James Milburn ^1 2, Ookeditse Ntwayagae ³, Rachita Suresh ¹, Kebatshabile Ngoni ¹, Cassie Northcott ¹, James Penney ¹, Matthew Kinsella ¹, Imogen Mechie ¹, Samuel Ensor ¹, Goitseone Thamae ¹, Tshepo Leeme ¹, David S Lawrence ^1 2, Tony Chebani ⁴, Daniel Grint ⁵, Mark W Tenforde ⁶, Ava Avalos ¹, Dinah Ramaabya ⁴, Justus Ogando ⁷, Margaret Mokomane ⁸, Madisa Mine ⁹, Joseph N Jarvis ^1 2

Affiliations Expand

• PMID: 38330295
• PMCID: PMC11327789
• DOI: 10.1093/cid/ciae066

Abstract

Background: Cryptococcal meningitis (CM) causes substantial mortality in African countries with a high prevalence of human immunodeficiency virus (HIV), despite advances in disease management and increasing antiretroviral therapy (ART) coverage. Reliable diagnosis of CM is cheap and more accessible than other indicators of advanced HIV disease burden such as CD4 testing or investigation for disseminated tuberculosis; therefore, monitoring CM incidence has the potential to serve as a valuable metric of HIV programmatic success.

Methods: Botswana national meningitis surveillance data from 2015 to 2022 were obtained from electronic health records. All electronic laboratory records from cerebrospinal fluid samples analyzed within government healthcare facilities in Botswana were extracted from a central online repository. Adjustments for missing data were made through triangulation with prospective cohort study datasets. CM case frequency was enumerated using a case definition and incidence calculated using national census data.

Results: A total of 1744 episodes of CM were identified; incidence declined from 15.0 (95% confidence interval [CI], 13.4-16.7) cases/100 000 person-years in 2015 to 7.4 (95% CI, 6.4-8.6) cases/100 000 person-years in 2022. However, the rate of decline slowed following the introduction of universal treatment in 2016. The highest incidence was observed in men and individuals aged 40-44 years. The proportion of cases diagnosed through cryptococcal antigen testing increased from 35.5% to 86.3%.

Conclusions: CM incidence has decreased in Botswana following expansion of ART coverage but persists at a stubbornly high incidence. Most cases are now diagnosed through the cheap and easy-to-use cryptococcal antigen test, highlighting the potential of using CM as key metric of program success in the Treat All era.

Keywords: Botswana; advanced HIV disease; cryptococcal meningitis; opportunistic infections.

© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

PubMed Disclaimer

Conflict of interest statement

Potential conflicts of interest. J. M. and J. N. J. have received investigator-initiated funding from bioMérieux. J. N. J. has received grants from the Centers for Disease Control and Prevention (CDC). D. S. L. has received salary support from Janssen, CDC, and NIHR. A. A. has received research support from ViiV Healthcare; research support and support for meetings and/or travel from Viatris Pharmaceuticals; contract from Botswana Harvard Health Partnership; consulting fees from UNAIDS; participation on an advisory board and support for meetings and/or travel from the World Health Organization; and membership on the University of Botswana Institutional Review Board. S. E. reports support for meetings and/or travel from the International AIDS Society. J. O. reports support for meetings and/or travel from the Clinton Health Access Initiative. I. M. reports support for meetings and/or travel from the Jill & Herbert Hunt Scholarship, Oxford University. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Cited by

• The Impact of GeneXpert Cerebrospinal Fluid Testing on Tuberculous Meningitis Diagnosis in Routine Care in Botswana.Milburn J, Ntwayagae O, Ngoni K, Suresh R, Lemme N, Northcott C, Penney J, Kinsella M, Mechie I, Ensor S, Chebani T, Grint D, Tenforde MW, Avalos A, Ramaabya D, Doyle R, Mokomane M, Mine M, Kranzer K, Jarvis JN.Open Forum Infect Dis. 2024 Aug 28;11(9):ofae489. doi: 10.1093/ofid/ofae489. eCollection 2024 Sep.PMID: 39301107 Free PMC article.

References

1. 1. Rajasingham R, Govender NP, Jordan A, et al. . The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis. Lancet Infect Dis 2022; 22:1748–55. – PMC – PubMed
   1. Stover J, Fidzani B, Molomo BC, Moeti T, Musuka G. Estimated HIV trends and program effects in Botswana. PLoS One 2008; 3:e3729. – PMC – PubMed
   1. Vinikoor MJ, Hachaambwa L. Advanced HIV disease during the ‘Treat All’ era in Botswana. AIDS 2020; 34:2321–3. – PMC – PubMed
   1. Joint United Nations Programme on HIV/AIDS (UNAIDS) . HIV and AIDS estimates Botswana. 2022. Available at: https://www.unaids.org/en/regionscountries/countries/botswana. Accessed 26 June 2023.
   1. Jarvis JN, Lawrence DS, Meya DB, et al. . Single-dose liposomal amphotericin B treatment for cryptococcal meningitis. N Engl J Med 2022; 386:1109–20. – PMC – PubMed
   1. Lebelonyane R, Mills LA, Mogorosi C, et al. . Advanced HIV disease in the Botswana combination prevention project: prevalence, risk factors, and outcomes. AIDS 2020; 34:2223–30. – PubMed
   1. Leeme TB, Mine M, Lechiile K, et al. . Utility of CD4 count testing in the era of universal ART: an analysis of routine laboratory data in Botswana. HIV Med 2021; 22:1–10. – PMC – PubMed
   1. Tenforde MW, Milton T, Rulaganyang I, et al. . Outcomes of reflex cryptococcal antigen (CrAg) screening in human immunodeficiency virus (HIV)-positive patients with CD4 counts of 100–200 cells/μL in Botswana. Clin Infect Dis 2021; 72:1635–8. – PMC – PubMed
   1. Tenforde MW, Mokomane M, Leeme T, et al. . Advanced human immunodeficiency virus disease in Botswana following successful antiretroviral therapy rollout: incidence of and temporal trends in cryptococcal meningitis. Clin Infect Dis 2017; 65:779–86. – PMC – PubMed
   1. Desanto DJ, Bangdiwala AS, Van Schalkwyk E, et al. . Evaluation of the effectiveness of a South African laboratory cryptococcal antigen screening programme using a retrospective cohort and a cluster-randomised trial design. BMJ Open 2022; 12:e054057.
   1. Huang HR, Fan LC, Rajbanshi B, Xu JF. Evaluation of a new cryptococcal antigen lateral flow immunoassay in serum, cerebrospinal fluid and urine for the diagnosis of cryptococcosis: a meta-analysis and systematic review. PLoS One 2015; 10:e0127117. – PMC – PubMed
   1. Pham MD, Agius PA, Romero L, et al. . Acceptability and feasibility of point-of-care CD4 testing on HIV continuum of care in low and middle income countries: a systematic review. BMC Health Serv Res 2016; 16:343. – PMC – PubMed
   1. Bateman M, Oladele R, Kolls JK. Diagnosing Pneumocystis jirovecii pneumonia: a review of current methods and novel approaches. Med Mycol 2020; 58:1015–28. – PMC – PubMed
   1. Sharma SK, Mohan A, Kohli M. Extrapulmonary tuberculosis. Expert Rev Respir Med 2021; 15:931–48. – PubMed
   1. Tenforde MW, Mokomane M, Leeme T, et al. . Epidemiology of adult meningitis during antiretroviral therapy scale-up in southern Africa: results from the Botswana national meningitis survey. J Infect 2019; 79:212–9. – PMC – PubMed
   1. Tenforde MW, Mokomane M, Leeme TB, et al. . Mortality in adult patients with culture-positive and culture-negative meningitis in the Botswana national meningitis survey: a prevalent cohort study. Lancet Infect Dis 2019; 19:740–9. – PMC – PubMed
   1. Soko RN, Burke RM, Feasey HRA, et al. . Effects of coronavirus disease pandemic on tuberculosis notifications, Malawi. Emerg Infect Dis 2021; 27:1831–9. – PMC – PubMed
   1. McFall AM, Menezes NP, Srikrishnan AK, et al. . Impact of the COVID-19 pandemic on HIV prevention and care services among key populations across 15 cities in India: a longitudinal assessment of clinic-based data. J Int AIDS Soc 2022; 25:e25960. – PMC – PubMed
   1. Ensor S, Mechie I, Ryan R, et al. . Measuring the impact of COVID-19 social distancing measures on sexual health behaviours and access to HIV and sexual and reproductive health services for people living with HIV in Botswana. Front Global Womens Health 2023; 4:981478. – PMC – PubMed
   1. Walker AS, Prendergast AJ, Mugyenyi P, et al. . Mortality in the year following antiretroviral therapy initiation in HIV-infected adults and children in Uganda and Zimbabwe. Clin Infect Dis 2012; 55:1707–18. – PMC – PubMed
   1. Boyd AT, Oboho I, Paulin H, et al. . Addressing advanced HIV disease and mortality in global HIV programming. AIDS Res Ther 2020; 17:40. – PMC – PubMed
   1. Munthali C, Taegtmeyer M, Garner PG, et al. . Diagnostic accuracy of the WHO clinical staging system for defining eligibility for ART in sub-Saharan Africa: a systematic review and meta-analysis. J Int AIDS Soc 2014; 17:18932. – PMC – PubMed

Related information

• MedGen

Grants and funding

• National Institute for Health and Care Research
• UK Department of Health and Social Care
• NH/NIH HHS/United States

LinkOut – more resources

• Full Text Sources
  • Ovid Technologies, Inc.
  • PubMed Central
  • Silverchair Information Systems
• Medical
  • MedlinePlus Health Information
• Research Materials
  • NCI CPTC Antibody Characterization Program