**2. Current malaria situation**

#### **2.1. Brazil**

Brazil had been reporting the highest number of malaria cases in Latin America for many years, but this shifted in 2015. Venezuela, with the growing economic and political crisis, had the dubious distinction of the highest estimated incidence of malaria in the region [38]. Recently, Brazil reported the second highest number of malaria cases (18%), down from 24% of cases in 2015 [1, 38]. Furthermore, Brazil recorded a 76.8% decrease in malaria incidence during 2000–2014 [4], even though transmission was observed to be ongoing in 808 municipalities in 2013 [13]. Nearly all malaria cases (99.5%) in Brazil are reported in the Amazon region, an enormous territory that covers an estimated 60% of Brazil and consists of nine States: Acre, Amazonas, Amapá, Maranhão, Mato Grosso, Pará, Rondônia, Roraima, and Tocantins [4]. The State with the most malaria cases and highest API since 2005 is Acre; the region within Acre with the highest-risk cluster is Vale do Juruá [39] including the municipalities of Cruzeiro do Sul, Mâncio Lima, and Rodrigues Alves that are persistent malaria hot-spots [40]. Other States with API >50 as of 2015 include Amapá, Amazonas, Pará, and Roraima (**Figure 1**).

Across the Brazilian Amazon, the proportion of *P. falciparum* cases has been declining steadily for several years (**Table 1**), and in 2015, this parasite comprised approximately 11% of all cases, with *P. vivax* responsible for the remaining 89% [4]. In 2015, the Brazilian Ministry of Health (MOH) launched The Plan for Elimination of Malaria in Brazil, which focuses on the elimination of *P. falciparum* [46]. It is comprehensive, but substantial challenges remain: behavioral heterogeneity of the primary vector *Ny. darlingi* means that LLINs are only partially effective; most Amazonian housing structures do not meet criteria for routine IRS application; larviciding is most effective for accessible stagnant water bodies, e.g., fish ponds, especially those associated with hot-spots, but not effective for many natural water bodies, which may be difficult to identify and reach, or for streams and rivers with slow-moving water, which are typical *Ny. darlingi* habitats [47, 48]. By the end of 2016, *P. falciparum* still accounted for 11% of all malaria infections reported, and near the end of 2017, this was 10.8% (**Table 1**). In 2016–2017, Brazil was challenged by malaria resurgence, including in municipalities that were in the prevention phase and others with low malaria transmission. Furthermore, the total number of malaria cases in Brazil has increased from 105,057 cases during the period January 1 to December 31, 2016, to 154,343 cases during the period January 1 to October 31, 2017, an increase of 47% [42]. Some of the roadblocks in reducing and eliminating *P. vivax* include the high frequency of low-density *P. vivax* infections and the difficulty of their diagnosis by microscopy, particularly in areas approaching elimination and the persistence of liver stage hypnozoites that may be responsible for relapses [2, 4, 49]. Peri-urban and urban malaria transmission has been difficult to eliminate in cities such as Manaus (Amazonas State) and Cruzeiro do Sul (Acre State). In 2015, Manaus reported 7300 cases, most of which were acquired during work or other activities in neighboring municipalities, suggesting that interventions need to be focused on the mobile proportion of the human population [13]. Better transmission control is thought to lead to a lower *P. falciparum:P. vivax* ratio, reflecting the rapid and stable reduction of cases in urban settings compared with a lower and more heterogeneous reduction in rural and indigenous areas [13]. In a study based in and around the small cities of Mâncio Lima and Rodrigues Alves, Acre State; three development gradients, i.e., urban-rural, rural-riverine, and housing location were analyzed for multiple households. The lowest risk (OR = 0.55, 1.23–1.12) of

Note: Source of malaria case numbers 2014–2016 is WHO (2017); 2017 data are from individual Ministry of Health

**Table 1.** Number of malaria cases of *Plasmodium vivax* and *P. falciparum* in Brazil, Colombia, Peru, and Venezuela

Number of malaria positive cases

Malaria Transmission in South America—Present Status and Prospects for Elimination

*P. vivax P. falciparum P. vivax P. falciparum P. vivax P. falciparum P. vivax P. falciparum*

Number of malaria positive cases

285

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**Country 2014 2015 2016 2017**

Number of malaria positive cases

Brazil 117,009 22,234 122,743 15,445 110,343 13,829 172,876 21,017 Colombia 20,129 20,634 21,987 26,061 32,635 49,974 22,405 29,404 Peru 54,819 10,416 49,287 12,569 41,287 15,319 40,564 12,697 Venezuela 62,850 27,843 100,880 35,509 179,554 61,034 246,859 53,330

Number of malaria positive cases

websites from each of the four countries.

(2014–2017) [1, 42–45].

**Figure 1.** Geographical location of municipalities in Brazil, Colombia, Peru and Venezuela reporting Annual Parasite Index (API) >50 for data based on 2015 [38, 41].


**2. Current malaria situation**

284 Towards Malaria Elimination - A Leap Forward

Brazil had been reporting the highest number of malaria cases in Latin America for many years, but this shifted in 2015. Venezuela, with the growing economic and political crisis, had the dubious distinction of the highest estimated incidence of malaria in the region [38]. Recently, Brazil reported the second highest number of malaria cases (18%), down from 24% of cases in 2015 [1, 38]. Furthermore, Brazil recorded a 76.8% decrease in malaria incidence during 2000–2014 [4], even though transmission was observed to be ongoing in 808 municipalities in 2013 [13]. Nearly all malaria cases (99.5%) in Brazil are reported in the Amazon region, an enormous territory that covers an estimated 60% of Brazil and consists of nine States: Acre, Amazonas, Amapá, Maranhão, Mato Grosso, Pará, Rondônia, Roraima, and Tocantins [4]. The State with the most malaria cases and highest API since 2005 is Acre; the region within Acre with the highest-risk cluster is Vale do Juruá [39] including the municipalities of Cruzeiro do Sul, Mâncio Lima, and Rodrigues Alves that are persistent malaria hot-spots [40]. Other States with API >50 as of 2015 include Amapá, Amazonas, Pará, and

**Figure 1.** Geographical location of municipalities in Brazil, Colombia, Peru and Venezuela reporting Annual Parasite

**2.1. Brazil**

Roraima (**Figure 1**).

Index (API) >50 for data based on 2015 [38, 41].

Note: Source of malaria case numbers 2014–2016 is WHO (2017); 2017 data are from individual Ministry of Health websites from each of the four countries.

**Table 1.** Number of malaria cases of *Plasmodium vivax* and *P. falciparum* in Brazil, Colombia, Peru, and Venezuela (2014–2017) [1, 42–45].

Across the Brazilian Amazon, the proportion of *P. falciparum* cases has been declining steadily for several years (**Table 1**), and in 2015, this parasite comprised approximately 11% of all cases, with *P. vivax* responsible for the remaining 89% [4]. In 2015, the Brazilian Ministry of Health (MOH) launched The Plan for Elimination of Malaria in Brazil, which focuses on the elimination of *P. falciparum* [46]. It is comprehensive, but substantial challenges remain: behavioral heterogeneity of the primary vector *Ny. darlingi* means that LLINs are only partially effective; most Amazonian housing structures do not meet criteria for routine IRS application; larviciding is most effective for accessible stagnant water bodies, e.g., fish ponds, especially those associated with hot-spots, but not effective for many natural water bodies, which may be difficult to identify and reach, or for streams and rivers with slow-moving water, which are typical *Ny. darlingi* habitats [47, 48]. By the end of 2016, *P. falciparum* still accounted for 11% of all malaria infections reported, and near the end of 2017, this was 10.8% (**Table 1**). In 2016–2017, Brazil was challenged by malaria resurgence, including in municipalities that were in the prevention phase and others with low malaria transmission. Furthermore, the total number of malaria cases in Brazil has increased from 105,057 cases during the period January 1 to December 31, 2016, to 154,343 cases during the period January 1 to October 31, 2017, an increase of 47% [42].

Some of the roadblocks in reducing and eliminating *P. vivax* include the high frequency of low-density *P. vivax* infections and the difficulty of their diagnosis by microscopy, particularly in areas approaching elimination and the persistence of liver stage hypnozoites that may be responsible for relapses [2, 4, 49]. Peri-urban and urban malaria transmission has been difficult to eliminate in cities such as Manaus (Amazonas State) and Cruzeiro do Sul (Acre State). In 2015, Manaus reported 7300 cases, most of which were acquired during work or other activities in neighboring municipalities, suggesting that interventions need to be focused on the mobile proportion of the human population [13]. Better transmission control is thought to lead to a lower *P. falciparum:P. vivax* ratio, reflecting the rapid and stable reduction of cases in urban settings compared with a lower and more heterogeneous reduction in rural and indigenous areas [13]. In a study based in and around the small cities of Mâncio Lima and Rodrigues Alves, Acre State; three development gradients, i.e., urban-rural, rural-riverine, and housing location were analyzed for multiple households. The lowest risk (OR = 0.55, 1.23–1.12) of having a household with malaria was along the rural-riverine gradient, the most forested of the three; in contrast, the highest risk (OR = 1.92, 1.03–3.92) was along the urban-rural gradient, where urbanization was associated with roads, basic services, water treatment, electricity from a power grid, and less forest access [40]. This is an interesting and important finding, because malaria is so often assumed to be rural, associated with nearby water bodies and often linked to the forest environment. However, malaria risk is clearly linked with poverty, as another important finding of this study was that malaria risk is higher for poor individuals living in rural areas than those living in urban areas [40]. The poor in urban areas generally are exposed less frequently to biting, infected *Nyssorhynchus* and *Anopheles* mosquitoes, and have better access to health services than the poor in rural areas [40].

Malaria transmission in Colombia has mainly been rural, but a recent study indicated that between 2008 and 2012, urban and peri-urban malaria transmission described as endemic, unstable and of low intensity, occurred in many municipalities in the Pacific Coast and a few in eastern Colombia [53]. However, the authors indicated that a serious limitation was not having a clear consensus on the definition of urban and peri-urban. Nevertheless, there appears to be a trend of decreasing rural and a concurrent progressive increase of urban malaria. Possible explanations of this phenomenon are human migration resulting from ongoing-armed conflict, illegal mining, or illicit crop activities, and the movement of asymptomatic carriers.

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In western and northwestern Colombia, with the existing healthcare and disease prevention programs, gold-mining (mostly illegal) has played an important role in the maintenance of malaria as shown by public health surveillance data based on 2010–2013 [26]. This study showed that gold-mining was predominant in seven Colombian Departments that contributed 89.3% (270,753 cases) of the national malaria cases during this period; of which, 31.6% of the cases were from mining areas. The worst of these were located in Antioquia, Córdoba, and

Vector control interventions in Colombia rely on the use of insecticides, larvicides, and ITNs [54] to reduce human-vector contact. Some research groups focused on mosquito vector biology aiming to provide baseline information for the development and implementation of appropriate vector control interventions by the evaluation of ecology and biology of vector species, improved species identification, spatio-temporal distribution, biting behavior and

A comprehensive early warning system, as part of the Integrated National Adaptation Pilot project and the Integrated Surveillance and Control System at the municipality level, has been implemented in four pilot sites in Colombia, where it showed promise, providing new data on malaria incidence and seasonality, vector species presence and abundance, entomological indices and feeding frequencies, climate variables, human population information, and some data on vector control activities [61]. Limitations that remained included the scarcity and difficulty of accessing cultural qualitative and quantitative factors and the limited preparedness

of State and municipal health authorities to implement malaria dynamic models [61].

The most recent WHO data showed that Peru reported an estimated 14.3% of all malaria cases in the region for 2016; this amounted to 56,606 cases, of which 73% were *P. vivax* [1]. This estimate has been rising fairly steadily since 2010–2011, ever since cessation of the international financial support provided by the Global Fund Malaria Project "PAMFRO" that had successfully reduced the annual incidence to <1 case/1000 inhabitants for 2010 and 2011 [62]. After 2011, there was a surprisingly rapid malaria resurgence, hypothesized to be due to: (1) budgetary constraints; (2) the perception that malaria was under control; and (3) a concurrent regional dengue epidemic in Loreto [63]. Transmission may have been worsened due to the historic Loreto flood of 2011–2012 that inundated and damaged many riverine communities [62]. During the period between 2002 and 2013, 79% of cases were *P. vivax* and 21% *P. falciparum* [11]. A worrisome trend has been the recent increase in the proportion of *P.* 

Buenaventura municipalities in Valle del Cauca.

**2.3. Peru**

preferences, and natural infection by *Plasmodium* [55–60].

*falciparum* in 2016 (27%) and 2017 (24%) (**Table 1**).

A valuable epidemiological tool was developed in 2010 to identify malaria outbreaks via an automated algorithm [50]. Use of the algorithm aimed to mobilize local control managers to act as rapidly as possible and they identified *P. vivax* as the primary causative pathogen for nearly all outbreaks, most of which occur in low or interrupted transmission areas where the likelihood of reintroduction is high. In 2014 and 2015, as many 112 and 111 outbreaks were identified, respectively [13]. The effectiveness of this tool has not been validated but it demonstrated usefulness in transmission reduction, which could lead to widespread adoption in Brazil.

#### **2.2. Colombia**

In 2016, Colombia recorded 83,227 cases, the third highest number in Latin America, which comprised 15.3% [1, 41]. Thus, malaria continues to be a serious public health problem and transmission is heterogeneous, presenting zones of low unstable transmission with endemicepidemic patterns including various hot-spots [12]. From 2000 to 2014, Colombia made solid gains against malaria (50–75% reduction in cases), mainly due to interventions such as diagnostic health posts and vector control. However, these gains have been undermined since the Colombia Malaria Project ended in 2015; case numbers doubled between 2015 and 2016 [41].

For the past decade, *P. vivax* accounted for approximately 70% of reported cases, with the remainder exclusively *P. falciparum* [12]. However, in 2016, this proportion shifted alarmingly in favor of *P. falciparum* constituting 60% of reported cases [1, 41, 43, 51, 52]. This parasite species predominates along the Pacific Coast, one of the endemic hot-spots, where there is a high occurrence of Colombian Afro-descendant individuals who are Duffy-negative [53].

Taken together, eight Colombia Departments accounted for 90.8% of all the 2016 noncomplicated malaria cases. These are Chocó, Nariño, and Cauca (western Colombia), Antioquia and Córdoba (northwestern), Guainía and Vichada (central-eastern along the border with Venezuela), and Amazonas (southeastern). Among various Departments, Chocó was worst affected and contributed 53% of all reported cases during 2014–2015 [38]. Nevertheless, up to the 49th epidemiologic week of 2017, Chocó registered a lower proportion of cases (30.7% [43]) compared with the same period in 2015, because several health posts ceased reporting due to national, State, and municipal budgetary constraints with the closure of the Colombia Malaria Project (2015). In the Departments of Arauca and Guajira in eastern Colombia, bordering Venezuela, there was an increase in cases compared to the average number registered during 2012–2016. Of the 860 non-autochthonous cases reported overall, most (76.7%) were *P. vivax* and nearly all (93.1%) were from Venezuelan patients [43].

Malaria transmission in Colombia has mainly been rural, but a recent study indicated that between 2008 and 2012, urban and peri-urban malaria transmission described as endemic, unstable and of low intensity, occurred in many municipalities in the Pacific Coast and a few in eastern Colombia [53]. However, the authors indicated that a serious limitation was not having a clear consensus on the definition of urban and peri-urban. Nevertheless, there appears to be a trend of decreasing rural and a concurrent progressive increase of urban malaria. Possible explanations of this phenomenon are human migration resulting from ongoing-armed conflict, illegal mining, or illicit crop activities, and the movement of asymptomatic carriers.

In western and northwestern Colombia, with the existing healthcare and disease prevention programs, gold-mining (mostly illegal) has played an important role in the maintenance of malaria as shown by public health surveillance data based on 2010–2013 [26]. This study showed that gold-mining was predominant in seven Colombian Departments that contributed 89.3% (270,753 cases) of the national malaria cases during this period; of which, 31.6% of the cases were from mining areas. The worst of these were located in Antioquia, Córdoba, and Buenaventura municipalities in Valle del Cauca.

Vector control interventions in Colombia rely on the use of insecticides, larvicides, and ITNs [54] to reduce human-vector contact. Some research groups focused on mosquito vector biology aiming to provide baseline information for the development and implementation of appropriate vector control interventions by the evaluation of ecology and biology of vector species, improved species identification, spatio-temporal distribution, biting behavior and preferences, and natural infection by *Plasmodium* [55–60].

A comprehensive early warning system, as part of the Integrated National Adaptation Pilot project and the Integrated Surveillance and Control System at the municipality level, has been implemented in four pilot sites in Colombia, where it showed promise, providing new data on malaria incidence and seasonality, vector species presence and abundance, entomological indices and feeding frequencies, climate variables, human population information, and some data on vector control activities [61]. Limitations that remained included the scarcity and difficulty of accessing cultural qualitative and quantitative factors and the limited preparedness of State and municipal health authorities to implement malaria dynamic models [61].

#### **2.3. Peru**

having a household with malaria was along the rural-riverine gradient, the most forested of the three; in contrast, the highest risk (OR = 1.92, 1.03–3.92) was along the urban-rural gradient, where urbanization was associated with roads, basic services, water treatment, electricity from a power grid, and less forest access [40]. This is an interesting and important finding, because malaria is so often assumed to be rural, associated with nearby water bodies and often linked to the forest environment. However, malaria risk is clearly linked with poverty, as another important finding of this study was that malaria risk is higher for poor individuals living in rural areas than those living in urban areas [40]. The poor in urban areas generally are exposed less frequently to biting, infected *Nyssorhynchus* and *Anopheles* mosquitoes, and

A valuable epidemiological tool was developed in 2010 to identify malaria outbreaks via an automated algorithm [50]. Use of the algorithm aimed to mobilize local control managers to act as rapidly as possible and they identified *P. vivax* as the primary causative pathogen for nearly all outbreaks, most of which occur in low or interrupted transmission areas where the likelihood of reintroduction is high. In 2014 and 2015, as many 112 and 111 outbreaks were identified, respectively [13]. The effectiveness of this tool has not been validated but it demonstrated usefulness in transmission reduction, which could lead to widespread adoption in Brazil.

In 2016, Colombia recorded 83,227 cases, the third highest number in Latin America, which comprised 15.3% [1, 41]. Thus, malaria continues to be a serious public health problem and transmission is heterogeneous, presenting zones of low unstable transmission with endemicepidemic patterns including various hot-spots [12]. From 2000 to 2014, Colombia made solid gains against malaria (50–75% reduction in cases), mainly due to interventions such as diagnostic health posts and vector control. However, these gains have been undermined since the Colombia Malaria Project ended in 2015; case numbers doubled between 2015 and 2016 [41]. For the past decade, *P. vivax* accounted for approximately 70% of reported cases, with the remainder exclusively *P. falciparum* [12]. However, in 2016, this proportion shifted alarmingly in favor of *P. falciparum* constituting 60% of reported cases [1, 41, 43, 51, 52]. This parasite species predominates along the Pacific Coast, one of the endemic hot-spots, where there is a high

occurrence of Colombian Afro-descendant individuals who are Duffy-negative [53].

*P. vivax* and nearly all (93.1%) were from Venezuelan patients [43].

Taken together, eight Colombia Departments accounted for 90.8% of all the 2016 noncomplicated malaria cases. These are Chocó, Nariño, and Cauca (western Colombia), Antioquia and Córdoba (northwestern), Guainía and Vichada (central-eastern along the border with Venezuela), and Amazonas (southeastern). Among various Departments, Chocó was worst affected and contributed 53% of all reported cases during 2014–2015 [38]. Nevertheless, up to the 49th epidemiologic week of 2017, Chocó registered a lower proportion of cases (30.7% [43]) compared with the same period in 2015, because several health posts ceased reporting due to national, State, and municipal budgetary constraints with the closure of the Colombia Malaria Project (2015). In the Departments of Arauca and Guajira in eastern Colombia, bordering Venezuela, there was an increase in cases compared to the average number registered during 2012–2016. Of the 860 non-autochthonous cases reported overall, most (76.7%) were

have better access to health services than the poor in rural areas [40].

**2.2. Colombia**

286 Towards Malaria Elimination - A Leap Forward

The most recent WHO data showed that Peru reported an estimated 14.3% of all malaria cases in the region for 2016; this amounted to 56,606 cases, of which 73% were *P. vivax* [1]. This estimate has been rising fairly steadily since 2010–2011, ever since cessation of the international financial support provided by the Global Fund Malaria Project "PAMFRO" that had successfully reduced the annual incidence to <1 case/1000 inhabitants for 2010 and 2011 [62]. After 2011, there was a surprisingly rapid malaria resurgence, hypothesized to be due to: (1) budgetary constraints; (2) the perception that malaria was under control; and (3) a concurrent regional dengue epidemic in Loreto [63]. Transmission may have been worsened due to the historic Loreto flood of 2011–2012 that inundated and damaged many riverine communities [62]. During the period between 2002 and 2013, 79% of cases were *P. vivax* and 21% *P. falciparum* [11]. A worrisome trend has been the recent increase in the proportion of *P. falciparum* in 2016 (27%) and 2017 (24%) (**Table 1**).

Numerous malaria endemic riverine and highway villages exist near the Iquitos-Nauta highway and along the Itaya and Nanay Rivers to the south and west of Iquitos. Inhabitants of two of these villages, Lupuna and Cahuide, took part in a cross-sectional survey in January 2013 (off-peak malaria season), with census data taken in mid-2012. One substantial determination was that prevalence of *P. vivax* and *P. falciparum* was many times higher by packed red blood cell (PRBC)-PCR compared with microscopy (25 vs. 3.6% and 5 vs. 0.2%, respectively) [33]. Routine surveillance, using the more sensitive PCR detection method and treatment that includes individuals with very low parasitemia who maintain local transmission even during the off-peak malaria season, acting as potential parasite reservoirs, could be an effective addition to prompt diagnosis and treatment to further reduce malaria regionally. In addition, the overall heterogeneous distribution patterns of *P. vivax* and *P. falciparum* differ sharply in Lupuna and Cahuide, i.e., *P. vivax* is transmitted more locally within villages and *P. falciparum* is more often acquired at a distance, related to occupation, and transported on a regional basis [33].

prevented the procurement of malaria commodities (insecticides, drugs, diagnostic supplies, mosquito nets, etc.), epidemiological surveillance, reporting activities, vector-control and disease-treatment efforts, high internal human migration associated with illegal gold mining, and underlying malnutrition due to a general lack of provision and implementation of services. In 2016, *P. vivax* malaria accounted for 76% of all cases, followed by *P. falciparum* (18%),

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Although *P. falciparum* malaria occurs mostly in the lowland rain forests of the Venezuelan Guayana region, *P. vivax* malaria is endemic in the coastal plains and savannas, as well as the lowland Guayana forests [17]. Currently, an estimated 80% of malaria in Venezuela is associated with gold mining areas in the forest ecosystem of the southeastern region, where local transmission is maintained in few but persistent disease hot-spots by *Ny. darlingi* and *Ny. albitarsis* s.l. ([77–79]; Grillet unpublished). Infection Rates (IR) of *Ny. albitarsis* s.l. and *Ny. darlingi* collected during 2009–2012 in Sifontes, Bolivar State, were very high: 5.4 and 4.0%, respectively [80]. Gold mining extraction activities substantially reduce forest vegetation cover, which seems to favor aquatic vector habitat production, especially for *Ny. albitarsis* s.l. ([79]; Grillet unpublished). Mining activities in turn result in highly mobile human populations that migrate in search of jobs, working, and sleeping outdoors, exposed to continuous mosquito biting for long periods of time. Many of these economic migrants are previously unexposed to *Plasmodium* and some of them return to nonendemic malaria regions, e.g., near the capital Caracas, with circulating gametocytes, reintroducing *Plasmodium* to areas where malaria had been eliminated previously [81]. Although, most disease transmission in Venezuela has been rural, recent observations suggest a significant change in the landscape epidemiology of malaria since 2013—urban and peri-urban malaria transmission are now associated with some cities close to Caracas [Grillet unpublished]. Finally, case spillover has overloaded frontier health care infrastructure in Brazil and Colombia where in 2016, 78 and 81%, respectively, of imported malaria cases originated from Venezuela [2]. The continued upsurge of malaria in Venezuela threatens to become uncontrollable, jeopardizing the hard-

*P. malariae* (<1%), and *P. vivax/P. falciparum* mixed (6%) infections [1].

won gains in the Americas' elimination agenda and global malaria targets.

envision elimination as a viable outcome.

For decades, Venezuela was a leader in vector control and public health policies in Latin America, especially after being the first WHO-certified country to eliminate malaria in much of its territory in 1961 as a result of a very aggressive, vertical malaria control campaign [82]. This campaign consisted of the interruption of malaria transmission through systematic and integrative infection and vector control. Additionally, the program included the detailed knowledge of malaria microepidemiology (at local level, case management, consisting of diagnosis, patient treatment, and mass drug administration), mapping malaria cases, malaria health information system updated weekly, community participation through volunteer community health workers, application of larvicides, and sanitary engineering such as housing improvement and water management. This public health success helped to galvanize interest in global elimination [82]. The Venezuelan approach for malaria elimination in the past differs little from current prevention, control and elimination, except that it was implemented in an epidemiological landscape where insecticide and parasite resistance were absent, political will was significant, and government support was very strong. Vector control and case prevention require long-term investment and sustainability without which it is difficult to

Most years, between 90 and 95% of all malaria cases and 99.4% of *P. falciparum* are reported from Loreto Department, in northern Amazonian Peru [64]. In 2017, this amounted to 50,702 cases (96.2% of those across Peru); there were also small foci in Amazonas State (822 cases in 2017), west of Loreto, and in San Martin (415 cases in 2017), south of Loreto [64]. There was a serious *P. vivax* outbreak in the gold-mining region of the southern Amazon, in Madre de Dios and neighboring Ucayali until about 2011 [65], but only 6 cases were reported in Madre de Dios and 79 in Ucayali in 2017 [64]. In Tumbes and Piura, along the northwestern coast, malaria has greatly diminished and what remains is epidemic, sporadic, and peri-urban, likely the result of reintroduction [64, 66–68].

Loreto Department comprises an estimated 30% of Peruvian territory and there are about one million inhabitants [69]. Malaria transmission is highly seasonal, coinciding mainly with the heavy rainy season (January to June) and Andean snowmelt, that together increase river levels up to 10 m, causing major fluctuations in the abundance of the main regional malaria vector *Ny. darlingi* [70, 71]. Most malaria infections are found in rural and remote villages whose inhabitants live along the Amazon River, and its many tributaries, in enclosed or partially enclosed wooden houses [62, 72]. There has been increasing recognition, beginning with a ground-breaking study [73], of hyperendemic foci linked to occupational activities (such as timber extraction, farming, and charcoal production) and human mobility [33].

#### **2.4. Venezuela**

Whereas the continent achieved a significant decline in malaria-related morbidity (62%) and mortality (61%) between 2000 and 2015 as part of the implementation of the Global Malaria Action Plan 2008–2015 [41], Venezuela, in contrast, was the alarming exception in the region, displaying an unprecedented 365% increase in malaria cases between 2000 and 2015 [6]. In 2016 alone, 240,588 malaria cases were officially reported [1], whereas by the end of 2017, this number had increased to 300,189 total cases [45]. Astonishingly, the number of cases reported in 2017 in Venezuela is higher than that reported in the last 29 years (1988–2016) [74].

Economic and political mismanagement have precipitated a general collapse of Venezuela's health system creating an ongoing humanitarian crisis with severe social consequences [75, 76]. Consequently, a malaria epidemic has been fueled by financial constraints that prevented the procurement of malaria commodities (insecticides, drugs, diagnostic supplies, mosquito nets, etc.), epidemiological surveillance, reporting activities, vector-control and disease-treatment efforts, high internal human migration associated with illegal gold mining, and underlying malnutrition due to a general lack of provision and implementation of services. In 2016, *P. vivax* malaria accounted for 76% of all cases, followed by *P. falciparum* (18%), *P. malariae* (<1%), and *P. vivax/P. falciparum* mixed (6%) infections [1].

Numerous malaria endemic riverine and highway villages exist near the Iquitos-Nauta highway and along the Itaya and Nanay Rivers to the south and west of Iquitos. Inhabitants of two of these villages, Lupuna and Cahuide, took part in a cross-sectional survey in January 2013 (off-peak malaria season), with census data taken in mid-2012. One substantial determination was that prevalence of *P. vivax* and *P. falciparum* was many times higher by packed red blood cell (PRBC)-PCR compared with microscopy (25 vs. 3.6% and 5 vs. 0.2%, respectively) [33]. Routine surveillance, using the more sensitive PCR detection method and treatment that includes individuals with very low parasitemia who maintain local transmission even during the off-peak malaria season, acting as potential parasite reservoirs, could be an effective addition to prompt diagnosis and treatment to further reduce malaria regionally. In addition, the overall heterogeneous distribution patterns of *P. vivax* and *P. falciparum* differ sharply in Lupuna and Cahuide, i.e., *P. vivax* is transmitted more locally within villages and *P. falciparum* is more often acquired

Most years, between 90 and 95% of all malaria cases and 99.4% of *P. falciparum* are reported from Loreto Department, in northern Amazonian Peru [64]. In 2017, this amounted to 50,702 cases (96.2% of those across Peru); there were also small foci in Amazonas State (822 cases in 2017), west of Loreto, and in San Martin (415 cases in 2017), south of Loreto [64]. There was a serious *P. vivax* outbreak in the gold-mining region of the southern Amazon, in Madre de Dios and neighboring Ucayali until about 2011 [65], but only 6 cases were reported in Madre de Dios and 79 in Ucayali in 2017 [64]. In Tumbes and Piura, along the northwestern coast, malaria has greatly diminished and what remains is epidemic, sporadic, and peri-urban,

Loreto Department comprises an estimated 30% of Peruvian territory and there are about one million inhabitants [69]. Malaria transmission is highly seasonal, coinciding mainly with the heavy rainy season (January to June) and Andean snowmelt, that together increase river levels up to 10 m, causing major fluctuations in the abundance of the main regional malaria vector *Ny. darlingi* [70, 71]. Most malaria infections are found in rural and remote villages whose inhabitants live along the Amazon River, and its many tributaries, in enclosed or partially enclosed wooden houses [62, 72]. There has been increasing recognition, beginning with a ground-breaking study [73], of hyperendemic foci linked to occupational activities (such as

Whereas the continent achieved a significant decline in malaria-related morbidity (62%) and mortality (61%) between 2000 and 2015 as part of the implementation of the Global Malaria Action Plan 2008–2015 [41], Venezuela, in contrast, was the alarming exception in the region, displaying an unprecedented 365% increase in malaria cases between 2000 and 2015 [6]. In 2016 alone, 240,588 malaria cases were officially reported [1], whereas by the end of 2017, this number had increased to 300,189 total cases [45]. Astonishingly, the number of cases reported

Economic and political mismanagement have precipitated a general collapse of Venezuela's health system creating an ongoing humanitarian crisis with severe social consequences [75, 76]. Consequently, a malaria epidemic has been fueled by financial constraints that

in 2017 in Venezuela is higher than that reported in the last 29 years (1988–2016) [74].

timber extraction, farming, and charcoal production) and human mobility [33].

at a distance, related to occupation, and transported on a regional basis [33].

likely the result of reintroduction [64, 66–68].

288 Towards Malaria Elimination - A Leap Forward

**2.4. Venezuela**

Although *P. falciparum* malaria occurs mostly in the lowland rain forests of the Venezuelan Guayana region, *P. vivax* malaria is endemic in the coastal plains and savannas, as well as the lowland Guayana forests [17]. Currently, an estimated 80% of malaria in Venezuela is associated with gold mining areas in the forest ecosystem of the southeastern region, where local transmission is maintained in few but persistent disease hot-spots by *Ny. darlingi* and *Ny. albitarsis* s.l. ([77–79]; Grillet unpublished). Infection Rates (IR) of *Ny. albitarsis* s.l. and *Ny. darlingi* collected during 2009–2012 in Sifontes, Bolivar State, were very high: 5.4 and 4.0%, respectively [80]. Gold mining extraction activities substantially reduce forest vegetation cover, which seems to favor aquatic vector habitat production, especially for *Ny. albitarsis* s.l. ([79]; Grillet unpublished). Mining activities in turn result in highly mobile human populations that migrate in search of jobs, working, and sleeping outdoors, exposed to continuous mosquito biting for long periods of time. Many of these economic migrants are previously unexposed to *Plasmodium* and some of them return to nonendemic malaria regions, e.g., near the capital Caracas, with circulating gametocytes, reintroducing *Plasmodium* to areas where malaria had been eliminated previously [81]. Although, most disease transmission in Venezuela has been rural, recent observations suggest a significant change in the landscape epidemiology of malaria since 2013—urban and peri-urban malaria transmission are now associated with some cities close to Caracas [Grillet unpublished]. Finally, case spillover has overloaded frontier health care infrastructure in Brazil and Colombia where in 2016, 78 and 81%, respectively, of imported malaria cases originated from Venezuela [2]. The continued upsurge of malaria in Venezuela threatens to become uncontrollable, jeopardizing the hardwon gains in the Americas' elimination agenda and global malaria targets.

For decades, Venezuela was a leader in vector control and public health policies in Latin America, especially after being the first WHO-certified country to eliminate malaria in much of its territory in 1961 as a result of a very aggressive, vertical malaria control campaign [82]. This campaign consisted of the interruption of malaria transmission through systematic and integrative infection and vector control. Additionally, the program included the detailed knowledge of malaria microepidemiology (at local level, case management, consisting of diagnosis, patient treatment, and mass drug administration), mapping malaria cases, malaria health information system updated weekly, community participation through volunteer community health workers, application of larvicides, and sanitary engineering such as housing improvement and water management. This public health success helped to galvanize interest in global elimination [82]. The Venezuelan approach for malaria elimination in the past differs little from current prevention, control and elimination, except that it was implemented in an epidemiological landscape where insecticide and parasite resistance were absent, political will was significant, and government support was very strong. Vector control and case prevention require long-term investment and sustainability without which it is difficult to envision elimination as a viable outcome.
