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Cryptococcal meningitis is the second most common cause of death in people living with HIV/AIDS, yet we have a limited understanding of how cryptococcal isolates change over the course of infection. Cryptococcal infections are environmentally acquired, and the genetic diversity of these infecting isolates can also be geographically linked. Here, we employ whole genome sequences for 372 clinical Cryptococcus isolates from 341 patients with HIV-associated cryptococcal meningitis obtained via a large clinical trial, across both Malawi and Cameroon, to enable population genetic comparisons of isolates between countries. We see that isolates from Cameroon are highly clonal, when compared to those from Malawi, with differential rates of disruptive variants in genes with roles in DNA binding and energy use. For a subset of patients (22) from Cameroon, we leverage longitudinal sampling, with samples taken at days 7 and 14 post-enrollment, to interrogate the genetic changes that arise over the course of infection, and the genetic diversity of isolates within patients. We see disruptive variants arising over the course of infection in several genes, including the phagocytosis-regulating transcription factor GAT204. In addition, in 13% of patients sampled longitudinally, we see evidence for mixed infections. This approach identifies geographically linked genetic variation, signatures of microevolution, and evidence for mixed infections across a clinical cohort of patients affected by cryptococcal meningitis in Central Africa. [ABSTRACT FROM AUTHOR]

Background An increasing proportion of patients with HIV-associated cryptococcal meningitis have received antiretroviral therapy (ART) before presentation. There is some evidence suggesting an increased 2-week mortality in those receiving ART for <14 days compared with those on ART for >14 days. However, presentation and outcomes for cryptococcal meningitis patients who have recently initiated ART, and those with virologic failure and/or nonadherence, are not well described. Methods Six hundred seventy-eight adults with a first episode of cryptococcal meningitis recruited into a randomized, noninferiority, multicenter phase 3 trial in 4 Sub-Saharan countries were analyzed to compare clinical presentation and 2- and 10-week mortality outcomes between ART-naïve and -experienced patients and between patients receiving ART for varying durations before presentation. Results Over half (56%; 381/678) the study participants diagnosed with a first episode of cryptococcal meningitis were ART-experienced. All-cause mortality was similar at 2 weeks (17% vs 20%; hazard ratio [HR], 0.85; 95% CI, 0.6–1.2; P  = .35) and 10 weeks (38% vs 36%; HR, 1.03; 95% CI, 0.8–1.32; P  = .82) for ART-experienced and ART-naïve patients. Among ART-experienced patients, using different cutoff points for ART duration, there were no significant differences in 2- and 10-week mortality based on duration of ART. Conclusions In this study, there were no significant differences in mortality at 2 and 10 weeks between ART-naïve and -experienced patients and between ART-experienced patients according to duration on ART. [ABSTRACT FROM AUTHOR]

Cryptococcal antigen (CrAg) detection could direct the timely initiation of antifungal therapy. We searched MEDLINE and Embase for studies where CrAg detection in serum/cerebrospinal fluid (CSF) and CSF fungal culture were done on adults living with human immunodeficiency virus (HIV) who had suspected cryptococcal meningitis (CM). With Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2), we evaluated the risk of bias in 11 included studies with 3600 participants, and used a random-effects meta-analysis to obtain summary sensitivity and specificity of serum and CSF CrAg, as well as agreement between CSF CrAg and CSF culture. Summary sensitivity and specificity of serum CrAg were 99.7% (97.4–100) and 94.1% (88.3–98.1), respectively, and summary sensitivity and specificity of CSF CrAg were 98.8% (96.2–99.6) and 99.3% (96.7–99.9), respectively. Agreement between CSF CrAg and CSF culture was 98% (97–99). In adults living with HIV who have CM symptoms, serum CrAg negativity may rule out CM, while positivity should prompt induction antifungal therapy if lumbar puncture is not feasible. In a first episode of CM, CSF CrAg positivity is diagnostic. [ABSTRACT FROM AUTHOR]

Among 472 patients with human immunodeficiency virus-associated cryptococcal meningitis, 16% had severe visual loss at presentation, and 46% of these were 4-week survivors and remained severely impaired. Baseline cerebrospinal fluid opening pressure ≥40 cmH2O (adjusted odds ratio [aOR], 2.56; 95% confidence interval [CI], 1.36–4.83; P =.02) and fungal burden >6.0 log10 colonies/mL (aOR, 3.01; 95% CI, 1.58–5.7; P =.003) were independently associated with severe visual loss. [ABSTRACT FROM AUTHOR]

Background Mortality from cryptococcal meningitis remains very high in Africa. In the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) trial, 2 weeks of fluconazole (FLU) plus flucytosine (5FC) was as effective and less costly than 2 weeks of amphotericin-based regimens. However, many African settings treat with FLU monotherapy, and the cost-effectiveness of adding 5FC to FLU is uncertain. Methods The effectiveness and costs of FLU+5FC were taken from ACTA, which included a costing analysis at the Zambian site. The effectiveness of FLU was derived from cohorts of consecutively enrolled patients, managed in respects other than drug therapy, as were participants in ACTA. FLU costs were derived from costs of FLU+5FC in ACTA, by subtracting 5FC drug and monitoring costs. The cost-effectiveness of FLU+5FC vs FLU alone was measured as the incremental cost-effectiveness ratio (ICER). A probabilistic sensitivity analysis assessed uncertainties and a bivariate deterministic sensitivity analysis examined the impact of varying mortality and 5FC drug costs on the ICER. Results The mean costs per patient were US $847 (95% confidence interval [CI] $776–927) for FLU+5FC, and US $628 (95% CI $557–709) for FLU. The 10-week mortality rate was 35.1% (95% CI 28.9–41.7%) with FLU+5FC and 53.8% (95% CI 43.1–64.1%) with FLU. At the current 5FC price of US $1.30 per 500 mg tablet, the ICER of 5FC+FLU versus FLU alone was US $65 (95% CI $28–208) per life-year saved. Reducing the 5FC cost to between US $0.80 and US $0.40 per 500 mg resulted in an ICER between US $44 and US $28 per life-year saved. Conclusions The addition of 5FC to FLU is cost-effective for cryptococcal meningitis treatment in Africa and, if made available widely, could substantially reduce mortality rates among human immunodeficiency virus–infected persons in Africa. [ABSTRACT FROM AUTHOR]

Background Mortality from cryptoccocal meningitis remains high. The ACTA trial demonstrated that, compared with 2 weeks of amphotericin B (AmB) plus flucystosine (5FC), 1 week of AmB and 5FC was associated with lower mortality and 2 weeks of oral flucanozole (FLU) plus 5FC was non-inferior. Here, we assess the cost-effectiveness of these different treatment courses. Methods Participants were randomized in a ratio of 2:1:1:1:1 to 2 weeks of oral 5FC and FLU, 1 week of AmB and FLU, 1 week of AmB and 5FC, 2 weeks of AmB and FLU, or 2 weeks of AmB and 5FC in Malawi, Zambia, Cameroon, and Tanzania. Data on individual resource use and health outcomes were collected. Cost-effectiveness was measured as incremental costs per life-year saved, and non-parametric bootstrapping was done. Results Total costs per patient were US $1442 for 2 weeks of oral FLU and 5FC, $1763 for 1 week of AmB and FLU, $1861 for 1 week of AmB and 5FC, $2125 for 2 weeks of AmB and FLU, and $2285 for 2 weeks of AmB and 5FC. Compared to 2 weeks of AmB and 5FC, 1 week of AmB and 5FC was less costly and more effective and 2 weeks of oral FLU and 5FC was less costly and as effective. The incremental cost-effectiveness ratio for 1 week of AmB and 5FC versus oral FLU and 5FC was US $208 (95% confidence interval $91–1210) per life-year saved. Clinical Trials Registration ISRCTN45035509. Conclusions Both 1 week of AmB and 5FC and 2 weeks of Oral FLU and 5FC are cost-effective treatments. [ABSTRACT FROM AUTHOR]

Cryptococcal antigen (CrAg) screening and targeted preemptive fluconazole in antiretroviral-naive human immunodeficiency virus–infected adults with CD4 cell counts <100/μL seems promising as a strategy to reduce the burden of cryptococcal meningitis (CM). We searched MEDLINE, EMBASE, and Web of Science and used random-effect meta-analysis to assess the prevalence of blood CrAg positivity (31 studies; 35644 participants) and asymptomatic CM in CrAg-positive participants and the incidence of CM and the all-cause mortality rate in screened participants. The pooled prevalence of blood CrAg-positivity was 6% (95% confidence interval [CI], 5%–7%), and the prevalence of asymptomatic CM in CrAg-positive participants was 33% (95% CI, 21%–45%). The incidence of CM was 21.4% (95% CI, 11.6%–34.4%) without preemptive fluconazole and 5.7% (95% CI, 3.0%–9.7%) with preemptive fluconazole therapy initiated at 800 mg/d. In CrAg-positive participants, postscreening lumbar puncture before initiating preemptive fluconazole at 800 mg/d further reduced the incidence of CM to null and showed some survival benefits. However, the all-cause mortality rate remained significantly higher in CrAg-positive than in CrAg-negative participants (risk ratio, 2.2; 95% CI, 1.7–2.9; P <.001). [ABSTRACT FROM AUTHOR]

Cryptococcal meningitis (CM) is the primary cause of meningitis in adults with human immunodeficiency virus (HIV) infection and an emerging disease in HIV-seronegative individuals. No literature review has studied the long-term outcome of CM. We performed a systematic review on the long-term (≥3-month) impact of CM (Cryptococcus neoformans and Cryptococcus gattii) on mortality and disability in HIV-infected and non--HIV-infected adults. Although the quality of current evidence is limited, the long-term impact of CM on survival and disability seems to be high. One-year mortality ranged from 13% in an Australian non--HIV-infected C. gattii--infected cohort to 78% in a Malawian HIV-infected cohort treated with fluconazole monotherapy. One-year impairment proportions among survivors ranged from 19% in an Australian C. gattii cohort to >70% in a Taiwanese non--HIV- and HIV-infected cohorts. Ongoing early therapeutic interventions, early detection of impairments and access to rehabilitation services may significantly improve patients' survival and quality of life. [ABSTRACT FROM AUTHOR]