Cryptococcus belongs to the phylum Basidiomycetes, which is classified under the kingdom Fungi. Cryptococcus is widely distributed in nature and has a spherical or oval cell wall surrounded by a capsule. Cryptococcus includes more than 30 species; however, two main species complexes cause diseases in humans: Cryptococcus neoformans and Cryptococcus gattii (Ferry et al., 2015; May et al., 2016; Soare et al., 2019). Cryptococcus neoformans is the primary etiological agent of cryptococcal disease and a leading cause of AIDS-related infection (World Health Organization, 2018; Rajasingham et al., 2022). Cryptococcus is usually transmitted through the inhalation of fungal spores and can colonize the human respiratory tract. The inhaled Cryptococcus spores or yeast cells may be cleared by the host or enter a latent phase. Once the immune system is weakened, Cryptococcus may activate, proliferate, and spread through the blood to other organs in the body. The interaction between Cryptococcus and the host’s immune response is complicated. In addition, the mechanism of recognition of Cryptococcus by the immune system and the activation and effects of the immune response on the fungus are not completely clear.

Due to its neurophilic nature, Cryptococcus is more likely to break through the blood–brain barrier than other pathogens (Silva et al., 2020; Chen et al., 2022; Hamed et al., 2023), eventually leading to cryptococcal meningitis, which can be fatal if untreated. Despite the increasing efforts to expand access to antiretroviral therapy (ART) in recent years, the incidence of cryptococcal meningitis in HIV-infected patients has not significantly declined (Hevey et al., 2019; Dantas et al., 2023). Cryptococcal infection in HIV-infected patients should be viewed as a major health concern because of its clinically challenging nature, widespread incidence, and high morbidity and mortality rates. Extensive research and focused education regarding its management are essential for improved patient outcomes (Ndlovu et al., 2020; Sun et al., 2020; Chang et al., 2024). Therefore, we conducted the present study to investigate the clinical features and prognostic factors of cryptococcal infections in HIV-infected patients.

Cryptococcus neoformans was ranked the first fungus of concern in the critical priority group in the Priority List of Pathogenic Fungi published by the WHO (World Health Organization, 2022). Cryptococcus neoformans is highly likely to cause invasive infections in individuals with impaired immune function, especially HIV-infected individuals. Cryptococcus neoformans is neurophilic, and cryptococcal meningitis is common after infection. The mortality rate of cryptococcal meningitis in low-and middle-income countries can be as high as 70% (Skipper et al., 2022). The number of people infected with HIV in China has been increasing every year (Nation Health Commission of China, 2023). Although antiretroviral treatment regimens can improve the quality of life of patients with HIV infection, no complete cure for AIDS has been discovered yet. The diagnosis and treatment of HIV infection combined with cryptococcal infection in clinical practice is challenging. Thus, the clinical characteristics and related prognostic factors of HIV infection combined with cryptococcal infection require further investigation to facilitate the improvement of management and patient outcomes. The present study was conducted to advance our understanding of HIV infection complicated with cryptococcal infection and provide valuable information that can optimize its management.

We retrospectively analyzed the case data and relevant laboratory test results of patients with HIV infection complicated with cryptococcal infections between 2013 and 2023. The results showed that most of the patients were middle-aged and young men. The peak age range for HIV infection combined with cryptococcal infection was 31 to 40 years, which is slightly different from the 31-50 years peak age range for HIV infection reported in previous studies (Oliveira et al., 2023). Data analysis showed that the proportion of patients living in urban areas was slightly higher than that of patients living in rural areas. Moreover, patients living in urban areas had better prognoses than those from rural areas. This may be attributed to the fact that patients living in urban areas have access to better medical resources, making the diagnosis and treatment of diseases easier. This suggests that the medical environment affects patient prognosis, and that high-quality medical resources are beneficial for disease diagnosis and treatment, which is consistent with the findings of other studies (Klein et al., 2020). Classification of the patients according to the occupational background revealed that patients with higher education levels and stable jobs had lower mortality rates than those with lower education levels and no stable job. Education level affects a patient’s understanding and prognosis of the disease. Regarding the rout of infection, most patients in our study cohort did not indicate the source of infection, and those who provided the information reported that homosexual behavior was the main route of HIV infection. HIV-positive individuals often conceal their identities, which makes them susceptible to being invisible disease carriers. Multivariate regression analysis showed that the duration of HIV infection was an independent risk factor for the 3-month prognosis of HIV infection complicated with cryptococcal infection. The results also showed that the shorter the duration of HIV infection, the better the prognosis. China is a populous country among developing countries, and the distribution of medical resources is still uneven. Most of the populace are still low-income earners, and the overall perception of HIV infection still needs to be improved. Based on the current status and epidemic trends of HIV infection, it is important to educate the general public on prevention of HIV infection. Improving public awareness of HIV infection can promote its prevention and treatment.

In the present study, approximately 70% of the patients diagnosed with HIV infection were infected with Cryptococcus within 3 months. Of these, 79% had a CD4 cell count lower than 50 cells/µL, indicating that most of the patients may have had latent Cryptococcus colonization; thus, Cryptococcus was activated once the immune system was weakened (Lazera et al., 2000). In addition, 95% (74/76) of the patients were diagnosed with cryptococcal meningitis, with fever and headache as the first symptoms. Regarding laboratory test results, 93%, 88%, and 24% of the patients had positive Cryptococcus culture in CSF, blood, and both CSF and blood samples, respectively. This finding supports the neurotropism of Cryptococcus, which easily breaks through the blood–brain barrier and causes brain infection after entering the blood. Regarding methods used for the detection of Cryptococcus, culture and cryptococcal antigen (CrAg) detection has a high positive rate and good consistency rate, whereas the traditional India ink staining method has a relatively low positive rate owing to the method being personnel-dependent. The CrAg test is simple, rapid, and highly accurate for screening cryptococcal infections and is very helpful for timely clinical diagnosis.

The mortality rate of HIV-related cryptococcal meningitis higher than 15%, even with access to sufficient medical resources (Skipper et al., 2019; Rajasingham et al., 2022; Boulware and Jarvis, 2023). Early initiation of ART can quickly restore immune function in immunosuppressed patients, eliminate Cryptococcus, and prevent other fatal opportunistic infections. However, if ART is initiated while a patient has a cryptococcal infection, it is necessary to balance its benefits with the risk of immune reconstitution inflammatory syndrome (IRIS) (Boulware et al., 2010). The findings of the final COAT trial led by Boulware, which were included in the guidelines for Diagnosing, Preventing and Managing Cryptococcal Disease Among Adults, Adolescents and Children Living with HIV approved by WHO, showed that early initiation of ART is associated with an absolute mortality rate 15% higher than that for delayed initiation of ART (Boulware et al., 2014); however, this trial was conducted in Africa, and the patient population is different from those in high-income regions. To gain a deeper understanding of the impact of timing of ART, Ingle led a study based on three US/European cohorts and found that early initiation of ART did not significantly increase mortality in high-income areas (Boulware and Jarvis, 2023). These findings indicate that the optimal time for initiation of ART for cryptococcal meningitis in HIV-infected individuals remains controversial. In addition, whether further clinical trials are needed and whether the guidelines should be changed and refined are still debatable. In the present study, cryptococcal infection was used as the observation point for timing of ART initiation, and the results showed that patients who initiated ART within 4-6 weeks of starting treatment for cryptococcal infection had a lower mortality rate at 3 months than those who initiated ART at other timepoints. This is slightly different from the general guideline that recommends initiation of ART after 4-6 weeks of antifungal therapy for cryptococcal coinfection; notably, this recommendation does not include a specific time interval. Patients who initiated ART more than 6 weeks after the start of treatment for cryptococcal infection showed lower mortality rates at 6 and 9 months than those who initiated ART at other timepoints. Patients who initiated ART within 4 weeks of starting cryptococcal therapy showed lower mortality at 12 months than those who initiated ART at other timepoints. Our study provides reference for the selection of ART therapy timing for HIV/AIDS patients with cryptococcal infection, and provides a basis for the revision of treatment guidelines for HIV/AIDS patients with cryptococcal infection.

In addition, when HIV infection was used as the observation point for initiation of ART, time of ART initiation was found to be an independent risk factor for Cryptococcus infection in HIV-infected patients at 3, 6, 9, and 12 months. The later the initiation of ART after HIV infection, the worse the prognosis. Although it is necessary to balance the benefits of ART in patients with HIV and cryptococcal infections with the risks of IRIS, the results of the present study suggest that HIV-infected individuals should not start ART too late, even if they have cryptococcal infection. Starting ART within 6 months of HIV infection is associated with a better prognosis than starting it later or not starting it at all, implying that the earlier ART is administered after HIV infection, the better the overall survival. The present study provides data regarding the timing of ART treatment in real-world settings and a reference for the determination of ART timing guidelines. However, further research is necessary to determine the optimal timing of ART initiation. The limitation of this study include it is an observational design, insufficient sample size, not long enough follow-up time, potential biases and limited data. In the future, the study cohort can be further expanded by increasing observation cases, monitoring indicators, and follow-up time to obtain more comprehensive and in-depth studies.

HIV-infection complicated with cryptococcal infection is a critical case with a median survival time of less than 1 year. This study demonstrated that ART is a key factor that affects the prognosis of such cases. Specifically, the results indicated that the later ART after HIV infection is started, the worse the prognosis of cryptococcal infection in HIV-infected patients. The time of ART initiation and the timing of treatment for cryptococcal infections should be further refined and balanced based on different clinical courses. Clinicians should pay closer attention to cryptococcal infection in patients with HIV infection and actively initiate ART and other appropriate measures based on each patient’s clinical condition.