Treatment for HIV‐associated cryptococcal meningitis.

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Mark W Tenforde1, Adrienne E Shapiro2, Benjamin Rouse1, Joseph N Jarvis3, Tianjing Li4, Ingrid Eshun‐Wilson5, Nathan Ford6

1 Department of Epidemiology, University of Washington School of Public Health, Seattle, USA
Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, USA
Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA
Centre for Evidence Based Health Care, Division of Epidemiology and Biostatistics, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
Department of HIV & Global Hepatitis Programme, World Health Organization, Geneva, Switzerland

Tenforde  MW, Shapiro  AE, Rouse  B, Jarvis  JN, Li  T, Eshun‐Wilson  I, Ford  N. Treatment for HIV‐associated cryptococcal meningitis. Cochrane Database of Systematic Reviews 2018, Issue 7. Art. No.: CD005647. DOI: 10.1002/14651858.CD005647.pub3

Access the full text article here: DOI: 10.1002/14651858.CD005647.pub3/full

What is the aim of this review?

The aim of this Cochrane Review was to find the best therapy to reduce the risk of death from cryptococcal meningitis in HIV‐positive individuals. The Cochrane review authors analysed data from relevant clinical trials to answer this question and found 13 relevant studies.

Key messages

Shorter initial treatment with one week of combined amphotericin B deoxycholate and flucytosine probably results in lower risk of death than longer treatment with two weeks of combination amphotericin B deoxycholate and flucytosine that has traditionally been recommended in treatment guidelines. The shorter treatment likely results in similar clearance of the infection with less toxicity from the drugs used for treatment. Where amphotericin B deoxycholate cannot be given, two weeks of combined flucytosine with fluconazole is likely a good treatment option. Given the absence of data from studies in children, and limited data from high‐income countries, our findings provide limited guidance for treatment in these patients and settings.

What was studied in this review?

HIV‐associated cryptococcal meningitis is a severe fungal infection of the brain and surrounding membranes that causes about 15% of HIV‐related deaths worldwide. Infection occurs mostly in people with advanced HIV/AIDS and most deaths from cryptococcal meningitis occur in resource‐limited countries. Treatment includes initial antifungal therapy followed by continuation treatment with oral fluconazole. Previous guidelines have recommended two weeks of combination intravenous amphotericin B and oral flucytosine as the best available treatment. However, due to the high cost of treatment and limited availability of these potent antifungal drugs as well as challenges in managing common drug toxicities, resource‐limited countries often use less effective therapies such as oral fluconazole alone.

The review authors compared different antifungal drugs used for initial therapy of HIV‐associated cryptococcal meningitis to determine the best treatment to reduce the risk of death. Several recent clinical trials included in this review studied shorter initial treatment courses or all‐oral treatments for cryptococcal meningitis to reduce drug toxicity and improve affordability in resource‐limited countries where most infections occur.

What are the main results of the review?

The 13 studies included 2426 people and directly compared 21 different therapies. All studies were carried out in adults, and all but two studies were conducted in resource‐limited settings, including 11 of 12 studies with 10‐week mortality data. One recent large study conducted in adults from four countries in Africa contributed to 10 of these comparisons. This study found that one week of combination intravenous amphotericin B deoxycholate and oral flucytosine followed by fluconazole probably resulted in a lower risk of death within 10 weeks than two weeks of combination amphotericin B deoxycholate and flucytosine (moderate‐certainty evidence). The rate of fungal reduction measured in cerebrospinal fluid did not differ between the treatment groups but a shorter duration of amphotericin B deoxycholate and flucytosine was associated with lower risk of life‐threatening toxicities measured through blood testing. These results suggest that shorter one week treatment with amphotericin B deoxycholate and flucytosine is probably better than two weeks of amphotericin B deoxycholate and flucytosine.

In this same study, one week of amphotericin B deoxycholate and flucytosine probably resulted in a lower risk of death than a combination of oral flucytosine and fluconazole (moderate‐certainty evidence). However, risk of death was similar between oral flucytosine and fluconazole and two weeks of amphotericin B deoxycholate and flucytosine (moderate‐certainty evidence). Where intravenous amphotericin B therapy is not available or cannot be safely given to patients, this suggests that combination therapy with oral flucytosine and fluconazole is a good alternative treatment.

Due to the lack of data from studies in children, and limited data from high‐income countries, our findings provide limited guidance for treatment in these patients and settings.

How up‐to‐date is this review?

The review authors initially searched for studies up to 9 July 2018.