Title: Discontinuation of secondary prophylaxis against cryptococcosis in patients with AIDS receiving highly active antiretroviral therapy
Abstract: Cryptococcal meningitis is a common and often fatal infection in HIV-infected patients [1]. Secondary prophylaxis against Cryptococcus neoformans is indicated in patients with a history of cryptococcal meningitis [2]. The use of highly active antiretroviral therapy (HAART) has dramatically changed the course of HIV infection, resulting in a reduction in the morbidity and mortality rates [3]. It has been suggested that the discontinuation of secondary prophylaxis against Pneumocystis carinii pneumonia and cytomegalovirus retinitis is safe in HIV-infected patients who have an immunological response to HAART [4,5]. No prospective data are available concerning the discontinuation of secondary prophylaxis for cryptococcosis. We studied the safety of discontinuing secondary prophylaxis against C. neoformans in patients with cured cryptococcal meningitis during antiretroviral treatment with at least three anti-HIV drugs. Between January 1990 and December 1999, a diagnosis of cryptococcal meningitis was made in 67 patients at our department (41 are dead, 12 are lost to follow-up, and eight are still receiving secondary prophylaxis). A total of six patients with a history of cured cryptococcal meningitis was evaluated in the study. All the patients were men. At the time of the meningitis (between 1996 and 1998), the mean age was 38.5 years, the median CD4 cell count was 8/mm3 (1–40), and the median HIV-1-RNA level was 102 000 copies/ml (25 000–517 000). None of the patients was treated with HAART. Four patients were initially treated with amphotericin B alone, and two were treated with amphotericin B and flucytocine. All patients were receiving secondary prophylaxis against C. neoformans with oral fluconazole (400–600 mg/day). The institution of antiretroviral treatment with at least three drugs was started in all patients (two nucleoside analogues and a protease inhibitor: n = 4; three nucleoside analogues: n = 2). At the moment of discontinuation of secondary prophylaxis, the median duration of HAART was 30 months and the median duration of secondary prophylaxis was 31 months (9–62). When the prophylactic treatment was stopped, the median CD4 cell count was 244/mm3 (130–390) and the median HIV-1-RNA level was less than 200 copies/ml (all patients had undetectable HIV-1-RNA levels). C. neoformans antigen detection in serum was negative in five patients (median duration 6 months), whereas the remaining patient showed low levels (+1/10). After a median follow-up period of 18 months, there were no episodes of cryptococcal meningitis in these six patients who discontinued secondary prophylaxis. This indicates that secondary prophylaxis against cryptococcal meningitis can be safety discontinued in HIV-infected patients receiving HAART. It is difficult to establish clear criteria for discontinuing prophylaxis against C. neoformans after HAART has begun. However, the results of this study suggest that secondary prophylaxis against C. neoformans may be safely discontinued during HAART in patients who have an immunological response to HAART (increase in the CD4 cell count to 100 cells/mm3 or greater), particularly those who have a negative C. neoformans antigen detection in the serum, or it has been at very low levels for at least 6 months. Florence Rollot Philippe Bossi Roland Tubiana Eric Caumes Valérie Zeller Christine Katlama François Bricaire