Can cryptococcal antigen screening and treatment improve outcomes?

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

Longley N, Jarvis JN, Meintjes G, Boulle A, Cross A, Kelly N, Govender NP, Bekker LG, Wood R, Harrison TS. Clin Infect Dis. 2015 Nov 12. pii: civ936. [Epub ahead of print]

Background: Retrospective data suggest that cryptococcal antigen (CrAg) screening in patients with late-stage HIV initiating antiretrovirals may reduce cryptococcal disease and deaths. Prospective data are limited.

Methods: CrAg was measured using lateral flow assays (LFA) and latex agglutination (LA) tests in 645 HIV-positive, ART-naive patients with CD4 counts ≤100 cells/µL in Cape Town, South Africa. CrAg-positive patients were offered lumbar puncture (LP) and treated with antifungals. Patients were started on ART between 2-4 weeks and followed up for 1 year.

Results: 4.3% (28/645) of patients were CrAg-positive in serum and plasma with LFA. These included 16 also positive by urine LFA (2.5% of total screened) and 7 by serum LA (1.1% of total). In 4 of 10 LFA-positive cases agreeing to LP, the cerebrospinal fluid (CSF) CrAg-LFA was positive. A positive CSF CrAg was associated with higher screening plasma/serum LFA titres. Among the 28 CrAg-positive patients, mortality was 14.3% at 10 weeks and 25% at 12 months. Only one CrAg-positive patient, who defaulted from care, died from cryptococcal meningitis (CM). Mortality in CrAg-negative patients was 11.5% at 1 year. Only 2 possible CM cases were identified in CrAg-negative patients.

Conclusions: Cryptococcal antigen screening of individuals initiating ART and pre-emptive fluconazole treatment of CrAg-positive patients resulted in markedly fewer cases of cryptococcal meningitis compared to historic unscreened cohorts. Studies are needed to refine management of CrAg positive patients, who have high mortality that does not appear to be wholly attributable to cryptococcal disease.

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Editor’s notes: In sub-Saharan Africa, cryptococcal meningitis is the leading cause of adult meningitis. Even with current antifungal therapies, mortality remains high. Asymptomatic cryptococcal antigenemia precedes cryptococcal meningitis and independently predicts mortality in people initiating antiretroviral therapy (ART). Therefore, preventing disease in people found to be cryptococcal antigen (CrAg) positive at ART initiation has potential to reduce morbidity and mortality.

In this prospective study in Cape Town, South Africa, people initiating ART with low CD4 counts (≤100 cells/ μL) underwent CrAg screening. People without proven cryptocococcal meningitis but with a positive cryptococcal antigen test were pre-emptively treated with oral fluconazole, and were started on ART within two to four weeks. They were followed up for a year. This approach did not lead to delays in ART initiation, and resulted in fewer cryptococcal meningitis cases. However, despite pre-emptive antifungal therapy, mortality remained twice as high among people who were CrAg positive, even after adjustment for CD4 cell count. This high mortality appears not completely attributable to cryptococcal disease, and the authors hypothesize that cryptococcal antigen positivity in itself is a marker for severe immunosuppression.

Interestingly, the authors found a lower prevalence of asymptomatic antigenaemia than expected: about 4% in this study (2011-2014) compared to 6% in a similar population in 2002 to 2005. The authors suggest that earlier HIV diagnosis and improved access to care may be the main reasons for this, proposing that reducing the duration of severe immunosuppression may reduce the risk of cryptococcal disease, either due to reactivation or rapid progression of new infection.

The authors conclude that the optimal strategies for implementing screening and the optimal pre-emptive antifungal regimen remain to be defined. Screening may best be delivered as part of a combined opportunistic infection screening and treatment package for people presenting with low CD4 counts. 

Avoid TB deaths
Comorbidity, HIV Treatment
Africa
South Africa
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