and effective antifungal therapy are essential to reduce mortality rates in
HIV-positive people with cryptococcal meningitis (CM), results of a study
published in the online edition of Clinical
Infectious Diseases show. The research also indicated that early
antiretroviral therapy (ART) did not lead to immune reconstitution illnesses
and would prevent deaths.
“This is the
largest study examining factors determining outcome in HIV-associated CM,”
comment the authors. “Earlier diagnosis,
more rapidly fungicidal amphotericin-based regimens, and prompt immune
reconstitution with ART are priorities for improving outcomes.”
meningitis accounts for between 10 and 20% of HIV-related deaths in
sub-Saharan Africa. It is normally associated with advanced immune suppression
and the median time to death following admission to hospital is just 10 to 13
team of researchers wanted to establish a firm understanding of the factors
associated with mortality so as to inform more effective treatment strategies.
pooled the results of nine trials conducted between 2002 and 2010 involving
HIV-positive people newly diagnosed with cryptococcal meningitis in Thailand,
South Africa, Malawi and Uganda. All the participants were antiretroviral-naive at baseline.
The participants were
followed for ten weeks after diagnosis. To establish the factors associated
with longer-term outcomes, participants in the South African cohort were monitored
for one year.
population comprised 501 participants. The median age was 34 years and 52% were
men. Three-quarters were already known to be HIV positive when cryptococcal
meningitis was diagnosed. Median CD4 cell count was only 23 cells/mm3.
with amphotericin B (0.7-1mg/kg/day) was initiated in 80% of participants and 20%
received fluconazole-based treatment (median 1200mg/day). Almost all (97%) of
the participants treated with fluconazole were located in Malawi and Uganda.
were high. All-cause mortality was 17% at week two and by week ten 34% of
participants had died.
ART was started by
244 of the 410 people who were still in care at week two. HIV therapy was
initiated a median of 30 days after starting antifungal treatment.
Baseline factors associated
with mortality at week two were older age (p = 0.009), seizures (p = 0.007),
altered mental state (p < 0.001), low CD4 cell count (p = 0.05), low
haemoglobin (p = 0.02), high white cell count (p < 0.001), high
cerebrospinal fluid fungal burden (p < 0.001) and treatment with fluconazole
(p = 0.005). After controlling for CD4 cell count and fungal burden, older age
(p = 0.02), altered mental state (p < 0.001), high white cell count (p =
0.002) and fluconazole therapy (p = 0.05) remained significant.
independently associated with mortality at week ten were age (p = 0.009),
altered mental status (p< 0.001), low body weight (p = 0.004), low haemoglobin
(p = 0.02), elevated white blood cell count (p= 0.02), cerebrospinal fluid
opening pressure (p = 0.002), fungal burden (p = 0.007) and fluconazole therapy
(p = 0.02).
longer-term outcomes among participants in South Africa was restricted to the
people who received treatment with amphotericin B (263 of 266). There was a
13% mortality rate among these participants at week two. This increased to 30% at
week ten and to 41% at the end of follow-up.
Of the patients
surviving to week two, 85% started ART a median of 31 days after initiating
antifungal treatment. Immune reconstitution inflammatory syndrome (IRIS)
developed in 13% (n = 22) of individuals, of whom 18% (n = 4) died. IRIS was
associated with fungal burden at day 14 (p = 0.007) but not ART (p = 0.4).
The majority of
deaths during the first two weeks of follow-up were attributed to cryptococcal
meningitis (85%). Subsequent deaths were mainly due to other HIV-related
complications (67%). Neither earlier initiation of ART nor IRIS was associated
with an increased risk of death for participants who started HIV therapy.
believe their findings have a number of important clinical implications.
“Earlier diagnosis of CM should be possible, resulting in lower fungal loads at
presentation and reduced mortality,” they conclude. “Screening for sub-clinical
infection with point-of-care antigen tests and pre-emptive antifungal
treatment, along with early ART, could prevent a substantial proportion of
clinical disease from developing.” The investigators also suggest that increasing
access to amphotericin B therapy should be a priority that and “prompt
initiation of ART is required to address the substantial proportion of deaths
in these patients that are HIV[-] but not CM-related.”