Updating the Insecticide Resistance Status of Aedes aegypti and Aedes albopictus in Asia: A Systematic Review and Meta-Analysis

Background: Aedes aegypti and Aedes albopictus are two important vectors of several important arboviruses, including the dengue, chikungunya, and Zika viruses. Insecticide application is an important approach to reduce vector abundance during Aedes spp.-borne outbreaks in the absence of effective vaccines and treatments. However, insecticide overuse can result in the development of resistance, and careful monitoring of resistance markers is required. Methods: This meta-analysis and systematic review explored the spatial and temporal patterns of insecticide resistance in Asia from 2000 to 2021. PubMed, Scopus, EbscoHost, and Embase were used to enhance the search capability. The random-effects model was applied for the 94 studies that met our inclusion criteria for qualitative synthesis and meta-analysis. Results: Four major insecticides were studied (malathion, dichlorodiphenyltrichloroethane, permethrin, and deltamethrin). Dichlorodiphenyltrichloroethane resistance rates were high in both Ae. aegypti and Ae. albopictus (68% and 64%, respectively). Conversely, malathion resistance was less prevalent in Ae. aegypti (3%), and deltamethrin resistance was less common in Ae. albopictus (2%). Ae. aegypti displayed consistently high resistance rates (35%) throughout the study period, whereas the rate of insecticide resistance in Ae. albopictus increased from 5% to 12%. The rates of the major kdr mutations F1534C, V1016G, and S989P were 29%, 26%, and 22%, respectively. Conclusions: Insecticide resistance in both Ae. aegypti and Ae. albopictus is widespread in Asia, although the rates vary by country. Continuous monitoring of the resistance markers and modification of the control strategies will be important for preventing unexpected outbreaks. This systematic review and meta-analysis provided up-to-date information on insecticide resistance in dengue-endemic countries in Asia.


Introduction
Vector-borne diseases (VBDs) have become critical issues globally, being responsible for more than 700,000 deaths per year [1]. Dengue, chikungunya, and Zika are the major VBDs transmitted by Aedes mosquitoes, especially in tropical and subtropical regions [1]. These diseases are transmitted by Aedes aegypti and Aedes albopictus [2,3]. These vectors are prevalent in tropical and subtropical regions in Southeast Asia and Latin America [1]. Dengue has become endemic in 129 countries, and it is responsible for almost 390 million new infections annually [4][5][6][7]. The World Health Organization (WHO) reported that the incidence of dengue fever has increased eight-fold over the past two decades [8]. Chikungunya epidemics mainly occur in Latin America and South/Southeast Asia. Approximately 1.5 million people have contracted chikungunya in India, which has the most cases globally [9][10][11], and the disease has also spread to Indonesia, Maldives, Sri Lanka, Myanmar, 2 of 17 and Thailand [12][13][14]. Since 2013, chikungunya outbreaks have been reported in Brazil, Bolivia, Colombia, Argentina, Cuba, Costa Rica, Ecuador, and Peru [10,[15][16][17][18][19][20]. Zika outbreaks significantly impacted Latin America in 2016, causing more than 500,000 cases and nearly 2000 cases of microcephaly and/or central nervous system malformation in infants with congenital infection [21,22].
Dengue outbreaks place a significant burden on the population, economy, and health systems of the affected countries. Some countries in Asia have reported significant numbers of cases, including Bangladesh (101,000), Malaysia (131,000), the Philippines (420,000), and Vietnam (320,000) [8]. In addition, the first locally acquired cases of dengue fever in France and Spain were reported in October 2018 [23], and the recent re-emergence of dengue fever in the US [24] and Japan [25] indicates that the disease no longer has an exclusively tropical distribution.
Zika virus was first isolated from a sentinel rhesus monkey in Uganda in 1947 [33]. Before rapidly spreading across the Pacific Islands in the 21st century, Zika was documented in a small number of people in sub-Saharan Africa and then in Southeast Asia by the middle of the 20th century [34]. An unprecedented outbreak of Zika, which is linked to microcephaly and Guillain-Barré syndrome, was reported in Brazil and other Latin American countries in 2015 [35]. Zika was declared a public health emergency of international concern (PHEIC) by the WHO in February 2016 [36]. Cases of Zika have also been recently reported in several countries in Southeast Asia, including the Philippines [37], Vietnam [38], Indonesia [39][40][41], Malaysia [42], and Thailand [43].
The cocirculation of dengue, chikungunya, and Zika might have serious public health consequences for several reasons. First, the three diseases are transmitted by the same vectors, namely Ae. aegypti and Ae. albopictus, implying that their geographical distributions overlap. Second, the clinical symptoms of the diseases are similar, and misdiagnosis occurs if molecular assays are not used for diagnosis. Moreover, if a misdiagnosis were to occur, it might delay appropriate treatment or health care for severe dengue or result in brain/nervous system complications associated with Zika.
Currently, there are no effective treatments for dengue, and vaccines are under development. The one available vaccine, named Dengvaxia, has several limitations. Dengvaxia is recommended for people aged 6-45 years with previous dengue infection [44]. These limitations make it difficult to use Dengvaxia to prevent dengue transmission among vulnerable populations, such as young children and elderly persons, in dengue-endemic areas. Therefore, vector control (e.g., chemical control, biological control, source reduction, and public knowledge) is an important strategy to combat these mosquito-borne diseases. Source reduction is an extremely important strategy to reduce mosquito breeding sites through various habitat management approaches. Although community involvement in habitat management is critical, it is challenging to eliminate all breeding sites in the environment. During outbreak seasons, chemical control, such as the use of insecticides, is widely used to mitigate disease transmission quickly.
Well-managed insecticide spraying can reduce the abundance of mosquitoes effectively when outbreaks occur. There are four main classes of insecticides commonly used for vector control programs: pyrethroids, organophosphates (OPs), organochlorines (OCs), and carbamate.
OCs are chlorinated hydrocarbons that are frequently employed in the pest control industry. Insecticides belonging to this family include dieldrin, chlordane, chlorobenzoate, and dichlorodiphenyltrichloroethane (DDT). There are two subclasses of OC mechanisms: chlorinated insecticides (DDT type) and chlorinated alicyclic insecticides [45]. In mosquitoes, voltage-gated sodium channels (VGSCs) are the primary targets of DDT-type insecticides. DDT induces toxicity by maintaining the open state of sodium channels, prolonging the activation status, and gradually causing excitatory paralysis and mosquito death [46]. By contrast, chlorinated alicyclic insecticides bind to the gamma-aminobutyric acid (GABA) receptor, which is responsible for inhibiting neurotransmission, causing hyperexcitation of the nervous system [47,48].
OPs are derivatives of phosphoric acid. The most commonly used OPs are malathion, parathion, chlorpyrifos, and diazinon. The primary mechanism of OP insecticides is the inhibition of acetylcholinesterase (AChE), which can degrade acetylcholine into choline and acetic acid to halt nerve impulse transmission [49]. In the absence of AChE activity, acetylcholine continues to accumulate at the junction of the nerve cell and receptor site. Then, the continuation of nerve impulses results in the paralysis of a mosquito's muscles and, eventually, death [50,51].
Pyrethroids are synthetic analogs of pyrethrin. Similar to DDT, type I pyrethroids (permethrin, tetramethrin, allethrin, and phenothrin) interfere with the function of VGSCs to prolong neurotransmission and paralyze mosquitoes [52][53][54]. Type-II pyrethroids that contain an α-cyano group (cyfluthrin, cyhalothrin, deltamethrin, and cypermethrin) induce choreoathetosis-salivation syndrome by modulating GABA receptors [52,54,55]. GABA binds GABA A receptors on ligand-gated chloride ion channels, which control the chloride (Cl − ) influx that maintains the membrane potential of neurons. The GABA A receptor is the target of type-II pyrethroids. When the receptor is blocked by type-II pyrethroids, Cl − influx and inhibitory functions are prevented, resulting in convulsions and death [56].
The major challenge of utilizing chemical control is the emergence of insecticide resistance in the targeted populations. Insecticide resistance can be divided into four main mechanisms. Metabolic resistance involves elevated levels or activities of esterases, which metabolize or degrade insecticides before their toxic effects appear [59]. Esterase, monooxygenases, and glutathione S-transferases are the three main enzyme systems responsible for metabolic resistance [60,61]. Target site resistance refers to the genetic modification of structures targeted by certain insecticides. Resistance caused by multiple mutations in the knockdown resistance (kdr) gene on VGSCs has been studied for pyrethroids and DDT [62]. Point mutations in kdr might change the structure of specific binding sites to reduce the binding efficiency of certain insecticides [56]. In the reduced penetration mechanism, mosquito cuticles are modified to prevent or slow the absorption of insecticides [63]. Behavioral resistance refers to the behavioral response of mosquitoes that avoid contact with insecticides.
Growing urbanization and the frequent movements of people, along with climate changes, might accelerate the propagation of Ae. aegypti and Ae. albopictus and cause unexpected outbreaks in Asia [64][65][66][67]. The application of large-scale insecticide spray to control more frequent outbreaks can be expected, and the risk of emerging insecticide resistance has also been raised in Asia. Insecticide resistance has become an important public health issue that could jeopardize vector control and disease prevention. Moyes et al. reviewed multiple datasets of insecticide resistance in Ae. aegypti and Ae. albopictus from 2008 to 2015 and revealed that the patterns of resistance to two commonly used insecticides, deltamethrin for Ae. aegypti and temephos for Ae. albopictus, varied by geographical area [68]. Widespread insecticide resistance has been reported in several Asian countries, including Thailand, India, Malaysia, China, Vietnam, and Indonesia, which have a high burden of mosquito-borne diseases [69][70][71][72][73][74][75][76][77]. These studies were conducted in different settings, and they lack an integrated approach to summarizing the overall patterns of insecticide resistance in Asia. Thus, providing updated and comprehensive information on insecticide resistance in Asia is critical for insecticide sensitivity monitoring and vector control strategies. This study conducted a meta-analysis to summarize the up-to-date information on insecticide resistance in Ae. aegypti and Ae. albopictus in the Asia region from 2000 to 2021. These data will help governments and public health policymakers understand the current insecticide resistance status and modify vector control strategies accordingly.

Study Design and Search Strategy
This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement [78]. The study has been registered on PROSPERO (CRD42022291803) and reported following the Meta-analysis of Observational Research in Epidemiology guidelines [79]. We reviewed the existing published studies that reported the prevalence of insecticide resistance in Ae. aegypti and Ae. albopictus. Four databases, namely, PubMed, Scopus, EbscoHost, and Embase, were used to enhance the search capability. The search keywords were established by combining "Aedes aegypti" OR "Aedes albopictus", "Organophosphate" OR "Organochlorine" OR "Pyrethroid," AND "Resistance" The details of the search strategy are provided in Table S1.

Study Eligibility
The articles were extracted from the aforementioned databases using the aforementioned keywords. Studies utilizing insecticide bioassays and examining kdr mutations in Ae. aegypti or Ae. albopictus were included in the literature review. In addition, we limited the study region to Asia and the study period to 2000-2021. Studies based on laboratory-maintained rather than field-maintained treatment populations, those lacking quantitative data, and those focusing on behavior or biology/ecology were excluded. The detailed information of the eligible articles is presented in Table S2.

Data Extraction and Quality Assessment
Two reviewers separately extracted the data, and disagreements were resolved via discussion. The insecticide resistance rate was extracted or recalculated from eligible articles. The following variables were included in the analysis: first author's name and publication year, study period, country, bioassay method, insecticide type, insecticide class, and kdr mutation site.
We utilized the checklist created by Hoy et al. (2012) to evaluate the consistency of each study's reporting and the risk of bias [78]. This instrument contains 10 items, including 4 items assessing external validity and 6 items assessing internal validity. The items are formulated as binary questions (yes/no). Low, moderate, and high risks of bias are indicated by scores of 9-10, 7-8, and ≤6, respectively [80]. The risk of bias was moderate in 43 studies and low in 51 studies (Table S3).

Data Analysis
In total, 28 insecticide types within 5 classes were tested in this study ( Figure S1). Malathion (OP), DDT (OC), permethrin (Pyrethroid), and deltamethrin (pyrethroid) are the four major types of insecticides used in Asia and the number of studies for the four types of insecticides are 40, 34, 50, and 45, respectively ( Figure S1). Thus, the 4 types of insecticide were selected in the meta-analysis. The study outcome was the determination of the insecticide resistance prevalence rates of each insecticide in Ae. aegypti and Ae. albopictus. We also analyzed three prevalent kdr mutations (F1534C, V1016G, and S989P) in Ae. aegypti. The kdr analysis was not performed in Ae. albopictus because of the insufficient sample size. Random-effects models were applied to estimate the prevalence with a 95% confidence interval [81]. The between-study heterogeneity was evaluated using the I 2 statistic. To identify the possible sources of heterogeneity, we evaluated country, human development index (HDI), and study quality as variables in the meta-regression models. Study quality refers to the risk of bias. Lastly, visual inspection of the Doi plot and the Luis Furuya-Kanamori index (LFK index) was used to assess publication bias [82]. An asymmetrical Doi plot indicates the existence of publication bias. An LFK index of −1 to 1 indicates a symmetrical plot, an index within ±2 indicates minor asymmetry, and an index of <−2 or >2 indicates major asymmetry [83].
The meta-analysis was performed using the "metaprop" package in R (version R.3.6.3 Foundation for Statistical Computing). The spatial distributions of insecticide resistance in Asia were visualized using the geographic information system technique. The resistance maps were produced by ArcGIS Pro 2.9 (ESRI, Redlands, CA, USA).

Literature Survey
In total, 11,325 publications were extracted from the databases (Figure 1). Three additional articles were recruited from other sources. After removing duplicates and unqualified articles, 94 articles met our inclusion criteria for qualitative synthesis and meta-analysis.
Ae. aegypti. The kdr analysis was not performed in Ae. albopictus because of the insufficient sample size. Random-effects models were applied to estimate the prevalence with a 95% confidence interval [81]. The between-study heterogeneity was evaluated using the I 2 statistic. To identify the possible sources of heterogeneity, we evaluated country, human development index (HDI), and study quality as variables in the meta-regression models. Study quality refers to the risk of bias. Lastly, visual inspection of the Doi plot and the Luis Furuya-Kanamori index (LFK index) was used to assess publication bias [82]. An asymmetrical Doi plot indicates the existence of publication bias. An LFK index of −1 to 1 indicates a symmetrical plot, an index within ±2 indicates minor asymmetry, and an index of <−2 or >2 indicates major asymmetry [83].
The meta-analysis was performed using the "metaprop" package in R (version R.3.6.3 Foundation for Statistical Computing). The spatial distributions of insecticide resistance in Asia were visualized using the geographic information system technique. The resistance maps were produced by ArcGIS Pro 2.9 (ESRI, Redlands, CA, USA).

Literature Survey
In total, 11,325 publications were extracted from the databases (Figure 1). Three additional articles were recruited from other sources. After removing duplicates and unqualified articles, 94 articles met our inclusion criteria for qualitative synthesis and meta-analysis.

Spatial Patterns of Insecticide Resistance in Asia
The spatial distribution of insecticide resistance in Ae. aegypti and Ae. albopi presented in Figure 4. Ae. aegypti exhibited higher insecticide resistance rates than bopictus, especially in Southeast Asia (Figure 4a). Studies on Ae. aegypti were mainl ducted in Thailand, Malaysia, Indonesia, Singapore, Vietnam, Laos, Cambodia, Indi Pakistan. Studies on Ae. albopictus were conducted in Malaysia, Thailand, China, Ind Lanka, South Korea, and Pakistan (Figure 4b).

Spatial Patterns of Insecticide Resistance in Asia
The spatial distribution of insecticide resistance in Ae. aegypti and Ae. albopictus is presented in Figure 4. Ae. aegypti exhibited higher insecticide resistance rates than Ae albopictus, especially in Southeast Asia (Figure 4a). Studies on Ae. aegypti were mainly conducted in Thailand, Malaysia, Indonesia, Singapore, Vietnam, Laos, Cambodia, India, and Pakistan. Studies on Ae. albopictus were conducted in Malaysia, Thailand, China, India, Sri Lanka, South Korea, and Pakistan (Figure 4b).

Spatial Patterns of Insecticide Resistance in Asia
The spatial distribution of insecticide resistance in Ae. aegypti and Ae. albopictus is presented in Figure 4. Ae. aegypti exhibited higher insecticide resistance rates than Ae albopictus, especially in Southeast Asia (Figure 4a). Studies on Ae. aegypti were mainly conducted in Thailand, Malaysia, Indonesia, Singapore, Vietnam, Laos, Cambodia, India, and Pakistan. Studies on Ae. albopictus were conducted in Malaysia, Thailand, China, India, Sri Lanka, South Korea, and Pakistan (Figure 4b).  albopictus. The sizes of the circles correspond to the insecticide resistance rates.

Prevalence of Insecticide Resistance
The summarized meta-analysis results of the four major insecticides are presented in Figure 6a. The comprehensive forest plots for the major insecticides on Ae aegypti and Ae. albopictus are presented in Figure S2A-H. The overall prevalence of insecticide resistance to Ae. aegypti was 3% for malathion, 68% for DDT, 58% for permethrin, and 27% for deltamethrin. On the other hand, the prevalence of insecticide resistance to Ae. albopictus was 21% for malathion, 64% for DDT, 6% for permethrin, and 2% for deltamethrin. A subgroup analysis examined the temporal patterns of insecticide resistance by dividing the published articles into two groups (2000-2010 vs. 2011-2021; Figure 6b), and an increasing prevalence of insecticide resistance was observed in Ae. albopictus (5% vs. 12%, respectively; Figure 6b, Figure S2I-L).

Prevalence of Insecticide Resistance
The summarized meta-analysis results of the four major insecticides are presented in Figure 6a. The comprehensive forest plots for the major insecticides on Ae aegypti and Ae. albopictus are presented in Figure S2 (1-8). The overall prevalence of insecticide resistance to Ae. aegypti was 3% for malathion, 68% for DDT, 58% for permethrin, and 27% for deltamethrin. On the other hand, the prevalence of insecticide resistance to Ae. albopictus was 21% for malathion, 64% for DDT, 6% for permethrin, and 2% for deltamethrin. A subgroup analysis examined the temporal patterns of insecticide resistance by dividing the published articles into two groups (2000-2010 vs. 2011-2021; Figure 6b), and an increasing prevalence of insecticide resistance was observed in Ae. albopictus (5% vs. 12%, respectively; Figure 6b, Figure S2   Ae. aegypti featured seven kdr mutations in six codons in VGSC (Table S4), and F1534C, V1016G, and S989P were the major mutations. The F1534C, V1016G, and S989P mutation rates in Ae. aegypti were 29%, 26%, and 22%, respectively (Figure 7).  Ae. aegypti featured seven kdr mutations in six codons in VGSC (Table S4), and F1534C, V1016G, and S989P were the major mutations. The F1534C, V1016G, and S989P mutation rates in Ae. aegypti were 29%, 26%, and 22%, respectively (Figure 7).

Heterogeneity and Publication Bias
Substantial heterogeneity was observed in this analysis, and therefore, meta-regression analysis was performed to evaluate whether insecticide resistance was influenced by the country, HDI, and study quality. Significant country effects were observed in the metaregression model for Ae. aegypti (p = 0.0014). Using Thailand as the reference country, Malaysia and Vietnam displayed positive country effects (Tables S5 and S6). Country effects were also detected (p = 0.0237) for Ae. albopictus. The HDI only exhibited a statistically significant effect (p = 0.0121) for Ae. aegypti, as a higher HDI increased the insecticide resistance rate (Tables S7 and S8). The development level also affected insecticide resistance rates in Ae. aegypti. The study quality exerted a nonsignificant effect on insecticide resistance in both Ae. aegypti and Ae. albopictus (Tables S9 and S10).
Publication bias was evaluated using the Doi plot and LFK index. The Doi plot of Ae. aegypti featured minor asymmetry (LFK index = 1.34; Figure S3a), whereas major asymmetry was noted for Ae. albopictus (LFK index = 5.23; Figure S3b). The Doi plots and LFK index indicated that studies recording high insecticide resistance rates are more likely to be published.

Discussion
Our study summarized insecticide resistance patterns in both Ae. aegypti and Ae. albopictus in Asian countries, primarily focusing on malathion, DDT, permethrin, and deltamethrin, the most commonly used insecticides for vector control. In summary, malathion is the most effective insecticide against Ae. aegypti in Asia, whereas permethrin and deltamethrin remain useful for controlling Ae. albopictus.
The present results echoed previous studies in Thailand that reported high rates of deltamethrin and permethrin resistance in Ae. aegypti [74,75,77]. Conversely, the results suggested that permethrin and deltamethrin remain effective against Ae. albopictus in Malaysia. Meanwhile, the widespread use of deltamethrin and permethrin as adulticides in place of DDT could explain the emergence of insecticide resistance in Indonesia. Furthermore, the extensive resistance of Ae. aegypti to malathion in Indonesia suggested that policies supporting the widespread use of malathion fogging to control Ae. aegypti require further evaluation [68]. Similar to the findings in other Southeast Asian countries, Ae. aegypti in Singapore and Cambodia was strongly resistant to permethrin and deltamethrin, whereas malathion has retained efficacy for vector control. Moderate resistance to DTT and low-tomoderate resistance to permethrin and deltamethrin were observed for both Ae. aegypti and Ae. albopictus in South Asia.
The recent emergence of COVID-19 and the resulting lockdown policies might have contributed to an increased prevalence of dengue in Asia. Thailand, Malaysia, and Singapore implemented lockdown policies to prevent the spread of COVID-19. Thailand experienced a dengue outbreak during a lockdown for COVID-19 [84]. According to a follow-up study, the dengue prevalence in Singapore increased by approximately 37.2% among working adults because of the lockdown policy [85]. The recent dengue outbreak during the COVID-19 outbreak might have increased intensive vector control and potentially enhanced the emergence of insecticide resistance in those countries.
A previous study revealed an uncommon mutation (I1532T) in Ae. albopictus in China [86]. Another study stated that the I1532T variant has only been found in Ae. albopictus in Italy. In addition, mutations in codons 989 and 1016, which are normally found in Ae. aegypti, were also found in Ae. albopictus in Asia [68]. This finding suggests that the same mutations might arise in both species.
F1534C is the most common point mutation in kdr in Ae. aegypti. This mutation confers resistance to permethrin and deltamethrin when combined with other mutations [87,88]. The V1016G mutation is commonly found in Asia, whereas V1016I is commonly found in the Americas [68]. In some cases, coincident V1016G and S989P mutations have been found to cause a higher level of resistance [87]. Triple-mutant haplotypes (989P, 1016, and 1534C) were found in a previous study, implying the evolution of higher resistance [68]. Future studies to understand kdr mutation sites relevant to phenotypic effects are critical in Asia.
The efficiency of disease control will be jeopardized if the resistant strains become dominant in the vector populations. Furthermore, insecticides can have a significant impact on the environment and on ecosystems [89]. Alternative control measures to reduce mosquito abundance and disease transmission are being assessed in the field [90]. Genetically engineered Ae. aegypti infected with Wolbachia is a promising approach to control dengue transmission that has been tested in many countries [91]. Utarini et al. demonstrated that the Ae. aegypti wMel strain successfully reduced symptomatic dengue and hospitalization in a randomized controlled trial in Yogyakarta, Indonesia [92]. Similar evidence has been reported in Brazil and Australia [93][94][95]. Despite the successful implementation of Wolbachia-infected mosquitoes into communities, the impact of insecticide usage and Wolbachia-infected vectors is unknown. Tantowijoyo et al. compared mosquito abundance and insecticide resistance between the Wolbachia-treated and control areas in Yogyakarta. The results revealed similar insecticide resistance rates between the two groups, and the researchers concluded that insecticide resistance might not confound the Wolbachia trial [96]. At the current stage, both the novel control strategy and insecticide treatment are being implemented in a parallel manner. Thus, monitoring insecticide resistance remains critical for disease control.
This study applied meta-analysis to reveal updated insecticide resistance patterns in Asia. However, our study had some limitations. First, there is no standardized protocol or system to monitor insecticide resistance in different Asian countries. The effort to test or report resistance varied by region, and thus, reporting bias was unavoidable in our analysis. The heterogeneity and meta-regression models also reflected these issues. Second, we only included articles written in English. Collaboration with local public health workers might be important to access resistance surveys written in other languages in the future to improve the diversity of the analysis. Third, although we observed statistical evidence of publication bias in both Ae. aegypti and Ae. albopictus populations, the bias was stronger for Ae. albopictus. Additional studies focusing on Ae. albopictus are required in the future to reduce the bias and enhance knowledge regarding insecticide resistance in secondary, but more widely distributed, vectors of dengue, Zika, and chikungunya.
In summary, this study has revealed some types of insecticides that are still effective for controlling Ae. aegypti and Ae. albopictus in Asia; however, the standardized protocols for monitoring insecticide resistance should be developed and administered by public health sectors in different countries in Asia. Timely information is critical for public health workers to modify vector control strategies to prevent outbreaks

Conclusions
Insecticide resistance, especially DDT resistance, is widely distributed in both Ae. aegypti and Ae. albopictus in Asia. Ae. aegypti also displayed moderate resistance to deltamethrin and permethrin. Malathion remains effective for Ae. aegypti control, whereas deltamethrin and permethrin are effective against Ae. albopictus. Moderate rates of F1534F, V1016G, and S989P mutations in kdr were detected in Ae. aegypti. The country and HDI had different effects on the heterogeneity of the analysis, indicating that insecticide resistance in Asia is highly variable with respect to space, time, and socioeconomic factors.
Asian countries are major hotspots for dengue, Zika, and chikungunya. The emergence of insecticide resistance is a critical public health issue. Integrated vector control strategies combined with new techniques might effectively reduce the transmission of mosquitoborne disease. This study provided updated and comprehensive information on insecticide resistance in Ae. aegypti and Ae. albopictus in Asia. This information can help public health authorities in different countries to modify their control strategies and prevent future outbreaks.