4. Impact of current insecticide resistance in parasite transmission: a global warning based on reported level of resistance?

#### 4.1. Fitness cost of resistant lab and field Anopheles populations

The use of insecticide selects small proportion of individuals possessing resistance genes allowing them to resist and survive the effects of the insecticide, transferring the genetic modifications conferring resistance to the progeny. This should most likely increase the proportion of resistant individuals within the population. However, mutations or genes conferring resistance are usually associated with a fitness cost and may disrupt normal physiological functions [106, 107]. For example, resistant vectors may have lower mating success [108, 109], lower fecundity and fertility, higher developmental time and lower longevity. Resistant individuals may be also more susceptible to natural predators [110] or more prone to mortality during overwintering. Most insecticide resistance management strategies rely on the fact that fitness cost may impact the spread and persistence of resistance alleles in the vector populations [7].

#### 4.2. Impact of resistance on life traits: longevity, fecundity and mating male competitiveness

Resistance caused by overproduction of metabolic enzymes generally shows lower fitness cost than target site resistance, most probably because the primary function of the enzyme is not disrupted [111]. But to date, little is known about the effective impact of metabolic resistance on the life traits of the vector due to the absence of DNA-based molecular marker. Nevertheless, many studies demonstrated that resistant strains of arthropods often present lower fitness compared to their susceptible counterparts [112]. For example, it was shown that resistance strains may be associated with relatively slower larval development, reduced survival rates among larvae and adults, reduced fecundity in females and reduced fertility [106, 113, 114]. It was shown that target-site resistance due to kdr and rdl mutations is able to impact negatively the male mating competitiveness in the malaria vector An. gambiae, whereas metabolic resistance had no effect [109]. Among all the parameter elucidated above, vector longevity is an essential parameter in disease transmission because it increases the potential for infective bites to hosts. Furthermore, the effect of longevity on disease transmission is crucial for parasites like Plasmodium that need a minimum incubation period in the vector before being transmitted to a new host. Insecticide resistance is generally thought to increase longevity of resistant

vectors, thereby increasing infectiousness of parasites and threatening vector control. However, the development of resistance in a mosquito often comes with a price subsequently affecting the fitness of the vector [115]. As a consequence of the fitness cost of insecticide resistance on the life traits (mentioned above) of the vectors, reversion to susceptibility is expected. A good example of reversal to susceptibility occurred in An. arabiensis in Sudan. In this country, after antimalarial house spraying in the early 1980s, resistance to malathion was noticed. This prompted a switch of insecticide treatment to fenitrothion (OP insecticide), and susceptibility to malathion was restored in the following years [10]. However, reversal rates are variable and may be very slow, particularly when an insecticide has been used for many years. For example, the same rdl gene has been reported to be maintained in field populations of Sri Lanka despite the withdrawal of cyclodiene insecticides for mosquito control for more than 30 years [116]. Before implementing any resistance management strategy in the field, knowledge of the reversal rate is crucial.

#### 4.3. Epidemiological consequences of the insecticide resistance on malaria incidence

#### 4.3.1. Past and current evidences

conferred by other mechanisms. This mechanism has not been extensively studied as compared to the other mechanisms because there are very few examples. Recently, Yahouédo et al. [104] studied the role of the cuticular resistance in PY-resistant strain of An. gambiae called MRS, free of kdr mutations. They succeeded to show that lower amount of insecticide was absorbed in the MRS strain than in the susceptible strain and also that the MRS strain had a significantly thicker cuticle layers than those of the susceptible strain. CPLCG3 gene, which codes for a structural protein contributing to the cuticle thickness, was found to be constitutively upregulated. Similar evidences of cuticular resistance were shown for An. funestus with

4. Impact of current insecticide resistance in parasite transmission:

The use of insecticide selects small proportion of individuals possessing resistance genes allowing them to resist and survive the effects of the insecticide, transferring the genetic modifications conferring resistance to the progeny. This should most likely increase the proportion of resistant individuals within the population. However, mutations or genes conferring resistance are usually associated with a fitness cost and may disrupt normal physiological functions [106, 107]. For example, resistant vectors may have lower mating success [108, 109], lower fecundity and fertility, higher developmental time and lower longevity. Resistant individuals may be also more susceptible to natural predators [110] or more prone to mortality during overwintering. Most insecticide resistance management strategies rely on the fact that fitness cost may impact

Resistance caused by overproduction of metabolic enzymes generally shows lower fitness cost than target site resistance, most probably because the primary function of the enzyme is not disrupted [111]. But to date, little is known about the effective impact of metabolic resistance on the life traits of the vector due to the absence of DNA-based molecular marker. Nevertheless, many studies demonstrated that resistant strains of arthropods often present lower fitness compared to their susceptible counterparts [112]. For example, it was shown that resistance strains may be associated with relatively slower larval development, reduced survival rates among larvae and adults, reduced fecundity in females and reduced fertility [106, 113, 114]. It was shown that target-site resistance due to kdr and rdl mutations is able to impact negatively the male mating competitiveness in the malaria vector An. gambiae, whereas metabolic resistance had no effect [109]. Among all the parameter elucidated above, vector longevity is an essential parameter in disease transmission because it increases the potential for infective bites to hosts. Furthermore, the effect of longevity on disease transmission is crucial for parasites like Plasmodium that need a minimum incubation period in the vector before being transmitted to a new host. Insecticide resistance is generally thought to increase longevity of resistant

proofs of cuticle thickening in PY-resistant mosquitoes [105].

160 Towards Malaria Elimination - A Leap Forward

a global warning based on reported level of resistance?

the spread and persistence of resistance alleles in the vector populations [7].

competitiveness

4.2. Impact of resistance on life traits: longevity, fecundity and mating male

4.1. Fitness cost of resistant lab and field Anopheles populations

There are large number of confounding factors threatening the assessment of epidemiological consequences of the insecticide resistance on malaria incidence and data interpretation [117]. For this reason, only few studies have assessed the epidemiological impact of insecticide resistance. Impact of PY resistance on control failure was reported from the borders of Mozambique and South Africa. In 1996, the malaria control programme in KwaZulu-Natal (South Africa) switched from using DDT to deltamethrin for indoor spraying [118]. After four years of deltamethrin spraying, reported malaria cases increased approximately fourfold. An. funestus, previously eradicated, had reappeared and was observed emerging alive from PY-sprayed houses. Bioassays showed that this species was resistant to PYs but susceptible to DDT [119]. The decision to revert to IRS with DDT was accompanied by a decline in malaria cases by 91% [120]. On the Bioko Island on the West African coast, increased density of PY-resistant An. gambiae was also reported after IRS campaign with lambda-cyhalothrin, although a significant reduction in transmission index and malaria reported cases was observed [121, 122]. High frequencies of the L1014F kdr allele were observed in the local An. gambiae population. When PYs were replaced by CAs (bendiocarb), mosquito population declined [122]. Nevertheless, in an operational scale programme such as this, the possible contribution of other factors to the failure of PY IRS to control mosquito population density cannot be overlooked; thus, the direct consequence of the high kdr frequency is uncertain. After initiation of interventions combining IRS with PYs and ITNs in the highland provinces of Burundi in 2002, significant reduction was recorded in Anopheles density by 82% [123]. Consequently, transmission intensity was reduced by 90% and occurrence of malaria cases by 43% in children, despite high frequencies of the L1014S kdr allele in the main vector An. gambiae s.s. [123]. Many interventions took place in Africa in order to investigate the efficacy of ITNs for malaria prevention [124]. However, the extent to which PY resistance might affect the effectiveness of such interventions is not well elucidated. In Korhogo area, north of Côte d'Ivoire where the 1014F kdr allele frequency in An. gambiae is up to 80% [125], and malaria is endemic, lambda-cyhalothrin-treated nets had a significant impact on the entomological inoculation rate with around 55% reduction. Malaria incidence in children <5 years of age decreased also (56% reduction of clinical attacks) compared to a control group having no nets [126]. This was the first clear-cut evidence of ITNs continuing to provide effective personal protection against malaria in an area with a high frequency of kdr in the vector populations. However, absence of a physical barrier in the control group might have overestimated the impact of PY-treated nets against kdr mosquitoes in this study. In southern Benin, a randomised controlled trial was carried out in a mesoendemic area to assess the impact of LLINs scale-up on malaria morbidity in children <5 years of age [127]. In this area, where the kdr frequency is around 50–60% in An. gambiae s.s., transmission increased during the rainy season but was not followed by a seasonal variation in parasite infection and clinical incidence. The evidence is clear that implementation of vector control tools (ITNs and/or IRS) has significantly decreased malaria incidence and parasite infection prevalence in children in endemic countries across Africa, despite moderate-to-high PY resistance observed in local malaria vectors.

debilitating disease. It is therefore of the utmost importance that novel insecticides and new control tools be designed to help manage and mitigate the impact of resistance. Through the work of various partners such as Innovative Vector Control Consortium (IVCC), UNITAID and several manufacturers, the challenge of producing new insecticides and tools is beginning to be met. This is exemplified by the recent prequalification by the WHO of the new insecticide Sumishield (clothianidin, a neonicotinoid) in October 2017. This new insecticide together with the organophosphate Actellic (pirimiphos-methyl) could now allow countries to effectively design and implement suitable resistance management strategies for IRS interventions according to WHO's Global Plan for Insecticide Resistance Management (GPIRM). With other new insecticides expected to enter the market in the near future, resistance management strategies such as rotation of insecticides could become more realistic to implement. However, even with new insecticides available, the community should avoid being complacent as the mosquitoes will surely develop resistance with time if consideration is not given to how to use such new insecticides including between public health and agriculture sectors. Detection of resistance markers notably for metabolic resistance is also urgently needed to not only track the spread of resistance but to better assess its impact on control interventions or mosquito fitness and malaria transmission. The recent detection of markers such as L119F-GSTe2 in An. funestus shows that this is possible, but more efforts are needed focusing importantly on cytochrome P450s, the key metabolizers. It will be important to take advantage of the advances in genomics with the power of next-generation sequencing tools to detect potential resistance markers early enough to allow control programmes to track resistance when it is still at early stage when it could easily be managed. This will allow avoiding repeating the situation observed with PY resistance and ensure a continued effectiveness of current and future

Insecticide Resistance in Malaria Vectors: An Update at a Global Scale

http://dx.doi.org/10.5772/intechopen.78375

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This work was supported by a Wellcome Trust Senior Fellowship in Biomedical Sciences

insecticide-based interventions.

Acknowledgements

(WT101893MA) to CSW.

Conflict of interest

No conflict of interest.

CA carbamate

CDC Centers for Disease Control and Prevention

DDT dichlorodiphenyltrichloroethane

DNA deoxyribonucleic acid

Acronyms

#### 5. Behavioural resistance to insecticides used in public health

As we have mentioned previously, the extraordinary success of malaria reduction in Africa is largely due the use of insecticides applied indoors through LLINs and IRS [6]. This malaria control approach takes advantage of the strong human preference, as well as the indoor feeding and resting behaviour of African malaria-transmitting mosquitoes [128]. As we have shown in this chapter, progress has been made in understanding the genetic basis of the ability of mosquitoes to survive insecticide entering the body. However, little is known about the causes of increasingly reported changes in blood-feeding behaviour developed by certain species of malaria-transmitting mosquitoes to avoid exposure to insecticides [7]. This phenomenon is known as behavioural resistance and it is defined as any modification in insect behaviour that helps to circumvent the lethal effects of insecticides. Thus, through intraspecific behavioural shifts in biting time, location and host preference, malaria-transmitting mosquitoes avoid exposure to insecticides, feeding on humans when most people are not protected [129], jeopardising the current control strategy in Africa primarily based on indoor application of insecticides [130–132]. Recent studies conducted in West and East Africa have shown that indoor application of insecticides may induce intraspecific behavioural shifts towards early biting, exophagic biting and exophilic resting behaviour in malaria-transmitting mosquitoes [130, 131, 133]. Similarly, current studies conducted in Central Africa showed a comparable shift towards exophilic resting behaviour [134]. Mathematical modelling and field evidences have proved that these shifts in blood-feeding behaviour could threaten and impact on the current control programmes [132, 135]. The mechanisms driving these shifts have not yet been elucidated, although some studies have shown that both genetic and environmental factors play a key role [135, 136].

#### 6. Conclusion and perspectives

Insecticide resistance is undoubtedly a major challenge to the control of malaria vectors worldwide as it limits the tools available to achieve the goal of controlling and eliminating this debilitating disease. It is therefore of the utmost importance that novel insecticides and new control tools be designed to help manage and mitigate the impact of resistance. Through the work of various partners such as Innovative Vector Control Consortium (IVCC), UNITAID and several manufacturers, the challenge of producing new insecticides and tools is beginning to be met. This is exemplified by the recent prequalification by the WHO of the new insecticide Sumishield (clothianidin, a neonicotinoid) in October 2017. This new insecticide together with the organophosphate Actellic (pirimiphos-methyl) could now allow countries to effectively design and implement suitable resistance management strategies for IRS interventions according to WHO's Global Plan for Insecticide Resistance Management (GPIRM). With other new insecticides expected to enter the market in the near future, resistance management strategies such as rotation of insecticides could become more realistic to implement. However, even with new insecticides available, the community should avoid being complacent as the mosquitoes will surely develop resistance with time if consideration is not given to how to use such new insecticides including between public health and agriculture sectors. Detection of resistance markers notably for metabolic resistance is also urgently needed to not only track the spread of resistance but to better assess its impact on control interventions or mosquito fitness and malaria transmission. The recent detection of markers such as L119F-GSTe2 in An. funestus shows that this is possible, but more efforts are needed focusing importantly on cytochrome P450s, the key metabolizers. It will be important to take advantage of the advances in genomics with the power of next-generation sequencing tools to detect potential resistance markers early enough to allow control programmes to track resistance when it is still at early stage when it could easily be managed. This will allow avoiding repeating the situation observed with PY resistance and ensure a continued effectiveness of current and future insecticide-based interventions.
