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Cryptococcal antigen screening beneficial among HIV patients initiating ART
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Screening for cryptococcal antigen in patients with late-stage HIV initiating ART could identify candidates for pre-emptive treatment and significantly reduce cases of cryptococcal meningitis, according to data recently published in Clinical Infectious Diseases.
“In many low-resource settings, patients continue to present late to ART treatment programs with advanced immunosuppression, and many die of HIV-related illness in the weeks just prior to, and the months following, initiation of ART,” Nicky Longley, of the Desmond Tutu HIV Center and Institute of Infectious Disease and Molecular Medicine at the University of Cape Town, South Africa, and colleagues wrote. “Retrospective data have shown that routine screening for cryptococcal antigen (CrAg) to detect subclinical disease in patients presenting to ART programs can identify which patients are at risk of developing [cryptococcal meningitis (CM)]. Once identified, these patients could then be given pre-emptive treatment with high-dose fluconazole to prevent them from developing severe disease.”
To examine the benefits of CrAg testing and early CM treatment, researchers enrolled 645 adult HIV patients with CD4 counts equal to or fewer than 100 cells/μL presenting to two Cape Town ART clinics from May 2011 to April 2014. Participants had no prior history of ART or cryptococcal disease, and provided serum, plasma, urine samples and in some cases whole blood for CrAg screening upon initiation of ART. Tests were conducted using lateral flow assay (LFA) as well as latex agglutination assay (LA). Those testing positive were questioned and examined for signs of clinical or subclinical CM, and were treated with recommended antifungals based on case characteristics. Follow-ups for patients testing positive were conducted every 2 weeks for 10 weeks, and then every 3 months throughout the first year of ART, while those screening negative were seen every 3 months for the first year of ART. The primary study outcome was CM incidence within the first year of ART, with other areas of examination including the proportion of CrAg-positive patients who developed cryptococcal immune reconstitution inflammatory syndrome, concordance among various testing samples, time to ART in positive and negative patients, potential relationships between antigen titer and cerebrospinal fluid results, and all-cause mortality. Study results were compared with outcomes previously recorded among cohorts without routine screening.
Screening reduces cryptococcal meningitis, all-cause mortality
The researchers reported positive LFA results from 4.3% of patients, and positive LA results from 1.1%. Diagnoses from all tests and sample sources were found to be 100% concordant, and no clinical or laboratory differences were observed between patients with positive or negative results. Of the 10 patients with positive serum or plasma LFA results who consented to lumbar puncture, 40% were cerebral spinal fluid CrAg LFA-positive and demonstrated higher serum or plasma LFA titers. Two possible CM cases were identified among participants with negative results.
Mortality among CrAg-positive patients was 14.3% at 10 weeks and 25% at 12 months, while rates among CrAg-negative patients were 5.3% and 11.5% at the same cutoffs, according to the researchers. Cryptococcal disease was related to the deaths of two patients within the first year of ART, both of whom did not adhere to ART. Comparisons to CM mortality rates as high as 20% seen in previous unscreened cohorts suggest that screening and pre-emptive antifungal treatment reduce the incidence of CM-related deaths, according to the researchers; however, mortality due to other causes among immunosuppressed patients are still in need of investigation.
“Optimal strategies for implementing screening still need to be defined,” Longley and colleagues wrote. “The very high mortality in CrAg-positive patients despite antifungal therapy suggests that CrAg screening may be best implemented as part of a combined [opportunistic infection] screening and intervention package for patients in this high risk group. Further work is needed to better understand the persisting high mortality, and how best to incorporate screening for CM and other [opportunistic infections] into routine care pathways.”
Previous data support testing, but treatment questions remain
Earlier studies have identified the benefits of CrAg testing in regions outside of Africa reporting lower incidences of HIV.
In 2014, Jennie McKenney, a doctoral student at the Fielding School of Public Health at the University of California, Los Angeles, and colleagues examined 1,872 stored serum specimens collected from U.S. HIV patients between 1982 and 2012, and found that 2.9% were positive for CrAg. When reviewing patient records they observed a significant decrease in patient survival among those whose specimens tested CrAg-positive, and concluded that incidence rates in the U.S. were “above the published cost-effectiveness threshold for routine screening and treatment in those with CD4 count less than 100 cells/μL.”
Another study presented earlier this year at the European Congress of Clinical Microbiology and Infectious Diseases found evidence of frequent cryptococcal antigenemia among German patients at various stages of HIV infection. CrAg results correctly identified clinically relevant cryptococcal disease in nearly all cases, and average overall time to diagnosis was reduced among patients who received testing.
Charles Michael van der Horst
As more evidence suggests CrAg testing as a potential addition to routine HIV care, it may be worthwhile to focus research on determining optimal antifungal treatments for the highly lethal condition, according to Charles Michael van der Horst, MD, professor in the department of medicine at the University of North Carolina, and Arthur Timothy Jackson, MB BCh BAO, specialist consultant in infectious diseases at Mercy University Hospital, Cork, Ireland. In an editorial published alongside the data from Longley and colleagues, the two researchers wrote that future studies examining various treatments among subclinical infection populations identified through CrAg testing could further reduces deaths resulting from CM.
“Given its wide availability and low cost in areas of high HIV prevalence, fluconazole certainly seems to be the most reasonable first option to investigate, and it has performed well in this study,” van der Horst and Jackson wrote. “Although both the NIH and USAID have not been funding studies such as this, larger randomized clinical trials comparing dosing regimens, alternative antifungals, possible combination therapies and possibly incorporating a control group who only receive ART could be useful to answer some of the questions raised by this study.” – by Dave Muoio
References:
Jackson AT, et al. Clin Infect Dis. 2015;doi:10.1093/cid/civ939.
Katchanov J, et al. Abstract P0526. Presented at: European Congress of Clinical Microbiology and Infectious Diseases; April 25-28, 2015; Copenhagen, Denmark.
Longley N, et al. Clin Infect Dis. 2015;doi:10.1093/cid/civ936.
McKenney J. Clin Infect Dis. 2014;doi:10.1093/cid/ciu937.
Disclosure: Jackson, Longley, McKinney and van der Horst report no relevant financial disclosures. Please see the full studies for a list of all other authors’ relevant financial disclosures.