Half a million deaths from cryptococcal meningitis a year in people with HIV

Researchers have estimated that there were about one million infections and half a million deaths from HIV-related cryptococcal meningitis worldwide in 2006. The findings published in the February 20^th edition of the journal AIDS also show that sub-Saharan Africa had the highest global burden of cryptococcal meningitis among people living with HIV.

The scientists (led by Benjamin J Park of the US Centers for Disease Control) did the study because although cryptococcal meningitis is one of the most widely reported HIV-related opportunistic infections, the global burden is unknown.

In regions with higher HIV burdens, particularly sub-Saharan Africa, cryptococcal meningitis has been reported to be on the increase (more than any other type of meningitis).

Studies from Zimbabwe, Rwanda, Central African Republic, Kenya and Tanzania have all shown increased incidence of cryptococcal meningitis as an AIDS-defining illness and a leading cause of AIDS mortality. Away from Africa, similar reports have emerged from India, Thailand and Asia-Pacific (see the December 2007 edition of HATIP, a clinical review on meningitis, for more information).

The investigators said that understanding the burden of cryptococcal meningitis is an important public health goal that would enable adequate planning and prioritisation of resources to enable effective prevention of the disease.

The investigators carried out a systematic review of all available literature published in English after 1996. Articles were selected if they used prospective or retrospective cohort study design, reported incidence among people living with HIV (PLHIV) or reported results which could allow calculation of incidence among PLHIV. The researchers found 19 studies which met eligibility criteria.

The scientists used the 2007 United Nations Programme on HIV/AIDS (UNAIDS) estimates for prevalence in adults and children as the global HIV estimates. They used median incidence rates from available studies to estimate region-specific cryptococcal incidence. For those regions where data were not available, the investigators imputed the rates using medians from regions of geographic proximity and similar economic development level.

The researchers estimated the regional cryptococcal burdens by multiplying the median incidence rate by the 2007 UNAIDS population prevalence estimate for each region. They then got the sum of all regional estimates to get the global burden of cryptococcal meningitis.

Due to variations in regional mortalities, the investigators estimated the deaths by using case-fatality rates from clinical trials conducted in high- and middle-income countries. They also reviewed case series, surveillance reports and reports on outcomes of cryptococcal meningitis and consulted with clinical experts. The scientists assumed a ten-week case-fatality rate of 9% among infected people in high-income countries and 55% for middle- and low-income countries, except sub-Saharan Africa where the estimate was 70%.

The investigators found cryptococcal incidence ranged from 4% to 12% per year in the the reports. They had at least one eligible report per region except for Eastern Europe and Central Asia, North Africa and the Middle East, and the Caribbean. The incidence for Eastern Europe and Central Asia, and North Africa and Middle East were estimated at 1.7% per year (the same as East Asia). For the Caribbean, the researchers assumed an incidence of 3.4% per year (the same as Latin America).

The scientists estimated 957,900 (range 371,700 to 1.54 million) cases of cryptococcal meningitis in 2006. Sub-Saharan Africa had the highest numbers of infection (720,000; range 144,000 to 1.3 million) followed by South and South-East Asia (120,000; range 24,000 to 216,000). Oceania had the fewest estimates (100 cases) followed by Western and Central Europe (500 cases). The researchers said these estimates of both infections and deaths will be useful for public health efforts to prevent, diagnose and treat the disease.

The researchers further estimated about 624,725 (range 124,956 to 1.2 million) cryptococcal meningitis deaths in 2006. Again sub-Saharan Africa had the highest (504,000; range 100,800 to 907,200) and Oceania had the fewest (9) death estimates.

When the scientists compared the death estimates for sub-Saharan Africa with other diseases other than HIV, they found that cryptococcal deaths were higher than tuberculosis (350,000), which has received greater public health attention, and were closely comparable to the childhood cluster diseases combined (530, 000), diarrhoeal diseases (708,000) and malaria (1.1million).

The researchers acknowledged that their estimates were restricted by limited availability of studies and the limitations of the available studies themselves. They also noted that provider-based cohort studies may be limited by incomplete follow-ups.

However, they felt the estimates were fairly accurate (particularly for sub-Saharan Africa) because their estimates are consistent with possible calculations from HIV-cohort and natural history studies which have reported that about 13 to 44% of AIDS deaths in the region result from cryptococcal meningitis.

Although most of the estimates in their study were determined prior to antiretroviral roll-out efforts, the researchers said the expansion of treatment is not likely to impact on the global burden soon because access to treatment is not yet universal and in some cases (such as South Africa) the rates of cryptococcal meningitis have actually gone up despite increased access to treatment.

Acknowledging that access to treatment can substantially reduce the disease among PLHIV, the scientists noted that the introduction of antiretroviral therapy has led to a drop in incidence of cryptococcal meningitis mainly in North America and Western Europe.

The researchers said their findings emphasise the growing and future need for attention to the problem in regions with higher HIV burden. They suggest the expansion of accurate and simple to implement diagnostic technologies, further research into the disease and expansion of treatment options .

In his commentary, Thomas S. Harrison of St. George’s, University of London, acknowledged that, despite study biases, there is little doubt that HIV-related cryptococcal mortality in Africa has been underestimated over the years..

He further said that the current study is important in stressing the need to address the problem of cryptococcal disease. Apart from fluconazole prophylaxis, he suggested pre-emptive fluconazole therapy for those who screen positive for cryptococcal antigen before starting antiretroviral treatment, suggesting that such strategy would prevent one third of cases that present after starting antiretroviral therapy.

He concluded that many patients in Africa simply present too late for current antifungal therapy to be effective. He also called for efforts to facilitate earlier diagnosis and treatment and trials to compare amphotericin B-based and oral antifungal regimens as well as to determine the best time to start anti-HIV treatment for those diagnosed with cryptococcal infection.