Screening for cryptococcal meningitis and adherence support reduce mortality among people starting ART in Africa

Screening and treatment for cryptococcal meningitis combined with a short period of adherence support has the potential to significantly reduce mortality rates among people with very low CD4 counts starting antiretroviral therapy (ART) in resource-limited settings, investigators report in The Lancet.

Twelve-month mortality rates were 28% lower for patients who received the enhanced care package including meningitis screening/treatment and adherence support compared to individuals who received the standard of care.

“Just four short home visits by lay workers to provide adherence support combined with screening for cryptococcal meningitis led to a significant reduction in mortality in patients infected with HIV starting ART with advanced disease,” comment the investigators. “The trial was large, done under real-life conditions, had a low loss to follow-up.”

Approximately 10 million people are now receiving ART in Africa. High loss to follow-up and mortality rates have been observed in this setting. Often, patients have a very low CD4 count when they start therapy and many deaths during the first year of ART are due to tuberculosis (TB) and cryptococcal meningitis.

An international team of investigators wanted to see if antigen screening and pre-emptive anti-fungal treatment for cryptococcal meningitis coupled with adherence support from lay workers reduced short-term mortality rates among people starting antiretroviral therapy.

They therefore designed an open-label, randomised controlled trial involving approximately 2000 adults living with HIV who had CD4 counts below 200 cells/mm³ and who started ART after February 2012.

Participants were recruited in Dar es Salaam, Tanzania, and Lusaka, Zambia. They were equally randomised to receive the intervention – meningitis screening/anti-fungal therapy and up to four visits from an adherence support worker in their homes – in addition to standard of care, or standard of care alone.

All participants were screened for TB at enrolment and participants randomised to the intervention arm in Zambia were also re-screened for TB six to eight weeks after starting ART.

The primary end-point was all-cause mortality twelve months after enrolment.

Median CD4 count at enrolment was very low (52 cells/mm³ in Tanzania and 77 cells/mm³ in Zambia).

In all, 11% of trial participants were newly diagnosed with TB at enrolment. A further 5% of individuals in the intervention arm in Tanzania tested positive for the infection when re-screened six to eight weeks later, an incidence of 28 per 100 person-years.

Overall, 4% of patients (n = 38) in the intervention arm were positive for cryptococcal meningitis antigen at enrolment. All but one of these patients started pre-emptive anti-fungal therapy within 24 hours of their diagnosis.

The loss-to-follow-up rate was 2% for both study arms.

Twelve months after starting ART, 13% of patients in the intervention arm had died compared to 18% of patients who received started of care alone. Mortality was a significant 28% lower in the intervention group compared to the standard-of-care group (p = 0.004).

The proportion of patients alive and retained in care after twelve months was 84% in the intervention arm compared to 80% in the standard-of-care group (p = 0.008).

Adherence rates were equally good in both study arms.

The mean per-participant cost of home support was $43 in Tanzania and $46 in Zambia.

“In a real-life scale-up of the intervention, the costs could be substantially lower because lay workers could be paid a lower salary than we paid to attract people quickly for trial purposes,” not the authors. “They could do more home visits per day because patients would be less scattered than our participants, and the costs of the cryptococcal antigen test might fall.”

They conclude, “findings of this large trial have shown that a simple intervention consisting of screening of patients presenting to African health services with advanced disease for cryptococcal meningitis combined with a short period of community support from lay workers reduces mortality substantially.”

The authors of an editorial praise the investigators for their study, and suggest its results “reiterate that targeted interventions within ART clinics for individuals with the highest mortality risk can be affordable and provide a significant survival benefit.”