Country-level operational implementation of the Global Plan for Insecticide Resistance Management

Malaria control is reliant on the use of long-lasting pyrethroid-impregnated nets and/or indoor residual spraying (IRS) of insecticide. The rapid selection and spread of operationally significant pyrethroid resistance in African malaria vectors threatens our ability to sustain malaria control. Establishing whether resistance is operationally significant is technically challenging. Routine monitoring by bioassay is inadequate, and there are limited data linking resistance selection with changes in disease transmission. The default is to switch insecticides when resistance is detected, but limited insecticide options and resistance to multiple insecticides in numerous locations make this approach unsustainable. Detailed analysis of the resistance situation in Anopheles gambiae on Bioko Island after pyrethroid resistance was detected in this species in 2004, and the IRS program switched to carbamate bendiocarb, has now been undertaken. The pyrethroid resistance selected is a target-site knock-down resistance kdr-form, on a background of generally elevated metabolic activity, compared with insecticide-susceptible A. gambiae, but the major cytochrome P450-based metabolic pyrethroid resistance mechanisms are not present. The available evidence from bioassays and infection data suggests that the pyrethroid resistance mechanisms in Bioko malaria vectors are not operationally significant, and on this basis, a different, long-lasting pyrethroid formulation is now being reintroduced for IRS in a rotational insecticide resistance management program. This will allow control efforts to be sustained in a cost-effective manner while reducing the selection pressure for resistance to nonpyrethroid insecticides. The methods used provide a template for evidence-based insecticide resistance management by malaria control programs.Malaria control activities in Africa have been scaled up during the last decade. Disease control is predominantly dependent on the distribution and use of pyrethroid-impregnated long lasting insecticide-treated nets (LLINs) and/or indoor residual spraying (IRS) of insecticides. The choice of insecticides for IRS is currently limited to four classes with only two modes of action. One of these insecticide classes, pyrethroids, is also the only class recommended for use by the World Health Organization (WHO) on LLINs. The recent rapid selection and spread of pyrethroid resistance in malaria vectors has stimulated the WHO to develop a Global Plan for Insecticide Resistance Management (1), encouraging countries to plan and implement insecticide resistance management strategies and to underpin these strategies with proper, timely entomological resistance monitoring and effective data management. This must be implemented in the short term at the same time medium- to long-term efforts are made to expand the available insecticide choice (2). To be effective, resistance management plans need to be closely aligned with local evidence supported by an effective monitoring system.Here we detail how this process has been undertaken in Equatorial Guinea, resulting in a detailed Operational Plan for Insecticide Resistance Management, which is owned by the National Malaria Control Program, Ministry of Health and Social Welfare, Equatorial Guinea. The plan was formally adopted in 2012.Bioko, the main island of Equatorial Guinea, has a population of ∼200,000 people. It is situated 30 miles off the coast of Cameroon, experiences high annual rainfall (∼2,000 mm/y), and has in recent years undergone major economic and infrastructural development as a result of offshore oil and gas production. Malaria is endemic, with Entomological Inoculation Rates of 281 and 787 infective bites per year recorded for Anopheles gambiae and Anopheles funestus, respectively, in 2002 (3), which was before the scaling-up of malaria control activities. Comprehensive malaria control interventions were introduced jointly by the Bioko Island Malaria Control Project (BIMCP) and the Ministry of Health and Social Welfare in 2004, with the aim of drastically reducing disease burden and, ultimately, eliminating malaria from the island. Serological markers suggest heterogeneity of effectiveness of malaria control activities across the island to date (4). The BIMCP is funded by a private sector consortium led by Marathon Oil Company. Malaria vector control, managed by Medical Care Development International, consists primarily of IRS of all houses on the island. The first round of IRS using a pyrethroid (deltamethrin) was carried out between March and July 2004, followed by two rounds per year of bendiocarb spraying from 2005 onward. In 2007, a mass distribution of LLINs PermaNet (Vestergaard Frandsen) 2.0, containing 55 mg/m² deltamethrin] was undertaken, providing one net per sleeping area. Although net coverage was initially high, numbers on the island declined rapidly as nets were redistributed by the recipient population.During the first round of deltamethrin IRS in 2004, a large proportion of A. gambiae s.s. mosquitoes sampled from window exit traps were shown to possess the West African form of the kdr mutation (leu¹⁰¹⁴–phe), which confers dichlorodiphenyltrichloroethane resistance and a low level of cross-resistance to all pyrethroids through insecticide target-site insensitivity (5). Pyrethroid resistance assessed by WHO susceptibility tests and the kdr mutation were present in both the M and S forms of A. gambiae s.s. on Bioko. The presence or absence of metabolically conferred pyrethroid resistance was not assessed at this time, although data from neighboring Cameroon suggests that this form of pyrethroid resistance is now widespread in the A. gambiae complex (6, 7). The detection of pyrethroid resistance, and an apparent lack of response to the IRS treatment by A. gambiae compared with A. funestus, prompted a switch from deltamethrin to a carbamate insecticide from the second spray round onward. However, malaria indicator surveys carried out both prespraying in February to March 2004 and postspraying in the same months in 2005 showed a large reduction in the prevalence of malaria infection in children aged from 2 to <15 y, going from 46% 95% confidence interval (CI), 40–51%] to 31% 95% CI, 24–40%] (8), indicating that the deltamethrin spray round had a substantial epidemiological effect. Routine entomological surveys from 2004 to 2012 suggested that A. funestus had been eliminated or virtually eliminated from Bioko, leaving the vectors A. gambiae s.s. and Anopheles melas. Subsequent routine bioassays and PCR analysis for the kdr mutation showed that despite replacement of deltamethrin with bendiocarb for IRS during a 7-y period, the frequency of pyrethroid resistance and the kdr mutation remained high in A. gambiae s.s.To determine retrospectively whether the presence of the kdr gene in A. gambiae compromised the operational effectiveness of deltamethrin IRS in Bioko in 2004, an analysis of ∼4,000 A. gambiae specimens caught in window traps after the spray round in 2004 was carried out. The aim was to determine whether sporozoite rates in kdr-positive mosquitoes were higher than in kdr-negative mosquitoes.In addition, the poor alignment of kdr positivity with survival in WHO pyrethroid susceptibility tests suggested that multiple pyrethroid resistance mechanisms were circulating in the Bioko population of A. gambiae. Metabolically based resistance mechanisms were assessed using microarrays and quantitative (q)PCR in A. gambiae specimens collected from Bioko in 2011.The retrospective sporozoite–kdr analysis of the A. gambiae specimens collected after the pyrethroid spray round in 2004, and the results of the metabolic resistance testing of A. gambiae samples collected in 2011, coupled with a reassessment of the mosquito density data from 2004 onward, has allowed us to develop an evidence-based operational resistance management program. This will underpin cost-effective maintenance of operational IRS activity for Equatorial Guinea and serve as a template that other malaria-endemic countries faced with similar insecticide resistance issues could follow.