Treatment of Leishmaniasis in HIV-Positive Patients
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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, is not 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/HIVcases develop 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 is particularly 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 ´ninterval(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; Montalba´n 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; Montalba´n 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 early 1990s, 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–Tc interval 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);and amphoteric 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%)