Associating the scale-up of insecticide-treated nets and use with the decline in all-cause child mortality in the Democratic Republic of Congo from 2005 to 2014.

BACKGROUND: To reduce the malaria burden and improve the socioeconomic status of its citizens, the Democratic Republic of Congo scaled up key malaria control interventions, especially insecticide-treated nets (ITNs), between 2005 and 2014. Since then, the effects of these interventions on malaria mortality and morbidity have not been assessed. This study aimed to measure the impact of the National Malaria Control Programme's efforts and to inform future control strategies. METHODS: The authors used data from the Demographic and Health Surveys 2007 and 2013-2014 to assess trends in all-cause childhood mortality (ACCM) against trends in coverage of malaria interventions at national and subnational levels. The authors used the plausibility argument to assess the impact of the malaria control interventions and used Kaplan-Meier survival probability and Cox proportional hazard models to examine the effect of ITN ownership on child survival. Contextual factor trends affecting child survival were also considered. RESULTS: Countrywide, household ownership of at least one ITN increased, from 9% in 2007 to 70% in 2013-2014. All provinces experienced similar increases, with some greater than the national level. ITN use increased between 2007 and 2013-2014 among children under five (6% to 55%). Severe anaemia (haemoglobin concentration < 8 g/dl) prevalence among children aged 6-59 months significantly decreased, from 11% (95% confidence interval [CI] 9-13%) in 2007 to 6% (95% CI 5-7%) in 2013-2014. During the same period, ACCM declined, from 148 (95% CI 132-163) to 104 (95% CI 97-112) deaths per 1000 live births. The decline in ACCM was greater among children aged 6-23 months (relative reduction of 36%), compared to children aged 24-59 months (relative reduction of 12%). Cox regression indicated that household ownership of at least one ITN reduced the risk of mortality by 24% among children under five (risk ratio = 0.76, 95% CI 0.64-0.90). Contextual factor analysis revealed marginal improvements in socioeconomic indicators and other health interventions. CONCLUSIONS: Given the patterns of the coverage of malaria control interventions, patterns in ACCM by province, and marginal improvements in contextual factors, the authors conclude that the malaria control interventions have plausibly contributed to the decrease in ACCM in the Democratic Republic of Congo from 2005 to 2014.

Cost-effectiveness of district-wide seasonal malaria chemoprevention when implemented through routine malaria control programme in Kita, Mali using fixed point distribution.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a strategy for malaria control recommended by the World Health Organization (WHO) since 2012 for Sahelian countries. The Mali National Malaria Control Programme adopted a plan for pilot implementation and nationwide scale-up by 2016. Given that SMC is a relatively new approach, there is an urgent need to assess the costs and cost effectiveness of SMC when implemented through the routine health system to inform decisions on resource allocation. METHODS: Cost data were collected from pilot implementation of SMC in Kita district, which targeted 77,497 children aged 3-59 months. Starting in August 2014, SMC was delivered by fixed point distribution in villages with the first dose observed each month. Treatment consisted of sulfadoxine-pyrimethamine and amodiaquine once a month for four consecutive months, or rounds. Economic and financial costs were collected from the provider perspective using an ingredients approach. Effectiveness estimates were based upon a published mathematical transmission model calibrated to local epidemiology, rainfall patterns and scale-up of interventions. Incremental cost effectiveness ratios were calculated for the cost per malaria episode averted, cost per disability adjusted life years (DALYs) averted, and cost per death averted. RESULTS: The total economic cost of the intervention in the district of Kita was US $357,494. Drug costs and personnel costs accounted for 34% and 31%, respectively. Incentives (payment other than salary for efforts beyond routine activities) accounted for 25% of total implementation costs. Average financial and economic unit costs per child per round were US $0.73 and US $0.86, respectively; total annual financial and economic costs per child receiving SMC were US $2.92 and US $3.43, respectively. Accounting for coverage, the economic cost per child fully adherent (receiving all four rounds) was US $6.38 and US $4.69, if weighted highly adherent, (receiving 3 or 4 rounds of SMC). When costs were combined with modelled effects, the economic cost per malaria episode averted in children was US $4.26 (uncertainty bound 2.83-7.17), US $144 (135-153) per DALY averted and US $ 14,503 (13,604-15,402) per death averted. CONCLUSIONS: When implemented at fixed point distribution through the routine health system in Mali, SMC was highly cost-effective. As in previous SMC implementation studies, financial incentives were a large cost component.

Comparing the durability of the long-lasting insecticidal nets DawaPlus® 2.0 and DuraNet© in northwest Democratic Republic of Congo.

BACKGROUND: Anecdotal reports from DRC suggest that long-lasting insecticidal nets (LLIN) distributed through mass campaigns in DRC may not last the expected average three years. To provide the National Malaria Control Programme with evidence on physical and insecticidal durability of nets distributed during the 2016 mass campaign, two brands of LLIN, DawaPlus® 2.0 and DuraNet©, were monitored in neighbouring and similar health zones in Sud Ubangi and Mongala Provinces. METHODS: This was a prospective cohort study of representative samples of households from two health zones recruited at baseline, 2 months after the mass campaign. All campaign nets in these households were labelled, and followed up over a period of 31 months. Primary outcome was the "proportion of nets surviving in serviceable condition" based on attrition and integrity measures and the median survival in years. The outcome for insecticidal durability was determined by bio-assay from subsamples of campaign nets. RESULTS: A total of 754 campaign nets (109% of target) from 240 households were included in the study. Definite outcomes could be determined for 67% of the cohort nets in Sud Ubangi and 74% in Mongala. After 31 months all-cause attrition was 57% in Sud Ubangi and 76% in Mongala (p = 0.005) and attrition due to wear and tear was 26% in Sud Ubangi and 48% in Mongala (p = 0.0009). Survival in serviceable condition at the last survey was 37% in Sud Ubangi and 17% in Mongala (p = 0.003). Estimated median survival was 1.6 years for the DawaPlus® 2.0 in Mongala (95% CI 1.3-1.9) and 2.2 years for the DuraNet in Sud Ubangi (95% CI 2.0-2.4). Multivariable Cox proportionate hazard models suggest that the difference between sites was mainly attributable to the LLIN brand. Insecticidal effectiveness was optimal for DuraNet©, but significantly dropped after 24 months for DawaPlus® 2.0. CONCLUSIONS: In the environment of northwest DRC the polyethylene LLIN DuraNet© performed significantly better than the polyester LLIN DawaPlus® 2.0, but both were below a three-year median survival. Improvement of net care behaviours should be able to improve physical durability.

Intensity of pyrethroid resistance in Anopheles gambiae before and after a mass distribution of insecticide-treated nets in Kinshasa and in 11 provinces of the Democratic Republic of Congo.

BACKGROUND: Between 2011 and 2018, an estimated 134.8 million pyrethroid-treated long-lasting insecticidal nets (LLINs) were distributed nationwide in the Democratic Republic of Congo (DRC) for malaria control. Pyrethroid resistance has developed in DRC in recent years, but the intensity of resistance and impact on LLIN efficacy was not known. Therefore, the intensity of resistance of Anopheles gambiae sensu lato (s.l.) to permethrin and deltamethrin was monitored before and after a mass distribution of LLINs in Kinshasa in December 2016, and in 6 other sites across the country in 2017 and 11 sites in 2018. METHODS: In Kinshasa, CDC bottle bioassays using 1, 2, 5, and 10 times the diagnostic dose of permethrin and deltamethrin were conducted using An. gambiae s.l. collected as larvae and reared to adults. Bioassays were conducted in four sites in Kinshasa province 6 months before a mass distribution of deltamethrin-treated LLINs and then two, six, and 10 months after the distribution. One site in neighbouring Kongo Central province was used as a control (no mass campaign of LLIN distribution during the study). Nationwide intensity assays were conducted in six sites in 2017 using CDC bottle bioassays and in 11 sites in 2018 using WHO intensity assays. A sub-sample of An. gambiae s.l. was tested by PCR to determine species composition and frequency of kdr-1014F and 1014S alleles. RESULTS: In June 2016, before LLIN distribution, permethrin resistance intensity was high in Kinshasa; the mean mortality rate was 43% at the 5× concentration and 73% at the 10× concentration. Bioassays at 3 time points after LLIN distribution showed considerable variation by site and time and there was no consistent evidence for an increase in pyrethroid resistance intensity compared to the neighbouring control site. Tests of An. gambiae s.l. in 6 sites across the country in 2017 and 11 sites in 2018 showed all populations were resistant to the diagnostic doses of 3 pyrethroids. In 2018, the intensity of resistance varied by site, but was generally moderate for all three pyrethroids, with survivors at ×5 the diagnostic dose. Anopheles gambiae sensu stricto (s.s.) was the most common species identified across 11 sites in DRC, but in Kinshasa, An. gambiae s.s. (91%) and Anopheles coluzzii (8%) were sympatric. CONCLUSIONS: Moderate or high intensity pyrethroid resistance was detected nationwide in DRC and is a serious threat to sustained malaria control with pyrethroid LLINs. Next generation nets (PBO nets or bi-treated nets) should be considered for mass distribution.

A village level cluster-randomized entomological evaluation of combination long-lasting insecticidal nets containing pyrethroid plus PBO synergist in Southern Mali.

BACKGROUND: There is growing concern that malaria vector resistance to pyrethroid insecticides may reduce the effectiveness of long-lasting insecticidal nets (LLINs). Combination LLINs are designed to control susceptible and pyrethroid-resistant mosquito populations through a mixture of pyrethroid with piperonyl butoxide (PBO) synergist. A cluster randomized trial with entomology outcome measures was conducted in Mali to determine the added benefit over mono-treated pyrethroid predecessors. Four LLIN treatments; permethrin + PBO, permethrin, deltamethrin + PBO, and deltamethrin, were randomly allocated to four villages each (16 villages total) and distributed to cover every sleeping place. Entomological monitoring of indoor Anopheles resting densities, host preference, vector longevity, and sporozoite rates were monitored every 2 months over 2 years in 2014 and 2015. RESULTS: Bottle bioassays confirmed permethrin and deltamethrin resistance in Anopheles gambiae sensu lato (s.l.), (the predominant species throughout the study) with pre-exposure to PBO indicating partial involvement of oxidases. Between 2014 and 2015 the mean indoor resting density was greater in the deltamethrin + PBO LLIN arm than the deltamethrin LLIN arm at 3.05 (95% CI 3.00-3.10) An. gambiae s.l. per room per day compared with 1.9 (95% CI 1.87-1.97). There was no significant difference in sporozoite rate at 3.97% (95% CI 2.91-5.02) for the deltamethrin LLIN arm and 3.04% (95% CI 2.21-3.87) for deltamethrin + PBO LLIN arm (P = 0.17). However, when analysed by season there was some evidence that the sporozoite rate was lower in the deltamethrin + PBO LLIN arm than deltamethrin LLIN arm during the rainy/high malaria transmission seasons at 1.95% (95% CI 1.18-2.72) and 3.70% (95% CI 2.56-4.84) respectively (P = 0.01). CONCLUSIONS: While there was some evidence that An. gambiae s.l. sporozoite rates were lower in villages with deltamethrin + PBO LLINs during the high malaria transmission seasons of 2014-2015, there was no reduction in parity rates or indoor resting densities. There was also no evidence that permethrin + PBO LLINs provided any improved control when compared with permethrin LLINs. Combination nets may have a greater impact in areas where mixed function oxidases play a more important role in pyrethroid resistance.

Measuring the impact of seasonal malaria chemoprevention as part of routine malaria control in Kita, Mali.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a new strategy recommended by WHO in areas of highly seasonal transmission in March 2012. Although randomized controlled trials (RCTs) have shown SMC to be highly effective, evidence and experience from routine implementation of SMC are limited. METHODS: A non-randomized pragmatic trial with pre-post design was used, with one intervention district (Kita), where four rounds of SMC with sulfadoxine + amodiaquine (SP + AQ) took place in August-November 2014, and one comparison district (Bafoulabe). The primary aims were to evaluate SMC coverage and reductions in prevalence of malaria and anaemia when SMC is delivered through routine programmes using existing community health workers. Children aged 3-59 months from 15 selected localities per district, sampled with probability proportional to size, were surveyed and blood samples collected for malaria blood smears, haemoglobin (Hb) measurement, and molecular markers of drug resistance in two cross-sectional surveys, one before SMC (July 2014) and one after SMC (December 2014). Difference-in-differences regression models were used to assess and compare changes in malaria and anaemia in the intervention and comparison districts. Adherence and tolerability of SMC were assessed by cross-sectional surveys 4-7 days after each SMC round. Coverage of SMC was assessed in the post-SMC survey. RESULTS: During round 1, 84% of targeted children received at least the first SMC dose, but coverage declined to 67% by round 4. Across the four treatment rounds, 54% of children received four complete SMC courses. Prevalence of parasitaemia was similar in intervention and comparison districts prior to SMC (23.4 vs 29.5%, p = 0.34) as was the prevalence of malaria illness (2.4 vs 1.9%, p = 0.75). After SMC, parasitaemia prevalence fell to 18% in the intervention district and increased to 46% in the comparison district [difference-in-differences (DD) OR = 0.35; 95% CI 0.20-0.60]. Prevalence of malaria illness fell to a greater degree in the intervention district versus the comparison district (DD OR = 0.20; 95% CI 0.04-0.94) and the same for moderate anaemia (Hb < 8 g/dL) (DD OR = 0.26, 95% CI 0.11-0.65). The frequency of the quintuple mutation (dhfr N51I, C59R and S108N + dhps A437G and K540E) remained low (5%) before and after intervention in both districts. CONCLUSIONS: Routine implementation of SMC in Mali substantially reduced malaria and anaemia, with reductions of similar magnitude to those seen in previous RCTs. Improving coverage could further strengthen SMC impact. Trial registration clinical trial registration number NCT02894294.

Characterizing the insecticide resistance of Anopheles gambiae in Mali.

BACKGROUND: The impact of indoor residual spraying (IRS) and long-lasting insecticide nets (LLINs), key components of the national malaria control strategy of Mali, is threatened by vector insecticide resistance. The objective of this study was to assess the level of insecticide resistance in Anopheles gambiae sensu lato populations from Mali against four classes of insecticide recommended for IRS: organochlorines (OCs), pyrethroids (PYs), carbamates (CAs) and organophosphates (OPs). Characterization of resistance was done in 13 sites across southern Mali and assessed presence and distribution of physiological mechanisms that included target-site modifications: knockdown resistance (kdr) and altered acetycholinesterase (AChE), and/or metabolic mechanisms: elevated esterases, glutathione S-transferases (GSTs), and monooxygenases. METHODS: The World Health Organization (WHO) tube test was used to determine phenotypic resistance of An. gambiae s.l. to: dichlorodiphenyltrichloroethane (DDT) (OC), deltamethrin (PY), lambda-cyhalothrin (PY), bendiocarb (CA), and fenitrothion (OP). Identification of sibling species and presence of the ace-1 (R) and Leu-Phe kdr, resistance-associated mutations, were determined using polymerase chain reaction (PCR) technology. Biochemical assays were conducted to detect increased activity of GSTs, oxidases and esterases. RESULTS: Populations tested showed high levels of resistance to DDT in all 13 sites, as well as increased resistance to deltamethrin and lambda-cyhalothrin in 12 out of 13 sites. Resistance to fenitrothion and bendiocarb was detected in 1 and 4 out of 13 sites, respectively. Anopheles coluzzii, An. gambiae sensu stricto and Anopheles arabiensis were identified with high allelic frequencies of kdr in all sites where each of the species were found (13, 12 and 10 sites, respectively). Relatively low allelic frequencies of ace-1 (R) were detected in four sites where this assessment was conducted. Evidence of elevated insecticide metabolism, based on oxidase, GSTs and esterase detoxification, was also documented. CONCLUSION: Multiple insecticide-resistance mechanisms have evolved in An. coluzzii, An. gambiae s.s. and An. arabiensis in Mali. These include at least two target site modifications: kdr, and ace-1 (R) , as well as elevated metabolic detoxification systems (monooxygenases and esterases). The selection pressure for resistance could have risen from the use of these insecticides in agriculture, as well as in public health. Resistance management strategies, based on routine resistance monitoring to inform insecticide-based malaria vector control in Mali, are recommended.

Net use, care and repair practices following a universal distribution campaign in Mali.

BACKGROUND: The Government of Mali and the President's Malaria Initiative conducted a long-lasting, insecticidal net (LLIN) distribution campaign in April 2011 in the Sikasso region of Mali, with the aim of universal coverage, defined as one insecticide-treated net for every two persons. This study examines how households in post- and pre-campaign regions value and care for nets. METHODS: The study was conducted in October 2012 in Sikasso and Kayes in the southeast and western regions of Mali, respectively. The regions were purposively selected to allow for comparison between areas that had already had a mass distribution campaign (Sikasso) and areas that had not yet had a mass distribution campaign (Kayes). Study sites and households were randomly selected. Sleeping space questionnaires and structured interviews with household heads were conducted to obtain information on net use, perceived value of free nets in relation to other malaria prevention activities, and net care and repair practices. RESULTS: The study included 40 households, split evenly across the two regions. Forty interviews were conducted with household heads and 151 sleeping spaces were inventoried using the sleeping space questionnaire. Nets obtained through the free distribution were reported to be highly valued in comparison to other malaria prevention strategies. Overall, net ownership and use were higher among households in areas that had already experienced a mass distribution. While participants reported using and valuing these nets, care and repair practices varied. CONCLUSION: National net use is high in Mali, and comparatively higher in the region covered by the universal distribution campaign than in the region not yet covered. While the Government of Mali and implementing partners have made strides to ensure high net coverage, some gaps remain related to communication messaging of correct and consistent net use throughout the year, and on improving net care and repair behaviour. By focusing on these areas as well as improved access to nets, coverage and use rates should continue to increase, contributing to improvements in malaria control.

Therapeutic Efficacy of Artemisinin-Based Combination Therapies in Democratic Republic of the Congo and Investigation of Molecular Markers of Antimalarial Resistance.

Routine assessment of the efficacy of artemisinin-based combination therapies (ACTs) is critical for the early detection of antimalarial resistance. We evaluated the efficacy of ACTs recommended for treatment of uncomplicated malaria in five sites in Democratic Republic of the Congo (DRC): artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ), and dihydroartemisinin-piperaquine (DP). Children aged 6-59 months with confirmed Plasmodium falciparum malaria were treated with one of the three ACTs and monitored. The primary endpoints were uncorrected and polymerase chain reaction (PCR)-corrected 28-day (AL and ASAQ) or 42-day (DP) cumulative efficacy. Molecular markers of resistance were investigated. Across the sites, uncorrected efficacy estimates ranged from 63% to 88% for AL, 73% to 100% for ASAQ, and 56% to 91% for DP. PCR-corrected efficacy estimates ranged from 86% to 98% for AL, 91% to 100% for ASAQ, and 84% to 100% for DP. No pfk13 mutations previously found to be associated with ACT resistance were observed. Statistically significant associations were found between certain pfmdr1 and pfcrt genotypes and treatment outcome. There is evidence of efficacy below the 90% cutoff recommended by WHO to consider a change in first-line treatment recommendations of two ACTs in one site not far from a monitoring site in Angola that has shown similar reduced efficacy for AL. Confirmation of these findings in future therapeutic efficacy monitoring in DRC is warranted.

High frequency of PfCRT 76T in two Malian villages and its prevalence in severe relative to non-severe malaria.

We investigated PfCRT 76T mutation in severe and non-severe malaria in Southern Mali. One hundred and ninety three severe malaria cases were each matched against two non-severe malaria cases. Patients with G6PD deficiency and any known hemoglobin abnormality were excluded. PfCRT 76T was present in 60.8% (n=386) non-severe malaria cases and in 77.2% (n=193) severe malaria cases (p<0.0001). In children 5 years or younger, these proportions were 62.9% (n=294) vs. 73.5% (n=147), respectively (p<0.01). PfCRT 76T was therefore associated with malaria severity in this setting of Mali.