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1997 Halofantrine and for radical cure of in Irian Jaya, Indonesia D. J. Fryauff U.S. NAMRU-2 (Jakarta), Box 3, APO AP 96520-8132, U.S.A.

J. Kevin Baird U.S. NAMRU-2 (Jakarta), Box 3, APO AP 96520-8132, U.S.A., [email protected]

H. Basri U.S. NAMRU-2 (Jakarta), Box 3, APO AP 96520-8132, U.S.A.

I. Wiady U.S. NAMRU-2 (Jakarta), Box 3, APO AP 96520-8132, U.S.A.

U.S. NAMRU-2 (Jakarta), Box 3, APO AP 96520-8132, U.S.A.

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Fryauff, D. J.; Baird, J. Kevin; Basri, H.; Wiady, I.; U.S. NAMRU-2 (Jakarta), Box 3, APO AP 96520-8132, U.S.A.; Bangs, M. J.; Subianto, B.; Harjosuwarno, S.; Tjitra, E.; Richie, T. L.; and Hoffman, S. L., "Halofantrine and primaquine for radical cure of malaria in Irian Jaya, Indonesia" (1997). Public Health Resources. 376. http://digitalcommons.unl.edu/publichealthresources/376

This Article is brought to you for free and open access by the Public Health Resources at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Public Health Resources by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Authors D. J. Fryauff; J. Kevin Baird; H. Basri; I. Wiady; U.S. NAMRU-2 (Jakarta), Box 3, APO AP 96520-8132, U.S.A.; M. J. Bangs; B. Subianto; S. Harjosuwarno; E. Tjitra; T. L. Richie; and S. L. Hoffman

This article is available at DigitalCommons@University of Nebraska - Lincoln: http://digitalcommons.unl.edu/ publichealthresources/376 Annals ofTropical Medicine &Parasitology, Vol. 91, No. 1, 7±16 (1997)

Halofantrineandprimaquineforradicalcure ofmalaria inI rianJaya,Indonesia

BY D.J.FRYAUFF*,J.K.BAIRD,H.BASRI,I.WIADY,PURNOMO,M.J.BANGS U.S.NAMRU-2 (Jakarta),Box3, APOAP96520-8132,U.S.A.

B.SUBIANTO,S.HARJOSUWARNO KANWILOf® ce, ProvincialHealth Service, Jayapura, IrianJaya, Indonesia

E. TJITRA P3M,Kompleks LITBANGKES/P2MPLP,Ministry ofH ealth,Jakarta,Indonesia T. L. RICHIE U.S.NAMRU-2 (Jakarta),Box3, APOAP96520-8132,U.S.A.

AND S.L.HOFFMAN Naval MedicalResearchInstitute,Bethesda,Maryland, U.S.A.

Received 30July19 96,Revised 29Au gust 1996, Accepted 2September 1996

Thecombinationof halofantrineandprim aquinetherapies wasevaluatedasaregimen forachievingradical cure offalciparumorvivaxm alariain Irian Jaya,Ind onesia, andcomparedw ithco mbined chloroquineand primaquine therapies. Thepatientsw hov olunteered forthestu dy{ adult, male, Indonesianim migrants withno prev iousexp osureto en demic malaria, normal glucose-6-phosphatedehy drogenase(G 6PD) activity,uncomplicated malariaillness, noprioruse ofantimalarials, andparasitaemiasof0.001%±1.0%} were randomized toreceive either halofantrine (24m gbase/kgbodyweight,in three equal dosesov er 12h) orchloroquine (25m gbase/kgbodyweightover 48h,in dosesof 10 ,10a nd5 mgbase/kgat 24 -h intervals). Eachp atientalso receive dconcurrentdaily primaquine (0.5m gbase/kgbodyweight)fo r14days followed byth esamedoseo nalternated aysto day 28 .Arecurrentparasitaemia duringthe28 d aysof follow-upconstituted drugfailure.Ofthe4 0cases offalciparummalaria and26cases ofvivaxmalaria treatedwithhalofa ntrine-primaquine, nonehad a recurrentparasitaemia (100%ef® cacy).In contrast,20 of30pa tientswithfalcip arumm alaria andthree of27 w ithv ivaxm alariahad recurr entparasitaemiasafter -primaquine, givingef® cacies of33%an d89%,respectively. Halofantrine-primaquinewas signi® cantlym oreeffecti veth anchloro quine-primaquine againstfalcip arumm alaria( P , 0.001)butwas similarly ef® caciousaga instv ivaxm alaria( P 5 0.23).O naverage,feverassoci atedw ithfalcip arumo rvivax malariacleared 17hfasterw ithhalo fantrine-primaquine ( P , 0.01)alth oughthere were nosigni® cant differences ( P . 0.4)in parasite-clearance times between thetw oregimens. Thehalofantrine-primaquine regimen wasalsoassocia tedw itha morerap id andsigni® cantdeclinein malaria-related physical complaints.

Radical cureo fmalaria, theelim inationof relapsing malaria is endemic. Instu diesthat both theb loodandtissuestages ofthepara- measureattack rates of malaria, with orwith- sitesbychemotherapeutic agents, is desirable out chemoprophylactic intervention,radical forprevention ofrecurrenceof infection after cure is also necessary to eliminate interference returningfrom worko rtravel in places where andconfoundingb yrelapsingorrecrudescing parasitaemias. Thereis currently nosingle *E-mail: [email protected]; fax: 1 6221 424 drugw ith suf® cientsafety anddualbloodand 4507. tissueschizonticidal propertiesto achieveth is

0003-4983/97/010007-10$9.00 Ó 1997Liverpoo lSchool ofTropical Medicine CarfaxPublishing Company 8 FRYAUFF ET AL. sterilizingcure. Most ofourstudies haveused fantrineandp rimaquineth erapies. A`control’ acombination ofthreedrugs, ,doxy- group, givensim ultaneouschloroquineand cyclineandp rimaquine,to achieveradical primaquinetherapies, wasincludedin orderto cures(Jones et al.,1994; Fryauff et al., 1995; estimate properly theeffect ofprimaquineon C.J.Church,T.L.Richie,C.Ohrt, E.Tjitra, patencyof parasitaemia after chloroquine B.Subianto,B.Sandjaya, E.Gomez,J. K. therapeutic failure. Baird,D.J.Fryauff andA .L.Richards, unpubl. obs.; C.K.Ohrt, T.Richie, H.Wid- jaja, G.D.Shanks, D.J.Fryauff, E.Tjitra, B. Sandjaja, H.Basri, W.Widjaja, C.Church PATIENTSANDMETHODS andG.Watt, unpubl. obs.). Thefrequ ent, prolongeddo sing of quinineandtheundesir- StudySite andP atients ableside effects of this drugcompoundth e Thestudywas conductedin then ew,trans- problemof full compliancewith therapy.The migrant villages ofArso XandX Iin north- drug-relatedillness whichfrequently occurs in eastern Irian Jaya, Indonesia (Baird et al., otherwise healthysubjects discouragestheir 1995b; Fryauff et al.,1995)betweenJanuary voluntary participation and, evenamong andJuly 1993. Most of theapproximately symptomatic cases, rigid supervisionand in- 2000village rshadm ovedfromJava,where the centives are required to achievecompletionof risk ofmalaria infectionhas beenab out1 therapy.Thedoxycyclineco mponentisgener- case/1000 0person-years since19 65(B aird et ally well-tolerated as longas it is nottakeno n al., 1995c).Pointprevalencesofmalaria atthe ane mpty stomachbut, dueto its effecton timeofenrolmentwere2 4%in Arso Xand bonegro wth andtoothd evelopment, useof 38%in Arso XI,despite theprovision of this drugis contra-indicatedin childrenu nder bednets to all householdsandtheavailability theageo f8years andin females during offree chloroquineat thevillag ehealth clinics. pregnancyan dnursing (Anon.,1995).Despite theeffectiveness ofthecurrent, quinine-based radical cure, there is interestin developinga Enrolment morebroad ly acceptabledrug reg imenfor Overall, 123Javaneseor Balinesem ales aged radical cure of chloroquine-resistantmalaria. . 15y ears, with uncomplicatedmalaria and Halofantrine is aneffe ctivean dgenerally parasitaemias of 0.001%±1.0%,quali® edfor well-tolerated bloodschizonticideforuse enrolment. Informedconsent, aphysical against chloroquine-resistant Plasmodiumfalci- examinationanda negativeq ualitativetest for parum in areas where me¯oqu ineresistan ce glucose-6-phosphate dehydrogenase(N ADPH has notalso developed(H ortonandParr, spot test; Sigma) precededth eir randomas- 1989). Trials havealso demonstratedthis drug signmentto oneo ftwotreatmentgroups: to behighly effectiveagainst P. vivax, includ- halofantrine-primaquine(H F-PQ)or ingthech loroquine-resistant strainsoccurring chloroquine-primaquine(CQ-PQ). in Irian Jaya,Indonesia (Parkinson et al., 1989; Baird et al., 1995a).Theuse ofhalofantrineas analtern ativecomponentfor achievingrad ical TreatmentandFollow-up cureo fmalaria wasthereforeex plored;theuse Patients in theHF-PQgroupre ceivedh alo- ofthree, well tolerateddosesof halofantrine fantrine(a total of24mgbase/kgbo dyweight, over12hmayb esubstantially betterthan in threeeq ual doses over 12h)andpri- treatmentwith 12poorly tolerateddoses of maquine(0.5 mgbase/kgbodyweightdaily for quinineover 4daysgivencon currently with 14days andthereafter onaltern ate daysuntil 20dosesofdoxycyclineover10days.Theaim day28 ).Those in theC Q-PQgroupwere ofthepresent studyw as to seeif falciparum givench loroquine(a total of 25mgbase/kg andvivaxm alaria acquiredin Irian Jaya could bodyweightin threeun equal doses over 48h: becuredradic ally byu sing combinedhalo- 10mg/kgonD ay0 ;10mg/kgonD ay1 ;and HALOFANTRINE-PRIMAQUINECUREFORMALARIA 9

5mg/kgonDay2 )andp rimaquine(as variancew as usedto compare age,w eight, above). Threedrugformulations wereused : density ofparasitaemia, PCT,frequencyof HalfanÒ (halofantrine;250mgbase hydrochlo- fever andFCTbetweenth etwotreatment ridesalt in uncoatedtab lets, kindly provided groups. Thein cidencedensity (ID)of physi- byDrJ.Horton ofSmithKline Beecham, calco mplaints not associatedw ith para- Brentford,U.K.);primaquine(1 5mgbase as sitaemia was calculatedfrom thenumber of diphosphate salt in coatedtab lets; Sano®- complaints reportedp er person-month of ob- Winthrop,NewY ork, NY);andR esochin Ò servation after discountingday-0co mplaints (chloroquine;150mgbase as phosphate salt in andthoseasso ciatedw ith unremittingor re- uncoatedtablets; P.T.Bayer Indonesia, current parasitaemias. Thedeclineof all Jakarta). Everydo se was supervisedby a physical complaints, includingthose associ- memberoftheresearchteam.Dry biscuits atedw ith theinitial parasitaemias, was esti- andbottled water were providedand p atients matedfromtheproportionofpatients were encouragedto eat immediately prior to reporting anycomplaintconsistentwith orjust after consumingthem edication. Pa- malaria (fever, chills, headache,m alaise,ab- tients werev isited in their homesdaily forthe dominal pain,nausea, vomiting, diarrhoea, ®rst 2weeksandtheno nalternate days until arthralgia, myalgia) andtheincidenced ensity day28. V isits consisted ofadministering perperson-dayo fspeci®c complaints reported medications, recordinganswers to aphysical- oneachoftest days 0±7. Proportionsand complaint questionnaire,andmakingblood incidenced ensitieswere comparedu sing smears forparasitological examination. Fisher’sexacttest or c 2 with Yate’scorrection Patients sufferingtreatmentfailure were of- applied.Two-tailed P values are reportedand feredstan dardqu ininetherapy. thecut-off forstatisticalsigni® cancew as a P value # 0.05. ParasitologicalExamination Diagnosis of malaria was basedu ponmicro- scopical examination ofGiemsa-stained, thick RESULTS andthin,blood® lmsusingoil-immersion op- tics ( 3 1000). Atleast 300ocular ®eldswere BaselineC haracteristics examinedb eforea slidewas consideredn ega- Therew eren ostatistically signi® cant differ- tive.T henumberof asexual parasitesper200 encesbetweentre atmentgroups at enrolment white bloodc ells (WBC)wascountedandth e in termsof meanage, w eightor parasitaemia number of parasites/ m lbloodwas thenesti- (Table1). Moreth an92 %ofthestudyp a- matedby m ultiplyingthis valueby40(Shute, tients in eachtreatm entgroupp resentedwith 1988). malarial symptomsat enrolmentandthetw o treatmentgroupswere similar in thenumber Analysiso fData andtypesof physical complaints reported Theef® cacyo fcombinedH F-PQtherapies (Fig. 1). Malaise, headache,ab dominal pain relativeto that ofcombinedC Q-PQtherapies andnausea wereth emost frequently reported was determinedusin gFisher’sexact test. The physical complaints.Feverw as observedin number of hours from startingtreatment 50%(35 /70)of the P.falciparum cases and in to thepointat whichp arasites becameun- 49%(26 /53)of the P. vivax. detectablean dremainedso forat least 2 consecutived ays constituted thep arasite- clearancetime(PCT).Axillary temperatures ComparativeEf® cacy $ 37.5°Cindicatedfev er andfever-clearance HF-PQwascompletely effectiveandnotreat- time(FCT)was thenumber ofhours from mentfailure s(persistentorrecurrent para- startingtreatment to thepointat whicha sitaemias) occurred amongthe 4 0 P. normaltemperature ofatleast twoconsecutive falciparum and 26 P. vivax cases during 28 days’ duration began.One-wayan alysis of days offollow-up(100%ef® cacy).Inco ntrast, 10 FRYAUFF ET AL. ) s 3 p 3 u 9 o Q ± r P g 4 - 1 t ) ) 7 Q 2 n 9 6 2 ( e ( ( C 7 m 3 9 x t 5 a 3 4 a 4 v e i r t v ) m Q u i P - d o Q m C s ( ) a l 9 e 9 P n i 7 Q u 1 q P ± - a 9 ) ) 7 F m 6 i 8 7 4 2 ( ( r ( H p 3 7 1 - 3 2 5 e 9 n i u q o r o l h c r o ) ) 9 1 Q 9 P 1 Q - ± P F ) 1 - 0 ) 7 H Q 0 1 7 3 ( m 3 ( ( ( C e u 1 1 2 r n 1 i 3 5 3 a u 8 p E q i c a L l a m B f i r A p m - T e u i n i d r o t ) 2 n m a 8 s f 3 a o l l 2 Q a P ± P h 3 - ) ) 3 o 0 F 8 7 7 t 4 ( ( ( H d 8 0 8 e 2 5 1 z i 3 1 m o d n a r s t n e i t a p y d u d t s n a f o ) a d i s ) c o l i m a o t l e s v i a b r r ) t e ) i e l g t t s s m c k r n a ( i a r a / r a s e t e a e y p h c t ( h i g n c i s n e e e a a s e g d r t e n a w a ® i n c l i m p e ) ) n t e i . . s s o l t c i D D i c a a a r . . r e u p S S t B t ( ( x e c f % e a o 5 n n s m r a a a 9 . o a ( ( e e o e h C N M M G e 2 fa d failure (b h m F ®f® 7 alofan y ays ig aquine ) lciparu c cases. . ac p 1. nin atien ) y). s Pro trine-p fof 020 ( m h po sts C ) (33 H o tosrtions o Q f rim r F infec 100 % the -P 100 ch % with complaints % with complaints -P 20 40 60 80 20 40 60 80 aqu lo 0 0 Q Q o f ef® ro 3 f e ted n ine th 0 su qu cacy w erap p jcsbjects in Ð(Ð 0 0 atie sas w e-prim ) ith ) y t nts an or w sign oc t ith d chloro cu 1 P 1 in aqu ®i® . in m rdrred fecte c alaria- in H vivax an th qu e A e ree l tly ( L d 2 w ine-p 2 6 O ti ithin eae related w ) FA o ith n and (89 m f rim N o th 2 % P 3 m Test 3 re Test T aqu ph 8 e . a ean RIN sclysical n ine day day th sig v ( ef® nu P E-P iva ±(± nan 4 4 , m i ni® cacio com x RIM esbers ± 0 ag atycantly ± .0 ( p ) P ain sus 01 lain am fof A 5 5 5 Q ) st p o th sts U 0.23 b hy ng m P u nan fe after IN sica tst t . o ere ). E sim falciparu the C 6 6 l treatm C Q co A f ef® lryilarly U .P. -P s m R cacio lit plaints Q fa e (b) E (a) en xp 7 lciparum 7 m FO ag f ef® t ected sus w ( ain R P t ith cacio fe after , ag M st 0 1 2 3 4 2 3 4 0 1 halo , (a) ainst A 0 .P. treatm sus .00 C Complaints/person-day Complaints/person-day L and fan Q A falciparu agains 1). RIA -P P trine-p P. en . Q v t v iv w t iv w ith ax 11 ri- P ax as m . 12 FRYAUFF ET AL.

TABLE 2 Them eans(andran ges) of theparasite- andfever-clearance times fromth estart of therapywith halofantrine-primaquine(HF-PQ)orchloroqu ine-primaquine(CQ-PQ)

Parasite-clearance time(h) Fever-clearancetim e(h)

Infection HF-PQ CQ-PQ P HF-PQ CQ-PQ P

Plasmodiumfalciparum 42(24±72 )51(24±72)0 .6128(24±72)45(24±7 2)0 .003 P. vivax 58(24±19 2)5 3(24±120)0.4424(24) 42(24±7 2)0 .008

Clearanceo fParasitaemia andFever portedbyapatient( P , 0.001 for P. falci- There was nod ifferencein PCTbetweenth e parum; P 5 0.005 for P. vivax).Inco ntrast, twotreatmentregimensfo reither P. falci- CQ-PQtreatment required48±7 2hto pro- parum (P 5 0.61) or P. vivax (P 5 0.44). Un- duceastatistically signi® cantred uctionin der either regimenor infection,them ean physical complaints. PCTwas about 50h(Table2). Inco ntrast, FCTin malaria cases treated with HF-PQwas ameanof 17hshorter thanin thosegive n DISCUSSION CQ-PQandthed ifferencew as signi® cantfor both P.falciparum (P 5 0.003) and P. vivax Therationalefo rthep rimaquined osingused (P 5 0.008). in thepresentstudywas that cure of P. vivax ofNewGuinea-IrianJaya origin requires PhysicalComplaints 0.5 mg/kgratherthanthestandard regimenof Inth eabsenceo fapatent parasitaemia, physi- 0.25mg/kg(ClydeandMcCarthy,1977).The cal complaints in bothtre atmentgroups were unconventional, alternate-dayd osingof infrequent, but theID per person-weekof 0.5 mg/kgfollowingthe 14 -dayth erapy malaria-likeco mplaints during thefollow-up periodw as applied as causal prophylaxis, to periodwas consistently loweramongp atients preventre-infectionan d/orrelapse while not treatedw ith HF-PQandcollectivelyw ere interferingwith recrudescence(A rnold et al., reported 3.7±4.0tim esless oftenth anb ycases 1954, 1955;Schmidt et al.,1982;Wernsdorfer offalciparumandv ivaxm alaria treated with andPayne,1 988). It is recognized,however, CQ-PQ (P , 0.005;Fig. 2). that chloroquinean dprimaquinedoappar- Figure 1showsacomparisonoftheinterval ently actsynergistically against P. vivax (Baird (daily)proportionsof patients registeringany et al., 1995a).Alternate-dayu se ofpri- physical complaint consistentwith malaria and maquine,alo ne,at 0.5m gbase/kghas been theID/person-dayo fthese speci®c malarial shownto bea well toleratedprophylactic complaints during test days 0±7, between regimen,affordingp rotective ef® cacies of74% treatmentgroupsfor eachm alaria species. against P.falciparum and90%against P. vivax Day-0p hysical complaints were similar in the amongn on-immunechildrenan dadults living twotreatmentgroupsandmost complaints in Irian Jaya (Baird et al., 1995b). were registeredd uringthe® rst 48hofevalu- CombinedH F-PQtherapyclearedpara- ation,before andduringtheperiod ofparasite sitaemia from all of thestudypatients andno clearance.W ithin 24hof havingreceivedth e treatmentfailures occurredwithin 28days of last HF-PQdose, there was ahighly beginningtreatment, in cases of uncompli- signi® cantdeclinein theproportion ofpa- catedfalciparumorvivaxm alaria acquired in tients reportinganyphysical complaint( P 5 north-eastern Irian Jaya. This regimenappar- 0.003 for P.falciparum ; P 5 0.02 for P. vivax) ently provideda100%ef® caciousradical cure. andin thenu mber ofspeci®c complaints re- Thetherapeutic failuresseenam ongsimilar HALOFANTRINE-PRIMAQUINECUREFORMALARIA 13

**Diarrhoea 0.01 0.1 (a) *Chills 0.01 0.1

**URI complaint 0.03 0.2

**Fever 0.02 0.26

**Vomiting 0.01 0.16

**Nausea 0.05 0.28

**Abdominal pain 0.08 0.31

**Headache 0.3 0.64

**Malaise 0.2 0.79

**ALL COMPLAINTS 0.71 2.84 3 2 1 0 1 2 3 Incidence/person-week

Diarrhoea 0.01 0.02 (b) Chills 0.03 0.04

**URI complaint 0.14

Fever 0.08 0.19

**Vomiting 0.12

**Nausea 0.02 0.26

**Abdominal pain 0.05 0.3

**Headache 0.25 0.67

**Malaise 0.22 0.63

**ALL COMPLAINTS 0.65 2.39 3 2 1 0 1 2 3 Incidence/person-week

Fig. 2. Incidence densities ofph ysical complaintsno tassociated withpatent p arasitaemia amongstthe P. falciparum (a) and P. vivax (b)cases treatedwithh alofantrine-primaquine( j )orchloroquine-primaquine (6 ).URI,Upperrespiratoryinfection;(*),signi® cantdifferencebetween treatmentgroups( P , 0.05);(**), verysig ni® cantdifference between treatmentgroups( P , 0.005). patients treated with CQ-PQproveth is be- therefore demonstrates completeclearan ceof causeit showsthat primaquine, per se, was not theasexual bloodstages of P.falciparum and suf® cientto prevent theap pearanceof blood- P. vivax.Theseresu lts accord with thoseof stageparasites.Theabsenceofrecurrentpara- another studyin whichtre atmentof P. vivax sitaemias amongpatients treatedw ith HF-PQ with chloroquineor halofantrine,alone,was 14 FRYAUFF ET AL. comparedin thesamelocationin Irian Jaya (Q4D10P14)andnosubsequent chemopro- (Baird et al., 1995a).Inth at study,just oneof phylaxis. Not oneof these subjects developed 19patients treated with halofantrinehada apatent parasitaemia within 2weeks of the recurrenceof parasitaemia andthis singlein- endof the14-dayth erapy(Jones et al., 1994; fection,whichap peared25 d ays post-therapy, Fryauff et al.,1995;C .J.Church,T.L. was consideredto havebeena re-infectionor Richie, C.Ohrt, E.Tjitra, B.Subianto, B. relapse.Subsequent, more extensive useof Sandjaya, E.Gomez,J.K.Baird, D.J. halofantrinealoneagains t P.falciparum or of Fryauff andA.L.Richards, unpubl. obs.; C. halofantrinewith primaquineagainst P. vivax K.Ohrt, T.Richie,H.Widjaja, G.D.Shanks, in theArso district of Irian Jaya has achieved D.J.Fryauff, E.Tjitra, B.Sandjaja, H.Basri, comparably highsuccess rates (A.Richards W.Widjaja, C.Churchan dG.Watt, unpubl. andT.Richie,unpubl. obs.). Aclinicaltrial of obs.). Hadan yparasitaemia appearedw ithin halofantrinealonein East Kalimantan,In- theusual 8±14-dayin cubationperiod,this donesia, achieveda cure rate for uncompli- wouldh avem arkedth efailure of primaquine catedfalcip arum malaria of . 98% (Tjitra et to clear theliver. Extrapolating from there- al.,1992),with FCTandPCTsimilar to sults forthestu dypopulationsinvolved thoseseen in thepresentstudywhenh alo- (N 5 651)andassu minga conservative two fantrine andp rimaquinew ereused tog ether. malaria infections/person-year fortheA rso Physical complaints reported in theabsence region,anex pected50 parasita emias would ofdetectableparasita emias wereco nsistently haveap pearedw ithin theco llective5 0person- higher amongpatients treated with CQ-PQ years of post-radical-cure susceptibility which thanin those givenHF-PQ,buttheseco m- were contributedbythese6 51vo lunteers if plaints mayn ot havebeendrug-related.Al- primaquinehadn ot beenan effec tivecausal thoughtherew ere nod ifferencesb etween prophylactic.Theabsenceof anysuchpara- treatmentgroupsin PCT,theslowerdecline sitaemia is acon®rmation ofprimaquine’spo- ofmalaria-likeillness seenin cases treated tenteffect onthe liver stages of falciparum with CQ-PQ,andcertainly thehighfailu re andvivaxm alaria whend osedat0.5mgbase/ rate obtainedw ith this combination against P. kgdaily for 14day s. Parasitaemias following falciparum,indicateth at thephysical com- the14-dayp rimaquineregimen,as applied plaints were relatedmoreto subpatentpara- with halofantrine in thecurrent study, could sitaemias in thenon-immunepopulation onlyhav eresulted fromre-infections. sampledthanto sideeffects ofthedrugs. Reports ofcardiotoxicity associatedwith the Primaquineadministeredat asingledaily high-dose halofantrineregimen(Castot et al., doseof 0.5m gbase/kgfo r14d ays apparently 1993;Nosten et al.,1993) andch angesin clears theliver of thetissuestages of P. recommendations forits use (WHO,1993) falciparum and P. vivax.Althoughth epresent were only publishedafte rtheco mpletion of results donot proveth is, theresults of other thepresentstudy.While thead ministrationof studies demonstrate this effect. Theadult reg- halofantrinewith foodis nowcontra-indi- imeno f30mgdaily for 14dayswas com- cated, theprovisi onoffoodin this studyw as pletely effective against theC hesson strain of intendedto protect against thestomachu psets P. vivax from NewG uinea, whereas the15- associatedw ith primaquineuse (Clayman et mgregimenh as beenrepeatedly unsuccessful al.,1952; Clyde,1981).It nowsee msclear (Clydeand M cCarthy,1977;R ombo et al., that foodsmayhav eenhancedth ebio-avail- 1987; Jelinek et al.,1995).Ina series of four ability andpe rhapstheef® cacyo fhalofantrine trials conductedin theArso regionof Irian in thepresen tstudy(S hanks et al., 1992). Jayabetween1993and1995, atotal of651 Insum mary,combinedh alofantrineand studyvolunteers, most ofthemn on-immune primaquinetherapiesachievedrad ical cureof to malaria, and . 25%w ith patent malaria falciparumandv ivaxm alaria amongn on- infections, were curedradically with acombi- immune,G 6PD-normal, Indonesian men. nation ofquinine,doxycyclineandprimaquine TheHF-PQregimenw as associatedw ith HALOFANTRINE-PRIMAQUINECUREFORMALARIA 15 signi® cantly fewer occasions ofphysical com- supported bytheU.S.Naval Medical Re- plaintand/or drugintolerancethan w eree x- searchan dDevelopmentCommandwork unit periencedbypatients randomizedto CQ-PQ forthepreventionandtreatmentof infectious therapy, andamorerap id declineofmalaria diseases ofmilitary importance(w ork unit symptoms. Thesere sults indicatethat the 623002A810.00101.HFX.143). Informedcon- HF-PQregimenm ayb epreferredover sent from patients or guardianswas obtained quinine--primaquinefo rradical forall subjects. Aprotocoldescribingth e cureo fmalaria amongG6PD-normal men work was reviewedan dapprovedb yboth with nocontra-indicating,cardiac risk factors. Americanand Ind onesianin stitutional com- mittees for theprotectionof humansu bjects ACKNOWLEDGEMENTS .Theauth or gratefully in medical research, in accordancewith U.S. acknowledgestheassistan ceo ftheA rso Navyregulation (SECNAVINST3900.39B) Malaria Team andsupport providedb ythe governingtheu se of humansu bjects in medi- staff of NAMRU-2 in conductingth is work. calre search. Thankfulappreciationis extendedto Smith Theo pinionsorassertionsexpressed herein Kline Beecham Pharmaceuticals forprovision are theprivate viewsof theauthors andare ofthehalofantrineandto Sano®-W inthrop not to beconstruedas representingthose of Pharmaceuticals for thep rovision ofthepri- theU.S.Navy,the D epartmentofDefense, or maquineusedin this study.This researchw as theIndonesian Ministry ofHealth.

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