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To the Editor: Isolated cryptococcal antigenemia (ICA) is defined as the presence of cryptococcal antigen (CrAg) in the blood in the absence of clinical or radiological evidence of cryptococcal infection in target organs.[1–3] ICA is an established predictor of cryptococcal meningitis (CM) and mortality among patients infected with human immunodeficiency virus (HIV), underscoring the importance of timely preemptive antifungal treatment.[1–3] However, real-world data on the prevalence of ICA and the use of preemptive fluconazole treatment in China remain limited. This multicenter retrospective cohort study included 14,678 HIV-infected patients from eight tertiary hospitals across China who underwent CrAg testing between January 2019 and December 2022. Patients with confirmed cryptococcal infections (CM, cryptococcemia, and pulmonary cryptococcosis) or incomplete data were excluded. ICA was defined as CrAg positivity in the absence of organ involvement. Patients with at least 1 year of follow-up (n = 123) were stratified into preemptive fluconazole treatment (n = 81) and nontreatment (n = 42) groups. Among those treated, 32 patients received preemptive fluconazole treatment according to the 2018 World Health Organization’s (WHO’s) guidelines (800 mg/day for 2 weeks, followed by consolidation and maintenance therapy),[4] whereas 49 received oral fluconazole 400 mg/day for 1 year. We evaluated the prevalence of ICA and the cumulative incidence of CM and/or death at the 1-year follow-up point. Secondary outcomes included: time to CM and/or death, CrAg clearance within 1 year, time from CrAg positivity to negativity, and adverse events. Cox regression analyses were adjusted for age, sex, and CD4+ T-cell counts. This study was approved by the Ethics Committee of Chongqing Public Health Medical Center (Approval No. KY202201504). The requirement for written informed consent was waived by the institutional review board due to the retrospective nature of the study, and all patient data were analyzed anonymously. A total of 10,649 patients were included in the prevalence analysis after excluding 4029 patients due to age <18 years (n = 21), confirmed cryptococcal disease (CM [n = 369], pulmonary cryptococcosis [n = 101], and cryptococcemia [n = 67]), or incomplete clinical data (n = 3471). [Supplementary Figure 1A, https://links.lww.com/CM9/C753]. Of these, 433 tested CrAg positive, yielding an overall ICA prevalence of 4.1% (433/10,649, 95% confidence interval [CI]: 3.7%–4.5%) among the patients infected with HIV. ICA prevalence increased with immunosuppression: 5.2% (247/4750) in patients with CD4+ <200 cells/μL, 6.6% (230/3495) in patients with CD4+ <100 cells/μL, and 7.3% (180/2477) in patients with CD4+ ≤50 cells/μL. Notably, ICA was also observed in patients with CD4+ counts from 201 to 500/μL (0.4%), supporting potential benefit from broader CrAg screening strategies beyond just those with severe immunosuppression [Supplementary Table 1, https://links.lww.com/CM9/C753]. Of the 433 HIV/ICA patients, 310 were excluded for inadequate follow-up. The remaining 123 were included in the treatment outcome analysis [Supplementary Figure 1B, https://links.lww.com/CM9/C753]. The cohort was predominantly male (82.9% [102/123]), with a median age of 46 years (interquartile range [IQR]: 34–55) and a median CD4+ T-cell count of 41 cells/μL (IQR: 19–83 cells/μL). In addition, 31.7% (39/123) patients had two or more concurrent opportunistic infections, excluding ICA [Supplementary Table 2, https://links.lww.com/CM9/C753]. Among the 123 patients, 81 received preemptive fluconazole treatment, whereas the remaining 42 patients did not receive treatment because of concerns regarding adverse effects, pill burden, potential drug–drug interactions, or financial barriers. Baseline characteristics were comparable between the treatment and non-treatment groups. [Supplementary Table 3, https://links.lww.com/CM9/C753]. CM and/or death occurred in 19.0% (8/42) of patients who did not receive preemptive fluconazole, compared with 8.6% (7/81) in those who received treatment. Kaplan–Meier analysis demonstrated a trend toward lower cumulative event-free survival in the untreated group (log-rank P = 0.072; Figure 1). In Cox proportional hazards regression analysis adjusted for age, sex, and CD4+ T-cell count, absence of preemptive fluconazole treatment was associated with a threefold higher risk of CM and/or death (aHR = 3.035, 95% CI 1.067–8.635; P = 0.037). CrAg clearance within 1 year was significantly more frequent in the treatment group than in the nontreatment group (72.6% [53/73] vs. 44.1% [15/34]; P = 0.004). The median time to CM and/or death was also longer in treated patients (32.0 days, IQR: 22.0–56.0 days) compared to untreated patients (7.0 days, IQR: 5.0–20.5 days; P = 0.009).Figure 1: Cumulative survival rate without CM and/or death in 123 HIV/ICA patients with or without preemptive fluconazole treatment within 1-year follow-up. CM: Cryptococcal meningitis; ICA: Isolated cryptococcal antigenemia.Subgroup analysis revealed no significant differences between the WHO-recommended regimens and the non-WHO-recommended regimens in terms of CM and/or death (9.4% [3/32] vs. 8.7% [4/49]; aHR = 0.854, 95% CI: 0.191–3.824; P = 0.836) [Supplementary Figure 2, https://links.lww.com/CM9/C753], CrAg clearance rates (60.0% vs. 54.5%; P = 0.779), or median time to CrAg negativity (both 14 days; P = 1.000). Adverse events (grade ≥3) occurred in 30.9% (25/81) of treated patients, 28.1% (9/32) in the WHO-recommended regimens and 32.7% (16/49) in the non-WHO-recommended regimens (P = 0.429) [Supplementary Table 4, https://links.lww.com/CM9/C753]. All adverse events resolved with supportive care, and no patients discontinued treatment. This study demonstrates a relatively high ICA prevalence (4.1%) among Chinese patients who were infected with HIV, surpassing rates reported in other countries despite comparable CD4+ distributions.[1–3] This may reflect differences in environmental exposure, diagnostic practices, or healthcare access.[5] The steep rise in ICA prevalence with lower CD4+ T-cell counts supports WHO CrAg screening guidelines for advanced HIV disease.[3] Importantly, untreated patients with HIV/ICA had a threefold higher risk of CM and/or death, reinforcing ICA as a key clinical marker in HIV care. Although our findings are consistent with African data showing 20–30% mortality reduction with preemptive fluconazole, the residual 8.6% event rate in treated individuals suggests room for improvement, perhaps via earlier drug initiation, enhancement of central nervous system penetration, or augmented resistance surveillance.[5] Notably, the 400 mg/day fluconazole regimen achieved outcomes comparable with the WHO-recommended regimen, possibly due to pharmacokinetic differences inherent to the Chinese population (e.g., lower body weight and increased drug exposure). However, the high rate of severe adverse events emphasizes the need for close monitoring, especially in settings with limited laboratory access. This study’s limitations include its retrospective design, potential selection bias due to follow-up loss, and a relatively small sample size for treatment efficacy analysis. Future prospective studies should aim to optimize antifungal dosing strategies, monitor emerging antifungal resistance, and expand CrAg screening, particularly among the aging HIV population in China with advanced immunosuppression. In conclusion, ICA prevalence in Chinese HIV-infected patients exceeds the 3% threshold, indicating a substantial endemic burden. Preemptive fluconazole therapy significantly reduces CM and mortality risk, underscoring the urgent need to integrate CrAg screening and antifungal prophylaxis into routine HIV care for individuals with advanced immunosuppression in China. Funding This study was supported by grants from Prevention and Control of Emerging and Major Infectious Diseases-National Science and Technology Major Project (No. 2025ZD01904904), the Chongqing Medical Scientific Research Project (Joint Project of Chongqing Health Commission and Science and Technology Bureau) (No. 2026DBXM001), the Chongqing AIDS Medical Research Center Construction Program, and the Chongqing Public Health Key Disciplines Construction Program. Conflicts of interest None.