An analysis of national guidelines for the prevention, diagnosis and treatment of cryptococcal meningitis in sub-Saharan African countries: gaps and opportunities

Abstract

Introduction

Cryptococcal meningitis (CM) is an infection of the central nervous system that accounts for approximately 19% of AIDS-related mortality worldwide, with the highest burden being in sub-Saharan Africa (SSA). In 2022, the WHO released clinical guidelines on the prevention, diagnosis and treatment of CM, based on strong evidence-based studies. It is not known how these WHO guidelines are being integrated at the national level. This study aims to highlight national clinical guidelines for the prevention, diagnosis and management of CM across SSA and how these guidelines compare to WHO 2022 CM guidelines.

Methods

A comprehensive search was conducted to gather the current national clinical CM guidelines from all 46 countries in SSA. Methods to acquire copies of national guidelines included using online search engines, official government websites, WHO country office websites, direct contact with WHO officials and officers in national ministries of health as well as surveying the data repository of the International AIDS Society and HIV Policy Lab’s Advanced HIV Disease Dashboard. National CM guidelines were analysed to determine if they incorporated the recommendations in the 2022 WHO CM guidelines.

Results

Of the 46 countries in SSA, 37% (17/46) did not have established national CM screening and diagnostic guidelines and 35% (16/46) did not have established national CM treatment guidelines accessible through our methodology. Among the countries with CM guidelines, 21% (10/46) follow WHO recommendations for prevention, 30% (14/46) for diagnosis and 13% (6/46) for treatment.

Conclusion

Despite recent evidence to support diagnostic techniques and treatment approaches to improve CM outcomes, most national CM guidelines in SSA are not in accordance with the updated WHO recommendations, stressing a persistent gap in national adoption of CM international evidence-based guidelines.

WHAT IS ALREADY KNOWN ON THIS TOPIC.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• We believe that we have sufficient evidence to stress the importance of adopting evidence-based protocols and the need for continued support from global stakeholders to ensure the long-term sustainability of these efforts.

Introduction

Cryptococcal meningitis (CM) continues to be the leading cause of meningitis among people living with HIV (PLHIV). CM leads to approximately 152 000 new cases and accounts for over 112 000 deaths globally, with around 70% of this burden in sub-Saharan Africa (SSA).¹ The strategic framework surrounding CM has shifted considerably in recent years, marked by significant advances in both early detection and intervention strategies. In 2022, the WHO released updated universal guidelines for the prevention, diagnosis and management of CM.² These guidelines emphasise cryptococcal antigen (CrAg) screening for patients with advanced HIV disease (AHD) and CD4 count less than 100 cells/mm³, the use of lumbar puncture (LP) as a key diagnostic tool, preferred induction treatment regimen with a single liposomal amphotericin B (L-AmB) followed by flucytosine, the inclusion of CM medications in national essential medicines lists and pre-emptive antifungal therapy for patients with AHD. Identifying barriers to evidence-based care is an essential first step to improving CM outcomes in SSA. A principal factor in CM care starts at the national health policy level. This report aims to offer a comprehensive and updated descriptive analysis of national CM guidelines across SSA and their alignment with international WHO recommendations to gain insight into potential areas of improvement in policies regarding CM care aimed at reducing CM-associated morbidity and mortality in SSA.

Methods

The process of identification and extraction of data from national guidelines is detailed in figure 1. To identify national guidelines, a comprehensive online search was conducted across official national government websites and WHO country office websites for each SSA country (17 June 2024 to 12 August 2024). We also searched a website published by the non-government organisation International AIDS Society that gathers HIV-associated clinical guidelines across the world, and an issuance of documents from the HIV Policy Lab, a group working at the O’Neill Institute for National and Global Law at Georgetown University.^{3 4}

Figure 1. Framework for evaluating CM guidelines in sub-Saharan Africa. CM, cryptococcal meningitis.

Data on the national guidelines for the prevention, diagnosis and treatment of CM were gathered through relevant documents identified within national HIV clinical guidelines, antiretroviral therapy (ART) guidelines and standard treatment protocols. A total of 46 countries across SSA were surveyed, including 21 countries from Eastern and Southern Africa and 25 from Western and Central Africa. Guidelines were excluded if a more recent national HIV/AIDS or ART policy document was identified through our search, or if the guideline contained no relevant information on CM management.

15 core components from the 2022 WHO guidelines for the screening, diagnosis and treatment of CM were evaluated, as detailed in table 1. Two reviewers reviewed national guidelines of the surveyed SSA countries and categorised the incorporation of each WHO core component as fully included, partially included or not included. Any discrepancies that arose during the process were resolved through discussions between the two reviewers. Guidelines that were not available in English, such as Togo, the Central African Republic and Mozambique, were translated before being included in our review.

Table 1. Adaptation of 2022 WHO CM guidelines into National CM guidelines in sub-Saharan Africa.

WHO guidelines core component	Countries successfully incorporated/countries in sub-Saharan Africa
Screening and prevention
CrAg screening for all PLHIV with a CD4 count of less than 100.	22/46
Proper CM preventative measures following a positive CrAg screening which includes all four components of (1) pre-emptive antifungal treatment, (2) LP and CSF examination following + CrAg screening, (3) evaluation of signs and symptoms following CrAg + screening and (4) fluconazole prophylaxis given to all PLHIV with a CD4 <100 when CrAg screening unavailable.	10/46
Diagnosis
A preferred diagnostic approach of LP with opening pressure and CSF CrAg assay.	14/46
A secondary diagnostic approach of India Ink stain of CSF following LP.	9/46
A third preferred diagnostic approach of serum/whole blood CrAg assay when LP is unavailable or contraindicated.	11/46
Diagnostic approach of recurrent or persistent CM symptoms after proper treatment administration includes four components: (1) reviewing patient history for underlying treatment failure, (2) a second diagnostic LP with opening pressure, (3) an advisory to consider paradoxical immune reconstitution inflammatory syndrome, (4) sending CSF sample for fungal culture.	1/46
Treatment
Preferred induction phase regimen includes a single dose of high-dose liposomal amphotericin B, 14 days of flucytosine at 100 mg/kg/day and fluconazole at 1200 mg/day.	6/46
Consolidation phase of 800 mg/day of fluconazole for 8 weeks following induction phase.	16/46
Maintenance phase of 200 mg/day of fluconazole until immune reconstitution.	27/46
Contains an advisory against corticosteroid use in treating CM.	9/46
Advises delaying ART for 4–6 weeks following antifungal treatment initiation to avoid IRIS.	13/46
Recommends a periodic therapeutic LP for ICP management.	16/46
An advisory/recommendation for amphotericin B toxicity management that emphasise monitoring of nephrotoxicity.	13/46
Management recommendations for cryptococcal IRIS that included all four components: (1) continue ART, (2) manage ICP, (3) optimise or restart induction phase, (4) consider corticosteroid use if IRIS is life-threatening.	2/46
CM relapse management recommendations that contained all five components: (1) start or restart induction treatment, (2) manage ICP with therapeutic LP, (3) reinforce adherence, (4) ART delay 4–6 weeks (if not started yet), (5) consider fluconazole sensitivity testing.	1/46

ART, antiretroviral therapy; CM, cryptococcal meningitis; CrAg, cryptococcal Antigen; CSF, cerebrospinal Fluid; ICP, intracranial pressure; IRIS, immune reconstitution inflammatory syndrome; LP, lumbar puncture; PLHIV, people living with HIV.

Descriptive analyses were conducted to summarise the availability and alignment of national CM guidelines with the 2022 WHO recommendations across SSA countries.

Patient and public involvement

There was no direct involvement from patients or the public in the process, as this study is a review of existing guidelines and focused on analysing current approaches.

Results

Of the 46 countries in SSA, 63% (29/46) (figures2 3) were found to have CM screening, prevention and diagnostic guidelines and 65% (30/46) (figure 4) were found to have relevant CM treatment guidelines identified through our methodology. As shown in table 1, a total of 48% (22/46) of countries have adopted policies on screening for CrAg among those with CD4 counts below 100 cells/µL. 22% (10/46) of the countries fully included the four meningitis prevention guidelines following a positive CrAg. While 28% (13/46) followed only a subset of these meningitis preventive guidelines (online supplemental table 1). 30% (14/46) of countries have adopted policies on the preferred diagnostic approach of using an LP with a cerebrospinal fluid (CSF) CrAg assay, while 20% (9/46) of countries included the LP with a CSF India ink test as an alternative when CrAg assays are unavailable. Additionally, 24% (11/46) of countries use serum or whole blood CrAg assays when an LP cannot be performed. Lastly, Lesotho is the only country that has adopted an approach to persistent or recurrent CM symptoms (online supplemental table 1).

Figure 2. National CM prevention guidelines map. CM, cryptococcal meningitis; CrAg, cryptococcal antigen; PLHIV, people living with HIV.

Figure 3. National CM diagnostic guidelines map. CM, cryptococcal meningitis.

Figure 4. National CM treatment guidelines map. CM, cryptococcal meningitis.

As part of the induction treatment phase, only 13% (6/46) of SSA countries with accessible CM treatment policies have incorporated the use of single high-dose L-AmB. While the 14-day course of Flucytosine and 14-day course of fluconazole are only aligned with the guidelines of 26% (12/46) and 33% (15/46) of SSA countries, respectively. Lastly, alternative induction regimens are observed in only 8% (4/46) of SSA countries with accessible CM treatment guidelines. In the consolidation phase, 35% (16/46) of countries are using a protocol of 800 mg/day of fluconazole for 8 weeks and 59% (27/46) followed a 200 mg/day of fluconazole for the maintenance phase. Notably, 20% (9/46) of countries have advisories against the use of corticosteroids in treating CM while only 28% (13/46) have recommendations in delaying ART. Furthermore, 35% (16/46) of countries have policies around periodic therapeutic LP for managing intracranial pressure (ICP). Guidelines on managing amphotericin B toxicity were incorporated in 28% (13/46) of countries. For cases of cryptococcal immune reconstitution inflammatory syndrome (IRIS), only Malawi and Botswana have comprehensive management recommendations. Lastly, only Uganda has management recommendations for CM relapse (online supplemental table 2).

In high HIV burden Southern African countries (online supplemental tables 3,4), CrAg screening for PLHIV with low CD4 counts was consistently recommended, with guidance on meningitis prevention following a positive CrAg. LP with CSF CrAg assay was the preferred diagnostic approach, and serum or whole blood testing was advised when LP was not possible. Botswana and Eswatini included all key induction therapies such as L-Amb, flucytosine and fluconazole, while other countries generally followed WHO-recommended consolidation and maintenance protocols but had variable induction coverage. Periodic LPs for ICP management, monitoring for amphotericin B toxicity, ART delay and IRIS management were more consistently addressed than in lower-burden countries, which often lacked comprehensive screening, induction therapy and ICP guidance. Overall, high-burden Southern African countries demonstrated more complete CrAg screening and CM management guidance, though some elements, particularly L-AmB use, remain inconsistently implemented.

The distribution of the most recent CM guidelines that were identified through our methodology (online supplemental figures 1,2). Mauritania is operating under guidelines produced in 2013, and similarly, we were only able to access guidelines from the Central African Republic published in 2014. Four countries have guidelines from 2015 while Burundi and Somalia are following 2016 and 2017, respectively. Currently, 10 countries have accessible guidelines from 2019 to 2020 while only 2 have them for 2021. The largest proportion has their latest guidelines published in 2022. Finally, only Ethiopia and Uganda were found to have guidelines that were published in 2023. National CM guidelines were unavailable by our search methods for 16 countries.

Discussion

In SSA, Cryptococcus remains the most common cause of meningitis in adults living with HIV, contributing to the highest global burden of the disease and associated mortality. Despite global initiatives to combat CM guided by strong evidence-based randomised control studies, it continues to present a formidable challenge to public health.⁵ In this study, we analysed the different national CM clinical practice guidelines in SSA and compared them to WHO’s 2022 recommendations.

The ability to detect CrAg before the onset of meningitis has transformed the landscape of CM screening. This advancement paved the way for the WHO’s provisional recommendation for CrAg screening in 2011, which ultimately led to the first randomised controlled trial of CrAg screening in Africa.⁶ In 2016, a national reflex screening programme was launched and shed light on the epidemiology of CM in SSA. This approach was then proven to be cost-effective, reducing overall costs (US$17 629 lower) and saving more lives when compared with provider-initiated screening.⁷ However, despite this success, there seems to be a significant inter-regional disparity in adherence to the WHO recommendations on the screening for CrAg, with only 48% of regions aligning with these guidelines. Although there have been efforts focused on improving these programmes, a significant challenge persists. The lack of widespread availability and accessibility of these tests continues to hamper the adaptation and implementation of these guidelines.⁸ In addition, issues such as delays in CD4 testing, which is a crucial indicator of AHD and a gateway to HIV care, patient loss to follow-up and coordination challenges further disrupt the screening and prevention cascade.⁹

The persistent issue of delayed diagnosis of cryptococcal infections also remains prevalent in SSA.² Consistent with our findings, only a few countries have aligned with the four diagnostic guidelines suggested by WHO.² This frequent delay is not only compounded by logistical challenges, such as limited access to healthcare facilities, transportation difficulties and shortages of trained medical personnel, but is also heavily influenced by deep-rooted cultural and traditional beliefs that shape health-seeking behaviours.¹⁰ Along with the rising prevalence of self-medication and the ongoing reluctance to undergo LPs in several SSA countries, these factors highlight that the diagnostic challenge of CM in the region is multifaceted, involving both health system and sociocultural barriers.¹¹

Affordability remains a critical concern in the treatment paradigm for CM in SSA. In 2022, the WHO recommended the use of a single, high dose of L-Amb following its successful demonstration of both efficacy and reduced toxicity in the treatment of CM.⁸ However, despite this evidence, only six SSA countries have adopted this new regimen into their national guidelines. A possible key reason for this is its high cost and the inequitable distribution. Previously priced at US$16.25 per vial, with a full treatment course costing around US$195 per patient, this price-demand situation was poised to worsen in 2024 due to a 40% price hike to US$23 per vial.¹² This, combined with the imbalance in the allocation of generic L-AmB to low- and middle-income countries, may explain why some SSA countries continue to follow older guidelines and depend on conventional amphotericin B, fluconazole and flucytosine, which are available at a lower price.¹³ Further emphasising the urgent need for comprehensive strategies for increasing medication access, such as negotiating lower prices with manufacturers, offering subsidies to enhance the affordability of L-AmB and improving supply chain management to ensure its consistent availability.

On the policy front, there is a pressing need for governments to prioritise equitable access to medical services and ensure that clinical guidelines reflect the realities of these resource-limited settings. Although numerous global health funders are involved, successful collaboration requires a steadfast commitment to consistency in implementation and funding mechanisms. This is essential to ensure that resources are allocated effectively and that healthcare initiatives are sustained over time. As of 2023, approximately 39 million people live with HIV, with 65% in SSA.¹⁴ Despite all these developments, numerous individuals in these regions still find these resources unaffordable, inaccessible and inadequate.

Overall, our review provides an analysis of existing CM guidelines, shedding light on their clinical recommendations and assessing challenges faced in SSA. Our analysis further revealed both consistencies with WHO standards and notable gaps, emphasising the need for context-specific adjustments to improve their practical application in SSA. Nevertheless, our review does have limitations. Variability in data quality among SSA countries and the lack of updated information on CM guidelines in specific areas may impact our overall findings. Furthermore, our dependence on existing published and uploaded guidelines available online and the scarcity of direct field data may result in the omission of local adaptations or unreported practices that influence CM management. Additionally, internet access may also impact the availability of information, and our assessment of whether these guidelines exist, are being revised or carried out is subjective, as it relies only on our evaluation of the available resources. Also, some policies reflected older or partial guidance rather than being entirely absent, which may affect interpretation of guideline alignment. In the future, efforts should focus on equipping HIV care professionals through training with key stakeholders and fostering research on policy changes, particularly in CM care and consulting in-country experts to better interpret guidelines and assess local adherence.

Conclusion

Approximately 70% of CM guidelines in SSA we identified in our search do not align with WHO recommendations. Moreover, some countries may indeed lack specific CM guidelines altogether, further exacerbating the health inequalities across the region. By implementing evidence-based protocols, strengthening healthcare systems and promoting global collaboration, we can strive to minimise these disparities and improve patient outcomes throughout the region.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.