Treatment of Leishmaniasis in HIV-Positive Patients

Home , Miltefosine, Pentavalent antimonial

Annals ofTropical Medicine &Parasitology ,Vol. 97,Supplement No. 1,S135–S142 (2003)

Treatment of leishmaniasis inHIV-positive patients

F. LAGUNA Serviciode Enfermedades Infecciosas, HospitalCarlos III, Sinesio Delgado12, 28029 Madrid, Spain Received andaccepted 30 May 2003

Although, in southernEurope, there has beenconsiderable experience in the treatmentof visceral leishmaniasis (VL)in HIV-positivepatients, the optimal therapy has yetto be established. Pentavalentantimony salts, free amphotericin Bdeoxycholate(ABD) and lipidic formulations ofamphotericin Barethe drugsmost commonly used. Treatmentwith pentavalent antimonials requiresdaily injectionsfor 28 days, isnot welltolerated and leads toinitial clinicalcure in only 66%of the co-infectedcases. Free ABD has to be given,intravenously, forjust as long, has signicant toxicity and leadsto initial clinicalcure in evenfewer cases (62%). Ina prospective, comparative trial, treatmentof co-infected cases with apentavalent antimonial was found to have similar e Ycacy and toxicityto treatmentwith freeABD. Theduration oftreatment and the associatedtoxicity may both be reducedby the useof lipidic formulations ofamphotericin B. Anecdotalevidence and the resultsof non-randomized trialsindicate that treatmentwith liposomal amphotericin Bis highly e Vective.In a comparative trial, amphotericin Blipid complexwas found to be not only as e Vectiveas apentavalent antimonial but also bettertolerated. At the moment, however,such lipidic formulations have only beentested against VL/ HIVcases in Europe,not elsewherein the world, and they remain veryexpensive. Howeversuccessful the treatmentin termsof initial clinicalcure, almost all VL/HIVcasesdevelop VLrelapses. Although the data available on secondaryprophylaxis arelimited and ofteninconclusive, it appears that regular treatmentwith apentavalent antimonial drug,liposomal amphothericin Boramphotericin Blipid complexcan reducethe incidenceof leishmanial relapsesin HIV-positivepatients with VL. Thedevelopment ofnew regimens, use of new oral drugs(such as miltefosine)and the development ofnew antileishmanial drugscould all improve the treatmentof HIV-related VL in the future.

Thebest way to treat leishmaniasisin well informed decision. Experience in the HIV-positivepatients isstill the subjectof treatmentof leishmaniasisin HIV-positive considerablecontroversy. Few HIV-infected patients has beenmore-or-less limited to the casesof cutaneousleishmaniasis (CL) or countriesin the Mediterraneanbasin. There muco-cutaneousleishmaniasis (MCL) have are insuYcientdata onthe e Vectivenessof beenreported, and observations on the treat- antileishmanialdrugs in HIV-positives from mentof suchcases of co-infectionare largely otherparts of the worldto makeany valid anecdotal(Alvar et al.,1997). Evenfor the generalisationsabout the resultsof treat- muchmore common cases of visceralleish- ment. maniasis(VL) with HIVco-infection,there AsHIV-positive patients usuallydevelop have beentoo few comparativestudies on VL when suVeringfrom severe immuno- the eVectivenessof the varioustreatments depressionand frequently from other serious possible,both interms of the drugsand illnesses,the evaluationof the e Vectiveness regimesused, for any clinicianto makea andtoxicity of antileishmanialdrugs in those co-infectedwith VLandHIV isparticularly diYcult.Although 11%– 27% of suchcases Reprint requeststo: F.Laguna. diein the monthfollowing the diagnosisof E-mail: [email protected]; fax: +34917336614. theirVL, thesedeaths are rarely attributed to

©2003The Liverpool Schoolof Tropical Medicine DOI:10.1179/ 000349803225002606 136 LAGUNA leishmaniasisor to the toxicityof the drugsHIV, and no onehad much experience with givento treat the disease(Laguna et al., the useof otherantileishmanial drugs in the 1997; Lo´pez-Ve´lez et al.,1998; Pintadotreatment of HIV-associatedVL. Laguna et al.,2001). Theclinical criteria used to et al.(1999) thereforecarried out a multi- assessresponse to the antileishmanialtreat- centre,prospective, randomized and open ment,so useful in the immunocompetent studyof HIV-positiveSpanish patients who patient, have lessvalue in the immuno-were su Veringfrom their rstepisode of VL. decient. Only initial cure must be con- Inthis study,the e Vectivenessand toxicity sideredsince, if the immunodepressionof 4weeks’treatment with meglumineanti- continues,the probability of total recovery moniate(at 20 mgSb v/kg.day) werecompared isalmost nil and the patients tendto have with thoseof treatmentwith amphotericin severalrelapses of theirVL. Theparasito- Bdeoxycholate(at 0.7 mg/kg.day) for4 weeks. logicalresponse to antileishmanialtreatment Intention-to-treat analysis of the data showed of HIV-positivecases of VLhas onlybeen that only29 [65.9%, with a95% condence assessedon avery few occasions(Montalba ńinterval(CI) of50%–79%] ofthe 44 patients et al.,1990; Alte´s et al.,1991; Medrano et al., treatedwith the antimonialsachieved initial 1992; Laguna et al., 1997; Lo´pez-Ve´lezparasitological recovery, although another et al.,1998; Pintado et al.,2001). Finally, 10 of the 44 failedto completetreatment otherdrugs given to HIV-positivepatients can ( ve becauseof toxicityand ve becauseof increasethe toxicityof someantileishmanial death). Twenty-nine(85%; CI =68%–94%) drugs. outof the 34 patients whocompleted antimonialtreatment showed a clearingof parasitesfrom their bone-marrow (Laguna PENTAVALENT ANTIMONIALS et al.,1999). Asthe patients didnot receive secondaryprophylaxis, many relapsed; the Thepentevalent antimonials are the most probability of relapseat 12 monthswas frequentlyused drugs in the treatmentof estimatedto beabout 70%. VLinHIV-positive patients. Theresults Theresults of mostof the relevantstudies of severalretrospective studies indicate a highlightthe particulardi Ycultiesthat exist highlevel of clinicalresponse to suchdrugs inthe antimonialtreatment of VLinpatients (Berenguer et al.,1989; Montalbań et al.,infectedwith HIV,both interms of the 1990; Alte´s et al.,1991; Medrano et al., poor eVectivenessand toxicity. In thosewith 1992; Lo´pez-Ve´lez et al.,1998). However,HIV, antimonials cause more toxicity than the drugdoses and criteria used to identify inHIV-negative patients (Pintado et al., clinicalrecovery were not uniform, the obser-2001), with clinicalpancreatitis, myocarditis vation of clinicalcure was madedi Ycult andrenal insu Yciencyall beingreported by the co-existenceof other,AIDS-related (Berenguer et al.,1989; Montalbań et al., diseases,and clinical improvement does not 1990; Alte´s et al.,1991; Medrano et al., necessarilymean that therehas beenpara- 1992; Laguna et al.,1997, 1999; Lo´pez- sitologicalrecovery (Laguna et al., 1994); Ve´lez et al.,1998; Delgado et al., 1999; inall of theseseries a highpercentage of Pintado et al.,2001). Biochemicalpancreatitis patients relapsedin the year followingthe isa very frequentadverse e Vectin both the endof treatment.Three-week treatments with immunodecient and immunocom petent. pentavalent antimonialsappear lesse Vective MostHIV-infected patients showa slight than thoselasting 4 weeks(Rosenthal et al.,butasymptomatic increasein serum concen- 1995; Laguna et al., 1997). Inthe early1990s, trationsof amylase andlipase. Antimonial nooneknew very muchabout the frequencytoxicity leads to 11%–28% of HIV-positive of initialrecovery or the toxicityassociated patients discontinuingtreatment, mainly with antimonialuse in those co-infected with becauseof clinicalpancreatitis (Laguna et al., TREATMENTOF HIV-ASSOCIATED LEISHMANIASIS 137

1997, 1999; Delgado et al.,1999; Pintadoof the patients had <8ghaemoglobin/dl et al.,2001). Electrocardiographicchanges, and36% showedrenal toxicity, although suchas asmallincrease in the Q–Tcinterval only20% requiredthe suspensionof their andalterations in the Twave, aredetected in treatment. upto 14% of HIV-infectedpatients (Laguna et al.,1999). Thetrue signi cance of these LIPIDICAMPHOTERICIN B slightelectrocardiographic alterations is not knownand treatment need only be stopped whenthe Q–Tcinterval rises above 500 ms Inan attempt to reducethe toxicity orseriousarrhythmias appear (Herwaldtand associatedwith ABtreatment,the drughas beencombined with phospholipidswhich, Berman,1992; Laguna et al., 1999). ondispersing in water, spontaneouslyform vesicularstructures, some of themspherical, AMPHOTERICINB DEOXYCHOLATE composedof drugsolution surrounded by oneof morelayers of phospholipids.Such lipidicpreparations allowed a greatadvance Although,amphotericin B deoxycholate(AB) inthe treatmentof VLduringthe 1990s. has beenfound to beone of the mostactive Threecommercial preparations of lipidicAB anti- drugsin experimental VL, Leishmania have beenused: amphotericin B lipidiccom- its clinicaluse has beenlimited by di Yculties plex(ABLC; Abelcet 1 ;LiposomeCompany, inits administrationand its toxicity.Only Princeton,NJ );liposomalamphotericin B inareas where VL casesshow a highlevel (ABL;AmBisome 1 ;NeXstar, SanDimas, of resistanceto antimonialshas ABbeen CA);andamphoteric inB cholesterol muchused, with greate Vectiveness(Murray, dispersion(ABCD;Amphotec 1 ; Sequus 2000). Therehas beenlittle useof ABin Pharmaceuticals,Menlo Park, CA).Although HIV-positivepatients with VL(Rosenthal theselipidic AB formulationshave di Verent et al.,1995; Lo´pez-Ve´lez et al., 1998; pharmacodynamiccharacteristi cs,all are Pintado et al.,2001). Thoughthe results taken upby tissuemacrophages, especially obtainedso far aregenerally encouraging, thoseof the liverand spleen. Once taken only28 (62.2%; CI =47%–76%) of the 45 insidea macrophageby endocytosis,the patients treatedwith ABinthe comparative cell’s phospholipasesbreak open the lipo- studyby Laguna et al. (1999) recovered, some,freeing the AB.Inthis way, the ABis givinga recovery‘ rate’similar to that seen targetedat the hostcells of the leishmanial with meglumineantimoniate. Many (33%) amastigote( Janknegt et al., 1992). of the patients treatedwith ABfailedto Inexperimental VL, suchlipidic ampho- completetreatment (because of toxicity, tericinshave beenfound to besuperior to failureto complyor death) but,as with the antimonialsand free AB, allowinggreater antimonial,most (93%; CI =76%–98%) of dosesof ABandhigher frequencie sof thosewho did complete treatment achieved recoveryyet givingless toxicity. Comparative aninitial parasitological recovery. The fre- studiesin experimen tal VLwith similar quencyof relapsewith 12 monthsof com- dosesof ABCD,ABLCandABL have pletingtreatment was similarfor AB and provedthat everypreparation of lipidicAB meglumineantimoniate (Laguna et al., 1999). has a diVerent eYcacy against Leishmania Aswith the antimonials,AB inducesa andthat the intensityof parasite suppression higherlevel of toxicityin patients infected with isgreater in the liverthan inthe spleen HIVthan intheir HIV-negative counterparts. (Mullen et al., 1997). Inthe studyby Laguna et al.(1999), upto 60% ofpatients showedsome adverse e Vect LiposomalAmphotericin B duringtreatment with AB,especially anaemia, ABLhas beentested in immunocompetent nephrotoxicityand hypopotassaemia; 40% patients fromEurope, Brazil, Kenya and 138 LAGUNA

India.This preparation, in a total doseof ABLwith that of otherantileishmanial drugs at least 20mg/kggivenin ve ormore doses have notbeen carried out on HIV-positive of 3–4 mg/kg,has proveditself to bevery cases of VL. eVectivein European patients with VL (Davidson et al.,1994, 1996). InIndia andKenya, respectivetotal dosesof 6mg/kg AmphotericinB Lipidic Complex (2 mg/kg.dayon days 1, 5and10) and Infusionsof ABLChave beentested clinic- 14 mg/kg(2 mg/kg.dayon days 1–6 and10) ally inseveral open studies, with immuno- curedall the patients treated(Berman et al., competentIndian cases of VLwhohad no 1998). InBrazil, however, a total doseof responseor who had relapsed after receiving 20 mg/kg(2 mg/kg.dayon days 1–10) only apentavalent antimonial.The results indi- cured83% of thosetreated (Berman et al., catedthat dosesof 2or3 mg/kg.dayfor 1998). Itseems, therefore, that the relatively 5days cured80% and100% of patients, low eVectivedoses of ABLusedin India respectively(Sundar and Murray, 1996; wouldnot be useful in Europe, Africa or Sundar et al.,1997). Theonly signi cant Brazil.In India, even a singledose of 5mg toxicityobserved was the frequentoccur- ABL/kgcured 91% of the patients givenit renceof shiversand fever during infusion. (Murray,2000). Adversee Vectsfollowing Theseside-e Vectslasted for <1h, couldnot ABLtreatmentare rare and usually mild beprevented with paracetamol,and had dis- (MeyerhoV, 1999). appearedin half of the patients by the fth Treatmentwith ABLhas alsobeen doseadministered. It remainsunclear if usedon European patients with VL/HIV theseencouraging results are reproducible co-infection,almost always after the patients inother parts ofthe worldsince, as has been have developedrelapses. The doses and observedwith otherlipidic AB preparations, lengthsof treatmenthave varied,although the eVectivedoses of ABLCfor treatment total doseshave usuallybeen at least of VLseemto vary fromone country to 20 mg/kg(Lazanas et al.,1993; Lo´pez et al., another. 1993; Torre-Cisneros et al.,1993; Davidson Experienceof ABLCfor the treatmentof et al.,1994; Laguna et al.,1995). Onlytwo VLinthe HIV-infectedis limitedto asingle, prospective,non-comparative studies have open,randomized, prospective and multi- evaluatedthe e Vectivenessand toxicity of centrepilot trial (Laguna et al., 2003), in ABLonItalianpatients duallyinfected with whichSpanish patients su Veringfrom their HIVandVL. Inthe rstof thesestudies, rstepisodes of VLweretreated with ABLC sevenpatients weretreated with 100 mg (3 mg/kg.dayfor 5 or10 days) ormeglumine ABL/day for21 days (givinga total dose antimoniate(20 mgSb v/kg.dayfor 28 days). of 29–38.9 mg/kg);the ve patients who Overall,57 patients wereincluded in the showedinitial parasitological recovery all study:18 onABLCfor 5 days, 20 onABLC hadpost-treatment relapses (Davidson et al., for10 days, and19 onmeglumine anti- 1994). Inthe secondstudy, in an attempt to moniate.In an intention-to-treat analysis, a reducethe numberof relapses,and knowing similar,generally low level of e Vectiveness that ABfromABL has alongtissue half- was foundfor the threegroups (with 33%, life, Russo et al.(1996) usedhigh and inter- 42% and37% of thosetreated showing mittentdoses (4 mg/kg.dayon days 1–5, 10, initialresponse, respectively) .Theanti- 17, 24, 31 and38) to treat 10 HIV-positive monialappeared the mosttoxic, 10 of the patients. Thisregimen appeared similar in 19 patients givenmeglumine antimoniate eYcacy to the lowerdosage used by Davidsonstopping treatment early becauseof serious et al.(1994) anddid not manage to preventside-e Vects.These preliminary results indi- relapses.Studies comparing the e Ycacy of cate that the total doseof ABLCneeded TREATMENTOF HIV-ASSOCIATED LEISHMANIASIS 139 to cureVL inHIV-positive patients inthe benets of addingIFN- c to apentavalent Mediterraneanarea is >30 mg/kg.Further antimonial,in the treatmentof VLinHIV- studiesare necessary to conrm theseobser- positives, was suspendedafter the resultsof vations andto test otherdoses. aninterim analysis indicated that the com- binationwas nobetter than the antimonial alone(unpubl. obs.) OTHERTREATMENTS

Therehave beennumerous observations TREATMENTOF RELAPSES onother treatments for VL inpatients co-infectedwith HIVbutthese have been Aftertheir rstepisode of VL, patients madein uncontrolled studies and many are co-infectedwith HIVtendto have further merelyanecdotal, weakening their scienti c episodes,even after achievingan initial para- signicance. A few caseshave beentreated sitologicalrecovery. These new episodes with pentamidine(Montalba ´n et al., 1990; areusually recrudescences resulting from the Lo´pez-Ve´lez et al.,1998) andthere are inability of the host’s immunesystem to con- unconrmed reports of the useof paro- trolthe leishmanialinfection. The character- momicynor azoles, either alone or combined ization of Leishmania isolatescollected from with antimonials(Alvar et al., 1997). the samepatients duringdi Verentepisodes Thecombination of Sb v with allopurinol ofVLindicatesthat very few of the relapses iswell tolerated in HIV-positive patients arethe resultof post-treatmentre-infection (Laguna et al.,1994; Delgado et al., 1999) (Morales et al., 2001). and,as seenwith treatmentsbased only Relapsesare often treated with the same on Sbv,the highestfrequency of recovery drugused against the initialepisode of VL requiredtreatment for at least 4weeks. (Lo´pez-Ve´lez et al.,1998; Pintado et al., Thereis, however, no goodevidence to show 2001). Ifthe drugused is an antimonial, that this combinationis any betterthan Sb v however,the re-treatmentsmay bemarkedly alone(Dellamonica et al.,1989; Mora et al., less eVectivethan the rsttreatment because 1990; Herwaldtand Berman, 1992; Laguna of the appearanceof resistancein the leish- et al.,1994; Rosenthal et al., 1995). manialparasites (Alvar et al.,1987; Lortholary HIVinfectionis known to producesa et al.,1990). Theuse of adrugto treat sharpdrop in the host’s secretionof inter- relapsesthat isdi Verentto the oneused against feron-c (IFN-c)andthe combinationof a the initialepisode has notbeen adequately pentavalent antimonialwith IFN- c appears explored.There have beennumerous reports to have asynergistice Vectin the treat- showingthat liposomalamphotericin B is mentof VLinimmunocompetent patients highly eVectiveand not very toxicwhen used (Go´rgolas et al.,1994). Thecombined treat- to treat relapsesfollowing Sb v treatment, mentof HIV-positiveVL caseswith anSb v althoughsuch re-treatment does not prevent drugand IFN- c thereforeseems an attractive furtherrelapses (Davidson et al., 1994; idea.Only a few co-infectedcases have yet Laguna et al.,1995; Russo et al., 1996). beentreated with sucha combination,however,and the resultshave beeninconclusive (Lortholary et al.,1990; Torre-Cisneros et al., 1993; Go´rgolas et al.,1994). Worryingly, SECONDARYPROPHYLAXIS intwo patients with VLandKaposi’ s sarcoma,treatment with IFN- c induceda Manyof the opportunisticinfections that rapidprogression of the tumour(Albrecht appear inHIV-positive patients showa et al.,1994). Inthe early 1990s, aSpanish,relapsing course but there are highly e Vective multi-centrestudy investigating the potential primaryor secondary prophylactic treatments 140 LAGUNA available formost of them.Pentamidine toxicities early on.Liposomal amphotericin every3 or4weeks,ABL infortnightly doses, B may oVer better eVectivenessand much allopurinolor itraconazolhave all beenused lesstoxicity and can be administered to out- as prophylaxisagainst VL episodesin cases patients andin short cycles. However, use of VL/HIVco-infection.Although none of of this drugin HIV-positives has onlybeen thesetreatments has clearlybeen shown to exploredin a few studiesand with arelatively be eVective,there are some data available smallnumber of patients. Therehas been that indicatethat secondaryprophylaxis evenless experience with the useof lipidic couldbe useful in the preventionof VL amphotericinB complex,although this relapsesin HIV-positive patients. Thus in formulationseems better tolerated and at anopen, retrospective but non-randomized least as eVectiveas the antimonials. study,it was observedthat monthlytreat- Onemajor drawback with all the mentwith apentavalent antimonialseemed lipidicamphotericins is their relatively high to preventrelapses (Ribera et al., 1996). In cost,although adequate pharmaco– economic anotherstudy, also retrospective, it was studies,which evaluate notonly the direct shownthat patients treatedmonthly with a costof eachof the available antileishmanial pentavalent antimonialor liposomalampho- drugsbut also the associatedhospital costs, tericinB weresigni cantly lesslikely to have notbeen carried out. Lipidic ampho- relapsethan patients whodid not receive tericinsare expensive to buybut, as they can beadministered in the outpatientsection of suchprophylaxis (Pintado et al., 2001). ahospital andas part of aregimenlasting Finally inthe onlyopen, prospective and 2weeks,they may berelatively cheap randomizedclinical assay doneto date, < to use.The introduction of highlye Vective patients treatedwith ABLC(3 mg/kgevery antiretroviraltreatment (HAART) has meant 21 days) werecompared with patients not aprofoundchange in the epidemiologyof receivingprophylaxis. After a year of follow- VL/HIVco-infection,with asharpdrop in up,50% of thosereceiving prophylaxis but the annualnumber of newcases of VL 78% of the otherpatients hadrelapsed, (Tumbarello et al.,2000; Lo´pez-Ve´lez et al., indicatingthat ABLCcouldbe e Vective 2001). Nevertheless,cases of VLandCL as secondaryprophylaxis against VL in inHIV-positives will continue to occur, HIV-positivepatients (R.Lo´pez-Ve´lezand especiallyin those areas where the HIV S.Videla,unpubl. obs). pandemicis spreading into new areas where leishmaniasisis already endemic. Thedevelopment of newregimens based CONCLUSIONSAND FUTURE onalready-tested drugs, experimentation with TREATMENTS oraldrugs such as miltefosine( Jha et al., 1999), andthe developmentof newantile- ishmanialdrugs will hopefully improve the Theresponse to treatmentof VLinHIV- futuretreatment of leishmaniasisin HIV- infectedpatients isworse than that in positivepatients. immunocompetentpatients. Treatmentwith pentavalent antimonialdrugs or ampho- tericinB deoxycholatefor a periodof 4 REFERENCES weeksproduces a highlevel of toxicityand fewerthan 70% of the patients whostart treatmentachieve an initial parasitological Albrecht, H., Stellbrink, H.J., Gross,G., Berg,B., cure.These drugs require prolonged treat- Helmchen,U. &Mensing,H. (1994). Treatmentof atypical leishmaniasis with interferon- c resultingin ment,usually involving hospitalization and progressionof Kaposi’ s sarcoma in an AIDS patient. strictclinical and analytical controlto detect Clinical Investigation , 72, 1041–1047. TREATMENTOF HIV-ASSOCIATED LEISHMANIASIS 141

Alte´s, J., Salas, A., Riera, M., Udina, M., Galme´s, A., Go´rgolas,M., Castrillo, J.M.&Fernańdez-Guerrero, Balazant, J., Ballesteros,A., Buades, J., Salva´,F.& M.L.(1994). Visceralleishmaniasis in patients with Villalonga, C.(1991). Visceralleishmaniasis: another AIDS: reportof three cases treated with pentavalent HIV-associatedopportunistic infection?Report of antimony and interferon c. Clinical Infectious Diseases , eightcases and reviewof the literature. AIDS, 5, 17, 56–58. 201–207. Herwaldt,B. L.&Berman, J.D.(1992). Alvar, J., Verdejo,J., Osuna, J. &Na´jera, R.(1987). Recommendations fortreating leishmaniasis with Visceralleishmaniasis in apatient seropositivefor sodium stibogluconate(Pentostam) and reviewof HIV. European Journal ofClinical Microbiology , 6, pertinentclinical studies. American Journal ofT ropical 604–606. Medicine andHygiene , 46, 296–306. Alvar, J., Can˜ avate, C., Gutie´rrez-Solar,B., Jimeńez, Janknegt, T., deMarie, S., Bakker-Woudenmberg, M.I., Laguna, F., Lo´pez-Ve´lez,R., Molina, R.& I.A.J. M.&Crommelin, D.J.A. (1992). Liposomal Moreno,J. (1997). Leishmania and human immuno- and lipid formulations ofamphotericin B.Clinical Pharmacokinetics. , 23, deciency virus coinfection: the rst10 years. Clinical Clinical Pharmacokinetics 279–291. Microbiology Reviews , 10, 298–319. Jha, T.K.,Sundar, S., Thakur, C.P., Bachmann, P., Berenguer,J., Moreno,S., Cercenado,E., Bernaldo Karbwang,J., Fischer,C., Voss, A.&Berman, J. de Quiro´s, J.C.L., Garc ´õ adela Fuente,A. & (1999). Miltefosine,an oral agent,for the treatment Bouza, E.(1989). Visceralleishmaniasis in patients ofIndian visceralleishmaniasis. New England Journal infectedwith human immunodeciency virus (HIV). of Medicine, 341, 1795–1800. Annals ofInternal Medicine , 111, 129–132. Laguna, F., Lo´pez-Ve´lez,R., Soriano, V., Montilla, P., Berman, J. D., Badaro ,R., Thakur, C.P., Wasunna, K. ´ Alvar, J.&Gonza´lez-Lahoz,J. M.(1994). Assess- M., Behbehani, K., Davidson, R., Kuzoe,F., ment ofallopurinol plus meglumineantimoniate in Pang, L., Weerasuriya,K. &Bryceson,A. D.M. the treatmentof visceral leishmaniasis in patients with (1998). EYcacyand safetyof liposomal amphotericin HIV. Journal ofInfection , 28, 255–259. B(AmBisome) forvisceral leishmaniasis in endemic Laguna, F., Torre-Cisneros,J., Moreno,V., Villanueva, developingcountries. Bulletin WorldHealth Organ- J.L.&Valencia,E. (1995). E Ycacyof intermittent ization, 76, 25–32. liposomal amphotericin Bin the treatmentof visceral Davidson, R.N., di Martino, L., Gradoni, L., leishmaniasis in patients infectedwith HIV. Clinical Giacchino,R., Russo, R., Gaeta,G. B., Infectious Diseases , 21, 711–712. Pempinello, R., Scott, S., Raimondi, F., Cascio, A., Laguna, F., Adrados, M., Alvar, J., Soriano, V., Prestileo,T., Caldeira, L., Wilkinson, R.J.& Valencia,M. E., Moreno,V., Polo, R., Verdejo,J., Bryceson,A. D.M.(1994). Liposomal amphotericin Jimeńez,M. I., Mart ´õ nez,P., Mart ´õ nez, M. L. & B(AmBisome) in Mediterraneanvisceral leish- Gonza´lez-Lahoz,J. M.(1997). Visceralleishmaniasis maniasis: amulti-centretrial. Quarterly Journal of in patients infectedwith the human immuno- Medicine, 87, 75–81. deciency virus. European Journal ofClinical Micro- Davidson, R.N., di Martino, L., Gradoni, L., biology andInfectious Diseases , 16, 898–903. Giacchino,R., Gaeta,G. B., Pempinello, R., Laguna, F., Lo´pez-Ve´lez,R., Pulido, F., Salas, A., Scott, S., Cascio, A., Castagnola, E., Maisto, A., Torre-Cisneros,J., Torres,J., Medrano,F. J., Gramiccia,M., di Crapio, D., Wilkinson, J.R. & Sanz, J., Pico´,G.,Go´mez-Rodrigo,J., Pasquau, J. & Bryceson,A. D.M.(1996). Short-coursetreatment Alvar, J., forthe Spanish HIV–Leishmania Study ofvisceral leishmaniasis with liposomal amphotericin Group(1999). Treatmentof visceral leishmaniasis in HIV-infectedpatients: arandomizedtrial comparing B(AmBisome). Clinical Infectious Diseases , 22, meglumineantimoniate with amphotericin B. AIDS, 938–943. 13, 1063–1070. Delgado, J., Mac ´õ as, J., Pineda, J. A., Corzo, J.A., Laguna, F., Videla,S., Jimeńez-Mej ´õ as, M.E., Sirera,G., Gonza´lez-Moreno,M. P., dela Rosa, R., Sańchez- Torre-Cisneros,J., Ribera, E., Prados, D., Clotet, B., Quijano, A., Leal,M. &Lissen,E. (1999). High Sust, M., Lo´pez-Ve´lez,R. &Alvar, J., on behalf of frequencyof serious side e Vectsfrom meglumine the Spanish HIV–Leishmania Study Group(2003). antimoniate givenwithout an upper limit dosefor Amphotericin Blipid complexversus meglumine the treatmentof visceral leishmaniasis in human antimoniate in the treatmentof visceral leishmaniasis immunodeciency virus type-1-infected patients. in patients infectedwith HIV:a randomizedpilot American Journal ofTropical Medicine andHygiene , study. Journal ofAntimicrobial Chemotherapy , 52, 61, 766–769. 464–468. Dellamonica, P., Bernard,E., LeFichoux, Y., Lazanas, M.C., Tsekes,G. A., Papandreou, S., Politano, S., Carles,M. M., Durand, J. & Harhalakis, N., Scandali, A., Nikiforakis, E.& Mondain, V.(1989). Allopurinol fortreatment of Saroglou, G.(1993). Liposomal amphotericin Bfor visceralleishmaniasis in patients with AIDS. Journal leishmaniasis treatmentof AIDS patients unresponsive ofInfectious Diseases , 160, 904–905. to antimonium compounds. AIDS, 7, 1018–1019. 142 LAGUNA

Lo´pez, M.,Gil,A., Lavilla, P., Pintado, V., Royal Society ofTropical Medicine andHygiene , 95, Valencia,E., Mart ´õ nez,P. &Garc ´õ a-Puig, J.(1993). 104–107. EYcacyof liposomal amphotericin Bin the treatment Mullen,A. B., Carter,K. C.&Baillie, A.J. (1997). and secondaryprophylaxis ofvisceral leishmaniasis Comparison ofthe e Ycaciesof various formulations in HIVinfectedpatients: reportof two cases. Journal ofamphotericin Bagaints murinevisceral leish- ofAntimicrobial Chemotherapy , 32, 657–659. maniasis. Antimicrobial Agents andChemotherapy , 41, Lo´pez-Ve´lez,R., Pe´rez-Molina,J. A., Guerrero,A., 2089–2092. Baquero, F., Villarrubia, J., Escribano, L., Murray,H. W.(2000). Treatmentof visceral leish- Bellas, C., Pe´rez-Corral,F. &Alvar, J.(1998). Clinic- maniasis (kala-azar): adecadeof progress and future epidemiologiccharacteristics, prognostic factors, and approaches. International Journal ofInfectious Diseases , survival analysis ofpatients with human immuno- 4, 158–177. deciency virus and Leishmania in an areaof Madrid, Pintado, V., Mart ´õ n-Rabadań, P., Rivera, M.L., Spain. American Journal ofT ropicalMedicine and Moreno,S. &Bouza, E.(2001). Visceralleish- Hygiene, 58, 436–443. maniasis in human-immunodeciency virus (HIV)- Lo´pez-Ve´lez,R., Casado, J. L.&Pintado, V.(2001). infectedand non HIV-infectedpatients. Medicine, Declineof visceral leishmaniasis epidemicin HIV- 80, 54–73. infectedpatients afterthe introductionof highly Ribera, E.,Ocanã, I., Otero,J., Corte´s, E., Gasser,I. activeantiretroviral therapy (HAART). Clinical &Pahissa, A.(1996). Prophylaxis ofvisceral leish- Microbiology andInfection , 7, 394–395. maniasis in human immunodeciency virus-infected Lortholary, O., Mechali,D., Christiaens, D., patients. American Journal ofMedicine , 100, 496–501. Rosenthal, E., Marty, P., Poizot-Martin,I., Reynes,J., Gougerot,M., Brandel, M.&Babinet, P.(1990). Pratlong, F., Lafeuillade,A., Jaubert, D., Boulat, O., Interferon c associatedwith convencionaltherapy for Dereure,J., Gambarelli, F., Gastaut, J. A., recurrentvisceral leishmaniasis in apatients with Dujardin, P., Dellamonica, P.&Cassuto, J. P. AIDS. Review ofInfectious Diseases , 12, 370–371. (1995). Visceralleishmaniasis and HIV-1co-infection Medrano,F. J., Hernańdez-Quero,J., Jimeńez,E., in southernFrance. Transactions ofthe Royal Society Pineda, J.A., Rivero, A., Sańchez-Quijano, A., ofT ropicalMedicine andHygiene , 89, 159–162. Ve´lez,I. D., Vicaiana, P., Castillo, R., Reyes,M. J., Russo, R., Nigro,L. C., Minniti, S., Montineri,A., Carvajal, F., Leal,M. &Lissen,E. (1992). Gradoni, L., Caldeira, L.&Davidson, R.N.(1996). Visceralleishmaniasis in HIV-1infected individuals: Visceralleishmaniasis in HIVinfectedpatients with acommon opportunistic infectionin Spain? , AIDS high doseliposomal amphotericin B(AmBisome). 6, 1499–1503. Journal ofInfection , 32, 133–137. V Meyerho ,A.(1999). U.S. Food and DrugAdmini- Sundar, S.&Murray,H. W.(1996). Cureof antimony- stration approval ofAmBisome (liposomal ampho- unresponsiveindian visceralleishmaniasis with ampho- tericinB) fortreatment of visceral leishmaniasis. tericinB lipid complex. Journal ofInfectious Diseases , Clinical Infectious Diseases , 28, 42–48. 173, 762–765. Montalbań, C., Calleja, J.L., Erice,A., Laguna, F., Sundar, S., Agrawal, N.K.,Sinha, P.R., Clotet, B., Podzamczer,D., Cobo, J., Mallolas, J., Hoewith, G.S.&Murray,H. W.(1997). Short- Yebra, M., Gallego,A. &the Co-operative Group course,low-dose amphotericin Blipid complex forthe Study ofLeishmaniasis in AIDS. (1990). therapy forvisceral leishmaniasis unresponsiveto Visceralleishmaniasis in patients infectedwith antimony. Annals ofInternal Medicine , 127, 133–137. human immunodeciecy virus. Journal ofInfection , Torre-Cisneros,J., Villanueva, J.L., Kindelan, J.M., 21, 161–170. Jurado, R. &Sańchez-Guijo,P. (1993). Succesful Mora,A., Borrell,M., Galofre´,J. &Grau,J. M.(1990). treatmentof antimony-resistant visceralleishmaniasis Alopurinol eneltratamiento depacientes infectados with liposomal amphotericin Bin patients with HIV. por elVIH con leishmaniasis visceral. Enfermedades Clinical Infectious Diseases , 17, 625–627. Infecciosas yMicrobiolog ´õ a Cl´õ nica, 8, 257–258. Tumbarello, M., Tacconelli,E., Bertagnolio,S. Morales,M. A., Chicharro, C., Canãvate, C., Barker, &Cauda, R.(2000). Highly activeantiretroviral D.C.&Alvar, J.(2001). Moleculartracking of therapy decreasesincidence of visceral leishmaniasis infectionsby Leishmaniainfantum . Transactions ofthe in HIV-infectedindividuals. AIDS, 14, 2948–2949.