Cryptococcus neoformans population diversity and clinical outcomes of HIV-associated cryptococcal meningitis patients in Zimbabwe

Abstract

HIV and cryptococcal meningitis co-infection is a major public health problem in most developing countries. Cryptococcus neoformans sensu stricto is responsible for the majority of HIV-associated cryptococcosis cases in sub-Saharan Africa. Despite the available information, little is known about cryptococcal population diversity and its association with clinical outcomes in patients with HIV-associated cryptococcal meningitis in sub-Saharan Africa. In a prospective cohort, we investigated the prevalence and clinical outcome of Cryptococcusneoformans sensu stricto meningitis among HIV-infected patients in Harare, Zimbabwe, and compared the genotypic diversity of the isolates with those collected from other parts of Africa. Molecular typing was done using amplified fragment length polymorphism genotyping and microsatellite typing. The majority of patients with HIV-associated Cryptococcusneoformans sensu stricto meningitis in this cohort were males (n=33/55; 60.0 %). The predominant Cryptococcus neoformans sensu stricto genotype among the Zimbabwean isolates was genotype AFLP1/VNI (n=40; 72.7 %), followed by AFLP1A/VNB/VNII (n=8; 14.6 %), and AFLP1B/VNII was the least isolated (n=7; 12.7 %). Most of the isolates were mating-type α (n=51; 92.7 %), and only four (7.3 %) were mating-type a. Overall in-hospital mortality was 55.6 % (n=30), and no difference between infecting genotype and clinical outcome of patient (P=0.73) or CD4+ counts (P=0.79) was observed. Zimbabwean Cryptococcusneoformans sensu stricto genotypes demonstrated a high level of genetic diversity by microsatellite typing, and 51 genotypes within the main molecular types AFLP1/VNI, AFLP1A/VNB/VNII and AFLP1B/VNII were identified. This study demonstrates that Cryptococcusneoformans sensu stricto in Zimbabwe has a high level of genetic diversity when compared to other regional isolates.

The Mouse Inhalation Model of Cryptococcus neoformans Infection Recapitulates Strain Virulence in Humans and Shows that Closely Related Strains Can Possess Differential Virulence

“…neoformans isolates with the same sequence type were observed in patients who lived and patients who died. The association between clinical outcome and the C. neoformans MLST-based sequence type (ST) is controversial, with some studies showing differences in patient clinical outcomes associated with specific sequence types and others showing no association (5,(7)(8)(9)12). To explore this phenomenon, we examined individual patient mortality in HIV-infected cryptococcal meningitis participants enrolled in the Cryptococcal Optimal ART Timing (COAT) clinical trial who were infected with C. neoformans strains of the same sequence type (Fig.…”

The antifungal pipeline: a reality check

“…These weaknesses are clearly emphasized by the mortality rates attributable to invasive mycoses, which remain substantial. For instance, in invasive candidiasis, the mortality rate has been estimated to be around 40% 23 ; the mortality rate among individuals with disseminated cryptococcosis is 20–30% in well-resourced health-care systems 24 , and this rate is substantially higher in resource-limited areas (50% or greater) 25 . By contrast, the mortality rate among individuals with invasive aspergillosis has been reduced over the past decade but has now plateaued at approximately 20% 26 .…”

Mortality from HIV‐associated meningitis in sub‐Saharan Africa: a systematic review and meta‐analysis

“…In 10% (4/41) of included studies, the period of observation began prior to 2000. Seventeen countries were represented, with greatest representation from South Africa (14 studies) [34,[37][38][39][40][41][42][43][44][45][46][47][48][49], Ethiopia (three studies) [50][51][52] and Uganda (three studies) [53][54][55]; other countries had two or fewer studies [11,35,36,[56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74]. Amphotericin B-based induction therapy (with or without fluconazole) was the predominant induction regimen in 16 studies, fluconazole in 13 studies, and a mix of treatments (45% fluconazole and 43% amphotericin B) in one study [44], with antifungal regimens not specified in 11 studies.…”