**Introduction**

**Chapter 1**

**Provisional chapter**

**Malaria Elimination: Challenges and Opportunities**

In 2016, 91 countries reported a total of 216 million cases of malaria, an increase of 5 million cases over the previous year, and the estimated malaria deaths worldwide were 445,000 like in 2015. This suggests that despite a substantial reduction in the malaria burden observed since 2010, largely attributed to the scale-up of effective control measures (vector control interventions, efficacious antimalarial treatment), the rate of decline of both clinical cases and malaria deaths has stalled since 2014 and in some regions even reversed. Achieving universal access to standard control interventions, such as case management, implementation of vector control methods, seasonal malaria chemoprevention, and intermittent preventive treatment for pregnant women, remains a priority. It is essential to contain emerging drug resistance in malarial parasite and insecticide resistance in mosquito vector species. Additional new interventions to accelerate interruption of transmission are in crucial need for their rapid integration within the standard control activities. These integrated control approaches must be implemented at community level with the active involvement of the local populations to reach high coverage. Finally, political and financial supports should be maintained and even doubled to reach the 2030 targets of the

**Keywords:** malaria elimination, mass drug administration, drug resistance, insecticide

In 2016, 91 countries reported a total of 216 million cases of malaria, an increase of 5 million cases over the previous year. The estimated number of malaria deaths worldwide was 445,000, about the same number reported in 2015 [1]. This suggests that, despite a substantial reduction in the malaria burden observed since 2010, largely attributed to the scale-up of effective control measures, including vector control interventions and treatment with

**Malaria Elimination: Challenges and Opportunities**

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

DOI: 10.5772/intechopen.77092

Umberto D'Alessandro

Umberto D'Alessandro

**Abstract**

resistance

**1. Introduction**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

WHO global technical strategy for malaria.

http://dx.doi.org/10.5772/intechopen.77092

#### **Malaria Elimination: Challenges and Opportunities Malaria Elimination: Challenges and Opportunities**

DOI: 10.5772/intechopen.77092

Umberto D'Alessandro Umberto D'Alessandro

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.77092

**Abstract**

In 2016, 91 countries reported a total of 216 million cases of malaria, an increase of 5 million cases over the previous year, and the estimated malaria deaths worldwide were 445,000 like in 2015. This suggests that despite a substantial reduction in the malaria burden observed since 2010, largely attributed to the scale-up of effective control measures (vector control interventions, efficacious antimalarial treatment), the rate of decline of both clinical cases and malaria deaths has stalled since 2014 and in some regions even reversed. Achieving universal access to standard control interventions, such as case management, implementation of vector control methods, seasonal malaria chemoprevention, and intermittent preventive treatment for pregnant women, remains a priority. It is essential to contain emerging drug resistance in malarial parasite and insecticide resistance in mosquito vector species. Additional new interventions to accelerate interruption of transmission are in crucial need for their rapid integration within the standard control activities. These integrated control approaches must be implemented at community level with the active involvement of the local populations to reach high coverage. Finally, political and financial supports should be maintained and even doubled to reach the 2030 targets of the WHO global technical strategy for malaria.

**Keywords:** malaria elimination, mass drug administration, drug resistance, insecticide resistance

## **1. Introduction**

In 2016, 91 countries reported a total of 216 million cases of malaria, an increase of 5 million cases over the previous year. The estimated number of malaria deaths worldwide was 445,000, about the same number reported in 2015 [1]. This suggests that, despite a substantial reduction in the malaria burden observed since 2010, largely attributed to the scale-up of effective control measures, including vector control interventions and treatment with

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

efficacious antimalarial medicines, the rate of decline of both clinical cases and malaria deaths has stalled since 2014 and in some regions (the Americas mainly and marginally in the Southeast Asia, Western Pacific, and African regions) even reversed [1]. The World Health Organization (WHO) has estimated that to meet the 2030 targets of global malaria strategy, a minimum investment of US\$ 6.5 billion per year by 2020 is required [2]. In 2016, such investment was US\$ 2.7 billion, less than half of that required amount, and since 2014 in many high-burden countries, investments in malaria control have declined [1]. The call for malaria eradication launched at the Malaria Forum in October 2007 by the Bill & Melinda Gates Foundation and then supported by the WHO, Roll Back Malaria (RBM) Partnership, and many other organizations and institutions seems to be at crossroads [3].

point mutations in the propeller region of a *P. falciparum* protein gene on chromosome 13 (K13) [9]. Artemisinin resistance may have spread to or emerged in Bangladesh [10] and has extended across much of Myanmar with a high prevalence of *P. falciparum* parasites carrying K13-propeller mutations reported next to the north-western border of India [11]. Resistance may have also emerged in South America, including Guyana, Suriname, French Guiana, and bordering areas of Brazil and Venezuela, [12, 13] that shares several characteristics with the GMS, increasing the risk of selecting resistant parasites. These include higher *P. falciparum* transmission than the rest of the Amazon Basin, highly mobile populations, availability and widespread use of several antimalarial drugs of questionable quality, including artemisinin monotherapies, and poor access and use of formal malaria diagnostic and treatment facilities [14]. Besides artemisinin resistance, the prevalence of molecular markers correlated to resistance to the partner drugs has increased. For example, changes in the prevalence of *pfcrt* and *pfmdr1* alleles have been observed in many areas where ACTs including amodiaquine or lumefantrine have been intensively used [4]. However, outside the GMS, recommended ACTs' efficacy remains acceptable (4). In Southeast Asia, the intensive use of dihydroartemisininpiperaquine (DP) has resulted in selection of parasites with multiple resistance mechanisms, and in Cambodia high levels of treatment failure to DP are now observed [15]. Resistance to piperaquine (clinical and *in vitro*) may be associated to *plasmepsins* 2–3, but other markers

Malaria Elimination: Challenges and Opportunities http://dx.doi.org/10.5772/intechopen.77092 5

**4. Resistance of** *Anopheles* **mosquito vectors to insecticides**

Resistance of malaria vectors to the 4 insecticide classes (pyrethroids, organochlorines, organophosphates, and carbamates) used for vector control interventions threatens malaria prevention and control efforts. Of the 76 malaria endemic countries that reported standard monitoring data from 2010 to 2016, resistance was detected in 61 countries to at least one insecticide in one malaria vector from one collection site, and 50 countries had resistance to 2 or more insecticides [1]. Resistance to pyrethroids, insecticides used in all long-lasting insecticidal nets (LLINs), is widespread though its impact on LLIN effectiveness is unclear [16]. There was no association between malaria disease burden and the level of resistance in a WHO-coordinated study implemented in 5 countries (Sudan, Kenya, India, Cameroon, and Benin) [1]. However, given the complexity in measuring the impact of insecticide resistance, it

is not possible to equate lack of evidence of impact with evidence for no impact [16].

**5. Asymptomatic malaria infections and mass drug administration** 

One of the major problems to achieve malaria elimination is represented by the hidden parasite reservoir in the human host. Microscopy (and rapid diagnostic tests (RDTs)) underestimates by about half the prevalence of *Plasmodium* infection, and this difference is greatest in lowtransmission settings—many asymptomatic infections can persist for significant periods of

could be involved [4].

**(MDA)**

#### **2. Components of malaria elimination strategy**

The WHO currently considers malaria elimination at the national level as a continuum rather than the achievement of milestones for specific phases [2]. It is structured in 4 components (A–D), each of them to be implemented according to the malaria transmission intensity. Component "A" consists of enhancing and optimizing vector control and case management, which includes universal access to malaria preventions, diagnosis, and treatment for at-risk populations, and once elimination has been achieved, "focalized" vector control programs rather than scaling back these activities; component "B" aims at increasing the sensitivity and specificity of surveillance to detect, characterize, and monitor all cases (individual and in foci), namely, to transform malaria surveillance into a core intervention; component "C" aims at accelerating transmission reduction in which new interventions such as mass drug administration (MDA) or new vaccines are included; and component "D" is implemented when transmission intensity is low to very low, which includes the search for the few remaining infections and any foci of ongoing transmission, clearing them with appropriate treatment and possibly additional vector control activities [2].

#### **3. Resistance of** *Plasmodium falciparum* **to anti-malaria drugs**

Resistance to first-line treatments for *Plasmodium falciparum* malaria and to the insecticides used for *Anopheles* vector control is threatening malaria elimination efforts [4]. Artemisinin and its derivatives provide the fastest parasite clearance among available antimalarial drugs and have been combined with an antimalarial drug of a different class in order to (i) enhance complete cure rates, (ii) shorten the duration of therapy for artemisinin monotherapies, and (iii) delay the selection and spread of resistant parasites [5, 6]. Artemisinin-based combination treatments (ACTs) are currently recommended for the management of uncomplicated malaria cases. In 2007, the first cases of delayed parasite clearance, suggesting artemisinin resistance, were observed at the Thailand-Cambodia border [7, 8]. Artemisinin resistance has now been reported in 5 countries of the Greater Mekong Subregion (GMS), which includes Cambodia, Myanmar, Laos, Thailand, and Vietnam, and delayed parasite clearance has been linked to point mutations in the propeller region of a *P. falciparum* protein gene on chromosome 13 (K13) [9]. Artemisinin resistance may have spread to or emerged in Bangladesh [10] and has extended across much of Myanmar with a high prevalence of *P. falciparum* parasites carrying K13-propeller mutations reported next to the north-western border of India [11]. Resistance may have also emerged in South America, including Guyana, Suriname, French Guiana, and bordering areas of Brazil and Venezuela, [12, 13] that shares several characteristics with the GMS, increasing the risk of selecting resistant parasites. These include higher *P. falciparum* transmission than the rest of the Amazon Basin, highly mobile populations, availability and widespread use of several antimalarial drugs of questionable quality, including artemisinin monotherapies, and poor access and use of formal malaria diagnostic and treatment facilities [14]. Besides artemisinin resistance, the prevalence of molecular markers correlated to resistance to the partner drugs has increased. For example, changes in the prevalence of *pfcrt* and *pfmdr1* alleles have been observed in many areas where ACTs including amodiaquine or lumefantrine have been intensively used [4]. However, outside the GMS, recommended ACTs' efficacy remains acceptable (4). In Southeast Asia, the intensive use of dihydroartemisininpiperaquine (DP) has resulted in selection of parasites with multiple resistance mechanisms, and in Cambodia high levels of treatment failure to DP are now observed [15]. Resistance to piperaquine (clinical and *in vitro*) may be associated to *plasmepsins* 2–3, but other markers could be involved [4].
