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Primary prophylaxis with triazoles for fungal infections in HIV patients with low absolute CD4 count: a meta-analysis of randomized controlled trials

Authors:

Abstract

Background: Fungal infections are a major cause of mortality and morbidity in HIV patients. These infections range from mucosal in- volvements to deep mycoses. Methods: We searched PubMed and EMBASE databases for ran- domized controlled trials (RCT) on triazoles for primary prophylaxis in HIV patients using the search term “HIV AND (fluconazole OR itra- conazole OR posaconazole OR voriconazole OR isavuconazole) AND prophylaxis AND randomized controlled trial [Publication Type]” and found 27 results. Both authors filtered the results independently by titles, abstracts and full text. Seven papers met the inclusion criteria. Data extraction and analysis was carried out using RevMan 5.3 soft- ware. Four outcomes were selected- mucosal candidiasis, deep fungal infections, adverse drug reactions and death. Outcome analysis was carried out in two subgroups- fluconazole and itraconazole, using ran- dom effect models. Results: The total number of subjects was 4535, among them 2271 received a triazole drug and 2264 received placebo. Included stud- ies used different cut-off for absolute CD4 count, median being 200 cells/μL. The odds-ratio of developing mucosal candidiasis was 0.42 (0.21- 0.83) for triazole drugs, the overall effect being Z=2.49 (P=0.01). Sub- group analysis showed 0.31 (0.10-0.96) odds-ratio for fluconazole group, and 0.59 (0.33-1.05) odds-ratio for itraconazole group. Heterogeneity was high (I2=89%) probably due to different cut-offs for absolute CD4 count. The odds-ratio of developing deep fungal infection was 0.27 (0.15- 0.50). The overall effect was Z=4.22 (P<0.0001). The odds-ratio in the fluconazole group was 0.29 (0.10-0.86) and in the itraconazole group it was 0.22 (0.10-0.50). Heterogeneity was low (I2=19%). Analysis of adverse reactions showed no significant difference be- tween drugs and placebo, overall effect being Z=0.31 (P=0.76). The odds-ratio was 1.04 (0.79-1.37) and heterogeneity was I2 =0%. There was no significant mortality benefit for the drugs. Odds-ratio for death was 0.94 (0.68-1.28) and overall effect was Z=0.41 (P=0.68). Heterogeneity was I2=63 Conclusion: Primary prophylaxis with triazole drugs have the ben- efit of preventing mucosal candidiasis (fluconazole better) and deep fungal infections (itraconazole better). Both drugs are well tolerated, but none of them have any mortality benefit.
Primary prophylaxis with triazoles for fungal infections in HIV
patients with low absolute CD4count: a meta-analysis of
randomized controlled trials
Agnibho Mondal1, Bishal Gupta2
1. Department of Tropical Medicine
2. Department of Microbiology
School of Tropical Medicine, Kolkata
Introduction
Around 37.9 million people all over the
world are living with HIV [1]. Although
WHO recommends ART initiation regardless
of the CD4 level, a large number of people
living with HIV {PLHIV) continue to die from
different fungal infections, with some
estimates being as high as 50% of all HIV
related death [2].
One strategy to reduce fungal infections can
be to use anti-fungal drugs prophylactically.
In this meta-analysis we seek to find out
whether the anti-fungal drugs in the
triazole group are effective as prophylaxis
against fungal infections in HIV infected
people.
Study Question
Are triazoles effective in preventing fungal
infections in people living with HIV?
Outcome
1.Development of mucosal fungal infections
2.Development of deep fungal infections
3.Mortality
4.Adverse reactions
Literature Search
We searched PubMed and Cochrane
database for randomized controlled trials.
We used the search term “HIV AND
(fluconazole OR itraconazole OR
posaconazole OR voriconazole OR
isavuconazole) AND prophylaxis AND
randomized controlled trial [Publication
Type]”
Both authors independently filtered the
search results first by title, then by
abstract and finally by the full text.
Inclusion Criteria
1.Randomized controlled trials
2.Compares any triazole drug with placebo
for prothylaxis in PLHIV
3.Has data on the 4 outcomes selected for
analysis
Inclusion of Studies
Among 75 search results (28 in Pubmed and
47 in Cochrane Database), 7 studies met
the inclusion criteria.
Statistical Analysis
Statistical analysis was performed by
RevMan 5.3 software by the Cochrane
Collaboration.
Risk of Bias analysis was done by RoB tool
version 2, also by the Cochrane
Collaboration.
A random effect model was used for
analysis.
All outcome data were dichotomous and
expressed as risk ratio.
Study heterogeneity was measured with I2
value.
Publication bias was also assessed with
funnel plots
Data Extraction
Data regarding the study characteristics,
risk of bias and the selected outcomes were
extracted from the 7 selected studies and
tabulated.
Results:
Risk ratio of mucosal candidiasis 0.51 (0.29-0.92)
Fluconazole 0.38 (0.11-1.33)
Itraconazole 0.69 (0.51-0.93)
Overall effect size Z = 2.26 (P = 0.02)
Risk ratio of deep fungal infections 0.29 (0.16-0.53)
Fluconazole 0.31 (0.11-0.90)
Itraconazole 0.25 (0.11-0.54)
Overall effect size Z = 4.05 (P < 0.0001)
Risk ratio of adverse reactions 1.01 [0.88-1.16]
Fluconazole 0.97 (0.76-1.25)
Itraconazole 1.54 (0.53-4.51)
Overall effect size Z = 0.13 (P = 0.90).
Risk ratio of death 0.96 (0.74-1.23)
Fluconazole 0.90 (0.67-1.20)
Itraconazole 1.12 (0.70-1.80)
Overall effect size Z = 0.36 (P = 0.72).
Discussion
Primary prophylaxis with triazoles in HIV patients can prevent
prevent both mucosal cansidiasis (P = 0.02) and deep fungal
infections (P < 0.0001). Fluconazole is better at preventing mucosal
candidiasis whereas itraconazole is better at preventing deep fungal
infections.
Both fluconazole and itraconazole are remarkably well tolerated
with no significant difference with placebo (P = 0.90).
However triazoles do not show any significant mortality benefit (P =
0.72)
Studies
Overall
Risk of Bias
schuman1997
High risk
chetchotisakd2004
High risk
parkes
-ratanshi2011
Some concerns
hakim2017
Some concerns
mckinsey1999
Some concerns
smith2001
High risk
chariyalertsak2002
High risk
Studies
Locatio
n
Drug
Dosage
Population
Duration
Endpoint
Schuman
1997
USA
Fluconazole
200
mg/week
Age > 13
years
CD4 <300/µL
29
months
Mucosal candidiasis
Chetchotisak
d
2004
Thailand
Fluconazole
400
mg/week
Age >14
years
CD4 <100/µL
~ 600 days
Cryptococcosis
/
invasive fungal
infection
parkes
-
ratanshi
2011
Uganda
Fluconazole
200 mg
thrice
weekly
ART naïve
CD4
<200
/µL
60 weeks
Cryptococcosis
/
cadidiasis
/
hospitalization /
death
Hakim 2017
Africa
Fluconazole
100 mg/day
ART naïve
Age > 5 years
CD4 <100/µL
48 weeks
Death /
cryptococcosis
/
candidiasis
Mckinsey
1999
USA
Itraconazole
200 mg/day
CD4 <150/µL
16
months
Systemic fungal
infection /
candidiasis
Smith 2001
Not
mention
ed
Itraconazole
200 mg/day
CD4 <300/µL
104 weeks
Systemic fungal
infection /
candidiasis
Chariyalerts
ak
2002
Thailand
Itraconazole
200 mg/day
Age 18
-60
years
CD4
<200
/µL
104 weeks
Systemic fungal
infection /
candidiasis
Conclusion
Primary prophylxis with triazole drugs in HIV patients with low CD4
count can prevent mucosal candidiasis as well as deep fungal
infections. They are well tolerated. However they do not have any
significant mortality benefit.
Analysis: Mucosal Candidiasis Analysis: Deep Fungal Infections
Analysis: Adverse Reactions Analysis: Mortality
Funnel plots of mucosal candidiasis, deep fungal infections, adverse
reactions and mortality respectively
Presented at ASICON (AIDS Society of India) on November 23, 2019
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