Screening for cryptococcal antigens in HIV-positive patients before the initiation of antiretroviral therapy (ART) is a highly effective way of identifying those at risk of developing cryptococcal meningitis, researchers from South Africa have found.
Cryptococcal meningitis is one of the leading causes of death in ART patients who die during the first year of treatment, accounting for up to 20% of all deaths.
The majority of patients at risk of cryptococcal meningitis have detectable Cryptococcus antigen more than three weeks prior to developing meningitis, so a screening test could prevent many cases if patients are then able to receive prompt preventive treatment with the anti-fungal drug fluconazole, or with amphotericin B if a lumbar puncture shows evidence of central nervous system involvement.
Fluconazole has been shown to protect against the development of cryptococcal meningitis in people with low CD4 counts, whether they are taking ART or not, a randomised study in Uganda has shown.
If antigenaemia is left untreated, clinical disease may develop. Once ART is initiated, rapid restoration of pathogen-specific immune responses may cause the unmasking of subclinical disease, or it is possible that ART could lead to the clearance of asymptomatic infection. Screening for cryptococcal antigens would allow clinicians to treat pre-emptively prior to initiation of ART, according to factors such as baseline CD4 cell count.
Researchers from the University of Cape Town and St George’s, University of London, investigated the value of cryptococcal antigen screening in identifying patients who subsequently developed cryptococcal meningitis after commencing antiretroviral therapy.
The retrospective study, published in the April 1st 2009 issue of Clinical Infectious Diseases, found that of 707 HIV-positive ART-naive cohort patients tested for cryptococcal antigenemia, 7% were positive. 91% of these cases had a CD4 cell count below 100 cells/mm3. Cryptococcal antigenemia also remained a strong independent risk factor for death.
Patients who were cryptococcal antigen-positive were found to have lower baseline CD4 cell counts, were more likely to have a history of cryptococcal disease and were more likely to develop new cases of cryptococcal meningitis during ART. During the first year of ART, 28% of those who tested positive for cryptococcal antigens developed new or relapse cases of cryptococcal meningitis a median of 35 days after starting ART, while no cases developed in 661 patients with negative cryptococcal antigen test results during the first year of follow up.
If relapse cases were excluded, the researchers say, 98 patients would need to be screened in this cohort to identify one case, but if screening was restricted to those with a CD4 count below 100 cells/mm3, the number that would need to be screened to identify one case would fall to 52, with a cost per identified case of $206.
An analysis of those patients with lower baseline CD4 cell count (below 100 cells/mm3) showed that 13% had a positive cryptococcal antigen screening result.
Multivariate analysis showed that cryptococcal antigenaemia remained a strong independent risk factor for death even after adjustments for CD4 cell count, viral load, age and sex were made. 34% of those who tested antigen-positive died during the first year of ART, compared to only 11% of the antigen-negative patients. Once adjusted, the risk of death was 3.2 times greater in the antigen-positive patients than in the antigen-negative patients.
The antigen test used (Meridian Cryptococcal Latex Agglutination System) were found to be both highly sensitive and specific.
The researchers suggest that prospective studies to test the benefits of antigen-based screening need to be conducted, especially in relation to the use of fluconazole prophylaxis at lower antigen titres. Further research is also needed to determine whether lumbar puncture to determine central nervous system involvement is always necessary in antigenaemic patients.
Cryptococcal antigen screening for patients with a CD4 cell count below 100 cells/mm3 would allow for a targeted pre-emptive strategy, avoiding clinical disease and death, the researchers conclude.
Jarvis JN et al. Screening for cryptococcal antigenemia in patients accessing an antiretroviral treatment program in South Africa. Clinical Infectious Diseases. 48: 856-862, 2009.