BACKGROUND: Cryptococcal meningitis accounts for 15% of AIDS-related mortality. Cryptococcal antigen (CrAg) is detected in blood weeks before onset of meningitis, and CrAg positivity is an independent predictor of meningitis and death. CrAg screening for patients with advanced HIV and preemptive treatment is recommended by the World Health Organization, though implementation remains limited. Our objective was to evaluate costs and mortality reduction (lives saved) from a national CrAg screening program across Uganda. METHODS: We created a decision analytic model to evaluate CrAg screening. CrAg screening was considered for those with a CD4<100 cells/muL per national and international guidelines, and in the context of a national HIV test-and-treat program where CD4 testing was not available. Costs (2016 USD) were estimated for screening, preemptive therapy, hospitalization, and maintenance therapy. Parameter assumptions were based on large prospective CrAg screening studies in Uganda, and clinical trials from sub Saharan Africa. CrAg positive (CrAg+) persons could be: (a) asymptomatic and thus eligible for preemptive treatment with fluconazole; or (b) symptomatic with meningitis with hospitalization. RESULTS: In the base case model for 1 million persons with a CD4 test annually, 128,000 with a CD4<100 cells/muL were screened, and 8,233 were asymptomatic CrAg+ and received preemptive therapy. Compared to no screening and treatment, CrAg screening and treatment in the base case cost $3,356,724 compared to doing nothing, and saved 7,320 lives, for a cost of $459 per life saved, with the $3.3 million in cost savings derived from fewer patients developing fulminant meningitis. In the scenario of a national HIV test-and-treat program, of 1 million HIV-infected persons, 800,000 persons were screened, of whom 640,000 returned to clinic, and 8,233 were incident CrAg positive (CrAg prevalence 1.4%). The total cost of a CrAg screening and treatment program was $4.16 million dollars, with 2,180 known deaths. Conversely, without CrAg screening, the cost of treating meningitis was $3.09 million dollars with 3,806 deaths. Thus, despite the very low CrAg prevalence of 1.4% in the general HIV-infected population, and inadequate retention-in-care, CrAg screening averted 43% of deaths from cryptococcal meningitis at a cost of $662 per death averted. CONCLUSION: CrAg screening and treatment programs are cost-saving and lifesaving, assuming preemptive treatment is 77% effective in preventing death, and could be adopted and implemented by ministries of health to reduce mortality in those with advanced HIV disease. Even within HIV test-and-treat programs where CD4 testing is not performed, and CrAg prevalence is only 1.4%, CrAg screening is cost-effective.

Although HIV/AIDS has been anything but neglected over the last decade, opportunistic infections (OIs) are increasingly overlooked as large-scale donors shift their focus from acute care to prevention and earlier antiretroviral treatment (ART) initiation. Of these OIs, cryptococcal meningitis, a deadly invasive fungal infection, continues to affect hundreds of thousands of HIV patients with advanced disease each year and is responsible for an estimated 15%–20% of all AIDS-related deaths [1, 2]. Yet cryptococcal meningitis ranks amongst the most poorly funded “neglected” diseases in the world, receiving 0.2% of available relevant research and development (R&D) funding, according to Policy Cures’ 2016 Global Funding of Innovation for Neglected Diseases (G-Finder) Report [3, 4]. | Although cryptococcal meningitis is not formally recognised by the World Health Organisation (WHO) or PLOS Neglected Tropical Diseases (PLOS NTDs) as a neglected tropical disease (NTD), it is listed in the G-Finder report, as it disproportionately affects people in low- and middle-income countries (LMICs), with market failure evident for existing essential antifungal medicines and an urgent need for new, effective, and less toxic medicines. PLOS NTDs defines NTDs as a “group of poverty-promoting chronic infectious diseases, which primarily occur in rural areas and poor urban areas of LMICs” [5] and according to the WHO, NTDs are “a proxy for poverty and disadvantage”, have “an important impact on morbidity and mortality”, and are relatively “neglected by research” [6]. Although the greatest burden of cryptococcal disease is undoubtedly related to HIV, we demonstrate herein that cryptococcal meningitis meets both the WHO and PLOS NTDs definitions of an NTD, as the disease (1) disproportionately affects populations in poverty and causes substantial morbidity and mortality, (2) primarily affects populations living in tropical and subtropical areas, (3) is immediately amenable to broad control, elimination, or eradication, and (4) is neglected by research [7].

BACKGROUND: In 2015 South Africa established a national cryptococcal antigenemia (CrAg) screening policy targeted at HIV-infected patients with CD4+ T-lymphocyte (CD4) counts <100 cells/ mul who are not yet on antiretroviral treatment (ART). Two screening strategies are included in national guidelines: reflex screening, where a CrAg test is performed on remnant blood samples from CD4 testing; and provider-initiated screening, where providers order a CrAg test after a patient returns for CD4 test results. The objective of this study was to compare costs and effectiveness of these two screening strategies. METHODS: We developed a decision analytic model to compare reflex and provider-initiated screening in terms of programmatic and health outcomes (number screened, number identified for preemptive treatment, lives saved, and discounted years of life saved) and screening and treatment costs (2015 USD). We estimated a base case with prevalence and other parameters based on data collected during CrAg screening pilot projects integrated into routine HIV care in Gauteng, Free State, and Western Cape Provinces. We conducted sensitivity analyses to explore how results change with underlying parameter assumptions. RESULTS: In the base case, for each 100,000 CD4 tests, the reflex strategy compared to the provider-initiated strategy has higher screening costs ($37,536 higher) but lower treatment costs ($55,165 lower), so overall costs of screening and treatment are $17,629 less with the reflex strategy. The reflex strategy saves more lives (30 lives, 647 additional years of life saved). Sensitivity analyses suggest that reflex screening dominates provider-initiated screening (lower total costs and more lives saved) or saves additional lives for small additional costs (< $125 per life year) across a wide range of conditions (CrAg prevalence, patient and provider behavior, patient survival without treatment, and effectiveness of preemptive fluconazole treatment). CONCLUSIONS: In countries with substantial numbers of people with untreated, advanced HIV disease such as South Africa, CrAg screening before initiation of ART has the potential to reduce cryptococcal meningitis and save lives. Reflex screening compared to provider-initiated screening saves more lives and is likely to be cost saving or have low additional costs per additional year of life saved.

OBJECTIVE: Worldwide, HIV-associated cryptococcal meningitis affects approximately 1 million persons and causes 600,000 deaths each year mostly in sub-Sharan Africa. Limited data exist on cryptococcal meningitis and antigenemia in Nigeria, and most studies are geographically restricted. We determined the prevalence of cryptococcal antigenemia (CrAg) among HIV-infected treatment-naive individuals in Nigeria. DESIGN: /Methods: This was a retrospective, cross-sectional study across four geographic regions in Nigeria. We performed CrAg testing using a lateral flow immunoassay on archived whole blood samples collected from HIV-infected participants at US PEPFAR-supported sites selected to represent the major geographical and ethnic diversity in Nigeria. Eligible samples were (1) stored in an -80 degrees freezer; (2) collected from consenting patients (>15 years) naive to antiretroviral therapy with CD4+ count less than 200 cells/mm3. RESULTS: A total of 2,752 stored blood samples were retrospectively screened for CrAg. A majority of samples were from participants aged 30 - 44 (57.6%), and 1,570 (57.1%) were from women. The prevalence of CrAg positivity in specimens with CD4 < 200 cells/mm3 was 2.3% (95% CI = 1.8%-3.0%), and varied significantly across the four regions (p < 0.001). At 4.4% (3.2%-5.9%), the South East contained the highest prevalence. CONCLUSION: The significant regional variation in CrAg prevalence found in Nigeria should be taken into consideration as plans are made to integrate routine screening into clinical care for HIV-infected patients.