Faculty Opinions recommendation of Combination antifungal therapy for cryptococcal meningitis.

Abstract Background. Amphotericin-based combination antifungal therapy reduces mortality from human immunodeficiency virus (HIV)-associated cryptococcal meningitis. However, 40%–50% of individuals have positive cerebrospinal fluid (CSF) fungal cultures at completion of 2 weeks of amphotericin induction therapy. Residual CSF culture positivity has historically been associated with poor clinical outcomes. We investigated whether persistent CSF fungemia was associated with detrimental clinical outcomes in a contemporary African cohort. Methods. Human immunodeficiency virus-infected individuals with cryptococcal meningitis in Uganda and South Africa received amphotericin (0.7–1.0 mg/kg per day) plus fluconazole (800 mg/day) for 2 weeks, followed by “enhanced consolidation” therapy with fluconazole 800 mg/day for at least 3 weeks or until cultures were sterile, and then 400 mg/day for 8 weeks. Participants were randomized to receive antiretroviral therapy (ART) either 1–2 or 5 weeks after diagnosis and observed for 6 months. Survivors were classified as having sterile or nonsterile CSF based on 2-week CSF cultures. Mortality, immune reconstitution inflammatory syndrome (IRIS), and culture-positive relapse were compared in those with sterile or nonsterile CSF using Cox regression. Results. Of 132 participants surviving 2 weeks, 57% had sterile CSF at 2 weeks, 23 died within 5 weeks, and 40 died within 6 months. Culture positivity was not significantly associated with mortality (adjusted 6-month hazard ratio, 1.2; 95% confidence interval, 0.6–2.3; P = .28). Incidence of IRIS or relapse was also not significantly related to culture positivity. Conclusions. Among patients, all treated with enhanced consolidation antifungal therapy and ART, residual cryptococcal culture positivity was not found to be associated with poor clinical outcomes.

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Evaluation of the Initial 12 Months of a Routine Cryptococcal Antigen Screening Program in Reduction of HIV-Associated Cryptococcal Meningitis in Uganda

10.21203/rs.3.rs-778682/v1 ◽

2021 ◽

Author(s):

Kagimu Enock ◽

Kiwanuka Julius ◽

Bridget C Griffith ◽

Derrick Bary Abila ◽

Morris K Rutakingirwa ◽

...

Keyword(s):

Antifungal Therapy ◽

Cryptococcal Meningitis ◽

Screening Program ◽

Health Facilities ◽

Cross Sectional Survey ◽

Cross Sectional ◽

Number Of Patients ◽

Fluconazole Therapy ◽

Screening Cascade

Abstract Background: Asymptomatic Cryptococcal Antigenemia (CrAg) patients develop meningitis within a month of testing positive. Pre-emptive antifungal therapy can prevent progression to Cryptococcal meningitis(CM). In April 2016, a national CrAg screening program was initiated in 206 high-volume health facilities that provide antiretroviral therapy in Uganda. We report the evaluation of the CrAg screening cascade focusing on linkage to care, fluconazole therapy for 10 weeks, and ART initiation in a subset of facilities.Methods: We conducted a retrospective, cross-sectional survey of patients with CD4<100 at seven urban and seven rural facilities after one year of program implementation. We quantified the number of patients who transitioned through the steps of the CrAg screening cascade over six-months follow-up. We defined cascade completion as a prophylactic fluconazole prescription. We conducted semi-structured interviews with lab personnel and clinic staff to assess functionality of the CrAg screening program. Data was collected using REDCap.Results:We evaluated 359 patient records; the majority (358/359, 99.7%) were from government owned health facilities and just over half (193/359, 53.8%) had a median baseline CD4 cell count of <50 cell/µL. Overall, CrAg screening had been performed in 255/359 (71.0%, 95% CI, 66.0-75.7) of patients’ records reviewed, with a higher proportion among urban facilities (170/209 (81.3%, 95% CI, 75.4-86.4)) than rural facilities (85/150 (56.7%, 95% CI, 48.3-64.7)). Among those who were CrAg screened, 56/255 (22.0%, 95% CI, 17.0-27.5%) had cryptococcal antigenemia, of whom 47/56 (83.9%, 95% CI, 71.7-92.4%) were initiated on pre-emptive therapy with fluconazole and 8/47 (17.0%, 95% CI, 7.6-30.8%) of these were still receiving antifungal therapy at 6 months follow up. Atleast one CNS symptom was present in 70% (39/56) of those with antigenemia. In patients who had started ART, almost 40% initiated ART prior to CrAg screening. Inadequacy of equipment/supplies was reported by 15/26 (58%) of personnel as a program barrier, while 13/26 (50%) reported a need for training about CM and CrAg screening.Conclusion:There was a critical gap in the follow-up of patients after initiation on fluconazole therapy. ART had been initiated in almost 40% of patients prior to CrAg screening, which predisposes them to unmasking Cryptococcal IRIS. Higher antigenemia patients presenting with CNS symptoms could be related to late presentation. There is need to address these gaps after a more thorough evaluation.

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The Effect of Early vs. Deferred Antiretroviral Therapy Initiation in HIV-Infected Patients With Cryptococcal Meningitis: A Multicenter Prospective Randomized Controlled Analysis in China

Frontiers in Medicine ◽

10.3389/fmed.2021.779181 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ting Zhao ◽

Xiao-lei Xu ◽

Yan-qiu Lu ◽

Min Liu ◽

Jing Yuan ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Adverse Events ◽

Antifungal Therapy ◽

Cryptococcal Meningitis ◽

Antifungal Treatment ◽

Optimal Timing ◽

Probability Of Survival ◽

Intention To Treat ◽

Art Initiation ◽

Therapy Initiation

Background: The optimal timing for initiation of antiretroviral therapy (ART) in HIV-positive patients with cryptococcal meningitis (CM) has not, as yet, been compellingly elucidated, as research data concerning mortality risk and the occurrence of immune reconstitution inflammatory syndrome (IRIS) in this population remains inconsistent and controversial.Method: The present multicenter randomized clinical trial was conducted in China in patients who presented with confirmed HIV/CM, and who were ART-naïve. Subjects were randomized and stratified into either an early-ART group (ART initiated 2–5 weeks after initiation of antifungal therapy), or a deferred-ART group (ART initiated 5 weeks after initiation of antifungal therapy). Intention-to-treat, and per-protocol analyses of data for these groups were conducted for this study.Result: The probability of survival was found to not be statistically different between patients who started ART between 2–5 weeks of CM therapy initiation (14/47, 29.8%) vs. those initiating ART until 5 weeks after CM therapy initiation (10/55, 18.2%) (p = 0.144). However, initiating ART within 4 weeks after the diagnosis and antifungal treatment of CM resulted in a higher mortality compared with deferring ART initiation until 6 weeks (p = 0.042). The incidence of IRIS did not differ significantly between the early-ART group and the deferred-ART group (6.4 and 7.3%, respectively; p = 0.872). The percentage of patients with severe (grade 3 or 4) adverse events was high in both treatment arms (55.3% in the early-ART group and 41.8% in the deferred-ART group; p=0.183), and there were significantly more grade 4 adverse events in the early-ART group (20 vs. 13; p = 0.042).Conclusion: Although ART initiation from 2 to 5 weeks after initiation of antifungal therapy was not significantly associated with high cumulative mortality or IRIS event rates in HIV/CM patients compared with ART initiation 5 weeks after initiation of antifungal therapy, we found that initiating ART within 4 weeks after CM antifungal treatment resulted in a higher mortality compared with deferring ART initiation until 6 weeks. In addition, we observed that there were significantly more grade 4 adverse events in the early-ART group. Our results support the deferred initiation of ART in HIV-associated CM.Clinical Trials Registration:www.ClinicalTrials.gov, identifier: ChiCTR1900021195.

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Faculty Opinions recommendation of Combination antifungal therapy for cryptococcal meningitis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718001041.793475653 ◽

2013 ◽

Author(s):

Tania Sorrell ◽

Sharon Chen

Keyword(s):

Antifungal Therapy ◽

Cryptococcal Meningitis

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Cryptococcal Antigen in Serum and Cerebrospinal Fluid for Detecting Cryptococcal Meningitis in Adults Living With Human Immunodeficiency Virus: Systematic Review and Meta-Analysis of Diagnostic Test Accuracy Studies

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1243 ◽

2020 ◽

Cited By ~ 1

Author(s):

Elvis Temfack ◽

Jean Joel Bigna Rim ◽

Rene Spijker ◽

Angela Loyse ◽

Tom Chiller ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Cerebrospinal Fluid ◽

Sensitivity And Specificity ◽

Antifungal Therapy ◽

Cryptococcal Meningitis ◽

Meta Analysis ◽

Test Accuracy ◽

Fungal Culture ◽

Cryptococcal Antigen ◽

Immunodeficiency Virus

Abstract 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.

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