Cryptococcal meningitis in people living with human immunodeficiency virus in Nepal: Perspectives from resource limited setting.

Early diagnosis of cryptococcal meningitis among people living with HIV (PLHIV) is crucial for its therapeutic success. The objective of this study was to diagnose cryptococcal meningitis in PLHIV cases using the available laboratory techniques for its confirmation in resource limited setting. This cross-sectional prospective study was conducted among 72 PLHIV with clinical suspicion of meningitis. Each cerebrospinal fluid (CSF) sample received at the National Public Health Laboratory, Kathmandu was processed for India ink staining, cryptococcal antigen lateral flow assay, and fungal culture following standard protocols. The laboratory-confirmed cryptococcal meningitis cases were between 24 and 69 years of age (median age 39 years) with 87.5% (12/14) of cases being male. Cryptococcus was detected in 22.22% (16/72) by any of the three tests, 19.44% (14/72) by cryptococcal antigen lateral flow assay, 16.66% (12/72) by India ink staining, and 8.33% (6/72) by culture. High percentage of cryptococcal meningitis among PLHIV warrants early microbiological diagnosis for better case management. Cryptococcal antigen detection immunoassay should be the priority test for laboratory diagnosis of cryptococcal meningitis in PLHIV. Alternatively, very simple and economic India ink staining of CSF specimens could be used in resource limited settings.

Retrospective Assessment of a National Reflex Cryptococcal Antigen Screening Program in South Africa Through Interlaboratory Comparison of Lateral Flow Assay Results.

OBJECTIVE: Reflex cryptococcal antigen (CrAg) screening of blood specimens with a CD4 count of <100 cells/µL was performed at 45 South African CD4 laboratories using a lateral flow assay (LFA). Our objective was to evaluate the reliability of routine LFA results through comparative interlaboratory testing. METHODS: All CrAg-positive and a selected number of CrAg-negative samples from the CD4 laboratories were retested at paired microbiology laboratories using the same LFA. Samples with discordant results were tested at a reference laboratory, using the LFA (with CrAg titers). RESULTS: During interlaboratory testing, 12,502 samples were retested, with 93 (0.7%) discordant results and a between-laboratory agreement of 99.3% (Cohen's kappa, 0.98). The proportion of retested samples with discordant results ranged from 0.17% to 5.31% per laboratory pair (median 0.28%), with 3 reporting >3% of results as discordant. CONCLUSION: Routine CrAg screening results were reliable, with <1% of samples having discordant results, mainly due to interpretation and transcription errors.

Determinants of cryptococcal antigen (CrAg) screening uptake in Kampala, Uganda: An assessment of health center characteristics.

Cryptococcal antigen (CrAg) screening and pre-emptive antifungal therapy for people with CD4 cell counts <100 cells/µl are recommended by the World Health Organization and several national HIV guidelines. We sought to evaluate CrAg screening program implementation across Uganda, in relation to health center level and distance from the capital. We conducted a cross-sectional study of 22 health centers across southern Uganda from April to June 2019. We reviewed laboratory records regarding number of CD4 cell count tests performed, proportion of outpatients with CD4 counts <200 cells/µl, and number of CrAg screening tests performed. We administered surveys to health center staff to understand barriers to advanced HIV care. We observed no significant difference in health center level and performance of CrAg screening; with each subsequent health center level, there was 1.17-fold (95% CI: 0.92-1.41) higher odds of CrAg screening performed per level. CrAg screening uptake was not associated with distance from the capital city (odds ratio = 0.96, 95% CI: 0.89-1.04). Qualitative data from surveys indicated that limitations to uptake of CrAg screening were secondary to dysfunctional CD4 machines, lack of provider awareness of CrAg screening guidelines, and inadequate/intermittent supply of CrAg tests. There were no significant associations between CrAg screening uptake and level of health center or distance of health center from the capital city. We identified systemic barriers to CrAg screening related to inadequate CD4 testing, insufficient knowledge regarding national screening guidelines, and irregular laboratory testing supplies. LAY SUMMARY: The objective of this study was to evaluate cryptococcal antigen (CrAg) screening program implementation in Uganda, by type of healthcare center and by distance from the capital city. CrAg screening uptake was not associated with distance from the capital city, or the type of healthcare center.

Cost-Effectiveness Analysis of the Implementation of Cryptococcal Antigen Lateral Flow Assay for the Diagnosis of Cryptococcal Meningitis in Symptomatic People Living With Human Immunodeficiency Virus in Brazil.

OBJECTIVES: Cryptococcal meningitis constitutes a significant source of mortality in the developing world. Annually, approximately 625 000 deaths occur worldwide among patients with human immunodeficiency virus (HIV) infection. This study aims to assess the cost-effectiveness of implementing cryptococcal antigen lateral flow assay (CRAG-LFA) screening in Brazil compared with the current practice. METHODS: An economic evaluation using a Monte Carlo microsimulation was conducted, considering the perspective of the Brazilian Public Health System, to calculate the cost-effectiveness of 4 diagnosis tests: (1) CRAG-LFA, (2) the cryptococcal antigen latex agglutination (CRAG-LA) test, (3) India ink, and (4) nontracking as a baseline. The time horizon comprised 1 year for the intervention and 5 years for the budgetary impact analysis. Two primary effectiveness outcomes were considered: years of life and quality-adjusted life-years. RESULTS: CRAG-LFA has extended dominance vis à vis CRAG-LA and India ink. CRAG-LFA would cost $418.46 more than CRAG-LA for the treatment of each symptomatic patient living with HIV, with an incremental cost effectiveness ratio of $2478.75/quality-adjusted life year. The budgetary impact analysis estimated that the incorporation of CRAG-LFA would have an additional cost of $1 959 236.50 in 5 years. CONCLUSIONS: These findings suggest that, for patients living with HIV in the Brazilian Public Health System, the adoption of CRAG-LFA screening is cost-effective compared with the use of CRAG-LA and India ink. It represents an opportunity to prevent cryptococcal meningitis and its mortality in Brazil.

Teste diagnóstico, point of care, de Cryptococcal Antigen Lateral Flow Assay (CRAG-LFA) para detecção de infecção por Cryptococcus e diagnóstico de meningite criptocócica em pessoas vivendo com o vírus da imunodeficiência humana (PVHIV) / Cryptococcal diagnostic test, point of care Lateral Antigen Flow Assay (CRAG-LFA) for detection of Cryptococcus infection and diagnosis of cryptococcal meningitis in people living as human immunodeficiency virus (PVHIV)

CONTEXTO: A criptococose é uma micose sistêmica causada por duas espécies do basidiomiceto encapsulado do gênero Cryptococcus. A infecção acomete principalmente o sistema nervoso central (SNC) e o trato respiratório e sua apresentação mais comum é a meningite criptocócica (MC) ou meningoencefalite. Mundialmente, a MC é resultado de cerca de 15% de todas as mortes relacionadas ao HIV. Estima-se que os 223.100 casos de MC, em 2014, resultaram em 181.100 óbitos, sendo 75% (135.900) na África Subsaariana, seguida pelo Sudeste Asiático e América Latina. Após o surgimento da terapia antirretroviral (TARV) para o HIV, a incidência da criptococose diminuiu significativamente em países desenvolvidos (39%), entretanto, a incidência e a mortalidade pela infecção criptocócica ainda é extremamente alta em países com epidemia de HIV incontrolada e acesso limitado aos medicamentos e aos cuidados de saúde. TECNOLOGIA: Teste diagnóstico, point of care, de Cryptococcal Antigen Lateral Flow Assay (CRAG-LFA). PERGUNTAS DE PESQUISA: 1) O teste CRAG-LFA é sensível e específico na detecção da infecção por Cryptococcus em PVHIV com células CD4+ ≤ 200 cél/mm³ comparado ao teste de aglutinação do látex? 2) O teste CRAG-LFA é sensível e específico no diagnóstico da meningite criptocócica em PVHIV sintomáticos, independente da contagem de células CD4+, se comparado ao teste de aglutinação do látex e tinta da China, em amostra de líquor? EVIDÊNCIAS CLÍNICAS: Para a Pergunta 1 de pesquisa, a estimativa de sensibilidade de CRAG-LFA na detecção da infecção criptocócica foi de 100% e as estimativas de especificidade variaram de 99% a 100%, em relação ao teste de aglutinação por látex (CRAG-LA). Já a sensibilidade combinada dos dois estudos primários incluídos foi 100% (IC95%; 96 - 100) e a especificidade combinada de 99% (IC95%; 99 - 100). Para a Pergunta 2 de pesquisa, a estimativa de sensibilidade de CRAGLFA no diagnóstico de meningite criptocócica em PVHIV foi de 100% e as estimativas de especificidade variaram de 98% a 99%. A sensibilidade combinada dos três estudos primários meta-analisados foi de 100% (IC95%; 92 - 100) e a especificidade combinada de 99% (IC95%; 97 - 100), em relação ao teste de tinta da China. Como evidências analisadas para responder à Pergunta 2 de pesquisa, também foram incluídas duas revisões sistemáticas com meta-análise, a primeira reportou que os valores de sensibilidade e especificidade combinados de CRAG-LFA no líquor foram 98,9% (IC 95%, 97,9% a 99,5%) e 98,9% (IC 95%, 98,0% a 99,5%), respectivamente, já a segunda revisão descreveu que, no líquor, CRAG-LA (10 coortes diagnósticas, 1810 participantes) teve uma sensibilidade resumida de 97,1% (91,9 - 99) e uma especificidade de 99,1% (93,8 - 99,9) enquanto o teste CRAG-LFA (6 coortes diagnósticas, 3.099 participantes) teve uma sensibilidade resumida de 99,5% (97,2 - 99,9) e especificidade de 99,5% (94,2 - 99,9). Embora houvesse alguma evidência estatística fraca de que o CRAG-LFA pode ter melhor sensibilidade no líquor (p = 0,07) do que CRAG-LA, suas especificidades foram comparáveis (p = 0,54). EVIDÊNCIAS ECONÔMICAS: Foi conduzida avaliação econômica do tipo Microssimulação de Monte Carlo, com horizonte temporal de um ano. Considerou-se dois desfechos primários de efetividade: anos de vida e anos de vida ajustados por qualidade (QALY). A análise de custo-efetividade mostrou que os dois testes, CRAG-LA e CRAG-LFA, são custo-efetivos, dominando a alternativa tinta da China e o cenário de não realização da detecção. Para o diagnóstico de meningite criptocócica em PVHIV sintomáticas o uso do teste diagnóstico CRAG-LFA revelou-se custo-efetivo comparado ao teste CRAG-LA, e ao teste tinta da China. A análise de sensibilidade determinística e probabilística indica um favorecimento, na maioria das vezes, do teste CRAG-LFA. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: A análise de impacto orçamentário (AIO) foi realizada para um horizonte temporal de cinco anos, assumindo-se um market share inicial de 20% para o LFA, com incrementos anuais no mesmo valor, chegando a 100% no quinto ano. Para a pergunta 1 de pesquisa a incorporação de LFA teria um custo adicional de aproximadamente 52,7 milhões de reais. Estimou-se também o impacto orçamentário de 100% de adoção da detecção em PVHIV CD4≤ 200 cél/mm³ assintomáticos. Nesse contexto, ocorreria uma economia da ordem de 55 milhões de reais em cinco anos, considerando detecção precoce e tratamento preemptivo, em relação ao custo de tratamento da meningite. Para a pergunta 2, para cada 1.000 PVHIV por ano, em cinco anos teríamos 809 indivíduos tratados a um custo adicional de R$ 10.697.431,27. RECOMENDAÇÕES INTERNACIONAIS: Foi realizada busca por recomendações de uso do teste CRAG-LFA por outras instituições e agências de ATS, a recomendação identificada é proveniente da Organização Mundial da Saúde (OMS). De acordo com a OMS, o diagnóstico e o tratamento precoce da meningite criptocócica são essenciais para reduzir a mortalidade por doença criptocócica em pacientes com infecção pelo vírus da imunodeficiência humana (HIV). A recomendação do órgão é para que os países deem prioridade a ensaios de antígeno criptocócico de diagnóstico rápido, de preferência ensaios de fluxo lateral como o CRAG-LFA, para uso no líquor, soro, plasma ou sangue total. Para adultos, adolescentes e crianças vivendo com HIV com suspeita de um primeiro episódio de meningite criptocócica, a punção lombar imediata com medição da pressão de abertura do líquor e aplicação de um teste diagnóstico rápido para o antígeno criptocócico é recomendado como o preferido abordagem diagnóstica. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram identificados dois outros testes registrados no segundo semestre de 2020 na Anvisa: CRAG Lateral Flow Assay e Biosynex® CryptoPS como testes rápidos CRAG-LFA. Na técnica de LA foram localizados 4 (quatro) registros sanitários na ANVISA. Já no FDA foram encontrados 3 (três) registros sanitários, sendo 1 (um) utilizando a técnica de sonda de DNA. Também foram consultadas as bases de dados de Propriedade Intelectual da WIPO e Espacenet Patent para buscar depósitos de testes de diagnósticos para meningite criptocócica. A consulta buscou os dados recentes de depósitos concedidos entre 2017 e 2020. Foram localizadas 05 patentes concedidas, sendo 04 (quatro) para metodologias em biologia molecular e um (1) para espectroscopia de Raman. CONSIDERAÇÕES FINAIS: Dadas as evidências apresentadas, o teste CRAG-LFA tem potencial custo-efetivo para a detecção da infecção criptocócica e prevenção da mortalidade relacionada à meningite criptocócica em PVHIV. RECOMENDAÇÃO PRELIMINAR: Diante do exposto, a Conitec, em sua 95ª reunião ordinária, realizada no dia 03 de março de 2021, deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à incorporação no SUS do teste point of care de Cryptococcal Antigen Lateral Flow Assay (CRAG-LFA) para detecção de infecção por Cryptococcus em pessoas vivendo com o vírus da imunodeficiência humana (PVHIV) com CD4+ ≥200 células/mm³ e diagnóstico de meningite criptocócica em PVHIV independente da contagem de células CD4+. Os membros do plenário concordaram, a partir das evidências apresentadas que o teste diagnóstico é custo-efetivo, tem baixo impacto orçamentário e, além disso, foi considerado um teste de fácil aplicação na prática clínica, superando os testes já disponíveis, utilizados como comparadores. A matéria foi disponibilizada em consulta pública. CONSULTA PÚBLICA: A Consulta Pública nº 18/2021 foi realizada entre os dias 18/03/2021 e 06/04/2021. Foram recebidas 82 contribuições, sendo 45 pelo formulário para contribuições técnico-científicas e 38 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Foram consideradas apenas as contribuições encaminhadas no período estipulado e por meio do site da Conitec, em formulário próprio. As contribuições recebidas destacaram as vantagens clínicas do uso do teste CRAG-LFA, considerando economia de recursos, na identificação precoce da condição e tratamento preemptivo. Vantagens relacionadas ao manuseio do teste, sua aplicabilidade e facilidade na interpretação também foram citadas. Não FORAM ADICIONADAS REFERÊNCIAS QUE ALTERASSEM A ANÁLISE DA EVIDÊNCIA APRESENTADA NO RELATÓRIO. RECOMENDAÇÃO FINAL: Os membros do plenário presentes na 97ª reunião ordinária da Conitec, no dia 05 de maio de 2021, deliberaram, por unanimidade, recomendar a incorporação, no SUS, do teste diagnóstico, point of care, de Cryptococcal Antigen Lateral Flow Assay (CRAG-LFA) para detecção da infecção por Cryptococcus em pessoas vivendo com o vírus da imunodeficiência humana (PVHIV) com células CD4+ ≤ 200 cél/mm³ e diagnóstico de meningite criptocócica em PVHIV sintomáticos, independente da contagem de células CD4+, conforme estabelecido pelo Ministério da Saúde. Não foram adicionadas referências que alterassem a análise da evidência apresentada. Foi assinado o Registro de Deliberação nº 610/2021. DECISÃO: Incorporar o teste diagnóstico, point of care, de Cryptococcal Antigen Lateral Flow Assay (CRAG-LFA) para detecção de infecção por Cryptococcus em pessoas vivendo com o vírus da imunodeficiência humana (PVHIV) com CD4+ ³200 células/mm³ e diagnóstico de meningite criptocócica em PVHIV independente da contagem de células CD4+, no âmbito do Sistema Único de Saúde ­ SUS, conforme Portaria nº 28, publicada no Diário Oficial da União nº 108, Seção 1, página 177, em 11 de junho de 2021.(AU)

The utility of cerebrospinal fluid white cell count during the prognostic assessment for cryptococcal meningitis patients: a retrospective study.

BACKGROUND: The incidence of cryptococcal meningitis (CM) has gradually increased in recent years. Cerebrospinal fluid (CSF) cytology and cell count are very important for CM on etiology diagnosis and assessment of disease status and therapeutic response. However, the clinical significance of CSF white cell count (WCC) in CM patients is not fully understood. Using longitudinal data of CSF WCC and its relationship with clinical outcomes in CM patients, we aimed to elucidate the clinical significance of this test. METHODS: We retrospectively analyzed the medical records of 150 CM patients admitted to our hospital between January 2008 and December 2018. RESULTS: CM patients with lower baseline CSF WCC, CSF protein concentration or CD4/CD8 ratio, and those with altered mentation or HIV coinfection were more likely to have poor clinical outcome (P<0.05). CM patients with triple therapy during the induction period presented with a better clinical outcome (P<0.05). Baseline CSF WCC had a moderate positive correlation with peripheral CD4+ T lymphocyte count (r = 0.738, P < 0.001) and CD4+ T lymphocyte percentage (r = 0.616, P < 0.001). The best cut-off value to predict a poor clinical outcome was 40 cells/µL during baseline CSF WCC. The predictive model incorporating longitudinal data of CSF WCC had better sensitivity, specificity, and accuracy than a model incorporating only baseline CSF WCC data. CONCLUSIONS: Our results indicated that baseline CSF WCC and changes in CSF WCC over time could be used to assess the prognosis of CM patients.

Cryptococcal antigenemia and its predictors among HIV infected patients in resource limited settings: a systematic review.

BACKGROUND: Cryptococcosis is an opportunistic fungal infection that primarily affects people with advanced HIV/AIDS and is an important cause of morbidity and mortality around the globe. By far the most common presentation of the disease is cryptococcal meningitis (CM), which leads to an estimated 15-20% of all HIV related deaths worldwide, 75% of which are in sub-Saharan Africa. However, to the best of our knowledge there is quite limited reviewed data on the epidemiology of cryptococcal antigenemia in a large HIV-infected population in resource limited settings. METHODS: Articles published in English irrespective of the time of publication were systematically searched using comprehensive search strings from PubMed/Medline and SCOPUS. In addition, Google Scholar and Google databases were searched manually for grey literature. Two reviewers independently assessed study eligibility, extracted data, and assessed risk of bias. The pooled prevalence of cryptococcal antigenemia was determined with 95% confidence interval (CI). RESULTS: Among 2941 potential citations, we have included 22 studies with a total of 8338 HIV positive individuals. The studies were reported in ten different countries during the year (2007-2018). Most of the articles reported the mean CD4 count of the participants below 100 cells/µl. The pooled prevalence of cryptococcal antigenemia at different CD4 count and ART status was at 8% (95%CI: 6-10%) (ranged between 1.7 and 33%). Body mass index (BMI) < 18.5 kg/m2, CD4 count < 100 cells, patients presenting with headache and male gender were reported by two or more articles as an important predictors of cryptococcal antigenemia. CONCLUSIONS: Implementing a targeted screening of HIV patients with low BMI, CD4 count < 100 cells, having headache and males; and treatment for asymptomatic cryptococcal disease should be considered. Additional data is needed to better define the epidemiology of cryptococcal antigenemia and its predictors in resource limited settings in order to optimize the prevention, diagnosis, and treatment strategies.

Cryptococcal Meningitis Screening and Community-based Early Adherence Support in People With Advanced Human Immunodeficiency Virus Infection Starting Antiretroviral Therapy in Tanzania and Zambia: A Cost-effectiveness Analysis.

BACKGROUND: A randomized trial demonstrated that among people living with late-stage human immunodeficiency virus (HIV) infection initiating antiretroviral therapy, screening serum for cryptococcal antigen (CrAg) combined with adherence support reduced all-cause mortality by 28%, compared with standard clinic-based care. Here, we present the cost-effectiveness. METHODS: HIV-infected adults with CD4 count <200 cells/µL were randomized to either CrAg screening plus 4 weekly home visits to provide adherence support or to standard clinic-based care in Dar es Salaam and Lusaka. The primary economic outcome was health service care cost per life-year saved as the incremental cost-effectiveness ratio (ICER), based on 2017 US dollars. We used nonparametric bootstrapping to assess uncertainties and univariate deterministic sensitivity analysis to examine the impact of individual parameters on the ICER. RESULTS: Among the intervention and standard arms, 1001 and 998 participants, respectively, were enrolled. The annual mean cost per participant in the intervention arm was US$339 (95% confidence interval [CI], $331-$347), resulting in an incremental cost of the intervention of US$77 (95% CI, $66-$88). The incremental cost was similar when analysis was restricted to persons with CD4 count <100 cells/µL. The ICER for the intervention vs standard care, per life-year saved, was US$70 (95% CI, $43-$211) for all participants with CD4 count up to 200 cells/µL and US$91 (95% CI, $49-$443) among those with CD4 counts <100 cells /µL. Cost-effectveness was most sensitive to mortality estimates. CONCLUSIONS: Screening for cryptococcal antigen combined with a short period of adherence support, is cost-effective in resource-limited settings.

Healthcare Costs and Life-years Gained From Treatments Within the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) Trial on Cryptococcal Meningitis: A Comparison of Antifungal Induction Strategies in Sub-Saharan Africa.

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.

Evaluation of a national cryptococcal antigen screening program for HIV-infected patients in Uganda: A cost-effectiveness modeling analysis.

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/µL 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/µL 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.

Estimating the cost-per-result of a national reflexed Cryptococcal antigenaemia screening program: Forecasting the impact of potential HIV guideline changes and treatment goals.

INTRODUCTION: During 2016, the National Health Laboratory Service (NHLS) introduced laboratory-based reflexed Cryptococcal antigen (CrAg) screening to detect early Cryptococcal disease in immunosuppressed HIV+ patients with a confirmed CD4 count of 100 cells/µl or less. OBJECTIVE: The aim of this study was to assess cost-per-result of a national screening program across different tiers of laboratory service, with variable daily CrAg test volumes. The impact of potential ART treatment guideline and treatment target changes on CrAg volumes, platform choice and laboratory workflow are considered. METHODS: CD4 data (with counts < = 100 cells/µl) from the fiscal year 2015/16 were extracted from the NHLS Corporate Date Warehouse and used to project anticipated daily CrAg testing volumes with appropriately-matched CrAg testing platforms allocated at each of 52 NHLS CD4 laboratories. A cost-per-result was calculated for four scenarios, including the existing service status quo (Scenario-I), and three other settings (as Scenarios II-IV) which were based on information from recent antiretroviral (ART) guidelines, District Health Information System (DHIS) data and UNAIDS 90/90/90 HIV/AIDS treatment targets. Scenario-II forecast CD4 testing offered only to new ART initiates recorded at DHIS. Scenario-III projected all patients notified as HIV+, but not yet on ART (recorded at DHIS) and Scenario-IV forecast CrAg screening in 90% of estimated HIV+ patients across South Africa (also DHIS). Stata was used to assess daily CrAg volumes at the 5th, 10th, 25th, 50th, 75th, 90th and 95th percentiles across 52 CD4-laboratories. Daily volumes were used to determine technical effort/ operator staff costs (% full time equivalent) and cost-per-result for all scenarios. RESULTS: Daily volumes ranged between 3 and 64 samples for Scenario-I at the 5th and 95th percentile. Similarly, daily volumes ranges of 1-12, 2-45 and 5-100 CrAg-directed samples were noted for Scenario's II, III and IV respectively. A cut-off of 30 CrAg tests per day defined use of either LFA or EIA platform. LFA cost-per-result ranged from $8.24 to $5.44 and EIA cost-per-result between $5.58 and $4.88 across the range of test volumes. The technical effort across scenarios ranged from 3.2-27.6% depending on test volumes and platform used. CONCLUSION: The study reported the impact of programmatic testing requirements on varying CrAg test volumes that subsequently influenced choice of testing platform, laboratory workflow and cost-per-result. A novel percentiles approach is described that enables an overview of the cost-per-result across a national program. This approach facilitates cross-subsidisation of more expensive lower volume sites with cost-efficient, more centralized higher volume laboratories, mitigating against the risk of costing tests at a single site.

Cost-effectiveness of CRAG-LFA screening for cryptococcal meningitis among people living with HIV in Uganda.

BACKGROUND: Cryptococcal meningitis (CM) constitutes a significant source of mortality in resource-limited regions. Cryptococcal antigen (CRAG) can be detected in the blood before onset of meningitis. We sought to determine the cost-effectiveness of implementing CRAG screening using the recently developed CRAG lateral flow assay in Uganda compared to current practice without screening. METHODS: A decision-analytic model was constructed to compare two strategies for cryptococcal prevention among people living with HIV with CD4 < 100 in Uganda: No cryptococcal screening vs. CRAG screening with WHO-recommended preemptive treatment for CRAG-positive patients. The model was constructed to reflect primary HIV clinics in Uganda, with a cohort of HIV-infected patients with CD4 < 100 cells/uL. Primary outcomes were expected costs, DALYs, and incremental cost-effectiveness ratios (ICERs). We evaluated varying levels of programmatic implementation in secondary analysis. RESULTS: CRAG screening was considered highly cost-effective and was associated with an ICER of $6.14 per DALY averted compared to no screening (95% uncertainty range: $-20.32 to $36.47). Overall, implementation of CRAG screening was projected to cost $1.52 more per person, and was projected to result in a 40% relative reduction in cryptococcal-associated mortality. In probabilistic sensitivity analysis, CRAG screening was cost-effective in 100% of scenarios and cost saving (ie cheaper and more effective than no screening) in 30% of scenarios. Secondary analysis projected a total cost of $651,454 for 100% implementation of screening nationally, while averting 1228 deaths compared to no screening. CONCLUSION: CRAG screening for PLWH with low CD4 represents excellent value for money with the potential to prevent cryptococcal morbidity and mortality in Uganda.

The costs of providing antiretroviral therapy services to HIV-infected individuals presenting with advanced HIV disease at public health centres in Dar es Salaam, Tanzania: Findings from a randomised trial evaluating different health care strategies.

BACKGROUND: Understanding the costs associated with health care delivery strategies is essential for planning. There are few data on health service resources used by patients and their associated costs within antiretroviral (ART) programmes in Africa. MATERIAL AND METHODS: The study was nested within a large trial, which evaluated screening for cryptococcal meningitis and tuberculosis and a short initial period of home-based adherence support for patients initiating ART with advanced HIV disease in Tanzania and Zambia. The economic evaluation was done in Tanzania alone. We estimated costs of providing routine ART services from the health service provider's perspective using a micro-costing approach. Incremental costs for the different novel components of service delivery were also estimated. All costs were converted into US dollars (US$) and based on 2012 prices. RESULTS: Of 870 individuals enrolled in Tanzania, 434 were enrolled in the intervention arm and 436 in the standard care/control arm. Overall, the median (IQR) age and CD4 cell count at enrolment were 38 [31, 44] years and 52 [20, 89] cells/mm3, respectively. The mean per patient costs over the first three months and over a one year period of follow up following ART initiation in the standard care arm were US$ 107 (95%CI 101-112) and US$ 265 (95%CI 254-275) respectively. ART drugs, clinic visits and hospital admission constituted 50%, 19%, and 19% of the total cost per patient year, while diagnostic tests and non-ART drugs (co-trimoxazole) accounted for 10% and 2% of total per patient year costs. The incremental costs of the intervention to the health service over the first three months was US$ 59 (p<0.001; 95%CI 52-67) and over a one year period was US$ 67(p<0.001; 95%CI 50-83). This is equivalent to an increase of 55% (95%CI 51%-59%) in the mean cost of care over the first three months, and 25% (95%CI 20%-30%) increase over one year of follow up.

Recent advances in AIDS-related cryptococcal meningitis treatment with an emphasis on resource limited settings.

INTRODUCTION: Recent advances in the treatment and prevention of cryptococcal meningitis have the potential to decrease AIDS-related deaths. Areas covered: Targeted screening for asymptomatic cryptococcal antigenemia in persons with AIDS is a cost effective method for reducing early mortality in patients on antiretroviral therapy. For persons with symptomatic cryptococcal meningitis, optimal initial management with amphotericin and flucytosine improves survival compared to alternative therapies; however, amphotsericin is difficult to administer and flucytosine has not been available in middle or low income countries, where cryptococcal meningitis is most prevalent. Expert commentary: Improved care for cryptococcal meningitis patients in resource-limited settings is possible, and new treatment possibilities are emerging.

Cryptococcal antigen screening and early antifungal treatment to prevent cryptococcal meningitis: a review of the literature.

BACKGROUND: Screening individuals with AIDS for serum cryptococcal antigen (CrAg), followed by treatment of CrAg positives with antifungals, may prevent cryptococcal meningitis. This review examined data on CrAg screening and treatment in resource-limited settings. METHODS: We searched articles published during 2007-2014 on the effectiveness and cost-effectiveness of CrAg screening and treatment on the outcomes of mortality, morbidity, retention in care, quality of life, and/or prevention of ongoing HIV transmission. We rated overall quality of individual articles, summarized the body of evidence, the expected impact, and cost-effectiveness for each outcome. RESULTS: We identified 2613 articles. Eight met all inclusion criteria. Five studies addressed mortality and/or morbidity outcomes; all were observational and had small sample sizes; 3 lacked a comparison group. Ratings of study quality ranged from "medium" to "weak," and the quality of the overall body of evidence for mortality and morbidity outcomes was rated as "fair." The intervention's expected impact on mortality and morbidity was rated as "moderate." The 4 cost-effectiveness studies included in the analysis showed that CrAg screening and treatment interventions are highly cost-effective. No studies addressed retention in care, quality of life, or HIV transmission. CONCLUSIONS: Although limited, the body of evidence regarding CrAg screening and treatment suggests that the intervention may have an impact on preventing cryptococcal meningitis and death in persons with AIDS. Additional research is needed to quantify the intervention's effectiveness and identify optimal treatment dosing and implementation best practices.

Cost effectiveness of cryptococcal antigen screening as a strategy to prevent HIV-associated cryptococcal meningitis in South Africa.

OBJECTIVES: Cryptococcal meningitis (CM)-related mortality may be prevented by screening patients for sub-clinical cryptococcal antigenaemia (CRAG) at antiretroviral-therapy (ART) initiation and pre-emptively treating those testing positive. Prior to programmatic implementation in South Africa we performed a cost-effectiveness analysis of alternative preventive strategies for CM. DESIGN: Cost-effectiveness analysis. METHODS: Using South African data we modelled the cost-effectiveness of four strategies for patients with CD4 cell-counts <100 cells/µl starting ART 1) no screening or prophylaxis (standard of care), 2) universal primary fluconazole prophylaxis, 3) CRAG screening with fluconazole treatment if antigen-positive, 4) CRAG screening with lumbar puncture if antigen-positive and either amphotericin-B for those with CNS disease or fluconazole for those without. Analysis was limited to the first year of ART. RESULTS: The least costly strategy was CRAG screening followed by high-dose fluconazole treatment of all CRAG-positive individuals. This strategy dominated the standard of care at CRAG prevalence ≥0.6%. Although CRAG screening followed by lumbar puncture in all antigen-positive individuals was the most effective strategy clinically, the incremental benefit of LPs and amphotericin therapy for those with CNS disease was small and additional costs were large (US$158 versus US$51 per person year; incremental cost effectiveness ratio(ICER) US$889,267 per life year gained). Both CRAG screening strategies are less costly and more clinically effective than current practice. Primary prophylaxis is more effective than current practice, but relatively cost-ineffective (ICER US$20,495). CONCLUSIONS: CRAG screening would be a cost-effective strategy to prevent CM-related mortality among patients initiating ART in South Africa. These findings provide further justification for programmatic implementation of CRAG screening.

The utility of cerebrospinal fluid parameters in the early microbiological assessment of meningitis.

The measurement of cerebrospinal fluid (CSF) protein, glucose, and white cell count (WCC) is an essential part of the initial examination of CSF. The aim of this study was to determine the utility of CSF parameters in assessing the likely aetiological agent. A total of 2290 CSF samples from a 13-year period were retrospectively reviewed. The initial parameters were compared between bacterial, viral, and cryptococcal meningitis and cases where no pathogen was found. A protein concentration of <600 mg/L and a WCC <90 × 10(6)/L were found to be optimal cut-offs for excluding bacterial meningitis. A WCC of <25 × 10(6)/L was found to be optimal for excluding cryptococcal meningitis and a WCC of <10 × 10(6) for excluding viral meningitis. Decreased glucose concentration was found to be a poor indicator of the aetiological agent.

Integrating cryptococcal antigen screening and pre-emptive treatment into routine HIV care.

Cryptococcal meningitis is a leading cause of death in AIDS patients in sub-Saharan Africa. Cryptococcal antigen (CRAG) can be detected weeks before onset of symptoms, and those who are asymptomatic but CRAG positive have a high risk of subsequent cryptococcal meningitis and mortality. A new CRAG point of care immunochromatographic test is available that is remarkably easy to administer without laboratory infrastructure or expertise and has excellent sensitivity and specificity. We review the benefits of targeted CRAG screening, developments in CRAG diagnostics, and evidence regarding treatment options that can be implemented into routine HIV care in areas of high cryptococcal burden. Based on published CRAG+ prevalence rates of 2%-12%, the cost to save one life is between $20 to $140 in sub-Saharan Africa. We provide recommendations for implementation, pre-emptive treatment, and identify the gaps in our current knowledge.