Cryptococcal meningitis persists in Botswana, despite high antiretroviral coverage

A study of cryptococcal meningitis incidence in people with HIV in Botswana shows that incidence has halved since 2015 and that the decline is correlated to increased antiretroviral coverage. But the study found that men were more likely to be diagnosed with cryptococcal meningitis than women and that illness related to advanced HIV remains a substantial problem despite achieving near-universal treatment coverage.

Writing in Clinical Infectious Diseases, Dr James Milburn of the Botswana Harvard AIDS Institute Partnership and colleagues say that cryptococcal meningitis data can be used to evaluate progress in tackling advanced HIV.

Cryptococcal meningitis and advanced HIV

Advanced HIV disease refers to a CD4 count below 200 (advanced immunodeficiency) or severe HIV-related symptoms and AIDS-defining opportunistic infections. The development of HIV-related symptoms can be prevented by early HIV diagnosis and treatment.

Advanced HIV is not just a sign of late presentation for care. It can also be a consequence of loss from care; people with HIV suffer a rapid CD4 cell decline after stopping treatment and may soon become vulnerable to opportunistic infections.

A modelling analysis published in 2022 estimated that 4.3 million people worldwide were living with advanced HIV (defined as a CD4 count below 200) in 2020 and that 580,000 people with HIV died from AIDS-defining illnesses in the same year. And last month, a World Health Organization study estimated almost two million people are living with advanced HIV in Africa, more than half already diagnosed with HIV but either untreated or virally unsuppressed despite treatment.

Since the World Health Organization recommended antiretroviral treatment for everyone as soon as possible after HIV diagnosis in 2015 guidance, most countries have adopted ‘treat all’ policies that seek to streamline care and speed up treatment initiation. These policies are intended to limit HIV transmission and reduce HIV-related illness through earlier diagnosis and treatment.

But the prevalence of advanced HIV is hard to track because CD4 counts – until recently the most reliable indicator of advanced HIV – are being carried out less regularly in low- and middle-income countries. Programme implementation of ‘treat all’ guidelines has tended to emphasise viral load testing and viral suppression as the goal of treatment, with less priority given to CD4 testing.

In the absence of CD4 count data, national HIV programmes need to consider other measures that can show the extent of advanced HIV and the impact of progress towards the 90-90-90 goals on illness and death related to advanced HIV.

Few high-HIV prevalence countries have national systems that can produce reliable data on mortality or causes of death. Knowing what proportion of deaths is due to advanced HIV remains challenging, so programmes need a reliable surrogate. Without measurement, there is likely to be little action to reduce the burden of death and illness caused by advanced HIV.

Cryptococcal meningitis remains one of the most common causes of death in people with HIV in Africa and is estimated to account for one in five deaths in people with HIV globally.

As the majority of people with symptoms of cryptococcal meningitis – severe headache, neck pain and fever – will present to a healthcare facility, information on the number of positive tests for cryptococcal infection provides a more reliable indicator of the incidence of advanced HIV-related illness than the monitoring of disseminated tuberculosis or pneumocystis jirovecii pneumonia. These conditions often have non-specific symptoms that are missed until too late or are undiagnosed due to lack of equipment or clinical inexperience in differentiating the symptoms.

However, there is a lack of information about the impact of antiretroviral treatment expansion on the incidence of cryptococcal meningitis, one of the easier opportunistic infections to monitor at a national level. Cryptococcal meningitis can be diagnosed using a cryptococcal antigen (CrAg) lateral flow test, a dipstick test that detects cryptococcal antigen in a sample of cerebrospinal fluid in less than 15 minutes. This testing method means faster diagnosis compared to laboratory culture or microscopy, although it still requires insertion of a needle into the spine (lumbar puncture) to obtain a sample of cerebrospinal fluid.

Data from Botswana

To assess the impact of its ‘treat all’ policy on the incidence of cryptococcal meningitis, Botswana’s national HIV treatment programme reviewed laboratory reports between 2015 and 2022. Botswana has one of the highest levels of antiretroviral treatment coverage in the world and reached the UNAIDS 95-95-95 target for diagnosis, treatment and viral suppression in 2022.

In this study, a case of cryptococcal meningitis was defined as a positive CrAg result (86% of diagnoses in 2022), a positive cerebrospinal India ink stain or a positive culture of Cryptococcus neoformans from cerebrospinal fluid. Data on cases were collected from national electronic records for laboratory tests.

Between 2015 and 2022, 1744 cases of cryptococcal meningitis were diagnosed in Botswana in 1440 people with HIV (15% of cases were recurrences more than 14 days after an initial diagnosis). Almost two-thirds (65%) of cases occurred in men, the median age at diagnosis was 38 years and the median CD4 count at diagnosis (within six months of diagnosis) was 48 cells.

Find out more: Huge fall in deaths after improving meningitis care for people with HIV in African hospitals

National incidence halved between 2015 and 2022, from 15 cases per 100,000 person-years to 7.4 cases per 100,000 person-years. When the population at risk was restricted to people with HIV, the incidence also halved, falling from 92 cases to 49 cases per 100,000 between 2015 and 2022.

Incidence was three times higher in men than in women (11.2 vs 4 per 100,000) in 2022.

Every 5% increase in antiretroviral coverage was associated with a 2.5 per 100,000 person-years decrease in incidence. However, when the analysis was restricted to the two national referral hospitals, as these sites had longitudinal data from prior to 2015, there was no difference in the rate of decline in cryptococcal meningitis cases after the implementation of the Treat-All policy in January 2017.

The study authors say that further research is needed to establish whether cryptococcal meningitis is still a frequent cause of illness or death in people with advanced HIV.

A neglected disease?

In a recent editorial commentary in The New England Journal of Medicine, researchers from three major institutions in the field of global health say that advanced HIV is in danger of becoming a neglected disease due to the focus on viral suppression as the key metric of treatment success.

A lack of research on tools to diagnose and treat opportunistic infections is accompanied by “a shrinking ability to diagnose the problem,” say the authors. Laboratory capacity to carry out CD4 count monitoring is declining, but “we believe that donors should continue supporting CD4 testing for diagnosing advanced HIV and guiding diagnosis and treatment of opportunistic infections,” they conclude.