Antimalarial drugs are key tools for the control and elimination of malaria. Recent decreases in the global malaria burden are likely due, in part, to the deployment of artemisinin-based combination ...therapies. Therefore, the emergence and potential spread of artemisinin-resistant parasites in southeast Asia and changes in sensitivities to artemisinin partner drugs have raised concerns. In recognition of this urgent threat, the International Centers of Excellence for Malaria Research (ICEMRs) are closely monitoring antimalarial drug efficacy and studying the mechanisms underlying drug resistance. At multiple sentinel sites of the global ICEMR network, research activities include clinical studies to track the efficacies of antimalarial drugs, ex vivo/in vitro assays to measure drug susceptibilities of parasite isolates, and characterization of resistance-mediating parasite polymorphisms. Taken together, these efforts offer an increasingly comprehensive assessment of the efficacies of antimalarial therapies, and enable us to predict the emergence of drug resistance and to guide local antimalarial drug policies. Here we briefly review worldwide antimalarial drug resistance concerns, summarize research activities of the ICEMRs related to drug resistance, and assess the global impacts of the ICEMR programs.
Asymptomatic reservoirs of malaria parasites are common yet are difficult to detect, posing a problem for malaria control. If control programmes focus on mosquito control and treatment of symptomatic ...individuals only, malaria can quickly resurge if interventions are scaled back. Foci of parasite populations must be identified and treated. Therefore, an active case detection system that facilitates detection of asymptomatic parasitaemia and gametocyte carriers was developed and tested in the Macha region in southern Zambia.
Each week, nurses at participating rural health centres (RHC) communicated the number of rapid diagnostic test (RDT) positive malaria cases to a central research team. During the dry season when malaria transmission was lowest, the research team followed up each positive case reported by the RHC by a visit to the homestead. The coordinates of the location were obtained by GPS and all consenting residents completed a questionnaire and were screened for malaria using thick blood film, RDT, nested-PCR, and RT-PCR for asexual and sexual stage parasites. Persons who tested positive by RDT were treated with artemether/lumefantrine (Coartem). Data were compared with a community-based study of randomly selected households to assess the prevalence of asymptomatic parasitaemia in the same localities in September 2009.
In total, 186 and 141 participants residing in 23 case and 24 control homesteads, respectively, were screened. In the case homesteads for which a control population was available (10 of the 23), household members of clinically diagnosed cases had a 8.0% prevalence of malaria using PCR compared to 0.7% PCR positive individuals in the control group (p = 0.006). The case and control groups had a gametocyte prevalence of 2.3% and 0%, respectively but the difference was not significant (p = 0.145).
This pilot project showed that active case detection is feasible and can identify reservoirs of asymptomatic infection. A larger sample size, data over multiple low transmission seasons, and in areas with different transmission dynamics are needed to further validate this approach.
The World Health Organization recommends the provision of intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) at 4-week intervals from gestational week 13 to ...delivery in areas of moderate to high malaria transmission intensity. However, the effect of IPTp-SP has been compromised in some areas due to parasite resistance, raising the importance of parasitological and chemoprophylactic surveillance, and monitoring SP-resistance markers in the Plasmodium falciparum population.
Between November 2013 and April 2014 in Nchelenge, Zambia, 1086 pregnant women received IPTp-SP at antenatal-care bookings. Blood samples were collected on day 0, and on day 28 post-treatment to test for malaria parasites and to estimate SP parasitological efficacy in the treatment and prevention of parasitaemia. A random sample of 96, day 0 malaria-positive samples were analysed to estimate the prevalence of SP-resistance markers in the P. falciparum population.
The overall parasitological and prophylactic failure among women who had paired day 0 and day 28 blood slides was 18.6% (95% CI 15.5, 21.8; 109 of 590). Among pregnant women who had asymptomatic parasitaemia on day 0, the day 28 PCR-uncorrected parasitological failure was 30.0% (95% CI 23.7, 36.2; 62 of 207) and the day 28 PCR-corrected parasitological failure was 15.6% (95% CI: 10.6, 20.6; 32 of 205). Among women who tested negative at day 0, 12.3% (95% CI: 9.0, 15.6; 47 of 383) developed parasitaemia at day 28. Among the 96 malaria-positive samples assayed from day 0, 70.8% (95% CI: 60.8, 79.2) contained the DHPS double (Gly-437 + Glu-540) mutation and 92.7% (95% CI: 85.3, 96.5) had the DHFR triple (Asn-108 + Ile-51 + Arg-59) mutation. The quintuple mutation (DHFR triple + DHPS double) and the sextuple mutant (DHFR triple + DHPS double + Arg-581) were found among 68.8% (95% CI: 58.6, 77.3) and 9.4% (95% CI: 4.2, 16.0) of samples, respectively.
The parasitological and chemoprophylactic failure of SP, and the prevalence of resistance markers in Nchelenge is alarmingly high. Alternative therapies are urgently needed to safeguard pregnant women against malarial infection.
Zimbabwe is one of the thirty countries globally with a high burden of multidrug-resistant tuberculosis (TB) or rifampicin-resistant TB (MDR/RR-TB). Since 2010, patients diagnosed with MDR/RR-TB are ...being treated with 20-24 months of standardized second-line drugs (SLDs). The profile, management and factors associated with unfavourable treatment outcomes of MDR/RR TB have not been systematically evaluated in Zimbabwe.
To assess treatment outcomes and factors associated with unfavourable outcomes among MDR/RR-TB patients registered and treated under the National Tuberculosis Programme in all the district hospitals and urban healthcare facilities in Zimbabwe between January 2010 and December 2015.
A cohort study using routinely collected programme data. The 'death', 'loss to follow-up' (LTFU), 'failure' and 'not evaluated' were considered as "unfavourable outcome". A generalized linear model with a log-link and binomial distribution or a Poisson distribution with robust error variances were used to assess factors associated with "unfavourable outcome". The unadjusted and adjusted relative risks were calculated as a measure of association. A 𝑝value< 0.05 was considered statistically significant.
Of the 473 patients in the study, the median age was 34 years interquartile range, 29-42 and 230 (49%) were males. There were 352 (74%) patients co-infected with HIV, of whom 321 (91%) were on antiretroviral therapy (ART). Severe adverse events (SAEs) were recorded in 118 (25%) patients; mostly hearing impairments (70%) and psychosis (11%). Overall, 184 (39%) patients had 'unfavourable' treatment outcomes 125 (26%) were deaths, 39 (8%) were lost to follow-up, 4 (<1%) were failures and 16 (3%) not evaluated. Being co-infected with HIV but not on ART adjusted relative risk (aRR) = 2.60; 95% CI: 1.33-5.09 was independently associated with unfavourable treatment outcomes.
The high unfavourable treatment outcomes among MDR/RR-TB patients on standardized SLDs were coupled with a high occurrence of SAEs in this predominantly HIV co-infected cohort. Switching to individualized all oral shorter treatment regimens should be considered to limit SAEs and improve treatment outcomes. Improving the ART uptake and timeliness of ART initiation can reduce unfavourable outcomes.
Insecticide-treated nets (ITNs) reduce malaria morbidity and mortality in endemic areas. Despite increasing availability, the use of ITNs remains limited in some settings. Poor malaria knowledge is a ...barrier to the widespread use of ITNs. The goal of this study was to assess the levels of malaria knowledge and evaluate factors associated with bed net use among individuals residing in three regions of southern Africa with different levels of malaria transmission and control.
A cross-sectional study was conducted on a sample of 7535 residents recruited from 2066 households in Mutasa District, Zimbabwe (seasonal malaria transmission), Choma District, Zambia (low transmission) and Nchelenge District, Zambia (high transmission), between March 2012 and March 2017. A standardized questionnaire was used to collect data on demographics, malaria-related knowledge and use of preventive measures. Multivariate logistic regression analyses were used to assess determinants of bed net use.
Most of the 3836 adult participants correctly linked mosquito bites to malaria (85.0%), mentioned at least one malaria symptom (95.5%) and knew of the benefit of sleeping under an ITN. Bed net ownership and use were highest in Choma and Nchelenge Districts and lowest in Mutasa District. In multivariate analyses, knowledge of ITNs was associated with a 30-40% increased likelihood of bed net use after adjusting for potential confounders across all sites. Other factors significantly associated with bed net use were age, household size and socioeconomic status, although the direction, strength and size of association varied by study site. Importantly, participants aged 5-14 years had reduced odds of sleeping under a bed net compared to children younger than 5 years.
Relevant knowledge of ITNs translated into the expected preventive behaviour of sleeping under a bed net, underscoring the need for continued health messaging on malaria prevention. The implementation and delivery of malaria control and elimination interventions needs to consider socioeconomic equity gaps, and target school-age children to ensure access to and improve utilization of ITNs.
Human mobility is a driver for the reemergence or resurgence of malaria and has been identified as a source of cross-border transmission. However, movement patterns are difficult to measure in rural ...areas where malaria risk is high. In countries with malaria elimination goals, it is essential to determine the role of mobility on malaria transmission to implement appropriate interventions.
A study was conducted in Mutasa District, Zimbabwe, to investigate human movement patterns in an area of persistent transmission along the Mozambique border. Over 1 year, a convenience sample of 20 participants/month was recruited from active malaria surveillance cohorts to carry an IgotU
GT-600 global positioning system (GPS) data logger during all daily activities. Consenting participants were tested for malaria at data logger distribution using rapid antigen diagnostic tests and completed a survey questionnaire. GPS data were analyzed using a trajectory analysis tool, and participant movement patterns were characterized throughout the study area and across the border into Mozambique using movement intensity maps, activity space plots, and statistical analyses.
From June 2016-May 2017, 184 participants provided movement tracks encompassing > 350,000 data points and nearly 8000 person-days. Malaria prevalence at logger distribution was 3.7%. Participants traveled a median of 2.8 km/day and spent a median of 4.6 h/day away from home. Movement was widespread within and outside the study area, with participants traveling up to 500 km from their homes. Indices of mobility were higher in the dry season than the rainy season (median km traveled/day = 3.5 vs. 2.2, P = 0.03), among male compared to female participants (median km traveled/day = 3.8 vs. 2.0, P = 0.0008), and among adults compared to adolescents (median total km traveled = 104.6 vs. 59.5, P = 0.05). Half of participants traveled outside the study area, and 30% traveled into Mozambique, including 15 who stayed in Mozambique overnight.
Study participants in Mutasa District, Zimbabwe, were highly mobile throughout the year. Many participants traveled long distances from home, including overnight trips into Mozambique, with clear implications for malaria control. Interventions targeted at mobile populations and cross-border transmission may be effective in preventing malaria introductions in this region.
Abstract
Background
In 2002, Zambia withdrew chloroquine as first-line treatment for
Plasmodium falciparum
malaria due to increased treatment failure and worldwide spread of chloroquine resistance. ...The artemisinin combination regimen, artemether–lumefantrine, replaced chloroquine (CQ) as first choice malaria treatment. The present study determined the prevalence of CQ resistance molecular markers in the
Pfcrt
and
Pfmdr1
genes in Eastern Zambia at 9 and 13 years after the removal of drug pressure.
Methods
Samples collected from Katete District during the drug therapeutic efficacy assessments conducted in 2012 and 2016 were assayed by polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLP) to determine the prevalence of genetic mutations, K76T on the
Pfcrt
gene and N86Y on the
Pfmdr1
gene. A total of 204
P. falciparum
-positive DBS samples collected at these two time points were further analysed.
Results
Among the samples analysed for
Pfcrt
K76T and
Pfmdr1
N86Y in the present study, 112 (82.4%)
P. falciparum-
infected samples collected in 2012 were successfully amplified for
Pfcrt
and 94 (69.1%) for
Pfmdr1
, while 69 (65.7%) and 72 (68.6%) samples from 2016 were successfully amplified for
Pfcrt
and
Pfmdr1
, respectively. In 2012, the prevalence of
Pfcrt
76K (sensitive) was 97.3%, 76T (resistant) was 1.8%, and 0.8% had both 76K and 76T codons (mixed). Similarly in 2012, the prevalence of
Pfmdr1
86N (sensitive) was 97.9% and 86Y (resistant) was 2.1%. In the 2016 samples, the prevalence of the respective samples was 100%
Pfcrt
76K and
Pfmdr1
86N.
Conclusion
This study shows that there was a complete recovery of chloroquine-sensitive parasites by 2016 in Katete District, Eastern Zambia, 13 years following the withdrawal of CQ in the country. These findings add to the body of evidence for a fitness cost in CQ-resistant
P. falciparum
in Zambia and elsewhere. Further studies are recommended to monitor resistance countrywide and explore the feasibility of integration of the former best anti-malarial in combination therapy in the future.
Microscopy and rapid diagnostic tests (RDTs) are the main techniques used to diagnose malaria. While microscopy is considered the gold standard, RDTs have established popularity as they allow for ...rapid diagnosis with minimal technical skills. This study aimed to compare the diagnostic performance of two Plasmodium falciparum histidine-rich protein 2 (PfHRP2)-based RDTs (Paracheck Pf® Test (Paracheck) and Malaria Pf™ ICT (ICT)) to polymerase chain reaction (PCR) in a community survey.
A cross-sectional study was conducted between October 2012 and December 2014 in Mutasa District, Manicaland Province, eastern Zimbabwe. Households were randomly selected using satellite imagery, and 224 households were visited. Residents present in the household on the date of the visit were recruited for the study. Participants of all age groups from the selected households were screened with Paracheck and ICT RDTs in parallel. Dried blood spots (DBS) and thin and thick smears were collected. Parasite DNA extracted from the DBS was subjected to nested PCR targeting the Plasmodium cytochrome b mitochondrial gene. Data analysis was performed using the Cohen's Kappa test to determine the interrater agreement and the sensitivity and specificity of the diagnostic test were reported.
Results from a total of 702 participants were analysed. Most were females, 397 (57%), and the median age of participants was 21 years with an interquartile range of 9-39 years. Of those who were screened, 8 (1.1%), 35 (5.0%), and 21 (2.9%) were malaria parasite positive by microscopy, RDT and PCR, respectively. Paracheck and ICT RDTs had a 100% agreement. Comparing RDT and PCR results, 34 participants (4.8%) had discordant results. Most of the discordant cases were RDT positive but PCR negative (n = 24). Half of those RDT positive, but PCR negative individuals reported anti-malarials to use in the past month, which is significantly higher than reported anti-malarial drug use in the population (p < 0.001). The participant was febrile on the day of the visit, but relying on PfHRP2-based RDT would miss this case. Among the diagnostic methods evaluated, with reference to PCR, the sensitivity was higher with the RDT (52.4%) while specificity was higher with the microscopy (99.9%). The positive predictive value (PPV) was higher with the microscopy (87.5%), while the negative predictive values were similar for both microscopy and RDTs (98%). Overall, a strong correlated agreement with PCR was observed for the microscopy (97.9%) and the RDTs (95.2%).
Paracheck and ICT RDTs showed 100% agreement and can be used interchangeably. As malaria transmission declines and Zimbabwe aims to reach malaria elimination, management of infected individuals with low parasitaemia as well as non-P. falciparum infection can be critical.
The burden of malaria has decreased dramatically within the past several years in parts of sub-Saharan Africa. Further malaria control will require targeted control strategies based on evidence of ...risk. The objective of this study was to identify environmental risk factors for malaria transmission using remote sensing technologies to guide malaria control interventions in a region of declining burden of malaria.
Satellite images were used to construct a sampling frame for the random selection of households enrolled in prospective longitudinal and cross-sectional surveys of malaria parasitaemia in Southern Province, Zambia. A digital elevation model (DEM) was derived from the Shuttle Radar Topography Mission version 3 DEM and used for landscape characterization, including landforms, elevation, aspect, slope, topographic wetness, topographic position index and hydrological models of stream networks.
A total of 768 individuals from 128 randomly selected households were enrolled over 21 months, from the end of the rainy season in April 2007 through December 2008. Of the 768 individuals tested, 117 (15.2%) were positive by malaria rapid diagnostic test (RDT). Individuals residing within 3.75 km of a third order stream were at increased risk of malaria. Households at elevations above the baseline elevation for the region were at decreasing risk of having RDT-positive residents. Households where new infections occurred were overlaid on a risk map of RDT positive households and incident infections were more likely to be located in high-risk areas derived from prevalence data. Based on the spatial risk map, targeting households in the top 80th percentile of malaria risk would require malaria control interventions directed to only 24% of the households.
Remote sensing technologies can be used to target malaria control interventions in a region of declining malaria transmission in southern Zambia, enabling a more efficient use of resources for malaria elimination.
More than half of malaria cases in Zimbabwe are concentrated in Manicaland Province, where seasonal malaria epidemics occur despite intensified control strategies. Recently, high levels of pyrethroid ...and carbamate resistance were detected in Anopheles funestus, the major malaria vector in eastern Zimbabwe. In response, a single round of indoor residual spraying (IRS) using pirimiphos-methyl (an organophosphate) was implemented in four high burden districts of Manicaland Province from November 1, 2014 to December 19, 2014. The objective of this study was to evaluate the effect of this programmatic switch in insecticides on malaria morbidity reported from health care facilities in Mutasa District, one of the worst affected districts in Manicaland Province.
The number of weekly malaria cases for each health facility 24 months prior to the 2014 IRS campaign and in the subsequent high transmission season were obtained from passive case surveillance. Environmental variables were extracted from remote-sensing data sources and linked to each health care facility. Negative binomial regression was used to model the weekly number of malaria cases, adjusted for seasonality and environmental variables.
From December 2012 to May 2015, 124,206 malaria cases were reported from 42 health care facilities in Mutasa District. Based on a higher burden of malaria, 20 out of 31 municipal wards were sprayed in the district. Overall, 87.3% of target structures were sprayed and 92.1% of the target population protected. During the 6 months after the 2014 IRS campaign, a period when transmission would have otherwise peaked, the incidence of malaria was 38% lower than the preceding 24 months at health facilities in the sprayed wards.
Pirimiphos-methyl had a measurable impact on malaria incidence and is an effective insecticide for the control of An. funestus in eastern Zimbabwe.
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