Liposomal Amphotericin B for HIV-Associated Cryptococcal Meningitis
NEW YORK (Reuters Health) – When treating HIV-associated cryptococcal meningitis, a single dose of liposomal amphotericin B is just as effective as seven days of therapy with amphotericin B deoxycholate, the treatment recommended by the World Health Organization, according to results of a new clinical trial.
The drug was given in conjunction with 14 days of flucytosine and fluconazole. Conventional treatment calls for flucytosine and amphotericin B deoxycholate for seven days, followed by seven days of fluconazole.
“The easy-to-administer and less toxic single-dose liposomal amphotericin treatment will be feasible in many settings which are currently unable to deliver the 7-day conventional treatment regimen due to a lack of toxicity-monitoring reagents and equipment, or shortages of nursing staff,” said chief author Dr. Joseph Jarvis of the London School of Hygiene and Tropical Medicine.
“This will have significant benefits for patients who would otherwise be receiving inadequate treatment with oral fluconazole alone, which carries a mortality risk of 50-70%, saving many lives,” he told Reuters Health by email.
The trial included 814 patients in its intention-to-treat population, all from sub-Saharan Africa, where most deaths from HIV-related cryptococcal meningitis occur. There, the fungal infection that infects the brain kills an estimated 135,900 people annually.
The new study, reported in the New England Journal of Medicine, was an open-label randomized test done at eight hospitals with patients experiencing their first episode of cryptococcal meningitis. The drugs were either donated or purchased.
A week of intravenous amphotericin B deoxycholate therapy, as recommended by the WHO, can lead to kidney problems, anemia and electrolyte abnormalities. In contrast, liposomal amphotericin B, also given intravenously, can be administered at a high dose, has fewer side effects, penetrates the brain and has a long half-life there.
After 10 weeks, the death rate was 24.8% in the liposomal therapy group versus 28.7% among volunteers in the control group.
The noninferiority margin was 10 percentage points. An adjusted secondary analysis showed that the liposomal treatment was actually superior, which “gives us extra confidence in recommending the new regimen,” said Dr. Jarvis, a professor of tropical medicine and international health.
The rate of grade-3 or -4 adverse events was significantly lower with the liposomal combination than with the deoxycholate drug (50% vs. 62%).
When the team looked at potentially life-threatening adverse events, the rates were 22% with liposomal amphotericin B compared with 30% with amphotericin B deoxycholate (P=0.005).
Amphotericin B deoxycholate also produced a greater drop in hemoglobin levels during the first week of therapy, a decline that was six times more likely to occur than among liposomal amphotericin B recipients (P<0.001). That was reflected in the need for a blood transfusion, seen in 18% of the control group and 8% in the experimental group (P<0.001).
Control group patients were also three and a half times more likely to develop thrombophlebitis (P=0.001).
Because the study was done “in a range of health care settings across five countries in southern and eastern Africa with no loss to follow-up, our results are likely to be generalizable to other African settings with a high prevalence of HIV,” the researchers write.
“The trial results are already changing clinical practice,” Dr. Jarvis reported. “Based on the trial findings, national treatment guidelines have already been updated in several of the countries where the trial was conducted, including Botswana and Malawi, and patients in Malawi are already receiving the new treatment through their national HIV program. We are very hopeful that the World Health Organization will soon update their guidance based on the trial findings.”
A single dose of liposomal amphotericin B treatment is a bit more expensive than seven days of therapy with amphotericin B deoxycholate, “however, in real-world clinical practice it is likely that the new single-dose treatment will either be cost-neutral or even cost-saving,” Dr. Jarvis said. “Hospitalization costs can be considerable, particularly in South Africa and Botswana, and the savings made by being able to discharge some patients from hospital earlier with the new shorter treatment course could easily offset this slight cost difference.”
But he noted that “many of these patients are critically unwell, and will require at least 7 days of hospitalization anyway.”
“There is clear potential for the liposomal amphotericin B-based regimen proposed by Jarvis and colleagues to simplify management and improve outcomes of cryptococcal meningitis in high-burden settings,” write Drs. Mahomed-Yunus Moosa and Richard Lessells of the University of KwaZulu-Natal in Durban, South Africa, in a linked editorial.
However, “the fact that one in four patients still dies within 10 weeks is unacceptable,” they said.
SOURCE: https://bit.ly/3CRsyUy and https://bit.ly/36ul4uD The New England Journal of Medicine, online March 23, 2022.
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