Plasmodium vivax Landscape in Brazil: Scenario and Challenges
Plasmodium vivax Landscape in Brazil: Scenario and Challenges
Andre M. Siqueira 1 3
Oscar Mesones-Lapouble 0
Paola Marchesini 7
Vanderson de Souza Sampaio 1 6
Patricia Brasil 3
Pedro L. Tauil 5
Cor Jesus Fontes 4
Fabio T. M. Costa 9
Cláudio Tadeu Daniel-Ribeiro 8
Marcus V. G. Lacerda 1 2 10
Camila P. Damasceno 7
Ana Carolina S. Santelli 7
0 Pan American Health Organization , Brasilia , Brazil
1 Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas , Manaus , Brazil
2 Fundação de Medicina Tropical Dr. Heitor Vieira Dourado , Manaus , Brazil
3 Instituto Nacional de Infectologia Evandro Chagas , Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro , Brazil
4 Universidade Federal do Mato Grosso , Cuiabá , Brazil
5 Núcleo de Medicina Tropical, Universidade de Brasília , Brasilia , Brazil
6 Fundação de Vigilância em Saúde , Manaus , Brazil
7 Coordenação Geral do Programa Nacional de Controle da Malaria , Ministério da Saúde, Brasilia , Brazil
8 Instituto Oswaldo Cruz , Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro , Brazil
9 Universidade Estadual de Campinas , Campinas , Brazil
10 Instituto Leônidas e Maria Deane , Fundação Oswaldo Cruz (Fiocruz), Manaus , Brazil
Brazil is the largest country of Latin America, with a considerable portion of its territoritory within the malaria-endemic Amazon region in the North. Furthermore, a considerable portion of its territory is located within the Amazon region in the north. As a result, Brazil has reported half of the total malaria cases in the Americas in the last four decades. Recent progress in malaria control has been accompanied by an increasing proportion of Plasmodium vivax, underscoring a need for a better understanding of management and control of this species and associated challenges. Among these challenges, the contribution of vivax malaria relapses, earlier production of gametocytes (compared with Plasmodium falciparum), inexistent methods to diagnose hypnozoite carriers, and decreasing efficacy of available antimalarials need to be addressed. Innovative tools, strategies, and technologies are needed to achieve further progress toward sustainable malaria elimination. Further difficulties also arise from dealing with the inherent socioeconomic and environmental particularities of the Amazon region and its dynamic changes.
Brazil is the largest country in South America, with an area
of more than 8.5 million square kilometers and a total
population surpassing 200 million inhabitants. With much of its
territory lying within the tropical zone (of which almost 60% is in
the Amazon region) and a highly diverse flora and fauna,
there is a remarkable high receptivity to mosquito-borne
infections such as yellow fever, dengue, chikungunya, Zika
virus, and malaria.1 Malaria transmission is almost entirely
restricted to the Amazon region. For the last four decades,
Brazil has been responsible for over 30% of the malaria cases
in the Americas; in 2014, Brazil reported around 37% of the
cases in the American continent.2
The history of malaria control in Brazil comprises relevant
successes as well as major challenges and barriers.3 Until the
first half of the 20th century, malaria transmission occurred
within most of its territory, with an estimated 6 million episodes
per year in a population of 50 million inhabitants. The
strengthening of malaria control actions during the Global Malaria
Eradication Campaign in the 1950–1960s achieved transmission
interruption in the south and northeastern regions of the
country.3 In the late 1960s, malaria incidence fell below 53,000 cases
per year, with almost all of them in the northern region.4 Vastly
covered by the Amazon rainforest, this territory was
characterized by very low population densities and limited mobility
between scattered villages, explaining both the low number
of cases and even lower presumed fatality rate, attributed to
acquired immunity of those populations during that period.4,5
However, this scenario began changing in the 1970s when two
initiatives of the federal government—1) the creation of a
taxfree industrial park in the city of Manaus, located in the western
Amazon region; and 2) incentives to cattle and agricultural
colonization—led to a massive influx of people to the Amazon
region.5 The combination of a nonimmune migrant population,
inadequate housing conditions, and a vector-abundant
environment provided conditions for a rapid and sustained upsurge in
the number of malaria cases which only more recently started
showing stable signs of reduction, both in absolute numbers
(Figure 1) and in annual parasite incidence (Figure 2).
Malaria transmission in Brazil is greatly affected by
sociodemographic, political, and environmental particularities of
the Amazon region. Although there has been a reduction in
the absolute incidence of malaria in the country, an increasing
proportion of cases are caused by Plasmodium vivax, which
has become the predominating malaria-causing species in
Brazil.3 Its distinct characteristics, along with an incomplete
understanding of this species’ clinical and epidemiological
consequences create even greater challenges for transmission
control. There is an urgent need for innovative strategies,
tools, and technologies to be developed and implemented by
scientists and policy makers, especially in a scenario of rapid
socioeconomic, political, and environmental changes.4,6 Herein,
we aim to describe and discuss the dynamic landscape of
malaria epidemiology in Brazil, focusing on the challenges
for controlling P. vivax using both national and regional data.
PLASMODIUM VIVAX EPIDEMIOLOGY
Malaria incidence and species proportion. Malaria
incidence has fluctuated in Brazil, with a clear rising trend
FIGURE 1. Malaria incidence in Brazil. Absolute number of malaria cases in Brazil in the 1960–2015 period are shown as total cases (red bars)
and due to Plasmodium vivax (pale blue bars) corresponding to the left y axis. The Plasmodium falciparum:P. vivax ratio is shown as a blue line
(right y axis, Pf:Pv ratio).
starting in the late 1970s (Figures 1 and 2). The low number
of cases reported in the 1960s was restricted to small villages;
this scenario changed in the late 1970s due to a massive
migration into the Amazon region promoted by the Federal
Government during the military dictatorship.4,5
The number of cases increased from as low as 52,000 per
year in the 1960s to 550,000 in the 1980–1990s, peaking
at 637,470 in 1999, followed by a decreasing trend starting
in 2008, reaching the lowest number of cases in the last
35 years in 2015, with a total of 142,314 (Figure 1). This trend
was also shown by annual parasite index (API) restricted to
transmission areas in the Amazon region, which fell from
35 cases per 1,000 persons per year in the early 1990s to
slightly above five in 2015 (Figure 2). The decrease in malaria
incidence in recent years is a result of efficient control efforts
implemented in part due to considerable advocacy by the Roll
Back Malaria Initiative reinforced by the Federal
Government with support of local innitiatives.4
However, despite the relative success of control efforts,
malaria transmission is still ongoing in the Amazon region
and national-level outbreaks were registered in 1999 and 2005,
respectively. A variety of factors can contribute to an upsurge
including environmental ones, a lack of appropriate sanitary
conditions, and unstable socioeconomic and political scenarios.
Specifically, lack of funding and management related to
control measures, decentralization of the responsibility for
conducting surveillance from the federal to the municipality
level, and a more intense rainy season are believed to
explain the high incidence observed in 2005. A reduction
in malaria incidence leading to discontinuation of control
efforts and resources dedicated to malaria control have been
also described in other areas.7
A steady decline in the proportion of cases due to Plasmodium
falciparum starting in 1990 with a simultaneous progressive
increase in P. vivax led to the latter species becoming
predominant, and responsible for over 90% of malaria episodes in 2011.
Reasons behind this trend, apart from explanations offered in
the Biology and Epidemiology reviews in this supplement,
may include some important public health landmarks. The
creation of the National Universal Health System (SUS) in 1988,
based on free, universal health care, resulted in improved
access to diagnosis and treatment. Plasmodium vivax
proportion increased from slightly above 50% on 1983 to around
65% in 1995. During the second half of the 1990s, the Ministry
of Health implemented the Intensified Malaria Control
Program, expanding and improving diagnosis and treatment of
malaria with a focus on reducing time to treatment resulting in
around 50% of cases treated within 48 hours of symptoms.
The proportion of P. vivax reached 80% of the total in 1999,
with an increase in the overall number of cases in that year.3,4
During the following 6 years, the number of cases decreased
considerably with a decreasing proportion of P. vivax reaching
73% of the total in 2005. This coincided with the decision of
the National Malaria Control Program (NMCP) to change
the first-line treatment of P. falciparum to artemisinin-based
combinantion therapies (ACTs) following evidence of
increasing resistance of this species to quinine and doxycycline.8
Between 2005 and 2015, although the population at risk
increased by 13%, malaria incidence decreased considerably
as evidenced by reductions in API (79.2%) and total number
of cases (76.5%). This trend was accompanied by an even
more pronounced decline in the proportion of P. falciparum,
with P. vivax predominance progressively increasing to reach
88.4% in 2015.
A recent study evaluated the epidemiology impact of adopting
artesunate–mefloquine fixed-dose combination (ASMQ) for
P. falciparum in a specific area of the southwestern Amazon.9
There was a substantial decrease in total malaria incidence,
P. falciparum:P. vivax ratio and hospital admission rates. One
interesting observation was the loss of the characteristic
seasonal peak of transmission, which could result from an
increasing burden imposed by P. vivax relapses, although this was not
further investigated.9 Additional factors possibly contributing
to the relative increase of P. vivax need to be considered. For
example, due to the longer time for gametocyte production
required by P. falciparum, enhanced case detection and
prompt treatment (especially if initiated up to 72 hours after
the onset of symptoms) is considerably more effective at
controlling P. falciparum than P. vivax.10 This strategy is more
likely to have a high impact in urban areas due to
betterestablished health systems.
Sociodemographic and environmental influences. The
Amazon’s vast territory, largely composed by rainforest
intersected by numerous rivers with scattered cities and villages,
often experiences environmental changes as well as human
occupation patterns influencing malaria transmission. Since
2003, information and surveillance systems have been used to
obtain more detailed assessments of malaria epidemiology.
More than 60% of transmission occurred in rural areas, with
an impressive reduction of urban malaria corresponding to
less than 15% of cases since 2010.
During this period, malaria transmission in indigenous areas
had increased, contributing to increased mobility of some
groups and specific cultural and logistic challenges of
providing appropriate health care and controlling transmission for
this population, which involve a specific health-care
subsystem.11 As a result of strategic partnerships between the
health sector and the indigenous authorities, including the
provision of medical doctors to the indigenous communities
through the “Mais Médicos” program,12 recent improvement
in this area has been reported as a result of better logistics,
increased resources leading to more opportune diagnostics
and treatment, and the distribution of long-lasting insecticide
treated nets (LLINs).
The upward trend for P. vivax proportion was shown for
all ecotypes from 2005 until 2010, reaching a plateau at
around 90% that persisted in following years. Although a
higher proportion of P. vivax cases were detected in the
urban areas, remaining above 90% between 2008 and 2013
(94%), there was a decrease of this proportion to 88% in
2014, with a recovery in 2015 to 91%. Reasons for the drop
observed in 2014 can be related to a longer time to diagnose
and treat malaria episodes, which could be related to the
dissemination of dengue and other arboviral infections to these
areas during this period,13 which still needs to be properly
investigated. A similar pattern was observed for rural and
indigenous areas, although for the latter, it only occurred
between 2012 and 2015. These differences are consistent with
the proposition that better transmission control leads to lower
P. falciparum:P. vivax ratios, therefore reflecting the rapid and
stable reduction of cases in the urban settings as compared
with a lower and more heterogeneous rate of reduction in the
rural and indigenous areas.
The marked seasonality of malaria transmission correlates
with the rainy season, explaining the variations observed
between different subregions of the Amazon (Figure 3). This
is due to the vector population density. The most important
vector is Anopheles darlingi, which peaks at the beginning of
the dry season, with a minor peak occurring in the beginning
of the rainy season.14,15 This species has a high vectorial
capacity with high anthropophilic profile.14,16 Nontraditional vector
species infected with P. vivax have been identified in the
western Amazon, such as Anopheles braziliensis and Anopheles
nuneztovari.17 Although the vectorial potential of these species
is probably lower than that of An. darlingi,18 these findings
support an urgent need to better understand how these
mosquito-related changes affect malaria transmission.
Hydroelectric dams and gas mining fields lead to important
changes affecting the sociodemographic and environmental
landscapes and altering malaria transmission dynamics. In the
area of the Santo Antonio Dam, near the city of Porto Velho
in the southwestern Amazon region, An. darlingi was the
main vector between 2010 and 2011, with a density peak
occurring simultaneously with increasing dam water levels.19,20
Migration of workers and families into the area combined
with increasing mosquito density led to an upsurge on malaria
incidence, mainly caused by P. vivax.19,21 Discontinued
incentives to building fish farms in some areas had the adverse
effect, as many of these ended up abandoned leading to
perennial mosquito breeding sites altering the seasonality of
FIGURE 3. (A) Monthly time-series of malaria episodes of Plasmodium vivax (light-grey) and Plasmodium falciparum (dark-grey) in Brazil,
and selected states: (B) Roraima, (C) Amazonas, and (D) Acre. Acronyms in the map correspond to each state in the north region: AC = Acre;
AM = Amazonas; AP = Amapa; MT = Mato Grosso; MA = Maranhao; PA = Para; RO = Rondonia; RR = Roraima; TO = Tocantins. SC
corresponds to Santa Catarina State in the south region.
malaria as demonstrated in the municipality of Cruzeiro do
Sul.22 Sophisticated geostatistical methods have also shown an
association between fish farming pond locations and endemic
and epidemic malaria transmission.23 All these introduced
elements affecting malaria transmission need to be addressed by
specific actions and policies.
The malaria incidence male-to-female ratio has remained
unchanged between 2003 and 2015 at 2:1, supporting a
workbased risk. The malaria API according to age group decreased
for all ages in the same period. Interestingly, the highest
burden of disease is reported among the youngest age groups,
which suffer proportionally more of P. vivax than older
individuals. This may be a reflection of both particular
transmission patterns and a faster acquisition of immunity against
this species compared with P. falciparum, as suggested by
previous studies.24 Younger individuals have been shown to suffer
more from anemia when infected, with more pronounced
The contribution of relapses. Recurring P. vivax episodes
can arise from three sources: 1) reinfections in areas of
active transmission; 2) recrudescence as a result of a lack
of antischizontocidal efficacy of antimalarials; or 3) relapses,
which are the result of the activation of hypnozoites in the
liver.26 Each of these requires specific control strategies, such
as vector management, most efficacious antischizontocidal
drugs and antirelapse treatment, respectively. However, there
are currently no tools to distinguish between these three
sources, which is considered a major hindrance to the design
of tailored control actions depending on the epidemiology
characteristics of a given area.26,27
A study in Porto Velho reported in 2010 addressed this
issue by counting the number of repeated episodes within a
household. Although reinfection could not be ruled out,
authors suggested that relapses could account for as high as
30% of malaria episodes in the region.28 This finding was
similar to a more recent study conducted in a rural
settlement in the municipality of Careiro, in the western Amazon,
where a rapid decline in malaria incidence occurred between
2008 and 2011.29 Although the overall proportion of
recurring episodes within 90 days was 29.4%, this rose to 50% in
the low-incidence period, suggesting that as vector control
measures are successful, the contribution of relapses to the
disease epidemiology increases.29 Using routine surveillance
data, the number of P. vivax episodes per person per year
was evaluated for 2011 to show that from 23,365 reported
episodes at least 23% could be classified as possible relapses.
In this study, the number of episodes per person varied from
one to more than seven,30 despite regular prescription of
primaquine. The median time reported from the first episode
to first recurrence was 65 days, longer than expected, and
the interval to subsequent episodes tended to decrease
progressively.30 However, the NMCP operational definition
classifies episodes occurring within 60 days as relapses, leading
to possible missed relapses that occur with longer intervals
as well as to inappropriate classification as reinfection and
recrudescence can also be an important cause of repeated
episodes within this interval range.
Migrants and travelers followed in nonendemic reference
centers provide relevant and more unbiased information on
vivax malaria relapses, although primaquine use can confound
some of the findings. In a study undertaken in Sao Paulo,
one-third of P. vivax–infected patients treated with
chloroquine and primaquine (15 mg/day for 14 days) presented
relapses between 1 to more than 6 months after the initial
episode.31 A recent series of patients followed up in a
reference center in Rio de Janeiro described 39.6% of patients
presenting relapse, where receiving a total primaquine dose
below 3.5 mg/kg (administered during 14 days) was the most
important factor associated with recurrence.32 Six individuals
who acquired P. vivax in the Brazilian Amazon region
presented incubation periods longer than 3 months,33 with
important implications for control of this parasite in an
elimination context. Molecular studies suggest that relapses in
the region are usually the result of multiclone activation of
hypnozoites,34 as observed also in southeast Asia.35,36
Malaria hospitalization and deaths. Plasmodium falciparum
hospital admissions decreased from 5,396 in 2000 to 697 in
2012, further dropping to 288 in 2015 (Figure 4). A reduction
in malaria incidence as well as in hospital admissions, which
went from slightly below 5% in 2000–2001 to slightly above
2% in 2008, and around 1.5% between 2012 and 2015,
attributed to the result of health system improvements in the
region (Figure 4). The P. vivax admission rate remained low
around 1% from 2000 to 2006, further decreasing to 0.73%
in 2007 and 2008; however, it increased from 2009 reaching a
peak of 1.5% in 2011. It then dropped to 0.98% and 0.9% in
2013 and 2015, respectively. In a restricted setting, this same
trend had been reported in 2007 in a tertiary center in
Manaus.37 Reasons for this change are not clear and could
be related to infection-related complications, as P. vivax is
recognizably associated with severe disease,38,39 concurrent
infections,40 or treatment-related complications, as
primaquine is given without assessment of glucose-6-phosphate
dehydrogenase (G6PD) deficiency status, a topic that is
currently under investigation.
The number of malaria deaths decreased from 245 in 2000
to only 39 in 2015 Mortality in the Amazon region; however,
it is 100-fold lower (0.017%) compared with non-Amazon
regions (1.8%), a difference that could be due to delays in
diagnosis and to a higher proportion of imported P. falciparum.41
Although the malaria surveillance system registry
(SIVEP_Malaria) provides reliable case report data, there is
no communication with the national mortality registry (SIM),
resulting in 40% of reported deaths due to malaria lacking
parasite species information. As an example, among the
39 deaths in 2011 with species information, two-thirds were
due to P. vivax infection. The possibility of underreporting
cannot be underestimated, as it could be a contributing
factor not reported by the attending physicians. An autopsy
study of P. vivax–related deaths demonstrated that this
infection could be a direct or indirect cause of death.42
Malaria outbreaks. Dynamic socioeconomic changes and
favorable environmental conditions may lead to malaria
outbreaks. The predominance of P. vivax with an associated
high proportion of recurrence illustrates the resilience of this
parasite to the usual control measures in the Amazon region.
An effort to develop an automated algorithm to detect malaria
epidemics identified 338 municipalities presenting outbreaks
in 2010.43 Plasmodium vivax was the main or sole species
involved in most localities. Most epidemics were detected in
localities where transmission was low or interrupted,
demonstrating high vulnerability to reintroduction. In 2014 and 2015,
this same system identified 112 and 111 municipalities in an
outbreak situation, with alerts sent to local control managers
on a weekly basis. The impact of this online real-time system
is yet to be evaluated at local level.
FIGURE 4. Plasmodium falciparum and Plasmodium vivax hospital admissions in the period from 2000 to 2015. The left y axis shows number
of hospital admissions corresponding to P. falciparum infections (red bars) or P. vivax (purple bars). The right y axis shows percent of hospital
admissions due to P. falciparum infections (yellow line) or P. vivax infections (brown line).
No. of reported cases
“Imported case” (%)
Manaus, in the Brazilian Western Amazon region, is
among the municipalities with highest incidence of malaria
in the country.3 The intensification of the malaria control
actions led to a reduction from more than 69,000 cases in
2003 to slightly above 10,000 cases in 2012 and 7,300 cases in
2015. This decrease was accompanied by an increase in the
proportion of “imported cases,” acquired mostly during work
or leisure-related activities in neighboring municipalities
(Table 1), and indicating a need for changes in control
strategies by health authorities.
Although malaria outside the Amazon region is a relatively
small problem, it is of considerable public health importance
for two main reasons. High mobility of people from areas
of malaria transmission (nationally and internationally), results
in a need to promptly diagnose and treat new cases. The
higher lethality associated with malaria in the extra-Amazon
centers underscores the need to improve health systems in this
region to provide proper care. The second reason regards the
risk of transmission reintroduction, as anophelines are present
in most areas, including An. darlingi and other species that
usually breed in bromeliads of the Atlantic forest.44 Proper
monitoring and evaluation of innovative strategies should be
considered as tools to address non-Amazon malaria
transmission risk. An autochthonous outbreak of P. vivax occurred in
(year) in the southern state of Santa Catarina, where a mass
screening and treatment strategy could not eliminate
transmission. The population was screened by serology and every
positive case was treated, which combined with intensification of
case detection and vector control measures led to accelerated
reduction in transmission followed by sustainable elimination.45
Prevalence of G6PD deficiency. The prevalence of G6PD
deficiency in an endemic region of the Brazilian Amazon has
been estimated to be between 3.4 and 5.6% in adult males,
with the majority being of moderate activity associated to
the A-genetic variant and a small proportion of severe
ciency associated with the Mediterranean variant.46 Although
there was strong evidence of the deficient status being
protective to malaria infection, individuals with reduced G6PD activity
reported a higher incidence of jaundice and blood transfusion
when presenting malaria, probably due to primaquine-induced
hemolysis. Primaquine has been prescribed in Brazil for
decades without prior assessment of G6PD status, posing a
potential risk to the small proportion of G6PD-deficient
individuals receiving this drug, demonstrated by series of
hospitalized patients and fatal cases.42,47,48 A large population survey
of G6PD deficiency in the Amazon region is ongoing and
should provide valuable information that will help to guide
MALARIA CONTROL INTERVENTIONS
In Brazil, elimination of a species of the Anopheles
gambiae complex from the northeast region was achieved in
the 1940s, and in (year) interruption of transmission in the
southern and coastal regions was an important success during
the malaria elimination campaign.3 However, malaria in the
Amazon region is a more difficult scenario due to its low
population density and scarcity of reliable transport routes
making it operationally difficult to deliver and sustain health
care and health preventive measures. One of the mainstays of
Brazil’s universal health system is decentralization. Although
there has been some opposition to decentralize surveillance
and control activities, this process begun in 2000. Monitoring
and guidance by the NMCP is paramount for the success of
malaria control activities as there is broad variation in
management of local actions, especially in municipalities that have
recently taken these responsibilities.
Vector control. Vector-related control measures include
routine indoor residual spraying (IRS) and, since 2011, the
distribution of LLINs acquired in a Global Fund Project.
The coverage of bed nets distribution in malaria-endemic areas
increased rapidly; a distribution policy was undertaken by
each state. The impact of bed net distribution in regions
where P. vivax is predominant and relapses are supposed to
contribute to a high proportion of cases is still to be properly
evaluated. The Ministry of Health issues instructions and
provides training on the performance of vector control actions,
recommending that IRS is repeated every 4 months and
aiming for at least 80% coverage in each locality, what is not
usually achieved. A new information system for reporting
vector-control activities and entomological indicators is being
developed to allow monitoring and assessment of the extent
and also the compliance, of LLINs.
In a specific Western Amazon setting, the combination of
control measures including the distribution of LLINs and
indoor IRS, with the increase of cattle breeding activity was
associated with lower densities of An. darlingi and reduced
incidence of malaria.17
Diagnosis. There are more than 3,000 microscopy diagnostic
units in the Amazon region that performed more than
2.5 million thick blood smears in the year of 2011.49 Malaria
diagnosis in Brazil is based on both passive and active case
detection. Since 2007, most blood slides had been part of
active detection (55.9% in 2010), demonstrating the extent of
the malaria surveillance and control activities. More than 55%
of symptomatic malaria cases are treated within 48 hours of
symptoms, which is probably one of the main reasons behind
the marked reduction in the proportion of P. falciparum cases.
Despite a recent increase in rapid diagnostic test (RDT)
distribution and use from 1,486 tests in 2011 growing to 14,655 in
2015, 98% of malaria diagnosis in Brazil is still based on
microscopy. There is a high coverage of microscopy-equipped
health units, as microscopists are part of the health family
teams in the Amazon region. Microscopists are subject to
constant training and evaluation, and they also participate in other
disease control programs as they are additionally trained to
identify trypanosome, filarial, and helminthic infections in
many regions. A recent accomplishment has been the inclusion
of a malaria result field in the prenatal card to ensure that
pregnant women in endemic areas are tested for malaria, as
well as RDTs. To identify P. falciparum and non-P. falciparum
infections. Although RDT distribution was initially focused on
hard-to-reach areas, its use has been increasing both in the
Amazon and non-Amazon regions as a tool in areas where
microscopy capacity is lacking and a delay in diagnosing
malaria can lead to higher rates of complications.41
Treatment. Antimalarials in Brazil are free of charge and
only available through government facilities. Administration
requires a confirmed positive test. The malaria treatment
recommendation for P. vivax is chloroquine (25 mg/kg divided in
3 days) and primaquine (3.5 mg/kg in 7 or 14 days), apart
from pregnant women and children under 6 months of age,
which should not receive primaquine.50 The Ministry of
Health recommends the 7-day regimen in endemic regions to
ensure higher compliance with the radical cure treatment.
Directly observed therapy is not an established policy in Brazil.
There is no recommendation to assess the patient’s G6PD
deficiency status before prescribing primaquine. The compliance
with treatment in a southern Amazon location has been
estimated to be around 86%,51 but representative assessments and
research of risk factors are still necessary.
Both chloroquine and primaquine are produced by
Farmaguinhos, the public health Brazilian drug plant,
considerably reducing costs. The company has worked on a coated
chloroquine pill, to reduce bitterness, and on a coformulated
blister of chloroquine with primaquine to facilitate
compliance, especially among illiterate populations. There are no
specific pediatric formulations of antimalarials, and children
have not been routinely included in drug evaluation studies.
However, there is some evidence of more pronounced side
effects in children in response to treatment.52
In Brazil, P. falciparum infections are treated with fixed-dose
ACTs; addition of single-dose primaquine as a gametocytocide
is recommended. Artemeter–lumefantrine is the ACT used in
the Amazon region, whereas artesunate–mefloquine is used in
nonendemic regions. This decision was made based on a
preoccupation of promoting artemisinin resistance due to
mefloquine’s longer half-life. However, a recent study in the
southern amazon demonstrated that ASMQ use for a period
of 6 years (between 2006 and 2012) has not led to clinical or
molecular evidence of resistance,53 supports the decision taken
by the Therapeutics Subcommittee of the NMCP of adopting
ASMQ for the whole country. Neither chemoprophylaxis
nor mass drug administration are common practice in Brazil.
Parenteral artemisinins are recommended for severe malaria
caused by any parasite species.50
Pharmacovigilance. There is no systematic antimalarial
pharmacovigilance in Brazil, although different reports
illustrate its need. Though oral chloroquine is usually safe, it has
been demonstrated that pruritus can occur in around 20% of
patients being treated for P. vivax infection,54 with risk of
noncompletion of treatment. Adverse events associated with
primaquine use, especially hemolysis, are of greater concern55
as they can lead to severe complications.48 An autopsy series
of P. vivax patients found severe primaquine-induced
hemolysis and associated complications as the main cause of death in
two individuals.42 The lack of laboratory facilities and tests for
G6PD status assessment in the field certainly leads to G6PD
deficiency underdiagnosis and underreporting. G6PD status
and follow-up of patients receiving primaquine should be a
main focus of antimalarial pharmacovigilance system.
Drug resistance. Evidence of chloroquine-resistant P. vivax
in Brazil dates as early as 1999, with the report of a child
with parasite resistance to chloroquine and mefloquine.56 A
study of chloroquine monotherapy efficacy detected 10.1%
resistance among 107 cases in the Manaus region,57 with a
subsequent study evaluating the 28-day efficacy of
chloroquine and primaquine finding a recurrence rate of 5.2%.34
These findings, all from the Manaus region, support the
maintenance of chloroquine as first-line therapy in Brazil.
However, a recently completed trial comparing an ACT
(artesunate–amodiaquine) to chloroquine following patients
for 42 days demonstrated a considerably larger failure rate
in the chloroquine arm (under review), raising the need for
systematic and representative monitoring.
Primaquine treatment failure has been reported in settings
with expected high compliance31 even from individuals in
transmission-free areas receiving adequate doses.32 In a recent
multicenter tafenoquine trial, although only six patients from
Brazil received primaquine for 14 days the efficacy of this
regimen was considerably high, at 83%.58 More research on
possible causes of primaquine failure is needed, as well as
primaquine delivery systems that may be more effective.
SURVEILLANCE AND INFORMATION SYSTEM
The Ministry of Health, through its NMCP, is responsible
for issuing malaria recommendations and monitoring overall
and local trends on malaria incidence, intervening when
necessary. The widespread diagnosis and treatment network is
also part of the surveillance information system. For each
malaria diagnostics procedure case, either positive or negative,
is notified, a surveillance form is filled, and data are entered
online at the health center or at the corresponding regional
post. The supply of antimalarials and laboratory materials is
based on the information of number of cases, stimulating
prompt reporting of all cases, ensuring reliability of
information, and facilitating real-time monitoring of malaria
transmission. The information system underwent several changes
throughout the years and since 2003, under the acronym
SIVEP_Malaria, it is available through an online platform
with online data entering and issuing of reports.
There is, however, considerable room for improvement,
such as the implementation of a unique identifier number for
each person that will allow the routine assessment of repeated
malaria episodes per individual, as well as linkage with other
health and welfare databases. The automated algorithm to
detect epidemics has been recently made available, and is
programmed to send a weekly report to locations where the
number of cases surpasses a threshold established based on
previous years. Its efficacy is yet to be evaluated. As mentioned,
an information system specifically designed to register
vectorrelated assessments and control measures is under development
and planned to be implemented later in 2016.
Plans for malaria elimination. NMCP has recently launched
a plan for malaria elimination with a first phase goal of
eliminating P. falciparum from most of the territory in the next
(how many?) years, following World Health Organization’s
Global Technical Strategy. Although initially focused on
P. falciparum, this plan will certainly lead to a reduction of
P. vivax incidence and allow for more specific actions to be
directed toward its better management and control.
Stratification of areas according to transmission levels and
socioenvironmental characteristics is also being pursued to tailor
measures to each setting. The development and evaluation
of innovative strategies is also a priority, which needs
involvement of academia and scientists collaborating with
the NMCP to design cost-effective actions.
Key challenges for P. vivax control. Some of the main
challenges for malaria control in Brazil are the maintenance
of control actions and investments in areas of low
transmission; the use of surveillance data more readily to respond to
changing scenarios; the lack of more reliable measures of the
contribution of relapses to disease incidence; and the risk of
reemergence from neighboring countries with high transmission
rates. Specific measures need to be taken to secure that funding
and control actions are maintained at local level, requiring
collaboration with public partners outside the health sector.
It is usual for local malaria control authorities to conduct
microscopic surveys, especially in areas of outbreaks or high
transmission. However, this strategy does not detect hypnozoite
carriers and it likely misses asymptomatic individuals with low
parasitemia. Innovative diagnostic tools and strategies for
more effective screening and treatment are therefore urgently
needed. Successful experiences should be reviewed to aid in
designing and evaluating new strategies. Strategies and tools
that can identify the infectious reservoir are paramount, such
as the use of more sensitive diagnostic methods that could be
deployed in the field. An interest prospect, following the
successful experience in Santa Catarina in the 1980s is the use of
serosurveys to guide control actions, as this strategy seems to
provide reliable estimates of transmission.59
Brazil’s recent progress in malaria control can be attributed
to a combination of factors, from political commitment to
socioeconomic improvements, which leads the country toward
new needs including a better understanding and management
of P. vivax infection. This new stage will require further
involvement and boldness of both policy makers and the
scientific community for development and application of creative
and innovative tools and strategies toward better malaria
control and elimination in the Amazon context. The malaria
epidemiology history in Brazil and neighboring countries where
transmission has increased after some degree malaria control
success was achieved reveals a need for better sustained and
progressive control actions in this Latin American region.
Received March 14, 2016. Accepted for publication August 19, 2016.
Published online October 5, 2016.
Authors’ addresses: Andre M. Siqueira, Instituto Nacional de
Infectologia, Fundacao Oswaldo Cruz (Fiocruz), Rio de Janeiro,
Brazil, E-mail: . Oscar Mesones-Lapouble,
Pan American Health Organization, Brasilia, Brazil, E-mail: oscar
.. Paola Marchesini, Camila P. Damasceno, and
Ana Carolina S. Santelli, National Malaria Control Program, Brazilian
Ministry of Health, Brasilia, Brazil, E-mails: paola.b.marchesini@gmail
.com, , and anacarolina.santelli@gmail
.com. Vanderson de Souza Sampaio, Fundação de Vigilância em Saúde
do Amazonas, Manaus, Brazil, E-mail: . Patricia
Brasil, Doenças Febris Agudas, Instituto Nacional de Infectologia
Evandro Chagas, Fundacao Oswaldo Cruz (Fiocruz), Rio de Janeiro,
This is an open-access article distributed under the terms of the
Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the
original author and source are credited.
The authors are staff members of the World Health Organization.
The authors alone are responsible for the views expressed in this
article and they do not necessarily represent the decisions, policy or
views of the World Health Organization.
1. Barreto ML , Teixeira MG , Bastos FI , Ximenes RA , Barata RB , Rodrigues LC , 2011 . Successes and failures in the control of infectious diseases in Brazil: social and environmental context, policies, interventions, and research needs . Lancet 377 : 1877 - 1889 .
2. World Health Organization , 2015 . World Malaria Report 2015 . Geneva, Switzerland: World Health Organization.
3. Oliveira-Ferreira J , Lacerda MV , Brasil P , Ladislau JL , Tauil PL , Daniel-Ribeiro CT , 2010 . Malaria in Brazil: an overview . Malar J 9 : 115 .
4. Griffing SM , Tauil PL , Udhayakumar V , Silva-Flannery L , 2015 . A historical perspective on malaria control in Brazil . Mem Inst Oswaldo Cruz 110 : 701 - 718 .
5. Sampaio VS , Siqueira AM , Alecrim M , Mourao MP , Marchesini PB , Albuquerque BC , Nascimento J , Figueira EA , Alecrim WD , Monteiro WM , Lacerda MV , 2015 . Malaria in the State of Amazonas: a typical Brazilian tropical disease influenced by waves of economic development . Rev Soc Bras Med Trop 48 (Suppl 1): 4 - 11 .
6. Val FF , Sampaio VS , Cassera MB , Andrade RT , Tauil PL , Monteiro WM , Lacerda MV , 2014 . Plasmodium vivax malaria elimination: should innovative ideas from the past be revisited ? Mem Inst Oswaldo Cruz 109 : 522 - 524 .
7. Cohen JM , Smith DL , Cotter C , Ward A , Yamey G , Sabot OJ , Moonen B , 2012 . Malaria resurgence: a systematic review and assessment of its causes . Malar J 11 : 122 .
8. Alecrim MG , Lacerda MV , Mourao MP , Alecrim WD , Padilha A , Cardoso BS , Boulos M , 2006 . Successful treatment of Plasmodium falciparum malaria with a six-dose regimen of artemether-lumefantrine versus quinine-doxycycline in the western Amazon region of Brazil . Am J Trop Med Hyg 74 : 20 - 25 .
9. Santelli AC , Ribeiro I , Daher A , Boulos M , Marchesini PB , dos Santos RL , Lucena MB , Magalhaes I , Leon AP , Junger W , Ladislau JL , 2012 . Effect of artesunate-mefloquine fixed-dose combination in malaria transmission in Amazon basin communities . Malar J 11 : 286 .
10. Bousema T , Drakeley C , 2011 . Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and elimination . Clin Microbiol Rev 24 : 377 - 410 .
11. Coimbra CE Jr, Santos RV , Welch JR , Cardoso AM , de Souza MC , Garnelo L , Rassi E , Foller ML , Horta BL , 2013 . The First National Survey of Indigenous People's Health and Nutrition in Brazil: rationale, methodology, and overview of results . BMC Public Health 13 : 52 .
12. Oliveira FPd , Vanni T , Pinto HA , Santos JTRd , Figueiredo AMd , Araújo SQd , Matos MFM , Cyrino EG , 2015 . Mais Médicos: um programa brasileiro em uma perspectiva internacional . Interface (Botucatu) 19 : 623 - 634 (online).
13. Mourao MP , Bastos Mde S , Figueiredo RM , Gimaque JB , Alves Vdo C , Saraiva M , Figueiredo ML , Ramasawmy R , Nogueira ML , Figueiredo LT , 2015 . Arboviral diseases in the western Brazilian Amazon: a perspective and analysis from a tertiary health and research center in Manaus, State of Amazonas . Rev Soc Bras Med Trop 48 (Suppl 1): 20 - 26 .
14. Tadei WP , Thatcher BD , Santos JM , Scarpassa VM , Rodrigues IB , Rafael MS , 1998 . Ecologic observations on anopheline vectors of malaria in the Brazilian Amazon . Am J Trop Med Hyg 59 : 325 - 335 .
15. Vasconcelos CH , Novo EM , Donalisio MR , 2006 . Uso do sensoriamento remoto para estudar a influencia de alteracoes ambientais na distribuicao da malaria na Amazonia brasileira . Cad Saude Publica 22 : 517 - 526 .
16. Klein TA , Lima JB , Tada MS , Miller R , 1991 . Comparative susceptibility of anopheline mosquitoes in Rondonia, Brazil to infection by Plasmodium vivax . Am J Trop Med Hyg 45 : 463 - 470 .
17. Martins-Campos KM , Pinheiro WD , Vitor-Silva S , Siqueira AM , Melo GC , Rodrigues IC , Fe NF , Barbosa M , Tadei WP , Guinovart C , Bassat Q , Alonso PL , Lacerda MV , Monteiro WM , 2012 . Integrated vector management targeting Anopheles darlingi populations decreases malaria incidence in an unstable transmission area, in the rural Brazilian Amazon . Malar J 11 : 351 .
18. Scarpassa VM , Cunha-Machado AS , Saraiva JF , 2016 . Evidence of new species for malaria vector Anopheles nuneztovari sensu lato in the Brazilian Amazon region . Malar J 15 : 205 .
19. Morais SA , Urbinatti PR , Sallum MA , Kuniy AA , Moresco GG , Fernandes A , Nagaki SS , Natal D , 2012 . Brazilian mosquito (Diptera: Culicidae) fauna: I. Anopheles species from Porto Velho , Rondonia state, western Amazon, Brazil. Rev Inst Med Trop Sao Paulo 54 : 331 - 335 .
20. Gil LH , Rodrigues Mde S , de Lima AA , Katsuragawa TH , 2015 . Seasonal distribution of malaria vectors (Diptera: Culicidae) in rural localities of Porto Velho , Rondonia, Brazilian Amazon . Rev Inst Med Trop Sao Paulo 57 : 263 - 267 .
21. Katsuragawa TH , Cunha RP , de Souza DC , Gil LH , Cruz RB , Silva Ade A , Tada MS , da Silva LH , 2009 . Malaria e aspectos hematologicos em moradores da area de influencia dos futuros reservatorios das hidreletricas de Santo Antonio e Jirau , Rondonia, Brasil. Cadernos de saude publica/Ministerio da Saude, Fundacao Oswaldo Cruz. Escola Nacional de Saude Publica 25 : 1486 - 1492 .
22. Costa KM , de Almeida WA , Magalhaes IB , Montoya R , Moura MS , de Lacerda MV , 2010 . Malaria em Cruzeiro do Sul (Amazonia Ocidental brasileira): analise da serie historica de 1998 a 2008 . Rev Panam Salud Publica 28 : 353 - 360 .
23. Reis IC , Honorio NA , Barros FS , Barcellos C , Kitron U , Camara DC , Pereira GR , Keppeler EC , da Silva-Nunes M , Codeco CT , 2015 . Epidemic and endemic malaria transmission related to fish farming ponds in the Amazon frontier . PLoS One 10 : e0137521 .
24. Ladeia-Andrade S , Ferreira MU , de Carvalho ME , Curado I , Coura JR , 2009 . Age-dependent acquisition of protective immunity to malaria in riverine populations of the Amazon Basin of Brazil . Am J Trop Med Hyg 80 : 452 - 459 .
25. Siqueira AM , Cavalcante JA , Vítor-Silva S , Reyes-Lecca RC , Alencar AC , Monteiro WM , Alexandre MAA , Maria Paula GM , Guinovart C , Bassat Q , Alecrim Md GC , Lacerda MVG , 2014 . Influence of age on the haemoglobin concentration of malaria-infected patients in a reference centre in the Brazilian Amazon . Mem Inst Oswaldo Cruz 109 : 569 - 576 .
26. Shanks GD , 2012 . Control and elimination of Plasmodium vivax . Adv Parasitol 80 : 301 - 341 .
27. Battle KE , Karhunen MS , Bhatt S , Gething PW , Howes RE , Golding N , Van Boeckel TP , Messina JP , Shanks GD , Smith DL , Baird JK , Hay SI , 2014 . Geographical variation in Plasmodium vivax relapse . Malar J 13 : 144 .
28. Katsuragawa TH , Gil LH , Tada MS , de Almeida e Silva A , Costa JD , Araujo Mda S , Escobar AL , da Silva LH , 2010 . The dynamics of transmission and spatial distribution of malaria in riverside areas of Porto Velho, Rondonia, in the Amazon region of Brazil . PLoS One 5 : e9245 .
29. Vitor-Silva S , Siqueira AM , de Souza Sampaio V , Guinovart C , Reyes-Lecca RC , de Melo GC , Monteiro WM , Del Portillo HA , Alonso P , Bassat Q , Lacerda MV , 2016 . Declining malaria transmission in rural Amazon: changing epidemiology and challenges to achieve elimination . Malar J 15 : 266 .
30. Simões LR , Alves ER Jr, Ribatski-Silva D , Gomes LT , Nery AF , Fontes CJF , 2014 . Factors associated with recurrent Plasmodium vivax malaria in Porto Velho , Rondonia State , Brazil, 2009 . Cad Saude Publica 30 : 1403 - 1417 .
31. Boulos M , Amato Neto V , Dutra AP , Di Santi SM , Shiroma M , 1991 . Analise da frequencia de recaidas de malaria por Plasmodium vivax em regiao nao endemica (Sao Paulo, Brasil) . Rev Inst Med Trop Sao Paulo 33 : 143 - 146 .
32. Pedro RS , Guaraldo L , Campos DP , Costa AP , Daniel-Ribeiro CT , Brasil P , 2012 . Plasmodium vivax malaria relapses at a travel medicine centre in Rio de Janeiro, a non-endemic area in Brazil . Malar J 11 : 245 .
33. Brasil P , de Pina Costa A , Pedro RS , da Silveira Bressan C, da Silva S , Tauil PL , Daniel-Ribeiro CT , 2011 . Unexpectedly long incubation period of Plasmodium vivax malaria, in the absence of chemoprophylaxis, in patients diagnosed outside the transmission area in Brazil . Malar J 10 : 122 .
34. de Araujo FC , de Rezende AM , Fontes CJ , Carvalho LH , Alves de Brito CF , 2012 . Multiple-clone activation of hypnozoites is the leading cause of relapse in Plasmodium vivax infection . PLoS One 7 : e49871 .
35. Imwong M , Snounou G , Pukrittayakamee S , Tanomsing N , Kim JR , Nandy A , Guthmann JP , Nosten F , Carlton J , Looareesuwan S , Nair S , Sudimack D , Day NP , Anderson TJ , White NJ , 2007 . Relapses of Plasmodium vivax infection usually result from activation of heterologous hypnozoites . J Infect Dis 195 : 927 - 933 .
36. Imwong M , Boel ME , Pagornrat W , Pimanpanarak M , McGready R , Day NP , Nosten F , White NJ , 2012 . The first Plasmodium vivax relapses of life are usually genetically homologous . J Infect Dis 205 : 680 - 683 .
37. Santos-Ciminera PD , Roberts DR , Alecrim M , Costa MR , Quinnan GV Jr, 2007 . Malaria diagnosis and hospitalization trends , Brazil. Emerg Infect Dis 13 : 1597 - 1600 .
38. Lacerda MV , Mourao MP , Alexandre MA , Siqueira AM , Magalhaes BM , Martinez-Espinosa FE , Filho FS , Brasil P , Ventura AM , Tada MS , Couto VS , Silva AR , Silva RS , Alecrim MG , 2012 . Understanding the clinical spectrum of complicated Plasmodium vivax malaria: a systematic review on the contributions of the Brazilian literature . Malar J 11 : 12 .
39. Siqueira AM , Lacerda MV , Magalhaes BM , Mourao MP , Melo GC , Alexandre MA , Alecrim MG , Kochar D , Kochar S , Kochar A , Nayak K , Del Portillo H , Guinovart C , Alonso P , Bassat Q , 2015 . Characterization of Plasmodium vivax-associated admissions to reference hospitals in Brazil and India . BMC Med 13 : 57 .
40. Magalhaes BM , Siqueira AM , Alexandre MA , Souza MS , Gimaque JB , Bastos MS , Figueiredo RM , Melo GC , Lacerda MV , Mourao MP , 2014 . P. vivax malaria and dengue fever co-infection: a cross-sectional study in the Brazilian Amazon . PLoS Negl Trop Dis 8 : e3239 .
41. Pina-Costa Ad , Brasil P , Di Santi SM , de Araujo MP , Suárez-Mutis MC , Santelli AC , Oliveira-Ferreira J , Lourenço-de-Oliveira R , Daniel-Ribeiro CT , 2014 . Malaria in Brazil: what happens outside the Amazonian endemic region . Mem Inst Oswaldo Cruz 109 : 618 - 633 .
42. Lacerda MV , Fragoso SC , Alecrim MG , Alexandre MA , Magalhaes BM , Siqueira AM , Ferreira LC , Araujo JR , Mourao MP , Ferrer M , Castillo P , Martin-Jaular L , Fernandez-Becerra C , del Portillo H , Ordi J , Alonso PL , Bassat Q , 2012 . Postmortem characterization of patients with clinical diagnosis of Plasmodium vivax malaria: to what extent does this parasite kill? Clin Infect Dis 55 : e67 - e74 .
43. Braz RM , Duarte EC , Tauil PL , 2013 . Caracterizacao das epidemias de malaria nos municipios da Amazonia Brasileira em 2010 . Cad Saude Publica 29 : 935 - 944 .
44. Foley DH , Linton YM , Ruiz-Lopez JF , Conn JE , Sallum MA , Povoa MM , Bergo ES , Oliveira TM , Sucupira I , Wilkerson RC , 2014 . Geographic distribution, evolution, and disease importance of species within the Neotropical Anopheles albitarsis Group (Diptera, Culicidae) . J Vector Ecol 39 : 168 - 181 .
45. Siqueira AM , 2014 . Sleepless in the Liver . Available at: http://www .malariaworld. org/blog/column-sleepless-liver-would-revisiting-pastgive-any-directions-how-deal-hypnozoite-carriers-p . Accessed December 29 , 2014 .
46. Santana MS , Monteiro WM , Siqueira AM , Costa MF , Sampaio V , Lacerda MV , Alecrim MG , 2013 . Glucose-6-phosphate dehydrogenase deficient variants are associated with reduced susceptibility to malaria in the Brazilian Amazon . Trans R Soc Trop Med Hyg 107 : 301 - 306 .
47. Monteiro WM , Franca GP , Melo GC , Queiroz AL , Brito M , Peixoto HM , Oliveira MR , Romero GA , Bassat Q , Lacerda MV , 2014 . Clinical complications of G6PD deficiency in Latin American and Caribbean populations: systematic review and implications for malaria elimination programmes . Malar J 13 : 70 .
48. Ramos WM Junior, Sardinha JF , Costa MR , Santana MS , Alecrim MG , Lacerda MV , 2010 . Clinical aspects of hemolysis in patients with P. vivax malaria treated with primaquine, in the Brazilian Amazon . Braz J Infect Dis 14 : 410 - 412 .
49. Ministério da Saúde (Brasil), 2013 . Situação epidemiológica da malária no Brasil , 2000 a 2011 . Boletim Epidemiológico 44 : 1 - 16 .
50. Ministério da Saúde , 2010 . Guia prático de tratamento da malária no Brasil . Brasília, Brazil: Ministerio da Saúde .
51. Pereira EA , Ishikawa EA , Fontes CJ , 2011 . Adherence to Plasmodium vivax malaria treatment in the Brazilian Amazon Region . Malar J 10 : 355 .
52. Siqueira AM , Coutinho LI , Gurgel RL , Su WC , Carvalho LM , Benzecry SG , Alencar AC , Alexandre MA , Alecrim MG , Lacerda MV , 2014 . Slow clearance of Plasmodium vivax with chloroquine amongst children younger than six months of age in the Brazilian Amazon . Mem Inst Oswaldo Cruz 109 : 540 - 545 .
53. Ladeia-Andrade S , de Melo GN , de Souza-Lima Rde C , Salla LC , Bastos MS , Rodrigues PT , Luz F , Ferreira MU , 2016 . No clinical or molecular evidence of Plasmodium falciparum resistance to artesunate-mefloquine in northwestern Brazil . Am J Trop Med Hyg 95 : 148 - 154 .
54. Ballut PC , Siqueira AM , Orlando AC , Alexandre MA , Alecrim MG , Lacerda MV , 2013 . Prevalence and risk factors associated to pruritus in Plasmodium vivax patients using chloroquine in the Brazilian Amazon . Acta Trop 128 : 504 - 508 .
55. Santana MS , da Rocha MA , Arcanjo AR , Sardinha JF , Alecrim WD , Alecrim MG , 2007 . Associacao de metemoglobinemia e deficiencia de glicose-6-fosfato desidrogenase em pacientes com malaria tratados com primaquina . Rev Soc Bras Med Trop 40 : 533 - 536 .
56. Alecrim Md G , Alecrim W , Macedo V , 1999 . Plasmodium vivax resistance to chloroquine (R2) and mefloquine (R3) in Brazilian Amazon region . Rev Soc Bras Med Trop 32 : 67 - 68 .
57. de Santana Filho FS , Arcanjo AR , Chehuan YM , Costa MR , Martinez-Espinosa FE , Vieira JL , Barbosa M , Alecrim WD , Alecrim M , 2007 . Chloroquine-resistant Plasmodium vivax, Brazilian Amazon. Emerg Infect Dis 13 : 1125 - 1126 .
58. Llanos-Cuentas A , Lacerda MV , Rueangweerayut R , Krudsood S , Gupta SK , Kochar SK , Arthur P , Chuenchom N , Mohrle JJ , Duparc S , Ugwuegbulam C , Kleim JP , Carter N , Green JA , Kellam L , 2014 . Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study . Lancet 383 : 1049 - 1058 .
59. Cunha MG , Silva ES , Sepulveda N , Costa SP , Saboia TC , Guerreiro JF , Povoa MM , Corran PH , Riley E , Drakeley CJ , 2014 . Serologically defined variations in malaria endemicity in Para state, Brazil . PLoS One 9 : e113357 .