Atovaquone/Proguanil for Malaria • CID 2002:35 (1 October) • 825
M A J O R A R T I C L E
Randomized, Placebo-Controlled Trial
of Atovaquone/Proguanil for the Prevention
of Plasmodium falciparum or Plasmodium
vivax Malaria among Migrants
to Papua, Indonesia
Judith Ling,1,5,aJ. Kevin Baird,1David J. Fryauff,3Priyanto Sismadi,2Michael J. Bangs,1Mark Lacy,1
Mazie J. Barcus,1Robert Gramzinski,1Jason D. Maguire,1Marti Kumusumangsih,3Gerri B. Miller,4Trevor R. Jones,3
Jeffrey D. Chulay,4,aStephen L. Hoffman,3,aand the Naval Medical Research Unit 2 Clinical Trial Teamb
1Naval Medical Research Unit 2 and
4GlaxoSmithKline, Research Triangle Park, North Carolina; and
2Indonesian Ministry of Health, Jakarta, Indonesia;
3Naval Medical Research Center, Silver Spring, Maryland;
5Children’s National Medical Center and George Washington University,
The increasing prevalence of resistance to antimalarial drugs reduces options for malaria prophylaxis.
Atovaquone/proguanil (Malarone; GlaxoSmithKline) has been 195% effective in preventing Plasmodium
falciparum malaria in lifelong residents of areas of holoendemicity, but data from persons without clinical
immunity or who are at risk for Plasmodium vivax malaria have not been described. We conducted a
randomized, double-blinded study involving 297 people from areas of nonendemicity in Indonesia who
migrated to Papua (where malaria is endemic) ?26 months before the study period. Subjects received
prophylaxis with 1 Malarone tablet (250 mg of atovaquone and 100 mg of proguanil hydrochloride; n p
) or placebo () per day for 20 weeks. Hematologic and clinical chemistry values did not change148
n p 149
significantly. The protective efficacy of atovaquone/proguanil was 84% (95% confidence interval [CI],
44%–95%) for P. vivax malaria, 96% (95% CI, 72%–99%) for P. falciparum malaria, and 93% (95% CI,
77%–98%) overall. Atovaquone/proguanil was well tolerated, safe, and effective for the prevention of drug-
resistant P. vivax and P. falciparum malaria in individuals without prior malaria exposure who migrated
to Papua, Indonesia.
Although malaria is one of the oldest known diseases
among humans, it remains a global health threat, be-
cause the parasite and itsvectorcontinuetoevademod-
ern approaches to prevention and treatment. Malaria
Received 19 March 2002; revised 20 May 2002; electronically published 11
aPresent affiliations: Kaiser Permanente MidAtlantic, Rockville (J.L.), and
Sanaria, Gaithersburg (S.L.H.), Maryland; and AlphaVax, Research Triangle Park,
North Carolina (J.D.C.).
bStudy group members are listed at the end of the text.
Reprints or correspondence: Dr. J. Kevin Baird, US Naval Medical Research
Unit 2, American Embassy Jakarta, FPO AP 96520-8132 (firstname.lastname@example.org
Clinical Infectious Diseases2002;35:825–33
? 2002 by the Infectious Diseases Society of America. All rights reserved.
kills or debilitates nonimmune travelers, migrants, and
returning emigres who do not receive adequate pro-
tection. Personal protective measures, such as insect
repellents and bed nets, diminish risk and may be ad-
equate where risk is low, but high risk demands che-
moprophylaxis as well. Theglobalresurgenceofmalaria
and the increasing prevalence of resistance to standard
antimalarial drugs increases the risk for travelers.Chlo-
roquine-resistant Plasmodium falciparum is present
throughout Africa, Asia, and South America, and
Financial support: GlaxoSmithKline through a Cooperative Research and
Development Agreement with the US Navy.
The views of the authors are their own and do not purport to reflect those of
the US Navy or the US Department of Defense.
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826 • CID 2002:35 (1 October) • Ling et al.
multidrug-resistant P. falciparum is present in parts of South-
east Asia, including Indonesia [1–3]. Chloroquine-resistant
Plasmodium vivax also poses a serious threat to public health
in eastern Indonesia and perhaps other parts of Asia [1, 3–6].
Neuropsychiatric side-effects associated with mefloquine ,
severe cutaneous side-effects associated with pyrimethamine/
sulfadoxine , and photosensitivity and adverse effects on
tooth and bone development associated with doxycycline 
preclude the use of these standard chemoprophylactic drugs
need broader options for chemoprophylaxis.
A fixed-dose combination of atovaquone and proguanil hy-
drochloride (Malarone; GlaxoSmithKline) has been approved
by the US Food and Drug Administration for the prevention
and treatment of malaria caused by P. falciparum . Ato-
vaquone is a hydroxynaphthoquinone that kills parasites via
inhibition of mitochondrial electron transport and blockage of
de novo pyrimidine synthesis . Proguanil inhibits dihy-
drofolate reductase (via its metabolite cycloguanil) and is also
directly synergistic with atovaquone in vitro [12, 13]. Random-
ized, double-blinded, placebo-controlled trials supporting the
use of atovaquone/proguanil for prophylaxis for malariacaused
by P. falciparum [14–17] were conducted in areas of holoen-
demicity in Africa, where clinical immunity to malaria may
confound estimates of protective efficacy. To corroborate data
from the studies in Africa and to estimate the drug’s protective
efficacy against P. vivax malaria, we conducted a randomized,
placebo-controlled, double-blinded trial of atovaquone/pro-
guanil for malaria prophylaxis in Indonesians who did nothave
sufficient clinical immunity to prevent febrile disease.
MATERIALS AND METHODS
Study sites and subjects.
demicity in Indonesia who reside in 3 villages in northeastern
Papua formed the study population. Recruitment of volunteers
occurred from April through December1999.Thevillages(SP4,
SP5, and SP6) were constructed as part of an Indonesian gov-
ernment program of sponsored migration from Java (trans-
migration). Each village was located in ∼4 km2of cleared forest
within 2 km of the coast. Homes of identical wood-plank and
tin-roof construction were situated along a grid of unpaved
roads at even intervals. Approximately 1500 people lived in
each village, a mixture of people from Java, other islands of
Indonesia, or the local area. Almost all residents engaged in
agriculture as their primary economic activity. All 4 species of
human malaria parasites occur in the region at a ratio of ∼2:
1:0.1:!.001 for P. falciparum:P. vivax:Plasmodium malariae:
Plasmodium ovale. Malaria in the region is hyper- to holoen-
demic and highly resistant to chloroquine [3–6]. The Anopheles
punctulatus complex (A. punctulatus, Anopheles farauti, and
Individuals from areas of nonen-
Anopheles koliensis), which feeds and breeds in the open, sunlit
spaces provided by new settlements, is the only important vec-
tor of malaria . Exposure to feeding anophelines occurs in
and around homes rather than in association withoccupational
A government-operated health station in each village pro-
vided weekly chloroquine prophylaxis at no cost to trans-
migrants during the first 3 months of residence. Chloroquine
prophylaxis appears to provide some relief from the symp-
toms of malaria, but it was no more effective than placebo
for the prevention of patent parasitemia . Compliance
with chloroquine prophylaxis before study enrollmentwasnot
monitored. Subjects did not have access to chloroquineduring
Eligible volunteers were aged 12–65 years and weighed ?40
kg. They had moved from Java or another area where malaria
was not endemic 3–26 months before enrollment, and theyhad
resided in these areas of nonendemicity for 2 years before mov-
ing. Exclusion criteria included pregnancy or unwillingness to
use reliable contraception, lactation, glucose-6-phosphate de-
hydrogenase (G6PD) deficiency, or any medical condition that,
in the physician’s judgment, would compromise participation
in the study. The study protocol and the process of informed
consent were reviewed and approved by Indonesian and US
committees for the protection of human subjects of medical
research in accordance with US Navy regulations governingthe
use of human subjects of medical research (SECNAVINST
3900.39B). All participants in the study provided informedvol-
Sample size estimate.
On the basis of incidence data col-
lected in this region during 1997 and 1998, we estimated a 20-
week P. vivax attack rate of 0.2 in the placebo group. In an-
ticipation of 95% protective efficacy, the expected attack rate
in the atovaquone/proguanil treatment armduringthe20-week
period was therefore predicted to be 0.01. By use of the like-
lihood scores method  with power set at 80% and the lower
95% confidence limit set at 65% protective efficacy, we deter-
mined that 121 subjects were needed in each arm to detect
differences between the atovaquone/proguanil and placebo
groups. In anticipation of a 25% dropout rate during the pro-
phylaxis period, we planned to randomize ∼300 subjects (150
subjects per arm) to receive either atovaquone/proguanil or
Study design and procedures.
distinct phases: a 17-day period of radical cure treatment, 20
weeks of prophylaxis, and 4 weeks of postprophylaxis follow-
up. Radical curative therapy eradicated preexisting malaria in-
fection that could confound the interpretation of outcomes.
This consisted of 1000 mg of atovaquone and 400 mg of pro-
guanil hydrochloride (i.e., 4 Malarone tablets, each of which
contains 250 mg of atovaquone and 100 mg of proguanil hy-
The study consisted of 3
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Atovaquone/Proguanil for Malaria • CID 2002:35 (1 October) • 827
drochloride) given once daily with food for 3 days, followed
by 2 primaquine phosphate tablets, each of which contained
15 mg of primaquine base (Sanofi-Winthrop), given once daily
for 14 days. Details of the safety and efficacy of this radical
curative regimen will be reported elsewhere.
After completing the radical cure regimen, subjects wereran-
domized in a 3:1 ratio to continue or discontinue the trial.
Those randomized to discontinue were offered the opportunity
to volunteer for a parallel trial of primaquine for prophylaxis,
which is reported elsewhere . Subjects randomized to con-
tinue were further randomized in a 1:1 ratio to receive 1 Ma-
larone tablet or 1 placebo tablet daily for 20 weeks. Study drugs
(film-coated tablets of Malarone or placebo) were identical in
appearance and packaging. Assignment to the active drug or
placebo groups was accomplished off site using computer-gen-
erated codes randomly assigned to placebo or drug. Subjects
were assigned blinded code numbers at enrollment. No subject
or member of the research team knew the assignment code.
The sealed key to the code was kept on site but was returned
unopened to monitors at the conclusion of the study.
A member of the research team visited each subject at home
daily throughout the study. At each visit, the health careworker
administered the study drug with sweet biscuits and asked “Do
you have any complaints?” An affirmative response prompted
recording of complaints as adverse events on a standard ques-
tionnaire. On-site physicians reviewed reports of adverseevents
each day. An adverse event was considered related to the drug
if the reviewing physician thought the adverse event could have
been caused by the study drug. Anadverseeventwasconsidered
serious if it was fatal, life threatening, or disabling, if it resulted
in hospitalization, or if it otherwise seriously jeopardized the
subject. Subjects were brought to the clinic for evaluationwhen
indicated. In addition, a physician or nurse visited each par-
ticipant every 2 weeks to assess general conditions and the use
of nonstudy medications.
Subjects were discontinued from participation if they missed
12 doses of the study drug or placebo during any 7-day period.
Urine pregnancy tests (Test Pack Plus; Abbot) were performed
monthly for female subjects. All subjects were screened for
G6PD deficiency using a commercial assay (G-6-PDH Defi-
ciency Screen Kit 202; Sigma Diagnostics). Laboratory assays
of hematology (QBC; Becton-Dickinson) and standard blood
chemistry parameters (Ektachem DT II System; Kodak) were
performed at enrollment and at weeks 4 and 20 of prophylaxis.
Plasma samples were obtained at weeks 4 and 20 of prophylaxis
to measure concentrations of atovaquone, proguanil, and cy-
cloguanil [22, 23].
Blood films were obtained from subjects just be-
fore they received the radical cure regimen and again imme-
diately before the start of prophylaxis. During prophylaxis,
blood films were collected weekly or whenever subjects com-
plained of symptoms consistent with malaria. Technicians
stained blood films with Giemsa reagents, and expert micros-
copists read ?200 fields at 1000? oil immersionmagnification.
Positive blood films revealed ?2 asexual parasites confirmed
by a second expert microscopist. A confirmed positive blood
film regimen prompted immediate rescue therapy. Parasitesper
microliter of blood were calculated as the number of asexual
parasites per 200 WBCs multiplied by 40 (the WBC count was
assumed to be 8000 cells/mL).
Rescue therapy consisted of atovaquone/proguanil for P. fal-
ciparum or atovaquone/proguanil followed by primaquine for
P. vivax infection, as for radical cure . Subjects who de-
veloped parasitemia during the 4 weeks after completing pro-
phylaxis received standard chloroquine, pyrimethamine/sulfa-
doxine, or quinine therapy, consistent with the Indonesian
national malaria treatment policy.
The primary efficacy end point was
the first occurrence of slide-proven P. vivax parasitemia. The
secondary efficacy end point was the first occurrence of slide-
proven P. vivax or P. falciparum parasitemia. Percentage of
efficacy was calculated as100?[1?(incidence
laria in atovaquone/proguanil recipients/incidence density of
the binomial distribution. Differences in the incidence density
of adverse events were compared using Yates’s corrected x2test.
density of ma-
Study subjects and compliance.
residents were screened, and 416 started receiving the radical
cure regimen. Among the 402 who completed the radical cure
regimen, 396 were randomized to receive either atovaquone/
proguanil () or placebo (n p 150
this study and to enter the parallel study of primaquine for
prophylaxis () . Of the 299 randomized to continue,n p 97
90 did not complete the 20-week prophylaxis period because
of withdrawal before they started the study drug regimen
( ), the presence of slide-confirmed malaria (n p 2
consent withdrawn while receiving study drug (
tocol violation (), loss to follow-up (n p 11
verse event that prompted withdrawal from the study (
At screening or immediately before commencement of the
radical cure regimen, 43 subjects (11%) had P. falciparum
parasitemia and 39 (10%) had P. vivax parasitemia. All sub-
jects had negative blood smear results 15 days after they
started receiving the radical cure regimen (2 days before
The atovaquone/proguanil and placebo groups had no sig-
nificant differences in age, sex, weight, or history of malaria
(table 1). The mean age was 32 years, 105 subjects (35%) were
Eight hundred thirty-seven
) or to discontinuen p 149
),n p 40
), or an ad-
n p 4
n p 28
n p 5
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828 • CID 2002:35 (1 October) • Ling et al.
Flow diagram of subject accountability during the trial of atovaquone/proguanil for the prevention of PlasmodiumfalciparumorPlasmodium
female, 122 (41%) had no knowledge of having been treated
for malaria, and 112 (37%) said they had received no treatment
for malaria before enrollment.
The mean (?SD) duration of exposure to study drug was
days for placebo and 110?42
proguanil. The duration of study drug exposure was 16–20
weeks for 100 placebo recipients (67%) and 128 atovaquone/
proguanil recipients (86%). The numbers of doses of study
drug missed or not witnessed were 55 (0.37%) in the placebo
group and 72 (0.48%) in the atovaquone/proguanil group; 146
(98%) subjects in the placebo group and 144 (96%) in the
atovaquone/proguanil group took 195% of prescribed doses.
Infection after the radical cure regimen.
agnosed in 40 subjects during the prophylaxis phase of the
study. Parasitemia occurred in 37 subjects in the placebo group
(14 cases due to P. vivax alone, 21 due to P. falciparum alone,
and 2 due to P. vivax–P. falciparum) and in 3 subjects in the
atovaquone/proguanil group (2 cases due to P. vivax alone and
1 case due to P. vivax–P. falciparum; figure 2). The protective
efficacy of atovaquone/proguanilwas 84%(95%CI,45%–95%)
for P. vivax, 96% (95% CI, 71%–99%) for P. falciparum, and
93% (95% CI, 77%–98%) overall (table 2). During the 4-week
days for atovaquone/129?29
Malaria was di-
follow-up period, parasitemia appeared in 5 subjects in the
placebo group (3 cases due to P. falciparum and 2 due to P.
vivax) and in 7 subjects in the atovaquone/proguanil group (2
cases due to P. falciparum and 5 due to P. vivax). Symptoms
of malaria were present on the day of or the day after diagnosis
in 95% of subjects with P. falciparum parasitemia and in 88%
of subjects with P. vivax parasitemia. All had resolution of these
symptoms after they received rescue treatment.
Drug concentrations in plasma among patients for whom
parasitemia while receiving atovaquone/proguanil, the drug
concentrations in plasma were consistent with normal absorp-
tion and good compliance (table 3). These subjects had missed
just 0, 1, or 2 of the prescribed doses of atovaquone/proguanil
during the 4 weeks before patency of parasitemia.
drug, 136 (91%) and 141 (94%), respectively, reported ?1
physical complaint during the prophylaxis period (
Figure 3 illustrates the incidence density of specific adverse
events, either all such events (figure 3, left) or those considered
possibly attributable to drug by the blinded supervising phy-
sicians (figure 3, right). In both analyses, stomatitis occurred
Among the 3 subjects whohad
).P p .25
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Atovaquone/Proguanil for Malaria • CID 2002:35 (1 October) • 829
receive chemoprophylaxis with atovaquone/proguanil or placebo,
Baseline characteristics of subjects randomized to
(n p 150)
(n p 149)
Mean ? SD
Height, mean cm ? SD
Weight, mean kg ? SD
Duration of residence in Papua,
mean months ? SD
History of malaria treatment
before arrival in Papua
History of malaria treatment
after arrival in Papua
More than twice
31.1 ? 10.0
33.3 ? 10.9
157 ? 8.5
50.9 ? 6.6
157 ? 7.2
51.2 ? 6.1
21.0 ? 3.420.5 ? 3.7
6 (4)3 (2)
Data are no. (%) of patients, unless otherwise indicated.
Cumulative incidence of parasitemia due to Plasmodium falciparum or Plasmodium vivax
more frequently in the atovaquone/proguanil group than it did
in the placebo group (P ! .001
pain ( and ) and malaise (P p .02P p .04
) occurred more frequently in the placebo group. Back pain.02
appeared more frequently among atovaquone/proguanil recip-
ients (), but the blinded supervising physicians didP p .009
and ), and abdominal
andP p .01
P p .009
not attribute most of these complaints to the study drug. Most
adverse events were mild (77.0% of events) ormoderate(22.6%
of events) in intensity. Four subjects had adverse events that
were classified as severe and considered by the blinded super-
vising physicians to be possibly drug related (3 patients had
abdominal pain and 1 had an exfoliative skin rash). The skin
rash was considered to be serious, and, although it was possibly
drug related, a similar rash occurred during the same period
in 2 other residents of the same village who were not study
subjects. Thus, we considered a viral etiology to be a more
likely explanation for the rash in the study subject.
Laboratory safety samples were obtained at baseline, week 4,
and week 20 from 150, 143, and 121 subjects who received
atovaquone/proguanil and from 149, 137, and 116 subjectswho
received placebo, respectively. For both men and women, there
were no significant differences between the treatment groups
at baseline or during follow-up with regard to any hematologic
and clinical chemistry test result, and no clinically important
laboratory abnormalities were identified.
Daily administration of atovaquone/proguanil provided safe,
P. vivax malaria in nonimmune migrants to Papua, Indonesia.
for 10 or 12 weeks by lifelong residents of countries where
malaria is endemic [14–16] or for an average of 4 weeks in
nonimmune travelers [26, 27] was safe and well tolerated. We
used atovaquone/proguanil for 20 weeks in the present study
and observed no evidence of toxicity, either clinically or in
longitudinal evaluations of hematologic and blood chemistry
parameters. This corroborates the reportedexperienceofothers
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830 • CID 2002:35 (1 October) • Ling et al.
modium falciparum and Plasmodium vivax parasitemia.
Efficacy of atovaquone/proguanil for the prevention of Plas-
(n p 149)
(n p 150)
P . falciparum
P . vivax
density in placebo group)].
density in atovaquone/proguanilgroup/incidenceratep 100?[1?(incidence
parasitemia while receiving atovaquone/proguanil.
Drug concentrations in plasma for subjects who developed
last dose, h
Drug concentration in plasmaa
2485: week 4b
asitemia at week 19. The other 2 subjects had P . vivax parasitemia at week 18. BQL,
below the limits of quantification; QNS, sample insufficient to perform assay.
aFor comparison, the mean (?SD) plasma drug concentrations in 100 adults who
received the recommended prophylactic dose of atovaquone/proguanil were 2.1?1.2
mg/mL for atovaquone,ng/mL for proguanil, and26.8?14.0
bFor subject 2485, a plasma sample at the onset of parasitemia was not available.
Subject 2398 had mixed Plasmodium vivax and Plasmodium falciparum par-
ng/mL for cy-10.9?5.6
who have administered atovaquone alone for up to 30 months
 or proguanil alone for many years . Except for sto-
matitis, which is an established side-effect of proguanil ,
and back pain, no adverse events occurred at a higher rate in
atovaquone/proguanil recipients compared with placebo recip-
ients. The blinded supervising physicians did notattributemost
complaints of back pain to the study drug, but recipients of
atovaquone/proguanil were more likely to report that com-
plaint. Placebo recipients were more likely to report abdominal
pain or malaise.
Naturally acquired immunity to malaria may confound the
findings of trials evaluating the protective efficacy of drugs
intended for use in nonimmune individuals. For example, ran-
domized, double-blinded, placebo-controlled trials of azith-
romycin for the prevention of P. falciparum malaria showed
reasonable efficacy (83% [95% CI, 68%–91%]) among African
adults  but somewhat lower efficacy (72% [95% CI,
50%–84%]) among nonimmune Indonesian soldiers and mi-
grants to Indonesian New Guinea , which suggests that
acquired immunity in African adults might have contributed
to higher drug efficacy. In our study, we corroborated the ex-
cellent protective efficacy (195%) of atovaquone/proguanil
against P. falciparum malaria reported from trials in Africa
[14–17] and demonstrated good protective efficacy against P.
vivax (84% [95% CI, 45%–95%]).
Although not all subjects in our study population were com-
pletely naive to malaria, the vast majority had no clinically
significant acquired immunity. Malaria has been exceedingly
rare on Java since the 1950s, when a campaign of DDT (di-
chlorodiphenyltrichloroethane) spraying eradicated endemic
malaria from East and West Java and dramatically reduced
transmission in Central Java [33–35]. Surveillance data from
1993 are typical for the period of 1960–1996 and reveal an
islandwide incidence of ∼1 infection per 10,000 persons per
year . Because most infections have occurred within a few
well-known foci of chronic hypoendemicity in Central Java,
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Atovaquone/Proguanil for Malaria • CID 2002:35 (1 October) • 831
Complaints are ordered from most to least frequent among recipients of atovaquone/proguanil (Malarone; GlaxoSmithKline). *Statistically significant
difference between treatment groups (i.e.,).P ! .05
Incidence density of all adverse events (left) and those considered by blinded supervising physicians to be possibly drug related (right).
the risk on most of the island is ∼1 infection per 100,000
persons per year. Thus, chronic exposure to malaria on Java
and attendant clinical immunity was virtually nonexistent in
our transmigrant population. Previous studies of malaria in
Javanese migrants to Indonesian New Guinea have indicated
that ?3 episodes of infection within 12 months are required
for the onset of clinical immunity to P. falciparum malaria in
adults [37–39]. Only 21% of the subjects in this study reported
receiving treatment for malaria on 12 occasions, during an
average of 21 months’ residence in Indonesian New Guinea
before study entry. The fact that 95% of subjects with P. fal-
ciparum parasitemia had symptomaticmalariaaffirmedthelack
of clinical immunity to malaria among subjects in our study.
Atovaquone/proguanil kills blood stages of P. falciparum and
P. vivax [40, 41]. In addition, atovaquone and proguanil have
causal prophylactic activity directed against the liver stages of
P. falciparum [42, 43]. This property allows a person to dis-
continue use of atovaquone/proguanil 7 days after leaving an
area of risk [17, 44]. However, atovaquone/proguanil appar-
ently does not eradicate hypnozoites of P. vivax . Although
it is possible that atovaquone/proguanil might prevent the for-
mation of hypnozoites, our study design did not address this
possibility by observing subjects for months after completion
of prophylaxis, because they continued to be at risk for new
infections. Until additional information is available, atova-
quone/proguanil should be considered to provide only sup-
pressive prophylaxis for P. vivax.
In summary, atovaquone/proguanil was safe, well tolerated,
and effectiveforpreventionof P.falciparumandP.vivaxmalaria
in clinically nonimmune persons exposed in Papua, Indonesia.
Our findings support the view that atovaquone/proguanil is an
important new option for nonimmune individuals, especially
those traveling to Southeast Asia, where infection with multi-
drug-resistant P. falciparum and chloroquine-resistant P. vivax
NAVAL MEDICAL RESEARCH UNIT 2
CLINICAL TRIAL TEAM
Drs. Hasan Basri, Iwa Wiady Sumawinata, Krisin, Max Syb-
handar, and Muslim Nashar, as well as Mr. Purnomo, Iqbal
Elyazar, Sofyan Masbar, Awalludin Sutanihardja, Suradi, and
We express our sincere gratitude to many officers of the
Ministry of Health, Republic of Indonesia, without whose sup-
port this trial would not have been possible, especially Dr.
Sumarijati in Jakarta and Drs. Kalalo and Budi Subianto in
Jayapura. We acknowledge the very hard work of our medical
monitor, Narain Punjabi. Many dedicated employees spent 11
year at the remote field sites, and their efforts and sacrifices
made our study possible. We acknowledge a few of them here:
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832 • CID 2002:35 (1 October) • Ling et al.
Suprianto, Ferrianto, Djeni, Gero, Prayogo, Su’id, Edyson, Jef-
fery, Hengky, and Tiot. Mr. Ata and Drs. Picarema, Faby, and
Ria at Naval Medical Research Unit 2 (NAMRU-2) in Jayapura
provided essential support. Hospital Corpsman First Class (US
Navy) Bing Deperalta provided essential support in severalcrit-
ical areas of the study. Lenny Ekawati and others in the Lab-
oratory Information Tracking System department at NAMRU-
2 provided essential specimen-archiving support. We thank
James Campbell (Washington, DC) and James Burans (Lima,
Peru), formerly of NAMRU-2, for their support of the present
work. We thank the staffs of the government health clinics in
each village and the District of Bonggo for their cooperative
assistance. Greg Platek and Janna Scott at GlaxoSmithKline
helped with the statistical analyses. Lena Ratulangi of Glaxo-
to be a valued colleague and friend. Finally, wethankthepeople
of SP4, SP5, and SP6 for welcoming us into their village and
homes and for volunteering to join this work with the highest
1. White NJ.Antimalarialdrugresistance:thepacequickens.JAntimicrob
2. Baird JK, Basri H,JonesTR,Purnomo,BangsMJ,RitongaA.Resistance
to antimalarials by Plasmodium falciparum in Arso PIR, Irian Jaya,
Indonesia. Am J Trop Med Hyg l991;44:640–4.
3. Baird JK, Wiady I, Fryauff DJ, et al. In vivo resistance to chloroquine
by P. vivax and P. falciparum at Nabire, Irian Jaya, Indonesia. Am J
Trop Med Hyg 1997;56:627–31.
4. Schuurkamp GJ, Spicer PE, Kereu RK, Bulungol PK, Rieckmann KH.
Chloroquine-resistant P. vivax in Papua, New Guinea. Trans R Soc
Trop Med Hyg 1992;86:121–2.
5. Baird JK, Basri H, Purnomo, et al. Resistance to chloroquine by P.
vivax in Irian Jaya, Indonesia. Am J Trop Med Hyg 1991;44:547–52.
6. Murphy GS, Basri H, Purnomo, et al. Vivax malaria resistant to treat-
ment and prophylaxis with chloroquine. Lancet 1993;341:96–100.
7. Nosten F, van Vugt M. Neuropsychiatric adverse effects of mefloquine:
what do we know and what should we do? CNS Drugs 1999;11:1–8.
8. Miller KD, Lobel HO, Satriale RF, Kuritsky JN, Stern R, Campbell CC.
Severe cutaneous reactionsamongAmericantravelersusingpyrimetha-
mine-sulfadoxine (Fansidar) for malaria prophylaxis. Am J Trop Med
9. Bryant SG, Fisher S, Kluge RM. Increased frequency of doxycycline
side effects. Pharmacotherapy 1987;7:125–9.
10. Atovaquone/proguanil (Malarone) for malaria. Med Lett Drugs Ther
11. Fry M, Pudney M. Site of action of the antimalarial hydroxy-
naphthoquinone, 2-[trans-4-(4?-chlorophenyl) cyclohexyl]-3-hy-
droxy-1,4-naphthoquinone (566C80). Biochem Pharmacol 1992;
12. Canfield CJ, Pudney M, Gutteridge WE. Interactions of atovaquone
with other antimalarial drugs against Plasmodium falciparum in vitro.
Exp Parasitol 1995;80:373–81.
13. Srivastava IK, Vaidya AB. A mechanism for the synergisticantimalarial
action of atovaquone and proguanil. Antimicrob Agents Chemother
14. Shanks GD, Gordon DM, Klotz FW, et al. Efficacy and safety of ato-
vaquone-proguanil for suppressive prophylaxisagainstPlasmodiumfal-
ciparum malaria. Clin Infect Dis 1998;27:494–9.
15. Lell B, Luckner D, Ndjave M, Scott T, Kremsner PG. Randomised
placebo-controlled study of atovaquone plusproguanilformalariapro-
phylaxis in children. Lancet 1998;351:709–13.
16. Sukwa TY, Mulenga M, Chisaka N, Roskell NS, Scott TR. A random-
ized, double-blind, placebo-controlled field trial to determine the ef-
ficacy and safety of Malarone (atovaquone-proguanil) for the prophy-
laxis of malaria in Zambia. Am J Trop Med Hyg 1999;60:521–5.
17. Shanks GD, Kremsner PG, Sukwa TY, et al. Atovaquone and proguanil
hydrochloride for prophylaxis of malaria. J Travel Med 1999;6(Suppl
18. Takken W, Knols BJG.A taxonomicandbionomicreviewofthemalaria
vectors of Indonesia. Wageningen Agricultural University Papers
19. Fryauff DJ, Baird JK, Basri H, et al. Randomised placebo-controlled
trial of primaquine for prophylaxis of falciparum and vivax malaria.
20. Blackwelder WC. Sample size and power for prospective analysis of
relative risk. Stat Med 1993;12:691–8.
21. Baird JK, Lacy MD, Basri H, et al. Randomized, parallel placebo-con-
trolled trial of primaquine for malaria prophylaxis in Papua,Indonesia.
Clin Infect Dis 2001;33:1990–7.
22. DeAngelis DV, Long JD, Kanics LL, Woolley JL. High-performance
liquid chromatographic assay for the measurement of atovaquone in
plasma. J Chromatogr 1994;652:211–9.
23. Hussein Z, Eaves CJ, Hutchinson DB, Canfield CJ. Population phar-
macokinetics of proguanil in patients with acute P. falciparum malaria
after combined therapy with atovaquone. Br J Clin Pharmacol 1996;
25. Lacy MD, Maguire JD, Barcus MJ, et al. Malarone (atovaquone/pro-
guanil) therapy for Plasmodium falciparum and Plasmodium vivax in
nonimmune Indonesians. Clin Infect Dis (in press).
24. Beerahee M. Clinical pharmacology of atovaquone and proguanil hy-
drochloride. J Travel Med 1999;6(Suppl 1):S13–7.
26. Høgh B, Clarke PD, Camus D, et al. Atovaquone-proguanil versus
chloroquine-proguanil for malaria prophylaxis in non-immune trav-
ellers: a randomised, double-blind study. Lancet 2000;356:1888–94.
27. Overbosch D, Schilthuis H, Bienzle U, et al. Atovaquone-proguanil
versus mefloquine for malaria prophylaxis in nonimmune travellers:
results from a randomized, double-blind study. Clin Infect Dis 2001;
28. El-Sadr WM, Murphy RL, Yurik TM, et al. A randomized trial of
atovaquone versus dapsone for the prevention of Pneumocystis carinii
pneumonia in patients with human immunodeficiency virus infection
who are intolerant to trimethoprim and/or sulfonamides. N Engl J
29. Erikkson B, Bjorkman A, Keiau M. How safe is proguanil? A post-
marketing investigation of side effects. Scand J Infect Dis 1991;23:
30. Drysdale SF, Phillips-Howard PA, Behrens RH. Proguanil,chloroquine,
and mouth ulcers. Lancet 1990;335:164.
31. Andersen SL, Oloo AJ, Gordon DM, et al. Successful double-blinded,
randomized, placebo-controlled field trial of azithromycin and doxy-
cycline as prophylaxis for malaria in western Kenya. Clin Infect Dis
32. Taylor WR, Richie TL, Fryauff DJ, et al. Malaria prophylaxis using
azithromycin: a double-blind, placebo-controlled trial in Irian Jaya,
Indonesia. Clin Infect Dis 1999;28:74–81.
33. Van Thiel PH, Winoto RMP. Control of hyperendemic malaria on Java
caused by Anopheles sundaicus by DDT house spraying. Trop Geogr
34. Atmosoedjono S. Malaria control in Indonesia since World War II.
Wageningen Agricultural University Papers 1990;90-7:141–54.
35. Arbani PR. Malaria control program in Indonesia. In: Salazar NP,
Chongsuphajaisiddhi TC, Harinasuta T, Karbwang J, eds. Advanced
knowledge on malaria in Southeast Asia. Vol. 23, Suppl. 4. 1992:29–38.
36. Baird JK, Sismadi P, Masbar S, et al. A focus of endemic malaria in
Central Java. Am J Trop Med Hyg 1996;54:98–104.
by guest on November 13, 2015
Atovaquone/Proguanil for Malaria • CID 2002:35 (1 October) • 833
37. Baird JK, Jones TR, Danudirgo EW, et al. Age-dependent acquired
immunity against Plasmodium falciparum among people with 2 years
exposure to hyperendemic malaria. Am J Trop Med Hyg 1991;45:
38. Baird JK, Purnomo, Basri H, et al. Age-specific prevalence of Plas-
modium falciparum among six populations with limited histories of
exposure to endemic malaria. Am J Trop Med Hyg 1993;49:707–19.
39. Baird JK. Host age as a determinant of naturally acquired immunity
to Plasmodium falciparum. Parasitol Today 1995;11:105–11.
40. Looareesuwan S, Chulay JD, Canfield CJ, Hutchinson DB. Malarone
(atovaquone and proguanil hydrochloride): a review of its clinical de-
velopment for treatment of malaria. Am J Trop Med Hyg 1999;60:
41. Looareesuwan S, Wilairatana P, Glanarongran R, et al. Atovaquone
and proguanil hydrochloride followed by primaquine for treatment
of Plasmodium vivax malaria in Thailand. Trans R Soc Trop Med
42. Shapiro TA, Ranasinha CD, Kumar N, Barditch-Crovo P. Prophylactic
activity of atovaquone against Plasmodium falciparum in humans. Am
J Trop Med Hyg 1999;60:831–6.
43. Fairley NH. Researches on paludrine (M.4888) in malaria: an exper-
imental investigation undertaken by the L.H.Q. Medical ResearchUnit
(A.I.F.), Cairns, Australia. Trans R Soc Trop Med Hyg 1946;40:105–51.
44. Berman JD, Nielsen R, Chulay JD, et al. Causal prophylactic efficacy
of atovaquone-proguanil (Malarone) in a human challenge model.
Trans R Soc Trop Med Hyg 2001;95:429–32.
by guest on November 13, 2015