The Cambodia Research Consortium: expediting research for malaria elimination with the emergency response to artemisinin resistance framework.

This commentary offers insight into how to best address barriers that may hinder the translation of malaria research findings into policy. It also proposes viable methods of implementing these policies in Cambodia. Currently, a wide range of malaria research is being conducted by in-country stakeholders, including Cambodia's National Programme for Parasitology, Entomology and Malaria Control's (CNM), non-governmental organizations, and academic institutions. Coordinating research amongst these partners, as well as within the Ministry of Health, is a challenge. Results are rarely disseminated widely and seldom inform programme and policy decisions. CNM and its research partners have severely limited access to each other's databases. This lack of accessibility, timeliness, engagement and cooperation between CNM and its partners greatly impacts overall research efficiency in this field, and is stifling innovation both within and beyond CNM. Cambodia has set a goal to eradicate all forms of malaria by 2030. As countries approach the elimination phase, there is a greater need for sharing research-generated evidence amongst partners, in order to ensure that appropriate and impactful activities are conducted. The Cambodian Research Consortium was established to serve as a framework for partners, stakeholders and researchers to share research projects, information and results, and to promote the goals of CNM. The sharing of malaria research results will help to inform prevention, control and elimination activities in the country. It will also determine and address the country's operational research needs, and could potentially become a framework model to be used in other countries aiming to transition from malaria control to elimination.

Establishing research priorities for malaria elimination in the context of the emergency response to artemisinin resistance framework-the Cambodian approach.

BACKGROUND: Countries of the greater Mekong subregion have made a transition from malaria control to an aim for falciparum and vivax malaria elimination. The elimination of falciparum malaria will have to be achieved against a background of increasing artemisinin and multi-drug resistance. This ambitious goal requires an operational research (OR) agenda that addresses the dynamic challenges encountered on the path to elimination, which will need to be flexible and developed in close relation with the cambodian national programme for parasitology, entomology and malaria control (CNM). In Cambodia, a number of meetings with stakeholders were convened by the CNM and emergency response to artemisinin resistance (ERAR) hub, producing an initial list of priority OR topics. The process and outcome of these meetings are described, which could serve as a template for other countries in the region. METHODS: A landscaping exercise was conducted to gather all past, on-going and planned malaria focussed OR activities conducted by the cambodian research consortium in Cambodia and categorized according to research theme. The six themes included (1) malaria epidemiology, surveillance and response, (2) malaria case management, (3) malaria vector control, (4) malaria behavioural issues, (5) malaria clinical studies, and (6) other vector-borne diseases (dengue, neglected tropical diseases, soil-transmitted helminths). The different themes were discussed in small focus groups, which made an initial prioritization list which was then presented to a plenary group for further discussion. This produced a list of research questions ranked according to priority. RESULTS: OR priorities produced by the thematic groups were discussed in the plenary meeting and given a priority score by group voting. A list of 17 OR questions were developed, finalized and listed, which included questions on surveillance, active case detection and treatment efficacy. CONCLUSION: This paper describes ERAR's work on supporting Cambodia's transition to malaria elimination by identifying national operational research priorities. ERAR has initiated and currently plays a critical role in the development of country specific research agendas for malaria elimination. The first example of this has been the described exercise in Cambodia, which could serve a template for setting OR priorities in the wider region.

Providing information for decision-making in the Nigerian Polio Eradication Program, 2016-2020.

Nigeria made a coordinated effort to be certified by the World Health Organization's African Region for interrupting endemic transmission of wild poliovirus type-1 (WPV1) in August 2020 as a response to the resurgence of WPV1 cases in August 2016 after going two years without a case. The NEOC Data Working Group (DWG) was instrumental in providing quality and timely surveillance and campaign information for decision-making in order to interrupt WPV1 transmission and provide data toward documentation of its elimination for regional certification. The polio pre-campaign dashboard was used to assess the level of preparedness for Oral Poliovirus Vaccine (OPV) polio supplementary immunization activities (SIA) at three weeks, two weeks, one week, and three days to the start of each campaign implemented during 2016-2020. The administrative tally sheet, independent monitoring survey, and Lot Quality Assurance Sampling (LQAS) survey data collected and shared from the implementation level were analyzed by the EOC DWG to provide information by person, place, and time. Using a 90% threshold in LQAS surveys defining quality SIAs, the proportion of Local Government Areas (LGAs) in Nigeria's states in which post-SIA LQAS surveys were conducted that met this threshold were assessed over time. The highest level of preparedness attained by 3 days to a polio campaign during August 2016-February 2020 was 95% and the lowest attained was 77%. The admin, independent monitoring, and LQAS data analysis results were given to EOC working groups for assessing the performance and quality of each campaign. Twenty-twenty five percent of LGAs that failed LQAS were identified for repeat vaccination. Further, acute flaccid paralysis and environmental surveillance data and laboratory results were analyzed and shared with NEOC and partners. The government and partners used the information generated by the Data Working Group to take evidence-based action including determining the scope of the polio campaign, intensification of surveillance and routine immunization activities, and special intervention activities. On average, 12% of the 774 LGAs were identified as polio high risk LGAs for intervention using selected surveillance, routine immunization (RI), SIAs, and other relevant data sets. National Emergency Operation Centre Data Working Group provided quality and timely information that supported decision-making processes for the polio program in Nigeria. The quality and timely information enabled the NEOC to make evidence-based and timely decisions that contributed to gap identification and decision-making.

dhfr and dhps genotype and sulfadoxine-pyrimethamine treatment failure in children with falciparum malaria in the Democratic Republic of Congo.

OBJECTIVE: To determine the relationship between mutations in dhfr and dhps and SP treatment failure in Plasmodium falciparum malaria in the Democratic Republic of the Congo (DRC). METHODS: Therapeutic efficacy trial was conducted in Rutshuru, Eastern DRC, between June and September 2002, comparing sulfadoxine-pyrimethamine (SP), SP plus amodiaquine (AQSP) and artesunate plus SP (ASSP) regimens for treating malaria in children under 5 years old. We genotyped 212 samples for mutations associated with SP resistance and investigated their association with treatment failure. RESULTS: In the SP arm, 61% of the subjects experienced treatment failure after 14 days. The failure rate was lower in the combination arms (AQSP: 32%, ASSP: 21%). The dhfr-108 and dhfr-51 mutations were nearly universal while 89% of the samples had at least one additional mutation at dhfr-59, dhps-437 or dhps-540. Dhps mutations had a bigger impact on treatment failure in children with high parasite density: for children with a parasite density <45 000 parasites/microl, the risk of treatment failure was 37% for mutations at dhps-437 and dhps-540 mutation and 21% for neither mutation [risk difference (RD) = 17%, 95% CI: -3%, 36%]. In children with a parasite density >45 000 parasites/microl, the treatment failure risk was 58% and 8% for children with both mutations or neither mutation, respectively (RD = 51%, 95% CI: 34%, 67%). CONCLUSIONS: Dhps-437 and dhps-540 are strongly associated with SP treatment failure and should be evaluated further as a method for surveillance of SP-based therapy in DRC.

Prevalence of pfcrt mutations in Congolese and Malawian Plasmodium falciparum isolates as determined by a new Taqman assay.

A real-time PCR assay was developed to detect the K76T point mutation in the Plasmodium falciparum putative chloroquine resistance transporter gene. The assay was used with malaria positive clinical isolates from Rutshuru in the eastern part of the Democratic Republic of the Congo (DRC) and from Malawi. The K76T mutation was found in 52/56 (93%) clinical isolates from the DRC, where chloroquine resistance is high, but in none of the 12 isolates tested from Malawi where chloroquine is now rarely used. Sixteen percent of specimens from the DRC had detectable levels of both wild-type and mutant alleles. The real-time PCR results were compared to results from a nested allele-specific PCR assay and from direct DNA sequencing. Using allele-specific PCR as the reference method, the new assay is 100% sensitive and specific towards the mutant allele. In addition to its low per-test cost, the new assay is fast, easily automated, sensitive and well-suited to large-scale epidemiological studies.

Malaria in primary school children and infants in kinshasa, democratic republic of the congo: surveys from the 1980s and 2000.

Kinshasa, the capital of the Democratic Republic of the Congo, has been a perennial malarious area and has grown almost 14 times from 380,000 people in 1960 to 5,293,000 in 2003. The most complete information on malaria prevalence in Kinshasa was first acquired in 1981-1983. Blood smears were obtained from 25,135 children (ages 5-15 years) from 245 schools in 16 of 24 zones. The mean Plasmodium falciparum parasite rate was 17%; the parasite rate was similar for both sexes and was higher (P < 0.001) in older students. The parasite rate varied from 4% (urban zone) to 46% (peri-urban zone). An infant survey confirmed malaria transmission. During the Roll Back Malaria situational analysis in 2000, malaria prevalence was reassessed by the National Malaria Control Program and its partners in schools from selected health zones. A mean parasite rate of 34% was found among school children 5-9 years old. The parasite rate varied from 14% (central urban zone) to 65% (peri urban zone). Plasmodium falciparum was not the only species found, but accounted for more than 97% of the infections. Malaria incidence may have increased in Kinshasa during the last two decades due to difficulties in provision of control and prevention measures. Along with deployment of insecticide-treated bed nets and improved patient management, currently ongoing, other measures that could impact the disease are being considered, including vector control, water management, and proper urban planning.

Epidemiology of yaws: an update.

Yaws, a neglected tropical disease, is targeted for eradication by 2020 through large-scale mass-treatment programs of endemic communities. A key determinant for the success of the eradication campaign is good understanding of the disease epidemiology. We did a review of historical trends and new information from endemic countries, with the aim of assessing the state of knowledge on yaws disease burden. Transmission of yaws is now present in Africa, Asia, and the South Pacific. At least 12 countries are known to harbor yaws cases and 21 to 42 million people live in endemic areas. Between 2008 and 2012 more than 300,000 new cases were reported to the World Health Organization. Yaws presented high geographical variation within a country or region, high seasonality for incidence of active disease, and evidence that low standards of hygiene predispose to suffering of the disease. Key data issues include low levels of reporting, potential misdiagnosis, and scarce documentation on prevalence of asymptomatic infections. Currently available data most likely underestimates the magnitude of the disease burden. More effort is needed in order to refine accuracy of data currently being reported. A better characterization of the epidemiology of yaws globally is likely to positively impact on planning and implementation of yaws eradication.

Haemophilus ducreyi as a cause of skin ulcers in children from a yaws-endemic area of Papua New Guinea: a prospective cohort study.

BACKGROUND: Skin infections with ulceration are a major health problem in countries of the south Pacific region. Yaws, caused by Treponema pallidum subspecies pertenue and diagnosed by the presence of skin ulcers and a reactive syphilis serology, is one major cause, but this infection can be confused clinically with ulcers due to other causative agents. We investigated T pallidum pertenue and another bacterium known to cause skin infections in the Pacific islands-Haemophilus ducreyi-as causes of skin ulceration in a yaws-endemic region. Additionally, we identified specific signs and symptoms associated with these causative agents of cutaneous ulcers and compared these findings with laboratory-based diagnoses. METHODS: We did a prospective cohort study of five yaws-endemic villages (total population 3117 people) during a yaws elimination campaign in Papua New Guinea in April, 2013. We enrolled all consenting patients with chronic moist or exudative skin ulcers. We undertook a detailed dermatological assessment, syphilis serology, and PCR on lesional swabs to detect the presence of T pallidum pertenue and H ducreyi. Patients with PCR-confirmed bacterial infections were included in a comparative analysis of demographics and clinical features. FINDINGS: Full outcome data were available for 90 people with skin ulcers. Of these patients, 17 (19%) had negative results in all molecular tests and were therefore excluded from the comparative analyses. A bacterial cause was identified in 73 (81%) participants-either H ducreyi (n=42), T pallidum pertenue (yaws; n=19), or coinfection with both organisms (dual infection; n=12). The demographic characteristics of the patients infected with yaws and with H ducreyi were similar. Skin lesions in patients with yaws and in those with dual infection were larger than those in patients infected with H ducreyi (p=0·071). The lesions in patients with yaws and dual infection were more circular in shape (79% and 67%) than in those infected with H ducreyi (21%; p<0·0001); more likely to have central granulating tissue (90% and 67% vs 14%; p<0·0001); and more likely to have indurated edges (74% and 83% vs 31%; p=0·0003). The prevalence of reactive combined serology (positive T pallidum haemagglutination test and rapid plasmin reagin titre of ≥1:8) was higher in cases of yaws (63%) and dual infections (92%) than in H ducreyi infections (29%; p<0·0001). INTERPRETATION: In this yaws-endemic community, H ducreyi is an important and previously unrecognised cause of chronic skin ulceration. Reactive syphilis serology caused by latent yaws can occur in ulcers with the presence of H ducreyi alone. The introduction of PCR for ulcer surveillance could improve the accuracy of diagnosis in countries with yaws eradication campaigns. FUNDING: Newcrest Mining Company.

Sensitivity and specificity of a rapid point-of-care test for active yaws: a comparative study.

BACKGROUND: To eradicate yaws, national control programmes use the Morges strategy (initial mass treatment and biannual resurveys). The resurvey component is designed to actively detect and treat remaining yaws cases and is initiated on the basis of laboratory-supported reactive non-treponemal serology (using the rapid plasma reagin [RPR] test). Unfortunately, the RPR test is available rarely in yaws-endemic areas. We sought to assess a new point-of-care assay-the Dual Path Platform (DPP) syphilis assay, which is based on simultaneous detection of antibodies to treponemal and non-treponemal antigens-for guiding use of antibiotics for yaws eradication. A secondary goal was to ascertain at what timepoint the DPP assay line reverted to negative after treatment. METHODS: 703 children (aged 1-18 years) with suspected clinical yaws living in two remote, yaws-endemic villages in Papua New Guinea were enrolled. Clinical suspicion of yaws was established according to a WHO pictorial guide. We obtained blood samples from all patients. We calculated the sensitivity and specificity of the DPP assay for detection of antibodies to treponemal (T1) and non-treponemal (T2) antigens and compared values against those obtained with standard laboratory tests (the Treponema pallidum haemagglutination assay [TPHA] and the RPR test). We followed up a subsample of children with dually positive serology (T1 and T2) to monitor changes in DPP optical density (using an automatic reader) at 3 and 6 months. This trial is registered with ClinicalTrials.gov, number NCT01841203. FINDINGS: Of 703 participants, 389 (55%) were reactive for TPHA, 305 (43%) for the RPR test, and 287 (41%) for both TPHA and the RPR test. The DPP T1 (treponemal) assay had a sensitivity of 88·4% (95% CI 84·8-91·4) and specificity of 95·2% (92·2-97·3). The DPP T2 (non-treponemal) assay had a sensitivity of 87·9% (83·7-91·3) and specificity of 92·5% (89·4-94·9). In subgroup analyses, sensitivities and specificities did not differ according to type of specimen (plasma vs whole blood). For specimens with an RPR titre of 1:8 or greater, the sensitivity of the DPP T2 assay was 94·1% (95% CI 89·9-96·9). Serological cure (including seroreversion or a fourfold reduction in optical density value) was attained at 6 months in 173 (95%) of 182 children with dual-positive serology. INTERPRETATION: The DPP assay is accurate for identification of antibodies to treponemal and non-treponemal antigens in patients with yaws and avoids the need for laboratory support. A change of diagnostic procedure from the currently implemented RPR test to the simpler DPP assay could ease the implementation of yaws eradication activities. FUNDING: Chembio Diagnostic Systems, Newcrest Mining, and the Papua New Guinea National Department of Health.

Lymphatic filariasis in Papua New Guinea: distribution at district level and impact of mass drug administration, 1980 to 2011.

BACKGROUND: Lymphatic filariasis (LF) caused by Wuchereria bancrofti is present at high prevalence in some parts of Papua New Guinea. However, there has been no rigorous data-based representative assessment of nationwide prevalence of LF. The LF programme has been daunted by the scope of the problem, and progress on mass drug administration (MDA) has been slow and lacking in resources. METHODS: A systematic literature review identified LF surveys in Papua New Guinea between 1980 and 2011. Results were extracted by location, time period and test used (blood slide, immunochromatographic test (ICT) or Og4C3 ELISA) and combined by district. Three criteria schemes based on the Global Programme to Eliminate Lymphatic Filariasis guidelines, with modifications, were developed to classify and prioritize districts by prevalence level. Results of repeated surveys in the same sites were used to investigate the impact of MDA on LF prevalence over the time period. RESULTS: There were 312 distinct survey sites identified in 80 of the 89 districts over the 31-year period. The overall LF prevalence in the sites tested was estimated at 18.5 to 27.5% by blood slide for microfilariae (Mf), 10.1% to 12.9% by ICT and 45.4% to 48.8% by Og4C3. Biases in site selection towards areas with LF, and change in type of assay used, affected the prevalence estimates, but overall decline in prevalence over the time period was observed. Depending on the criteria used, 34 to 36 districts (population 2.7 to 2.9 million) were classed as high endemic (≥5% prevalence), 15 to 25 districts (1.7 to 1.9 million) as low endemic (<5%) and 20 to 31 (1.3 to 2.2 million) as non-endemic. Nine districts (0.7 million) had no information. The strong impact of MDA, especially on microfilaria (Mf) prevalence, was noted in sites with repeat surveys. CONCLUSIONS: This analytical review of past surveys of LF in Papua New Guinea enables better estimation of the national burden, identifies gaps in knowledge, quantifies and locates the population at risk, and can be used to predict the likely impact of MDA and/or vector control. Better targeting of districts by level of prevalence will strengthen the control programme, facilitate monitoring of the disease trend and increase the likelihood of reaching the target of LF elimination by 2020.

Assessing the efficacy of chloroquine and sulfadoxine-pyrimethamine for treatment of uncomplicated Plasmodium falciparum malaria in the Democratic Republic of Congo.

We evaluated the in vivo responses to chloroquine (CQ), the first line antimalarial, and to sulfadoxine-pyrimethamine (SP), the most readily available and affordable alternative treatment, in children under 5 with acute uncomplicated Plasmodium falciparum malaria in seven sites of Democratic Republic of Congo (DRC) between May 2000 and November 2001, using the standard 14-day WHO protocol. In the CQ group, the overall treatment failure rate was 45.4% (95% CI: 40.1-50.8) of 350 infections successfully tested; in the SP group it was 7.5% (95% CI: 5.0-11.0) of 333 infections. Of 191 patients who had an adequate clinical response (ACR) in the CQ group, 127 (66.5%; range: 62.5-71.4) still had parasitaemia on day 14. In the SP group, only 21 (6.8%; range: 2.2-12.8) of 308 patients with an ACR were still parasitaemic on day 14. Using pooled data from three rural sites, haematological recovery was better in the SP group (mean of haematocrit difference between days 14 and 0 among anaemic children: 4.7 vs. 3.2; P < 0.01, Wilcoxon test). These findings suggest that CQ is no longer effective in DRC and that SP may be a good alternative for its replacement as first line antimalarial treatment. The Ministry of Health (MOH) therefore now recommends SP as the first line antimalarial drug in DRC, as an interim step, 18 months after launching the first study. Additional studies are needed to select alternative therapies that might replace SP or improve its efficacy, should it prove ineffective in the future.