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Cryptococcal antigen (CrAg) is detectable in blood prior to the onset of symptomatic cryptococcal meningitis (CM), a leading cause of death among people with advanced human immunodeficiency virus (HIV) disease globally. Highly sensitive assays can detect CrAg in blood, and screening people with HIV with low CD4 counts, followed by preemptive antifungal treatment, is recommended and widely implemented as part of a global strategy to prevent CM and end cryptococcal-related deaths. Cryptococcal antigenemia encompasses a spectrum of conditions from preclinical asymptomatic infection (cerebrospinal fluid [CSF] CrAg-negative) through subclinical (CSF CrAg-positive without overt meningism) to clinical symptomatic cryptococcal disease, usually manifesting as CM. In this review, we summarize current understanding of the pathophysiology, risk factors for, and clinical implications of cryptococcal antigenemia within this spectrum. We also provide an update on global prevalence, recommended screening and treatment strategies, and future considerations for improving outcomes among patients with cryptococcal antigenemia. [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]

In Malawi, 236 participants from the Advancing Cryptococcal Meningitis Treatment for Africa trial were followed for 12 months. The trial outcomes reported at 10 weeks were sustained to 1 year. One-week amphotericin B plus flucytosine was associated with the lowest 1 year mortality (27.5% [95% confidence interval, 16.3 to 44.1]). [ABSTRACT FROM AUTHOR]

Background We performed a phase 2 noninferiority trial examining the early fungicidal activity (EFA) of 3 short-course, high-dose liposomal amphotericin B (L-AmB) regimens for cryptococcal meningitis (CM) in Tanzania and Botswana. Methods Human immunodeficiency virus (HIV)-infected adults with CM were randomized to (i) L-AmB 10 mg/kg on day 1 (single dose); (ii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on day 3 (2 doses); (iii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on days 3 and 7 (3 doses); or (iv) L-AmB 3 mg/kg/day for 14 days (control). All patients also received oral fluconazole 1200 mg/day for 14 days. Primary endpoint was mean rate of clearance of cerebrospinal fluid cryptococcal infection (EFA). Noninferiority was defined as an upper limit of the 2-sided 95% confidence interval (CI) of difference in EFA between intervention and control <0.2 log10 colony-forming units (CFU)/mL/day. Results Eighty participants were enrolled. EFA for daily L-AmB was –0.41 log10 CFU/mL/day (standard deviation, 0.11; n = 17). Difference in mean EFA from control was –0.11 (95% CI, –.29 to.07) log10 CFU/mL/day faster with single dose (n = 16); –0.05 (95% CI, –.20 to.10) log10 CFU/mL/day faster with 2 doses (n = 18); and –0.13 (95% CI, –.35 to.09) log10 CFU/mL/day faster with 3 doses (n = 18). EFA in all short-course arms was noninferior to control. Ten-week mortality was 29% (n = 23) with no statistical difference between arms. All arms were well tolerated. Conclusions Single-dose 10 mg/kg L-AmB was well tolerated and led to noninferior EFA compared to 14 days of 3 mg/kg/day L-AmB in HIV-associated CM. Induction based on a single 10 mg/kg L-AmB dose is being taken forward to a phase 3 clinical endpoint trial. Clinical Trials Registration ISRCTN 10248064. [ABSTRACT FROM AUTHOR]

The article discusses the 2016 Global Funding of Innovation for Neglected Diseases of Policy Cures which shows that cryptococcal meningitis ranks amongst the most poorly funded neglected diseases in the world. It mentions cryptococcal meningitis disproportionately affects people in low- and middle-income countries (LMICs). It notes that cryptococcal meningitis is a deadly invasive fungal infection that continues to affect hundreds of thousands of HIV patients with advanced disease.

Background: Cryptococcal meningitis (CM) is a leading cause of mortality among HIV-infected individuals in Africa. Poor outcomes from conventional antifungal therapies, unavailability of flucytosine, and difficulties administering 14 days of amphotericin B are key drivers of this mortality. Novel treatment regimes are needed. This study examines whether short-course high-dose liposomal amphotericin B (AmBisome), given with high dose fluconazole, is non-inferior (in terms of microbiological and clinical endpoints) to standard-dose 14-day courses of AmBisome plus high dose fluconazole for treatment of HIV-associated CM. Methodology/design: This is an adaptive open-label phase II/III randomised non-inferiority trial comparing alternative short course AmBisome regimens. Step 1 (phase II) will compare four treatment arms in 160 adult patients (≥18 years old) with a first episode of HIV-associated CM, using early fungicidal activity (EFA) as the primary outcome: 1) AmBisome 10 mg/kg day one (single dose); 2) AmBisome 10 mg/kg day one and AmBisome 5 mg/kg day three (two doses); 3) AmBisome 10 mg/kg day one, and AmBisome 5 mg/kg days three and seven (three doses); and 4) AmBisome 3 mg/kg/d for 14 days (control); all given with fluconazole 1200 mg daily for 14 days. STEP 2 (phase III) will enrol 300 participants and compare two treatment arms using all-cause mortality within 70 days as the primary outcome: 1) the shortest course AmBisome regimen found to be non-inferior in terms of EFA to the 14-day control arm in STEP 1, and 2) AmBisome 3 mg/kg/d for 14 days (control), both given with fluconazole 1200 mg daily for 14 days. STEP 2 analysis will include all patients from STEP 1 and STEP 2 taking the STEP 2 regimens. All patients will be followed for ten weeks, and mortality and safety data recorded. All patients will receive consolidation therapy with fluconazole 400-800 mg daily and ART in accordance with local guidelines. The primary analysis (for both STEP 1 and STEP 2) will be intention-to-treat. Trial registration: ISRCTN10248064. Date of Registration: 22 January 2014 [ABSTRACT FROM AUTHOR]

Cryptococcal meningitis is the leading cause of adult meningitis in patients with HIV, and accounts for 15% of all HIV-related deaths in sub-Saharan Africa. The mainstay of management is effective antifungal therapy, despite a limited arsenal of antifungal drugs, significant progress has been made developing effective treatment strategies by using combination regimens. The introduction of fluconazole as a safe and effective step-down therapy allowed for shorter courses of more fungicidal agents to be given as induction therapy, with higher doses achieving more rapid CSF sterilisation and improved treatment outcomes. The development of early fungicidal activity (EFA), an easily measured surrogate of treatment efficacy, has enabled rapid identification of effective combinations through dose ranging phase II studies, allowing further evaluation of clinical benefit in targeted phase III studies. Recent clinical trials have shown that shorter course induction regimens using one week of amphotericin paired with flucytosine are non-inferior to traditional two-week induction regimens and that the combination of fluconazole and flucytosine offers a viable treatment alternative when amphotericin is unavailable. Access to drugs in many low and middle-income settings remains challenging but is improving, and novel strategies based on single high dose liposomal amphotericin B promise further reduction in treatment complications and toxicities. This review aims to summarise the key findings of the principal clinical trials that have led to the success story of combination therapy thus far. [ABSTRACT FROM AUTHOR]