Long-term outcome of AIDS-associated cryptococcosis in the era of combination antiretroviral therapy
Lortholary, Oliviera,b; Poizat, Gwendolinec; Zeller, Valéried; Neuville, Ségolènee; Boibieux, Andréf; Alvarez, Murielg; Dellamonica, Pierreh; Botterel, Françoisei; Dromer, Françoisea; Chêne, Genevièvec; The French Cryptococcosis Study Group
From the aCentre National de Référence Mycologie et Antifongiques, Unité de Mycologie Moléculaire, Institut Pasteur, Paris, France
bUniversité René Descartes, Hôpital Necker-Enfants malades, Centre d'Infectiologie Necker-Pasteur, Paris, France
cINSERM, Université Victor Segalen, Bordeaux, France
dPitié Salpétrière hospital, Paris, France
eSaint Louis hospital Paris, France
fLa Croix Rousse, Lyon, France
gPurpan hospital, Toulouse, France
hl'Archet hospital, Nice, France
iService de Parasitologie-Mycologie, Hôpital Henri Mondor, Créteil, France.
Received 18 May, 2006
Accepted 11 July, 2006
Correspondence to Olivier Lortholary, Center National de Référence Mycologie et Antifongiques, Institute Pasteur, Paris, France. Tel: +331 4568 8355; fax: +33 1 4565430; e-mail: email@example.com
This work was presented in part at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, September 2003 [abstract M-1752].
Note: The study databasis was approved by the ‘Commission Nationale Informatique et Libertés’.
Background: Immune restoration following combination antiretroviral therapy (cART) questions the maintenance of prophylaxis among HIV-infected patients with cryptococcosis.
Objective: To describe the long-term outcome after the diagnosis of cryptococcosis at the cART era.
Design: Multicentre cohort of patients with a diagnosis of cryptococcosis between 1996 and 2000, follow-up until December 2002. Comparison with a historical cohort (1990–1994) for survival.
Setting: Eighty-four French AIDS clinical centres.
Patients: Two-hundred and forty HIV-infected adult patients at the cART era and 149 at the pre-cART era experiencing a first episode of culture-confirmed cryptococcosis.
Results: In the cART era, 82/189 patients surviving more than 3 months after initiation of antifungal therapy had their maintenance therapy interrupted with a subsequent median follow-up of 19 months. Their relapse rate per 100 person-years was 0.9 [95%confidence interval (CI),0.0–2.0]. When considering the whole cART cohort, probability of reaching negative serum cryptococcal antigen was 71% after 48 months of follow-up. A CD4 cell count < 100/μl [relative risk (RR), 5.5; 95% CI, 1.3–22.2], antifungal therapy < 3 months over the past 6 months [RR, 5.0; 95% CI, 1.1–22.3] and serum cryptococcal antigen titre ≥ 1/512 [RR, 3.5; 95% CI, 1.1–10.8] were associated with a higher rate of cryptococcosis relapse. The mortality rate per 100 person-years was 15.3 [95% CI,12.2–18.4] in the cART era versus 63.8 [95% CI,53.0–74.9] in the pre-cART era although early mortality did not differ between the two periods.
Conclusion: Overall survival after cryptococcosis has dramatically improved at the cART era. Immune restoration and low serum cryptococcal antigen titres are associated with lower cryptococcosis relapse rates.
Extra-pulmonary cryptococcosis is a potentially life-threatening infection in severely immunocompromised HIV-infected individuals [1,2]. Therapeutic guidelines for this AIDS-defining illness are based on the results of major randomized trials . After 3 months of acute phase therapy, life-long maintenance therapy with fluconazole was classically recommended to prevent relapses [4,5]. However, prolonged maintenance therapy may be responsible for pharmacokinetic interactions  and selection of Candida sp. strains with reduced susceptibility to azoles . Furthermore, it may be limited by its cost, especially in developing countries where the disease is highly prevalent [8,9]. In countries with a large access to antiretrovirals, overall mortality and incidence of AIDS-defining opportunistic infections have been reduced dramatically , in particular the incidence of cryptococcosis [11–13]. In addition, the risk of cryptococcosis relapse decreased from 50–60% to 2–4% due to the introduction of maintenance antifungal therapy [4,5,14].
Reports based on limited samples have suggested that maintenance therapy could be safely withdrawn in HIV-infected patients treated by combination antiretroviral therapy (cART) presenting with stable immune restoration [15–20]. However, no study has documented the relapse rate, long-term survival and clearance of serum cryptococcal antigen since the introduction of cART. We thus took advantage of the nationwide surveillance of cryptococcosis in France [13,21] to describe the long-term outcome after a first episode of cryptococcosis at the cART era through a historical comparison with patients notified in the pre-cART era. We also estimated the incidence of cryptococcosis relapse and its determinants, and described the relationship between immune restoration, virological outcome and clearance of serum cryptococcal antigen overtime.
Patients and methods
Using the ongoing nationwide surveillance of cryptococcosis managed by the French National Reference Center for Mycoses (NRCM) [13,21], a retrospective multicenter cohort called CryptoStop was designed including HIV-infected adults who developed a first episode of culture-confirmed cryptococcosis between April 1996 and June 2000. Standardized questionnaires were used to collect information on epidemiological, clinical, microbiological and therapeutic characteristics at baseline (i.e., initiation of antifungal induction therapy) and after 3, 6 and 12 months of antifungal therapy, then annually until December 2002. Laboratory procedures for cryptococcosis diagnosis and follow-up (cultures condition, kit for the detection of cryptococcal antigen) as well as management of HIV and C. neoformans infections followed local guidelines.
Cases diagnosed between January 1990 and December 1994 (‘pre-cART era’) among HIV-infected patients were matched for clinical centre to build up a ‘historical cohort’ for survival comparison. Cases diagnosed between January 1995 and March 1996 were excluded because of potential access to cART in this transitional period. The detailed information requested by the protocol was collected for 389 patients, i.e., 240/252 patients of the cART period and 149/380 patients of the historical period. All the questionnaires were reviewed by two of us to minimize missing data.
Clinical severity of cryptococcal meningitis was defined as the presence of altered mental status and/or seizures and/or cranial nerve palsy at the time of diagnosis [1,22]. cART consisted in the initial association of two nucleoside reverse transcriptase inhibitors plus at least one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor. Time elapsed between cryptococcosis diagnosis and cART initiation was categorized as: < 8 days, within 7 days and ≥ 8 days.
Maintenance therapy was considered as started when the daily dosage of fluconazole was reduced to 200 mg/day before the third month of therapy and at month 3 in other cases. Relapses were defined as a new isolation of C. neoformans in culture, whatever the anatomic site, in a patient for whom initial fungal culture(s) had become negative. The underlying cause of death was considered to be cryptococcosis in the presence of clinical symptoms related to cryptococcosis together with a positive fungal culture within one month before death.
We used Chi2 tests to compare the distribution of categorical variables and Wilcoxon tests to compare the distribution of continuous variables. Survival time was calculated from the date of diagnosis of cryptococcosis (baseline) to death or the last available follow-up before December 2002. Time to a negative serum cryptococcal antigen was calculated from the date of diagnosis of cryptococcosis to the date of the first negative serum antigen result (when the result remained persistently negative after a positive one) or to the date of the last available serum antigen detection. Among the 189 patients who survived at least 3 months after diagnosis, time to relapse was calculated from the date of diagnosis of cryptococcosis to the date of diagnosis of relapse or death or the last available follow-up visit before December 2002. Incidence density of all three events was calculated as the ratio of the number of events in different patients over the total number of person-years at risk. Survival, probability of reaching a negative serum cryptococcal antigen and probability of occurrence of a relapse were all estimated using the Kaplan–Meier method. Cox proportional hazards models were used to study the association between patients' characteristics and either death, or cryptococcosis relapse.
Regarding cryptococcosis relapse analysis, variables associated with relapse in the univariate analysis with P < 0.25 were retained in the initial multivariate analysis. CD4 cell count, HIV-1 RNA plasma level, duration of antifungal therapy and serum cryptococcal antigen titre were considered as dichotomous time-dependent variables. For each variable, we chose a clinically relevant threshold.
Survival analysis included 240 patients at the cART era. Variables associated with survival in the univariate analysis with P < 0.25 were retained in the initial multivariate analysis. In addition, this model retained major known prognostic factors of survival, i.e., AIDS stage, injecting drug use, age, CD4 cell count and HIV RNA levels [23,24] as well as specific factors of cryptococcosis (severity, meningitis or dissemination at baseline). Information on meningitis or dissemination was considered missing when cerebrospinal fluid analysis (direct examination, antigen detection and culture) or culture was not performed in at least two non-contiguous body sites, respectively. SAS software (version 8.0, SAS Institute) was used for statistical analysis.
Long-term outcome of 240 patients with cryptococcosis at the era of cART
Among the 240 patients studied in the recent years, 41 died within the first 3 months, 10 were lost to follow-up and 189 survived beyond 3 months of antifungal therapy and had access to maintenance therapy. Among the 189 patients, 40/189 (21%) had received cART at least 8 days before cryptococcosis diagnosis, 26/189 (14%) within 7 days of diagnosis and 109/189 (58%) at least 8 days after. Finally, 14/189 (7%) never received cART. Baseline median CD4 cell count did not differ whether patients were receiving cART or not: 24 cells/μl [interquartile range (IQR), 12–52 cells/μl) and 18 cells/μl (IQR, 7–48 cells/μl), respectively, but HIV-1 RNA was slightly lower in the former group: 4.9 log10/ml (IQR, 3.4–5.2 log10/ml) and 5.1 log10/ml (IQR, 4.6–5.6 log10/ml), respectively (P < 0.01).
Description of patients for whom maintenance antifungal therapy was withdrawn
Eighty-two patients (43%) had their maintenance therapy interrupted – even if only transiently – and 107 patients (57%) never discontinued antifungal therapy. At baseline, the former group had a significantly higher proportion of cryptococcosis cases revealing AIDS, a reduced duration of antiretroviral treatment and cART intakes before cryptococcosis diagnosis and a trend towards higher CD4 cell count and lower frequency of meningitis (Table 1). These groups did not differ in terms of age (median, 38 years), sex (86% male), HIV transmission category (39% homosexual men, 42% heterosexual, 9% injecting drug users) and, among antiretroviral-naive patients, in terms of time to cART initiation (median, 1 month). In the 82 patients interrupting antifungal therapy, the median follow-up period was 53 months (IQR, 38–62 months). In the other 107 patients, the median follow-up duration was 27 months (IQR, 15–47 months). The median follow-up period after withdrawal of antifungal maintenance therapy was 19 months (IQR, 8–34 months). Median time between cryptococcosis diagnosis and withdrawal was 26 months (IQR, 13–37 months) and median time between cART and withdrawal was 26 months (IQR, 13–37 months). According to the physician in charge of the patient, maintenance antifungal therapy was stopped because of stable immune restoration (≥ 100 CD4 cells/μl, ≥ 6 months) in 65%, difficulties in taking long-term fluconazole in 16%, adverse events related to antifungal therapy in 5% and other reasons in 14%. At the time of withdrawal, all 82 patients were clinically well, their median reciprocal cryptococcal serum antigen titre was 82 (IQR, 8–400), their median CD4 cell count was 291 cells/μl (IQR, 165–418 cells/μl) and their median HIV-1 RNA was 2.3 log10 copies/ml (IQR, 1.7–3.9 log10 copies/ml). There was a non-significant trend towards higher median CD4 cells count 3, 6 and 12 months after diagnosis of cryptococcosis in patients who interrupted maintenance therapy (data not shown). The median time between cryptococcosis diagnosis and first negative serum cryptococcal antigen was 23 months (IQR, 13–40 months) in patients whose maintenance therapy was subsequently interrupted and it was 22 months (IQR, 12–38 months) in those with sustained maintenance therapy.
Antifungal therapy was resumed for 14 patients, leaving 68/82 patients for whom it was definitively interrupted. Among the 68 patients who experienced prolonged interruption as compared to those 14, median time between diagnosis of cryptococcosis and withdrawal of maintenance therapy was 27 months (range, 0–65 months) and 9 months (range, 2–44 months), respectively (P < 0.01). Characteristics differed significantly between the two groups with more severe fungal and HIV infections in the latter: baseline median CD4 cell count was 304 cells/μl (range, 8–972 cells/μl) and 109 cells/μl (range, 12–345 cells/μl), median HIV-1 RNA was 2.3 log10 copies/ml (range, 1.3–5.6log10 copies/ml) and 4.5 log10 copies/ml (range, 1.5–5.7 log10 copies/ml) and median serum cryptococcal reciprocal antigen titre was 10 (range, 0–8000) and 1000 (range, 8–16 000), respectively. At the time maintenance therapy had to be resumed in the 14 patients (after a median of 8 months), median CD4 cell count was 84 cells/μl (range, 3–142 cells/μl) and median HIV-1 RNA was 4.9 log10 copies/ml (range, 2.1–6.5 log10 copies/ml).
Factors associated with cryptococcosis relapse during follow-up
Among the 189 patients followed at the cART era, 15 culture-confirmed relapses were diagnosed, by positive cerebrospinal fluid samples in 13 cases. These patients differed from non-relapsing patients only in terms of baseline CD4 cell count. It was lower in those with subsequent relapse: 7 cells/μl (range, 0–40 cells/μl) than in other patients: 21 cells/μl (range, 0–480 cells/μl) (P < 0.001). Among the 68 patients whose maintenance therapy was definitely stopped, no relapse was recorded, while three relapses were observed at 15, 46 and 15 months after the initial diagnosis of cryptococcosis among the 14 patients with a transient interruption of maintenance therapy, and 12 relapses were diagnosed among the 107 patients for whom prolonged antifungal maintenance therapy was prescribed. Inconstant compliance to cART was notified by 7/12 patients (58%) and to fluconazole in 8/12 patients (67%). Overall, for the 15 patients experiencing relapse, the median time between diagnosis of the first episode of cryptococcosis and relapse was 12 months (range, 3–46 months). At the time of relapse, median CD4 cell count was 11 cells/μl (range, 1–169 cells/μl) and median HIV-1 RNA 4.6 log10 copies/ml (range, 1.3–5.3 log10 copies/ml).
Thus, the average relapse rate was 4.6 per 100 person-years [95%confidenceinterval(CI),2.0–7.2] for patients who continued maintenance therapy and 0.9 per 100 person-years (95% CI, 0.0–2.0) in those for whom antifungal therapy was interrupted. Of note, the relapse rate in our pre-cART cohort was 7.6 per 100 person-years (95% CI, 3.7–11.4).
The mean increase in CD4 cell count (cells/μl; 95% CI) between baseline and 6 months was significantly higher in patients without subsequent relapse than in the 15 patients experiencing relapse: +78 (+63 to +93) versus 21 (−21 to +64), respectively (P = 0.01). This difference remained true after 24 months of follow-up +187 (+156 to +219) versus +74 (+8 to +140) (P = 0.004). In the multivariate analysis (n = 189), a latest CD4 cell count (time-dependent variable) < 100 cells/μl was associated with a higher rate of cryptococcosis relapse: hazard ratio (HR), 5.5 (95% CI, 1.3–22.2; P = 0.02), as was a duration of antifungal therapy < 3 months over the past 6 months: HR, 5.0 (95% CI, 1.1–22.3; P = 0.03) and a latest serum cryptococcal antigen titre ≥ 1/512 (time-dependent variable): HR, 3.5 (95% CI, 1.1–10.8; P = 0.03).
Negativation of serum cryptococcal antigen over time
The probability of reaching a negative serum cryptococcal antigen was 4.9% at 6 months of antifungal therapy, 12.4% at 12 months, 35.4% at 24 months and 70.5% at 48 months of antifungal therapy (Fig. 1). The evolution of CD4 cell count paralleled the probability of negative serum cryptococcal antigen curve while the curve of HIV-1 RNA followed an inverse shape. Among the 107 patients with sustained prescription of antifungal maintenance therapy, serum cryptococcal antigen became negative in 34% as compared to 50% in the group for which maintenance therapy was interrupted (P = 0.04). The probability of reaching a negative serum cryptococcal antigen according to baseline CD4 cell count, baseline HIV-1 RNA and initiation of cART is shown in Fig. 2. The lower the initial CD4 cell count, the lower the probability that the serum cryptococcal antigen will become negative during follow-up (Fig. 2a). The negativation of serum cryptococcal antigen occurred faster in antiretroviral-naive patients at baseline for whom HIV-1 RNA was the highest (Fig. 2b). Of note, CD4 cell count was the highest in the group of patients with baseline viral load > 5.5 log10 copies/ml.
Comparison of mortality rate depending on the period of diagnosis and withdrawal or not of maintenance antifungal therapy at the cART era
Patients studied in the cART era were older and had higher CD4 cell counts compared with those diagnosed during the historical period (data not shown). Of 240 patients 147 (61%) presented cryptococcosis revealing AIDS including 120 with cryptococcosis alone, 22 with an associated AIDS classifying disease and five with at least two other associated AIDS classifying diseases, while in the pre-cART era cryptococcosis revealed AIDS in 71/149 (48%). In recent years, cryptococcosis was more often disseminated (53% versus 30%; P < 0.0001) and meningitis more severe (33% versus 13%; P < 0.001) while the number of patients treated by antiretroviral agents was lower (36% versus 52%; P = 0.002) as compared to the historical group. When considering antifungal therapy administered in both periods, among 195 patients with meningitis at baseline, 31 (16%) received fluconazole alone and 56 patients (29%) received amphotericin B alone at the cART era. When considering pre-cART era, among the 120 patients with meningitis at baseline, 47 (39%) received fluconazole alone and 50 (42%) received amphotericin B alone.
The median duration of follow-up was 30 months (range, < 1–74 months) versus 11 months (range, < 1–101 months) in the cART and pre-cART periods, respectively. The average mortality rate per 100 person-years was 15.3 (95% CI, 12.2–18.4 per 100 person-years) in the cART era versus 63.8 (95% CI, 53.0–74.9 per 100 person-years) in the pre-cART era. The probability of death at 3 months was 18% (95% CI, 13–23%) and 21% (95% CI, 14–27%) in the cART and pre-cART periods, respectively (Fig. 3). Mortality curves diverged from 6 months onwards, probability of death at 6, 12, 24 and 48 months being 22%, 25%, 34% and 41% in the cART and 32%, 54%, 76% and 92% in the pre-cART periods, respectively. Deaths related to cryptococcosis were 43/131 (33%) in the pre-cART period and 36/94 (38%) in the cART period. Of 82 patients patients with interruption of maintenance therapy 69 (84%) were alive without relapse compared to 57/107 (53%) in the other group (P < 0.0001). In the multivariate analysis, prescription of cART was significantly associated with a longer survival (HR, 0.13; 95% CI, 0.06–0.25), after adjustment for CD4 cell count, age, HIV transmission category, AIDS stage, and baseline HIV RNA.
Basing our observations on a large number of HIV-infected patients followed long term, we first confirm that withdrawing maintenance antifungal therapy can be safely considered in patients with stable immune restoration. Secondly, we document determinants of cryptococcosis relapse and describe the evolution towards negative cryptococcal antigen during the cART era. Thirdly, we report dramatic changes in the long-term outcome, although short-term survival after the diagnosis of cryptococcosis in the cART era remained as high as in the pre-cART period .
The safety of interrupting chemoprophylaxis against various opportunistic infections in patients presenting stable immune restoration over time has frequently been documented [18,25–30]. Recommendations for HIV management have suggested similar conclusions for cryptococcosis when a sustained increase of CD4 lymphocyte count (i.e., > 100–200 cells/μl for ≥ 6 months) is reached [31,32] as documented by studies of limited sizes [15–17]. Kirk et al. showed no relapse among 39 patients with cryptococcosis whose maintenance therapy was stopped providing their CD4 cell counts were > 50 cells/μl . It was further confirmed in a randomized study including 42 patients who received 48 weeks of cART . Finally, an international observational study including patients with a CD4 cell count > 100 cells/μl reported four cryptococcosis relapses in patients with stable immune restoration . However, the alternative diagnosis of immune reconstitution inflammatory syndrome that can occur up to several months after cryptococcosis diagnosis was not excluded in three of four patients [33,34]. It is unlikely that a randomized trial will be designed given the very low rate of relapse. Thus, our report from a very large observational cohort represents the best current available data on the safety of stopping maintenance antifungal therapy.
No previous study at the cART era questioned the incidence and factors potentially associated with cryptococcal relapse. Here, we show that the relapse rate was very low, i.e., 0.9 per 100 person-years in those for whom antifungal therapy was interrupted. Based on extended follow-up of these patients, it is unlikely that this incidence of relapse is underestimated. Before the availability of cART, the estimated risk of cryptococcosis relapse in the absence of maintenance therapy was high, varying between 37% in a trial  and 50–60% in early retrospective studies [1,2]. In patients receiving daily fluconazole (100–200 mg/day) therapy, the risk varied between 2 and 4% in the literature [4,5,14] and 7.6 per 100 person-years in the present cohort. Thus, we observe here a lower risk of relapse than in the period when the best maintenance antifungal therapy was available but cART was not.
The influence of CD4 cell count on the subsequent risk of cryptococcosis relapse had not been previously documented [18–20]. Here, not only do we show that patients presenting subsequent microbiologically-confirmed relapse had a lower CD4 cell count at baseline but also that they experienced a less pronounced increase of CD4 cells during the first weeks of cART compared to patients who will not relapse. Thus, the nadir of CD4 cell count and the ability to obtain an early immune restoration significantly influence the risk of cryptococcosis relapse. Moreover, a CD4 cell count remaining < 100 cells/μl during follow-up was associated with a 5.5-fold rate of cryptococcosis relapse. We acknowledge that the cut-off for CD4 cell count was empirically estimated; nevertheless since our observation was retrospective and physicians based their decisions on no available recommendation, we believe that this might be an appropriate CD4 threshold for the decision to stop maintenance therapy. In addition, our data also suggest that clinicians should resume antifungal prophylaxis when the CD4 cell count is declining below 100 cells/μl. This emphasizes the need for careful clinical and immunological follow-up of patients for whom maintenance therapy is interrupted. Of particular importance, a serum cryptococcal antigen titre ≥ 1/512 at any time during follow-up was associated with a 3.5-fold rate of cryptococcosis relapse. In the pre-cART period, a lower initial serum cryptococcal antigen titre has been associated with a significantly lower risk of relapse . However, sequential monitoring was not classically recommended as there was no relationship with outcome [35,36]. Based on our results, monitoring cryptococcal antigen titres together with CD4 T-cell counts should help determine when to stop or to resume antifungal maintenance therapy.
Finally, another major finding disclosed here is the still high early mortality related to cryptococcosis in the period of cART as compared to an historical period despite published guidelines . Several factors might explain this observation. First, the population developing AIDS-associated cryptococcosis in Western countries has changed over time [12,13] and is diagnosed with more severe cryptococcosis as evidenced here. Second, all patients did not receive optimal therapy for cryptococcal meningitis, i.e., a combination of flucytosine and amphotericin B and management of elevated intracranial pressure-which are known to be a determinant of mycological success in patients with meningitis [37,38]. However, adjunctive therapy such as recombinant interferon-γ1b might contribute to improve the early outcome .
The dramatically improved long-term outcome and unchanged short-term evolution described here for cryptococcosis are in accordance with results reported for AIDS-associated tuberculosis  or severe Pneumocystis jiroveci pneumonia .
In conclusion, cART is associated with longer overall survival after AIDS-associated cryptococcosis. CD4 cell-count and serum cryptococcal antigen titre together with an antifungal therapy regimen should be recorded carefully during follow-up to identify patients at risk of cryptococcosis relapse.
We thank Dr Karine Sitbon and Cécile Droz for their excellent collaboration to the study; Ensemble contre le SIDA for their grant for the CryptoStop study and the fellowship for Dr Karine Sitbon and the excellent collaboration of the French Cryptococcosis Study Group including 84 clinical centers in France.
1. Chuck SL, Sande MA. Infections with Cryptococcus neoformans
in the acquired immunodeficiency syndrome. N Engl J Med 1989; 321:794–799.
2. Zuger A, Louie E, Holzman RS, Simberkoff MS, Rahal JJ. Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Diagnostic features and outcome of treatment. Ann Intern Med 1986; 104:234–240.
3. Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG, et al
. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000; 30:710–718.
4. Powderly WG, Saag MS, Cloud GA, Robinson P, Meyer RD, Jacobson JM, et al
. A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. N Engl J Med 1992; 326:793–798.
5. Saag MS, Cloud GA, Graybill JR, Sobel JD, Tuazon CU, Johnson PC, et al
. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. Clin Infect Dis 1999; 28:291–296.
6. Charlier C, Hart E, Lefort A, Ribaud P, Dromer F, Denning DW, et al
. Fluconazole for the management of invasive candidiasis: where do we stand after 15 years? J Antimicrob Chemother 2006; 57:384–410.
7. Maenza JR, Keruly JC, Moore RD, Chaisson RE, Merz WG, Gallant JE. Risk factors for fluconazole-resistant candidiasis in human immunodeficiency virus-infected patients. J Infect Dis 1996; 173:219–225.
8. Tansuphasawadikul S, Amornkul PN, Tanchanpong C, Limpakarnjanarat K, Kaewkungwal J, Likanonsakul S, et al
. Clinical presentation of hospitalized adult patients with HIV infection and AIDS in Bangkok, Thailand. J Acquir Immune Defic Syndr 1999; 21:326–332.
9. Hakim JG, Gangaidzo IT, Heyderman RS, Mielke J, Mushangi E, Taziwa A, et al
. Impact of HIV infection on meningitis in Harare, Zimbabwe: a prospective study of 406 predominantly adult patients. AIDS 2000; 14:1401–1407.
10. Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al
. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338:853–860.
11. Chen S, and the Australasian Society for Infectious Diseases (ASID) Mycoses Interest Group. Cryptococcosis in Australasia and the treatment of cryptococcal and other fungal infections with liposomal amphotericin B. J Antimicrob Chemother 2002; 49(Suppl S1):57–61.
12. Mirza SA, Phelan M, Rimland D, Graviss E, Hamill R, Brandt ME, et al
. The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas. Clin Infect Dis 2003; 36:789–794.
13. Dromer F, Mathoulin-Pelissier S, Fontanet A, Ronin O, Dupont B, Lortholary O, et al
. Epidemiology of HIV-associated cryptococcosis in France (1985–2001): comparison of the pre- and post-HAART eras. AIDS 2004; 18:555–562.
14. Bozzette SA, Larsen RA, Chiu J, Leal MAE, Jacobsen J, Rothman P, et al
. A placebo-controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal meningitis in the acquired immunodeficiency syndrome. N Engl J Med 1991; 324:580–584.
15. Martinez E, Garcia-Viejo MA, Marcos MA, Perez-Cuevas JB, Blanco JL, Mallolas J, et al
. Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy. AIDS 2000; 14:2615–2617.
16. Nwokolo NC, Fisher M, Gazzard BG, Nelson MR. Cessation of secondary prophylaxis in patients with cryptococcosis. AIDS 2001; 15:1438–1439.
17. Aberg JA, Price RW, Heeren DM, Bredt B. A pilot study of the discontinuation of antifungal therapy for disseminated cryptococcal disease in patients with acquired immunodeficiency syndrome, following immunologic response to antiretroviral therapy. J Infect Dis 2002; 185:1179–1182.
18. Kirk O, Reiss P, Uberti-Foppa C, Bickel M, Gerstoft J, Pradier C, et al
. Safe interruption of maintenance therapy against previous infection with four common HIV-associated opportunistic pathogens during potent antiretroviral therapy. Ann Intern Med 2002; 137:239–250.
19. Vibhagool A, Sungkanuparph S, Mootsikapun P, Chetchotisakd P, Tansuphaswaswadikul S, Bowonwatanuwong C, et al
. Discontinuation of secondary prophylaxis for cryptococcal meningitis in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy: a prospective, multicenter, randomized study. Clin Infect Dis 2003; 36:1329–1331.
20. Mussini C, Pezzotti P, Miro JM, Martinez E, de Quiros JC, Cinque P, et al
. Discontinuation of maintenance therapy for cryptococcal meningitis in patients with AIDS treated with highly active antiretroviral therapy: an international observational study. Clin Infect Dis 2004; 38:565–571.
21. Dromer F, Mathoulin S, Dupont B, Laporte A, the French Cryptococcosis Study Group. Epidemiology of cryptococcosis in France: 9-year survey (1985–1993). Clin Infect Dis 1996; 23:82–90.
22. Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, Sharkey PK, et al
. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. N Engl J Med 1992; 326:83–89.
23. Egger M, May M, Chene G, Phillips AN, Ledergerber B, Dabis F, et al
. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002; 360:119–129.
24. Lundgren JD, Mocroft A, Gatell JM, Ledergerber B, D'Arminio Monforte A, Hermans P, et al
. A clinically prognostic scoring system for patients receiving highly active antiretroviral therapy: results from the EuroSIDA study. J Infect Dis 2002; 185:178–187.
25. Furrer H, Egger M, Opravil M, Bernasconi E, Hirschel B, Battegay M, et al
. Discontinuation of primary prophylaxis against Pneumocystis carinii
pneumonia in HIV-1-infected adults treated with combination antiretroviral therapy. Swiss HIV Cohort Study. N Engl J Med 1999; 340:1301–1306.
26. Jouan M, Saves M, Tubiana R, Carcelain G, Cassoux N, Aubron-Olivier C, et al
. Discontinuation of maintenance therapy for cytomegalovirus retinitis in HIV-infected patients receiving highly active antiretroviral therapy. AIDS 2001; 15:23–31.
27. Zeller V, Truffot C, Agher R, Bossi P, Tubiana R, Caumes E, et al
. Discontinuation of secondary prophylaxis against disseminated Mycobacterium avium
complex infection and toxoplasmic encephalitis. Clin Infect Dis 2002; 34:662–667.
28. Furrer H, Telenti A, Rossi M, Ledergerber B. Discontinuing or withholding primary prophylaxis against Mycobacterium avium
in patients on successful antiretroviral combination therapy. The Swiss HIV Cohort Study. AIDS 2000; 14:1409–1412.
29. Mussini C, Pezzotti P, Govoni A, Borghi V, Antinori A, d'Arminio Monforte A, et al
. Discontinuation of primary prophylaxis for Pneumocystis carinii
pneumonia and toxoplasmic encephalitis in human immunodeficiency virus type I-infected patients: the changes in opportunistic prophylaxis study. J Infect Dis 2000; 181:1635–1642.
30. Ledergerber B, Mocroft A, Reiss P, Furrer H, Kirk O, Bickel M, et al
. Discontinuation of secondary prophylaxis against Pneumocystis carinii
pneumonia in patients with HIV infection who have a response to antiretroviral therapy. Eight European Study Groups. N Engl J Med 2001; 344:168–174.
31. Masur H, Kaplan JE, Holmes KK. Guidelines for preventing opportunistic infections among HIV-infected persons—2002. Recommendations of the U S Public Health Service and the Infectious Diseases Society of America. Ann Intern Med 2002; 137:435–478.
32. Delfraissy JF. Prise en charge thérapeutique des personnes infectées par le VIH
. Paris: Flammarion, Medecine-Sciences; 2004. 280 pp.
33. Shelburne SA, Visnegarwala F, Darcourt J, Graviss EA, Giordano TP, White AC Jr, et al
. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005; 19:399–406.
34. Lortholary O, Fontanet A, Memain N, Martin A, Sitbon K, Dromer F. Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS 2005; 19:1043–1049.
35. Powderly WG, Cloud GA, Dismukes WE, Saag MS. Measurement of cryptococcal antigen in serum and cerebrospinal fluid: value in the management of AIDS-associated cryptococcal meningitis. Clin Infect Dis 1994; 18:789–792.
36. Aberg JA, Watson J, Segal M, Chang LW. Clinical utility of monitoring serum cryptococcal antigen (sCRAG) titers in patients with AIDS-related cryptococcal disease. HIV Clin Trials 2000; 1:1–6.
37. van der Horst CM, Saag MS, Cloud GA, Hamill RJ, Graybill JR, Sobel JD, et al
. Treatment of cryptococcal meningitis associated with acquired immunodeficiency syndrome. N Engl J Med 1997; 337:15–21.
38. Graybill JR, Sobel J, Saag M, van der Horst C, Powderly W, Cloud G, et al
. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. Clin Infect Dis 2000; 30:47–54.
39. Pappas PG, Bustamante B, Ticona E, Hamill RJ, Johnson PC, Reboli A, et al
. Recombinant interferon-gamma 1b as adjunctive therapy for AIDS-related acute cryptococcal meningitis. J Infect Dis 2004; 189:2185–2191.
40. Dheda K, Lampe FC, Johnson MA, Lipman MC. Outcome of HIV-associated tuberculosis in the era of highly active antiretroviral therapy. J Infect Dis 2004; 190:1670–1676.
41. Morris A, Wachter RM, Luce J, Turner J, Huang L. Improved survival with highly active antiretroviral therapy in HIV-infected patients with severe Pneumocystis carinii
pneumonia. AIDS 2003; 17:73–80.
The following members of the French Cryptococcosis Study Group enrolled patients in the present study and collected clinical data (by alphabetical order of the cities):
C. de Roux Serratrice, T. Bensaid: Aix en Provence; J.L. Schmitt, C. Raccurt: Amiens; E. Pichard, J.P. Bouchara: Angers; C. Michon, S. Blanc: Annecy; J.F. Dor, V. Blanc: Antibes; A. de la Blanchardière, H. Lefranc: Avignon; X. Lionet, F. Leturdu: Argenteuil; M. Ferrand, X. Larrouy: Bayonne; C. Drobacheff, L. Million: Besançon; O. Lortholary, C. Bouges Michel: Bobigny; J.F. Viallard, Bernard Couprie: Hôpital Haut Leveque, J.M. Ragnaud, B. Couprie, Hôpital Pellegrin, J. Beylot, B. Couprie, Hôpital St André – Bordeaux; E. Rouveix, M.E. Bougnoux: Boulogne; N. Canu, F. Laurent: Bourg en Bresse; J. Julien, M. Gavignet: Bourges; L. de St Martin, E. Moalic: Brest; S. Lefort, Brive; J.M. Korach, D. Toubas: Chalon en Champagne; B. Salles, C. Sire: Chalon sur Saone; C. Jacomet, M. Cambon: Clermont Ferrand; E. Mortier, M.L. Joly Guillou: Colombes; V. Garait, X. Fauchet, Centre hospitalier intercommunal, A.S. Lascaut, Stéphane Bretagne: Hôpital Henri Mondor – Creteil; R. Verdon: Caen; M. Duong, A. Bonnin: Dijon; A. Devidas, C. Malbrunot: Corbeil; P. de Truchis, J.L. Gaillard: Garches; J.P. Stahl, B. Lebeau, Grenoble; Y. Quertainmont, F. Botterel: Kremlin Bicêtre; I. Rivoal, M.A. de Sailly: La Roche sur Yon; J.P. Bedos, O. Eloy: Le Chesnay; P. Weinbreck, M.L. Darde: Limoges; A. Boibieux, M.A. Piens: Hôpital de la Croix Rousse, P. Mialhes, M.A. Piens: Hôpital Hôtel Dieu, C. Jourdan, M.A. Piens: Hôpital Wertheimer, M. Bret, M.A. Piens: Hôpital Edouard Herriot – Lyon; H. Tissot Dupont, A. Blancard: Hôpital de la Conception, N. Petit, A. Michel Nguyen: Hôpital Ste Marguerite – Marseille; M. Nezri, M. Bietrix: Martigues; Y. la Torre, C. Chandesris: Montargis; X. Kabbani, Montfermeil; V. le Moing, P. Rispail: Montpellier; C. Rabaud, M. Biava: Nancy; E. Billaud, O. Morin: Nantes; P. Del Giudice, M. Gari Toussaint: Fréjus; P. Dellamonica, E. Rosenthal, M. Garit Toussaint: Nice; T. Prazuck, D.M. Poisson: Orléans; J.L. Vildé, P. Yéni, O. Bouchaud, V. Descamps, C. Chochillon: Hôpital Bichat, C. Piketty, V. Lavarde: Hôpital Georges Pompidou, D. Salmon, N. Franck, A. Paugam: Hôpital Cochin, A. Compagnucci, M. Cornet: Hôtel Dieu, L. Bodard, Y. Péan: Institut Mutualiste Monsouris, C. le Maignan, V. Lavarde: Hôpital Laennec, J.P. Viard, L. Roudière, S. Challier: Hôpital Necker-Enfants malades, B. Dupont, F. Dromer: Hôpital de l'Institut Pasteur, V. Zeller, A. Datry: Hôpital Pitié Salpétrière, G. Pialoux, J.L. Poirot: Hôpital Rothschild, M.C. Meyohas, E. Frajdenrach, P. Roux: Hôpital St Antoine, J. Gilquin, A. Marmorat: Hôpital St Joseph, S. Neuville, C. Lacroix: Hôpital St Louis, I. Lecomte, P. Roux: Hôpital Tenon – Paris; G. Le Moal, C. Kaufman-Lacroix: Poitiers; C. Arvieux, S. Chevrier: Rennes; P. Aboud, L. Favennec, Hôpital Charles Nicolle, D. Benhamou, L. Favennec: Hôpital Bois Guillaume – Rouen; M.A. Khuong, N. Godineau: St Denis; T. Debord: St Mandé; B. Héry, O. Morin: St Nazaire; X. Line, X. Fiacre, Soissons; X. Martinot, J.M. Lang, J. Waller: Strasbourg; S. Chadapaud, A. Blancard: Hôpital Chalucet, J.P de Jaureguyberry, A. Blancard: Hôpital St Anne – Toulon; M. Alvarez, M.D. Linas: Toulouse; Y. Yazdanpanah, X. de Keyser: Tourcoing; D. Vittecoq, F. Botterel: Villejuif; S. Dellion, J. Breuil: Villeneuve St Georges, France.
cryptococcosis; c-ART; immune restoration; outcome; survival; polysaccharide
© 2006 Lippincott Williams & Wilkins, Inc.
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