Making data map-worthy-enhancing routine malaria data to support surveillance and mapping of Plasmodium falciparum anti-malarial resistance in a pre-elimination sub-Saharan African setting: a molecular and spatiotemporal epidemiology study.

BACKGROUND: Independent emergence and spread of artemisinin-resistant Plasmodium falciparum malaria have recently been confirmed in Africa, with molecular markers associated with artemisinin resistance increasingly detected. Surveillance to promptly detect and effectively respond to anti-malarial resistance is generally suboptimal in Africa, especially in low transmission settings where therapeutic efficacy studies are often not feasible due to recruitment challenges. However, these communities may be at higher risk of anti-malarial resistance. METHODS: From March 2018 to February 2020, a sequential mixed-methods study was conducted to evaluate the feasibility of the near-real-time linkage of individual patient anti-malarial resistance profiles with their case notifications and treatment response reports, and map these to fine scales in Nkomazi sub-district, Mpumalanga, a pre-elimination area in South Africa. RESULTS: Plasmodium falciparum molecular marker resistance profiles were linked to 55.1% (2636/4787) of notified malaria cases, 85% (2240/2636) of which were mapped to healthcare facility, ward and locality levels. Over time, linkage of individual malaria case demographic and molecular data increased to 75.1%. No artemisinin resistant validated/associated  Kelch-13 mutations were detected in the 2385 PCR positive samples. Almost all 2812 samples assessed for lumefantrine susceptibility carried the wildtype mdr86ASN and crt76LYS alleles, potentially associated with decreased lumefantrine susceptibility. CONCLUSION: Routine near-real-time mapping of molecular markers associated with anti-malarial drug resistance on a fine spatial scale provides a rapid and efficient early warning system for emerging resistance. The lessons learnt here could inform scale-up to provincial, national and regional malaria elimination programmes, and may be relevant for other antimicrobial resistance surveillance.

Effectiveness and cost-effectiveness of reactive, targeted indoor residual spraying for malaria control in low-transmission settings: a cluster-randomised, non-inferiority trial in South Africa.

BACKGROUND: Increasing insecticide costs and constrained malaria budgets could make universal vector control strategies, such as indoor residual spraying (IRS), unsustainable in low-transmission settings. We investigated the effectiveness and cost-effectiveness of a reactive, targeted IRS strategy. METHODS: This cluster-randomised, open-label, non-inferiority trial compared reactive, targeted IRS with standard IRS practice in northeastern South Africa over two malaria seasons (2015-17). In standard IRS clusters, programme managers conducted annual mass spray campaigns prioritising areas using historical data, expert opinion, and other factors. In targeted IRS clusters, only houses of index cases (identified through passive surveillance) and their immediate neighbours were sprayed. The non-inferiority margin was 1 case per 1000 person-years. Health service costs of real-world implementation were modelled from primary and secondary data. Incremental costs per disability-adjusted life-year (DALY) were estimated and deterministic and probabilistic sensitivity analyses conducted. This study is registered with ClinicalTrials.gov, NCT02556242. FINDINGS: Malaria incidence was 0·95 per 1000 person-years (95% CI 0·58 to 1·32) in the standard IRS group and 1·05 per 1000 person-years (0·72 to 1·38) in the targeted IRS group, corresponding to a rate difference of 0·10 per 1000 person-years (-0·38 to 0·59), demonstrating non-inferiority for targeted IRS (p<0·0001). Per additional DALY incurred, targeted IRS saved US$7845 (2902 to 64 907), giving a 94-98% probability that switching to targeted IRS would be cost-effective relative to plausible cost-effectiveness thresholds for South Africa ($2637 to $3557 per DALY averted). Depending on the threshold used, targeted IRS would remain cost-effective at incidences of less than 2·0-2·7 per 1000 person-years. Findings were robust to plausible variation in other parameters. INTERPRETATION: Targeted IRS was non-inferior, safe, less costly, and cost-effective compared with standard IRS in this very-low-transmission setting. Saved resources could be reallocated to other malaria control and elimination activities. FUNDING: Joint Global Health Trials.

Absence of kelch13 artemisinin resistance markers but strong selection for lumefantrine-tolerance molecular markers following 18 years of artemisinin-based combination therapy use in Mpumalanga Province, South Africa (2001-2018).

BACKGROUND: The ability of Plasmodium falciparum parasites to develop resistance to widely used anti-malarials threatens malaria control and elimination efforts. Regular drug efficacy monitoring is essential for ensuring effective treatment policies. In low transmission settings where therapeutic efficacy studies are often not feasible, routine surveillance for molecular markers associated with anti-malarial resistance provides an alternative for the early detection of emerging resistance. Such a longitudinal survey of changes in the prevalence of selected molecular markers of resistance was conducted in the malaria-endemic regions of Mpumalanga Province, South Africa, where malaria elimination at a district-level is being pursued. METHODS: Molecular analyses to determine the prevalence of alleles associated with resistance to lumefantrine (mdr86N, crt76K and mdr1 copy number variation) and sulfadoxine-pyrimethamine (dhfr triple, dhps double, SP quintuple) were conducted between 2001 and 2018, while artemisinin resistance markers (kelch13 mutations) were assessed only in 2018. RESULTS: Parasite DNA was successfully amplified from 1667/2393 (70%) of malaria-positive rapid diagnostic tests routinely collected at primary health care facilities. No artemisinin resistance-associated kelch13 mutations nor amplification of the mdr1 gene copy number associated with lumefantrine resistance were observed. However, prevalence of both the mdr86N and crt76K alleles increased markedly over the study period, with all isolates collected in 2018 carrying these markers. SP quintuple mutation prevalence increased steadily from 14% in 2001 to 96% in 2018. Mixed alleles at any of the codons assessed were rare by 2018. CONCLUSION: No kelch13 mutations confirmed or suspected to be associated with artemisinin resistance were identified in 2018. Although parasites carrying the mdr86N and crt76K alleles associated with reduced lumefantrine susceptibility were strongly selected for over the study period, nearing fixation by 2018, the marker for lumefantrine resistance, namely increased mdr1 copy number, was not observed in this study. The increase in mdr86N and crt76K allele prevalence together with intense regional artemether-lumefantrine drug pressure, raises concern regarding the sustained artemether-lumefantrine efficacy. Regular, rigorous anti-malarial resistance marker surveillance across all three South African malaria-endemic provinces to inform case management is recommended.

Safety and tolerability of single low-dose primaquine in a low-intensity transmission area in South Africa: an open-label, randomized controlled trial.

BACKGROUND: To reduce onward falciparum malaria transmission, the World Health Organization recommends adding single low-dose (SLD) primaquine to artemisinin-based combination treatment in low transmission areas. However, uptake of this recommendation has been relatively slow given concerns about whether individual risks justify potential community benefit. This study was undertaken to generate comprehensive local data on the risk-benefit profile of SLD primaquine deployment in a pre-elimination area in South Africa. METHODS: This randomized, controlled open-label trial investigated adding a single low primaquine dose on day 3 to standard artemether-lumefantrine treatment for uncomplicated falciparum malaria. Efficacy, safety and tolerability of artemether-lumefantrine and primaquine treatment were assessed on days 3, 7, 14, 28 and 42. Lumefantrine concentrations were assayed from dried blood spot samples collected on day 7. RESULTS: Of 217 patients screened, 166 were enrolled with 140 randomized on day 3, 70 to each study arm (primaquine and no primaquine). No gametocytes were detected by either microscopy or PCR in any of the follow-up samples collected after randomization on day 3, precluding assessment of primaquine efficacy. Prevalence of the CYP2D6*4, CYP2D6*10 and CYP2D6*17 mutant alleles was low with allelic frequencies of 0.02, 0.11 and 0.16, respectively; none had the CYP2D6*4/*4 variant associated with null activity. Among 172 RDT-positive patients G6PD-genotyped, 24 (14%) carried the G6PD deficient (A-) variant. Median haemoglobin concentrations were similar between treatment arms throughout follow-up. A third of participants had a haemoglobin drop > 2 g/dL; this was not associated with primaquine treatment but may be associated with G6PD genotype [52.9% (9/17) with A- genotype vs. 31% (36/116) with other genotypes (p = 0.075)]. Day 7 lumefantrine concentrations and the number and nature of adverse events were similar between study arms; only one serious adverse event occurred (renal impairment in the no primaquine arm). The artemether-lumefantrine PCR-corrected adequate clinical and parasitological response rate was 100%, with only one re-infection found among the 128 patients who completed 42-day follow-up. CONCLUSIONS: Safety, tolerability, CYP2D6 and G6PD variant data from this study support the deployment of the WHO-recommended SLD primaquine without G6PD testing to advance malaria elimination in South African districts with low-intensity residual transmission. Trial registration Pan African Clinical Trial Registry, PACTR201611001859416. Registered 11 November 2016, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=1859.

Effectiveness of 24-h mobile reporting tool during a malaria outbreak in Mpumalanga Province, South Africa.

BACKGROUND: As surveillance is a key strategy for malaria elimination in South Africa, ensuring strong surveillance systems is a National Department of Health priority. Historically, real time tracking of case trends and reporting within 24 h-a requirement in South Africa's National surveillance guidelines-has not been possible. To enhance surveillance and response efficiency, a mobile surveillance tool, MalariaConnect, was developed using Unstructured Supplementary Service Data (USSD) technology. It was rolled out in health facilities in malaria endemic areas of South Africa to provide 24-h reporting of malaria cases. METHODS: To evaluate the efficiency of the mobile tool to detect an outbreak data were extracted from the paper based and MalariaConnect reporting systems in Bushbuckridge from 1 January to 18 June 2017. These data were subject to time series analyses to determine if MalariaConnect provided sufficient data reliably to detect increasing case trends reported through the paper system. The Chi squared test was used to determine goodness of fit between the following indicator data generated using MalariaConnect and paper reporting systems: timeliness, completeness, and precision. RESULTS: MalariaConnect adequately tracked case trends reported through the paper system. Timeliness of reporting increased significantly using MalariaConnect with 0.63 days to notification compared to 5.65 days using the paper-system (p < 0.05). The completeness of reporting was significantly higher for the paper system (100% completion; p < 0.05), compared to confirmed MalariaConnect cases (61%). There was a moderate association between data precision and the reporting system (p < 0.05). MalariaConnect provided an effective way of reliably and accurately identifying the onset of the malaria outbreak in Bushbuckridge. CONCLUSION: Timeliness significantly improved using MalariaConnect and in a malaria elimination setting, can be used to markedly improve case investigation and response activities within the recommended 72-h period. Although data completeness and precision were lower compared to paper reporting, MalariaConnect data can be used to trigger outbreak responses.

Evaluating a 24-h mobile reporting system for malaria notifications in comparison with a paper-based system in South Africa, 2015.

BACKGROUND: As South Africa strives to achieve malaria elimination by 2018 (zero local cases) the country needs to strengthen its disease surveillance system by reducing the timeliness from case diagnosis to notification of key stakeholders in the malaria programme. This study evaluated the feasibility of a 24-h mobile reporting system, designed for speeding up malaria notifications, from primary healthcare facilities to district, provincial, and national malaria programmes in South Africa. METHODS: A prospective descriptive study utilizing primary data collected from structured interviews with healthcare workers in public healthcare facilities was used to compare two reporting systems (24-h mobile reporting system and the paper-based reporting system) in malaria endemic provinces (Limpopo, Mpumalanga and KwaZulu-Natal). Data on completeness of reporting, simplicity, user acceptability and technical limitations were analysed. A Wilcoxon signed-rank test was used to compare the time difference between the two reporting systems. RESULTS: There were 1819 cases of malaria reported through the paper-based system, and 63.2% (1149) of those cases were also reported through the 24-h mobile reporting system. Out of the 272 healthcare workers who were interviewed, 40% (108) had seen malaria patients and reported a case through the 24-h mobile reporting system. The median time for cases to be reported through the 24-h mobile reporting system was significantly shorter at < 1 day (range < 1 to 31 days) compared to the paper-based system at 3 days (range 2 to > 39 days) (p < 0.001). It was found that 26% (28) were able to use the system and send reports within 2 min, 94% (256) were willing to continue to use the system. Of the 108 healthcare workers who reported a case, 18.5% (20) experienced network challenges. CONCLUSIONS: The 24-h mobile reporting system is user friendly and trained healthcare workers are willing to use the system, despite network limitations. The 24-h mobile reporting system reduces the time required for diagnosed cases to be notified by the health care facility to district, provincial and national levels. The 24-h mobile reporting system is a feasible option for malaria notification in South Africa and will assist with early detection of malaria outbreaks.

Serology reveals heterogeneity of Plasmodium falciparum transmission in northeastern South Africa: implications for malaria elimination.

BACKGROUND: It is widely acknowledged that modifications to existing control interventions are required if South Africa is to achieve malaria elimination. Targeting indoor residual spraying (IRS) to areas where cases have been detected is one strategy currently under investigation in northeastern South Africa. This seroprevalence baseline study, nested within a targeted IRS trial, was undertaken to provide insights into malaria transmission dynamics in South Africa and evaluate whether sero-epidemiological practices have the potential to be routinely incorporated into elimination programmes. METHODS: Filter-paper blood spots, demographic and household survey data were collected from 2710 randomly selected households in 56 study wards located in the municipalities of Ba-Phalaborwa and Bushbuckridge. Blood spots were assayed for Plasmodium falciparum apical membrane antigen-1 and merozoite surface protein-119 blood-stage antigens using an enzyme linked immunosorbent assay. Seroprevalence data were analysed using a reverse catalytic model to determine malaria seroconversion rates (SCR). Geospatial cluster analysis was used to investigate transmission heterogeneity while random effects logistic regression identified risk factors associated with malaria exposure. RESULTS: The overall SCR across the entire study site was 0.012 (95% CI 0.008-0.017) per year. Contrasting SCRs, corresponding to distinct geographical regions across the study site, ranging from <0.001 (95% CI <0.001-0.005) to 0.022 (95% CI 0.008-0.062) per annum revealed prominent transmission heterogeneity. Geospatial cluster analysis of household seroprevalence and age-adjusted antibody responses detected statistically significant (p < 0.05) spatial clusters of P. falciparum exposure. Formal secondary education was associated with lower malaria exposure in the sampled population (AOR 0.72, 95% CI 0.56-0.95, p = 0.018). CONCLUSIONS: Although overall transmission intensity and exposure to malaria was low across both study sites, malaria transmission intensity was highly heterogeneous and associated with low socio-economic status in the region. Findings suggest focal targeting of interventions has the potential to be an appropriate strategy to deploy in South Africa. Furthermore, routinely incorporating sero-epidemiological practices into elimination programmes may prove useful in monitoring malaria transmission intensity in South Africa, and other countries striving for malaria elimination.

Exploring the seasonality of reported treated malaria cases in Mpumalanga, South Africa.

South Africa, having met the World Health Organisation's pre-elimination criteria, has set a goal to achieve malaria elimination by 2018. Mpumalanga, one of three provinces where malaria transmission still occurs, has a malaria season subject to unstable transmission that is prone to sporadic outbreaks. As South Africa prepares to intensify efforts towards malaria elimination, there is a need to understand patterns in malaria transmission so that efforts may be targeted appropriately. This paper describes the seasonality of transmission by exploring the relationship between malaria cases and three potential drivers: rainfall, geography (physical location) and the source of infection (local/imported). Seasonal decomposition of the time series by Locally estimated scatterplot smoothing is applied to the case data for the geographical and source of infection sub-groups. The relationship between cases and rainfall is assessed using a cross-correlation analysis. The malaria season was found to have a short period of no/low level of reported cases and a triple peak in reported cases between September and May; the three peaks occurring in October, January and May. The seasonal pattern of locally-sourced infection mimics the triple-peak characteristic of the total series while imported infections contribute mostly to the second and third peak of the season (Christmas and Easter respectively). Geographically, Bushbuckridge municipality, which exhibits a different pattern of cases, contributed mostly to the first and second peaks in cases while Maputo province (Mozambique) experienced a similar pattern in transmission to the imported cases. Though rainfall lagged at 4 weeks was significantly correlated with malaria cases, this effect was dampened due to the growing proportion of imported cases since 2006. These findings may be useful as they enhance the understanding of the current incidence pattern and may inform mathematical models that enable one to predict the impact changes in these drivers will have on malaria transmission.

The feasibility of malaria elimination in South Africa.

BACKGROUND: Following the last major malaria epidemic in 2000, malaria incidence in South Africa has declined markedly. The decrease has been so emphatic that South Africa now meets the World Health Organization (WHO) threshold for malaria elimination. Given the Millennium Development Goal of reversing the spread of malaria by 2015, South Africa is being urged to adopt an elimination agenda. This study aimed to determine the appropriateness of implementing a malaria elimination programme in present day South Africa. METHODS: An assessment of the progress made by South Africa in terms of implementing an integrated malaria control programme across the three malaria-endemic provinces was undertaken. Vector control and case management data were analysed from the period of 2000 until 2011. RESULTS: Both malaria-related morbidity and mortality have decreased significantly across all three malaria-endemic provinces since 2000. The greatest decline was seen in KwaZulu-Natal where cases decreased from 42,276 in 2000 to 380 in 2010 and deaths dropped from 122 in 2000 to six in 2010. Although there has been a 49.2 % (8,553 vs 4,214) decrease in the malaria cases reported in Limpopo Province, currently it is the largest contributor to the malaria incidence in South Africa. Despite all three provinces reporting average insecticide spray coverage of over 80%, malaria incidence in both Mpumalanga and Limpopo remains above the elimination threshold. Locally transmitted case numbers have declined in all three malaria provinces but imported case numbers have been increasing. Knowledge gaps in vector distribution, insecticide resistance status and drug usage were also identified. CONCLUSIONS: Malaria elimination in South Africa is a realistic possibility if certain criteria are met. Firstly, there must be continued support for the existing malaria control programmes to ensure the gains made are sustained. Secondly, cross border malaria control initiatives with neighbouring countries must be strongly encouraged and supported to reduce malaria in the region and the importation of malaria into South Africa. Thirdly, operational research, particularly on vector distribution and insecticide resistance status must be conducted as a matter of urgency, and finally, the surveillance systems must be refined to ensure the information required to inform an elimination agenda are routinely collected.

Malaria control in South Africa 2000-2010: beyond MDG6.

BACKGROUND: Malaria is one of the key targets within Goal 6 of the Millennium Development Goals (MDGs), whereby the disease needs to be halted and reversed by the year 2015. Several other international targets have been set, however the MDGs are universally accepted, hence it is the focus of this manuscript. METHODS: An assessment was undertaken to determine the progress South Africa has made against the malaria target of MDG Goal 6. Data were analyzed for the period 2000 until 2010 and verified after municipal boundary changes in some of South Africa's districts and subsequent to verifying actual residence of malaria positive cases. RESULTS: South Africa has made significant progress in controlling malaria transmission over the past decade; malaria cases declined by 89.41% (63663 in 2000 vs 6741 in 2010) and deaths decreased by 85.4% (453 vs 66) in the year 2000 compared to the year 2010. Coupled with this, malaria cases among children under five years of age have also declined by 93% (6791 in 2000 vs 451 in 2010). This has resulted in South Africa achieving and exceeding the malaria target of the MDGs. A series of interventions have attributed to this decrease, these include: drug policy change from monotherapy to artemisinin combination therapy, insecticide change from pyrethroids back to DDT; cross border collaboration (South Africa with Mozambique and Swaziland through the Lubombo Spatial Development Initiative- LSDI) and financial investment in malaria control. The KwaZulu-Natal Province has seen the largest reduction in malaria cases and deaths (99.1% cases- 41786 vs 380; and 98.5% deaths 340 vs 5), when comparing the year 2000 with 2010. The Limpopo Province recorded the lowest reduction in malaria cases compared to the other malaria endemic provinces (56.1% reduction- 9487 vs 4174; when comparing 2000 to 2010). CONCLUSIONS: South Africa is well positioned to move beyond the malaria target of the MDGs and progress towards elimination. However, in addition to its existing interventions, the country will need to sustain its financing for malaria control and support programmed reorientation towards elimination and scale up active surveillance coupled with treatment at the community level. Moreover cross-border malaria collaboration needs to be sustained and scaled up to prevent the re-introduction of malaria into the country.

Knowledge and practices towards malaria amongst residents of Bushbuckridge, Mpumalanga, South Africa

Background: Malaria remains one of the greatest public health challenges worldwide and it is amongst the top killers in sub-Saharan Africa. There is however, a general scepticism about the accuracy of Health Management Information Systems (HMIS) in recording all the episodes of malaria in Africa. Given the importance of community knowledge of malaria, its signs and symptoms, as well as prompt treatment-seeking behaviour, the study assessing adult residents' knowledge and practices in Bushbuckridge provided much needed insights into the Malaria Control Programme (MCP). Objectives: The objectives of this study were to determine the adult residents' knowledge and practices towards malaria in Bushbuckridge, Mpumalanga Province, South Africa. Method: The study was undertaken as a descriptive cross-sectional survey in Bushbuckridge in August 2008. Six hundred and two (602) household heads or their proxies from the randomly selected households in 20 localities were interviewed (one household member per household), using a structured field-piloted questionnaire. Results: Approximately 93% of the respondents had heard about malaria, 84.6% of whom correctly associated it with mosquito bites. The health facility (29.1%) and radio (19.8%) were the main sources of malaria information. Knowledge of signs and symptoms was low, whilst treatment-seeking intention at the health facility was high (99%) with 82% of which would be carried out promptly. Survey data showed an indoor residual spraying (IRS) coverage of approximately 70% and a good understanding of the reasons for spraying. Walls were re-plastered infrequently and no evidence was established linking it to the removal of insecticide marks on the wall. Conclusion: The study revealed not only that householders possessed an adequate knowledge of malaria, but also that they had positive malaria treatment-seeking intentions. Their knowledge of malaria signs and symptoms was inadequate and required attention. Whilst IRS coverage needed some improvements, the reasons for IRS were well known

Household and microeconomic factors associated with malaria in Mpumalanga, South Africa.

A household matched case-control study design was used to explore associations between household characteristics and malaria risk in seven study towns in the hypoendemic area of Mpumalanga Province, South Africa. Controls were identified from neighboring households of each case. Principle component analysis was used to calculate a wealth index for households to allow comparison across socioeconomic groups. Conditional univariate and multiple logistic regression analyses were used to assess associations between household malaria risk and potential risk factors. Univariate analysis demonstrated an increased household malaria risk for people living in mud-walled houses compared with those in brick dwellings (OR=5.10, 95% CI 2.03-12.80, P=0.001). Multivariate analysis confirmed the association between malaria risk and mud-wall construction (OR=6.12, 95% CI 2.26-16.59, P=0.001) and demonstrated an association with opening windows after retiring to sleep (OR=4.01, 95% CI 1.32-12.18, P=0.014). An inverse association between household wealth, third (OR=0.24, 95% CI 0.09-0.65, P=0.005) and fourth quartiles (OR=0.27, 95% CI 0.10-0.79, P=0.016), and malaria risk was observed. Associations found here include increased household malaria risk and mud-wall construction, the practice of opening of windows at night and relative household poverty. Education campaigns targeting risk behavior may reduce malaria risk, but economic development is a more important intervention.

Using the SaTScan method to detect local malaria clusters for guiding malaria control programmes.

BACKGROUND: Mpumalanga Province, South Africa is a low malaria transmission area that is subject to malaria epidemics. SaTScan methodology was used by the malaria control programme to detect local malaria clusters to assist disease control planning. The third season for case cluster identification overlapped with the first season of implementing an outbreak identification and response system in the area. METHODS: SaTScan software using the Kulldorf method of retrospective space-time permutation and the Bernoulli purely spatial model was used to identify malaria clusters using definitively confirmed individual cases in seven towns over three malaria seasons. Following passive case reporting at health facilities during the 2002 to 2005 seasons, active case detection was carried out in the communities, this assisted with determining the probable source of infection. The distribution and statistical significance of the clusters were explored by means of Monte Carlo replication of data sets under the null hypothesis with replications greater than 999 to ensure adequate power for defining clusters. RESULTS AND DISCUSSION: SaTScan detected five space-clusters and two space-time clusters during the study period. There was strong concordance between recognized local clustering of cases and outbreak declaration in specific towns. Both Albertsnek and Thambokulu reported malaria outbreaks in the same season as space-time clusters. This synergy may allow mutual validation of the two systems in confirming outbreaks demanding additional resources and cluster identification at local level to better target resources. CONCLUSION: Exploring the clustering of cases assisted with the planning of public health activities, including mobilizing health workers and resources. Where appropriate additional indoor residual spraying, focal larviciding and health promotion activities, were all also carried out.

Increased gametocytemia after treatment: an early parasitological indicator of emerging sulfadoxine-pyrimethamine resistance in falciparum malaria.

BACKGROUND: Although malaria treatment aims primarily to eliminate the asexual blood stages that cause illness, reducing the carriage of gametocytes is critical for limiting malaria transmission and the spread of resistance. METHODS: Clinical and parasitological responses to the fixed-dose combination of sulfadoxine and pyrimethamine in patients with uncomplicated falciparum malaria were assessed biannually since implementation of this treatment policy in 1998 in Mpumalanga Province, South Africa. RESULTS: Despite sustained cure rates of > 90% (P = .14), the duration of gametocyte carriage increased from 3 to 22 weeks (per 1000 person-weeks) between 1998 and 2002 (P < .001). The dhfr and dhps mutations associated with sulfadoxine-pyrimethamine resistance were the most important drivers of the increased gametocytemia, although these mutations were not associated with increased pretreatment asexual parasite density or slower asexual parasite clearance times. The geometric mean gametocyte duration and area under the gametocyte density time curve (per 1000 person-weeks) were 7.0 weeks and 60.8 gametocytes/microL per week, respectively, among patients with wild-type parasites, compared with 45.4 weeks (P = .016) and 1212 gametocytes/microL per week (P = .014), respectively, among those with parasites containing 1-5 dhfr/dhps mutations. CONCLUSIONS: An increased duration and density of gametocyte carriage after sulfadoxine-pyrimethamine treatment was an early indicator of drug resistance. This increased gametocytemia among patients who have primary infections with drug-resistant Plasmodium falciparum fuels the spread of resistance even before treatment failure rates increase significantly.

Evaluation of an operational malaria outbreak identification and response system in Mpumalanga Province, South Africa.

BACKGROUND AND OBJECTIVE: To evaluate the performance of a novel malaria outbreak identification system in the epidemic prone rural area of Mpumalanga Province, South Africa, for timely identification of malaria outbreaks and guiding integrated public health responses. METHODS: Using five years of historical notification data, two binomial thresholds were determined for each primary health care facility in the highest malaria risk area of Mpumalanga province. Whenever the thresholds were exceeded at health facility level (tier 1), primary health care staff notified the malaria control programme, which then confirmed adequate stocks of malaria treatment to manage potential increased cases. The cases were followed up at household level to verify the likely source of infection. The binomial thresholds were reviewed at village/town level (tier 2) to determine whether additional response measures were required. In addition, an automated electronic outbreak identification system at town/village level (tier 2) was integrated into the case notification database (tier 3) to ensure that unexpected increases in case notification were not missed.The performance of these binomial outbreak thresholds was evaluated against other currently recommended thresholds using retrospective data. The acceptability of the system at primary health care level was evaluated through structured interviews with health facility staff. RESULTS: Eighty four percent of health facilities reported outbreaks within 24 hours (n = 95), 92% (n = 104) within 48 hours and 100% (n = 113) within 72 hours. Appropriate response to all malaria outbreaks (n = 113, tier 1, n = 46, tier 2) were achieved within 24 hours. The system was positively viewed by all health facility staff. When compared to other epidemiological systems for a specified 12 month outbreak season (June 2003 to July 2004) the binomial exact thresholds produced one false weekly outbreak, the C-sum 12 weekly outbreaks and the mean + 2 SD nine false weekly outbreaks. Exceeding the binomial level 1 threshold triggered an alert four weeks prior to an outbreak, but exceeding the binomial level 2 threshold identified an outbreak as it occurred. CONCLUSION: The malaria outbreak surveillance system using binomial thresholds achieved its primary goal of identifying outbreaks early facilitating appropriate local public health responses aimed at averting a possible large-scale epidemic in a low, and unstable, malaria transmission setting.

Malaria pharmacovigilance in Africa: lessons from a pilot project in Mpumalanga Province, South Africa.

BACKGROUND AND OBJECTIVES: Prior to the introduction of artemisinin-based combination antimalarial therapy in Mpumalanga province, South Africa, a pharmacovigilance strategy was developed to pilot locally relevant surveillance methods for detecting serious adverse drug reactions (ADRs) and signals related to artesunate plus sulfadoxine/pyrimethamine. STUDY DESIGN: From 1 March 2002 to 30 June 2004, five methods for detecting ADRs in patients receiving antimalarials were piloted in the rural communities of Mpumalanga province in South Africa: (i) home follow-up of patients by malaria control staff; (ii) enhanced spontaneous reporting of suspected ADRs by health professionals at clinics and hospitals; (iii) active hospital surveillance for malaria-related admissions and patients recently treated for malaria; (iv) a confidential enquiry into malaria-related deaths; and (v) adverse events monitoring during two therapeutic efficacy studies conducted in 2002 and 2004. RESULTS: During the study period, the malaria control programme was notified of 4778 cases of malaria while sulfadoxine/pyrimethamine monotherapy was the recommended treatment and 7692 cases after the introduction of artesunate plus sulfadoxine/pyrimethamine in January 2003. Of 2393 home follow-up visits of reported cases of malaria, three fatal adverse events were identified where recent use of artesunate plus sulfadoxine/pyrimethamine treatment was reported. Two cases were attributed to poor response to treatment, while one case was considered possibly related to artesunate plus sulfadoxine/pyrimethamine treatment. Clinic and hospital surveillance reported six ADRs in association with sulfadoxine/pyrimethamine treatment, five being treatment failures and one being a non-serious rash. During active hospital surveillance, 38 inpatients exposed to sulfadoxine/pyrimethamine were identified, including one child who experienced pancytopenia following treatment with sulfadoxine/pyrimethamine 11 days before admission; this adverse effect was considered to be possibly due to sulfadoxine/pyrimethamine treatment. The confidential enquiry into malaria-related deaths identified three adverse events, including a death where the contribution of treatment could not be excluded. A therapeutic efficacy study of 95 patients followed over 42 days identified one case of repeated vomiting possibly associated with artesunate plus sulfadoxine/pyrimethamine. CONCLUSION: Multifaceted monitoring throughout the malaria patient journey is necessary in developing countries implementing new treatments to safeguard against missing serious complications associated with malaria treatment.