Dexamethasone Fails Against HIV-Related Fungal Meningitis

By Gene Emery

February 11, 2016

NEW YORK (Reuters Health) - Treating HIV patients with six weeks of dexamethasone added to standard antifungal therapy for cryptococcal meningitis increased the seriousness of their infection and may increase the mortality rate, according to a new Asian-African study.

The trial was halted after the enrollment of 451 volunteers because the rate of adverse events was so much higher than in the placebo group.

The infection is believed to kill about 600,000 people with HIV each year, mostly in South and Southeast Asia and sub-Saharan Africa. With conventional therapy, mortality is about 30% at 10 weeks.

There is evidence that dexamethasone therapy helps reduce mortality in cases of acute bacterial meningitis and tuberculous meningitis. In addition, the therapy is widely used against cryptococcal meningitis.

The new study, reported online February 10 in The New England Journal of Medicine, suggests that the treatment might cause more harm than good in HIV patients.

"We thought it was definitely worth trying," senior author Dr. Jeremy Day, head of the CNS-HIV infections research group for the Wellcome Trust Major Overseas Program Vietnam, told Reuters Health in a phone call from Ho Chi Minh City. "We thought it was likely to be safe because of its use in other conditions."

About 10% of patients in that region typically receive steroid therapy for cryptococcal meningitis.

Death rates with dexamethasone were elevated, although not significantly so.

At 10 weeks, 47% of the dexamethasone recipients had died versus 41% in the placebo group (hazard ratio 1.11, P=0.45). At six months, the rates were 57% and 49% respectively (HR 1.18, P=0.20).

But when patients were rated on degree of disability, only 13% of dexamethasone patients had a good outcome at the 10-week mark versus 25% of placebo recipients (P<0.001).

Renal events were three times more common with dexamethasone (P=0.004) and all of the eight cardiac events were in the dexamethasone group (P=0.004).

"We found compelling evidence that at the dose and regimen used in the study such use was harmful, with significantly increased rates of disability and excess severe adverse events, including infectious episodes and renal, gastrointestinal, and cardiac disorders," the researchers concluded.

"Certainly the lesson here is we shouldn't be giving steroids to all these patients," Dr. Day said.

The study was done at 13 hospitals in Vietnam, Indonesia, Laos, Thailand, Uganda and Malawi.

Daily doses were 0.3 mg/kg IV the first week, 0.2 mg/kg IV the second week, and 0.1 mg/kg orally the third week. In the fourth week they received 3 mg orally per day regardless of body weight, followed by 2 mg daily in week 5 and 1 mg daily in week 6.

All received combination antifungal therapy with amphotericin B and fluconazole.

One interesting aspect, Dr. Day said, was that the key findings didn't show up until the six month mark.

"If we had just stopped at 10 weeks follow-up, we wouldn't have had much evidence that dexamethasone was good or bad. That's the intensive period of treatment," he said. "We found that, if anything, the effect of dexamethasone was amplified at six months. So I think these trials we need to follow patients for at least six months."


N Engl J Med 2016.