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AIDS:
Research Letters

Discontinuation of secondary anti-Leishmania prophylaxis in HIV-infected patients who have responded to highly active antiretroviral therapy

Berenguer, Juan; Cosín, Jaime; Miralles, Pilar; López, Juan Carlos; Padilla, Belén

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Servicio de Microbiología y Enfermedades Infecciosas, Hospital Gregorio Marañón, Madrid, Spain.

Received: 26 July 2000;

revised: 7 September 2000; accepted: 12 September 2000.

Visceral leishmaniasis is an opportunistic infection of advanced HIV disease in European Mediterranean countries [1,2]. Before or at the time of the first episode of visceral leishmaniasis, approximately 50% of HIV-infected patients have an AIDS-defining condition and most of them are severely immunosuppressed. For the treatment of visceral leishmaniasis in HIV patients, both meglumine antimoniate and amphotericin B have similar efficacy and toxicity rates [3]; however, the relapse rate after a correctly treated first episode is 90% at 12 months [4]. A retrospective study [5] found that the relapse rate can be reduced to 9% at 12 months with the administration of 850 mg pentavalent antimony given once a month. To the best of our knowledge, no study has addressed the discontinuation of secondary prophylaxis against visceral leishmaniasis in HIV patients with immune recovery after highly active antiretroviral therapy (HAART).

In April 1998, we started a prospective study in which HIV-infected patients with visceral leishmaniasis were asked to stop secondary prophylaxis if they met the following criteria: quiescent visceral leishmaniasis for more than 4 months and a sustained response to HAART for more than 4 months, characterized by a CD4 cell count higher than 100/μl plus an HIV viral load less than 500 copies/ml or a CD4 cell count higher than 150/μl plus an HIV viral load lower than 10 000 copies/ml (by bDNA assay).

Patients were followed monthly with anamnesis, physical examination, complete blood count and serum biochemical profile. The measurement of CD4 cell counts and HIV viral load were performed bimonthly. A bone marrow aspirate with stains and culture for Leishmania was performed whenever there was a suspicion of relapse of leishmaniasis (i.e. unexplained fever, blood cytopenias and enlargement of liver and spleen). Biopsies of the potential involvement of unusual sites such as the skin were performed if indicated. The endpoint of the study was a relapse of visceral leishmaniasis defined by a compatible clinical picture and detection of the parasite in clinical specimens.

Since June 1997 we have randomly assigned, by an aleatory number table, all HIV-infected patients with new diagnosis of visceral leishmaniasis to two treatment arms: pentavalent antimony in the form of meglumine antimoniate at 20 mg/kg per day (Glucantime; Rhône-Poulenc Rorer, Alcorcón, Madrid, Spain) for 28 days or liposomal amphotericin B (AmBisome, NeXstar Pharmaceuticals Ltd., Blackrock, Dublin, Ireland) a total of 10 doses of 4 mg/kg per day given on days 1 to 5, 10, 17, 24, 31 and 38. After the completion of therapy, secondary prophylaxis was administered in all cases: one dose every month.

Since the introduction of HAART in our institution we have detected 23 patients with HIV and visceral leishmaniasis co-infection, 15 of whom fulfilled the inclusion criteria and gave their informed consent to enter the study (Table 1). When diagnosed with visceral leishmaniasis, their median CD4 cell count was 77/μl and seven had a previous diagnosis of AIDS. Six patients had a total of eight relapses of visceral leishmaniasis after the completion of the first treatment course. At inclusion in the study, they had received secondary prophylaxis for a median of 70 weeks and HAART for a median of 64 weeks. Their median CD4 cell count was 276/μl and 10 patients had an HIV load lower than 500 copies/ml.

Table 1
Table 1
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After the discontinuation of secondary prophylaxis, three (20%) patients relapsed a median time of 19 weeks later and 12 patients remained free of relapse after a median follow-up of 78 weeks. At relapse, the three patients had HIV viral loads below 50 copies/ml and a CD4 cell count below 200/μl. The median CD4 cell count on inclusion in the study was 165/μl for the patients with relapse and 365/μl for the patients without relapse (P = 0.061, Mann–Whitney U test). The incidence rate of relapse per 100 persons/month of follow-up was 3.85 (95% confidence interval 0.7–12.86) in the group that discontinued prophylaxis under 200 CD4 cells/μl and 0.68 (95% confidence interval 0.03–3.62) in the group that discontinued prophylaxis above 200 CD4 cells/μl.

The suppression of HIV replication after HAART produces a rapid and large redistribution of memory CD4 cells that had previously been sequestered in lymphoid tissues followed by a slow but steady increase in naive CD4 cells. CD4 cell regeneration is accompanied by a restoration of the T cell receptor repertoire and a recovery of the response to recall antigens [6,7]. This immune reconstitution has dramatically reduced the morbidity and mortality associated with HIV disease [8,9], and has made possible the discontinuation of secondary prophylaxis against several opportunistic infections.

Data from observational studies [10] show that the rates of decline in the incidence of specific opportunistic infections in patients receiving HAART may not protect equally against all causative microorganisms. Leishmania infantum, the species causing visceral leishmaniasis in European Mediterranean countries, is not only an opportunistic pathogen in patients with derangements in their cellular immune system, but is also a true pathogen able to cause disease in apparently normal individuals. It is conceivable that the immune reconstitution induced by HAART needed to prevent relapses of leishmaniasis should be higher than with other microorganisms such as Mycobacterium avium or cytomegalovirus.

In this study, we found that three out of 15 patients with visceral leishmaniasis in whom secondary prophylaxis was stopped relapsed a median time of 19 weeks later. At the time of relapse the CD4 cell count was below 200/μl in all three patients. We did not observe relapses among the patients who maintained a CD4 cell count above 200/μl. Strong recommendations cannot be made on the basis of our study because of the shortcomings of it not being randomized and the relatively low number of patients included. However, our results suggest that secondary prophylaxis against visceral leishmaniasis in the setting of HIV infection should not be discontinued in patients unable to achieve and maintain a CD4 cell count above 200/μl with HAART, and that it may be safe in patients with a CD4 cell count above 350/μl. Further studies are needed in order to define the optimal criteria for the discontinuation of secondary prophylaxis against this parasite.

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Acknowledgements

The authors sincerely appreciate the help of Thomas O'Boyle in the preparation of the manuscript.

Juan Berenguer

Jaime Cosín

Pilar Miralles

Juan Carlos López

Belén Padilla

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References

1. Berenguer J, Moreno S, Cercenado E, Bernaldo de Quiros JC, Garcia de la Fuente A, Bouza E. Visceral leishmaniasis in patients infected with human immunodeficiency virus (HIV). Ann Intern Med 1989, 111: 129 –132.

2. Montalban C, Martinez-Fernandez R, Calleja JL. et al. Visceral leishmaniasis (kala-azar) as an opportunistic infection in patients infected with the human immunodeficiency virus in Spain. Rev Infect Dis 1989, 11: 655 –660.

3. Laguna F, Lopez-Velez R, Pulido F, Salas A, Torre-Cisneros J, Torres E. et al. Treatment of visceral leishmaniasis in HIV-infected patients: a randomized trial comparing meglumine antimoniate with amphotericin B. :Spanish HIV–LeishmaniaStudy Group. AIDS 1999, 13: 1063 –1069.

4. Alvar J, Canavate C, Gutierrez-Solar B. et al. Leishmania and human immunodeficiency virus coinfection: the first 10 years. Clin Microbiol Rev 1997, 10: 298 –319.

5. Ribera E, Ocana I, de Otero J, Cortes E, Gasser I, Pahissa A. Prophylaxis of visceral leishmaniasis in human immunodeficiency virus-infected patients. Am J Med 1996, 100: 496 –501.

6. Autran B, Carcelain G, Li TS. et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997, 277: 112 –116.

7. Komanduri KV, Viswanathan MN, Wieder ED. et al. Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1. Nat Med 1998, 4: 953 –956.

8. Palella FJ Jr, Delaney KM, Moorman AC. et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. :HIV Outpatient Study Investigators. N Engl J Med 1998, 338: 853 –860.

9. Miller V, Mocroft A, Reiss P. et al. Relations among CD4 lymphocyte count nadir, antiretroviral therapy, and HIV-1 disease progression: results from the EuroSIDA study. Ann Intern Med 1999, 130: 570 –577.

10. Kovacs JA, Masur H. Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. N Engl J Med 2000, 342: 1416 –1429.

© 2000 Lippincott Williams & Wilkins, Inc.

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