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BRIEF REPORT Influence of Highly Active Antiretroviral Therapy on the Outcome of Subclinical Visceral Leishmaniasis in Human Immunodeficiency Virus–Infected Patients Rafael de la Rosa,1 Juan A. Pineda,2 Juan Delgado,1 Juan Macı́as,2 Francisco Morillas,3 Joaquina Martı́n-Sánchez,3 Manuel Leal,1 Armando Sánchez-Quijano,1 and Eduardo Lissen,1 1 Viral Hepatitis and AIDS Study Group, Department of Internal Medicine, Virgen del Rocı́o University Hospital, 2Viral Hepatitis and AIDS Study Group, Department of Internal Medicine, Valme University Hospital, Seville, and 3Department of Parasitology, Facultad de Farmacia, Universidad de Granada, Granada, Spain Seventeen human immunodeficiency virus–infected patients who were harboring untreated subclinical visceral leishmaniasis (VL) were prospectively followed up. None of the 11 patients who received highly active antiretroviral therapy (HAART) presented with symptomatic VL during follow-up, whereas 2 out of 6 patients who received therapy other than HAART had an episode of overt kala-azar. These findings suggest that HAART does not induce the evolution of latent VL into symptomatic disease. The introduction of highly active antiretroviral therapy (HAART) has modified the course of HIV infection. Because of this therapy, HIV-infected patients who receive HAART have fewer opportunistic infections and survive longer than do HIV-infected patients who do not receive HAART [1]. However, opportunistic diseases, such as cryptococcal meningitis [2], cytomegalovirus retinitis [3], lymphadenitis associated with Mycobacterium avium complex infection [4], and others, may appear a few weeks after HAART is started, despite a significant increase in the patient’s CD41 cell count. This fact has led some researchers to speculate that recovery of the inflammatory response that is induced by HAART could uncover latent disorders [5]. Visceral leishmaniasis (VL) occurs frequently in HIV-infected Received 30 March 2000; revised 11 July 2000; electronically published 6 February 2001. Reprints or correspondence: Dr. Juan A. Pineda, Urbanización Ntra. Sra. de la Salud, 63, 41510 Mairena del Alcor, Seville, Spain ([email protected]). Clinical Infectious Diseases 2001; 32:633–5 Q 2001 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2001/3204-0017$03.00 HIV/AIDS patients who live in the Mediterranean basin [6]. A significant proportion of leishmanial infections remain dormant in HIVinfected individuals [7], but some leishmanial infections evolve into overt kala-azar [7, 8]. To our knowledge, there have been no studies on the effect of HAART on VL. However, on the basis of a report of cases of symptomatic VL that appeared in patients shortly after initiation of HAART [9], we hypothesized that some patients with latent infections could develop symptoms after initiation of such therapy. In this report, we describe the evolution of infections in a group of patients with latent VL who received antiretroviral therapy after VL was diagnosed. Materials and methods. Three hundred fifty-five HIVinfected patients who attended our institution from January 1993 through August 1998 were invited, regardless of their symptoms, to participate in a study that aimed to assess the prevalence of VL in our area [6]. A total of 314 patients (88.5%) agreed to be studied and underwent sternal bone marrow aspiration. All individuals gave written informed consent to participate in the study. VL was diagnosed when amastigotes were found on Giemsa-stained slides and/or when promastigotes were cultured on Evans modified Tobie’s medium. VL was considered subclinical if the patient met the following criteria: no fever, no splenomegaly, and a hemoglobin level of !9 g/dL. If there was fever, splenomegaly, or a hemoglobin level of >9 g/ dL, these conditions had to be attributable to another concomitant disease, and they had to have abated with the specific treatment of the disease, without antileishmanial therapy. Nineteen (6%) of these patients had subclinical VL. These patients received antileishmanial therapy according to the discretion of the investigator and the patient’s wishes. Therefore, 2 patients were treated with antileishmanial drugs when the diagnosis of subclinical VL was made. The remaining 17 subjects were included in the study. The 17 patients with untreated subclinical VL were prospectively followed up every 12 weeks. At each visit, clinical, hematological, virological, and immunological evaluations were performed. At the least, analysis of a bone marrow aspirate for Leishmania species was performed when patients had unexplained fever, liver or spleen enlargement, or a significant decline in the leukocyte, platelet, or RBC count. When these symptoms coincided with a finding of Leishmania species in bone marrow aspirates by use of Giemsa staining and/or culture with Evans modified Tobie’s medium, a diagnosis of symptomatic VL was made. Patients received antiretroviral therapy according to the drugs available at the time of the study and according to inHIV/AIDS • CID 2001:32 (15 February) • 633 ternational recommendations. Protease inhibitors were not available at our hospital until January 1997. After this time, all patients who received care at our institution were offered HAART, a protease inhibitor–based regimen. The reported compliance rate among the 17 patients included in this study was 190%. Results. The characteristics of the study population at the time of diagnosis of subclinical VL are shown in table 1. The median duration of follow-up was 29 months (range, 6–66 months). Eleven patients received HAART (i.e., a combination that includes, at least, a transcriptase inhibitor for which the patient was naı̈ve plus 1 protease inhibitor) after a diagnosis of subclinical VL was made. Four of these individuals (patients 3, 4, 5, and 6; figure 1) were given HAART within 4 months after diagnosis. For the 11 patients who received HAART, the median CD41 cell count at the start of therapy was 65 cells/mm3 (range, 1–651 cells/mm3). Nine of the 11 patients who received HAART had increases in CD41 cell counts that were 125% of the CD41 T cell counts at baseline (the median increase in the CD41 cell count at week 12 after the start of HAART was 92 cells/mm3 [range, 26–336 cells/mm3]). In addition, 8 of these 11 patients had decreases in plasma virus load levels (at least 1 logarithmic unit below baseline values) 12 weeks after HAART was started. At this time, 6 patients had plasma HIV levels of !200 copies/mm3. None of the patients who received HAART presented with symptomatic VL. However, 2 of the 6 patients who did not receive HAART had an episode of overt kala-azar occur at 24 and 26 months after diagnosis of subclinical VL (for patients 1 and 2, respectively; figure 1). These patients had CD41 T cell counts of 20 cells/mm3 and 82 cells/mm3, respectively, at the time that HAART was begun. One of the 4 patients who started receiving HAART within the first few months after being given Table 1. Characteristics of HIV-infected patients who were receiving highly active antiretroviral therapy (HAART) at the time of diagnosis of subclinical visceral leishmaniasis. Characteristic Patients given HAART (n p 11) Patients not given HAART (n p 6) Men, no. (%) 11 (100) Age, median y (range) 31 (24–41) 33 (29–41) 5 (83.3) CD41cell count, median cells/mm3 (range) 119 (1–1358) 48.5 (20–120) Duration of follow-up, median mo (range) 32 (12–66) 28 (6–33) Patients with risk factor, no. (%) IDU 8 (72.7) 4 (66.7) Non IDU 3 (27.3) 2 (33.3) NOTE. IDU, injection drug use. 634 • CID 2001:32 (15 February) • HIV/AIDS Figure 1. Events during follow-up of HIV-infected patients who were receiving highly active antiretroviral therapy (HAART) after subclinical visceral leishmaniasis (VL) was diagnosed, month 0. Black bar, duration without antiretroviral treatment; dark gray bar, duration of antiretroviral treatment other than HAART; light gray bar, duration of HAART; black circle, death; white triangle, symptomatic VL; circle with diagonal line, lost to follow-up. a diagnosis of subclinical VL had an episode of herpes zoster 2 months later (patient 4; figure 1). Two patients were lost to follow-up. Discussion. In this study, none of the 11 HIV-infected patients with subclinical VL who were receiving HAART developed symptomatic VL, whereas 2 patients who were receiving an antiretroviral regimen other than HAART developed overt kala-azar during follow-up. Thus, HAART does not appear to induce evolution of latent VL into symptomatic disease. The present study is limited because of the relatively small sample size. However, studies about the influence of HAART on subclinical VL are lacking; to our knowledge, this is the first report of a prospective study of HIV-infected patients with latent VL who were receiving HAART. Antiretroviral therapy other than HAART was not randomly assigned to the patients that we studied, since antiretroviral drugs were used according to their availability. This fact might have introduced some bias. However, CD41 cell counts were similar for all patients at the start of both regimens, a fact that serves as an argument against the existence of a selection bias. Some patients included in this study received HAART more than 6 months after diagnosis of VL, but since leishmanial infection has been reported to be a persistent disorder [7, 10, 11], it was probably present in the patients when they began receiving HAART. In fact, 9 patients included in this study underwent sequential bone marrow examinations as part of another investigation; in 5 of these patients, Leishmania amastigotes were found at different times (authors’ unpublished data). In any case, the effect of HAART on the outcome of latent VL is undoubtedly shown by the 4 patients who started receiving HAART within 4 months after diagnosis of VL. After patients started receiving HAART, the appearance of symptoms of an established subclinical infection seems to be a consequence of the recovery of an appropriate inflammatory response against the pathogen [12]. The lack of evolution of latent VL into symptomatic VL in our patients should not be attributed to either a failure to control virus replication or a lack of increased T cell counts. In fact, significant increases in CD41 cell counts and decreases in plasma HIV levels were observed in most patients who were receiving HAART. Moreover, 1 patient had reactivation of an opportunistic disease (herpes zoster). In addition to increasing T cell counts and reducing immune system activation, HAART leads to increased levels of T-helper type 1 cytokines [13]. This fact could explain why patients who were receiving HAART did not develop overt kala-azar, since an adequate T-helper type 1 cytokine response is associated with control of leishmanial infection [14]. If the effect of HAART on HIV-infected patients with latent VL, as reported here, is confirmed, a drop in the incidence of symptomatic VL should be observed in conjunction with the use of HAART, as has been shown for other opportunistic disorders [15]. More studies that address this issue are needed. References 1. Hammer SM, Squieres KE, Hugues MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cells counts of 200 per cubic millimeter or less. N Engl J Med 1997; 337:725–33. 2. Woods ML II, MacGinley R, Eisen DP, et al. HIV combination therapy: partial immune restitution. Unmasking latent cryptococcal infection. AIDS 1998; 12:1491–4. 3. Jacobson MA, Zegans M, Pavan PR, et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 1997; 349: 1443–5. 4. Race EM, Adelson-Mitty J, Kriegel GR, et al. Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV disease. Lancet 1998; 351:252–5. 5. Michelet C, Arvieux C, François C, et al. Opportunistic infections occurring during highly active antiretroviral therapy. Lancet 1997; 349: 1443–5. 6. Pineda JA, Gallardo JA, Macı́as J, et al. Prevalence of and factors associated with visceral leishmaniasis in human immunodeficiency virus type 1–infected patients in southern Spain. J Clin Microbiol 1998; 36:2419–22. 7. Pineda JA, Hernández-Quero J, Gallardo JA, et al. Frequency of subclinical visceral leishmaniasis in HIV-1-infected patients in Spain. Eur J Clin Microbiol Infect Dis 1996; 15:263–4. 8. Kubar J, Marty P, Lelièvre A, et al. Visceral leishmaniasis in HIVpositive patients: primary infection. Impact of CD41 T-lymphocyte counts. AIDS 1998; 12:2147–53. 9. Allbrect H. Leishmaniasis: new perspectives on an underappreciated opportunistic infection. AIDS 1998; 12:2225–6. 10. De Rosell RA, de Jesús de Durán R, Rosell O, Rodrı́guez AM. Is leishmaniasis ever cured? Trans R Soc Trop Med Hyg 1992; 86:251–3. 11. Aebisher T. Recurrent cutaneous leishmaniasis: a role for persistent parasites. Parasitology Today 1994; 10:25–8. 12. Sepkowitz KA. Effect of HAART on the natural history of AIDS-related opportunistic disorders. Lancet 1998; 351:228–30. 13. Kaufmann GR, Zaunders J, Cooper DA. Immune reconstitution in HIV-infected subjects treated with a potent antiretroviral therapy. Sex Transm Infect 1999; 75:218–24. 14. Carvalho EM, Barral A, Pedral-Sampaio D, et al. Immunologic markers of clinical evolution in children recently infected with Leishmania donovani chagasi. J Infect Dis 1992; 165:535–40. 15. Palella FJ, Delaney K, Moorrman A, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338:853–60. HIV/AIDS • CID 2001:32 (15 February) • 635