined to ensure that sustainable malaria control using insecticide-treated nets is carried out on a national scale. CASE DESCRIPTION: Tanzania has been involved for two decades in the research process for developing insecticide-treated nets as a malaria control tool, from testing insecticides and net types, to assessing their efficacy and effectiveness, and exploring new ways of distribution. Since 2000, the emphasis has changed from a project approach to that of a concerted multi-stakeholder action for taking insecticide-treated nets to national scale (NATNETS). This means creating conditions that make insecticide-treated nets accessible and affordable to all those at risk of malaria in the country. This paper describes Tanzania's experience in (1) creating an enabling environment for insecticide-treated nets scale-up, (2) promoting the development of a commercial sector for insecticide-treated nets, and (3) targeting pregnant women with highly subsidized insecticide-treated nets through a national voucher scheme. As a result, nearly 2 million insecticide-treated nets and 2.2 million re-treatment kits were distributed in 2004. CONCLUSION: National upscaling of insecticide-treated nets is possible when the programme is well designed, coordinated and supported by committed stakeholders; the Abuja target of protecting 60% of those at high risk is feasible, even for large endemic countries

Introducing vouchers for malaria prevention in Ghana and Tanzania: context and adoption of innovation in health systems

There are striking similarities in health system and other contexts between Tanzania and Ghana that are relevant to the scaling up of continuous delivery of insecticide treated nets (ITNs) for malaria prevention. However, specific contextual factors of relevance to ITN delivery have led implementation down very different pathways in the two countries. Both countries have made major efforts and investments to address this intervention through integrating consumer discount vouchers into the health system. Discount vouchers require arrangements among the public, private and non-governmental sectors and constitute a complex intervention in both health systems and business systems. In Tanzania, vouchers have moved beyond the planning agenda, had policies and programmes formulated, been sustained in implementation at national scale for many years and have become as of 2012 the main and only publicly supported continuous delivery system for ITNs. In Ghana national-scale implementation of vouchers never progressed beyond consideration on the agenda and piloting towards formulation of policy; and the approach was replaced by mass distribution campaigns with less dependency on or integration with the health system. By 2011, Ghana entered a phase with no publicly supported continuous delivery system for ITNs. To understand the different outcomes, we compared the voucher programme timelines, phases, processes and contexts in both countries in reference to the main health system building blocks (governance, human resources, financing, informatics, technologies and service delivery). Contextual factors which provided an enabling environment for the voucher scheme in Tanzania did not do so in Ghana. The voucher scheme was never seen as an appropriate national strategy, other delivery systems were not complementary and the private sector was under-developed. The extensive time devoted to engagement and consensus building among all stakeholders in Tanzania was an important and clearly enabling difference, as was public sector support of the private sector. This contributed to the alignment of partner action behind a single co-ordinated strategy at service delivery level which in turn gave confidence to the business sector and avoided the ‘interference' of competing delivery systems that occurred in Ghana. Principles of systems thinking for intervention design correctly emphasize the importance of enabling contexts and stakeholder managemen

Intermittent preventive treatment for malaria and anaemia control in Tanzanian infants; the development and implementation of a public health strategy

Minimizing the time between efficacy studies and public health action is important to maximize health gains. We report the rationale, development and implementation of a district-based strategy for the implementation of intermittent preventive treatment in infants (IPTi) for malaria and anaemia control in Tanzania. From the outset, a research team worked with staff from all levels of the health system to develop a public-health strategy that could continue to function once the research team withdrew. The IPTi strategy was then implemented by routine health services to ensure that IPTi behaviour-change communication materials were available in health facilities, that health workers were trained to administer and to document doses of IPTi, that the necessary drugs were available in facilities and that systems were in place for stock management and supervision. The strategy was integrated into existing systems as far as possible and well accepted by health staff. Time-and-motion studies documented that IPTi implementation took a median of 12.4 min (range 1.6-28.9) per nurse per vaccination clinic. The collaborative approach between researchers and health staff effectively translated research findings into a strategy fit for public health implementatio

Routine delivery of artemisinin-based combination treatment at fixed health facilities reduces malaria prevalence in Tanzania: an observational study

BACKGROUND Artemisinin-based combination therapy (ACT) has been promoted as a means to reduce malaria transmission due to their ability to kill both asexual blood stages of malaria parasites, which sustain infections over long periods and the immature derived sexual stages responsible for infecting mosquitoes and onward transmission. Early studies reported a temporal association between ACT introduction and reduced malaria transmission in a number of ecological settings. However, these reports have come from areas with low to moderate malaria transmission, been confounded by the presence of other interventions or environmental changes that may have reduced malaria transmission, and have not included a comparison group without ACT. This report presents results from the first large-scale observational study to assess the impact of case management with ACT on population-level measures of malaria endemicity in an area with intense transmission where the benefits of effective infection clearance might be compromised by frequent and repeated re-infection. METHODS A pre-post observational study with a non-randomized comparison group was conducted at two sites in Tanzania. Both sites used sulphadoxine-pyrimethamine (SP) monotherapy as a first-line anti-malarial from mid-2001 through 2002. In 2003, the ACT, artesunate (AS) co-administered with SP (AS + SP), was introduced in all fixed health facilities in the intervention site, including both public and registered non-governmental facilities. Population-level prevalence of Plasmodium falciparum asexual parasitaemia and gametocytaemia were assessed using light microscopy from samples collected during representative household surveys in 2001, 2002, 2004, 2005 and 2006. FINDINGS Among 37,309 observations included in the analysis, annual asexual parasitaemia prevalence in persons of all ages ranged from 11% to 28% and gametocytaemia prevalence ranged from <1% to 2% between the two sites and across the five survey years. A multivariable logistic regression model was fitted to adjust for age, socioeconomic status, bed net use and rainfall. In the presence of consistently high coverage and efficacy of SP monotherapy and AS + SP in the comparison and intervention areas, the introduction of ACT in the intervention site was associated with a modest reduction in the adjusted asexual parasitaemia prevalence of 5 percentage-points or 23% (p < 0.0001) relative to the comparison site. Gametocytaemia prevalence did not differ significantly (p = 0.30). INTERPRETATION The introduction of ACT at fixed health facilities only modestly reduced asexual parasitaemia prevalence. ACT is effective for treatment of uncomplicated malaria and should have substantial public health impact on morbidity and mortality, but is unlikely to reduce malaria transmission substantially in much of sub-Saharan Africa where individuals are rapidly re-infected.Financial support for IMPACT-Tz came primarily from CDC, the U.S. Agency for International Development and the Wellcome Trust

Efficacy and safety of artemisinin-based antimalarial in the treatment of uncomplicated malaria in children in southern Tanzania

BACKGROUND\ud \ud Tanzania switched the antimalarial first line to sulphadoxine-pyrimethamine (SP) in 2001 from ineffective chloroquine (CQ). By 2003 higher levels of SP resistance were recorded, prompting an urgent need for replacing the first line drug with ACT, as currently recommended by the World Health Organization. Despite this recommendation country-specific evidence-based data to support efficacy and safety profile of ACT is still limited. A study on the efficacy and safety of artesunate plus amodiaquine (AS+AQ) and artemether plus lumefantrine (AL)(Coartem) was carried out in 2004 with the view of supporting the National Malaria Control Programme in the review of the policy in mainland Tanzania.\ud \ud METHODS\ud \ud An in vivo efficacy study was conducted at Ipinda and Mlimba health facilities between May and November 2004. The study recruited children aged 6-59 months presenting with symptoms of uncomplicated malaria, history of fever or an axillary temperature > or =37.5 degrees C; mono infection with Pasmodium falciparum (2,000-200,000 parasites/microl). Patients were randomized to received either SP or amodiaquine monotherapy or treated with standard doses of AS+AQ in Mlimba and Coartem in Kyela and followed-up for 28 days to assess treatment responses. This study reports results of the combination therapies.\ud \ud RESULTS\ud \ud A total of 157 children (76 in Mlimba and 99 in Kyela) who were enrolled in to the study and treated with either AL or AS+AQ were successfully followed-up. Both combinations were tolerated and effected rapid fever and parasite clearance. The crude ACPRs were 80 (87%) and 41 (63%) for AL and AS+AQ respectively. However, after PCR adjustments the corresponding figures raised to 100% (n = 86) and 93.8% (n = 45) in AL and AS+AQ groups, respectively. The mean haemoglobin improved moderately from day 0 to day 28 by 1 g/dl in AL and 0.4 g/dl in AS+AQ treatment group and was statistically significant (p < 0.001 both).\ud \ud CONCLUSION\ud \ud These findings provide substantial evidence that AL is highly efficacious in areas of high resistance of SP and supported the country's decision to switch from SP monotherapy to AL

Piloting the Global Subsidy: The Impact of Subsidized Artemisinin-Based Combination Therapies Distributed through Private Drug Shops in Rural Tanzania

BACKGROUND: WHO estimates that only 3% of fever patients use recommended artemisinin-based combination therapies (ACTs), partly reflecting their high prices in the retail sector from where many patients seek treatment. To overcome this challenge, a global ACT subsidy has been proposed. We tested this proposal through a pilot program in rural Tanzania. METHODS/PRINCIPAL FINDINGS: Three districts were assigned to serve either as a control or to receive the subsidy plus a package of supporting interventions. From October 2007, ACTs were sold at a 90% subsidy through the normal private supply chain to intervention district drug shops. Data were collected at baseline and during intervention using interviews with drug shop customers, retail audits, mystery shoppers, and audits of public and NGO facilities. The proportion of consumers in the intervention districts purchasing ACTs rose from 1% at baseline to 44.2% one year later (p<0.001), and was significantly higher among consumers purchasing for children under 5 than for adults (p = 0.005). No change in ACT usage was observed in the control district. Consumers paid a mean price of $0.58 for ACTs, which did not differ significantly from the price paid for sulphadoxine-pyrimethamine, the most common alternative. Drug shops in population centers were significantly more likely to stock ACTs than those in more remote areas (p<0.001). CONCLUSIONS: A subsidy introduced at the top of the private sector supply chain can significantly increase usage of ACTs and reduce their retail price to the level of common monotherapies. Additional interventions may be needed to ensure access to ACTs in remote areas and for poorer individuals who appear to seek treatment at drug shops less frequently. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN39125414

Presumptive treatment of fever cases as malaria: help or hindrance for malaria control?

BACKGROUND: Malaria incidence has been reported to be falling in several countries in sub-Saharan Africa in recent years. This fall appears to have started before the widespread introduction of insecticide-treated nets. In the new era of calls to eliminate and eradicate malaria in sub-Saharan Africa, exploring possible causes for this fall seem pertinent. PRESENTATION OF THE HYPOTHESIS: The authors explore an argument that presumptive treatment of fever cases as malaria may have played a role in reducing transmission of malaria by the prophylactic effect of antimalarials and their widespread use. This strategy, which is already in practise is termed Opportunistic Presumptive Treatment (OPT). TESTING THE HYPOTHESIS: Further comparison of epidemiological indicators between areas with OPT and more targeted treatment is required. If data suggest a benefit of OPT, combining long acting antimalarials that have an anti-gametocyticidal activity component plus using high levels of vector control measures may reduce transmission, prevent resistant strains spreading and be easily implemented. IMPLICATIONS OF THE HYPOTHESIS: OPT is practised widely by presumptive treatment of fever in health facilities and home management of fever. Improving diagnosis using rapid diagnostic tests and thus reducing the number of doses of antimalarials given may have counter intuitive effects on transmission in the context of elimination of malaria in high to moderate transmission settings

Design, implementation and evaluation of a national campaign to distribute nine million free LLINs to children under five years of age in Tanzania.

BACKGROUND\ud \ud After a national voucher scheme in 2004 provided pregnant women and infants with highly subsidized insecticide-treated nets (ITNs), use among children under five years (U5s) in mainland Tanzania increased from 16% in 2004 to 26.2% in 2007. In 2008, the Ministry of Health and Social Welfare planned a catch-up campaign to rapidly and equitably deliver a free long-lasting insecticidal net (LLIN) to every child under five years in Tanzania.\ud \ud METHODS\ud \ud The ITN Cell, a unit within the National Malaria Control Programme (NMCP), coordinated the campaign on behalf of the Ministry of Health and Social Welfare. Government contractors trained and facilitated local government officials to supervise village-level volunteers on a registration of all U5s and the distribution and issuing of LLINs. The registration results formed the basis for the LLIN order and delivery to village level. Caregivers brought their registration coupons to village issuing posts during a three-day period where they received LLINs for their U5s. Household surveys in five districts assessed ITN ownership and use immediately after the campaign.\ud \ud RESULTS\ud \ud Nine donors contributed to the national campaign that purchased and distributed 9.0 million LLINs at an average cost of $7.07 per LLIN, including all campaign-associated activities. The campaign covered all eight zones of mainland Tanzania, the first region being covered separately during an integrated measles immunization/malaria LLIN distribution in August 2008, and was implemented one zone at a time from March 2009 until May 2010. ITN ownership at household level increased from Tanzania's 2008 national average of 45.7% to 63.4%, with significant regional variations. ITN use among U5s increased from 28.8% to 64.1%, a 2.2-fold increase, with increases ranging from 22.1-38.3% percentage points in different regions.\ud \ud CONCLUSION\ud \ud A national-level LLIN distribution strategy that fully engaged local government authorities helped avoid additional burden on the healthcare system. Distribution costs per net were comparable to other public health interventions. Particularly among rural residents, ITN ownership and use increased significantly for the intended beneficiaries. The upcoming universal LLIN distribution and further behaviour change communication will further improve ITN ownership and use in 2010-2011