Long term survival among HIV-infected persons with cryptococcosis in Uganda.

<p>The Kaplan-Meier survival curve displays the long term survival of 25 asymptomatic persons who tested positive for serum cryptococcal antigen (CRAG+) treated with fluconazole and ART compared to 189 symptomatic patients with cryptococcal meningitis (CM) treated with amphotericin B induction and then fluconazole consolidation therapy and then ART. Diamonds represent censored data. Persons were right-hand censored if they were still living at the time of analysis (n = 82), if they transferred their care to another clinic (n = 7), or if they were lost to follow up (n = 9). Survival table showing survival rate, number of deaths, number censored, and number of survivors at yearly intervals for each cohort.</p

Characteristics of persons presenting with asymptomatic, subclinical cryptococcal antigenemia (CRAG+) and symptomatic cryptococcal meningitis.

a<p>Pre-ART CD4 and viral load data were only available for 117 symptomatic CM persons, collected pre-ART.</p

Performance of India ink and Acridine orange against culture.

<p>Performance of India ink and Acridine orange against culture.</p

Venn diagram of the distribution of Cryptococcal meningitis CSF diagnostics.

<p>Distribution of 194 CSF samples from 96 cryptococcal meningitis cases. All samples were positive for CSF cryptococcal antigen lateral flow assay. Only 66% of the samples were positive for India ink, acridine orange and culture.</p

<i>Cryptoccocus</i> yeasts stained with acridine orange and India ink.

<p>(a) Image of a positive acridine orange slide showing <i>Cryptococcus</i> yeasts fluorescing green against a dark background, using a blue filter on a fluorescent microscope. (b) Image of a negative acridine orange slide showing no <i>Cryptococcus</i> yeasts. (c) Image of a positive india ink slide showing a capsule of <i>Cryptococcus</i> yeasts on a bright field light microscope. (d) Image of a negative india ink slide showing no <i>Cryptococcus</i> yeasts. All images were taken at 40x magnification.</p

Baseline characteristics of the study population.

<p>Baseline characteristics of the study population.</p

Cryptococcal Meningitis Treatment Strategies in Resource-Limited Settings: A Cost-Effectiveness Analysis

<div><h3>Background</h3><p>Cryptococcal meningitis (CM) is the most common form of meningitis in Africa. World Health Organization guidelines recommend 14-d amphotericin-based induction therapy; however, this is impractical for many resource-limited settings due to cost and intensive monitoring needs. A cost-effectiveness analysis was performed to guide stakeholders with respect to optimal CM treatment within resource limitations.</p> <h3>Methods and Findings:</h3><p>We conducted a decision analysis to estimate the incremental cost-effectiveness ratio (ICER) of six CM induction regimens: fluconazole (800–1,200 mg/d) monotherapy, fluconazole + flucytosine (5FC), short-course amphotericin (7-d) + fluconazole, 14-d of amphotericin alone, amphotericin + fluconazole, and amphotericin + 5FC. We computed actual 2012 healthcare costs in Uganda for medications, supplies, and personnel, and average laboratory costs for three African countries. A systematic review of cryptococcal treatment trials in resource-limited areas summarized 10-wk survival outcomes. We modeled one-year survival based on South African, Ugandan, and Thai CM outcome data, and survival beyond one-year on Ugandan and Thai data. Quality-adjusted life years (QALYs) were determined and used to calculate the cost-effectiveness ratio and ICER. The cost of hospital care ranged from $154 for fluconazole monotherapy to$467 for 14 d of amphotericin + 5FC. Based on 18 studies investigating outcomes for HIV-infected individuals with CM in resource-limited settings, the estimated mean one-year survival was lowest for fluconazole monotherapy, at 40%. The cost-effectiveness ratio ranged from $20 to$44 per QALY. Overall, amphotericin-based regimens had higher costs but better survival. Short-course amphotericin (1 mg/kg/d for 7 d) with fluconazole (1,200 mg/d for14 d) had the best one-year survival (66%) and the most favorable cost-effectiveness ratio, at $20.24/QALY, with an ICER of$15.11 per additional QALY over fluconazole monotherapy. The main limitation of this study is the pooled nature of a systematic review, with a paucity of outcome data with direct comparisons between regimens.</p> <h3>Conclusions</h3><p>Short-course (7-d) amphotericin induction therapy coupled with high-dose (1,200 mg/d) fluconazole is “very cost effective” per World Health Organization criteria and may be a worthy investment for policy-makers seeking cost-effective clinical outcomes. More head-to-head clinical trials are needed on treatments for this neglected tropical disease.</p> <h3></h3><p> <em>Please see later in the article for the Editors' Summary.</em></p> </div

Estimated clinical outcomes by cryptococcal meningitis induction treatment regimen.

<p>5FC dosed at 100 mg/kg/d; amphotericin B deoxycholate dosed at 0.7–1.0 mg/kg/d. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001316#pmed.1001316.s007" target="_blank">Figure S2</a> displays the data.</p>a<p>Mayanja-Kizza et al. used fluconazole doses of 200 mg/d and 5FC doses of 150 mg/kg/d <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001316#pmed.1001316-MayanjaKizza1" target="_blank">[30]</a>.</p>b<p>Muzoora et al. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001316#pmed.1001316-Muzoora1" target="_blank">[13]</a> used 5 d of amphotericin and Jackson et al. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001316#pmed.1001316-Jackson1" target="_blank">[15]</a> used 7 d of amphotericin at 1.0 mg/kg/d with fluconazole at 1,200 mg/d, whereas 7 d of amphotericin was used by Bicanic et al. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001316#pmed.1001316-Bicanic1" target="_blank">[9]</a> (1.0 mg/kg/d) and Tansuphaswadikul et al. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001316#pmed.1001316-Tansuphaswadikul1" target="_blank">[31]</a> (0.7 mg/kg/d).</p

Input costs of cryptococcal meningitis induction therapy and medical care.

<p>LP includes initial diagnostic CSF analysis; 5FC dosed at 100 mg/kg/d; amphotericin B deoxycholate dosed at 0.7–1.0 mg/kg/d. Cost components displayed in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001316#pmed.1001316.s006" target="_blank">Figure S1</a>.</p>a<p>Assumes 7 d of hospitalization, with additional phlebotomy for 5FC monitoring.</p

Performance of Cryptococcal Antigen Lateral Flow Assay Using Saliva in Ugandans with CD4 <100

<div><p>Background</p><p>Cryptococcal meningitis can best be diagnosed by cerebrospinal fluid India ink microscopy, cryptococcal antigen detection, or culture. These require invasive lumbar punctures. The utility of cryptococcal antigen detection in saliva is unknown. We evaluated the diagnostic performance of the point-of-care cryptococcal antigen lateral flow assay (CrAg LFA) in saliva.</p><p>Methods</p><p>We screened HIV-infected, antiretroviral therapy naïve persons with symptomatic meningitis (n = 130) and asymptomatic persons with CD4+<100 cells/µL entering into HIV care (n = 399) in Kampala, Uganda. The diagnostic performance of testing saliva was compared to serum/plasma cryptococcal antigen as the reference standard.</p><p>Results</p><p>The saliva lateral flow assay performance was overall more sensitive in symptomatic patients (88%) than in asymptomatic patients (27%). The specificity of saliva lateral flow assay was excellent at 97.8% in the symptomatic patients and 100% in asymptomatic patients. The degree of accuracy of saliva in diagnosing cryptococcosis and the level of agreement between the two sample types was better in symptomatic patients (C-statistic 92.9, κ-0.82) than in asymptomatic patients (C-statistic 63.5, κ-0.41). Persons with false negative salvia CrAg tests had lower levels of peripheral blood CrAg titers (P<0.001).</p><p>Conclusion</p><p>There was poor diagnostic performance in testing saliva for cryptococcal antigen, particularly among asymptomatic persons screened for preemptive treatment of cryptococcosis.</p></div