Regimen change may halve cryptococcal meningitis deaths

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CryptococcalmeningitisThe Advancing Cryptococcal Treatment for Africa (ACTA) Trial shows relatively simple regimen changes can cut mortality rates in the region of 70% to 25-30%. In response, the World Health Organisation (WHO) has issued new cryptococcal disease guidelines.

Experts aim to halve the number of deaths from a type of meningitis by changing drug treatment as a result of the study.

The fungal infection cryptococcal meningitis is responsible for more than 180,000 deaths per year worldwide, mainly in HIV-infected patients.

Current treatment for this type of meningitis is difficult and mortality rates in Africa in routine care are in the region of 70% – as high as for the Ebola virus infection. Under the new suggested treatment regimen, the research indicates this would fall to 25-35% – potentially saving up to 80,000 lives a year.

An international team led by Professor Tom Harrison at St George’s University of London has published results of their Advancing Cryptococcal Treatment for Africa (ACTA) Trial, which shows relatively simple changes can save tens of thousands of lives a year.

In the light of the new findings, the World Health Organisation (WHO) has issued new cryptococcal disease guidelines recommending a one-week drug course.

The shorter, safer and more effective antifungal drug regimen treats cryptococcal meningitis with a one-week combination antifungal regimen of amphotericin B and flucytosine for the initial induction phase of treatment. This one-week regimen has been shown to reduce mortality by at least a third, compared to the previously recommended two-week regimen.

Tom Harrison, professor of infectious diseases, said: “The research programme has taken 15 years and has at times been a long hard journey but we are delighted to be able to show a way forward to dramatically cut the number of deaths from meningitis.

“We are calling for the generic manufacture and widespread availability of the drug flucytosine, and plan large-scale programmes of implementation with partner countries and international agencies that could result in the mortality from this dreaded infection being halved.

“Our trial has shown beyond doubt that flucytosine is an essential medicine for the treatment of meningitis related to HIV. However, it is currently completely unavailable in Africa which is where three quarters of the global cases occur.”

The St George’s team worked with partners at Liverpool School of Tropical Medicine, The Institut Pasteur, Paris Descartes Medical School and hospitals in Malawi, Zambia, Cameroon and Tanzania for the study whose results were announced at the International AIDS Society meeting in Paris on 24 July .

The trial, funded by the UK Medical Research Council and the ANRS (the French national agency for research on Aids and viral hepatitis), is the largest conducted to date, including over 700 participants, on the treatment of cryptococcal meningitis.

Abstract
Background: Cryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)–related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy.
Methods: We randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks.
Results: A total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P=0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen.
Conclusions: One week of amphotericin B plus flucytosine and 2 weeks of fluconazole plus flucytosine were effective as induction therapy for cryptococcal meningitis in resource-limited settings.

Authors
Síle F Molloy, Cecilia Kanyama, Robert S Heyderman, Angela Loyse, Charles Kouanfack, Duncan Chanda, Sayoki Mfinanga, Elvis Temfack, Shabir Lakhi, Sokoine Lesikari, Adrienne K Chan, Neil Stone, Newton Kalata, Natasha Karunaharan, Kate Gaskell, Mary Peirse, Jayne Ellis, Chimwemwe Chawinga, Sandrine Lontsi, Jean-Gilbert Ndong, Philip Bright, Duncan Lupiya, Tao Chen, John Bradley, Jack Adams, Charles van der Horst, Joep J van Oosterhout, Victor Sini, Yacouba N Mapoure, Peter Mwaba, Tihana Bicanic, David G Lalloo, Duolao Wang, Mina C Hosseinipour, Olivier Lortholary, Shabbar Jaffar, Thomas S Harrison

 

The guidelines will help to provide updated and evidence-informed recommendations to improve diagnosis, prevention and treatment of one of the most common opportunistic infections in adults, adolescents and children with HIV, focusing on settings with limited resources and a high burden of cryptococcal meningitis, potentially reducing the rate of HIV-related mortality.

“We need to find better ways to identify and manage HIV disease, in order to achieve the global target to reduce HIV deaths by 50% by 2020,” the guidelines state.

Cryptococcal meningitis accounts for an estimated 15% of all Aids-related deaths globally, 3 quarters of which are in sub-Saharan Africa. An estimated 223,100 cases of cryptococcal meningitis resulted in 181,000 deaths among people living with HIV in 2014.

Mortality from the infection remains highest in low-income countries, where the estimated 1-year mortality of people living with HIV who receive care for cryptococcal meningitis is 70% compared to 20–30% for high-income countries.

A major reason for the high mortality is due to a delay in diagnosis, mainly as a result of limited access to lumbar puncture and rapid diagnostic assays.

Another contributing factor to mortality is the limited ability in low-income countries to monitor and manage treatment-limiting toxicities and frequent complications of raised intracranial pressure and immune reconstitution inflammatory syndrome.

The newly released guidelines provide recommendations and good practice guidance in the following areas: optimally diagnosing cryptococcal meningitis; preventing cryptococcal meningitis by screening those with advanced HIV through a cryptococcal antigen test, and treat those who test positive with fluconazole; preventing, monitoring and managing complications from treatment including antifungal drug toxicity; find shorter, safer and more effective antifungal drug regimens to treat cryptococcal meningitis with a 1-week combination antifungal regimen of amphotericin B and flucytosine for the induction phase of treatment – the 1-week regimen has been shown to reduce mortality by 38% and reduces the risk of anaemia by 69% when compared to the previous regimen; warnings against using systemic corticosteroids routinely; and ideal time to begin antiretroviral therapy (ART) in those with cryptococcal meningitis.

According to the guidelines, advanced HIV disease remains a significant challenge. Despite major progress in expanding access to ART and reducing HIV-related deaths, many continue to die from HIV-related opportunistic infections.

WHO first published a rapid advice document for the diagnosis, prevention and management of cryptococcal meningitis in December 2011, and since then, several advances provide opportunities for improving the prevention, diagnosis and management of the infection in low- and middle-income countries.

The updated guidelines will be incorporated into the next full update of WHO consolidated antiretroviral guidelines planned for 2019. WHO plans on rapidly disseminating, adapting and implementing the new recommendations, with an evaluation process conducted in 2020 to assess the uptake of the recommendations in national guidelines.

 

The international medical humanitarian organisation Doctors Without Borders/Médecins Sans Frontières (MSF) has, meanwhile, taken issue with the updated guidelines, says a Regulatory Focus report.

MSF is raising concerns that the updated WHO guidelines include recommendations for a combination of amphotericin B deoxycholate and flucytosine as the first-line treatment option. The price of flucytosine is approximately $120 for a week-long course, which makes it out of reach for many, especially in sub-Saharan Africa, MSF said.

WHO acknowledges in the guidelines that flucytosine had just three manufacturers in 2017 and “is not registered and largely unavailable in most low- and middle-income countries, especially in sub-Saharan Africa … Although registering standard formulations of flucytosine is the current priority, 100 mg/kg/ day dosages of flucytosine given four times a day are problematic in resource-limited settings, and WHO has issued a Prequalification Expression of Interest for slow-release formulations of flucytosine that may permit twice-daily dosing.”

University of St George’s London material
New England Journal of Medicine abstract
MDMag material
WHO guidelines
Regulatory Focus report


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