Prevalence and mortality of cryptococcal disease in adults with advanced HIV in an urban tertiary hospital in Sierra Leone: a prospective study

Disseminated cryptococcal disease, most commonly manifesting as cryptococcal meningitis, is a serious opportunistic infection in people with advanced HIV infection. Globally it is estimated to kill over 180,000 people per year, with 75% of deaths occurring in sub-Saharan Africa [1]. Mortality of cryptococcal meningitis in low-income countries may exceed 70% [1].

In addition to scaling up HIV testing and antiretroviral therapy (ART) coverage, 2018 WHO guidelines recommend two strategies for the prevention of cryptococcal meningitis [2]. The preferred option is screening patients with CD4 below 100 for cryptococcal antigen (CrAg), which has been shown to be effective and cost-effective in a variety of low-resource settings [3]^, [4]. However, an alternative strategy of fluconazole primary prophylaxis for patients with CD4 below 100 may also be effective in reducing cryptococcal meningitis mortality [5, 6] and is recommended where CrAg screening is not available [2].

Sierra Leone has an estimated HIV prevalence of 1.5% [7]. Despite recent ART scale-up there continues to be a significant burden of undiagnosed infection, treatment failure, and advanced disease. There is a significant human resource for health gap [8] and the majority of HIV care is nurse-led. The only available treatment for cryptococcal meningitis is fluconazole monotherapy, which is known to be associated with inferior outcomes compared to highly recommended antifungal regimens [9].

There is no previous published study of the prevalence of cryptococcal disease and related mortality in Sierra Leone, or the prevalence of cryptococcal antigen in people living with HIV (PLHIV). We, therefore, performed a cross-sectional study to analyse a pilot programme of cryptococcal antigen screening in inpatients and outpatients PLHIVs with CD4 cell count< 100/μl at an urban referral hospital in Sierra Leone. We aimed to establish the prevalence of cryptococcal antigenaemia and diseases and to assess cryptococcal disease-related mortality in people living with HIV in this setting.

In total, 170 participants were screened (Table 1). 59% were female, with a median age of 36 years (IQR 30–43). At the time of testing, 54% were inpatients. 51% were newly diagnosed with HIV (defined as diagnosed with HIV less than 90 days prior to enrolment), and 56% were ART-naïve or had been newly initiated on ART (within the past 30 days), whereas 44% were ART-experienced. The median CD4 cell count was 45 cells/mm³ (IQR 23–63).

Of the eight participants who were CrAg positive, seven (87.5%) were female, with a median age of 35 (IQR 27.5–37) (Table 2). Six (75%) were inpatients at the time of diagnosis, and six (75%) were newly HIV-diagnosed and ART-naïve. The remaining two participants were taking ART at the time of CD4 testing (viral load results unavailable). On review by a clinician, seven (87.5%) had a history of at least one of headache, confusion or decreased conscious level (75, 50, and 50% respectively). Four (50%) had features of meningitis on examination. All eight participants underwent a lumbar puncture. Four (50%) had a CSF opening pressure greater than 20cmCSF, and five (62.5%) had a positive CSF CrAg.

The three participants with cryptococcal antigenaemia and a negative CSF CrAg were treated with oral fluconazole. CSF fungal cultures or polymerase chain reaction (PCR) were not performed as facilities for these techniques are not locally available. Two (67%) died as hospital inpatients at 0- and 1-days post-CrAg; both were confirmed as TB coinfected and neither participant was the cause of death felt clinically to be cryptococcal disease. The remaining participant was alive and established on ART at 8 weeks of follow-up. All five participants with cryptococcal meningitis were treated with high-dose fluconazole, and all received at least two therapeutic lumbar punctures. Three (60%) died at 3, 5 and 20 days after CrAg testing. Two (40%) were alive and established on ART at 8 weeks of follow-up.

Our study has demonstrated a prevalence of 4.7% (95% confidence interval 2.4–9.2) of cryptococcal infection among people with advanced HIV in a large tertiary hospital in Sierra Leone. To our knowledge, this is the first assessment of cryptococcal antigenaemia and cryptococcal disease-related mortality in this setting. This prevalence exceeds the previously recommended WHO threshold for the institution of routine screening for cryptococcal diseases [13]. In other published studies from West Africa, CrAg seroprevalence in PLHIV with CD4 < 100 cells/mm³ ranges from 2 to 21% [14‐18]. However, heterogeneity between study populations (for example, whether they include only newly-diagnosed ART-naïve individuals, and/or only outpatients) and evidence of regional variation [17] prohibits direct comparison.

It was feasible to conduct CrAg screening in this setting. Currently, there is no national policy on diagnosis, management and prevention of cryptococcal disease in Sierra Leone, but 2018 WHO guideline on cryptococcal diseases strongly recommends CrAg screening for adults and adolescents with CD4 cell count < 100 cells/mm³ [2]. This intervention has been shown to be cost-effective and effective in reducing cryptococcal-related mortality [4, 19], and it is hoped that this evidence will contribute to wider adoption in Sierra Leone.

The overall mortality among CrAg positive participants within 8 weeks of follow up was 62.5%. Sadly, this is comparable to other studies from the region [14] and to the overall estimate of 70% one-year mortality for people in LMICs with cryptococcal meningitis [1]. One contributor to the high mortality in our study is likely to be the use of fluconazole monotherapy in the treatment of cryptococcal meningitis. At the time of study initiation, this was still listed as an alternative treatment by the WHO guidelines but is no longer recommended for the treatment of cryptococcal meningitis given the abundance of evidence for superior antifungal regimens [2, 20]. Despite the new WHO recommendation of dual antifungal therapy as an induction regimen for cryptoccocal meningitis [2], fluconazole remains the only available treatment for cryptococcal disease in Sierra Leone. We, therefore, add our voices to those advocating for effective treatments for cryptococcal disease to be made more accessible to PLHIV in low-income countries [21]. Routinely screening patients with advanced HIV disease for CrAg as part of their pre-ART interventions and the provision of appropriate dual antifungal regimen should be instituted in Sierra Leone and similar countries to prevent the unwarranted morbidity and mortality [2, 22].

Given that several of the deceased participants were felt clinically to have a cause of death other than cryptococcal disease, it is important to deliver a “package” of care to those with advanced HIV (CD4 cell count < 200 cells/mm³) [23] which includes CrAg screening and other aspects including tuberculosis screening and prevention, and rapid ART initiation. Sierra Leone has recently operationalised a differentiated HIV service delivery guide which includes provisions directed towards people with advanced HIV.

Additional measures are also needed to reduce cryptococcal mortality in Sierra Leone. In a recent study, 21% of people with newly-diagnosed HIV in Freetown had a CD4 cell count below 100 cells/mm³, suggesting a need for earlier HIV testing, particularly given the limited resources for managing opportunistic infections [24]. Similar to other studies in sub-Saharan Africa [25], a significant proportion of participants in this study were ART-experienced, either with presumed treatment failure, poor adherence, or loss from care. This calls for prudent programmatic activities to improve treatment adherence. Many studies of cryptococcosis prevention exclusively focus on ART-naïve populations, but our finding that two (25%) of those with cryptococcal antigenaemia were ART-experienced suggests that CrAg screening should not be restricted to newly diagnosed HIV. PLHIV with virologic or immunologic treatment failure and those with symptoms who report after treatment interruptions should be considered for routine CrAg screening if their CD4 cell count is < 200 cells/mm³.

Our study has several limitations. First, as a single-site study in a tertiary hospital, it may not be representative of Sierra Leone with respect to both patient characteristics and feasibility of implementing screening. Secondly, 54% of participants were inpatients and those who presented with neurological symptoms were not excluded. Therefore, they may not truly represent the impact of a screening programme (ideally targeting asymptomatic outpatients.) However, this study was conducted in the context of implementation of a reflexive CrAg testing programme, and the study population does reflect those tested for CD4 cell count at the centre. Lack of fungal cultures and other diagnostic tests did not make it possible to confirm diagnoses of cryptococcosis or meningitis; nor was it possible to definitively establish the cause of death in deceased CrAg-positive participants.

Our study demonstrated a significant burden of cryptococcal disease at Connaught Hospital in Sierra Leone. We recommend for the national HIV programme and its partners to formulate and implement policies on screening and pre-emptive fluconazole therapy for cryptococcal diseases as part of a package of differentiated care for people with advanced HIV, in conjunction with programmatic strategies to improve HIV diagnosis and virological suppression. Affordable access to adequate antifungal regimens is required to improve outcomes for cryptococcal disease in sub-Saharan Africa.

Finally, antiretroviral treatment interruptions among the cohort of patients in this study are high. In order to prevent this, appropriate psychosocial counselling techniques and other programmatic strategies are needed.