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.
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.
In resource-limited settings, one-week AmBd- and 5FC-based therapy is probably superior to other regimens for treatment of HIV-associated cryptococcal meningitis. An all-oral regimen of two weeks 5FC and FLU may be an alternative in settings where AmBd is unavailable or intravenous therapy cannot be safely administered. We found no mortality benefit of combination two weeks AmBd and FLU compared to AmBd alone. 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.
Cryptococcal meningitis is a severe fungal infection that occurs primarily in the setting of advanced immunodeficiency and remains a major cause of HIV-related deaths worldwide. The best induction therapy to reduce mortality from HIV-associated cryptococcal meningitis is unclear, particularly in resource-limited settings where management of drug-related toxicities associated with more potent antifungal drugs is a challenge.
To evaluate the best induction therapy to reduce mortality from HIV-associated cryptococcal meningitis; to compare side effect profiles of different therapies.
We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE (PubMed), Embase (Ovid), LILACS (BIREME), African Index Medicus, and Index Medicus for the South-East Asia Region (IMSEAR) from 1 January 1980 to 9 July 2018. We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and the ISRCTN registry; and abstracts of select conferences published between 1 July 2014 and 9 July 2018.
We included randomized controlled trials that compared antifungal induction therapies used for the first episode of HIV-associated cryptococcal meningitis. Comparisons could include different individual or combination therapies, or the same antifungal therapies with differing durations of induction (less than two weeks or two or more weeks, the latter being the current standard of care). We included data regardless of age, geographical region, or drug dosage. We specified no language restriction.
Two review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardized forms. The main outcomes included mortality at 2 weeks, 10 weeks, and 6 months; mean rate of cerebrospinal fluid fungal clearance in the first two weeks of treatment; and Division of AIDS (DAIDS) grade three or four laboratory events. Using random-effects models we determined pooled risk ratio (RR) and 95% confidence interval (CI) for dichotomous outcomes and mean differences (MD) and 95% CI for continuous outcomes. For the direct comparison of 10-week mortality, we assessed the certainty of the evidence using the GRADE approach. We performed a network meta-analysis using multivariate meta-regression. We modelled treatment differences (RR and 95% CI) and determined treatment rankings for two-week and 10-week mortality outcomes using surface under the cumulative ranking curve (SUCRA). We assessed transitivity by comparing distribution of effect modifiers between studies, local inconsistency through a node-splitting approach, and global inconsistency using design-by-treatment interaction modelling. For the network meta-analysis, we applied a modified GRADE approach for assessing the certainty of the evidence for 10-week mortality.
We included 13 eligible studies that enrolled 2426 participants and compared 21 interventions. 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.
In the direct pairwise comparisons evaluating 10-week mortality, one study from four sub-Saharan African countries contributed data to several key comparisons. At 10 weeks these data showed that those on the regimen of one-week amphotericin B deoxycholate (AmBd) and flucytosine (5FC) followed by fluconazole (FLU) on days 8 to 14 had lower mortality when compared to (i) two weeks of AmBd and 5FC (RR 0.62, 95% CI 0.42 to 0.93; 228 participants, 1 study), (ii) two weeks of AmBd and FLU (RR 0.58, 95% CI 0.39 to 0.86; 227 participants, 1 study), (iii) one week of AmBd with two weeks of FLU (RR 0.49, 95% CI 0.34 to 0.72; 224 participants, 1 study), and (iv) two weeks of 5FC and FLU (RR 0.68, 95% CI 0.47 to 0.99; 338 participants, 1 study). The evidence for each of these comparisons was of moderate certainty. For other outcomes, this shortened one-week AmBd and 5FC regimen had similar fungal clearance (MD 0.05 log10 CFU/mL/day, 95% CI -0.02 to 0.12; 186 participants, 1 study) as well as lower risk of grade three or four anaemia (RR 0.31, 95% CI 0.16 to 0.60; 228 participants, 1 study) compared to the two-week regimen of AmBd and 5FC.
For 10-week mortality, the comparison of two weeks of 5FC and FLU with two weeks of AmBd and 5FC (RR 0.92, 95% CI 0.69 to 1.23; 340 participants, 1 study) or two weeks of AmBd and FLU (RR 0.85, 95% CI 0.64 to 1.13; 339 participants, 1 study) did not show a difference in mortality, with moderate-certainty evidence for both comparisons.
When two weeks of combination AmBd and 5FC was compared with AmBd alone, pooled data showed lower mortality at 10 weeks (RR 0.66, 95% CI 0.46 to 0.95; 231 participants, 2 studies, moderate-certainty evidence).
When two weeks of AmBd and FLU was compared to AmBd alone, there was no difference in 10-week mortality in pooled data (RR 0.94, 95% CI 0.55 to 1.62; 371 participants, 3 studies, low-certainty evidence).
One week of AmBd and 5FC followed by FLU on days 8 to 14 was the best induction therapy regimen after comparison with 11 other regimens for 10-week mortality in the network meta-analysis, with an overall SUCRA ranking of 88%.