ANNEX 3SYSTEMATIC REVIEW AND GRADE EVIDENCE PROFILE ON TREATMENT STRATEGIES FOR HIV-ASSOCIATED CRYPTOCOCCAL MENINGITIS
Adrienne E. Shapiro, Mark W. Tenforde, Tom M. Chiller, Nathan Ford, and Radha Rajasingham.
Author Information and AffiliationsAbstract
Objective: The purpose of this systematic review is to provide updated evidence on the preferred induction therapy for treating people with HIV-associated cryptococcal meningitis, considering the most recent evidence available, to inform the need for updates to WHO guidelines.
Design: Systematic review.
Methods: We searched Medline via PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov for published or completed randomized clinical trials that evaluated induction treatment of first-episode HIV-associated cryptococcal meningitis from 9 July 2018 (date of last search) through 1 September 2021.
Results: One randomized clinical trial of 844 people with HIV-associated cryptococcal meningitis met the inclusion criteria. The participants were randomized to: (1) amphotericin deoxycholate for seven days, with flucytosine and fluconazole (control); or (2) a single dose of liposomal amphotericin 10 mg/kg with flucytosine and fluconazole (intervention).
In the intention-to-treat analysis, 10-week mortality was 24.8% (95% confidence interval (CI) 20.7–29.3%) in the single-dose liposomal amphotericin group versus 28.7% (95% CI 24.4–33.4%) in the control group. The absolute difference in 10-week mortality was −3.9 percentage points, with an upper one-sided 95% CI of 1.2 percentage points, within the 10% pre-specified non-inferiority margin. Fewer participants had grade 3 and 4 adverse events in the intervention arm than in the control arm (50.0% versus 62.3%, P < 0.001).
Conclusions: In the single study included in this systematic review, single high-dose liposomal amphotericin B with flucytosine and fluconazole was non-inferior to the WHO-recommended standard-of-care induction therapy for HIV-associated cryptococcal meningitis, with significantly fewer adverse events.
Background
Cryptococcal meningitis is a leading cause of HIV-related mortality globally (1). A systematic review and network meta-analysis published in 2018 (2) provided evidence that, in resource-limited settings, one-week intravenous amphotericin B deoxycholate and oral flucytosine induction therapy was superior to other regimens that had been evaluated in clinical trials, and this formed the basis for guidelines published by WHO (3). Despite this highly effective antifungal regimen, 10-week mortality in clinical trials is estimated to be about 35% (95% confidence interval (CI) 29–42%) and higher outside clinical trial settings; this regimen is also associated with important drug-related adverse events and associated toxicity-monitoring requirements (4,5). There is a critical need to identify novel therapies to treat cryptococcal meningitis that are highly effective, more feasible to administer in resource-limited settings and cost-effective.
Since the last review in 2018, the results of a randomized trial conducted in five countries across southern and eastern Africa – Botswana, Malawi, Uganda, South Africa and Zimbabwe – have shown that a single high-dose of liposomal amphotericin B paired with two oral antifungals, fluconazole and flucytosine, is as effective as therapy based on seven-day amphotericin-B deoxycholate in reducing deaths (6).
The purpose of this systematic review is to provide updated evidence on the preferred induction therapy for treating people with HIV-associated cryptococcal meningitis, considering the most recent evidence available, to inform the revision of WHO guidelines.
Methods
Eligibility criteria
We included randomized controlled trials among people living with HIV with a first episode of cryptococcal meningitis evaluating induction regimens for treating people with cryptococcal meningitis not currently recommended by WHO guidelines. The standard-of-care arm had to include an induction regimen recommended by the WHO guidelines, either one week of amphotericin deoxycholate with flucytosine or two weeks of flucytosine plus fluconazole.
We excluded non-randomized studies. Additional exclusion criteria were laboratory or animal studies, trials that did not evaluate cryptococcal meningitis induction treatment, secondary analyses of randomized clinical trials, diagnostic studies and cryptococcal prevention trials.
Outcomes
The primary outcomes of interest were mortality at two weeks and 10 weeks; the secondary outcomes included early fungicidal activity – the mean rate of fungal clearance from the cerebrospinal fluid – and laboratory grade 3 and 4 serious drug-related adverse events as defined by the Division of AIDS criteria (7). Specifically, we evaluated the incidence of anaemia, neutropaenia, thrombocytopaenia, hypokalaemia and alanine aminotransferase elevation.
Search strategy
We sought to identify all published and unpublished studies regardless of language between 9 July 2018 (date of last search) and 1 September 2021. We searched the following electronic databases: Medline via PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov. The specific search terms used are included in the Appendix. Briefly, the search strategy included terms for HIV infection, cryptococcal meningitis and antifungal therapies.
We also searched conference abstracts and presentations from 1 January 2018 to 1 June 2021 for the following HIV-related conferences: the International AIDS Society and Conference on Retroviruses and Opportunistic Infections. After reviewing ClinicalTrials.gov and conference abstracts, we contacted lead researchers to identify unpublished data from clinical trials.
Study selection
The articles yielded from the search strategy were collected using Covidence systematic review software (8). Two reviewers (RR and AES) independently screened the abstracts and titles and for those that potentially met inclusion criteria; the same two reviewers independently screened the full text. Each reviewer completed a template with the specified selection criteria to document reasons for exclusion; any discrepancies regarding the eligibility criteria were discussed; no additional adjudication was needed. The reviewers contacted the study authors as needed. Fig. 1 highlights the screening and eligibility criteria in a flow diagram.
Data collection
The same reviewers collected outcome data from each included report using a standardized extraction template. The following variables of interest were collected: two-week mortality, 10-week mortality, two-week rate of cerebrospinal fluid clearance (log10 colony-forming units [CFU]/mL/day), number of grade 3 or 4 adverse events, number of participants who dropped out after randomization and number lost to follow-up.
Study risk of bias assessment
One author (AES) assessed the methodological quality for randomized controlled trials using the Cochrane Risk of Bias Tool. Studies were graded as low, high or unclear risk based on the following criteria: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias.
Effect measures
Point estimates and 95% confidence intervals (CI) were calculated for the main outcomes for each study. For pairwise comparisons, we present risk ratios with the associated 95% CI, and the risk difference between the intervention and control arms. Early fungicidal activity is presented as a mean difference with the associated 95% CI.
Certainty assessment
The GRADE approach was used to assess the overall certainty of the evidence, considering risk of bias, inconsistency, indirectness, imprecision and publication bias (9). Four levels of certainty ratings were possible: very low, low, moderate and high.
Results
Study selection
We identified 301 publications through database searches and one additional publication in press arising from an abstract from other sources (Fig. 1). After de-duplication, 276 records were available for reviewing titles and abstracts. Of these 276 records, 267 were excluded since they were not randomized clinical trials involving humans with results available. Nine records were available for full text review, of which eight were excluded; four did not use flucytosine in the comparator arm, three had been previously included in the previous systematic review and one was conducted in a population without HIV infection. As a result, this review included one randomized clinical trial.
Study characteristics
The included study was a randomized controlled trial of 844 participants with HIV-associated cryptococcal meningitis from five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The study design was a non-inferiority design. The participants were 18 years or older with confirmed cryptococcal meningitis (either with positive cerebrospinal fluid India ink or cryptococcal antigen test). Pregnant or breastfeeding people were excluded, as were people with a history of previous cryptococcal meningitis, previous adverse reactions to study drugs, previous receipt of >48 hours of antifungal therapy and people who were unable to consent.
Participants were randomized to: (1) WHO-recommended induction therapy of amphotericin deoxycholate 1 mg/kg/day + flucytosine 100 mg/kg/day for seven days, followed by fluconazole 1200 mg/day for seven days; or (2) the intervention of a single dose of liposomal amphotericin 10 mg/kg + flucytosine 100 mg/kg/day and fluconazole 1200 mg/day for 14 days. Consolidation therapy for both arms was fluconazole 800 mg/day for eight weeks followed by fluconazole 200 mg/day for maintenance therapy.
The primary outcome was mortality at 10 weeks. The secondary outcomes were early fungicidal activity and the proportion of participants in each arm with grade 3 and 4 adverse events.
Study results
In the intention-to-treat analysis, 10-week mortality was 24.8% (95% CI 20.7–29.3%) in the single-dose liposomal amphotericin group versus 28.7% (95% CI 24.4–33.4%) in the control group. The absolute difference in 10-week mortality was −3.9 percentage points, with an upper one-sided 95% confidence interval of 1.2 percentage points, within the 10% prespecified non-inferiority margin. The rate of fungal clearance, measured as early fungicidal activity, was higher in the control arm than in the intervention arm (–0.42 log10 CFU/mL/day versus −0.40 log10 CFU/mL/day, respectively), although not statistically significant. Fewer participants had grade 3 and 4 adverse events in the intervention arm than in the control arm (50.0% versus 62.3%, P < 0.001). Grade 4 adverse events, grade 3 or 4 anaemia and thrombophlebitis were significantly less common in the intervention group than in the control group.
Risk of bias
The study design was a randomized controlled trial; thus, the risk of bias was deemed not serious. We were unable to assess consistency since the data are from a single study. Imprecision was downgraded one level to serious for mortality and early fungicidal activity outcomes, because the data are from a single study with wide CI around the point estimate of effect, noting that the CI fell within the prespecified non-inferiority limit for the primary analysis. The indirectness was deemed not serious. The certainty of evidence was graded as low for the primary outcome, low for early fungicidal activity and moderate for grade 3 and 4 adverse events. Publication bias was not detected.
Discussion
This updated review identified one study of 844 participants comparing a novel induction strategy for treating people with a first episode of HIV-associated cryptococcal meningitis. In the single study included in this systematic review, single high-dose (10 mg/kg) liposomal amphotericin B with flucytosine and fluconazole was non-inferior to the WHO-recommended standard-of-care induction therapy for HIV-associated cryptococcal meningitis, with significantly fewer adverse events. Based on low-certainty evidence from one study, mortality within 10 weeks may be lower with single-dose liposomal amphotericin B with flucytosine and fluconazole than the WHO-preferred induction regimen. Based on moderate-certainty evidence, single-dose liposomal amphotericin B has less toxicity associated with treatment. In the context of existing WHO recommendations, a regimen that is non-inferior with respect to mortality, has fewer adverse events and may potentially lead to shorter hospitalization could be considered a preferred regimen.
The limitations of this review are related to only one study meeting the selection criteria, which also precluded further synthesis or meta-analysis. The single study that met our selection criteria excluded children and pregnant and breastfeeding women, and no study data came from high-income country settings. We excluded randomized controlled trials that did not use a WHO-recommended regimen containing flucytosine as a comparator from our review, although the majority of health-care centres in sub-Saharan Africa, Asia and Latin America do not have access to flucytosine-based induction regimens (10). Additional implementation science studies are warranted to confirm the effectiveness of single-dose liposomal amphotericin and to evaluate implementation in routine clinical settings in which standard-of-care pharmacy capacity, laboratory monitoring capacity, performance of therapeutic lumbar punctures and management of adverse events may differ from those provided in the context of a clinical trial.
Informed by these findings, WHO published updated guidelines in March 2022 to strongly recommend single-dose liposomal amphotericin B with flucytosine and fluconazole as preferred induction therapy. To provide this highly effective regimen, there is urgent need to expand access to liposomal amphotericin and flucytosine in resource-limited settings where HIV-associated cryptococcal meningitis is most common.
Acknowledgements
RR is supported by the National Institute of Allergy and Infectious Diseases (K23AI138851, R01AI162181). The content is solely the responsibility of the authors and does not necessarily represent the official views of the United States Centers for Disease Control and Prevention.
Risk of bias summary. Jarvis 2022
Appendix. Search strategy: utility and impact review
The following search terms were used:
- 1.
Search (HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tiab] OR hiv-1*[tiab] OR hiv-2*[tiab] OR hiv1[tiab] OR hiv2[tiab] OR hiv infect*[tiab]OR human immunodeficiency virus[tiab] OR human immune-deficiency virus[tiab] OR human immunodeficiency virus[tiab] OR human immunedeficiency virus[tiab] OR ((human immun*[tiab]) AND (deficiency virus[tiab])) OR acquired immunodeficiency syndrome[tiab] OR acquired immunedeficiency syndrome[tiab] OR acquired immunodeficiency syndrome[tiab] OR acquired immune-deficiency syndrome[tiab] OR ((acquired immun*[tiab]) AND (deficiency syndrome[tiab])).
- 1.
Search (“Meningitis, Cryptococcal”[11] OR cryptococcal meningitis[tiab] OR cryptococcal meningitis[tiab] OR cryptococcal meningitides[tiab] OR cerebral cryptococcosis[tiab] OR cerebral cryptococcoses[tiab] OR toruloma*[tiab] OR cryptococcus neoforman[mh] OR cryptococcus neoforman[tiab] OR ((cryptococcal[tiab] OR cryptococcal[tiab] OR cyptococcosis[tiab] OR cryptococcoses[tiab] OR Cryptococcus[tiab]) AND (meningitis[tiab])).
- 1.
Search (Antifungal agents[mh] OR azole*[tiab] OR fluconazole[tiab] OR amphotericin[tiab] OR flucytosine[tiab] OR sertraline[tiab] OR dexamethasone[tiab] OR voriconazole[tiab] OR acetazolamide[tiab] OR diflucan[tiab] OR itraconazole[tiab] OR rifampin[tiab] OR 5-FC[tiab]).
- 1.
Search (#1 AND #2 AND #3).
GRADE evidence profile on updated systematic review of HIV-associated cryptococcal meningitis treatment strategies
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| Certainty assessment | Summary of findings |
|---|
| Number of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | Number of patients in intervention | Number of patients in control | Relative effect (95% CI) | Absolute effect (95% CI) | Certainty | Importance |
|---|
| 10-week mortality |
|---|
| 1 | Randomized trial | Not serious | Seriousa | Not serious | Seriousb | None | 101/407 (24.8%) | 117/407 (28.7%) | RR 0.863 (0.690 to 1.080) | 39 fewer per 1000 (89 fewer to 23 more) | Low | Critical |
| Early fungicidal activity |
|---|
| 1 | Randomized trial | Not serious | Seriousa | Not serious | Seriousb | None | 363 | 381 | – | MD 0.017 log10 CFU/mL/day higher (0.001 lower to 0.036 higher) | Low | Important |
| Grade 3 or 4 adverse events |
|---|
| 1 | Randomized trial | Not serious | Seriousa | Not serious | Not serious | None | 210/420 (50.0%) | 263/422 (62.3%) | RR 0.80 (0.71 to 0.91) | 125 fewer per 1,000 (181 fwwer to 56 fewer) | Moderate | Critical |
- a
Unable to assess inconsistency with a single study.
- b
Downgraded one level for precision given wide confidence intervals and a single study; of note, the study design was non-inferiority and the confidence interval was within the prespecified non-inferiority limit for mortality.
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