Effectiveness of shortcourse quinine and singledose sulfadoxinepyrimethamine in the treatment of Plasmodium falciparum malaria in Mpumalanga Province, South Africa

Introduction. Quinine therapy for 7 days remains the mainstay for treating hospitalised malaria cases in South Africa. However, limited resources, including available beds and staff, often result in early discharge of non-severe cases, with quinine tablets for outpatient use. The effectiveness of shorter course quinine therapy coupled with a long-acting antimalarial drug has never been established in Africa, in particular in a population without malaria immunity.Methods. A study was conducted to evaluate the effectiveness of a 3-day course of therapy with quinine sulphate (10 mg/ kg 8-hourly) followed by a single dose of sulfadoxinepyrimethamine (SP) according to weight category, before discharge, for 133 hospitalised patients with uncomplicated Plasmodium falciparum malaria at Shongwe Hospital, Mpumalanga province, between February and July 1998. Study endpoints included clinical recovery and parasitological cure, including polymerase chain reaction (PCR) 42 days after initiating treatment.Results. One hundred and thirty of 131 patients (99%) successfully followed up for 42 days demonstrated clinical and parasitological cure. The remaining patient, who had evidence of a recrudescent infection on PCR, was 1 of 61 patients who were still parasitaemic on discharge from hospital.Conclusion. The abbreviated course of quinine therapy coupled with a single dose of SP for the treatment of nonsevere hospitalised cases of P. falciparum malaria, in an area with demonstrated low levels of SP resistance, was highly effective. This approach has potential benefits, including reduced duration of hospitalisation, fewer quinine-associated adverse events and protection against the evolution of quinine resistance by limiting unsupervised quinine therapy in the community. It may, however, be prudent to document a negative blood film before discharge from hospital

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

Therapeutic efficacy of sulfadoxine-pyrimethamine for plasmodium falciparum malaria

Objectives. To assess the therapeutic efficacy of sulfadoxinepyrimethamine (SP) after 5 years of use as first-line treatment of uncomplicated Plasmodium falciparum malaria, and thus guide the selection of artemisinin-based combination therapy in Mpumalanga, South Africa. Design. An open-label, in vivo therapeutic efficacy study of patients with uncomplicated P. falciparum malaria treated with a single oral dose of SP, with response to treatment monitored clinically and parasitologically on days 1, 2, 3, 7, 14, 21, 28 and 42. Setting. Mangweni and Naas public health care clinics, Tonga district in rural Mpumalanga. Subjects, outcome measures and results. Of 152 patients recruited sequentially, 149 (98%) were successfully followed up for 42 days. One hundred and thirty-four patients (90%) demonstrated adequate clinical and parasitological response. Of the 15 patients (10%) who failed treatment, 2 (1.3%) had an early treatment failure, and polymerase chain reaction confirmed recrudescent infection in all 13 patients (8.7%) who had late parasitological (N = 11) or clinical (N = 2) failure. Gametocyte carriage was prevalent following SP treatment (84/152) and this has increased significantly since implementation in 1998 (relative risk 2.77 (confidence interval 1.65 - 4.66); p = 0.00004). Conclusion. Asexual P. falciparum parasites in Mpumalanga remain sensitive to SP, with no significant difference between the baseline cure rate (94.5%) at introduction in 1998, and the present 90% cure rate (p = 0.14). However, since gametocyte carriage has increased significantly we recommend that SP be combined with artesunate in Mpumalanga to reduce gametocyte carriage and thus decrease malaria transmission and potentially delay antimalarial resistance. S Afr Med J 2005; 95: 346-349

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

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

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

Abstract 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=185

Predicting malaria cases using remotely sensed environmental variables in Nkomazi, South Africa

There has been a conspicuous increase in malaria cases since 2016/2017 over the three malaria-endemic provinces of South Africa. This increase has been linked to climatic and environmental factors. In the absence of adequate traditional environmental/climatic data covering ideal spatial and temporal extent for a reliable warning system, remotely sensed data are useful for the investigation of the relationship with, and the prediction of, malaria cases. Monthly environmental variables such as the normalised difference vegetation index (NDVI), the enhanced vegetation index (EVI), the normalised difference water index (NDWI), the land surface temperature for night (LSTN) and day (LSTD), and rainfall were derived and evaluated using seasonal autoregressive integrated moving average (SARIMA) models with different lag periods. Predictions were made for the last 56 months of the time series and were compared to the observed malaria cases from January 2013 to August 2017. All these factors were found to be statistically significant in predicting malaria transmission at a 2-months lag period except for LSTD which impact the number of malaria cases negatively. Rainfall showed the highest association at the two-month lag time (r=0.74; P<0.001), followed by EVI (r=0.69; P<0.001), NDVI (r=0.65; P<0.001), NDWI (r=0.63; P<0.001) and LSTN (r=0.60; P<0.001). SARIMA without environmental variables had an adjusted R2 of 0.41, while SARIMA with total monthly rainfall, EVI, NDVI, NDWI and LSTN were able to explain about 65% of the variation in malaria cases. The prediction indicated a general increase in malaria cases, predicting about 711 against 648 observed malaria cases. The development of a predictive early warning system is imperative for effective malaria control, prevention of outbreaks and its subsequent elimination in the region

Making data map-worthy—enhancing routine malaria data to support surveillance and mapping of <i>Plasmodium falciparum</i> 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.</br

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$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