Epidemiology of Plasmodium vivax in Indonesia
Epidemiology of Plasmodium vivax in Indonesia
Claudia Surjadjaja 2 3
Asik Surya 1 2
J. Kevin Baird 0 2 4
0 Eijkman-Oxford Clinical Research Unit , Jakarta , Indonesia
1 Sub-Directorate for Malaria Control, Ministry of Health , Jakarta , Indonesia
2 cal Research Unit , Jalan Diponegoro No. 69, Jakarta 10430 Indonesia
3 ALERTAsia Foundation , Jakarta , Indonesia
4 Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford , Oxford , United Kingdom
Endemic malaria occurs across much of the vast Indonesian archipelago. All five species of Plasmodium known to naturally infect humans occur here, along with 20 species of Anopheles mosquitoes confirmed as carriers of malaria. Two species of plasmodia cause the overwhelming majority and virtually equal shares of malaria infections in Indonesia: Plasmodium falciparum and Plasmodium vivax. The challenge posed by P. vivax is especially steep in Indonesia because chloroquine-resistant strains predominate, along with Chesson-like strains that relapse quickly and multiple times at short intervals in almost all patients. Indonesia's hugely diverse human population carries many variants of glucose-6-phosphate dehydrogenase (G6PD) deficiency, most of them exhibiting severely impaired enzyme activity. Therefore, the patients most likely to benefit from primaquine therapy by preventing aggressive relapse, may also be most likely to suffer harm without G6PD deficiency screening. Indonesia faces the challenge of controlling and eventually eliminating malaria across > 13,500 islands stretching > 5,000 km and an enormous diversity of ecological, ethnographic, and socioeconomic settings, and extensive human migrations. This article describes the occurrence of P. vivax in Indonesia and the obstacles faced in eliminating its transmission.
Endemic transmission of the human parasite Plasmodium
vivax occurs across most of the Indonesian archipelago.1 The
number of clinical attacks cannot yet be estimated with
precision, but probably at least several million Indonesians
suffer acute vivax malaria each year. Mortality due to vivax
malaria, despite the dogma of a benign character, has been
documented repeatedly in Indonesian hospitals over the past
decade.2 This parasite poses a very significant and especially
difficult threat to the health of the 130 million Indonesians
living at risk of this infection.1
The biology and ecology of P. vivax in Indonesia imposes
relatively difficult obstacles to diagnosis, treatment, and control.
There are 20 confirmed anopheline mosquito vivax malaria
vector species in Indonesia scattered across a wide variety of
habitats and conditions optimal for malaria transmission.3
Acute vivax malaria very often comes with relatively very
low levels of parasitemia, thereby increasing the probability
of a missed diagnosis, especially by rapid diagnostic tests.4
More importantly, P. vivax places dormant stages in the liver
called hypnozoites—a single infectious anopheline bite may
result in five to 15 clinical attacks over 2 years.5 This
phenomenon amounts to malaria “transmission” without a mosquito—
the silent forms in liver called hypnozoites cannot be
diagnosed and do the attacking after becoming active weeks,
months, or several years later. Chemotherapy of those forms,
and not just those causing the acute attack, thus emerges as
a crucial aspect of containing and eliminating vivax malaria.
In most of the world, chloroquine is the front-line therapy
against acute vivax malaria; but in Indonesia, resistance to
this drug arose, spread, and became dominant against
sensitive strains.6 It has been abandoned in favor of
artemisinincombined therapies (ACTs). Many clinical trials evaluating
those options in Indonesia found them consistently safe and
effective against the acute attack by asexual blood stages of
P. vivax. But there is, nonetheless, a serious problem with
these options. Only one has been very recently confirmed as
permitting safe and efficacious administration of primaquine
with it (dihydroartemisinin–piperaquine [DHA-PP]).7
Appropriate therapy for P. vivax is not simply treating the acute
attack, but also simultaneously preventing multiple relapses
with primaquine. Demonstrating the safety and efficacy of
primaquine with each new potential blood schizonticidal
partner in radical cure of vivax malaria is a laborious and
expensive undertaking that impedes the availability of validated
therapeutic options for radical cure of P. vivax.
Perhaps the greatest impediment to the control and
elimination of vivax malaria in Indonesia is the problem of
primaquine toxicity in glucose-6-phosphate dehydrogenase–deficient
(G6PDd) patients. This hugely diverse X-linked disorder is
highly prevalent among many of Indonesia’s hundreds of
ethnic groups. The relative sensitivity to primaquine among
any of these is not known, but threatening hemolytic
reactions to primaquine therapy are widely known by anecdote
in Indonesia.8 In the absence of the ability to screen patients
for G6PDd where most malaria patients live, Ministry of
Health policy recommends a relatively low dose of
primaquine, but many providers fail to offer even that for fear of
causing harm. Patients thus have limited access to
primaquine and probably suffer multiple repeated attacks—each
one coming with further opportunities for transmission,
delayed or inappropriate therapy of the acute attack,
sickness, and death. A robust point-of-care G6PDd screening
device would enable a practical and effective attack upon the
hypnozoite reservoir in endemic communities.
In summary, vivax malaria is a very serious and challenging
health problem in Indonesia, and the National Malaria Control
Program (NMCP) faces formidable technical, logistical, and
financial obstacles in dealing with it. Access to safe
primaquine therapy may be the most difficult and important among
these. Absent such, the elimination of endemic transmission of
this parasite would probably be greatly protracted and costly.
ANOPHELINE VECTOR DISTRIBUTION
Two comprehensive reviews of the anophelines of Indonesia,
one by Takken and others9 from the 1980s, and more recently
FIGURE 1. Distribution of species of anopheline mosquitoes confirmed as malaria vectors in Indonesia, reproduced from reference 3 with
by Elyazar and others,3 are available. In general, the human
plasmodia tend to favor discreet species of anophelines, and
malaria transmission tends to occur in the habitats in which
those species thrive. Unlike the Greater Mekong Subregion
where malaria transmission tends to be dominated by
forestdwelling anopheline vectors, the Indonesian archipelago
harbors many species commonly found in plantations, aquacultural
ponds, and within villages. Such species are confirmed as
malaria vectors by the identification of human parasite stages
within them. There is no known species of anopheline malaria
vector in Indonesia that will only host Plasmodium falciparum
but not P. vivax, and vice versa. If the anopheline carries one
species, it is very likely to carry the other as well (data on the
other more rare human plasmodia are lacking on this point).
Figure 1 illustrates the complexity of anopheline distribution
and ecology in Indonesia. Twenty confirmed vector species
are known, each with its own distinct geographic distribution,
feeding and breeding preferences, and seasonality of
abundance patterns (collectively referred to as “bionomics” of the
species). The reviews cited above3,9 offer encyclopedic
descriptions of the bionomics of Indonesia’s anopheline
vectors of malaria.
DISTRIBUTION OF ENDEMIC P. VIVAX
Elyazar and others1 assembled 4,658 community-based
blood surveys for malaria conducted between 1985 and 2011
to model a map of P. vivax prevalence (Figure 2). In another
paper, the same group10 summarized all known blood surveys
for Indonesia (Table 1). In short, risk of vivax malaria occurs
almost everywhere, with exceptional zones or pockets free of
risk on Java, Bali, and Sumatra (and fewer pockets on Sulawesi
and Papua). Most major cities in Indonesia are also free of risk,
even in otherwise high-risk areas. This is because Indonesia
has no urban anophelines (e.g., Anopheles stephensi of
India). Highest risk occurs in eastern Indonesia, especially
East Nusatenggara (Lesser Sundas archipelago), Maluku,
and Papua. Most of Kalimantan and Sumatra also have large
areas of transmission, but to a much lower level of
endemicity than in most of eastern Indonesia.
The dotted line drawn through the middle of map of
Figure 2, the Wallace Line, is a zoogeographic border
between Asian and Australian flora and fauna, including
anopheline mosquitoes (Figure 1). Although this may play
some role in the contrasting malaria risks between eastern
and western Indonesia, it seems more likely that the
relatively poor economic development of the eastern regions
drives the high risk of malaria.
ENDEMIC P. VIVAX EPIDEMIOLOGY
The distribution of vivax malaria in the human population,
where it is endemic, tends to be overwhelmingly relatively
low-level transmission. Syafruddin and others11 conducted an
exhaustive cross-sectional survey (over 8,000 slides at 45 sites)
across western Sumba. Figure 3 summarizes the microscopic
parasitological findings across age groups and season (wet
versus dry). Western Sumba may be considered typical of the
hypo- to mesoendemic malaria transmission that occurs in
much of Indonesia. The prevalence of P. vivax (in peripheral
blood smears) is uniformly low (< 5%) among age groups and
varying little with seasonal rains. Sumba does have rather
sharp differences in seasonal rainfall, with a distinct monsoon
and dry season. The absence of sharp differences between
these seasons is probably a product of hypnozoite activation
(in the absence of abundant mosquitoes), as well as sufficient
diversity of anopheline species to permit transmission during
any season (only slight seasonal differences in prevalence for
falciparum malaria). Transmission of malaria on Sumba, as in
much of Indonesia, thus occurs year round with little variance
according to wet versus dry season.
This prevalence survey, along with many others from all
across Indonesia, indicates an important epidemiological
principle with malaria—risk across demographic groups is practically
invariable between the two dominant species of Plasmodium.
This is clearly seen in Figure 3. This relative homogeneity
points to equal risk of exposure by the biting anophelines
carrying each species, that is, it appears to be the same
mosquitoes and any resident at risk of infection by one species is
essentially at equal risk of infection by the other. This has
important implications regarding policy for attacking vivax
malaria because a diagnosis of P. falciparum in such settings
also carries a very high probability of carriage of P. vivax
hypnozoites. Douglas and others12 in Thailand decisively dem
onstrated this phenomenon: 51% of patients having a primary
diagnosis of P. falciparum experienced a relapse of P. vivax
within just 2 months. A diagnosis of any species of plasmodia
anywhere in endemic Indonesia should rationally and
reasonably prompt therapy against P. vivax hypnozoites.13 Treatment
policy in Indonesia does not currently recommend
presumptive primaquine therapy against hypnozoites with a diagnosis
of P. falciparum malaria, principally due to the risk of harm
caused by primaquine.
Prevalence on Sumba rarely exceeded 10% in even the
highest risk groups. Typically, it was well below 5%.
Children (but not small children) tended to have the higher
prevalence, quite a bit so compared with adults, that is, 4%
versus < 1%. These differences are very probably driven by
naturally acquired immunity, where older residents are better
able to suppress parasitemia to subpatency (no sterilizing
immunity is known in malaria).14 Most malaria transmission
in Sumba occurs within villages, especially coastal villages
FIGURE 3. Mass blood survey findings of over 8,000 residents of western Sumba Island in eastern Indonesia during 2007, reproduced from
reference 11 with permission.
exposed to the efficient vector species, Anopheles sundaicus.
The young and old are attacked with equal frequency, but
the higher burden of parasites in younger age groups (both
prevalence and density of parasites in blood) is reflected in
the trends in hemoglobin levels reported by Syafruddin and
others11 on Sumba (Figure 4).
A very important consideration in malaria epidemiology is
subpatent parasitemia, that is, those beyond diagnostic reach
by standard microscopy. Kaisar and others15 conducted a
survey for malaria parasites in blood by both microscopy
and real-time polymerase chain reaction (PCR) techniques
at Flores Island in eastern Indonesia. In their sample of
1,509 people, 52 (3.4%) were diagnosed as having malaria
by microscopic examination, whereas 399 (26%) were positive
by PCR. These data, and others like it, consistently
demonstrate that microscopically subpatent parasitemia is the rule
in Indonesia, as elsewhere (Solomon Islands, the Mekong
Region, Horn of Africa, and Amazonia).16 The long-held
presumption that natural immunity to malaria required
sustained and intense transmission needs reconsideration.
This is a vitally important consideration in the context of
eliminating malaria from settings of relatively low
transmission intensity. Figure 5 illustrates the distribution of
P. falciparum and P. vivax across age groups detected by
PCR at the study site in Flores of Kaisar and others15
Thus, endemic malaria in Flores (and nearby Sumba and
much of Indonesia) may be appreciated as largely cryptic,
that is, not causing illness and staying below the level of
detection by standard microscopy. Comparing the microscopic
and PCR surveys exemplified here, the true prevalence of
malaria, even where historically considered hypoendemic
(i.e., < 5% prevalence by microscopy), may well exceed 40%
in many settings. Further work and evidence on this key
question is urgently needed against a backdrop of strategic
planning for elimination of such possibly vast reservoirs of
infection, that is, the asymptomatic and subpatent and
infectious carriers of malaria who apparently dominate many
OUTBREAKS AND IMPORTED P. VIVAX
Excepting a few isolated pockets of stable malaria
transmission, the island of Java is largely free of malaria
transmission.17 Nonetheless, much of the island to the south of its
volcanic spine remains highly receptive to malaria. These
very few remaining foci of transmission sometimes cause
wider epidemics. An example of this occurred in the Menoreh
Hills just to the west of Yogjakarta at south Central Java in
2000. This outbreak and its ecology and epidemiology were
described by Barcus and others18 and Figure 6 illustrates
The threat of imported malaria is especially acute on Java,
where 150 million of Indonesia’s 250 million people reside.
Javanese people migrate to the outer islands of Indonesia
and frequently return home. Military populations represent
one key piece of this much larger issue, as they routinely
deploy to some of the most malarious areas of Indonesia and
engage in relatively high-risk occupational exposure (e.g.,
sleeping in impermanent quarters and night patrols). This
problem is especially acute with P. vivax because while those
soldiers receive prompt and efficient diagnosis and treatment
of acute malaria, they do not typically receive primaquine
against hypnozoites for want of G6PDd screening and fear
of causing harm. The screening and surveillance of one
battalion of 650 men followed for 1 year after such a deployment
netted only nine cases of falciparum malaria and 143 cases of
vivax malaria.7 Moreover, most of those vivax cases did not
appear at mass screening upon return to Java, but over the
months that followed, that is, relapses. Figure 7 illustrates the
timing of attack by relapse in those soldiers.
In another battalion of 532 men similarly deployed later
and followed for clinical trial purposes, 18 soldiers were found
to have P. falciparum, whereas 214 were diagnosed with acute
P. vivax; again, most attacks occurred in the 4 months after
deployment rather than immediately upon return.19
Chemoprophylaxis or presumptive radical cure of such may mitigate
risk of chronic outbreaks at sites such as Java as Indonesia
progresses in its elimination agenda.
Importation of malaria by travelers between the Outer
Islands of Indonesia, especially those to the east, will continue
to threaten success of the elimination of malaria from Java. In
contrast, Bali also has very few isolated pockets of
hypoendemic malaria (in the sparsely populated northwest of the
island), but almost no problem with outbreaks. This may be
linked to the relative prosperity of the Balinese and the
relative infrequency of travel to other islands in search of
economic opportunity compared with their Javanese neighbors.
Elyazar and others10 summarized malaria outbreaks in 2011
as follows: “Malaria outbreaks occur in Indonesia every year.
For example, in 1998 and 1999 there were outbreaks in eight
provinces, covering 10 districts with 19,483 cases and 66 deaths
(case fatality rate, CFR 0.3%; Marwoto and Sekartuti, 2003).
Between 2000 and 2005, there were outbreaks in 19 provinces,
covering 65 districts/municipalities, with 58,152 malaria cases
and 536 reported deaths (CFR 0.9%; Departemen Kesehatan,
2006c). In 2006, outbreaks occurred in eight provinces with
3705 cases and 30 reported deaths (CFR 0.8%; Departemen
Kesehatan, 2007c). Later, between 2007 and 2008, outbreaks
were reported in 11 provinces, covering 20 districts, with
1864 cases and 93 reported deaths (CFR 5%; Departemen
Kesehatan, 2009a).” According to that author, P. vivax
consistently dominates as the cause of these outbreaks (I. Elyazar,
Malaria importation and outbreaks in receptive areas where
malaria has been brought under control or eliminated is not
only a serious public health problem, but also a direct threat to
sustaining elimination where it has been achieved in Indonesia.
TRENDS IN ANNUAL PARASITE INCIDENCE
The NMCP provided data on trends in annual parasite
incidence (API) and annual proportions of reported cases
represented by the two dominant species, P. vivax and
P. falciparum. All five of the known plasmodia naturally
infecting humans occur in Indonesia, but the other species
are not reliably diagnosed and reported through routine
surveillance. Nonetheless, reliable surveys or other research
efforts provide assurance that these other species indeed
represent a small minority of malaria cases in Indonesia
(probably < 1%).
Figure 8 illustrates the API for all of Indonesia, along with
the blood slide positivity rate. Further, the NMCP provided
data regarding the proportion of reported cases (i.e.,
those represented by the API) represented by P. vivax and
P. falciparum. Figure 9 illustrates those data. These data
accord with those of the aggregated cross-sectional surveys
shown in Table 1, that is, essentially equal risk of both of the
dominant species in Indonesia as a whole and through the
historical record of mass blood surveys (dating to 1899).
Although substantial gains against malaria appear to have
been made between 2005 and 2011 (with a 55% reduction in
API), there is no evidence of increasing dominance of P. vivax
as has been witnessed in many other settings in the wake of
successful control programs.
RELAPSE OF P. VIVAX
Relapse behaviors of P. vivax in Indonesia may be
representative of what is generally believed to be the southeast
Asian/west Pacific pattern represented by the single strain
called Chesson.20 That strain was obtained from an American
soldier probably infected in the area of Jayapura, Papua,
during 1944, and later extensively studied in experimentally
challenged human prisoner volunteers. The relapse behavior of
that strain may be generalized as rapid and frequent, with
most first relapses occurring at around day 21 postpatency of
the primary parasitemia, 75% or more relapsing before
day 28, and up to five relapses over 2 years being the rule.5
Studies in Thailand documented essentially similar relapse
behaviors there in more recent times.12,21 Further, a recent
trial in Indonesian soldiers diagnosed with P. vivax and
permitted to relapse also showed Chesson-like relapse
behaviors. Figure 10 illustrates the timing of first relapse with and
without primaquine therapy.7 The median day of relapse was
day 21, and 64% had relapsed by day 28. This study did not
permit study of multiplicity of relapses, but the diagnosis of
vivax malaria in these subjects was some weeks removed
from their 12-month exposure to infection and very probably
represented relapses rather than primary parasitemia. In other
words, multiple relapses appear to be the rule with P. vivax
from Papua (and Thailand).
One study of American soldiers infected in the Pacific
theater of World War II provides a glimpse at multiplicity of
relapses with endemic exposure in the region.5 Among the
659 soldiers evaluated, 213 suffered more than six relapses,
and 105 of those more than 11. What all the available data
indicate is that relapse is a very significant source of acute
attacks of vivax malaria in Indonesia and that the failure to
prevent it with primaquine therapy very probably contributes
substantially to the disease burden imposed by P. vivax.
Studies in neighboring Papua New Guinea lend substantial
support for this hypothesis.22
G6PD DEFICIENCY IN INDONESIA
The very significant problem of relapse in Indonesia gives
substantial weight to the directly linked problem of G6PD
deficiency, that is, the phenomenon largely driving poor
access to safe primaquine therapy. The great heterogeneity
of G6PD deficiency in Asia23 is mirrored on the Indonesian
archipelago, where several hundred distinct ethnolinguistic
groups reside, each with its own pool of inherited G6PD
deficiency types. It is impossible to generalize beyond “diverse”
the variants of G6PD deficiency occurring in Indonesia, and
the numbers of studies of such are limited. A map generated
by Howes and others23 further illustrates what is known with
respect to G6PD deficiency diversity in Indonesia (Figure 11).
Although the sampling on these data can only be described as
sparse and inadequate to the area and human diversity
inherent to Indonesia, one may draw some general conclusions
regarding the variants represented. Vanua Lava variant seems
to be especially common in the east and relatively dominant,
whereas in the west, there seems to be greater diversity with
Mediterranean, Viangchan, Union, and Kaiping variants all
Satyagraha and others8 evaluated G6PD activity
phenotypes among residents of Sumba in eastern Indonesia and
genotyped as Vanua Lava or Viangchan. Figure 12
summarizes those data. All these data provide reason for concern
regarding primaquine therapy in Indonesia. Mediterranean
variant is well known as being exquisitely sensitive to
primaquine, and it occurs with some frequency in the west. In the
east, both Vanua Lava and Viangchan (Figure 12) come with
very low residual levels of enzyme activity (< 5%). In
summary, primaquine sensitivity would appear to be relatively
high and common in Indonesia. This question, however,
requires a great deal more survey work before such
generalizations may be considered reliable.
CHEMOTHERAPY OF P. VIVAX IN INDONESIA
Therapeutic efficacy of standard therapies. A number of
clinical trials conducted at Timika, Papua, over the past
10 years provided a wealth of evidence of good efficacy of
various ACTs against the chloroquine-resistant blood stages
of P. vivax of that region.24–27 Those studies, along with
others from many regions of Indonesia28,29 provide assurance
of continuing good efficacy and safety with this class of
therapeutics against acute vivax malaria.
There is much less assurance regarding the same for
primaquine therapy. Only two trials of primaquine safety
and efficacy have been reported from Indonesia.7,19 The
therapeutic efficacy of primaquine against relapse when
administered after DHA-PP was 98% and 95% in the
published trials, but these both used 0.5 mg/kg daily dosing for
14 days, 2-fold dose recommended by the Ministry of Health.
Concern regarding potential harm at the higher dose without
FIGURE 11. Frequencies and distributions of variants of glucose-6-phosphate dehydrogenase deficiency along the Indonesian archipelago,
reproduced from reference 23, which was published under creative commons.
G6PD screening explains that recommendation (see section
Chemotherapeutic policy for vivax malaria).
Chemotherapeutic policy for vivax malaria. A high
prevalence of chloroquine-resistant P. vivax in Indonesia (see
section Drug-resistant P. vivax in Indonesia), prompted the
Ministry of Health to recommend an ACT, DHA-PP, as
firstline therapy against the acute attack. It also recommends
concurrent primaquine therapy (0.25 mg/kg/day × 14 days).
The most recent treatment policy guidelines (2014)
recommend antirelapse therapy without mention of G6PD deficiency
screening. The guidelines instead offer a warning regarding
signs and symptoms of acute hemolytic anemia in patients
receiving primaquine (and other drugs), and recommend
switching to a weekly dose of 0.75 mg/kg for 8–12 weeks
should such signs appear with daily dosing. These policies
largely align with those expressed in the new (2015)
guidelines for treatment of malaria issued by the World Health
Drug-resistant P. vivax in Indonesia. Resistance to
chloroquine by P. vivax dominates most of the Indonesian archipelago.
The problem seems to have originated in Papua sometime
during the 1980s or perhaps earlier. Elyazar and others10
summarized surveys of such in Indonesia up to 2011 (Table 2). The
report of resistance to chloroquine by P. vivax in Australian
travelers to Papua New Guinea in 198931 prompted studies in
Indonesian Papua (Irian Jaya in that era) that affirmed a
frequent and widespread problem in that far eastern province.10
During the 1990s, studies at Kalimantan, Sumatra, Java, and
Lombok also revealed resistance to chloroquine, but at much
lower frequencies.10 Isolates from Papua and Sumatra were
later demonstrated as resistant to chloroquine in monkey
models.32,33 In the decade that followed, some of these islands
would also be described with high frequencies of chloroquine
failure against P. vivax.34 The decision to abandon chloroquine
for treatment of the acute attack was made in 2006.35
Resistance to primaquine is a highly complex and difficult
question. In Indonesia, as elsewhere, it has yet to be
demonstrated. This is not to say sensitivity to primaquine has been
examined and proven as the rule. It is a remarkable fact that
being the only therapeutic option against relapse of P. vivax
since 1952, primaquine is only rarely evaluated for efficacy
for its primary therapeutic indication. There is no systematic or
standardized means of ascertaining a diagnosis of hypnozoites
resistant to standardized doses of primaquine. A number of
important confounding factors must be addressed, namely,
adherence to the prolonged dosing, quality of drug,
reinfection during the long period of risk of relapse, recrudescence
by drug-resistant asexual blood stages, pharmacokinetic or
pharmacodynamic interference with primaquine efficacy by
untried partner blood schizontocides, and possibly
polymorphisms in cytochrome-P450 2D6 isozyme.36 At present, we
know only that a regimen of 0.5 mg/kg primaquine (daily for
14 days) administered with DHA-PP for radical cure exerts
good efficacy against relapse of P. vivax acquired in eastern
Indonesia.7,19 Efficacy of the lower standard dose, 0.25 mg/kg
for radical cure is not currently known in Indonesia. Broader
global surveys of recurrence trends postprimaquine tend to
affirm poor efficacy of the lower dose regimen.37
The primaquine–G6PD deficiency–P. vivax dilemma. As
in other P. vivax–endemic nations, Indonesia faces a therapeutic
dilemma with primaquine due to its toxicity in patients with
G6PD deficiency. Most providers face patients of unknown
G6PD status and, absent such, must choose between potential
harm caused by repeated relapses that follow the withholding
of primaquine therapy, and potential harm in offering the
treatment. The long misunderstanding of P. vivax as benign, and of
treating relapse as futile where reinfection occurs, denied this
dilemma the attention it required. The NMCP of Indonesia
now actively explores options for coping with this dilemma.
Historically, the strategy has been to offer the less
threatening daily regimen of 0.25 mg/kg with monitoring to mitigate
Deaths caused by malaria
the risks to G6PD-deficient patients. That approach suffers
two key pitfalls: 1) probable poor efficacy and 2) poor ability
to closely monitor patients where most acquire infection and
seek treatment. Acknowledging that many or most variants
of G6PD deficiency exhibit severely limited enzyme activity,
suggests that strategy as both high risk and low benefit to
As WHO has very recently recommended,38 Indonesia
now weighs implementing G6PD screening at the point of
care. The hope is to safely provide primaquine to the majority
in whom it offers tremendous health benefits with little or no
risk of harm, while protecting the minority at risk of serious
harm caused by that drug. Finance and roll out of G6PD
screening is a challenge for Indonesia, but one offering very
substantial gains with respect to national control and
elimination goals. Acquiescence to the hypnozoite reservoir by an
inappropriate status quo regarding primaquine therapy is
considered no longer tenable.
Pregnant women and infants cannot be offered primaquine,
and some experts extend that prohibition to lactating women
and children under 4 years of age. WHO recently clarified its
recommendation concerning infants less than 6 months of age
not to receive primaquine.30 Dellicor and others39 estimated
the number of pregnancies in areas of endemic malaria
transmission in Indonesia. In 2007, they estimated 6.4 million
pregnancies (resulting in 3.8 million live births) occurred
where any species of malaria was actively transmitted. These
numbers take on special significance in light of the studies of
Poespoprodjo and others40,41 at a hospital in Timika, Papua.
They found vivax malaria to be an important cause of
morbidity in infancy and in pregnant women. Further, McGready and
others42 in Thailand (of over 17,000 pregnancies) concluded
that febrile P. falciparum or P. vivax malaria during the first
trimester of pregnancy elevated risk of spontaneous abortion
by a factor of 4, regardless of the species. Plasmodium vivax
threatens several million pregnant women, their fetuses, and
their newborns every year in Indonesia. This fact, taken
together with the lack of access to primaquine therapy against
hypnozoites, should raise very serious concerns in the global
health community. Indonesia, as many other nations, requires
optimized and validated means of preventing relapse without
primaquine in these highly vulnerable populations.
There are other vulnerable populations, as well, mostly
those also lacking access to prompt diagnosis and safe and
effective therapy for malaria for reasons of social, economic,
or geographic isolation. Primary among these will be patients
with G6PDd. The socially isolated may be communities of
illegal miners or loggers. The economically isolated may be
so impoverished as to be unable to afford even very
inexpensive diagnosis and treatment services, or the transport
necessary to access them. Likewise, many communities in Indonesia
reside at isolated locations where access to care delivery is
difficult, time consuming, and relatively expensive. These
vulnerable and hard-to-reach populations may suffer chronic vivax
malaria and the serious morbidity and mortality risks that
come with such isolation. Recently, a young Ministry of Health
physician died of vivax malaria at his isolated post in the
highlands of Papua because weather prevented his evacuation to
hospital by airplane (A. Surya, personal communication).
MORBIDITY AND MORTALITY DUE
TO VIVAX MALARIA
There are no reliable estimates for morbidity or mortality
burdens imposed by P. vivax in Indonesia. Reporting systems
do not include degrees of illness, but presumably case reporting
comes almost entirely from people seeking treatment of
febrile illness at government-sponsored care delivery centers.
As such, the API (already detailed) derived from these
reporting systems provide some insight on disease burdens.
The reported API for 2012 was 1.75/1,000; 256,592 reported
cases of malaria. The WHO translated that number (through
an estimate adjusting algorithm that takes reporting
inefficiencies into account) to 5,453,703 cases for Indonesia in
2012.43 In 2013, Indonesia reported 170,848 cases confirmed
as P. falciparum and 150,985 cases confirmed as P. vivax,
reflecting the consistency of parity between the two dominant
species with respect to both prevalence surveys over the
decades (Table 1), and API over recent years (Figure 10).
The burden of morbidity imposed by P. vivax in Indonesia may
be reasonably presumed to approximate that of P. falciparum.
In 2011, the Malaria Atlas Project estimated the burden of
clinical cases of P. falciparum malaria for Indonesia in 2010
at 12.3 million (95% confidence interval [CI] = 6–21).44 In
contrast, the WHO estimate for all species of malaria in
Indonesia during that year was just under 2 million cases.
This sort of discordance is also seen in the global estimates
of the burden of P. vivax attacks, that is, about 18 million
cases estimated by WHO38 versus 70–390 million by several
other groups.45 The great disparity in estimating morbidity
among methodologies reveals the extraordinary difficulty of
doing so. Work is in progress to estimate the burden of
clinical disease imposed by P. vivax globally using the Bayesian
statistical modeling of prevalent parasitemia.45
Even greater uncertainty haunts estimates of mortality due
to malaria in Indonesia and elsewhere. In 2011, the NMCP
recorded 388 deaths due to malaria and the WHO put the
estimated mortality at 8,631 for that year.43 Indonesia’s Central
Bureau of Statistics conducted nationwide health surveys in
1995 and 2001 and estimated that 30,000 to 38,000 Indonesians
died of malaria in each of those years.10 Similarly, although
WHO reported approximately 15,000 deaths due to malaria in
India in 2010, a systematic survey of mortality by verbal
autopsy generated an estimated 210,000 deaths annually due
to malaria in that nation.46
Although absolute numbers of fatalities due to P. vivax
may evade credible estimation for now, several
hospitalbased studies carried out in Indonesia since 2005 leave no
doubt that death often occurs in association with a diagnosis
of P. vivax malaria.2 The data reported by Nurleila and
others47 from a hospital at Sumba in eastern Indonesia may
be typical. In that retrospective study, patients admitted with
a diagnosis of P. falciparum were 2.9 times more likely to be
classified as seriously ill compared with P. vivax. However,
once classified as seriously ill, the odds ratio (OR) of not
surviving was equal between the two species (OR = 1.3; 95%
CI = 0.7–2.5). In the very large prospective study at a hospital
at Timika, Papua, Tjitra and others48 observed equal rates of
severe malaria between the species (0.8% versus 0.7% of
admissions for P. vivax and P. falciparum), and also found the
odds of death with a diagnosis of P. vivax indistinguishable
from a diagnosis of P. falciparum (adjusted OR = 1.13, P =
0.51). These trends raise the possibility of P. vivax
contributing a very substantial share of the mortality imposed by
malaria in Indonesia.
Note that 64 deaths attributed to malaria occurred at the
hospital at Sumba during 2008 and 2009.47 This number was
considered ordinary by the hospital staff, and yet for the
entire province of Nusa Tenggara Timor (Sumbawa, Flores,
Sumba, Alor, Savu, and other areas), only 48 deaths were
reported to the NMCP during the 3-year period, 2010–2012
(Table 3). Even patients admitted to hospital with a diagnosis
of malaria and not surviving are somehow lost to mortality
reporting systems. Improved surveillance of morbidity and
mortality with a primary diagnosis of malaria at both
treatment centers and hospitals are needed.
CHALLENGES TO ELIMINATION
Plasmodium vivax seriously challenges health in Indonesia.
The long misunderstanding of this species as benign and not
threatening drove its neglect by the communities of science,
medicine, and public health. The tools needed to combat this
threat were not developed, especially a means to safely and
effectively attack the tenacious and dangerous hypnozoite
reservoir residing in endemic communities. Overcoming the
serious problem of primaquine toxicity in G6PD-deficient
patients, and thus greatly improving access to this crucial
therapy is a top priority in Indonesia.
The NMCP faces challenges in meeting Indonesia’s
aspirations to eliminate malaria transmission by 2030. A highly
mobile population and natural receptivity to malaria
transmission across all of Indonesia’s islands will demand decades
of diligent surveillance and provision of expert diagnosis and
treatment services. The dormant and silent hypnozoite is
especially threatening in this respect, striking suddenly and
unexpectedly months or years after exposure. Further, P. vivax
circulates its infectious gametocytes even before patients
become ill. Health services against malaria must be maintained
even after transmission ceases.
Patients unable to receive primaquine pose another
important challenge. Pregnant women or lactating women and their
infants, who are especially vulnerable to P. vivax, must be
provided alternatives to primaquine to prevent repeated clinical
attacks. The same will be true of the many patients diagnosed
as G6PD deficient. Chemoprophylactic or presumptive
therapeutic regimens will need to be developed, optimized,
validated, and implemented for these patients.
The many people living in geographic isolation across
Indonesia also pose a special challenge to the NMCP. They
need knowledge, tools of personal protection, diagnostics,
and safe and effective therapies put into their hands.
Eliminating malaria will require reaching well beyond where health-care
providers live and work. Delivery of innovative implements
against malaria to those isolated from health services would
greatly advance the elimination agenda in Indonesia.
Plasmodium vivax occurs all across Indonesia as a
codominant species with P. falciparum. Both impose substantial
burdens of morbidity and mortality across an enormously
diverse landscape of anopheline vectors, habitats, and human
genetic diversity. Indonesian P. vivax is widely resistant to
chloroquine, tolerates lower doses of primaquine therapy,
exhibits the aggressive relapse behavior of Chesson-like
strains, and may have selected for some of the most severely
deficient G6PD variants known. Indonesia’s malaria research
community already works hand in hand with the NMCP to
address these challenges, and progress has and will continue
to be made against this very stubborn and difficult parasite.
Received February 7, 2016. Accepted for publication March 7, 2016.
Published online October 5, 2016.
Acknowledgments: Claudia Surjadjaja prepared this report as a paid
consultant to WHO Global Malaria Program. She interviewed many
key resource persons for this report, and most of them provided not
only expert opinion, but also materials and key references used in this
report. We thus express our gratitude for the generous cooperation of
Inge Sutanto (Faculty of Medicine, University of Indonesia); Iqbal
Elyazar (Eijkman-Oxford Clinical Research Unit); Ari Satyagraha
(Eijkman Institute for Molecular Biology); Din Syafruddin (Eijkman
Institute for Molecular Biology); Mehwahyu Dewi (Eijkman-Oxford
Clinical Research Unit); and Lenny Ekawati (Eijkman-Oxford Clinical
Research Unit). The WHO Indonesia office provided technical and
Financial support: J. Kevin Baird is supported by Wellcome Trust
grant no. B9RJIXO.
Authors’ addresses: Claudia Surjadjaja, ALERTAsia Foundation,
Jakarta, Indonesia, E-mail: . Asik Surya,
SubDirectorate for Malaria Control, Ministry of Health, Jakarta, Indonesia,
E-mail: . J. Kevin Baird, Eijkman-Oxford
Clinical Research Unit, Oxford University, Jakarta, Indonesia, E-mail:
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 alone are responsible for the views expressed in this
article and they do not necessarily represent the views, decisions or
policies of the institutions with which they are affiliated.
1. Elyazar IR , Gething PW , Patil AP , Rogayah H , Sariwati E , Palupi NW , Tarmizi SN , Kusriastuti R , Baird JK , Hay SI , 2012 . Plasmodium vivax endemicity in Indonesia in 2010 . PLoS One 7 : e37325 .
2. Baird JK , 2013 . Evidence and implications of mortality associated with acute Plasmodium vivax malaria . Clin Microbiol Rev 26 : 36 - 57 .
3. Elyazar IR , Sinka ME , Gething PW , Tarmidzi SN , Surya A , Kusriastuti R , Winarno Baird JK , Hay SI , Bangs MJ , 2013 . The distribution and bionomics of Anopheles malaria vector mosquitoes in Indonesia . Adv Parasitol 83 : 173 - 266 .
4. Francisca L , Kusnanto JH , Satoto TB , Supriyanto Andriyani E , Bangs MJ , 2015 . Comparison of rapid diagnostic test for Plasmotec-3, microscopy, and quantitative real time PCR for diagnoses of Plasmodium falciparum and Plasmodium vivax infections in Mimika Regency , Papua, Indonesia. Malar J 14 : 103 .
5. Hill E , Amatuzio DS , 1949 . Southwest Pacific vivax malaria: clinical features and observations concerning duration of clinical activity . Am J Trop Med Hyg 29 : 203 - 214 .
6. Price RN , von Seidlein L , Valecha N , Nosten F , Baird JK , White NJ , 2014 . Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis . Lancet Infect Dis 14 : 982 - 991 .
7. Sutanto I , Tjahjono B , Basri H , Taylor WR , Putri FA , Meilia RA , Setiabudy R , Nurleila S , Ekawati LL , Elyazar I , Farrar J , Sudoyo H , Baird JK , 2013 . Randomized, open-label trial of primaquine against vivax malaria relapse in Indonesia . Antimicrob Agents Chemother 57 : 1128 - 1135 .
8. Satyagraha AW , Sadhewa A , Baramuli V , Elvira R , Ridenour C , Elyazar I , Noviyanti R , Coutrier FN , Harahap AR , Baird JK , 2015 . G6PD deficiency at Sumba in eastern Indonesia is prevalent, diverse and severe: implications for primaquine therapy against relapsing vivax malaria . PLoS Negl Trop Dis 9 : e0003602 .
9. Takken W , Snellen WB , Verhave JP , Knols BGJ , Asmosoedjonon S , 1990 . Environmental Measures for Malaria Control in Indonesia: An Historical Review on Species Sanitation . Wageningen University Papers. Wageningen, The Netherlands: Wageningen Agricultural University.
10. Elyazar IR , Hay SI , Baird JK , 2011 . Malaria distribution, prevalence, drug resistance and control in Indonesia . Adv Parasitol 74 : 41 - 175 .
11. Syafruddin D , Krisin, Asih P , Sekartuti, Dewi RM , Coutrier F , Rozy IE , Susanti AI , Elyazar IR , Sutaminhardja A , Rahmat A , Kinzer M , Rogers WO , 2009 . Seasonal prevalence of malaria in West Sumba district , Indonesia. Malar J 8 : 8 .
12. Douglas NM , Nosten F , Ashley EA , Phaiphun L , van Vugt M , Sinhasivanon P , White NJ , Price RN , 2011 . Plasmodium vivax recurrence following falciparum and mixed species malaria: risk factors and effect of antimalarial kinetics . Clin Infect Dis 52 : 612 - 620 .
13. Baird JK , 2011 . Radical cure: the case for anti-relapse therapy against all malarias . Clin Infect Dis 27 : 11 - 16 .
14. Doolan DL , Dobano C , Baird JK , 2009 . Acquired immunity to malaria . Clin Microbiol Rev 22 : 13 - 36 .
15. Kaisar MM , Supali T , Wiria AE , Hamid F , Wammes LJ , Sartono E , Luty AJ , Brienen EA , Yazdanbakhsh M , van Lieshout L , Verweij JJ , 2013 . Epidemiology of Plasmodium infections in Flores Island, Indonesia using real-time PCR . Malar J 12 : 169 .
16. Tadesse FG , Pett H , Baidjoe A , Lanke K , Grignard L , Sutherland C , Hall T , Drakeley C , Bousema T , Mamo H , 2015 . Submicroscopic carriage of Plasmodium falciparum and Plasmodium vivax in a low endemic area in Ethiopia where no parasitemia was detected by microscopy or rapid diagnostic test . Malar J 14 : 303 .
17. Baird JK , Sismadi P , Ramzan A , Purnomo BW , Sekartuti Tjitra E , Rumoko BW , Arbani PR , 1996 . A focus of endemic malaria in Central Java . Am J Trop Med Hyg 54 : 98 - 104 .
18. Barcus MJ , Laihad F , Sururi M , Sismadi P , Marwoto H , Bangs MJ , Baird JK , 2002 . Epidemic malaria in the Menoreh Hills of Central Java . Am J Trop Med Hyg 66 : 287 - 292 .
19. Nelwan E , Ekawati LL , Tjahjono B , Sutanto I , Chand K , Ekasari T , Djoko D , Basri H , Taylor RW , Duparc S , Subekti D , Elyazar I , Noviyanti R , Sudoyo H , Baird JK , 2015 . Randomized trial of primaquine hypnozoitocidal efficacy when administered with artemisinin-combined blood schizontocides for radical cure of Plasmodium vivax in Indonesia . BMC Med 13 : 294 .
20. 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 .
21. Pukrittayakamee S , Chantra A , Simpson JA , Vanijanonta S , Clemens R , Looareesuwan S , White NJ , 2000 . Therapeutic responses to different antimalarial drugs in vivax malaria . Antimicrob Agents Chemother 44 : 1680 - 1685 .
22. Betuela I , Rosanas-Urgell A , Kiniboro B , Stanisic DI , Samol L , de Lazzari E , Del Portillo HA , Siba P , Alonso PL , Bassat Q , Mueller I , 2012 . Relapses contribute significantly to the risk of Plasmodium vivax infection and disease in Papua New Guinea children 1-5 years of age . J Infect Dis 206 : 1771 - 1780 .
23. Howes RE , Dewi M , Piel FB , Monteiro WM , Battle KE , Messina JP , Sakuntabhai A , Satyagraha AW , Williams TN , Baird JK , Hay SI , 2013 . Spatial distribution of G6PD deficiency variants across malaria-endemic regions . Malar J 12 : 418 .
24. Ratcliff A , Siswantoro H , Kenangalem E , Wuwung M , Brockman A , Edstein MD , Laihad F , Ebsworth EP , Anstey NM , Tjitra E , Price RN , 2007 . Therapeutic response of multidrug-resistant Plasmodium falciparum and P. vivax to chloroquine and sulfadoxine-pyrimethamine in southern Papua , Indonesia. Trans R Soc Trop Med Hyg 101 : 351 - 359 .
25. Ratcliff A , Siswantoro H , Kenangalem E , Maristela R , Wuwung RM , Laihad F , Ebsworth EP , Anstey NM , Tjitra E , Price RN , 2007 . Two fixed-dose artemisinin combinations for drug-resistant falciparum and vivax malaria in Papua, Indonesia: an openlabel randomized comparison . Lancet 369 : 757 - 765 .
26. Hasugian AR , Purba HL , Kenagnalem E , Wuwung RM , Ebsworth EP , Maristela R , Penttinen PM , Laihad F , Anstey NM , Tjitra E , Price RN , 2007 . Dihydro-artemisinin-piperaquine versus artesunate-amodiaquine: superior efficacy and posttreatment prophylaxis against multidrug-resistant Plasmodium falciparum and Plasmodium vivax malaria . Clin Infect Dis 44 : 1067 - 1074 .
27. Poespoprodja JR , Fobia W , Kengangalem E , Lampah DA , Sugiarto P , Tjitra E , Anstey NM , Price RN , 2014 . Dihydroartemisinin-piperaquine treatment of multidrugresistant falciparum and vivax malaria in pregnancy . PLoS One 9 : e84967 .
28. Gogtay N , Kannan S , Thatte UM , Olliaro PL , Sinclair D , 2013 . Artemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria . Cochrane Database Syst Rev 10 : CD008492 .
29. Harijanto PN , 2010 . Malaria treatment using artemisinin in Indonesia . Acta Med Indones 42 : 51 - 56 .
30. World Health Organization (WHO) , 2015 . Guidelines for the Treatment of Malaria, 3rd edition . Geneva, Switzerland: WHO.
31. Rieckmann KH , Davis DR , Hutton DC , 1989 . Plasmodium vivax resistance to chloroquine ? Lancet 2 : 1183 - 1184 .
32. Collins WE , Sullivan JS , Fryauff DJ , Kendall J , Jennings V , Galland GG , Morris CL , 2000 . Adaptation of a chloroquineresistant strain of Plasmodium vivax from Indonesia to New World monkeys . Am J Trop Med Hyg 62 : 491 - 495 .
33. Collins WE , Schwartz IK , Skinner JC , Morris C , Filipski VK , 1992 . The susceptibility of the Indonesian I/CDC strain of Plasmodium vivax to chloroquine . J Parasitol 78 : 344 - 349 .
34. Sutanto I , Endawati D , Ling LH , Laihad F , Setiabudy R , Baird JK , 2010 . Evaluation of the chloroquine therapy for vivax and falciparum malaria in southern Sumatra, western Indonesia . Malar J 9 : 52 .
35. Kusriastuti R , Surya A , 2012 . New treatment policy of malaria as part of malaria control program in Indonesia . Acta Med Indones 44 : 265 - 269 .
36. Ingram RJ , Crenna-Darusallam C , Soebianto S , Noviyanti R , Baird JK , 2014 . The clinical and public health problem of relapse despite primaquine therapy: a case review of repeated relapses of Plasmodium vivax acquired in Papua New Guinea . Malar J 13 : 488 .
37. John GK , Douglas NM , von Seidlein L , Nosten F , Baird JK , White NJ , Price RN , 2012 . Primaquine radical cure of Plasmodium vivax: a critical review of the literature . Malar J 11 : 280 .
38. World Health Organization (WHO) , 2015 . Control and Elimination of Plasmodium vivax Malaria: A Technical Brief. Geneva, Switzerland: WHO , 64.
39. Dellicour S , Tatem AJ , Guerra CA , Snow RW , ter Kuile FO , 2010 . Quantifying the number of pregnancies at risk of malaria in 2007: a demographic study . PLoS Med 7 : e1000221 .
40. Poespoprodja JR , Fobia W , Kenangalem E , Lampah DA , Hasanuddin A , Warikar N , Sugiarto P , Tjitra E , Anstey NM , Price RN , 2009 . Vivax malaria: a major cause of morbidity in early infancy . Clin Infect Dis 48 : 1704 - 1712 .
41. Poespoprodjo JR , Fobia W , Kenangalem E , Lampah DA , Warikar N , Seal A , McGready R , Sugiarto P , Tjitra E , Anstey NM , Price RN , 2008 . Adverse pregnancy outcomes in an area where multidrug-resistant Plasmodium vivax and Plasmodium falciparum infections are endemic . Clin Infect Dis 46 : 1374 - 1381 .
42. McGready R , Lee SJ , Wiladphaingern J , Ashley EA , Rijken MJ , Boel M , Simpson JA , Paw MK , Pimanpanarak M , Mu O , Singhasivanon P , White NJ , Nosten F , 2012 . Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study . Lancet Infect Dis 12 : 388 - 396 .
43. World Health Organization (WHO) , 2015 . World Malaria Report 2014 . Geneva, Switzerland: WHO.
44. Elyazar IR , Gething PW , Patil AP , Rogayah H , Kusriastuti R , Wismarini DM , Tarmizi SN , Baird JK , Hay SI , 2011 . Plasmodium falciparum endemicity in Indonesia 2010 . PLoS One 6 : e21315 .
45. Price RN , Tjitra E , Guerra CA , Yeung S , White NJ , Anstey NM , White NJ , 2007 . Vivax malaria: neglected and not benign . Am J Trop Med Hyg 77 (Suppl): 79 - 87 .
46. Dhingra N , Jah P , Sharma VP , Cohen AA , Jotkar RM , Rodriguez PS , Bassani DG , Suraweera W , Laxminaryan R , Peto R , 2010 . Adult and child mortality in India . Lancet 376 : 1768 - 1774 .
47. Nurleila S , Syafruddin D , Elyazar IR , Baird JK , 2012 . Serious and fatal illness associated with falciparum and vivax malaria among patients admitted to hospital at West Sumba in eastern Indonesia . Am J Trop Med Hyg 87 : 41 - 49 .
48. Tjitra E , Anstey NM , Sugiarto P , Warikar N , Kenangalem E , Karyana M , Lampah DA , Price RN , 2008 . Multidrug-resistant Plasmodium vivax associated with severe and fatal malaria: a prospective study in Papua , Indonesia. PLoS Med 5 : e128 .