gilang_atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune...

8/14/2019 Gilang_atovaquone-Proguanil Versus Chloroquine-proguanil for Malaria Prophylaxis in Non-immune Travellers

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Summary

Background Chloroquine plus proguanil is widely used for

malaria chemoprophylaxis despite low effectiveness in

areas where multidrug-resistant malaria occurs. Studies

have shown that atovaquone and proguanil hydrochloride is

safe and effective for prevention of falciparum malaria in

lifelong residents of malaria-endemic countries, but little is

known about non-immune travellers.

Methods In a double-blind equivalence trial, 1083

participants travelling to a malaria-endemic area were

randomly assigned to two treatment groups: atovaquone-

proguanil plus placebos for chloroquine and proguanil, or

chloroquine, proguanil, and placebo for atovaquone-

proguanil. Follow-up was by telephone 7 and 60 days after

travel and at a clinic at 28 days. Serum samples were

tested for antibodies to a malaria circumsporozoite protein.

Blood and serum samples of participants with a potential

malaria diagnosis were tested in a reference laboratory.

Findings 7 days after travel, at least one adverse event

was reported by 311 (61%) of 511 participants who

received atovaquone-proguanil and 329 (64%) of 511 whoreceived chloroquine-proguanil. People receiving

atovaquone-proguanil had a lower frequency of treatment-

related gastrointestinal adverse events (59 [12%] vs 100

[20%], p=0001), and of treatment-related adverse events

of moderate or severe intensity (37 [7%] vs 56 [11%],

p=005). There were fewer treatment-related adverse

events that caused prophylaxis to be discontinued in the

atovaquone-proguanil group than in the chloroquine-

proguanil group (one [02%] vs ten [2%], p=0015).

Interpretation Overall the two preparations were similarly

tolerated. However, significantly fewer adverse gastro-

intestinal events were observed in the atovaquone-

proguanil group in than in the chloroquine-proguanil group.

Lancet 2000; 356: 188894

IntroductionMalaria is one of the greatest threats to healthfor international travellers. The number of reported

cases of malaria in Europe increased from 6840 in 1985,to 8438 in 1995, with a case-fatality rate as high as36%.1 Imported malaria is also a problem in NorthAmerica, with more than 1000 cases reported annuallyin the USA and Canada.2,3

Imported malaria mainly occurs when travellers fail touse appropriate chemoprophylaxis or do not use itcorrectly.3 Widespread parasite resistance renderschloroquine poorly effective in most malaria-endemiccountries.4 Mefloquine is highly effective in preventingmalaria but has been associated with neuropsychiatricside-effects that may be severe and can restrict its use.5

The combination of chloroquine plus proguanil hasfewer serious side-effects than mefloquine6 and is moreeffective than chloroquine alone, but still less effective

than mefloquine.7

An additional drawback with drugswidely used for malaria prophylaxis is that they must becontinued for 4 weeks after leaving a malaria-endemicarea.8 There is a clear need for better drugs to preventmalaria.

In controlled clinical trials with more than600 participants, a fixed-dose combination ofatovaquone and proguanil hydrochloride was 98%effective in prophylaxis of malaria caused by Plasmodiumfalciparum and had a safety profile similar to that ofplacebo.912 However, these studies were done on lifelongresidents of malaria-endemic countries, who may havehad some immunity to malaria. Additionally, thefrequency and nature of adverse events might differbetween travellers and residents of endemic areas. We

have undertaken a randomised, double-blind trial tocompare the safety and efficacy of atovaquone-proguanilversus chloroquine-proguanil in non-immune travellers.The hypothesis was that the frequency of adverse eventsin participants receiving atovaquone-proguanil was nothigher than in those receiving chloroquine-proguanil.The frequency of treatment-limiting adverse events andefficacy of prophylaxis were secondary endpoints.

MethodsStudy participants

Participants were enrolled into study MAL30011 at21 travel clinics in Denmark, UK, France, Germany,Netherlands, South Africa, and Canada. They were ofboth sexes, at least age 14 years, weighed more than

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1888 THE LANCET Vol 356 December 2, 2000

Atovaquone-proguanil versus chloroquine-proguanil for

malaria prophylaxis in non-immune travellers: a randomised,

double-blind study

Birthe Hgh, Paul D Clarke, Daniel Camus, Hans Dieter Nothdurft, David Overbosch, Matthias Gnther, Izak Joubert,

Kevin C Kain, Dea Shaw, Neil S Roskell, Jeffrey D Chulay, and the Malarone International Study Team

International Travel Vaccination Centre, Copenhagen, Denmark

(B Hgh MD); Medical Advisory Services for Travellers Abroad

(MASTA), London, UK (P D Clarke FRCP); Institut Pasteur, Lille,

France (D Camus MD); Department for Infectious Diseases and

Tropical Medicine, Munich, Germany (H D Nothdurft MD); Harbour

Hospital and Institute of Tropical Medicine, Rotterdam,

Netherlands (D Overbosch MD); Institute for Tropical Medicine,

Berlin, Germany (M Gnther MD); Travelsafe Clinic, Cape Town,

Republic of South Africa (I Joubert MD); Toronto General Hospital,

Toronto, Canada (K C Kain MD); and Glaxo Wellcome, Research

Triangle Park, NC, USA and Greenford, UK (D Shaw RN,

N S Roskell MSc, J D Chulay MD)

Correspondence to: Malarone Publication Coordinator,

Room 50-3505B, Glaxo Wellcome Inc, 5 Moore Drive, Research

Triangle Park, NC 27709, USA

(e-mail: [email protected])

Copyright 2000 All Rights Reserved


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50 kg, were in good general health, and planned totravel for up to 28 days to an area where P falciparumwas endemic. Reasons for exclusion were: knownhypersensitivity to atovaquone, proguanil, orchloroquine; a history of seizures, psychiatric disorders,generalised psoriasis, or alcoholism; renal, hepatic, orcardiac dysfunction; severe blood or neurologicaldisorders; pregnancy or lactation; malaria within theprevious 12 months; or travel to a malaria-endemic areawithin the previous 60 days. Written informed consentwas obtained from all individuals or their parents. Thestudy was approved by the ethics committee at eachstudy site.

At enrolment, information was obtained aboutdemographic characteristics, malaria history, traveldestination, current medical conditions andmedications; a physical examination was done; and apregnancy test was carried out for women ofchildbearing potential.

Design and procedures

Participants were randomly assigned to one of twotreatment groups, atovaquone-proguanil orchloroquine-proguanil. Those in the atovaquone-

proguanil group received active atovaquone-proguaniland placebos for chloroquine and proguanil, and thosein the chloroquine-proguanil group receivedchloroquine, active proguanil and a placebo foratovaquone-proguanil (figure 1). For each active drug,capsules or film-coated tablets were identical inappearance to the matching placebo.

A computer-generated code was used to randomlyassign a treatment number to the three bottles of studydrug for every individual. At all sites consecutivelyenrolled individuals who satisfied all entry criteriareceived the next treatment number. Treatment codeswere provided to investigators in opaque sealedenvelopes, to be opened only if knowledge of study drugassignment was required for management of a medical

emergency.Atovaquone-proguanil hydrochloride (Malaronetablets, containing 250 mg atovaquone and 100 mgproguanil hydrochloride, GlaxoWellcome, Mississauga,Canada) or matching placebo was given according tostandard recommendations of the manufacturer(figure 1).12

Chloroquine phosphate (Avloclor, 250 mg tabletsequivalent to 155 mg chloroquine base) and proguanilhydrochloride (Paludrine, 100 mg tablets) weremanufactured by AstraZeneca and encapsulated byGlaxoWellcome to achieve blinding. Chloroquine andproguanil or matching placebos were given according tostandard recommendations of WHO (figure 1).8

At enrolment, participants were given a diary card to

record details of study drug administration, and amalaria diagnosis kit. They were instructed to use thiskit if they were diagnosed with malaria. The kitcontained a card on which a health care provider couldrecord details about the diagnosis; slides and a slideholder (to take blood films); filter strips (Isocode Stix,Schleicher and Schull, Keene, NH, USA) on whichblood could be spotted for parasite DNA analysis; tubesfor whole blood (for parasite DNA analysis) and plasma(to measure plasma drug concentrations); andinstructions on how to take samples and arrange forprepaid courier service to return samples to a centrallaboratory. Individuals were told that if they developedmalaria they should ask the health care provider makingthe diagnosis to obtain the samples and send the whole-

blood and plasma samples to the central laboratory. Theparticipant was instructed to bring the slides and filterstrips to the investigator at the follow-up visit.

Follow-up surveys

People were interviewed by telephone 7 and 60 daysafter leaving the malaria-endemic area and at a clinicvisit at 28 days after departure. At the 7-day contact,

information was obtained about the exact dates andlocations of travel in malaria-endemic areas. Atenrolment and each follow-up assessment, participantswere asked if they had been diagnosed with malaria andqueried about symptoms (fever, nausea, vomiting,abdominal pain, diarrhoea, mouth ulcers, itching,headache, insomnia, strange or vivid dreams, dizziness,anxiety, depression, visual difficulties, and fits orseizures). They were also asked an open-ended questionabout any other medical conditions or adverse eventsthey had had since the last visit. Each adverse event wasassessed for date of onset, duration, and intensity(mild=fairly trivial, moderate=interfered with dailyactivities, severe=sought medical advice). Investigatorsassessed whether there was a reasonable possibility that

the adverse event was caused by the study drug. Anadverse event was recorded as treatment-emergent if itstarted while the participant was taking the study drug,treatment-limiting if it resulted in permanentdiscontinuation of study drug, and serious if it werefatal, life-threatening, disabling, resulted in admission,or otherwise seriously jeopardised the participant.Compliance with study drug use was assessed at the 28day follow-up visit by interview, reviewing the diarycard, and counting unused pills.

Measurement of malarial indices

At the baseline and 28 day follow-up visits, serum wascollected from participants at all sites, and blood wasobtained for routine haematological tests (haemoglobin,

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THE LANCET Vol 356 December 2, 2000 1889

ATQ-PGN active

one tablet daily

Chloroquine placebo two capsules per week

Proguanil placebo two capsules daily

Atovaquone-

proguanil

Group

ATQ-PGN placebo

one tablet daily

Chloroquine active two capsules per week

Proguanil active two capsules daily

Chloroquine-

proguanil

1

2

days

7

days

7

days

28

days

Before During

Travel period

After

Figure 1: Drug dosing regimensATQ=atovaquone; PGN=proguanil.



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white blood cell count, platelet count) and chemistry(creatinine, alanine aminotransferase) from all people atone site. The serum was used to measure antibodies toP falciparum circumsporozoite protein by ELISA13 for allparticipants, and to measure antibodies to blood-stagesof the four human species of plasmodium byimmunofluorescence 14 for those diagnosed withpotential malaria. The circumsporozoite antibody testwas judged positive when the result for a post-travelserum sample was more than 2 SD above the mean ofresults for the negative control sera and also more than2 SD above the baseline serum sample result.Antibodies to blood-stage parasites were recorded aspositive when they were detected at a titre of 1/64 orgreater in a post-diagnosis serum sample and thebaseline sample was negative, or when there was a16-fold or greater increase in antibody titre in a post-diagnosis serum sample compared with baseline.14

Blood smears obtained at the time of malariadiagnosis were examined at the malaria referencelaboratory of the Toronto General Hospital. DNA wasextracted from whole blood samples and filter strips;parasite ribosomal RNA genes were amplified by PCRto identify the Plasmodium spp causing malaria.15 As

defined in the trial protocol, a potential diagnosis ofmalaria was thought definite if parasite DNA wasdetected by PCR or parasites were seen on a bloodsmear slide; possible if a diagnosis of malaria wasrecorded by a health care provider, but blood smearsand parasite DNA analyses were negative or missing andantibodies to blood-stage parasites were missing; andnegative if a diagnosis of malaria was recorded by ahealth care provider, but blood smears and parasiteDNA analyses were negative or missing and antibodiesto blood-stage parasites were negative.

P falciparum isolates obtained during the course of thisstudy underwent DNA analysis for putative molecularmarkers of chloroquine and proguanil resistance asdescribed1620 and by sequencing.

Statistical analyses

The primary study endpoint was the overall frequency ofadverse events assessed at 7 days after leaving themalaria-endemic area, analysed in the intent-to-treatpopulation of all participants who received at least onedose of study drug. The overall frequency of adverseevents at 28 days after leaving the malaria-endemic areawas also determined. The sample size was based onJones and colleagues formula.21 An equivalence trialwith 400 suitable participants per group has power of82% to detect non-inferiority of atovaquone-proguanilcompared with chloroquine-proguanil, if the overallproportion of adverse events is 40% and a 10%difference in adverse event proportions is regarded as

clinically important. The power is also more than 80% ifthe overall proportion of adverse events is 6070%.Non-inferiority was assessed by comparison of thetwo-sided 95% CI for the adverse eventproportion difference against the non-inferiority range(100%, +10%). The target enrolment was increased to1000 (500 per group) to allow for unsuitableparticipants.

Secondary study endpoints were the frequency oftreatment-limiting adverse events and the efficacy ofprophylaxis. Percentage efficacy was calculated from:100(1[number of participants with confirmedmalaria/number of participants at risk]). To estimate theminimum efficacy of each drug, the number ofparticipants regarded as at high risk was the number

who had confirmed malaria or who developedanticircumsporozoite antibodies and for whom 60-dayefficacy data were available. To estimate the maximumefficacy of each drug for prevention of malaria, the

number of those thought at risk was the number forwhom 60-day efficacy data were available. For bothminimum and maximum estimates of efficacy, the95% CI around the proportion was calculated from thebinomial distribution.

Proportions of people with adverse events werecompared with Yates corrected 2 test. Because thep-values are unadjusted and multiple comparisons willinflate the type I error, care should be taken wheninterpreting these comparisons.

ResultsFrom April to October, 1999, 1083 participants wererandomly assigned to receive atovaquone-proguanil(n=540) or chloroquine-proguanil (543). 61 people did

not receive their first dose of study drug because theydid not travel to a malaria-endemic area (25), were lostto follow-up (nine), withdrew consent (seven), or otherreasons (20). Of the 1022 who received at least one doseof study drug, 1008 (99%) completed the trial(figure 2).

The two groups were well balanced with respect tobaseline demographics, history of malaria, traveldestination, and duration of travel (table 1).24 participants were more than 65 years old.16 participants (16%) reported a previous episode ofmalaria a median of 12 (range 260) yearsbefore enrolment. The average duration of travel wasabout 25 weeks and 642 (63%) people travelled toAfrica.

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1083 eligible participants

540 randomised to receive

atovaquone-proguanil

11 did not travel 6 lost to follow-up

4 consent withdrawn

8 other/unknown*

511 received study drug

462 completed dosing

49 stopped dosing early

501 completed the trial

2 did not travel

2 lost to follow-up

1 adverse event

1 consent withdrawn

4 other

543 randomised to receive

chloroquine-proguanil

14 did not travel 3 lost to follow-up

3 consent withdrawn

12 other/unknown

511 received study drug

468 completed dosing

43 stopped dosing early

507 completed the trial

2 did not travel

1 lost to follow-up

1 adverse event

R

Figure 2: Trial profile*Unknown (3), work-related (2), wanted more protection from malaria (1),

permanently left country (1), and protocol violation (1). Unknown (9),

concern about potential side-effects (1), protocol violation (1), and

adverse event (1). Could not swallow capsules (1), drug lost (1),

protocol violation (1), and treatment with another antimalarial drug (1).



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Participants and study personnel remained unaware oftreatment assignment apart from ten individuals (sevenin the atovaquone-proguanil group and three in thechloroquine-proguanil group). Reasons for breaking thetreatment code were: an adverse event for whichknowledge of study treatment was deemed essential(n=five); participants who opened the chloroquine andproguanil capsules themselves (four) and loss of studydrug before completion of postexposure prophylaxis(one).

The mean (SD) duration of treatment was 26 (8) daysfor atovaquone-proguanil, 48 (11) days for chloroquine,

and 45 (10) days for proguanil. The proportion ofparticipants who took at least 80% of prescribed dosesin the pretravel, travel and post-travel periods was:484 (95%), 489 (96%), and 473 (93%), respectively, foratovaquone-proguanil; 478 (94%), 466 (91%), and408 (80%) for chloroquine; and 461 (90%), 480 (94%),and 443 (87%) for proguanil. In the post-travel periodthe difference from atovaquone-proguanil wassignificant for chloroquine (difference=65 [13%],p=0001) and proguanil (difference=30 [6%], p=0003).

At 7 days after return from a malaria-endemic area,one or more adverse events were reported by 311 of 511(61%) participants in the atovaquone-proguanil groupand 329 of 511 (64%) in the chloroquine-proguanilgroup. The difference in frequency of adverse events

in the intent-to-treat population was 35%(95% CI 95%, +24%, not significant). Because ofthe different pretravel dosing regimens, participantsrandomly assigned to atovaquone-proguanil startedchloroquine placebo about 5 days before startingatovaquone-proguanil. Excluding events that occurredwhile people were receiving only placebo, adverse eventswere reported by 296 of 511 (58%) of those receivingatovaquone-proguanil and 329 of 511 (64%) receivingchloroquine-proguanil. The difference in number ofparticipants who reported adverse events while receivingactive treatment was 33 (65%) (95% CI 124%,05%).

Most events were thought by the investigator to beunrelated to study drug. Treatment-emergent adverse

events attributed to study drug occurred in moreparticipants who received chloroquine-proguanil thanthose who received atovaquone-proguanil (142 [28%] vs110 [22%], p=0024). The difference was significant forgastrointestinal events but not for neuropsychiatricevents (table 2). Most adverse events were mild inintensity. Moderate or severe events attributable tostudy drug occurred in 37 (7%) participants (54 events)receiving atovaquone-proguanil and 56 (11%)(97 events) on chloroquine-proguanil (difference=19 [4%], p=005). These events were severe in five (1%)people (six events) receiving atovaquone-proguanil and11 (2%) (20 events) on chloroquine-proguanil. Oneparticipant receiving chloroquine-proguanil had anepileptic seizure.

49 people in the atovaquone-proguanil group and 43on chloroquine-proguanil discontinued study drugprematurely because of adverse events (11 vs 16),protocol violation (nine vs six), non-compliance (five vs

six), or other reasons (24 vs 15). Other reasons included:did not travel, drugs lost or stolen, or consent withdrawn.

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Characteristic Atovaquone-proguanil Chloroquine-proguanil

(n=511) (n=511)

Mean (SD) age (years) 360 (133) 350 (133)

Range 1372 1374

Male/Female 251/260 (49/51%) 276/235 (54/46%)

Race*

White 496 (97%) 486 (95%)

Black 6 (1%) 12 (2%)

Asian 3 (1%) 7 (1%)

Other 6 (1%) 6 (1%)

Mean (SD) height (cm) 1731 (96) 1737 (97)

Mean (SD) weight (kg) 714 (134) 723 (145)

History of malaria 9 (18%) 7 (14%)

Median (range) time since 13 (260) 11 (230)

last episode (years)

Travel destination

East Africa 132 (26%) 152 (30%)

West Africa 90 (18%) 102 (20%)

Southern Africa 77 (15%) 68 (14%)

Central Africa 15 (3%) 12 (2%)

South America 50 (10%) 39 (8%)

Other 151 (30%) 140 (27%)

Mean (SD) travel duration (days) 169 (75) 176 (69)

*Percentages may not add up to 100 because of rounding. Some participants visited

more than one part of Africa

Table 1: Baseline characteristics

Event Number of participants with adverse events

Atovaquone-proguanil Chloroquine-proguanil p-value

(n=511) (n=511)

Any adverse event* 110 (22%) 142 (28%) 0024

Any gastrointestinal event 59 (12%) 100 (20%) 0001

Diarrhoea 24 (5%) 37 (7%) 0113

Nausea 9 (2%) 34 (7%) 0001

Abdominal pain 15 (3%) 30 (6%) 0033

Mouth ulcers 18 (4%) 25 (5%) 0350

Vomiting 0 11 (2%) 0002

Any neuropsychiatric event 49 (10%) 53 (10%) 0754

Dizziness 17 (3%) 19 (4%) 0865

Strange or vivid dreams 19 (4%) 14 (3%) 0479

Insomnia 8 (2%) 12 (2%) 0498

Visual difficulties 10 (2%) 10 (2%) 0999

Anxiety 1 (


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Among those who discontinued study drug because ofan adverse event, the event was attributed to treatmentin 14 of 27. Five treatment-limiting adverse eventsattributed to study drug arose in four participants,randomly assigned to receive atovaquone-proguanil and26 such events happened in ten randomly assigned tochloroquine-proguanil (table 3). A serious adverse eventoccurred in six participants who received atovaquone-proguanil (infectious illnesses in four, Wolff-Parkinson-White syndrome in one, and pituitary tumour in one)and in six people who were on chloroquine-proguanil(malaria in three, other infectious illnesses in two, anddepression in one). None of these serious events was

thought to be caused by study drug.For the 180 people who had laboratory safety samplescollected, there were no significant differences in eithertreatment group between baseline and follow-up valuesfor haematological and clinical chemistry tests. Noclinically important laboratory abnormalities wereidentified.

A potential diagnosis of malaria was made in fourparticipants. In three, P falciparum malaria wasdiagnosed while they were receiving chloroquone-proguanil; 3, 6, or 11 days after leaving Mali, Nigeria, orUganda. The diagnoses were confirmed by review ofslides (two), parasite DNA analysis (three), anddiagnostic increase in blood-stage antibodies (three). Inone person, symptoms of malaria began 28 days after

completing prophylaxis with atovaquone-proguanil anda subsequent blood smear was reported as positive forP ovale. No blood smears or parasite DNA samples werereturned to the reference laboratory, but serologicaltesting for blood-stage antibodies showed a diagnostictitre increase against P ovale.

DNA from the three P falciparum isolates carried theK76T mutation in the pfcrt gene associated withchloroquine resistance.19 One of three isolates alsocontained the N86Y allele in pfmdr1.1618 All threeisolates contained the S108N mutation in dhfr, whichhas been associated with resistance to pyrimethamineand a 4-fold to 22-fold increase in the 50% inhibitoryconcentration to cycloguanil.20 Additionally, all threeisolates had N51I and C59R mutations associated with

high resistance to pyrimethamine.20

1008 participants completed the 60-day follow-upand had efficacy information recorded. 987 had pairedsamples available for serological testing, of these,circumsporozoite antibodies developed in 15 (15%),including one of three people with confirmedP falciparum malaria. The minimum efficacy forprevention of P falciparum malaria was estimated to be100% (95% CI 59100%) in the atovaquone-proguanilgroup and 70% (95% CI 3593%) in the chloroquine-proguanil group (table 4).

DiscussionChloroquine and proguanil are generally regarded as thesafest drugs available for malaria prophylaxis, and are

very rarely associated with severe adverse reactions inthe recommended doses.22 The favourable safety profileof these drugs accounts for their continued wide use,despite evidence of decreasing effectiveness as theprevalence of multidrug-resistant P falciparum increases.

In this study, the proportion of individuals who had atleast one adverse event was similar in the two treatmentgroups, but evaluation of several indices indicated thatatovaquone-proguanil was significantly better toleratedwith respect to gastrointestinal events. The findings thattreatment-emergent gastrointestinal adverse eventsattributed to study drug occurred more often in thechloroquine-proguanil group and were the mostcommon reason for premature discontinuation are inaccord with those of previous studies showing thatgastrointestinal symptoms are the most common adverseevents in people receiving chloroquine-proguanil formalaria prophylaxis.6,23,24

Failure to complete the full course of antimalarialprophylaxis will increase the risk of developing malaria.For this reason, a low frequency of treatment-limitingadverse events is important for the effectiveness ofprophylaxis. In our study, chemoprophylaxis wasdiscontinued prematurely in only one person receiving

atovaquone-proguanil, compared with ten onchloroquine-proguanil.We assessed the efficacy of chemoprophylaxis as a

secondary endpoint. Because many other illnesses canbe mistaken for malaria, we obtained blood specimens atthe time of suspected malaria and serum samples beforetravel and several weeks after treatment. Testing of thesespecimens in reference laboratories allowed us toconfirm a diagnosis of falciparum malaria in threepeople receiving chloroquine-proguanil and in none onatovaquone-proguanil. In-vitro drug susceptibilitytesting of parasite isolates was not feasible but, as asurrogate, isolates were analysed for mutations in genesassociated with resistance to chloroquine and proguanil-cycloguanil. All three isolates carried at least one

mutation previously linked to chloroquine resistance,and all three had mutations in the dhfr gene linked toantifolate drug resistance. These data provide apotential molecular basis for failure of prophylaxis withchloroquine-proguanil.

Prospective collection of paired serum samples tomeasure antibodies to the circumsporozoite protein ofP falciparum allowed us to estimate the minimumefficacy of chemoprophylaxis. In a study in which serumwas obtained every 10 days for 2 months from soldiersexposed to malaria, detection of anti-circumsporozoiteantibodies by ELISA was reported to have highsensitivity and specificity for identifying individuals whowere bitten by a P falciparum-infected mosquito anddeveloped clinical malaria.25 People taking effective

antimalarial prophylaxis can develop anti-circumsporozoite antibodies after being bitten byinfected mosquitoes without developing malaria.26

Because we obtained only one postexposure serumsample, the proportion of participants in our study whodeveloped a circumsporozoite-antibody response is aminimum estimate of the proportion actually bitten by amalaria-infected mosquito. This assumption is lentsupport by the observation that circumsporozoiteantibodies were detected in only one of threepeople with confirmed P falciparum malaria. Basedon the circumsporozoite antibody results, theminimum efficacy of chemoprophylaxis was higherfor atovaquone-proguanil than for chloroquine-proguanil.

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Atovaquone-propguanil Chloroquine-proguanil

Number of participants

60-day efficacy data available 501 507

CS* antibodies present 7 8

Confirmed P falciparum malaria 0 3

Minimum efficacy (95% CI) 100% (59100%) 70% (3593%)

Maximum efficacy (95% CI) 100% (99100%) 99% (9899%)

*CS=circumsporozoite.

One participant with confirmed malaria also developed CS* antibodies.

Table 4: Estimates of minimum and maximum efficacy for

malaria prophylaxis



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Because of the small number of endpoints, thedifference in efficacy rates between treatment groupswas not analysed statistically. The risk of developingmalaria for travellers to East Africa who take nochemoprophylaxis is about 12% per month andchloroquine-proguanil has prophylactic effectiveness of72%.7 If the average duration of travel is 25 weeks, theexpected rate of malaria in travellers taking prophylaxiswould be 02% per month with chloroquine-proguaniland 0035% per month with a drug that has 95%effectiveness. With these expected rates, and assuming is 5% and power is 80%, a study in travellers designedto show that a new antimalaria drug with 95% efficacy isbetter than chloroquine-proguanil would require morethan 16 000 participants.27 Although our study wasclearly underpowered to show higher efficacy than thechloroquine-proguanil combination, atovaquone-proguanil is more effective than these drugs fortreatment of falciparum malaria28 and thereforecould be more effective than chloroquine-proguanilfor prophylaxis in areas where multidrug resistantP falciparum infections occur.

One participant developed malaria caused by P ovale,28 days after completing the standard course of

prophylaxis with atovaquone-proguanil. Bothatovaquone and proguanil have causal prophylacticactivity directed against developing hepatic forms ofP falciparum,29,30 but neither drug is active againsthypnozoites. 29,31 Thus atovaquone-proguanil, likechloroquine and mefloquine, acts only as a suppressiveprophylactic agent against P vivax and P ovale. Afterdosing is discontinued and drug elimination occurs, adelayed onset of malaria caused by a relapsing type ofmalaria parasite can therefore occur, and is consistentwith the course of events we observed. Travellers withintense exposure to P vivax or P ovale, and those whodevelop malaria caused by either of these parasites, willrequire additional treatment with primaquine.31

ContributorsB Hgh, P D Clarke, D Camus, H D Nothdurft, D Overbosch,

M Gnther, and I Joubert did the study and contributed to data

review and interpretation of results. K C Kain did the parasite DNA

analyses and contributed to interpretation of results and writing the

paper. N S Roskell and J D Chulay contributed to study design and

data analysis. D Shaw supervised the study. B Hgh and

J D Chulay had primary responsibility for writ ing the paper.

Other members of the Malarone International Study Team include:

R H Behrens (London, UK), J Beytout (Clermont Ferrand, France),

U Bienzle (Berlin, Germany), O Bouchaud (Paris, France), J Delmont

(Marseilles, France), E Dutoit (Lille, France); K Fleischer

(Wrzburg, Germany), B Gachot (Paris, France), T J L M Goud

(Rotterdam, Netherlands), P Inglebert (Lille, France); J Knobloch,

Tbingen, Germany; B Marchoux (Toulouse, France), V Masson

(Lille, France); M Peters (Hamburg, Germany), E Petersen

(Copenhagen, Denmark), H Schilthius (Amsterdam, Netherlands);

R Tan (Vancouver, Canada), S Toovey (Sunninghill, South Africa),

S Waner (Johannesburg, South Africa), and B Zieger (Dresden,Germany). GlaxoWellcome members of the Study Team include:

Amod (South Africa), R Balschmidt (Denmark), C Brennan (USA),

A Goetschel (France), C Hedgley (UK), T Hendrickx (Netherlands),

P de Jonge (Netherlands), M Lebaddi (France), R Marina (Canada),

G B Miller (USA), M OHare (UK), J Olsen (Denmark), H Richter

(Germany), S van Delft (Netherlands), and T Scott (USA).

AcknowledgmentsWe thank Kent Kester and Carolyn Holland of the Walter Reed Army

Institute of Research, Washington, DC, USA, for the circumsporozoite

antibody assays, and Marianna Wilson of the Centers for Disease

Control and Prevention, Atlanta, GA, USA, for the blood-stage

antibody assays. K C Kain was supported in part by a career award

from the Ontario Ministry of Health and a grant from PSI. This study

was funded by GlaxoWellcome.

References

1 Muentener P, Schlagenhauf P, Steffen R. Imported malaria

(198595): trends and perspectives. Bull World Health Organ 1999;

77: 56066.

2 Williams HA, Roberts J, Kachur SP, et al. Malaria surveillance

United States, 1995.MMWR CDC Surveill Summ 1999;48:

123.

3 Kain KC, Harrington MA, Tennyson S, Keystone JS. Imported

malaria: prospective analysis of problems in diagnosis and

management. Clin Infect Dis 1998; 27: 14249.

4 Lobel HO, Kozarsky PE. Update on prevention of malaria for

travellers. JAMA 1997;278: 176771.5 Nosten F, van Vugt M. Neuropsychiatric adverse effects of

mefloquine. What do we know and what should we do? CNS Drugs

1999; 11: 18.

6 Barrett PJ, Emmins PD, Clarke PD, Bradley DJ. Comparison of

adverse events associated with use of mefloquine and

combination of chloroquine and proguanil as antimalarial

prophylaxis: postal and telephone survey of travellers. BMJ1996;

313: 52528.

7 Steffen R, Fuchs E, Schildknecht J, et al. Mefloquine compared with

other malaria chemoprophylactic regimens in tourists visiting East

Africa. Lancet1993; 341: 1299303.

8 WHO. International travel and health. Geneva: WHO, 1997:

6778.

9 Shanks GD, Gordon DM, Klotz FW, et al. Efficacy and safety of

atovaquone/proguanil for suppressive prophylaxis against

Plasmodium falciparum malaria. Clin Infect Dis 1998; 27:

49499.

10 Lell B, Luckner D, Ndjav M, Scott T, Kremsner PG.

Randomised placebo-controlled study of atovaquone plus

proguanil for malaria prophylaxis in children. Lancet1998; 351:

70913.

11 Sukwa TY, Mulenga M, Chisaka N, Roskell NS, Scott TR. A

randomized, double-blind, placebo-controlled field trial to

determine the efficacy and safety of Malarone

(atovaquone/proguanil) for the prophylaxis of malaria in Zambia.

Am J Trop Med Hyg1999; 60: 52125.

12 Shanks GD, Kremsner PG, Sukwa TY, et al. Atovaquone and

proguanil hydrochloride for prophylaxis of malaria.J Travel Med

1999; 6 (suppl 1): S21S27.

13 Ballou WR, Hoffman SL, Sherwood JA, et al. Safety and efficacy of

a recombinant DNA Plasmodium falciparum sporozoite vaccine.

Lancet1987;1: 127781.

14 Sulzer AJ, Wilson M, Hall EC. Indirect fluorescent-antibody tests

for parasitic diseases. V. An evaluation of a thick-smear antigen in

the IFA test for malaria antibodies. Am J Trop Med Hyg1969; 18:

199205.

15 Snounou G, Viriyakosol S, Zhu XP, et al. High sensitivity of

detection of human malaria parasites by the use of nested

polymerase chain reaction.Mol Biochem Parasitol1993; 61:

31520.

16 Foote SJ, Kyle DE, Martin RK, et al. Several allelles of the

multidrug-resistance gene are closely linked to chloroquine

resistance in Plasmodium falciparum.Nature 1990; 345:

25558.

17 Reed MB, Saliba KJ, Caruana SR, Kirk K, Cowman AF. Pgh1

modulates sensitivity and resistance to multiple antimalarials in

Plasmodium falciparum.Nature 2000; 403: 90609.

18 Duraisingh MT, Drakeley CJ, Muller O, et al. Evidence for

selection for the tyrosine-86 allele of the pfmdr 1 gene of Plasmodium

falciparum by chloroquine and amodiaquine. Parasitology 1997; 114:

20511.

19 Fidock DA, Nomura T, Talley AK, et al. Mutations in the

Plasmodium falciparum digestive vacuole transmembrane proteinPfCRT and evidence for their role in chloroquine resistance.

Mol Cell2000; 6: 86171.

20 Foote SJ, Galatis D, Cowman AF. Amino acids in the dihydrofolate

reductase-thymidylate synthase gene of Plasmodium falciparum

involved in cycloguanil resistance differ from those involved in

pyrimethamine resistance. Proc Nat Acad Sci USA 1990; 87:

301417.

21 Jones B, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess

equivalence: the importance of rigorous methods. BMJ1996;313:

3639.

22 Luzzi GA, Peto TE. Adverse effects of antimalarials: an update.

Drug Safety 1993;8: 295311.

23 Carme B, Peguet C, Nevez G. Compliance with and tolerance of

mefloquine and chloroquine + proguanil malaria chemoprophylaxis

in French short-term travellers to sub-Saharan Africa. Trop Med Int

Health 1997; 2: 95356.

24 Durrheim DN, Gammon S, Waner S, Braack LE. Antimalarial

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prophylaxisuse and adverse events in visitors to the Kruger

National Park. S Afr Med J1999;89: 17075.

25 Webster HK, Boudreau EF, Pang LW, Permpanich B, Sookto P,

Wirtz RA. Development of immunity in natural Plasmodium

falciparum malaria: antibodies to the falciparum sporozoite

vaccine 1 antigen (R32tet32).J Clin Microbiol1987; 25:

100208.

26 Bwire R, Slootman EJ, Verhave JP, Bruins J, Docters van Leeuwen

WM. Malaria anticircumsporozoite antibodies in Dutch soldiers

returning from sub-Saharan Africa. Trop Med Int Health 1998; 3:

6669.

27 Fleiss JL. Statistical methods for rates and proportions. 2nd edn.New York: John Wiley, 1981: 3842.

28 Looareesuwan S, Chulay JD, Canfield CJ, Hutchinson DB.

Malarone (atovaquone and proguanil hydrochloride): a review of its

clinical development for treatment of malaria.Am J Trop Med Hyg

1999; 60: 53341.

29 Fairley NH. Researches on paludrine (M.4888) in malaria. An

experimental investigation undertaken by the L.H.Q. Medical

Research Unit (A.I.F), Cairns, Australia. Trans R Soc Trop Med

1946; 40: 10551.

30 Shapiro TA, Ranasinha CD, Kumar N, Barditch-Crovo P.

Prophylactic activity of atovaquone against Plasmodium falciparum in

humans.Am J Trop Med Hyg1999; 60: 83136.

31 Looareesuwan S, Wilairatana P, Glanarongran R, et al. Atovaquone

and proguanil hydrochloride followed by primaquine for treatmentof Plasmodium vivax malaria in Thailand. Trans R Soc Trop Med

1999; 93: 63740.

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Short stature and rickets

A S Kashyap, Vivek Kumar

Clinical picture

A 14-year-old male was referred for growth arrest, muscle pain, and genu-valgum. On examination he was found to haveshort stature, moderate pelvic girdle muscle weakness, genu-valgum, and a painful waddling gait. Physical examinationwas otherwise normal. His pelvic radiograph showed homogeneous ground glass appearance and deformity. Kneeradiographs showed widened femoral, tibial, and fibular metaphyses with transverse growth arrest lines, abnormaltrabecular patterns, and a malunited femoral shaft fracture. Laboratory investigations were consistent with Fanconisyndrome with proximal renal tubular acidosis. He was being managed as a case of renal rickets. However, closerexamination revealed Kayser-Fleischer rings. With the combination of Kayser-Fleischer rings, clinical and radiologicalfeatures of rickets, and laboratory investigations consistent with renal tubular acidosis, a diagnosis of Wilson's diseasepresenting with Fanconis syndrome leading to rickets was made. The clinical diagnosis of Wilson's disease was confirmedby serum caeruloplasmin levels of 150 mg/L (270370 mg/L).

Department of Medicine, Armed Forces Medical College, Pune 411 040, India ( V Kumar MD, A S Kashyap MD)

C i h 2000 All Ri h R d

gilang_atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune...

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