International Journal of Infectious Diseases 14 (2010) e522–e525

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International Journal of Infectious Diseases

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Case Report Treatment of visceral leishmaniasis with intravenous pentamidine and oral fluconazole in an HIV-positive patient with chronic renal failure — a case report and brief review of the literature

Jan Rybniker a, Valentin Goede a, Jessica Mertens b, Monika Ortmann c, Wolfgang Kulas d, Matthias Kochanek a, Thomas Benzing e, Jose´ R. Arribas f, Gerd Fa¨tkenheuer a,* a 1st Department of Internal Medicine, University of Cologne, 50924 Cologne, Germany b Department of Gastroenterology, University of Cologne, Cologne, Germany c Institute of Pathology, University of Cologne, Cologne, Germany d Nephrologisches Zentrum Mettmann, Mettmann, Germany e Department of Medicine and Centre for Molecular Medicine, University of Cologne, Cologne, Germany f Enfermedades Infecciosas, Hospital Universitario La Paz, Madrid, Spain

ARTICLE INFO SUMMARY

Article history: We report the case of an HIV-positive patient with visceral leishmaniasis and several relapses after Received 3 March 2009 treatment with the two first-line anti-leishmanial drugs, liposomal amphotericin B and miltefosine. End- Accepted 4 June 2009 stage renal failure occurred in 2007 when the patient was on long-term treatment with miltefosine. A Corresponding Editor: William Cameron, relapse of leishmaniasis in 2008 was successfully treated with a novel combination regimen of Ottawa, Canada intravenous pentamidine and oral fluconazole. Secondary prophylaxis with fluconazole monotherapy did not prevent parasitological relapse of leishmaniasis. Keywords: ß 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Visceral leishmaniasis HIV Fluconazole Pentamidine Miltefosine Renal failure

1. Introduction uncontrolled multiplication of Leishmania parasites and often results in severe atypical clinical presentations of the disease Co-infection with HIV and Leishmania spp is a well known entity involving the skin, gastrointestinal tract, and the lungs.4 in southern Europe and an emerging problem in many low-income The major challenge in dually infected patients is the countries. As the incidence rate in Mediterranean Europe has administration of a successful treatment regimen during the acute stabilized with the advent of antiretroviral therapy (ART), the phase of leishmaniasis and to provide potent secondary prophy- numbers of co-infected patients are likely to increase substantially laxis to prevent relapses. This is complicated by the fact that in in other parts of the world.1 For example the rate of HIV-infected contrast to HIV-negative subjects, HIV-positive individuals show patients with visceral leishmaniasis (VL) in some Ethiopian higher rates of drug toxicity and relapses, as well as lower cure populations is as high as 15–30%.2 rates with initial treatment. First-line drugs for the treatment of VL The simultaneous infection with both pathogens has multiple in both HIV-infected and non-infected patients are the lipid negative sequelae on the outcome of both diseases, with devastating formulations of amphotericin B (L-AMB), miltefosine, and penta- effects for the patient. It is believed that parasitic infection leads to valent antimonials.1 However, several studies investigating these chronic immune activation, which induces increased viral load and drugs as a monotherapy in co-infected individuals have shown rapid progression to AIDS.3 Subsequently, this leads to the only moderate success rates with regard to initial cure and relapses. In a randomized comparative trial of European patients infected with HIV and Leishmania infantum, meglumine antimo- * Corresponding author. Tel.: +49 221 478 3324; fax: +49 221 478 5915. nate was tested against amphotericin B. The response rates were E-mail address: [email protected] (G. Fa¨tkenheuer). 66% (29 of 44 patients) for meglumine antimonate and 62% (28 of

1201-9712/$36.00 – see front matter ß 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2009.06.010 J. Rybniker et al. / International Journal of Infectious Diseases 14 (2010) e522–e525 e523

45 patients) for amphotericin B. Relapse rates for both compounds In 2002 VL manifested with multiple nodular subcutaneous were as high as 46%.5 Miltefosine, an orally administered drug, was lesions of the extremities, generalized arthralgia, and hepatos- studied in a randomized trial in Ethiopia with a favorable response plenomegaly. Before 2002 the patient had undertaken several rate of 89% (56 of 63 patients). However, relapses were seen in 31% journeys to southern European countries, making VL a possible (16 of 52 patients).6 Miltefosine has also been applied with some diagnosis. Histological examination of cutaneous lesions and a success in cases with recurrent leishmaniasis in HIV-infected bone marrow aspirate revealed amastigote parasites. Subsequent individuals.7,8 PCR assays of these samples were positive for the Leishmania Currently there are no data available on the efficacy of second- donovani complex. The patient received L-AMB at 300 mg per day line drugs such as pentamidine, paromomycin, or fluconazole in for 6 days, followed by 300 mg per week for 5 weeks. Secondary HIV-infected patients. In the absence of data from clinical trials, prophylaxis was performed with 300 mg L-AMB per month. many experts currently recommend combination therapy for both Initially this regimen led to a good clinical response. However, the co-infected and mono-infected VL patients.1 However, in pre- patient relapsed 6 months after initiation of treatment despite treated patients unresponsive to one or several first-line drugs, being under L-AMB prophylaxis. Subsequently oral treatment options are scarce and clinicians are forced to use unusual drug with miltefosine (50 mg twice daily) was initiated in March 2003 combinations with unknown outcome and side effects. Here we and given for 2 months. Clinical and parasitological cure was report the case of a Leishmania–HIV co-infected patient with achieved, which lasted for several years. In March 2007 the patient multiple relapses of VL. relapsed with multiple facial skin lesions (Figure 1A), hepatos- plenomegaly, and anemia (hemoglobin 10.7 g/dl). Both dermal 2. Case report scrapings and peripheral blood samples were positive for Leishmania in culture and in PCR assays. A second treatment A 49-year-old Caucasian HIV-positive patient was diagnosed course with miltefosine (50 mg twice daily) was started, which led with VL in 2002. The HIV-infection was diagnosed in 1986 and to a gradual clinical improvement. However, PCR-negativity of antiretroviral therapy (ART) was started in 1992. Antiretroviral peripheral blood could not be achieved. In September 2007, after 6 therapy regimens contained nucleoside reverse transcriptase months of treatment with miltefosine, the patient developed inhibitors (NRTI) only until 1996, when the protease inhibitor acute renal failure and all drugs were discontinued. Renal biopsy (PI) indinavir was added. Since 2005 the patient has been treated showed severe exudative and necrotizing glomerulonephritis with a regimen of two protease inhibitors (atazanavir and with extracapillary proliferation. As a consequence the patient saquinavir) boosted with ritonavir. Since 2002, when VL was developed chronic renal failure and he has required permanent diagnosed, viral load was permanently below the limit of hemodialysis since then. Antiretroviral therapy with boosted detection, except for a temporary rise in 2005, and the nadir atazanavir and saquinavir was successfully reinitiated. In January CD4+ T-cell count was 180 cells/ml. Due to an oropharyngeal 2008, the patient complained of epigastric pain, nausea, and candidiasis in 1989, the patient was classified as CDC stage B3 vomiting. Gastroscopy showed erosive gastritis and duodenitis, (Centers for Disease Control and Prevention). and the histopathological examination of gastric biopsies was

Figure 1. (A) Dermal inflammation of the nose during the second relapse; scrapings were Leishmania-PCR positive. (B) Gastric antrum (prepyloric area) with erosive gastritis due to VL. (C) and (D) Giemsa stains of duodenal mucosa; multiple Leishmania amastigotes inside macrophages of the duodenal lamina propria (C: Â630; D: Â1000). e524 J. Rybniker et al. / International Journal of Infectious Diseases 14 (2010) e522–e525 positive for Leishmania amastigotes (Figure 1B–D). Again, PCR of The case reported here should encourage the use of oral dermal scrapings from multiple cutaneous lesions as well as of fluconazole in combination with potent first-line anti-leishmanial peripheral blood samples were positive for Leishmania. Intrave- drugs in future trials of both co-infected and mono-infected nous pentamidine (300 mg once daily) together with oral patients. The well-known safety profile of fluconazole and its oral fluconazole (200 mg once daily) was administered for 3 weeks. application may be favorable aspects, especially during long-term A rapid improvement of all clinical symptoms was observed, and treatment and secondary prophylaxis. However, this case also biopsies of a second gastroscopy did not show Leishmania demonstrates the limitations of monotherapy. Therefore, flucona- amastigotes. Furthermore, PCR assays of peripheral blood zole should be regarded as a drug that always has to be samples were negative. After 3 weeks of treatment the patient accompanied by other active compounds in the treatment of complained of peripheral neuropathy and taste disorders. These leishmaniasis. symptoms gradually resolved after discontinuation of pentami- While renal failure in this patient occurred during long-term dine. For secondary prophylaxis a combination regimen of treatment with miltefosine and nephrotoxicity has been described intravenous pentamidine twice per month and oral fluconazole as a rare side effect of this drug,14 other factors such as HIV was proposed but declined by the patient due to his experience of infection itself and disseminated VL may have caused kidney adverse effects with pentamidine. Thus oral fluconazole (400 mg failure in this case. The patient presented with rapidly progressive daily) was administered for secondary prophylaxis. A Leishmania- glomerulonephritis. Kidney biopsy confirmed extracapillary PCR from blood after 2 months remained negative. However, a necrotizing nephritis, but the underlying cause of this condition blood PCR taken 5 months after termination of intravenous could not be definitively clarified. treatment was positive despite continuation of oral fluconazole as Several studies have shown a beneficial effect of ART on the secondary prophylaxis. At this time-point there were no clinical mortality of HIV-infected patients.15 However, recurrences of VL signs of relapse. are common in HIV-infected patients, and ART does not seem to reduce the relapse rate. ART in this patient consisted of the two 3. Discussion protease inhibitors atazanavir and saquinavir, boosted with ritonavir, without the addition of NRTIs. This regimen has led to This case illustrates several difficulties in the management of VL increases in CD4+ T-cells in a subgroup of patients with poor in HIV-infected patients. First, treatment with the first-line drugs immunological recovery despite virological suppression.16 liposomal amphotericin B and miltefosine was only temporarily Unfortunately, this effect was not present in the patient successful, and relapses of VL forced the administration of described here. Of note, there are reports showing in vitro combination therapy with second-line drugs of unknown efficacy. activity of PIs such as saquinavir against L. infantum and L. major.1 Although resistance testing of Leishmania was not performed, the In the absence of clinical studies, it cannot be concluded that this clinical course indicates the gradual development of multi-drug effect may have contributed to the treatment outcome in our resistance against amphotericin B and miltefosine. However, it was patient. recently shown that relapses after amphotericin B treatment do In conclusion, we have described an HIV-infected patient with not always correlate with in vitro drug resistance of the parasites, several episodes of VL, who was successfully treated with a novel and the authors of this study hypothesize that repetitive treatment combination of intravenous pentamidine and oral fluconazole. with L-AMB may be an option for the management of relapses in 9 HIV–VL co-infected patients. Acknowledgement Second, chronic renal failure occurred during long-term treatment with miltefosine and further limited therapeutic Jan Rybniker is supported by the German Ministry of Education options. Third, despite complete virological suppression under and Research (Bundesministerium fu¨ r Bildung und Forschung, ART, the patient presented with multiple relapses of severe BMBF) grant No. 01 KI 0771. disseminated VL, and his CD4+ T-cell count remained stable at Conflict of interest: No conflict of interest to declare. about 200 cells/ml. Thus, the vicious circle of chronic opportunistic infection and immune suppression is a major obstacle to long-term References remission of VL in this patient. Since pentavalent antimonials are known to cause serious side 1. Alvar J, Aparicio P, Aseffa A, Den Boer M, Canavate C, Dedet JP, et al. The effects at a much higher rate in HIV-infected patients,10 we relationship between leishmaniasis and AIDS: the second 10 years. Clin Micro- decided to use a second-line treatment with intravenous biol Rev 2008;21:334–59. 2. Lyons S, Veeken H, Long J. Visceral leishmaniasis and HIV in Tigray, Ethiopia. pentamidine and oral fluconazole. Dosage adjustments of penta- Trop Med Int Health 2003;8:733–9. midine are not recommended with the creatinine clearance as low 3. Bentwich Z. Concurrent infections that rise the HIV viral load. J HIV Ther as 35 ml/min and the plasma concentration is not affected by 2003;8:72–5. 11 4. Rosenthal E, Marty P, del Giudice P, Pradier C, Ceppi C, Gastaut JA, et al. HIV and hemodialyis. Due to the complicated course of VL in this patient Leishmania coinfection: a review of 91 cases with focus on atypical locations of we decided to administer pentamidine without dose reduction and Leishmania. Clin Infect Dis 2000;31:1093–5. to closely monitor for possible adverse effects. Major side effects of 5. Laguna F. Treatment of leishmaniasis in HIV-positive patients. Ann Trop Med Parasitol 2003;97(Suppl 1):135–42. intravenous pentamidine include rashes, hyper- or hypoglycemia, 6. Ritmeijer K, Dejenie A, Assefa Y, Hundie TB, Mesure J, Boots G, et al. A hypotension, leuko- and thrombocytopenia, as well as hepato- comparison of miltefosine and sodium stibogluconate for treatment of visceral toxicity. None of these complications were seen in our patient. leishmaniasis in an Ethiopian population with high prevalence of HIV infection. However, after 3 weeks of therapy the patient developed Clin Infect Dis 2006;43:357–64. 7. Schraner C, Hasse B, Hasse U, Baumann D, Faeh A, Burg G, et al. Successful peripheral neuropathy, which appears to be a rare side effect of treatment with miltefosine of disseminated cutaneous leishmaniasis in a pentamidine. severely immunocompromised patient infected with HIV-1. Clin Infect Dis Oral fluconazole is well tolerated in most patients and has a 2005;40:e120–4. 8. Rihl M, Stoll M, Ulbricht K, Bange FC, Schmidt RE. Successful treatment of post- proven effect on cutaneous leishmaniasis caused by Leishmania kala-azar dermal leishmaniasis (PKDL) in an HIV infected patient with multiple major.12 A series of 21 Indian VL patients were treated with oral relapsing leishmaniasis from Western Europe. J Infect 2006;53:e25–7. fluconazole leading to clinical and parasitological cure in 11 9. Lachaud L, Bourgeois N, Plourde M, Leprohon P, Bastien P, Ouellette M. Parasite susceptibility to amphotericin B in failures of treatment for visceral leishma- patients, however a high relapse rate was seen in these patients, for niasis in patients coinfected with HIV type 1 and Leishmania infantum. Clin Infect 13 which no secondary prophylaxis was received. Dis 2009;48:e16–22. J. Rybniker et al. / International Journal of Infectious Diseases 14 (2010) e522–e525 e525

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