An Association of Cryptococcus Neoformans/C. gattii Genotype and HIV Status in Asia: A Systematic Review

Abstract

Objective: It has been known that VNI molecular type of Cryptococcus neoformans/C. gattii is strongly associated with HIV patients. However, this paradigm has recently been challenged because of the high prevalence of VNI molecular type among non-HIV patients with cryptococcosis in East Asia. The purpose of this study was to answer the question: "Among cryptococcosis in Asia, is there an association between the genotype and the patient's HIV status?" Methods: Using a systematic review and meta-analysis study design, we included all relevant published data, which were any type of study designs, mainly studied clinical Cryptococcus neoformans/C. gattii strains isolated in Asia and had available molecular typing data. The primary study variables were Cryptococcus neoformans molecular type (VNI/non-VNI or ST5/non-ST5) and the HIV status of the patients at the time of diagnosis. We used a randomeffects meta-analysis model to estimate the prevalence of HIV infection. Results: Sixteen retrospective descriptive studies during 2005-2018 (1,584 isolates) were included. Most of the cryptococcosis cases in East Asian countries were in non-HIV patients (72.4-81.8%), which differed from non-East Asian countries (2.6-28.3% associated with non-HIV patients). In East Asia, the HIV prevalence among VNI and ST5 infected patients ranged from 7.5%-46.7% with the pooled prevalence of 19.8% (95% CI, 12.2%-30.4%) and 5.3%-52.4% with the pooled prevalence of 19.9% (95% CI, 6.9%-45.3%), respectively. In non-East Asia, the HIV prevalence among VNI and ST5 infected patients ranged from 48.3%-98.8% with the pooled prevalence of 81.9% (95% CI, 73.3%-88.2%) and 52.3%-88.0% with the pooled prevalence of 74.9% (95% CI, 40.7%-92.8%), respectively. Statistical heterogeneity was high in both analyses with the I 2 of 79-89% in all analyses. Conclusion: Our results confirmed the low prevalence of HIV prevalence among VNI and ST5 strains in East Asian countries. The emergence of high virulence genotype causing disease in non-HIV patient is highly unlikely, because the VNI and ST5 were associated with HIV patients in other Asian countries. It can be hypothesized that the low HIV prevalence among VNI and ST5 strains in East Asian is due to the high susceptibility to cryptococcosis of people living in this region. This requires further investigation.

Population diversity and virulence characteristics of Cryptococcus neoformans/C. gattii species complexes isolated during the pre-HIV-pandemic era

“…Further genotype analysis of C. neoformans by MLST showed that ST5/VNI was the most common genotype (43/164 isolates; 26.2%) among the clinical isolates of C. neoformans. This result is similar to the findings of a recent systematic review of Asian cryptococcosis in which ST5/VNI was reported to be the most common genotype among non-HIV patients in both East Asian (87.9%) and other Asian (39.3%) countries [52]. Our findings is also similar to what has been reported for Vietnam (83.7%) [47] and Laos (25%) [53].…”

“…Three other common genotypes-namely, ST2/VNI (13.2%), ST63/VNI (9.8%), and ST40/VNII (9.8%)-were reported in Asia, Africa, Europe, and the United States [4,10,11,23,54]. Interestingly, the most common genotype among the environmental isolates, ST4/VNI (25%), was also the most common (32.6%) sequence type isolated from HIV patients outside of the East Asian countries [52]. This result concurs with the proposal that HIV patients contracted cryptococcosis from their environment as the diversity of the genotypes in the environment is reflected in the clinical isolates [55].…”