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.”