Study finds new single-dose cryptococcal meningitis drug effective, has fewer serious side effects

doctors in a hospital ward
  • Malawi has already incorporated results of this landmark trial into the its HIV treatment guidelines

A new study has shown that a new short course of treatment for HIV-associated Cryptococcal Meningitis is as effective at preventing deaths as the current longer recommended regimen with far fewer serious side effects.

The research in the New England Journal of Medicine involved a randomised trial in southern and eastern Africa and was conducted by an international research team, including scientists from the London School of Hygiene and Tropical Medicine and partners in Botswana, France, Malawi, South Africa, Uganda, the United Kingdom and Zimbabwe.

The researchers indicated the new ‘one-dose’ approach offers a practical, easier-to-administer and better-tolerated treatment for HIV-associated Cryptococcal meningitis in Africa with the potential to reduce the length and cost of hospital admissions.

This new trial, the largest of its kind, investigated whether a single high dose of liposomal amphotericin-B (L-AmB, Ambisome) paired with two oral antifungals, fluconazole and flucytosine, was as effective at reducing deaths as the currently recommended WHO first-line treatment based on seven days of Amphotericin-B therapy.

Study author and lead research doctor at UNC Project Malawi Dr. Cecilia Kanyama, explained the disease remains the most common type of adult meningitis in Sub Saharan Africa.

Dr. Kanyama: It's a milestone worth celebrating

To illustrate the magnitude of the problem locally, on a single day our wards can have six or more patients being treated for Cryptococcal meningitis.  Now having demonstrated an alternative treatment which is effective, but less on side effects, nursing care and overall cost on health system, is a milestone worth celebrating.

“Suffice to say that the Ministry of Health(MOH)  in Malawi has already incorporated results of this landmark trial into the Malawi HIV treatment guidelines and the clinical team implementing the research findings greatly appreciates the new regimen,” she revealed.

More than 800 adult patients with a first episode of the HIV-associated meningitis from five countries in southern and eastern Africa took part in the trial.

UNC Project Malawi, in partnership with Kamuzu Central Hospital enrolled 110 of these trial participants.

Half received the new intervention (AmBisome arm) and half received the current recommended standard care (control arm).

After 10 weeks, 25 percent (101 out of 407) of people in the AmBisome arm died compared to 29 percent (117 out of the 407) in the control arm.

This is among the lowest mortality rate reported from a major Cryptococcal meningitis trial in Africa, despite more than a quarter of participants presenting with very severe disease.

A laboratory technician at UNC Project

As well as being as effective at saving lives, drug-related toxicity was significantly lower in the new ‘one-dose’ AmBisome arm with Anaemia occurring in 13 percent of AmBisome participants compared to 39 percent in the control arm.

More participants in the control arm needed blood transfusions. There was also a difference in the impact on kidney function with far less drug related kidney toxicity in the one dose AmBisome arm than in the control arm.

Professor Tom Harrison from St George’s, University of London, who co-led the trial with Professor Joe Jarvis from the London School of Hygiene & Tropical Medicine and Botswana Harvard AIDS Institute Partnership, said: “These exciting results represent the culmination of a long programme of collaborative work to optimise antifungal drug combinations and reduce deaths from this terrible infection, and provide the strong evidence needed for policymakers to decide how Cryptococcal meningitis should be treated going forward.

“Fortunately, with the support of advocates and funders, Ambisome and flucytosine are now becoming more available, which is essential to enable wide-scale implementation of this novel treatment regimen.”

The lead author of the study Professor Jarvis stated: “The results of this trial have the potential to transform how Cryptococcal meningitis is treated and the management of advanced HIV-related disease in sub-Saharan Africa. It has far fewer significant side effects, which is obviously hugely important, and has the potential to prevent a large number of deaths in low-resource settings by being both easier to administer and cost-effective.”

Chawinga: We need well-trained hospital staff to fully translate the research findings into practice

The authors cited the current lack of access to Ambisome and flucytosine, the key components of this novel treatment regimen, in many low-resource settings as some of the study’s limitations.

The Ministry of Health is now providing Ambisome and Flucytosine in secondary and tertiary level hospitals. Health centres will access the drugs soon.

Chimwemwe Chawinga, study coordinator for Ambition, UNC Project Malawi, is now helping with transitional of care to the hospital staff.

He noted that the next crucial step would be to train staff on proper management of the disease inclusive of the new regimen.

“We need well-trained hospital staff to fully translate the research findings into practice”.

It was funded by the European and Developing Countries Clinical Trials Partnership (EDCTP), the Swedish International Development Agency, the UK Department of Health and Social Care, the UK Foreign Commonwealth and Development Office, UK Medical Research Council and Wellcome Trust through the Joint Global Health Trials scheme.