Five-Week Delay in ART Improves Survival When Meningitis Hits HIV Patients

  • June 26, 2014

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By Gene Emery

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NEW YORK - Treatment delayed isn't always treatment denied.

A new study suggests that people infected with HIV and cryptococcal meningitis tend to have a better chance of survival if their antiretroviral therapy (ART) is deferred for five weeks after the meningitis is diagnosed, rather than started one to two weeks after diagnosis.

The difference in survival rates was pronounced enough for the trial to be halted early.

"It probably should change practice. It will change our practice," said Dr. Peter Pappas, professor of medicine at the University of Alabama at Birmingham, who was not connected with the study.

Lead author Dr. David Boulware of the University of Minnesota in Minneapolis said the findings have already altered World Health Organization guidelines, as word of the results has filtered out. The findings are reported in the June 26 New England Journal of Medicine.

Among people infected with HIV in Africa, cryptococcal meningitis is responsible for 20% to 25% of deaths. In the US, about 3400 people are hospitalized each year with the fungal infection and at least 20% die as a result. Roughly half of infected patients are also infected with HIV, Dr. Boulware said.

The new study looked at 177 HIV patients from Uganda and South Africa who had been diagnosed with cryptococcal meningitis and had yet to receive ART.

All received amphotericin B at a dose of 0.7 mg to 1.0 mg per kg of body weight per day, along with 800 mg of fluconazole daily for 14 days and at least 12 weeks of fluconazole consolidation therapy. The ART therapy was either zidovudine or stavudine, with lamivudine and efavirenz.

At the 26-week mark, 45% of the patients who received ART within two weeks of diagnosis had died, versus 30% for the participants whose ART was deferred for five weeks (P=0.03).

The death rate among those getting early treatment was nearly four times higher for patients who had white cell levels of less than 5 per cubic mm of cerebrospinal fluid (hazard ratio, 3.87; P=0.008).

Most of the extra deaths came two to five weeks after diagnosis.

Overall, there were 19 cryptococcal meningitis-related deaths among the 88 patients who received early treatment and 10 cryptococcal meningitis-related deaths among the 89 who received delayed ART. Other causes of death, such as bacterial sepsis, tuberculosis-related causes, immune reconstitution inflammatory syndrome, pulmonary embolism, and cryptococcal meningitis relapse, occurred at similar rates in the two groups.

"We believe the main finding of this multisite treatment-strategy trial is generalizable to affected persons in resource-limited and high-income countries," the researchers conclude.

Delaying therapy "goes against common standards with HIV, where earlier treatment is better. So it was kind of a shock when the study was stopped and delayed treatment turned out to be better," Dr. Boulware told Reuters Health. "But infections in the brain are different from other infections."

"There's this paradox where, as the immune system comes back, it actually causes more inflammation in the brain," Dr. Boulware said. "And that's why there's higher mortality in the early group."

In some ways, Dr. Pappas told Reuters Health, the results shouldn't be surprising.

"It may be that this is more intuitive than we might have thought, in that you need to get control of the organism and get it beat down before you do things that augment the immune response," he said. "If you don't, your immune response may be more than you can handle and when you get the buildup of pressure and inflammation in the closed space of the brain, it can cause more damage than most people can handle."

The study is called COAT or Cryptococcal Optimal ART Timing.


N Engl J Med 2014.

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