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    Actuarial curve of the time to visceral leishmaniasis relapse after the introduction of highly active antiretroviral therapy in the patients without secondary chemoprophylaxis.

  • 1

    Pineda JA, Gallardo JA, Macías J, Delgado J, Regordán C, Morillas F, Relimpio F, Martín-Sánchez J, Sánchez-Quijano A, Leal M, Lissen E, 1998. Prevalence of and factors associated with visceral leishmaniasis in human immunodeficiency virus type 1-infected patients in southern Spain. J Clin Microbiol 36 :2419–2422.

    • Search Google Scholar
    • Export Citation
  • 2

    Alvar J, Cañavete C, Gutiérrez-Solar B, Jiménez M, Laguna F, López-Vélez R, Molina R, Moreno F, 1997. Leishmania and human immunodeficiency virus coinfection: the first 10 years. Clin Microbiol Rev 10 :298–319.

    • Search Google Scholar
    • Export Citation
  • 3

    Gradoni L, Scalone A, Gramiccia M, Troiani M, 1996. Epidemiological surveillance of leishmaniasis in HIV-1 infected individuals in Italy. AIDS 10 :785–791.

    • Search Google Scholar
    • Export Citation
  • 4

    Delgado J, Pineda JA, Gallardo JA, Leal M, Macías J, Sánchez-Quijano A, Lissen E, 1998. Influencia de la actuación médica sobre la forma de presentación del sida definido por episodios clínicos. Med Clin (Barc) 110 :125–127.

    • Search Google Scholar
    • Export Citation
  • 5

    Laguna F, López-Vélez R, Pulido F, Salas A, Torre-Cisneros J, Torre E, Medrano FJ, Sanz J, Pico G, Gómez-Rodrigo J, Pasquau J, Alvar J, 1999. Treatment of visceral leishmaniasis in HIV-infected patients: a randomized trial comparing meglumine antimoniate with amphotericin B. AIDS 13 :1063–1069.

    • Search Google Scholar
    • Export Citation
  • 6

    Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD, 1998. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 338 :853–860.

    • Search Google Scholar
    • Export Citation
  • 7

    Kaplan JE, Hanson D, Dworkin MS, Frederick T, Bertolli J, Lindegren ML, Holmberg S, Jones JL, 2000. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis 30 :S5–S14.

    • Search Google Scholar
    • Export Citation
  • 8

    de la Rosa R, Pineda JA, Delgado J, Macías J, Morillas F, Mira JA, Sánchez-Quijano A, Leal M, Lissen E, 2002. Incidence of and risk factors for symptomatic visceral leishmaniasis among human immunodeficiency virus type 1-infected patients from Spain in the era of highly active antiretroviral therapy. J Clin Microbiol 40 :762–767.

    • Search Google Scholar
    • Export Citation
  • 9

    Berenguer J, Cosín J, Miralles P, López J, Padilla B, 2000. Discontinuation of anti-Leishmania prophylaxis in HIV-infected patients who have responded to highly active antiretroviral therapy. AIDS 14 :2946–2948.

    • Search Google Scholar
    • Export Citation
  • 10

    de la Rosa R, Pineda JA, Delgado J, Macías J, Morillas F, Martín-Sánchez J, Leal M, Sánchez-Quijano A, Lissen E, 2001. Influence of highly active antiretroviral therapy on the outcome of subclinical visceral leishmaniasis in human immunodeficiency virus-infected patients. Clin Infect Dis 32 :633–635.

    • Search Google Scholar
    • Export Citation
  • 11

    Casado JL, López-Velez R, Pintado V, Quereda C, Antela A, Moreno S, 2001. Relapsing visceral leishmaniasis in HIV-infected patients undergoing successful protease inhibitor therapy. Eur J Clin Microbiol Infect Dis 20 :202–205.

    • Search Google Scholar
    • Export Citation
  • 12

    Villanueva JL, Alarcón A, Bernabeu-Wittel M, Cordero E, Prados D, Regordán C, Alvar J, 2000. Prospective evaluation and follow-up of European patients with visceral leishmaniasis and HIV-1 coinfection in the era of the highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 19 :798–801.

    • Search Google Scholar
    • Export Citation
  • 13

    Tortajada C, Pérez-Cuevas B, Moreno A, Martínez E, Mallolas J, García F, Valls E, Miró JM, De Lazzari E, Gatell JM, 2002. Highly active antiretroviral therapy (HAART) modifies the incidence and outcome of visceral leishmaniasis in HIV-infected patients (letter). J Acquir Immune Defic Syndr 30 :364–366.

    • Search Google Scholar
    • Export Citation
  • 14

    Pineda JA, Macías J, Morillas F, Fernández-Ochoa J, Cara J, de la Rosa R, Mira JA, Martín-Sánchez J, González M, Delgado J, Acedo C, Lissen E, 2001. Evidence of increased risk for Leishmania infantum infection among HIV-seronegative intravenous drug users from southern Spain. Eur J Clin Microbiol Infect Dis 20 :354–357.

    • Search Google Scholar
    • Export Citation
  • 15

    Morales MA, Cruz I, Rubio JM, Chicharro C, Canavete C, Laguna I, Alvar J, 2002. Relapses versus reinfections in patients coinfected with Leishmania infantum and human immunodeficiency virus type 1. J Infect Dis 185 :1533–1537.

    • Search Google Scholar
    • Export Citation

 

 

 

 

FREQUENCY OF VISCERAL LEISHMANIASIS RELAPSES IN HUMAN IMMUNODEFICIENCY VIRUS–INFECTED PATIENTS RECEIVING HIGHLY ACTIVE ANTIRETROVIRAL THERAPY

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  • 1 Servicio de Medicina Interna e Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Seville, Spain; Unidad de Enfermedades Infecciosas, Hospital Universitario Reina Sofía, Cordoba, Spain

There are contradictory data about whether highly active antiretroviral therapy (HAART) prevents visceral leishmaniasis (VL) relapses in human immunodeficiency virus type 1 (HIV-1)-infected patients. The aim of this study was to assess the frequency of VL relapses in individuals receiving HAART. Thirty-one patients who received HAART after developing VL were included in a retrospective cohort study. Ten of them received secondary chemoprophylaxis and the rest did not. Eight (38%) patients without secondary chemoprophylaxis showed a VL relapse. None of the seven subjects with VL relapses and 6 of 11 without recurrence (P = 0.038), in whom all scheduled data were available, showed an increase of more than 100 CD4+ cells/mm3 during the follow-up. Patients with relapse showed higher levels of HIV RNA viral load at their last visit (P = 0.047). The frequency of VL relapses in patients receiving HAART is high. Relapses of VL are observed only in individuals with uncontrolled HIV replication and/or poor immunologic responses.

INTRODUCTION

Leishmania infantum is considered to be the causal agent of all cutaneous and visceral leishmaniasis (VL) cases in Spain. Symptomatic VL is a frequent disease among human immunodeficiency virus type 1 (HIV-1)-infected patients from the Mediterranean basin.1–3 Thus, VL is the fourth most frequent major opportunistic event associated with acquired immunodeficiency syndrome in southern Spain.4 Before highly active antiretroviral therapy (HAART) was extensively used, VL associated with HIV infection relapsed in 27% and 60% of the patients within 6 and 12 months after treatment, respectively.5

Since the introduction of HAART, the incidence of opportunistic infections and the mortality of HIV-infected patients has decreased sharply.6,7 In addition, the incidence of symptomatic VL has decreased after the use of this therapy.8 The data of recent studies have showed that secondary chemoprophylaxis against VL can be discontinued safely in patients with more than 350 CD4+ cells/mm3.9 Conversely, it is also known that HAART prevents the development of symptomatic VL in individuals with subclinical VL.10 Nevertheless, there are contradictory data about whether HAART prevents VL relapses.11–13 Thus, in one small series of patients with VL receiving HAART, relapses occurred in patients who maintained an undetectable HIV viral load and an adequate immunologic control.12 However, in another case series, relapses were seen in patients who showed a poorer recovery of CD4+ cells counts.11 Finally, in a third study, a decrease in the frequency of VL relapses was observed since the introduction of HAART.13 Thus, there is little consistency in the results. In addition, previous studies were conducted on a small number of patients. Therefore, other studies are needed to clarify these issues. Furthermore, the potential risk factors for VL relapse are also unknown. For these reasons, we undertook this study, whose aim was to assess the frequency of VL relapses in HIV-infected individuals treated with HAART and the factors associated with recurrences.

MATERIALS AND METHODS

Population and follow-up.

From April 1989 to September 2002, 1,715 HIV-infected patients have been followed in two university hospitals in southern Spain, the Hospital Universitario de Valme in Seville and the Hospital Universitario Reina Sofia in Cordoba. All individuals underwent scheduled clinical, hematologic, and immunologic examinations at baseline and every three months thereafter. Eighty-seven HIV-infected patients developed at least an episode of symptomatic VL during the follow-up. Thirty-one HIV-infected patients who received HAART after developing VL were included in a retrospective cohort study. All patients provided written informed consent before participation in the study. The study was reviewed and approved by the Ethics Committee of the Hospital Universitario de Valme and the Ethics Committee of the Hospital Universitario Reina Sofia.

Therapeutic strategies.

Patients received antiretroviral drugs depending on the specific drug availability at the time and according to international recommendations. Protease inhibitors (PIs) were extensively available for prescription since 1997 and non-nucleoside reverse transcriptase inhibitors (NNRTIs) since 1999. Highly active antiretroviral therapy was defined as a combination of at least two nucleoside analogs reverse transcriptase inhibitors and one PI or one NNRTI.

Drug compliance was assessed at all follow-up visits. Self-reported compliance to each antiretroviral drug was calculated as the percentage of prescribed doses that the patient indicated were taken during the period of time between visits. A patient was defined as non-compliant with HAART for the present study if an adherence of less than 90% to a drug was reported during at least one visit.

Thirteen individuals diagnosed with VL received meglumine antimoniate (20 mg/kg/day) for 28 days, two received pentamidine (4 mg/kg/day) for 28 days, five received amphotericin B desoxycholate (0.7 mg/kg/day) for 28 days, nine received liposomal amphotericin B (2.5–4 mg/kg/day) for 10 days, and two received amphotericin B lipid complex (5 mg/kg/day) for 14 days. Patients received secondary chemoprophylaxis after the first VL relapse according to the criteria of the clinician responsible for the case. Thus, two groups of patients have been included in this study: those were given secondary prophylaxis and those were not.

Diagnosis of VL.

During the follow-up, a search for Leishmania amastigotes in a bone marrow aspirate was performed when patients showed unexplained fever, spleen enlargement, or a decrease in blood cell counts of unexplained origin. When these symptoms coincided with the finding of Leishmania amastigotes by staining with Giemsa, a diagnosis of symptomatic VL was made. An investigation of the presence of Leishmania amastigotes in blood was done in every case and in other biologic specimens (lymph node or liver) when clinically appropriate.

Laboratory methods.

Plasma HIV-1 RNA was measured by a polymerase chain reaction (Amplicor; Hoffman-La Roche, Basel, Switzerland) or nucleic acid sequence-based amplification assays (Nuclisens; Organon Teknika, Boxtel, The Netherlands) depending on the availability at each hospital. The limits of detection varied between 20 and 200 copies/mL according to when the analysis was carried out and the procedure used. The CD4 cell counts were measured by standard flow cytometry.

Statistical analysis.

In this study, we assessed the frequency of VL relapses and the factors associated with recurrences both in patients with VL treated with secondary chemoprophylaxis and in those without secondary chemoprophylaxis. Continuous variables are expressed as median (range) and the categorical variables as number (percentage). Continuous variables were compared using the Mann-Whitney U test. The frequencies were compared using the chi-square test with the Yates’ correction or Fisher’s test if the expected frequency for any cell was five or lower. The Kaplan-Meier method was applied to estimate the time to relapse after the introduction of HAART in the patients without secondary chemoprophylaxis. Data were analyzed with the SPSS statistical software package (SPSS, Inc., Chicago, IL).

RESULTS

Characteristics of the population.

The main characteristics of the population are shown in Table 1. Ten (32.2%) patients with VL underwent secondary chemoprophylaxis and 21 (67.7%) patients did not. Four (12.9%) individuals were lost to the follow-up and 10 (32.2%) patients died. Two patients died due to a symptomatic VL relapse. Plasma HIV RNA load determinations were available in 20 patients during all of the follow-up. This parameter was permanently below the detection threshold in only seven patients. These low numbers were due to failures to comply with the visit schedule and the antiretroviral therapy. The individuals who received secondary chemoprophylaxis and those without secondary chemoprophylaxis were followed after the introduction of HAART for a median of 30 months (range = 4–53 months) and 25 months (range = 2–61 months), respectively.

Frequency of symptomatic VL relapses in patients without secondary chemoprophylaxis.

Eight (38%) patients without secondary chemoprophylaxis showed a VL relapse after receiving HAART. In this group, five individuals were active intravenous drug users at the time when VL relapse was diagnosed. There was no relationship between the therapy for the primary VL episode and the emergence of relapse. Thus, three individuals had been treated with meglumine antimoniate, three with amphotericin B in lipid formulations, one with amphotericin B desoxycholate, and one with pentamidine. The highest CD4+ cell count observed in a patient with relapse at the visit prior the episode of recurrence was 170 cells/mm3. Thus, no patient without secondary chemoprophylaxis and a CD4+ cell count of 200 cells/mm3 had a relapse. None of the seven patients with VL relapse in whom all scheduled data were available showed an increase of more than 100 CD4+ cells/mm3 over the level found at starting HAART. In contrast, six (55%) of 11 non-relapsing VL patients with available data during all the follow-up show an increase of such a magnitude (P = 0.038) (Table 2). The CD4+ cell counts at the end of the follow-up were higher among patients without VL relapse (P = 0.025). These patients also showed lower levels of HIV RNA viral load at their last visit (P = 0.047) (Table 2). In the actuarial study of the time to the relapse of VL since the start of HAART, we observed that nearly 75% of the patients were free of relapse after 24 months of HAART (Figure 1).

Frequency of symptomatic VL relapses in patients with secondary chemoprophylaxis.

One (10%) patient with secondary chemoprophylaxis had three relapses of VL after the beginning of HAART. This patient maintained undetectable viral load during the entire follow-up period and experienced a maximum increase of 93 CD4+ cells/mm3. He was completely compliant with the different chemoprophylaxis regimens prescribed, which were given as directly observed therapy in our outpatient clinic. This patient had four relapses of symptomatic VL undergoing secondary chemoprophylaxis before starting HAART.

DISCUSSION

These results show that the frequency of VL relapses in HIV-infected patients receiving HAART is high. However, relapses have been observed only in subjects showing poor control of viral replication and/or a low grade of CD4+ cell repopulation. These facts were attributable to a lack of adherence to HAART.

Our study is limited because of the relatively small sample size. This is due to the fact that the incidence of symptomatic VL is low since the introduction of effective antiretroviral therapy.8 It is possible that additional cases of relapsing VL would have been found in patients with good recovery of immune function if a larger sample had been studied. However, our series is the largest in which this issue has been evaluated. Thus, this study clearly shows that relapses of VL in patients receiving HAART are mainly seen in cases with poor or no response to therapy. In these patients, VL is observed as it was before the introduction of HAART, i.e., as a chronic, relapsing opportunistic disease that emerges in patients with uncontrolled viral replication and poor immune reconstitution.

The results obtained in this survey differ from those found in other studies dealing with the same issue. In the study carried out by Villanueva and others,12 there were no differences in HIV viral load at the end of the follow-up period and in the increase in CD4+ cell counts after HAART in patients with or without VL relapse. Casado and others11 found that patients with relapsing VL showed lower increases in CD4+ cell counts than those with limited disease. However, they did not find any differences in plasma viremia between these groups. Conversely, in the study of Tortajada and others,13 there was a decrease in the frequency of VL relapses in patients treated with HAART in comparison with individuals receiving monotherapy or bitherapy, although the difference was not statistically significant.

The recurring symptomatic VL cases diagnosed in this study could be theoretically due to actual relapses or reinfections. The fact that most of the patients were active intravenous drug users at the time when infection was diagnosed could lead us to consider these as newly acquired infections. In this regard, it is known that L. infantum infection can be spread among intravenous drug users.14 However, recent studies have demonstrated that the majority of VL recurrences are true relapses.15

In our study, VL probably relapsed because of a failure of immune reconstitution due to low adherence to HAART. Thus, no patients in whom CD4+ cell counts either reached the level of 200 cells/mm3 or increased 100 cells/mm3 over the baseline value had recurrences. This finding suggests that in HIV-infected patients with previous VL, secondary prophylaxis should be given until a safe degree of immunoreconstitution is reached. A CD4+ cell count of 350 cells/mm3 has been said to be high enough to discontinue safely secondary prophylaxis against VL.9 According to the results of this and other surveys, a CD4+ cell count greater than 200/mm3 may prove to be a safe level at which chemoprophylaxis can be ended.9 However, such recommendations must be based on further randomized studies with larger populations.

More than one relapse of VL was observed in a patient who received anti-Leishmania chemoprophylaxis after the first VL episode. This individual took HAART correctly, but he showed a poor increase in CD4+ cells counts. This fact underlines the importance of the immune response for the control of relapsing VL stated earlier, and conversely shows that secondary prophylaxis is not entirely effective against this disease.

Based on the results of this study, antiretroviral therapy compliance programs, and improvement of the efficacy of these drugs should be a priority to prevent VL relapses. In addition, a more adequate secondary chemoprophylaxis for the control of infection with this parasite should be investigated.

Table 1

Characteristics of the population*

CharacteristicGroup with secondary chemoprophylaxis (n = 10)Group without secondary chemoprophylaxis (n = 21)
* IDU = intravenous drug users; CDC = Centers for Disease Control and Prevention; HAART = highly active retroviral therapy; HIV = human immunodeficiency virus.
† Number/total available cases.
‡ Number/total patients who attended all visits and in whom all CD4+ cell count measurements scheduled were available.
§ Nine available cases.
¶ Twelve available cases.
# Five available cases.
** Fifteen available cases.
†† Number/total patients who attended all visits and in whom all plasma HIV RNA load measurements scheduled were available.
Median age in years (range)34 (26–37)33 (24–57)
Male sex, no. (%)10 (100)19 (90)
IDU, no. (%)10 (100)18 (86)
CDC clinical category C, no. (%)8 (80)16 (76)
Self-reported compliance with HAART >90% during the follow-up† (%)3/10 (30)6/19 (31)
Median (range) CD4+ cells/mm3 at the beginning of HAART33 (2–199)35 (2–407)
Median (range) CD4+ cells/mm3 at the end of the follow-up161 (126–282)158 (2–616)
Patients with a CD4+ >100 cells/mm3 increase during the follow-up‡ (%)2/8 (25)6/18 (30)
Median (range) log HIV RNA copies/mm3 at the beginning of HAART5.4 (3.8–6.35)§5 (3.8–6)¶
Median (range) log HIV RNA copies/mm3 at the end of the follow-up1.9 (1.7–4.75)#3.5 (1.7–6)**
Patients with undetectable viral load during the entire follow-up period†† (%)3/5 (60)4/15 (26)
Table 2

Characteristics of 21 patients with visceral leishmaniasis without chemoprophylaxis treated with highly active antiretroviral therapy*

CharacteristicPatients with VL relapse (n = 8)Patients without VL relapse (n = 13)P
* VL = visceral leishmaniasis; IDU = intravenous drug users; CDC = Centers for Disease Control and Prevention; HAART = highly active retroviral therapy; HIV = human immunodeficiency virus.
† Number/total available cases.
‡ Number/total patients who attended all visits and in whom all CD4+ cell count measurements scheduled were available.
§ Five available cases.
¶ Seven available cases.
# Seven available cases.
** Eight available cases.
†† Number/total patients who attended all visits and in whom all plasma HIV RNA load measurements scheduled were available.
Male sex, no.(%)8 (100)11 (84)0.5
IDU, no. (%)8 (100)10 (77)0.5
CDC clinical category C, no. (%)7 (87)9 (69)0.5
HAART self-reported compliance >90% during the follow-up† (%)1/8 (12)5/11 (45)0.2
Median (range) CD4+ cells/mm3 at beginning of HAART32 (2–176)35 (2–407)0.5
Median (range) CD4+ cels/mm3 in the first VL episode31 (2–277)26 (2–200)0.9
Median (range) CD4+ cells/mm3 at the end of the follow-up33 (2–162)188 (15–616)0.025
Patients with an increase of 100 CD4+ cells/mm3 during the follow-up‡ (%)0/76/11 (55)0.038
Median (range) log HIV RNA copies/mm3 at beginning of HAART5.2 (5–6)§4.8 (3.8–5.7)¶0.12
Median (range) log HIV RNA copies/mm3 at the end of the follow-up5.4 (1.9–6)#3.2 (1.7–4.6)**0.047
Patients with undetectable viral load during the follow-up†† (%)1/7 (14)3/8 (37)0.6
Figure 1.
Figure 1.

Actuarial curve of the time to visceral leishmaniasis relapse after the introduction of highly active antiretroviral therapy in the patients without secondary chemoprophylaxis.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 70, 3; 10.4269/ajtmh.2004.70.298

Authors’ addresses: José A. Mira, Juan Macias, and Juan A. Pineda, Servicio de Medicina Interna, Hospital Universitario de Valme, Carretera de Cádiz s/n, 41014-Seville, Spain, Telephone: 34-95-501-5887, Fax: 34-95-501-5747, E-mails: PEPINESCARTI@ono.com, jmacias@cica.es, and japineda@nacom.es. Juan E. Corzo, Fernando Lozano de León, and Jesús Gómez-Mateos, Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Carretera de Cádiz s/n, 41014-Seville, Spain, Telephone: 34-95-501-5787, Fax: 34-95-501-5757, E-mails: jecorzo@nacom.es, flozano@nacom.es, and gmateos@nacom.es. Antonio Rivero, Julián Torre-Cisneros, and Rafael Jurado, Unidad de Enfermedades Infecciosas, Hospital Universitario Reina Sofía, Avda. Menéndez Pidal s/n, 14004-Córdoba, Spain, Telephone and Fax: 34-95-701-1636, E-mails: arivero@hrs.sas.junta-andalucia.es, jtorres@hrs.sas.junta-andalucia.es, and jurado@hrs.sas.junta-andalucia.es.

REFERENCES

  • 1

    Pineda JA, Gallardo JA, Macías J, Delgado J, Regordán C, Morillas F, Relimpio F, Martín-Sánchez J, Sánchez-Quijano A, Leal M, Lissen E, 1998. Prevalence of and factors associated with visceral leishmaniasis in human immunodeficiency virus type 1-infected patients in southern Spain. J Clin Microbiol 36 :2419–2422.

    • Search Google Scholar
    • Export Citation
  • 2

    Alvar J, Cañavete C, Gutiérrez-Solar B, Jiménez M, Laguna F, López-Vélez R, Molina R, Moreno F, 1997. Leishmania and human immunodeficiency virus coinfection: the first 10 years. Clin Microbiol Rev 10 :298–319.

    • Search Google Scholar
    • Export Citation
  • 3

    Gradoni L, Scalone A, Gramiccia M, Troiani M, 1996. Epidemiological surveillance of leishmaniasis in HIV-1 infected individuals in Italy. AIDS 10 :785–791.

    • Search Google Scholar
    • Export Citation
  • 4

    Delgado J, Pineda JA, Gallardo JA, Leal M, Macías J, Sánchez-Quijano A, Lissen E, 1998. Influencia de la actuación médica sobre la forma de presentación del sida definido por episodios clínicos. Med Clin (Barc) 110 :125–127.

    • Search Google Scholar
    • Export Citation
  • 5

    Laguna F, López-Vélez R, Pulido F, Salas A, Torre-Cisneros J, Torre E, Medrano FJ, Sanz J, Pico G, Gómez-Rodrigo J, Pasquau J, Alvar J, 1999. Treatment of visceral leishmaniasis in HIV-infected patients: a randomized trial comparing meglumine antimoniate with amphotericin B. AIDS 13 :1063–1069.

    • Search Google Scholar
    • Export Citation
  • 6

    Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD, 1998. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 338 :853–860.

    • Search Google Scholar
    • Export Citation
  • 7

    Kaplan JE, Hanson D, Dworkin MS, Frederick T, Bertolli J, Lindegren ML, Holmberg S, Jones JL, 2000. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis 30 :S5–S14.

    • Search Google Scholar
    • Export Citation
  • 8

    de la Rosa R, Pineda JA, Delgado J, Macías J, Morillas F, Mira JA, Sánchez-Quijano A, Leal M, Lissen E, 2002. Incidence of and risk factors for symptomatic visceral leishmaniasis among human immunodeficiency virus type 1-infected patients from Spain in the era of highly active antiretroviral therapy. J Clin Microbiol 40 :762–767.

    • Search Google Scholar
    • Export Citation
  • 9

    Berenguer J, Cosín J, Miralles P, López J, Padilla B, 2000. Discontinuation of anti-Leishmania prophylaxis in HIV-infected patients who have responded to highly active antiretroviral therapy. AIDS 14 :2946–2948.

    • Search Google Scholar
    • Export Citation
  • 10

    de la Rosa R, Pineda JA, Delgado J, Macías J, Morillas F, Martín-Sánchez J, Leal M, Sánchez-Quijano A, Lissen E, 2001. Influence of highly active antiretroviral therapy on the outcome of subclinical visceral leishmaniasis in human immunodeficiency virus-infected patients. Clin Infect Dis 32 :633–635.

    • Search Google Scholar
    • Export Citation
  • 11

    Casado JL, López-Velez R, Pintado V, Quereda C, Antela A, Moreno S, 2001. Relapsing visceral leishmaniasis in HIV-infected patients undergoing successful protease inhibitor therapy. Eur J Clin Microbiol Infect Dis 20 :202–205.

    • Search Google Scholar
    • Export Citation
  • 12

    Villanueva JL, Alarcón A, Bernabeu-Wittel M, Cordero E, Prados D, Regordán C, Alvar J, 2000. Prospective evaluation and follow-up of European patients with visceral leishmaniasis and HIV-1 coinfection in the era of the highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 19 :798–801.

    • Search Google Scholar
    • Export Citation
  • 13

    Tortajada C, Pérez-Cuevas B, Moreno A, Martínez E, Mallolas J, García F, Valls E, Miró JM, De Lazzari E, Gatell JM, 2002. Highly active antiretroviral therapy (HAART) modifies the incidence and outcome of visceral leishmaniasis in HIV-infected patients (letter). J Acquir Immune Defic Syndr 30 :364–366.

    • Search Google Scholar
    • Export Citation
  • 14

    Pineda JA, Macías J, Morillas F, Fernández-Ochoa J, Cara J, de la Rosa R, Mira JA, Martín-Sánchez J, González M, Delgado J, Acedo C, Lissen E, 2001. Evidence of increased risk for Leishmania infantum infection among HIV-seronegative intravenous drug users from southern Spain. Eur J Clin Microbiol Infect Dis 20 :354–357.

    • Search Google Scholar
    • Export Citation
  • 15

    Morales MA, Cruz I, Rubio JM, Chicharro C, Canavete C, Laguna I, Alvar J, 2002. Relapses versus reinfections in patients coinfected with Leishmania infantum and human immunodeficiency virus type 1. J Infect Dis 185 :1533–1537.

    • Search Google Scholar
    • Export Citation

Author Notes

Reprint requests: Juan A. Pineda, Servicio de Medicina Interna, Hospital Universitario de Valme, Carretera de Cádiz s/n. 41014-Seville, Spain. Phone: 34-95-5015887. Fax: 34-95-5015747. E-mail: japineda@nacom.es.
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