Am. J. Trop. Med. Hyg., 64(5, 6), 2001, pp.

223–228
Copyright 䉷 2001 by The American Society of Tropical Medicine and Hygiene

CHLOROQUINE/DOXYCYCLINE COMBINATION VERSUS CHLOROQUINE ALONE,

AND DOXYCYCLINE ALONE FOR THE TREATMENT OF PLASMODIUM FALCIPARUM
AND PLASMODIUM VIVAX MALARIA IN NORTHEASTERN IRIAN JAYA, INDONESIA
W. R. J. TAYLOR, H. WIDJAJA, T. L. RICHIE, H. BASRI, C. OHRT, TJITRA, E. TAUFIK, T. R. JONES,
K. C. KAIN, AND S. L. HOFFMAN
United States Naval Medical Research Unit Number 2, Jakarta, Indonesia; Department of Tropical Medicine,
Tulane University School of Public Health, New Orleans, Louisiana; Division of Experimental Therapeutics,
Walter Reed Army Institute of Research, Washington District of Columbia; Indonesian Naval Hospital,
Jayapura, Irian Jaya, Indonesia; Centre for Health Research and Development, National Institutes of Health, Jakarta, Indonesia;
Naval Medical Research Center, Bethesda, Maryland; Tropical Disease Unit,
The Toronto Hospital and the University of Toronto, Toronto, Canada

Abstract. Combination therapy is one method of overcoming the global challenge of drug-resistant Plasmodium
falciparum malaria. We conducted a hospital-based 28-day in vivo test comparing chloroquine/doxycycline to chlo-
roquine or doxycycline alone for treating P. falciparum and Plasmodium vivax malaria in Irian Jaya, Indonesia.
Eighty-nine patients with uncomplicated falciparum malaria were randomized to standard dose chloroquine (n ⫽ 30),
doxycycline (100 mg every 12 hours [7 days], n ⫽ 20), or chloroquine with doxycycline (n ⫽ 39); corresponding
numbers for vivax malaria (n ⫽ 63) were 23, 16, 24. Endpoints were parasite sensitivity (S) or resistance (RI/RII/
RIII). Of the 105 evaluable patients, chloroquine/doxycycline cured (S) 20/22 (90.9% [95% CI 78.9–100%]) patients
with P. falciparum malaria; 2/22 (9.1% [0–21%]) were RIII resistant. Doxycycline cured 11/17 (64.7% [42.0–87.4%])
patients, and chloroquine 4/20 (20% [2.5–37.5%]). Against P. vivax, chloroquine/doxycycline cured (S) 12/17 (70.6%
[48.9–92.2%]) patients, doxycycline 4/12 (33.3% [6.6–59.9%]), and chloroquine 5/17 (29.4% [7.7–51.1%]).
Chloroquine/doxycycline was effective against P. falciparum but only modestly effective against P. vivax. These
findings support the use of chloroquine/doxycycline as an inexpensive alternative to mefloquine for treating chloro-
quine-resistant P. falciparum but not chloroquine-resistant P. vivax in this setting.

INTRODUCTION tivity against vivax or falciparum malaria.17–20 However,

Drug-resistant Plasmodium falciparum is a serious global
problem making treatment increasingly difficult.1 In Indo-
nesia, chloroquine is the recommended drug of first choice
for treating malaria2 despite its poor efficacy against falci-
parum malaria2–5and the recent emergence of chloroquine-
resistant Plasmodium vivax.3,5–8
Using combination treatment of currently available drugs
is a rational approach to combating drug resistance and
avoids the long wait for antimalarial drugs in development.9
Drugs with different mechanisms of action may enhance
their respective efficacies and extend their therapeutic ‘‘life
spans,’’ a major public health consideration for developing
countries whose need for effective drugs is pressing. Sulfa-
doxine/pyrimethamine (S/P) is widely used in malaria-en-
demic countries and has replaced chloroquine as first-line
treatment for uncomplicated falciparum malaria in several
African countries.10 However, S/P will not be the definitive
answer to chloroquine resistance because its life span in
Thailand was only five years11 and resistance to S/P has been
reported in several countries.1,11
Drug combinations have demonstrated improved efficacy
over single agents against uncomplicated falciparum malaria.
In Gabon, clindamycin improved the efficacy of a 3-day
course of quinine from 32% to 88%, and that of standard
dose chloroquine from 9% to 70%.12 Mefloquine/artesunate
cured 98% of patients with highly resistant falciparum ma-
laria acquired on the Thai-Burmese border13 and atovoquone/
proguanil was 100% effective in Thai adults.14 Chloroquine-
resistant vivax malaria is currently less problematic and can
be treated with mefloquine,15 halofantrine,15,16 and often with
chloroquine combined with primaquine.16
Doxycycline and tetracycline have modest antimalarial ac-
combining either drug for seven days with quinine, meflo-
quine, or artesunate resulted in treatment efficacies exceed-
ing 94% against falciparum malaria in Thailand,21–24 and the
addition of three days of doxycycline to standard-dose chlo-
roquine improved the cure rate of chloroquine from 36% to
75% in Gabonese adults with falciparum malaria.25 Doxy-
cycline has now replaced tetracycline for use in combination
with quinine against falciparum malaria15 because of its ther-
apeutic advantage of twice-daily dosing and low cost (US$
3.14/100 generic capsules in Indonesia).
Inexpensive, alternative treatments to chloroquine are
needed for chloroquine-resistant falciparum and vivax ma-
laria in northeastern Irian Jaya.2–6,16 We report the results of
treating uncomplicated P. falciparum and P. vivax malaria
with chloroquine/doxycycline, chloroquine alone, and doxy-
cycline alone.
MATERIALS AND METHODS
Study design, study site, and participants. This was an
open-label, randomized, clinical trial comparing chloroquine
combined with doxycycline to chloroquine alone or to doxy-
cycline alone for treating uncomplicated falciparum or vivax
malaria. The study took place from October 1995 to January
1998 in the Jayapura Public and Indonesian Navy hospitals
in Jayapura, northeastern Irian Jaya. This area has moderate
transmission26,27 of multidrug-resistant falciparum malar-
ia2,4,28–30 and chloroquine-resistant vivax malaria.6,7,16 Chlo-
roquine is first-line treatment in this area2 and has docu-
mented failure rates of 54% against uncomplicated P. fal-
ciparum4 and up to 78% against P. vivax.16 Patients were
recruited from Jayapura and Arso (the rural area around Jay-
apura); they were either life-long residents or recent arrivals

223
224 TAYLOR AND OTHERS
from other parts of Indonesia. We obtained written informed
consent from all patients. The study was conducted accord-
ing to the Indonesian Ministry of Health, the Indonesian
Navy, and the United States Navy and Army regulations
governing the protection of human subjects.
Sample size. The sample size calculations were based on
the assumption that the frequencies of resistance (RI/RII/
RIII) were 0.5 for chloroquine alone (C) and 0.05 for the
combination arm (CD). Using a two-sided alpha of 0.05,
sample sizes of 18 per arm (C versus CD) would detect these
resistance frequencies with a probability of 0.89. Although
not the primary aim of the study, a comparison of D versus
CD, with the same sample size of 18 per arm and anticipat-
ing a resistance frequency of 0.4 for doxycycline alone and
0.05 for the combination, would provide a power of 0.73.
Patient assessment and selection. Potential subjects were
referred to our team by local physicians and medically
screened: (i) medical history, (ii) physical examination, (iii)
malaria smear, (iv) urine pregnancy test (␤ HCG test pack,
Abbott, IL), and (v) qualitative glucose-6-phosphate dehy-
drogenase (G6PD) activity (G6PD spot test, Sigma). Eligible
subjects were healthy males or non-pregnant females aged
15 to 50 years with either acute uncomplicated falciparum
malaria or vivax malaria. Specific exclusions included mixed
infections, symptoms or signs of severe and complicated ma-
laria, malaria treatment within 7 days of presentation, and
known study drug hypersensitivity.
Conduct of clinical trial. Enrolled patients were admitted
to the hospital and sequentially randomized to treatment (C,
CD, or D); this was later changed to a system of using la-
belled tickets that were selected ‘‘out of a hat’’ by the team
physician. Patients with acute uncomplicated falciparum ma-
laria were arbitrarily classified as ‘‘mild’’ (ⱕ 0.25% parasit-
emia ⬅ parasite density ⱕ 12,500/␮L), or ‘‘moderate’’ (par-
asitemia ⬎ 0.25% to ⬍ 3% ⬅ parasite density ⬎ 12,500–⬍
150,000/␮L). This artificial division was designed so that no
randomized ‘‘moderate’’ patients would receive doxycycline
alone, due to concern over its slow onset of action. Patients
randomized to chloroquine (Malarex, Dumex, Indonesia)
were treated with chloroquine base: 10 mg/kg once on Days
0 and 1, and 5 mg/kg once on Day 2 (C and CD arms). The
dose of doxycycline (Pfizer) was 100 mg every 12 hours for
7 days (D and CD arms). All drugs doses were administered
and documented by ward nurses. Patients were hospitalized
for 28 days. The ward windows were screened with mos-
quito mesh and subjects slept under mosquito nets. Symp-
toms were recorded daily. Oral temperatures were taken ev-
ery 8 hours for the first week, and daily thereafter. Treatment
failures were treated with quinine (10 mg/kg thrice daily for
4 days) and doxycycline (100 mg twice daily for 10 days).
Patients with vivax malaria were given primaquine base (30
mg/day for 14 days) at the time of hospital discharge, pro-
vided they were not G6PD deficient.
Giemsa-stained malaria smears were read daily until neg-
ative; thereafter, three times per week until Day 28. A pos-
itive smear was defined as one or more asexual form/s seen
after examining 200 thick smear fields under ⫻ 1,000 mag-
nification. The parasite count (number/␮l) was quantified as
the number of asexual parasites/200 white cells on the thick
film ⫻ 40.31
Filter paper (No. 1 Whatman, Fairfield, NJ) blots for chlo-
roquine drug levels were made on Days 0, 3, and 28, or on
the day of recurrent parasitaemia. One hundred ␮l of whole
blood were drawn from a finger stick into a capillary tube
and spread evenly onto the filter paper. Blots were air dried
and stored in individual plastic bags at ambient temperatures
until analysed. Chloroquine and its main active metabolite,
desethylchloroquine, were measured in whole blood by
HPLC.32 The sum of chloroquine and desethylchloroquine is
reported as the total whole blood chloroquine concentration
(ng/ml).
End points. The parasitological end points were classified
as sensitive (S) or resistant (RI/RII/RIII). Sensitive: complete
and sustained clearance of asexual parasitemia by Day 7 to
Day 28; RI: complete clearance of asexual parasitemia by
Day 7 but recrudescence within 28 days of starting treat-
ment; RII: marked reduction (ⱖ 75%) of asexual parasitemia
within 48 hours but no clearance by Day 7; and RIII: no
marked reduction of asexual parasitemia by 48 hours.33 For
vivax malaria, we classified RI cases as RI/relapse because
clinical differentiation between recrudescence or relapse
(from liver hypnozoites) during follow-up may be problem-
atic. Genotyping by the polymerase chain reaction (PCR)
was performed on the recurrent and original (Day 0) para-
sitemias by a method previously described.34,35 A matching
genotype between primary and recurrent isolates indicates a
⬎ 90% probability of a RI treatment failure or a vivax re-
lapse caused by the same clone as the original infection.34,35
A non-matching genotype suggests a new infection or a vi-
vax relapse caused by an antecedent infection.
Secondary clinical end points were (i) the fever clearance
time (FCT/hours): the time taken for the patient to become
and remain afebrile (oral temperature ⱕ 37⬚C recorded at
least four consecutive times); (ii) the parasite clearance time
(PCT/days): the number of days taken for a malaria smear
to become negative for at least two consecutive days; and
(iii) the proportion of symptomatic patients (reporting either
fever, chills, headache, myalgia, weakness, anorexia, or nau-
sea) on Days 2, 4, and 7.
Statistical analysis. Data were double-entered and vali-
dated using Epi Info 6.04b (Centers for Disease Control and
Prevention, Atlanta, GA). Significance testing of proportion-
al data (Chi squared), and calculating the 95% confidence
intervals (CI) of continuous data were performed using
SPSS for Windows 8.0 (SPSS, Chicago, IL). Relative risks
and confidence intervals around proportions were calculated
using Epi Info 6.04b. Normally distributed data were com-
pared using the student’s t-test or ANOVA or the corre-
sponding non-parametric tests, Mann-Whitney U or Krus-
kall-Wallis, for skewed data. All statistical tests were two
sided and a P value of ⱕ 0.05 was considered statistically
significant. Only patients who completed the study were an-
alysed for the parasitological end points.
RESULTS
Of 164 screened patients, 152 patients entered the study:
89 P. falciparum and 63 P. vivax malaria (Figure 1); 28 of
152 were excluded from analysis because of violation of the
randomization system by one physician who allocated treat-
ment using clinical judgement. These 28 excluded study sub-
jects included all patients who were enrolled during the time
 TREATMENT OF MALARIA IN IRIAN JAYA 225

FIGURE 1. Trial profile of a clinical trial of chloroquine/doxy-

cycline versus chloroquine alone and doxycycline alone for treating
uncomplicated Plasmodium falciparum or Plasmodium vivax malar-
ia in Irian Jaya.
period of this physician’s participation, in order to eliminate
any possibility of bias. Patients in the treatment groups had
similar baseline characteristics except for the P. falciparum
cases randomized to doxycycline alone who had significantly
less residential time in Irian Jaya. Parasite counts of both
malaria species were similar between treatment groups (Ta-
ble 1). Reasons for non-completion of study were mixed
infection during follow-up, clinical failure due to persistent
vomiting, inadvertent primaquine administration for falci-
parum gametocytes or vivax hypnozoites before Day 28, and
voluntary withdrawal (Figure 1).
P. falciparum (Table 2). The cure rate (S) of chloroquine/
doxycycline (90.9%) was significantly higher than that of
chloroquine alone (20%), (RR ⫽ 4.55 [95% CI 1.87–11.03],
P ⬍ 0.0001) but not significantly different compared to
doxycycline alone (64.7%), (RR ⫽ 1.40 [0.97–2.04], P ⫽
0.059). The doxycycline cure rate (S) was significantly high-
er than that of chloroquine alone (RR ⫽ 3.24 [1.26–8.32],
P ⫽ 0.008). All three grades of resistance were present in
the chloroquine arm, RII/RIII in the doxycycline alone arm,
and only RIII resistance in the CD arm. PCR data were
available for 3 patients in the chloroquine-alone arm with
recurrent parasitemia; their genotypes matched those of their
respective Day 0 parasitemias. Overall resistance was 16/20
(80% [95% CI 62.5–97.5%]) for chloroquine alone, 6/17
(35.3% [12.5–58%]) for doxycycline alone, and 2/22 (9.1%
[0–21%]) for the combination. The mean FCTs and mean
PCTs did not differ significantly between arms. The fre-
quency of symptomatic patients on Days two and four post-
treatment was similar between the three arms (data not
shown) but was significantly higher on Day 7 for the doxy-
cycline arm (6/12 [50%]) compared to the chloroquine arm
(1/15 [6.7%], P ⫽ 0.023).
P. vivax (Table 2). The cure rate (S) of chloroquine/doxy-
cycline (70.6%) was significantly higher than that of chlo-
roquine alone (29.4%), (RR ⫽ 2.4 [1.08–5.33], P ⫽ 0.016)
but not significantly different compared to doxycycline alone
(33.3%), (RR ⫽ 2.12 [0.90–4.99], P ⫽ 0.067). Doxycycline
and chloroquine had similar cure rates (RR ⫽ 1.13 [0.38–
1.13], P ⫽ 1.0). RI/relapse and RII/RIII resistance were pre-
sent in the chloroquine arm, RI/relapse and RIII resistance
in the doxycycline arm, and RI/relapse only in the CD arm.
PCR data were available for 11 cases of recurrent parasit-
emia (by arm: C ⫽ 5, CD ⫽ 4, D ⫽ 2). Ten had matching
and one had mismatching genotypes compared to their re-
spective Day 0 parasitemias. The recurrent parasitemias oc-
curred between Days 11–23 (C arm), and Days 22–25 (CD
and D arms). Mean FCTs in all three treatment groups were
similar but the mean PCT was significantly longer in the
doxycycline arm compared to the combination and chloro-
quine alone arms. The proportions of symptomatic patients
were similar in all treatment arms on Days 2, 4, and 7 (data
not shown).
Chloroquine levels. The Day 3 whole-blood total chlo-
roquine levels in patients given chloroquine or chloroquine/
doxycycline ranged from 315–1,545 ng/ml, median 719 ng/

TABLE 1
Patient characteristics at enrollment

Falciparum malaria Vivax malaria

C CD D* C CD D
n ⫽ 30 n ⫽ 39 n ⫽ 20 n ⫽ 23 n ⫽ 24 n ⫽ 16

Male 28 33 19 22 21 14
Female 2 6 1 1 3 2
Mean (SD) age yr 24.5 (5.0) 23.7 (5.2) 24.9 (5.6) 23 (4.9) 23.8 (3.9) 24.9 (5.1)
Time in Irian Jaya† 17 (1m–40) 19 (4–30) 3 (3m–26) 2 (6m–24) 9.5 (2–30) 3 (2m–29)
Previous malaria‡ 2 (0–10) 3 (0–11) 3 (0–9) 5 (0–16) 1 (0–6) 3 (0–11)
No. (%) symptomatic 30 (100) 39 (100) 19 (95) 23 (100) 24 (100) 16 (100)
No. (%) febrile 25/29 (86.2) 35 (89.7) 15 (75) 19/22 (86.4) 23 (95.8) 14 (87.5)
No. (%) splenomegaly 11 (36.7) 21 (53.8) 6 (33.3) 7 (30.4) 3 (12.5) 1 (6.2)
Parasite count/␮l§ 5,280 (40–93,040) 7,040 (40–76,120) 1,740 (80–40,160) 3,320 (80–12,840) 1,980 (160–16,360) 3,800 (80–17,120)
C ⫽ chloroquine alone; CD ⫽ chloroquine and doxycycline in combination; D ⫽ doxycycline alone; SD ⫽ standard deviation.
* Includes one ⬎ moderate ⫽ falciparum subject inadvertently given doxycycline.
† Median (range) number of years in Irian Jaya pre-study, m ⫽ months. Falciparum cases: D versus CD, P ⫽ 0.01 (Mann-Whitney U test).
‡ Median (range) number of reported attacks of clinical malaria within the last two years (history only). Vivax cases: C versus CD, P ⫽ 0.007 (Mann-Whitney U).
§ Median (range). Only falciparum cases with parasitemias ⱕ 12,500/␮l were enrolled in the doxycycline arm alone.
226 TAYLOR AND OTHERS
TABLE 2
Results of evaluable patients with falciparum or vivax malaria
Falciparum malaria
C CD
n ⫽ 20 n ⫽ 22
S 4 (20.0)* 20 (90.9) 11 (64.7)
RI† 8 (40.0) 0 (0) 0 (0)
RII 5 (25.0) 0 (0) 2 (11.8)
RIII 3 (15.0) 2 (9.1) 4 (23.5)
Mean (95% CI) FCT/hours 41.2 (27.0–55.4) 59.1 (43.4–74.9) 61.6 (23.8–99.4)
Mean (95% CI) PCT/days 2.8 (2.0–3.6) 3.4 (2.7–4.1) 3.8 (2.6–5.1)
C ⫽ chloroquine alone; CD ⫽ chloroquine and doxycycline in combination; D ⫽ doxycycline alone; S ⫽ sensitive; RI, RII, and RIII ⫽ resistance (see text for definitions). FCT ⫽ fever
clearance time; PCT ⫽ parasite clearance time. CI ⫽ confidence interval.
* n (%)
† RI/relapse for Plasmodium vivax malaria.
ml. The median Day 3 levels were similar between (i) the
CD and chloroquine arms: 723 ng/ml versus 703 ng/ml, re-
spectively, P ⫽ 0.51, (ii) patients with resistant or sensitive
falciparum infections: 698 ng/ml versus 706 ng/ml, respec-
tively, P ⫽ 0.93, and (iii) patients with resistant or sensitive
vivax infections: 702 ng/ml versus 719 ng/ml, respectively,
P ⫽ 0.52.
DISCUSSION
This study has shown that the combination of chloroquine
and doxycycline markedly improved the cure rate of uncom-
plicated, multidrug-resistant falciparum malaria in north-
eastern Irian Jaya. Against vivax malaria, there was only
modest improvement over chloroquine alone.
Scant data exist on doxycycline or tetracycline monother-
apy of falciparum or vivax malaria. Malaysian children with
chloroquine-resistant falciparum malaria had higher cure
rates with 7 days of doxycycline compared to four days, 22/
26 (84.6%), and 4/9 (44.4%), respectively.18 Seven days
doxycycline cured 9/9 American volunteers with experimen-
tally-induced, low parasitemic P. falciparum malaria where-
as five days resulted in 4/4 cases of recrudescence.17 These
seven-day cure rates are higher than in our falciparum pa-
tients (65%). We have identified only one study of tetracy-
cline treatment of experimentally induced, Chesson strain
vivax malaria, the strain from New Guinea.17 Of twelve
American volunteers given tetracycline (2 or 4 gm/day for
7 or 14 days), only 4 subjects (33.3%) were fully sensitive;
a cure rate consistent with our vivax data. Tetracycline or
doxycycline monotherapy resulted in slow mean parasite and
fever clearance times against P. falciparum17–20 (PCT 5 days,
FCT 3–5 days)17–20 and P. vivax (PCT 7 days, FCT 6 days)17
malaria. Our study has re-documented the slow parasite
clearance times of falciparum (x̄ ⫽ 4 days), and vivax ma-
laria (x̄ ⫽ 5 days), but our mean fever clearance times were
faster, just over 2 days for both species.
Chloroquine was clearly inadequate against P. falciparum,
achieving a 20% cure rate and a high proportion (40%) of
RII/RIII infections. The cure rate against P. vivax was mar-
ginally better (29%) but the proportion of high-grade resis-
tance was lower at 12%. In Jayapura in 1984,36 16 patients
with falciparum malaria were treated with chloroquine in a
7-day in vivo test; only 9 (56.2%) were S/RI and the seven
resistant cases were RI (3), RII (2), and RIII (2 [12.5%]).
Twelve years on, our data and those of earlier studies con-
Vivax malaria
D C CD D
n ⫽ 17 n ⫽ 17 n ⫽ 17 n ⫽ 12
5 (29.4) 12 (70.6) 4 (33.3)
10 (58.8) 5 (29.4) 5 (41.7)
1 (5.9) 0 (0) 0 (0)
1 (5.9) 0 (0) 3 (25.0)
32.0 (18.8–45.2) 48.5 (28.9–68.0) 46.0 (19.1–72.9)
2.4 (1.9–2.9) 3.1 (2.7–3.4) 5.2 (3.8–6.6)
tinue to document the high degree of chloroquine resistance
of both falciparum and vivax malaria in this area.4–6,16,36
To date, only one randomized study comparing chloro-
quine/doxycycline with chloroquine for treating acute, un-
complicated falciparum malaria has been published. Adults
from Gabon (median parasite count of 13,500/␮l) received
three days of concurrent doxycycline/chloroquine. The cure
rate was 75% compared to 36% for standard-dose chloro-
quine alone.25 The cure rate may well have been higher had
doxycycline been given for seven days, as in our study, and
as suggested by the earlier trials of doxycycline monother-
apy.17,18
Chloroquine/doxycycline cured 90.9% of our patients with
falciparum malaria. However, this good result is tempered
by the occurrence of RIII resistance in two patients (9%).
These patients remained symptomatic and had rising parasite
counts at 48 hours but were not seriously ill. In Thailand, a
clinical trial assessing the efficacy of chloroquine/tetracy-
cline against falciparum malaria was prematurely abandoned
because two patients with RIII resistance became seriously
ill. The investigators concluded that the chloroquine/tetra-
cycline combination was potentially dangerous.37 Clinicians
should be aware that RIII resistance is the most serious form
of resistance because treatment has little or no effect in low-
ering the parasite count and patients may develop severe
falciparum malaria. In Irian Jaya, RIII chloroquine-resistant
P. falciparum has been documented as 16.2% on the north
coast3, 22.8% in Arso4, and 12.5% in Jayapura.36 Our figures
were 15% for chloroquine and 9.1% for the chloroquine/
doxycycline suggesting that the combination might have had
a small beneficial effect against RIII resistant parasites.
However, overcoming RIII resistance to chloroquine in this
area will require more efficacious antimalarial drugs or drug
combinations. Against vivax malaria, the high rate of initial
parasite clearance was offset by the relatively high rate of
apparent recrudescence, necessitating the use of alternative
treatment. In our setting of drug-resistant falciparum and vi-
vax malaria, optimal patient management would ideally re-
quire accurate speciation, targeted treatment, and follow-up;
clearly a challenge under field conditions. The cure rates of
the combination were achieved by administering doxycy-
cline for seven days, a major drawback for patient compli-
ance outside the research setting. Our results cannot be ex-
tended to two important vulnerable groups, young children
and pregnant women in both of whom doxycycline is con-
traindicated.
 TREATMENT OF MALARIA IN IRIAN JAYA
Chloroquine/doxycycline had a higher cure rate against P.
falciparum (90.9%) than P. vivax (70.6%), but this differ-
ence was not quite significant (P ⫽ 0.08). Intuitively, one
would have expected a higher vivax cure rate because vivax
malaria is a ‘‘benign’’ malaria. This finding underscores the
importance of studies aimed at understanding the mecha-
nisms of action and resistance of chloroquine and doxycy-
cline in the two major species of human malaria. Our data
suggest that different mechanisms of drug resistance may
exist between P. falciparum and P. vivax.
In this study we have shown that the combination was
effective against multidrug-resistant falciparum malaria and
highly effective for the initial clearance of chloroquine-re-
sistant vivax malaria. In Irian Jaya, it could offer a reason-
able alternative to chloroquine, the current standard of care,
which has a failure rate against P. falciparum well above
the 25% level recommended by the World Health Organi-
zation (WHO) for a change in antimalarial treatment against
this species.38 Seven days of generic doxycycline would in-
crease the cost of chloroquine alone from approximately
US$0.07 to 0.51. This compares to 13 cents for an adult
course of S/P, and US$2.35 for an adult course of generic
mefloquine of 15 mg/kg (five 250 mg tablets).
Chloroquine/doxycycline will not be the definitive answer
to chloroquine-resistant falciparum or vivax malaria. How-
ever, it may have a role as an interim measure in malaria-
control programs for treating either malaria species, provid-
ed P. falciparum RIII resistance is not a significant problem.
Acknowledgments: The authors wish to thank the following for their
contribution to the study: (i) the nurses at the Jayapura General
hospital and the Indonesian Navy hospital; (ii) Drs. Oyong and Baso
(Jayapura General Hospital) and Kristanto (Indonesian Naval Hos-
pital, Jayapura) for their support in study execution; (iii) Nona Nur-
jaya and Pak Ferry for slide reading, laboratory work, and data
management; (iv) Pak Purnomo, Pak Sofyan, Awalludin, and Suradi
for slide reading; (v) Dr. B. Subianto, (Provincial Health Office,
Jayapura) for facilitating study execution; and (vi) Dr. D. Fryauff
(US NAMRU-2) for critical review of the manuscript.
Financial support: This study was funded by the US Naval Medical
Research and Development Command (DoD 63002A M00101 HEX
2406)
Disclaimer: The views expressed in this paper are those of the au-
thors and do not in any way represent those of the Indonesian Navy,
the Indonesian Ministry of Health, or the US Navy.
Authors’ addresses: Walter R. J. Taylor, US NAMRU-2, Box 3, Unit
8132, APO, AP 96520-8132, and the Department of Tropical Med-
icine, Tulane University School of Public Health, Canal Street, New
Orleans, LA. Hendra Widjaja, Thomas L. Richie, and Hasan Basri,
US NAMRU-2, Box 3, Unit 8132, APO, AP 96520-8132. Colin
Ohrt, Division of Experimental Therapeutics, Walter Reed Army
Institute of Research, Washington, DC. Taufik, Indonesian Naval
Hospital, Jayapura, Irian Jaya. Emiliana Tjitra, Centre for Health
Research and Development, National Institutes of Health, Jalan Per-
kecatan Negara 29, Jakarta, Indonesia. Trevor Jones, and Stephen L.
Hoffman, Naval Medical Research Center, Bethesda, 12300 Wash-
ington Avenue, Rockville, MD 20853. Kevin C. Kain, Tropical Dis-
ease Unit, The Toronto Hospital and the University of Toronto, To-
ronto, Canada.
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