Advance Access published July 29, 2003
Journal of Antimicrobial Chemotherapy DOI: 10.1093/jac/dkg356
Amphotericin B lipid complex versus meglumine antimoniate in the treatment of visceral leishmaniasis in patients infected with HIV: a randomized pilot study Fernando Laguna1*, Sebastián Videla2, Manuel E. Jiménez-Mejías3, Guillem Sirera4, Julián Torre-Cisneros5, Esteban Ribera6, Dolores Prados3, Bonaventura Clotet4, Mariano Sust2, Rogelio López-Vélez7 and Jorge Alvar8 on behalf of the Spanish HIV–Leishmania Study Group† 1Servicio
Received 12 September 2002; returned 7 March 2003; revised 9 April 2003; accepted 4 June 2003
Optimal treatment for HIV-related visceral leishmaniasis (VL) has still to be established. A pilot clinical trial was carried out in 57 HIV–VL coinfected patients to compare the efficacy and safety of amphotericin B lipid complex (ABLC) versus meglumine antimoniate. The patients were randomized to receive either ABLC 3 mg/kg/day for 5 days (ABLC-5, 18 patients), ABLC 3 mg/kg/day for 10 days (ABLC-10, 20 patients) or meglumine antimoniate 20 mg Sbv /kg/day for 28 days (19 patients). Treatment was considered successful if parasites were not detected in a bone marrow aspirate after treatment. Parasitological cure was attained in 33% (95% CI: 13%–59%) of the ABLC-5 group, in 42% (95% CI: 16%–62%) of the ABLC-10 group and in 37% (95% CI: 16%–62%) of the meglumine antimoniate group (P = 0.94). Eight out of 19 patients administered antimoniate discontinued treatment prematurely following serious adverse events, compared with one in the ABLC groups (P = 0.0006). The efficacy of ABLC is similar to meglumine antimoniate, but the severity of toxicity in the treatment of HIV–VL is lower with ABLC. Keywords: clinical trials, Leishmania, anti-leishmanial drugs
Introduction Visceral leishmaniasis (VL) is a severe disease caused by intracellular protozoa of the genus Leishmania. VL is common in patients with HIV infection living in endemic areas, and it is estimated that 2%–9% of patients with AIDS in southern Europe will suffer new or reactivated VL.1 The pentavalent antimony (Sbv) salts, sodium stibogluconate and meglumine antimoniate, have been used for VL treatment both in immunocompetent and immunodepressed patients in most of the world.1–3 However, as evidence of efficacy from clinical trials in patients with HIV is scarce, first-line treatment of VL in this population remains controversial. In a previous clinical trial, the antileishmanial efficacy of amphotericin B deoxycholate was shown to be similar to meglumine antimoniate in HIV patients.4 However, both treatments are highly toxic, thus limiting their use. New lipid formulations of amphotericin B are less toxic than the conventional version5,6 and have shown good anti-leishmanial effic-
acy in experimental models.7 Some lipid formulations of amphotericin B have also been tested in immunocompetent patients with VL, and low toxicity and high efficacy were usually obtained.8–11 Also, previous results suggest that liposomal amphotericin B provides initially successful therapy of VL in HIV patients.9,12–14 However, no data are available on the efficacy and toxicity of other amphotericin B lipid formulations in HIV patients with VL. The present pilot study was designed to investigate the efficacy and tolerability of two dosing schedules of amphotericin B lipid complex, as compared to a reference treatment, meglumine antimoniate, in patients with HIV during a first episode of VL.
Subjects and methods Fifteen major Spanish teaching hospitals took part. The study was approved by the Ethics Committee of each centre and authorized by the Spanish
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*Corresponding author. Tel: +34-91-453-25-05; Fax: +34-91-733-66-14; E-mail:
[email protected] †Members are listed in the Acknowledgements ...................................................................................................................................................................................................................................................................
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de Enfermedades Infecciosas, Hospital Carlos III, Instituto de Salud Carlos III, C/Sinesio Delgado 12, 28029-Madrid; 2Laboratorios Dr Esteve, Barcelona; 3Hospital Virgen del Rocío, Sevilla; 4Hospital Germans Trias i Pujol, Badalona; 5Hospital Reina Sofía, Córdoba; 6Hospital Vall d’Hebron, Barcelona; 7Hospital Ramón y Cajal, Madrid; 8Centro Nacional de Microbiología, Majadahonda, Spain
F. Laguna et al. Health Authorities; it was conducted in accordance with Good Clinical Practice Guidelines. Written informed consent was obtained from all patients enrolled in the study.
Patient population and exclusion criteria From August 1997–September 1999, HIV patients who had undergone their first episode of VL were enrolled in the study. Male and female patients aged 18 years or older were eligible for inclusion if they had a diagnosis of HIV confirmed by Western blot, and a first episode of parasitologically confirmed VL. VL was diagnosed in patients showing compatible clinical symptoms and a positive Giemsa-stained smear or culture for Leishmania parasites in samples taken from bone marrow, spleen or liver. Exclusion criteria included patients with pancreatitis, prothrombin activity 500 ms, creatinine levels >twice the upper normal limit, allergy to either ABLC or meglumine antimoniate, concomitant treatment with dideoxycytidine or dideoxyinosine and a life expectancy of
