Articles
The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis

https://doi.org/10.1016/S1473-3099(22)00499-6Get rights and content

Summary

Background

Cryptococcal meningitis is the most common cause of meningitis in adults living with HIV in sub-Saharan Africa. The estimates of national, regional, and global burden of cryptococcal meningitis are essential to guide prevention strategies and determine needs for diagnostic tests and treatments. We present a 2020 estimate of the global burden of HIV-associated cryptococcal infection (antigenaemia), cryptococcal meningitis, and cryptococcal-associated deaths.

Methods

We defined advanced HIV disease as adults with a CD4 count of less than 200 cells/μL, as this group is at highest risk for cryptococcosis. We used UNAIDS estimates (2019–20) and population-based HIV impact assessment surveys (2016–18) to estimate the number of adults with CD4 counts of less than 200 cells/μL at risk for cryptococcosis, by country and region. Secondly, we summarised cryptococcal antigenaemia prevalence in those with a CD4 count of less than 200 cells/μL by reviewing published literature. Thereafter, we calculated the number of cryptococcal antigen (CrAg)-positive people in each country and region by multiplying the number with advanced HIV disease at risk for cryptococcal infection by the cryptococcal antigenaemia prevalence of the respective country or region. We estimated progression from cryptococcal antigenaemia to meningitis or death based on estimates from the published literature.

Findings

We estimated that there were 4·3 million (IQR 3·0–4·8) adults with HIV and CD4 counts of less than 200 cells/μL globally in 2020. We calculated a mean global cryptococcal antigenaemia prevalence of 4·4% (95% CI 1·6–7·4) among HIV-positive people with CD4 counts of less than 200 cells/μL, corresponding to 179 000 cases (IQR 133 000–219 000) of cryptococcal antigenaemia globally in 2020. Annually, we estimated that there are 152 000 cases (111 000–185 000) of cryptococcal meningitis, resulting in 112 000 cryptococcal-related deaths (79 000–134 000). Globally, cryptococcal disease accounts for 19% (13–24) of AIDS-related mortality.

Interpretation

Despite a reduction in the estimated absolute global burden of HIV-associated cryptococcal meningitis compared with 2014, likely to be due to antiretroviral therapy expansion, cryptococcal disease still accounts for 19% of AIDS-related deaths, similar to 2014 estimates. To end cryptococcal meningitis deaths by 2030, cryptococcal diagnostics, meningitis treatments, and implementation of preventive screening are urgently needed.

Funding

None.

Introduction

Cryptococcal meningitis is the most common cause of meningitis in adults living with HIV in sub-Saharan Africa.1 In 2014, an estimated 223 100 people developed cryptococcal meningitis globally, resulting in 181 100 deaths, which account for 15% of all AIDS-related deaths.2 In 2020, UNAIDS estimated that 580 000 (range 400 000–850 000) AIDS-related deaths occurred among adults globally.

Cryptococcosis is unique among AIDS-related opportunistic infections in that cryptococcal antigen (CrAg) is detectable in the blood (antigenaemia) weeks to months before the onset of meningitis symptoms. Cryptococcal antigenaemia represents early disseminated infection, which is initially subclinical or minimally symptomatic. CrAg screening and pre-emptive treatment with fluconazole for those with cryptococcal antigenaemia, coupled with antiretroviral therapy (ART), reduces mortality in people with advanced HIV disease.3, 4 Despite clinical trial data confirming the survival benefit of CrAg screening and pre-emptive treatment,4 only a few nations have adopted a national CrAg screening programme, with variable uptake from the population. However, other countries are also considering the cost–benefit trade-off of this screen-and-treat strategy.5, 6

Estimates of the current incidence of cryptococcal disease are needed to quantify the diagnostic strategies, treatment commodities needed, and the potential lives saved with implementation of prevention and improved treatment strategies. Furthermore, new therapeutic strategies are being evaluated to reduce the high mortality associated with cryptococcal meningitis.7 Since the last estimate of HIV infection prevalence of 223 100 cases of cryptococcal infection globally (using data from 2014),2 global AIDS-related deaths among adults have decreased by an estimated 28%, from 800 000 deaths in 2014 to 580 000 in 2020. By 2020, ART coverage had increased to 27·5 million adults, up from 15 million in 2014, and integrase inhibitors are now first-line therapy in many large HIV programmes.

Research in context

Evidence before this study

Cryptococcus neoformans is the most common cause of meningitis among adults in sub-Saharan Africa, due to the burden of HIV infection. We searched PubMed using the terms “cryptococcal meningitis” and “burden” on May 31, 2022, with no restrictions on language or date. Two studies have estimated the global burden of cryptococcal infection. One of the studies was published in 2008 and estimated the global incidence of cryptococcosis as 957 900 cases per year (range 371 700–1 544 000). This estimate was based on published cohorts primarily from the era before antiretroviral therapy became available, and the wide ranges indicate the high level of uncertainty of these estimates. The study used just three incidence publications to derive estimates for sub-Saharan Africa. The other study was published in 2017, and estimated the global burden of cryptococcal meningitis as 223 100 cases per year. This estimate used 2014 data from UNAIDS, and emerging country-specific data on cryptococcal antigen (CrAg) prevalence. Since the last estimate, AIDS-related deaths have declined by 28%. Antiretroviral therapy coverage has increased to 27·5 million adults (up from 15 million in 2014) and integrase inhibitors are now first-line therapy in many large HIV programmes.

Added value of this study

This is an updated global estimate of the burden of cryptococcal infection, using data from 2020. The landscape of HIV infection has changed drastically since the last estimate of global burden in 2014. We provide an updated estimate of the global incidence of HIV-associated cryptococcal disease using published UNAIDS data on HIV incidence, antiretroviral therapy access, retention in care, and published CrAg prevalence data.

Implications of all the available evidence

The estimates of national, regional, and global burden of cryptococcal meningitis are key to guide prevention strategies and determine needs for diagnostic tests, antifungal medicines, and medical supplies, such as diagnostics, lumbar puncture needles, and manometers. We estimate that cryptococcal disease still accounts for 19% of AIDS-related deaths, similar to 2014 estimates. To end cryptococcal meningitis deaths by 2030, cryptococcal diagnostics, meningitis treatments, and implementation of preventive screening are critically needed.

In this Article, we present an updated estimate of the global burden of HIV-associated cryptococcal infection (antigenaemia), cryptococcal meningitis, and cryptococcal-associated deaths using 2020 data.

Section snippets

Definition of advanced HIV disease

We defined advanced HIV disease as adults with a CD4 count of less than 200 cells/μL, as this group is at highest risk for cryptococcosis. WHO defines advanced HIV disease as a CD4 count of less than 200 cells/μL or those with WHO clinical stage 3 or 4 of HIV disease.8 We used only CD4 estimates, as WHO clinical staging is frequently inaccurate when assessed by non-medical health-care workers, and therefore might not appropriately identify those severely immunosuppressed.9 Although children

Results

In 2020, UNAIDS estimated that 36·7 million adults (range 28·9–43·2) worldwide were living with HIV, of which 23·8 million (19·5–28·5) reside in sub-Saharan Africa. Globally, 27·5 million (range 16·2–38·0) adults were receiving ART. We estimated that 4·3 million (IQR 3·0–4·8) adults globally had advanced HIV disease (defined as CD4<200 cells/μL and corresponding to 12% of people living with HIV [range 10–15]), of whom 2·5 million (58%) live in sub-Saharan Africa.

We identified 53 CrAg prevalence

Discussion

Although there has been a reduction in the estimated absolute global burden of HIV-associated cryptococcal meningitis since 2014, probably due to ART expansion and, to some degree, CrAg screening programmes, cryptococcosis still results in 19% of AIDS-related deaths; the latter is largely unchanged from previous estimates in 2014. The persistent burden of infection suggests that death from cryptococcal infection remains a marker for failure in the HIV cascade of care. People at risk of

Data sharing

Raw data tables and individual country information will be made available with publication; please email the corresponding author to make such a request.

Declaration of interests

We declare no competing interests.

References (33)

  • GERMS-SA Annual Report 2019

  • Global AIDS monitoring 2022

  • R Rajasingham et al.

    Cryptococcal meningitis diagnostics and screening in the era of point-of-care laboratory testing

    J Clin Microbiol

    (2019)
  • N Longley et al.

    Cryptococcal antigen screening in patients initiating ART in South Africa: a prospective cohort study

    Clin Infect Dis

    (2016)
  • E Letang et al.

    Cryptococcal antigenemia in immunocompromised human immunodeficiency virus patients in rural Tanzania: a preventable cause of early mortality

    Open Forum Infect Dis

    (2015)
  • R Rajasingham et al.

    Cryptococcal meningitis treatment strategies in resource-limited settings: a cost-effectiveness analysis

    PLoS Med

    (2012)
  • Cited by (0)

    View full text