Treatment for HIV‐associated cryptococcal meningitis

Mark W Tenforde; Adrienne E Shapiro; Benjamin Rouse; Joseph N Jarvis; Tianjing Li; Ingrid Eshun‐Wilson; Nathan Ford

doi:10.1002/14651858.CD005647.pub3

. 2018 Jul 25;2018(7):CD005647. doi: 10.1002/14651858.CD005647.pub3

Treatment for HIV‐associated cryptococcal meningitis

Mark W Tenforde ^1,^2,^✉, Adrienne E Shapiro ¹, Benjamin Rouse ³, Joseph N Jarvis ^4,⁵, Tianjing Li ³, Ingrid Eshun‐Wilson ⁶, Nathan Ford ⁷

Editor: Cochrane Infectious Diseases Group

PMCID: PMC6513250 PMID: 30045416

Abstract

Background

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.

Objectives

To evaluate the best induction therapy to reduce mortality from HIV‐associated cryptococcal meningitis; to compare side effect profiles of different therapies.

Search methods

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.

Selection criteria

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.

Data collection and analysis

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.

Main results

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%.

Authors' conclusions

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.

2 April 2019

Up to date

All studies incorporated from most recent search

Updated review: all eligible published studies found in the last search (9 Jul, 2018) were included and three ongoing studies have been identified (see 'Characteristics of ongoing studies' section)

Plain language summary

Treatment for HIV‐associated cryptococcal meningitis

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.

Summary of findings

Background

Description of the condition

Cryptococcal meningitis is a severe fungal infection primarily seen in people with compromised cell‐mediated immunity. Most cases occur in the context of advanced HIV disease (defined as cluster of differentiation 4 (CD4) cell count < 200 cells/mm³), with the risk increasing with decreasing CD4 cell count. Rollout of combined antiretroviral therapy (ART) in the 1990s led to a large decline in incident HIV‐associated cryptococcal meningitis in high‐income countries, but a large burden of disease still exists in resource‐limited settings (Dromer 2004; Pyrgos 2013; Rajasingham 2017). This reflects, in part, an enduring high proportion of HIV‐positive individuals who present late for care due to delays in HIV diagnosis and linkage to care (Anderegg 2017). However, a growing proportion of cases (approximately 50%) are now seen in ART‐experienced individuals, reflecting ART default and treatment failure (Beardsley 2016; Rhein 2016; Scriven 2016). In 2014, an estimated 223,100 incident cases and 181,100 deaths occurred globally, and cryptococcal meningitis is estimated to cause up to 15% of HIV‐related deaths (Rajasingham 2017). Approximately 73% of cases are estimated to occur in sub‐Saharan Africa.

Cryptococccal meningitis is caused by environmental yeast species Cryptococcus neoformans and Cryptococcus gattii. C neoformans has a worldwide distribution and causes clinical disease in immunocompromised individuals, whereas C gattii has a more limited geographical distribution and is also associated with disease in immunocompetent hosts (Chen 2000). A typically asymptomatic primary pulmonary infection occurs after inhalation of fungal spores or desiccated yeast. In the absence of an effective immune response to clear or contain infection, yeast can spread to the central nervous system (CNS) to cause a severe meningoencephalitis. Clinical presentation is subacute, and commonly includes fever, headache, neck stiffness, altered mental status, vomiting, and neurological deficits such as cranial nerve palsies (Moosa 1997; Day 2013).

Diagnostic confirmation of cryptococcal meningitis relies on lumbar puncture (LP), which is also an essential part of management to lower raised intracranial pressure. Use of India ink stain to detect yeast in cerebrospinal fluid (CSF) is commonly performed in resource‐limited settings. Testing is cheap, rapid, and requires limited laboratory infrastructure, but has poor sensitivity (Boulware 2014a). Culture, considered the gold standard for diagnosis, is more sensitive but is more expensive, requires additional laboratory infrastructure and expertise, and results are delayed while yeast grow in culture media. Various cryptococcal antigen (CrAg) assays are available that provide rapid results, and CrAg testing of CSF by latex agglutination or, preferably, lateral flow assay is recommended by the World Health Organization (WHO) (WHO 2018). Cryptococcal antigen testing can also be performed on serum or plasma. Although a positive test from a blood sample is not specific for CNS disease, initiation of treatment for cryptococcal meningitis based on a positive test of serum or plasma is recommended if LP cannot be performed or is clinically contraindicated (WHO 2018).

Description of the intervention

Polyenes, azoles, and the pyrimidine analog flucytosine (5FC), are the mainstays of treatment for cryptococcal meningitis. Per WHO guidelines (issued in 2011) and Infectious Disease Society of America guidelines (issued in 2010), the preferred induction therapy for adults includes intravenous (IV) amphotericin deoxycholate (AmBd) (0.7 to 1 mg/kg daily) and oral 5FC (100 mg/kg daily in four divided doses) for a minimum of two weeks, followed by maintenance oral fluconazole (400 to 800 mg daily) for a minimum of eight additional weeks (Perfect 2010; WHO 2011). Liposomal amphotericin (AmB) is less nephrotoxic but more expensive than AmBd, and IV liposomal AmB (3 to 4 mg/kg daily) or IV AmB lipid complex (5 mg/kg daily) may be substituted for AmBd during the induction phase of treatment (Perfect 2010). A phase three clinical trial conducted in Vietnam comparing AmBd 1 mg/kg daily and 5FC 100 mg/kg daily to AmBd 1 mg/kg daily alone found a statistically significant mortality benefit of combination therapy, providing evidence for these recommendations (Day 2013). Treatment guidelines provide tiered recommendations for alternative regimens if first‐line therapy cannot be administered.

Intravenous amphotericin has strong fungicidal activity, and treatment for at least 14 days has been considered first‐line therapy (Perfect 2010; WHO 2011). Major drug‐related adverse effects include nephrotoxicity, hypokalaemia, and anaemia, and therapy should include IV fluid hydration, potassium supplementation, and regular laboratory monitoring for haematological and metabolic toxicities (Bicanic 2015). The relatively high cost of treatment, requirement of IV administration, and limited ability to monitor for drug‐related toxicities in many settings often result in the use of alternative oral antifungal regimens, primarily fluconazole. To reduce the cost of treatment and promote greater use in resource‐limited settings, recent trials have evaluated the efficacy of AmB‐based induction therapy for a duration of less than 14 days (Muzoora 2012; Jarvis 2018; Molloy 2018).

Flucytosine, available orally or intravenously, is recommended in combination with amphotericin as first‐line therapy (Perfect 2010). The most serious drug‐related adverse effect of 5FC is bone marrow suppression. Hepatotoxicity is also a drug‐related toxicity, and patients commonly experience gastrointestinal symptoms (Vermes 2000). These serious adverse effects are uncommon with current dosing recommendations (Loyse 2013a). Flucytosine is practical because of oral availability but is expensive and unavailable in most high‐burden, resource‐limited settings and unregistered throughout Africa (Loyse 2013b).

Fluconazole, an azole drug, is recommended as maintenance therapy for cryptococcal meningitis. However, it is often used for induction therapy in resource‐limited settings due to its low cost (including through a donation programme) and oral formulation. Fluconazole monotherapy is associated with very high mortality compared to amphotericin‐based regimens (Bicanic 2006; Schaars 2006; Rothe 2013). Fluconazole demonstrates weak Cryptococcus spp. killing activity compared to amphotericin, although dose escalation studies show improved fungal killing at high doses without a significant increase in drug‐related side effects (Bicanic 2007; Longley 2008; Milefchik 2008).

Several adjunctive drugs have also been evaluated for the treatment of cryptococcal meningitis in combination with traditional antifungal therapies. These include therapies with immunomodulatory functions such as dexamethasone and interferon‐gamma, acetazolamide to lower intracranial pressure, and sertraline, an antidepressant that also demonstrates antifungal activity against Cryptococcus spp. in in vitro and in animal models (Jarvis 2012; Zhai 2012; Beardsley 2016; Rhein 2016).

In addition to the choice and dose of drug therapy, a number of other factors influence outcomes of treatment for HIV‐associated cryptococcal meningitis. The accumulation of yeast or shed capsular polysaccharides may obstruct CSF reabsorption at arachnoid granulations, leading to elevated intracranial pressure (Loyse 2010). Elevated intracranial pressure is independently associated with mortality, and therapeutic LP after initial diagnostic LP may decrease the risk of death (Bicanic 2009; Meda 2014; Rolfes 2014). Standard electrolyte supplementation and IV fluids with amphotericin therapy may also decrease mortality (Bahr 2014). Furthermore, several randomized controlled trials (RCTs) have demonstrated reduced mortality when ART is delayed for several weeks with either amphotericin‐ or fluconazole‐based regimens, which is possibly explained by early immune reconstitution with ART causing deleterious inflammation in response to living or dead yeast components within the contained CNS space (Makadzange 2010; Bisson 2013; Boulware 2014b).

How the intervention might work

Antifungal therapies with activity against Cryptococcus spp. act by various mechanisms (Table 22). Fluconazole and other azoles inhibit biosynthesis of ergosterol, which is essential in fungal cell membranes; polyenes bind to fungal membrane sterols and disrupt cell membranes; and flucytosine is a pyrimidine analog that blocks fungal ribonucleic acid (RNA) and protein biosynthesis. Among adjunctive treatments, sertraline is fungicidal against Cryptococcus spp. in in vitro and animal studies, although the mechanism of action is unclear. Other adjunctive therapies may improve outcomes through modulation of the immune response or by lowering elevated intracranial pressure.

1. Overview of drugs evaluated for the treatment of HIV‐associated cryptococcal meningitis.

Class	Mechanism of action	Drug examples for cryptococcal meningitis therapy	Major class side effects
Polyenes	Disrupt cell membranes	Amphotericin B (liposomal or non‐liposomal formulations)	Nephrotoxicity, electrolyte abnormalities, anaemia
Azoles	Inhibit ergosterol biosynthesis	Fluconazole, voriconazole, itraconazole	Hepatotoxicity, drug‐drug interactions, GI symptoms, rash
Pyrimidine analogue	Inhibit fungal RNA and protein biosynthesis	Flucytosine	Bone marrow suppression, hepatotoxicity, GI symptoms
Glucocorticoids	Various anti‐inflammatory effects	Dexamethasone	Hyperglycaemia, bleeding, psychiatric effects, secondary hypoaldosteronism, immunosuppression
Selective serotonin reuptake inhibitor (SSRI)	5‐hydroxytryptamine transporter inhibitor, antifungal mechanism of action unclear	Sertraline	Neurocognitive effects, GI symptoms
Carbonic anhydrase inhibitor	Reduces intracranial pressure by reducing cerebrospinal fluid production, likely through multiple mechanisms	Acetazolamide	Metabolic acidosis, nephrolithiasis, aplastic anaemia, GI symptoms, paraesthesias

One week of AmBd + 5FC compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis  Setting: randomized controlled trial  Intervention: 1 week of AmBd + 5FC  Comparison: 2 weeks of AmBd + 5FC
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (trials)	Certainty of the evidence  (GRADE)
	Risk with 2 weeks of AmBd + 5FC	Risk with 1 week of AmBd + 5FC
Mortality: 10 weeks	383 per 1000	237 per 1000  (161 to 356)	RR 0.62  (0.42 to 0.93)	228  (1 RCT)	⊕⊕⊕⊝  MODERATE¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

One week of AmBd + 5FC compared to one week of AmBd + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis  Setting: randomized controlled trial  Intervention: 1 week of AmBd + 5FC  Comparison: 1 week of AmBd + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (trials)	Certainty of the evidence  (GRADE)
	Risk with 1 week of AmBd + FLU	Risk with 1 week of AmBd + 5FC
Mortality: 10 weeks	486 per 1000	238 per 1000  (165 to 350)	RR 0.49  (0.34 to 0.72)	224  (1 RCT)	⊕⊕⊕⊝  MODERATE¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Two weeks of 5FC + FLU compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis  Setting: randomized controlled trial  Intervention: 2 weeks of 5FC + FLU  Comparison: 2 weeks of AmBd + 5FC
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (trials)	Certainty of the evidence  (GRADE)
	Risk with 2 weeks of AmBd + 5FC	Risk with 2 weeks of 5FC + FLU
Mortality: 10 weeks	383 per 1000	352 per 1000  (264 to 471)	RR 0.92  (0.69 to 1.23)	340  (1 RCT)	⊕⊕⊕⊝  MODERATE¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Two weeks of AmBd + 5FC compared to two weeks of AmBd for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis  Setting: randomized controlled trial  Intervention: 2 weeks of AmBd + 5FC  Comparison: 2 weeks of AmBd
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (trials)	Certainty of the evidence  (GRADE)
	Risk with 2 weeks of AmBd	Risk with 2 weeks of AmBd + 5FC
Mortality: 10 weeks	409 per 1000	270 per 1000  (188 to 388)	RR 0.66  (0.46 to 0.95)	231  (2 RCTs)	⊕⊕⊕⊝  MODERATE¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Two weeks of AmBd + FLU compared to two weeks of AmBd for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis  Setting: randomized controlled trial  Intervention: 2 weeks of AmBd + FLU  Comparison: 2 weeks of AmBd
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (trials)	Certainty of the evidence  (GRADE)
	Risk with 2 weeks of AmBd	Risk with 2 weeks of AmBd + FLU
Mortality: 10 weeks	338 per 1000	317 per 1000  (186 to 547)	RR 0.94  (0.55 to 1.62)	371  (3 RCTs)	⊕⊕⊝⊝  LOW^1,2
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  Abbreviations: AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Two weeks of AmBd + FLU + steroids compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis  Setting: randomized controlled trial  Intervention: 2 weeks of AmBd + FLU + steroids  Comparison: 2 weeks of AmBd + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (trials)	Certainty of the evidence  (GRADE)
	Risk with 2 weeks of AmBd + FLU	Risk with 2 weeks of AmBd + FLU + steroids
Mortality: 10 weeks	412 per 1000	473 per 1000  (383 to 584)	RR 1.15  (0.93 to 1.42)	450  (1 RCT)	⊕⊕⊕⊕  HIGH
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  Abbreviations: AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

One week of AmBd + FLU compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis  Setting: randomized controlled trial  Intervention: 1 week of AmBd + FLU  Comparison: 2 weeks of AmBd + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (trials)	Certainty of the evidence  (GRADE)
	Risk with 2 weeks of AmBd + FLU	Risk with 1 week of AmBd + FLU
Mortality: 10 weeks	412 per 1000	486 per 1000  (363 to 651)	RR 1.18  (0.88 to 1.58)	225  (1 RCT)	⊕⊕⊕⊝  MODERATE¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  Abbreviations: AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Two weeks of FLU compared to two weeks of 5FC + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis  Setting: randomized controlled trial  Intervention: 2 weeks of FLU  Comparison: 2 weeks of 5FC + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (trials)	Certainty of the evidence  (GRADE)
	Risk with 2 weeks of 5FC + FLU	Risk with 2 weeks of FLU
Mortality: 10 weeks	392 per 1000	573 per 1000  (376 to 875)	RR 1.46  (0.96 to 2.23)	98  (2 RCTs)	⊕⊝⊝⊝  VERY LOW^1,2,3
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  Abbreviations: 5FC: flucytosine; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Two weeks of L‐AmB compared to two weeks of AmBd for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis  Setting: randomized controlled trial  Intervention: 2 weeks of L‐AmB  Comparison: 2 weeks of AmBd
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (trials)	Certainty of the evidence  (GRADE)
	Risk with 2 weeks of AmBd	Risk with 2 weeks of L‐AmB
Mortality: 10 weeks	154 per 1000	66 per 1000  (6 to 654)	RR 0.43  (0.04 to 4.25)	28  (1 RCT)	⊕⊝⊝⊝  VERY LOW^1,2
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  Abbreviations: AmBd: amphotericin B deoxycholate; CI: confidence interval; L‐AmB: liposomal amphotericin B; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Short‐course L‐AmB + FLU compared to two weeks of L‐AmB + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis  Setting: randomized controlled trial  Intervention: short‐course L‐AmB + FLU  Comparison: 2 weeks of L‐AmB + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (trials)	Certainty of the evidence  (GRADE)
	Risk with 2 weeks of L‐AmB + FLU	Risk with short‐course L‐AmB + FLU
Mortality: 10 weeks	286 per 1000	294 per 1000  (134 to 643)	RR 1.03  (0.47 to 2.25)	79  (1 RCT)	⊕⊕⊝⊝  LOW¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  Abbreviations: CI: confidence interval; FLU: fluconazole; L‐AmB: liposomal amphotericin B; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

No.	Query
#4	Search (#1 AND #2 AND #3)
#3	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])
#2	Search ("Meningitis, Cryptococcal"[Mesh] 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 (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 immunedeficiency virus[tiab] OR human immuno‐deficiency virus[tiab] OR human immune‐deficiency virus[tiab] OR ((human immun[tiab]) AND (deficiency virus[tiab])) OR acquired immunodeficiency syndrome[tiab] OR acquired immunedeficiency syndrome[tiab] OR acquired immuno‐deficiency syndrome[tiab] OR acquired immune‐deficiency syndrome[tiab] OR ((acquired immun*[tiab]) AND (deficiency syndrome[tiab]))

No.	Query
#11	#1 AND #7 AND #8 AND #9 AND [1980‐2017]/py
#10	#1 AND #7 AND #8 AND #9
#9	‘antifungal agent'/syn OR azole*:ab,ti OR fluconazole:ab,ti OR amphotericin:ab,ti OR flucytosine:ab,ti OR sertraline:ab,ti OR dexamethasone:ab,ti OR voriconazole:ab,ti OR acetazolamide:ab,ti OR diflucan:ab,ti OR itraconazole:ab,ti OR rifampin:ab,ti OR ‘5‐fc':ab,ti
#8	‘cryptococcal meningitis'/de OR ‘cryptococcal meningitis':ab,ti OR ‘cryptococcus meningitis':ab,ti OR ‘cryptococcal meningitis':ab,ti OR ‘cryptococcal meningitides':ab,ti OR ‘cerebral cryptococcosis':ab,ti OR ‘cerebral cryptococcoses':ab,ti OR toruloma*:ab,ti OR ‘cryptococcus neoforman':ab,ti OR (cryptococcal:ab,ti OR cryptococcal:ab,ti OR cryptococcosis:ab,ti OR cryptococcoses:ab,ti AND meningitis:ab,ti)
#7	#2 NOT #6
#6	#3 NOT #5
#5	#3 AND #4
#4	‘human'/de OR ‘normal human'/de OR ‘human cell'/de
#3	‘animal'/de OR ‘animal experiment'/de OR ‘invertebrate'/de OR ‘animal tissue'/de OR ‘animal cell'/de OR ‘nonhuman'/de
#2	‘randomised controlled trial'/de OR ‘randomised controlled trial' OR random:ab,ti OR trial:ti OR allocat:ab,ti OR factorial:ab,ti OR placebo:ab,ti OR assign:ab,ti OR volunteer:ab,ti OR ‘crossover procedure'/de OR ‘crossover procedure' OR ‘double‐blind procedure'/de OR ‘double‐blind procedure' OR ‘single‐blind procedure'/de OR ‘single‐blind procedure' OR (doubl* NEAR/3 blind):ab,ti OR (singl:ab,ti AND blind:ab,ti) OR crossover:ab,ti OR cross+over:ab,ti OR (cross NEXT/1 over):ab,ti
#1	‘human immunodeficiency virus infection'/exp OR ‘human immunodeficiency virus infection' OR ‘human immunodeficiency virus'/exp OR ‘human immunodeficiency virus' OR ‘human immunodeficiency virus':ab,ti OR ‘human immuno+deficiency virus':ab,ti OR ‘human immunedeficiency virus':ab,ti OR ‘human immune+deficiency virus':ab,ti OR hiv:ab,ti OR ‘hiv‐1':ab,ti OR ‘hiv‐2':ab,ti OR ‘acquired immunodeficiency syndrome':ab,ti OR ‘acquired immuno+deficiency syndrome':ab,ti OR ‘acquired immunedeficiency syndrome':ab,ti OR ‘acquired immune+deficiency syndrome':ab,ti

ID	Search
#1	MeSH descriptor: [HIV Infections] explode all trees
#2	MeSH descriptor: [HIV] explode all trees
#3	hiv or hiv‐1* or hiv‐2* or hiv1 or hiv2 or (hiv near infect) or (human immunodeficiency virus) or (human immunedeficiency virus) or (human immune‐deficiency virus) or (human immuno‐deficiency virus) or (human immune deficiency virus) or (human immuno deficiency virus) or (acquired immunodeficiency syndrome) or (acquired immunedeficiency syndrome) or (acquired immuno‐deficiency syndrome) or (acquired immune‐deficiency syndrome) or (acquired immun deficiency syndrome)
#4	MeSH descriptor: [Lymphoma, AIDS‐Related] this term only
#5	MeSH descriptor: [Sexually Transmitted Diseases, Viral] this term only
#6	#1 or #2 or #3 or #4 or #5
#7	[mh "meningitis, cryptococcal"] or "cryptococcal meningitis":ti,ab,kw or "cryptococcal meningitis":ti,ab,kw or "cryptococcal meningitides":ti,ab,kw or "cerebral cryptococcosis":ti,ab,kw or "cerebral cryptococcoses":ti,ab,kw or toruloma*:ti,ab,kw or [mh "cryptococcus neoforman"] or "cryptococcus neoforman":ti,ab,kw or ((cryptococcal:ti,ab,kw or cryptococcal:ti,ab,kw or cyptococcosis:ti,ab,kw or cryptococcoses:ti,ab,kw or Cryptococcus:ti,ab,kw) and meningitis:ti,ab,kw) (Word variations have been searched)
#8	[mh "antifungal agents"] or azole*:ti,ab,kw or fluconazole:ti,ab,kw or amphotericin:ti,ab,kw or flucytosine:ti,ab,kw or sertraline:ti,ab,kw or dexamethasone:ti,ab,kw or voriconazole:ti,ab,kw or acetazolamide:ti,ab,kw or diflucan:ti,ab,kw or itraconazole:ti,ab,kw or rifampin:ti,ab,kw or "5‐FC":ti,ab,kw (Word variations have been searched)
#9	#6 and #7 and #8 in Trials

Review title	Treatment of HIV‐associated cryptococcal meningitis
Reviewer ID
Study ID (first author surname and year of publication)
Study characteristics	Review inclusion criteria	Yes/No/Unclear	Location in text *(pg & ¶/fig/table)*
1. Type of study	Randomized trial
	Non‐randomized trial
	Cohort study
	Quasi‐experimental study
	Other design (specify):
2. Participants	HIV‐infected with initial episode of cryptococcal meningitis?
3. Diagnosis	Diagnosis confirmed by CSF India ink stain, fungal culture, or CrAg testing?
4. Types of intervention	Two or more treatments compared?
5. Types of outcome measures	Included mortality, safety, or microbiological outcome(s)?
6. Decision:	(For inclusion, must answer YES for RCT for item 1 and YES for items 2‐6)
7. Reason for exclusion
8. Notes:

Two weeks of AmBd + 5FC + FLU compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis  Setting: randomized controlled trial  Intervention: 2 weeks of AmBd + 5FC + FLU  Comparison: 2 weeks of AmBd + 5FC
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (trials)	Certainty of the evidence  (GRADE)
	Risk with 2 weeks of AmBd + 5FC	Risk with 2 weeks of AmBd + 5FC + FLU
Mortality: 10 weeks	67 per 1000	187 per 1000  (22 to 1000)	RR 2.81  (0.33 to 24.16)	31  (1 RCT)	⊕⊝⊝⊝  VERY LOW^{1 2}
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

One week of AmBd + 5FC + FLU compared to one week of AmBd + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis  Setting: randomized controlled trial  Intervention: 1 week of AmBd + 5FC + FLU  Comparison: 1 week of AmBd + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (trials)	Certainty of the evidence  (GRADE)
	Risk with 1 week of AmBd + FLU	Risk with 1 week of AmBd + 5FC + FLU
Mortality: 10 weeks	350 per 1000	301 per 1000  (122 to 735)	RR 0.86  (0.35 to 2.10)	40  (1 RCT)	⊕⊕⊝⊝  LOW¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Two weeks of AmBd + 5FC + IFNg compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis  Setting: randomized controlled trial  Intervention: 2 weeks of AmBd + 5FC + IFNg  Comparison: 2 weeks of AmBd + 5FC
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (trials)	Certainty of the evidence  (GRADE)
	Risk with 2 weeks of AmBd + 5FC	Risk with 2 weeks of AmBd + 5FC + IFNg
Mortality: 10 weeks	323 per 1000	297 per 1000  (155 to 571)	RR 0.92  (0.48 to 1.77)	88  (1 RCT)	⊕⊕⊝⊝  LOW¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; IFNg: interferon gamma 1b; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Date	Event	Description
24 July 2018	New search has been performed	This is an update of a review last published in 2011 (Sloan 2011). The review author team updated the protocol extensively, and differences are highlighted in the ‘Differences between protocol and review' section.
24 July 2018	New citation required and conclusions have changed	We included 13 eligible studies that enrolled 2426 participants and compared 21 interventions. 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. 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 the certainty of the evidence using the GRADE approach.

Methods	Study design: Randomization method: Blinding:
Participants	Country/countries: Inclusion criteria: Exclusion criteria: Number of participants: Number dropped out: Age: Gender: Number on ART: Baseline CD4 count: Baseline Glasgow coma scale (GCS) score or altered mental status:
Intervention	For each intervention group Specific intervention Number of participants: Drug(s) and dose(s): Duration of induction therapy: Maintenance therapy and duration: General to all intervention groups Protocol for LP after diagnostic LP: Toxicity monitoring: ART started after initiation of treatment for CM: Timing of ART initiation:
Outcomes	Intention‐to‐treat or per‐protocol outcomes: Mortality Up to two weeks: Up to 10 weeks: Up to six months: Early fungicidal activity: Serious adverse events: Missing participant data:
Notes	Years study conducted: Sources of funding: Conflicts of interest: Potentially relevant studies in references:

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1 2 weeks	1	228	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.30, 1.03]
1.2 10 weeks	1	228	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.42, 0.93]
2 Early fungicidal activity	1	186	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.02, 0.12]
3 DAIDS grade 3/4 toxicities	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 Anaemia	1	228	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.16, 0.60]
3.2 Renal dysfunction	1	228	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.18, 1.93]
3.3 Neutropenia	1	228	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.43, 2.03]
3.4 Hypokalaemia	1	228	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.50, 3.39]
3.5 ALT abnormality	1	228	Risk Ratio (M‐H, Random, 95% CI)	3.05 [0.63, 14.81]

Methods	Study type: blinded RCT Setting: 13 hospitals in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi
Participants	Inclusion criteria: HIV infected; ≥ 18 years of age; diagnosed with cryptococcal meningitis by CSF India ink or CrAg or blood or CSF culture Exclusion criteria: pregnant; more than 7 days of anticryptococcal therapy; renal failure; receiving glucocorticoids or glucocorticoids indicated for a pre‐existing condition; gastrointestinal bleeding Number randomized: 451 (1 excluded after randomization due to administrative error) Age: median 35 years Gender: 62% male CD4 T‐cell count: median 18 cells/μL (AmBd and fluconazole with dexamethasone); 20 cells/μL (AmBd and fluconazole with placebo) Baseline ART: 40% with prior ART use Baseline GCS/AMS: GCS < 15 in 19% of participants
Interventions	Intervention AmBd 1 mg/kg/day and fluconazole 800 mg/day for 2 weeks with tapered dexamethasone (0.3 mg/kg/day for 1 week, then 0.2 mg/kg/day for 1 week, then 0.1 mg/kg/day for 1 week, then 3 mg/day for 1 week, then 2 mg/day for 1 week, then 1 mg/day for 1 week) AmBd 1 mg/kg/day and fluconazole 800 mg/day for 2 weeks with placebo therapy for 6 weeks Consolidation: Fluconazole 800 mg/day for 8 weeks then 200 mg/day maintenance dose Postdiagnosis ART: median time to ART 46 days (AmBd and fluconazole with dexamethasone); 42 days (AmBd and fluconazole with placebo) Lumbar puncture schedule: scheduled on days 1, 3, 7, and 14 and performed as clinically indicated Laboratory monitoring: haemoglobin, white blood cells, platelet count days 1, 7, and 14; Na, K, urea, Cr days 1, 3, 7, 11, and 14
Outcomes	Primary outcome Mortality at 10 weeks Secondary outcomes Mortality at 6 months Level of disability at 10 weeks and 6 months Visual acuity at 10 weeks Rate of decrease in cryptococcal counts in CSF during first 2 weeks Change in opening pressure during first 2 weeks Outcome assessment schedule: Daily while hospitalized and scheduled assessments on days 21, 28, 42, 80, and 182
Notes	Date of study: 2013 to 2014 (study stopped early after data and safety monitoring committee determined dexamethasone therapy was causing harm across key outcomes) Funding: UK Department for International Development; The Wellcome Trust (UK); Medical Research Council (UK) Joint Global Health Trials Scheme Declaration of conflict of interest by authors: None reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	1:1 randomization with variable block size of 4 and 6 with computer‐generated sequence, stratified by study site
Allocation concealment (selection bias)	Low risk	Computer‐generated randomization accessible only to central pharmacists
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Participants and clinicians blinded to intervention group.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Outcome assessors blinded to treatment group.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	6‐month outcome available for all participants.
Selective reporting (reporting bias)	Low risk	Authors reported on all primary and secondary outcomes.
Other bias	Low risk	None noted.

Methods	Study type: Unblinded RCT Setting: 1 hospital in Thailand
Participants	Inclusion criteria: HIV infected; diagnosed by CSF India ink or CrAg test Exclusion criteria: pregnant; previous cryptococcal meningitis; ALT > 5 times upper limit of normal; ANC < 500 x 10⁶/L; platelet count < 50 x 10⁶/L; previous serious reaction to study drugs Number randomized: 64 Age: median 33 years Gender: 60% male CD4 T‐cell count: median 9 cells/μL Baseline ART: no Baseline GCS/AMS: GCS < 15 or seizures in 19% of participants
Interventions	Intervention AmBd 0.7 mg/kg/day for 2 weeks AmBd 0.7 mg/kg/day and flucytosine 100 mg/kg/day for 2 weeks AmBd 0.7 mg/kg/day and fluconazole 400 mg/day for 2 weeks AmBd 0.7 mg/kg/day and flucytosine 100 mg/kg/day and fluconazole 400 mg/day for 2 weeks Consolidation: fluconazole 400 mg/day for 8 weeks, then 200 mg/day maintenance dose Postdiagnosis ART: no participants started on ART within 10 weeks of follow‐up Lumbar puncture schedule: scheduled on days 3, 7, and 14 and as clinically indicated Laboratory monitoring: not specified
Outcomes	Primary outcome Rate of decrease in cryptococcal counts in CSF during first 2 weeks Secondary outcome Mortality at 2 and 10 weeks Outcome assessment schedule: daily while hospitalized and scheduled assessments on days 21, 28, 42, 80, and 182
Notes	Date of study: 2002 Funding: Wellcome Trust; Lancet international fellowship; St George’s Hospital; Netherlands Foundation for the Advancement of Tropical Medicine Declaration of conflict of interest by authors: None reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	1:1:1:1 randomization with blocks of 16 with pre‐study generation of sealed envelopes prepared by an independent person
Allocation concealment (selection bias)	Low risk	Sealed envelopes prepared by independent person
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Treatment was not blinded.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Outcomes unblinded by assessors
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Outcomes up to 10 weeks for all participants
Selective reporting (reporting bias)	Low risk	Authors reported all primary and secondary outcomes.
Other bias	Low risk	None noted.

Methods	Study type: 2‐step, double‐blinded RCT Setting: Multiple hospitals in the USA
Participants	Inclusion criteria: ≥ 13 years of age; positive CSF culture Exclusion criteria: pregnant or breastfeeding; prior cryptococcal meningitis or more than 1 mg/kg amphotericin B or 1200 mg fluconazole, itraconazole, or ketoconazole for current episode; taking medications that affected metabolism or decreased absorption of itraconazole; receiving ≥ 50 mg/day hydrocortisone; history of acute hepatitis or moderate‐to‐severe haematologic, renal, or hepatic dysfunction; comatose; unable to take medications by mouth or nasogastric tube; had a history of other opportunistic infections requiring treatment during the first 2 weeks Number randomized: 408 randomized in step 1 randomization to AmBd and flucytosine or AmBd (27 ineligible due to negative CSF culture (19), receiving corticosteroids or rifampicin (4), prior cryptococcal disease (2), HIV‐negative (1), or pregnant (1)); 306 randomized in step 2 to fluconazole or itraconazole maintenance of stable or improved in step 1, receipt minimal dose of 7.5 mg/kg AmBd, ability to take oral medications, hepatic enzymes less than 10 times ULN and bilirubin less than 2 times ULN Age: median 37 years Gender: 87% male (AmBd and flucytosine); 91% male (AmBd) CD4 T‐cell count: median 20 cells/μL (AmBd and flucytosine); 18 cells/μL (AmBd) Baseline ART: 27% (AmBd and flucytosine); 26% (AmBd) Baseline GCS/AMS: 89% with normal mental status
Interventions	Step 1 induction AmBd 0.7 mg/kg/day and flucytosine 100 mg/kg/day for 2 weeks AmBd 0.7 mg/kg/day Step 2 consolidation Fluconazole 400 mg/day for 8 weeks with 800 mg/day loading dose for first 2 days Itraconazole 400 mg/day for 8 weeks with 600 mg/day loading dose for first 3 days Postdiagnosis ART: not specified Lumbar puncture schedule: scheduled lumbar punctures at weeks 2, 4, and 10 Laboratory monitoring: monitoring twice weekly for 2 weeks; weekly for next 2 weeks; then every 2 weeks until 10 weeks
Outcomes	Primary outcomes Negative CSF culture at 2 weeks and 10 weeks Stable or improved fever, headache, and meningismus at 2 weeks and 10 weeks Secondary outcome Drug toxicity Outcome assessment schedule: clinical monitoring twice weekly for 2 weeks; weekly for next 2 weeks; then every 2 weeks until 10 weeks
Notes	Date of study: 1991 to 1994 Funding: National Institute of Allergy and Infectious Diseases, AIDS Clinical Trial Group, National Center for Research Services, and Janssen Research Foundation; drugs provided by Bristol‐Myers Squibb (AmBd), Roche Laboratories (flucytosine), Roerig‐Pfizer (fluconazole), and Janssen Research Foundation (itraconazole) Declaration of conflict of interest by authors: research supported by several pharmaceutical companies as well as public sources
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomization not specified; stratified by altered mental status and institution in step 1 and baseline mental status and therapy received in step 2
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blinded
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not specified
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Outcomes reported for all participants.
Selective reporting (reporting bias)	Low risk	Authors reported on all primary and secondary outcomes.
Other bias	Unclear risk	Research funded in part by pharmaceutical companies, including manufacturer of study drug.

Study	Reason for exclusion
Bicanic 2008	Compared 2 interventions of the same combination antifungal drugs, 2 weeks of AmBd 0.7 mg/kg/day or AmBd 1 mg/kg/day both combined with flucytosine 100 mg/kg/day
Bisson 2013	Small trial evaluating early (within 7 days) versus delayed (after 4 weeks) ART initiation following diagnosis of cryptococcal meningitis; all participants received standard induction treatment of AmBd 0.7 mg/kg/day for 2 weeks
Boulware 2014b	RCT comparing early versus delayed ART initiation in participants treated with AmBd and fluconazole; patients were enrolled 1 week after initiating therapy, before which an estimated 12% of patients had already died
Bozzette 1991	RCT with participants randomized to maintenance therapy
Brouwer 2007	Subanalysis of included RCT, Brouwer 2004, comparing participants treated with IV versus oral formulations of flucytosine
Chariyalertsak 2002	RCT with participants randomized to consolidation therapy, not induction therapy
Chetchotisakd 2004	RCT of primary prophylaxis against cryptococcal meningitis, not induction therapy
Chotmongkol 1997	RCT of consolidation therapy with itraconazole versus no therapy after CSF culture clearance
Chotmongkol 2005	Small study of 40 participants in which participants in study arms were not well matched for severity of disease (45% in AmBd plus rifampicin arm versus 0% in AmBd arm had positive Cryptococcus blood cultures at baseline); important baseline characteristics including CD4 T‐cell count were not described
de Gans 1992	Small study of 25 participants randomized to itraconazole versus AmBd and flucytosine for induction therapy where 2/14 participants in itraconazole group crossed over within 4 hours and an additional 2 participants were lost to follow‐up
Hamill 2010	Included re‐treatment cases of cryptococcal meningitis
Jadhav 2010	Excluded patients who had not received a minimum of 8 doses of liposomal amphotericin treatment, introducing immortality bias
Joly 1996a	Included patients with relapsed cryptococcal meningitis
Joly 1996b	Included patients with relapsed cryptococcal meningitis
Larsen 1990	Small study of 20 participants comparing fluconazole to AmBd and flucytosine, which was excluded for several reasons: did not do intention‐to‐treat analysis; excluded significant number of participants (6/26) from analysis after enrolment; enrolled non‐HIV‐positive patient; final comparison groups poorly matched on CD4 count
Makadzange 2010	Evaluated timing of ART (within 72 hours of cryptococcal meningitis diagnosis or after 10 weeks); all participants received fluconazole induction therapy; a large proportion of patients died before enrolment, introducing a risk of immortality bias
Mfinanga 2015	RCT with participants randomized to intervention including cryptococcal antigen screening for prevention of cryptococcal meningitis
Mootsikapun 2003	RCT with participants randomized to consolidation therapy, not induction therapy
Newton 2002	Small RCT of adjunctive acetazolamide that did not limit inclusion to patients with HIV‐associated cryptococcal meningitis
Pappas 2004	Included patients with relapsed cryptococcal meningitis
Powderly 1992	RCT of secondary prophylaxis for prevention of recurrent cryptococcal meningitis
Powderly 1995	RCT of primary prophylaxis for fungal infections
Rhein 2016	Initially was a dose escalation study of adjunctive sertraline as therapy for cryptococcal meningitis; investigators compared outcomes to historic controls
Saag 1991	RCT that included patients with relapsed cryptococcal meningitis
Saag 1999	RCT of consolidation therapy for cryptococcal meningitis
Sharkey 1996	Small RCT comparing AmBd with different doses of liposomal amphotericin B in which CD4 count and other baseline characteristics were not well matched between groups
Tansuphaswadikul 2006	Small RCT comparing 1‐week and 2‐week induction therapy with AmBd with very high loss to follow‐up (33%) by 10 weeks, which could bias mortality results
Techapornroong 2007	Small RCT comparing daily and alternate‐day AmBd induction therapy with very high loss to follow‐up (25%) by 3 months, which could bias mortality results
Vaidhya 2015	RCT comparing AmBd with AmBd and fluconazole that did not include any primary or secondary outcomes (mortality, early fungicidal activity, or adverse events)
Vibhagool 2003	RCT of secondary prophylaxis for cryptococcal meningitis
Villanueva‐Lozano 2018	Small RCT of 12 participants comparing amphotericin and fluconazole with adjunctive sertraline and amphotericin and fluconazole with placebo that had significant imbalance in CD4 count between treatment arms; also excluded one patient from analysis for not receiving per‐protocol treatment

PERMALINK

Treatment for HIV‐associated cryptococcal meningitis

Mark W Tenforde

Adrienne E Shapiro

Benjamin Rouse

Joseph N Jarvis

Tianjing Li

Ingrid Eshun‐Wilson

Nathan Ford

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

1. Overview of drugs evaluated for the treatment of HIV‐associated cryptococcal meningitis.

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Inclusion criteria

Exclusion criteria

Types of interventions

Interventions

Comparisons

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Relative ranking

Unit of analysis issues

Cluster‐randomized trials

Cross‐over randomized clinical trials

Repeated observations on participants

Multiple treatment events

Trials with multiple treatment groups

Dealing with missing data

Assessment of heterogeneity

Assessment of transitivity and inconsistency

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Presentation of results

GRADE assessment

Study limitations

Imprecision

Inconsistency

Indirectness

Results

Description of studies

Results of the search

1.

Included studies

Setting

Participants and study procedures

Interventions

Outcomes

Mortality

Early fungicidal activity

DAIDS grade three/four laboratory toxicities

Excluded studies

Risk of bias in included studies

Trial name or title	High dose AMBISOME on a fluconazole backbone for cryptococcal meningitis induction therapy in sub‐Saharan Africa
Methods	Phase 3 non‐inferiority RCT from 6 sites in South Africa, Botswana, Zimbabwe, Malawi, and Uganda with planned enrolment of 850 participants
Participants	Age ≥ 18 years with first episode of HIV‐associated cryptococcal meningitis
Interventions	(i) Single dose of 10 mg/kg IV liposomal AmB with 2 weeks 5FC 100 mg/kg/day and FLU 1200 mg/day (ii) 1 week of AmBd 1 mg/kg/day and 5FC 100 mg/kg/day followed by FLU 1200 mg/day days 8 to 14
Outcomes	Primary: 10‐week mortality
Starting date	2017
Contact information	joseph.jarvis@lshtm.ac.uk
Notes	Original protocol was to compare short‐course L‐AmB and 2 weeks of AmBd with FLU as a second drug for both regimens; however, protocol was modified after results from Molloy 2018 study became available showing mortality benefit with 1 week of AmBd and 5FC followed by FLU days 8 to 14.

Trial name or title	High‐dose fluconazole for the treatment of cryptococcal meningitis in HIV‐positive individuals
Methods	Phase 1/2 dose‐finding RCT of high‐dose fluconazole for HIV‐associated cryptococcal meningitis with or without AmBd 0.7 to 1.0 mg/kg/day
Participants	Age ≥ 16 years with HIV‐associated cryptococcal meningitis
Interventions	Multistage study of high‐dose FLU with or without AmBd
Outcomes	Primary: discontinuation of study‐provided FLU or AmBd; qualitative and quantitative CSF culture results at entry, 2 weeks, and through 24 weeks; survival up to 24 weeks
Starting date	2010
Contact information	umeshlalloo@gmail.com
Notes	Completed study with results not published in peer‐reviewed journal but presented at Conference on Retroviruses and Opportunistic Infections 2018

Trial name or title	Adjunctive sertraline for the treatment of HIV‐associated cryptococcal meningitis (ASTRO‐CM)
Methods	Phase 3 RCT
Participants	≥ 18 years of age with HIV‐associated cryptococcal meningitis
Interventions	2 weeks of AmBd 0.7 to 1.0 mg/kg/day and FLU 800 to 1200 mg/day plus sertraline 400 mg/day for 2 weeks then sertraline 200 mg/day for 12 weeks then tapered over 3 weeks versus 2 weeks of AmBd 0.7 to 1.0 mg/kg/day and FLU 800 to 1200 mg/day
Outcomes	Primary: 18‐week survival
Starting date	2015
Contact information	david.meya@gmail.com
Notes	Study terminated during interim monitoring for futility, results not published in peer‐reviewed journal but presented at Conference on Retroviruses and Opportunistic Infections 2018.