Bosch-Nicolau et al. BMC Infectious Diseases (2019) 19:956 https://doi.org/10.1186/s12879-019-4608-9 CASE REPORT Open Access A case report of long treatment with Itraconazole in a patient with chronic Chagas disease Pau Bosch-Nicolau1,2*, Fernando Salvador1, Adrián Sánchez-Montalvá1, Elena Sulleiro3, Joaquín Burgos1 and Israel Molina1* Abstract Background: Current available treatments (benznidazole and nifurtimox) for Chagas disease (CD) show limited efficacy in chronic phase and frequent undesirable effects. Ergosterol synthesis inhibitors (ESI) had been considered as promising drugs for CD treatment and despite its recent poor results in several clinical trials, different strategies have been proposed to optimize its role in this infection. Case presentation: We present a case of chronic Chagas disease in patient diagnosed with HIV who received treatment for histoplasmosis with itraconazol during twelve months. Even though T. cruzi rt-PCR was persistently negative during treatment, when itraconazol was stopped she presented with a positive blood rt-PCR. Conclusion: Several studies using different ESI had been published for CD treatment. Either in vitro or in vivo assays demonstrated activity against T. cruzi of the different triazole derivatives so different clinical trials had been carried out to evaluate its efficacy and safety. Despite contradictory evidence in the animal model, longer treatments along with other treatment strategies previously proposed suggests that ESI failure rates in positive peripheral blood rt-PCR are higher than that obtained with the current treatments of choice. Keywords: Chagas disease, Ergosterol synthesis inhibitors, Trypanosoma cruzi Background Different strategies have been proposed to optimize its Despite of the growing consensus of treating Chagas dis- outcomes in CD. Here we present a treatment failure, ease (CD) in chronic stages to avoid the progression of after the longest treatment with ergosterol synthesis inhib- chagasic cardiomyopathy, current available treatments itors (ESI) reported in a patient with chronic CD. (benznidazole and nifurtimox) show limited efficacy reaching cure rates between 15 and 35% [1] and frequent undesirable effects, which leads to definitive withdrawal of Case presentation the treatment in 13–32% of patients [2]. Triazole deriva- A 38-Year-Old woman presented with a 2 months history tives (ketoconazole, itraconazole, posaconazole, voricona- of abdominal pain, weight loss and constipation. She was zole, ravuconazole) have been used for years as antifungal born in Bolivia (Sucre), and moved to Barcelona 7 years treatments with a good pharmacokinetic and safety pro- ago. She had no relevant pathological history. A Com- file. They act as selective inhibitors of T. cruzi ergosterol puted tomography (CT) showed an ileal stenosis causing synthesis showing potent intrinsic activity against the intestinal occlusion. Considering a differential diagnosis parasite in both in-vitro and in-vivo models, and had been including malignancies, inflammatory disease or infectious considered as promising drugs for CD treatment [3]. diseases an ileum resection with termino-terminal anasto- mosis was carried out. The biopsy revealed the presence of a granulomatous ileitis with a PAS and Gomori stain * Correspondence: pau.boschnicolau@gmail.com; israelmolina@ymail.com showing fungal microorganisms and a real-time quantita- 1 Department of Infectious Diseases, Vall d’Hebrón, University Hospital, Pº Vall d’Hebrón 119-129, 08035 Barcelona, Spain tive polymerase-chain-reaction (qPCR) with a positive re- Full list of author information is available at the end of the article sult for Histoplasma spp. An HIV serology was done © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Bosch-Nicolau et al. BMC Infectious Diseases (2019) 19:956 Page 2 of 3 showing an advanced HIV infection with a CD4 count of inhibitors were then tested and Venegas et al. demon- 63 cell/L (7%) and a viral load of 120,000 copies/mL. Due strated the effectivity of itraconazole on 20 patients with to the fact that was the first contact to health system a the negativization of the peripheral parasitemia in 50% of screening for imported diseases was offered including the patients using xenodiagnoses on previously positive hepatitis B and C, Treponema pallidum, Strongyloides patients and the decrease of sera lytic activity on the re- stercoralis and Trypanosoma cruzi serology and investiga- sponder patients [6]. Urbina et al. found better cure rates tion for parasites in feces. Two positive serologic tests with posaconazole in acute and chronic murine models were obtained for T. cruzi: one of them using recombinant compared to ketoconazole [4]. In the same line, Molina antigen (Bioelisa Chagas, Biokit, Lliçà d’ Amunt, Spain) et al. tested posaconazole in a murine model of acute and and the other one using a crude antigen (T. cruzi ELISA, chronic infection with cure rates of 90 and 60% respect- Ortho-Clinical Diagnostics, Johnson & Johnson, High ively, superior than those treated with benznidazole even Wycombe, United Kingdom). Cardiac and gastrointestinal in immunosuppressed mice [7]. In humans, case reports involvement was assessed by a 12-lead electrocardiog- of successful treatment with the triazole derivative posaco- raphy, chest radiography, an echocardiography, a barium nazole, have been published, even after benznidazole treat- enema examination, and an esophagogram showing no ment failure in immunosuppressed patients [8]. Hence, visceral involvement. We started antiretroviral therapy different clinical trials had been carried out to evaluate the with Tenofovir/Emtricitabine and Raltegravir with rapid efficacy and safety of different triazole derivatives. In the improve of CD4 count to normal values within 6 months. CHAGASAZOL trial, posaconazole at different doses was Histoplasmosis was treated with liposomal amphotericin compared to benznidazole in peripheral blood positive 3 mg/kg during 10 days followed by itraconazole 200 mg/ qPCR patients. Even when patients received the maximum 12 h during 12 months with monthly visits at the out- dose approved for human use, in the intention-to-treat patient clinic assessing adherence to treatment and ad- analysis, posaconazole showed higher treatment failure verse effects. After 6 months of ESI treatment a routine rates measured by peripheral blood qPCR of as much as qPCR [4] for T. cruzi in peripheral blood was repeated 80.7% compared to a 38.4% obtained with benznidazole with a negative result, but after 1 year of follow-up and [9]. To come up with an optimization of treatments, after once treatment was stopped, a positive qPCR for T. cruzi some promising combination studies performed in mice was obtain. Thus, she received first line treatment for CD [10], the STOP-CHAGAS trial compared benznidazole with benznidazole 5 mg/Kg/day for 60 days with good tol- and posaconazole in monotherapy and in combination. erability, with yearly T. cruzi qPCR in peripheral blood Benznidazole in monotherapy showed a parasitological negative during 3 years of follow-up (Fig. 1). cure of 86.7%, higher than posaconazole in monotherapy (13.3%) and even higher than both treatments in combin- Discussion and conclusions ation (80%) [3]. Later on, a ravuconazole prodrug, which Several studies have been published using different ESI for had a better biodisponibility and half-live, was also tested CD treatment, initially against benznidazole resistant T. in a clinical trial. In that study, treatment with different cruzi strains. Ketoconazole demonstrated in vitro activity doses of ravuconazole was compared to standard treat- against T. cruzi but failed to induce cure in patients with ment with benznidazole. After a 12-month follow-up, only chronic phase of the disease [5]. Other ergosterol 29% of patients treated with high-dose ravuconazol had Fig. 1 Timeline of case presentation Description: Timeline describing patient evolution regarding HIV, Histoplasma and Chagas disease. Legends: BZD: Benznidazole, CD: Chagas disease, CD4: CD4+ Leucocytes T count, HC: Histoplasmosis, HIV: Human immunodeficiency virus, L-AMB: Liposamal Amphotericine B, qPCR: real-time quantitative polymerase-chain-reaction, Tc: Trypanosoma cruzi, VL: Viral load Bosch-Nicolau et al. BMC Infectious Diseases (2019) 19:956 Page 3 of 3 sustained parasite response compared to 82% in patients Consent for publication treated with benznidazole [11]. Recently, different studies The patient gave written consent for their personal or clinical details along with any identifying images to be published in this study. testing ESI in mice using novel test of cure as the biolumin- escence, showed poor results. Francisco et al. performed a Competing interests chronic phase murine model whereas benznidazole showed The authors declare that they have no competing interests. a 100% of parasitological cure, posaconazole failed in al- Author details most all cases. These inferior cure rates were also observed 1 Department of Infectious Diseases, Vall d’Hebrón, University Hospital, Pº Vall when tested in the acute model when new cure standard d’Hebrón 119-129, 08035 Barcelona, Spain. 2Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. 3Department of were applied [12]. Different mechanisms were proposed to Microbiology, Vall d’Hebron, University Hospital, PROSICS Barcelona, explain these results. In the late chronic stage of CD, T. Barcelona, Spain. cruzi may have quiescent amastigote forms with low repli- Received: 6 June 2019 Accepted: 30 October 2019 cative rates, therefore treatment using ESI, which also acts during the replicative phase, could not be enough to elimin- ate the parasite [13]. Additionally, it has been stated that References 1. Viotti R, Vigliano C, Lococo B, et al. Long-term cardiac outcomes of treating the dose of posaconazole used in both clinical trials, al- chronic Chagas disease with benznidazole versus no treatment: a though being the maximum approved in humans, would nonrandomized trial. Ann Intern Med. 2006;144(10):724–34. suppose a drug exposure of 10 to 20% of the cure dose ad- 2. Molina I, Salvador F, Sánchez-Montalvá A, Treviño B, Serre N, Sao Avilés A, Almirante B. Toxic profile of Benznidazole in patients with chronic Chagas ministered in mice [14]. Hence, longer treatments with ESI disease: risk factors and comparison of the product from two different have been suggested to overcome that lack of efficacy. The manufacturers. Antimicrob Agents Chemother. 2015;59(10):6125–31. patient presented here received twelve months of itracona- 3. Urbina JA, Payares G, Contreras LM, et al. Antiproliferative effects and mechanism of action of SCH 56592 against Trypanosoma (Schizotrypanum) cruzi: in vitro and zole to treat an ileal histoplasma infection. However, erratic in vivo studies. Antimicrob Agents Chemother. 1998;42(7):1771–7. drug absorption and distribution could have occurred since 4. Piron M, Fisa R, Casamitjana N, et al. Development of a real-time PCR assay for drug levels during treatment were not obtained. Although Trypanosoma cruzi detection in blood samples. Acta Trop. 2007;103:195–200. 5. Brener Z, Cançado JR, Galvão LM, et al. An experimental and clinical assay little evidence is derived from a single case, our patient with ketoconazole in the treatment of Chagas disease. Mem Inst Oswaldo showed a positive qPCR persistence in peripheral blood at Cruz. 1993;88(1):149–53. the end of treatment, which is in line with a previous case 6. Venegas J, Zulantay I, Apt W, Solari A, Díaz E, Sánchez G. Effect of itraconazole on lytic antibodies levels in chronic Chagas disease. Parasite. published by Galhardo et al. [15] and previous murine 1997;4(3):259–62. models suggesting scarce benefit of prolonged ESI treat- 7. Molina J, Martins-Filho O, Brener Z, Romanha AJ, Loebenberg D, Urbina JA. ment [16]. In our opinion, despite the contradictory evi- Activities of the triazole derivative SCH 56592 (posaconazole) against drug- resistant strains of the protozoan parasite Trypanosoma (Schizotrypanum) dence of ESI in the animal model, all published data cruzi in immunocompetent and immunosuppressed murine hosts. including our case suggests that ESI failure rates in positive Antimicrob Agents Chemother. 2000;44(1):150–5. peripheral blood qPCR are higher than that obtained with 8. Pinazo MJ, Espinosa G, Gallego M, Lopez-Chejade PL, Urbina JA, Gascon J. Successful treatment with Posaconazole of a patient with chronic Chagas disease the current treatments of choice. Due to the fact that HIV and systemic lupus Erythematosus. Am J Trop Med Hyg. 2010;82(4):583–7. patients are at risk of reactivation, prompt etiological treat- 9. Molina I, Gómez i Prat J, Salvador F, et al. Randomized trial of Posaconazole and ment and close follow-up should be guaranteed. Benznidazole for chronic Chagas’ disease. N Engl J Med. 2014;370(20):1899–908. 10. de DinizL F, Urbina JA, de Andrade IM, et al. Benznidazole and posaconazole in experimental Chagas disease: positive interaction in concomitant and Abbreviations sequential treatments. PLoS Negl Trop Dis. 2013;7(8):e2367. CD: Chagas disease; ESI: Ergosterol synthesis inhibitors; qPCR: real-time 11. Torrico F, Gascon J, Ortiz L, et al. Treatment of adult chronic indeterminate quantitative polymerase-chain-reaction Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of- concept, randomised, placebo-controlled trial. Lancet Infect Dis. 2018;18:419–30. Acknowledgements 12. Francisco AF, Lewis MD, Jayawardhana S, Taylor MC, Chatelain E, Kelly JM. Not applicable. Limited ability of posaconazole to cure both acute and chronic Trypanosoma cruzi infections revealed by highly sensitive in vivo imaging. Authors’ contributions Antimicrob Agents Chemother. 2015;59(8):4653–61. PB-N, FS, AS-M, JB and IM analyzed and interpreted the patient data regarding 13. Sánchez-Valdéz FJ, Padilla A, Wang W, Orr D, Tarleton RL. Spontaneous dormancy Chagas disease and its treatment. ES performed the microbiological diagnosis. protects Trypanosoma cruzi during extended drug exposure. Elife. 2018;26:7. PB-N wrote the manuscript. All authors read and approved the final manuscript. 14. Urbina JA. Recent clinical trials for the etiological treatment of chronic chagas disease: advances, challenges and perspectives. J Eukaryot Microbiol. Funding 2015;62(1):149–56. This research received no specific grant from any funding agency in the 15. Galhardo MC, Martins IA, Hasslocher-Moreno A, et al. Reactivation of public, commercial, or not-for-profit sector. Trypanosoma cruzi infection in patients with acquired immunodeficiency syndrome. Rev Soc Bras Med Trop. 1999;32(3):291–4. 16. Khare S, Liu X, Stinson M, et al. Antitrypanosomal treatment with Availability of data and materials benznidazole is superior to posaconazole regimens in mouse models of Data sharing is not applicable to this article as no datasets were generated Chagas disease. Antimicrob Agents Chemother. 2015;59(10):6385–94. or analysed during the current study. Ethics approval and consent to participate Publisher’s Note The study was approved by the Ethics Committee of Vall d’Hebron Research Springer Nature remains neutral with regard to jurisdictional claims in Institute. published maps and institutional affiliations.