Dataset Information

Effect of azithromycin on incidence of acute respiratory exacerbations in children with HIV taking antiretroviral therapy and co-morbid chronic lung disease: a secondary analysis of the BREATHE trial.

ABSTRACT:

Background

In the BREATHE trial weekly azithromycin decreased the rate of acute respiratory exacerbations (AREs) compared to placebo among children and adolescents with HIV-associated chronic lung disease (CLD) taking antiretroviral therapy (ART). The aim of this analysis was to identify risk factors associated with AREs and mediators of the effect of azithromycin on AREs.

Methods

The primary outcome of this analysis was the rate of AREs by study arm up to 49 weeks. We analysed rates using Poisson regression with random intercepts. Interaction terms were fitted for potential effect modifiers. Participants were recruited from Zimbabwe and Malawi between15 June 2016 and 4 September 2018.

Findings

We analysed data from 345 participants (171 allocated to azithromycin and 174 allocated to placebo). Rates of AREs were higher among those with an abnormally high respiratory rate at baseline (adjusted rate ratio (aRR) 2.08 95% CI 1.10-3.95 p-value 0.02) and among those with a CD4 cell count <200 cells/mm³ (aRR 2.71; 95% CI 1.27-5.76; p-value 0.008). We found some evidence for variation in the effect of azithromycin by sex (p-value for interaction=0.07); males had a greater reduction in the rate of ARE with azithromycin treatment than females. We found that azithromycin had a greater impact on reducing AREs in participants with chronic respiratory symptoms at baseline, those on 1st line ART, with a FEV₁ score >-2 and participants without baseline resistance to azithromycin. However, there was no statistical evidence for interaction due to low statistical power.

Interpretation

These may represent subgroups who may benefit the most from treatment with weekly azithromycin, which could help guide targeted treatment.

Funding

There was no funding source for this post hoc analysis.

SUBMITTER: Price A

PROVIDER: S-EPMC8599092 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Publications

Effect of azithromycin on incidence of acute respiratory exacerbations in children with HIV taking antiretroviral therapy and co-morbid chronic lung disease: a secondary analysis of the BREATHE trial.

Price Amy A McHugh Grace G Simms Victoria V Semphere Robina R Ngwira Lucky G LG Bandason Tsitsi T Mujuru Hilda H Odland Jon O JO Ferrand Rashida A RA Rehman Andrea M AM

EClinicalMedicine 20211113

<h4>Background</h4>In the BREATHE trial weekly azithromycin decreased the rate of acute respiratory exacerbations (AREs) compared to placebo among children and adolescents with HIV-associated chronic lung disease (CLD) taking antiretroviral therapy (ART). The aim of this analysis was to identify risk factors associated with AREs and mediators of the effect of azithromycin on AREs.<h4>Methods</h4>The primary outcome of this analysis was the rate of AREs by study arm up to 49 weeks. We analysed ra ...[more]

PMID: 34820609

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Project description:BackgroundAcute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases.MethodsWe performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval.ResultsA total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George's Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04).ConclusionsAmong selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.).

Project description:BackgroundChronic lung disease (CLD) is common among children with HIV (CWH) including in those taking antiretroviral therapy (ART). Azithromycin has both antimicrobial and anti-inflammatory effects and has been effective in improving lung function in a variety of lung diseases. We investigated lung function trajectories among CWH with CLD on ART enrolled in a randomized controlled trial of adjuvant azithromycin. We also investigated factors that modified the effect of azithromycin on lung function.MethodsThe study used data from a double-blinded placebo-controlled trial conducted in Malawi and Zimbabwe of 48 weeks on azithromycin (BREATHE: ClinicalTrials.gov NCT02426112) among CWH aged 6 to 19 years taking ART for at least six months who had a forced expiratory volume in one second (FEV1) z-score <-1.0. Participants had a further follow-up period of 24 weeks after intervention cessation. FEV1, forced vital capacity (FVC) and FEV1/FVC were measured at baseline, 24, 48 and 72-weeks and z-scores values calculated. Generalized estimating equations (GEE) models were used to determine the mean effect of azithromycin on lung-function z-scores at each follow-up time point.ResultsOverall, 347 adolescents (51% male, median age 15 years) were randomized to azithromycin or placebo. The median duration on ART was 6.2 (interquartile range: 3.8-8.6) years and 56.2% had an HIV viral load < 1000copies/ml at baseline. At baseline, the mean FEV1 z-score was - 2.0 (0.7) with 44.7% (n = 155) having an FEV1 z-score <-2, and 10.1% had microbiological evidence of azithromycin resistance. In both trial arms, FEV1 and FVC z-scores improved by 24 weeks but appeared to decline thereafter. The adjusted overall mean difference in FEV1 z-score between the azithromycin and placebo arms was 0.004 [-0.08, 0.09] suggesting no azithromycin effect and this was similar for other lung function parameters. There was no evidence of interaction between azithromycin effect and baseline age, lung function, azithromycin resistance or HIV viral load.ConclusionThere was no observed azithromycin effect on lung function z-scores at any time point suggesting no therapeutic effect on lung function.Trial registrationClinicalTrials.gov NCT02426112. First registered on 24/04/2015.

Project description:BackgroundAlthough amoxicillin-clavulanate is the recommended first-line empirical oral antibiotic treatment for non-severe exacerbations in children with bronchiectasis, azithromycin is also often prescribed for its convenient once-daily dosing. No randomised controlled trials involving acute exacerbations in children with bronchiectasis have been published to our knowledge. We hypothesised that azithromycin is non-inferior to amoxicillin-clavulanate for resolving exacerbations in children with bronchiectasis.MethodsWe did this parallel-group, double-dummy, double-blind, non-inferiority randomised controlled trial in three Australian and one New Zealand hospital between April, 2012, and August, 2016. We enrolled children aged 1-19 years with radiographically proven bronchiectasis unrelated to cystic fibrosis. At the start of an exacerbation, children were randomly assigned to oral suspensions of either amoxicillin-clavulanate (22·5 mg/kg, twice daily) and placebo or azithromycin (5 mg/kg per day) and placebo for 21 days. We used permuted block randomisation (stratified by age, site, and cause) with concealed allocation. The primary outcome was resolution of exacerbation (defined as a return to baseline) by 21 days in the per-protocol population, with a non-inferiority margin of -20%. We assessed several secondary outcomes including duration of exacerbation, time to next exacerbation, laboratory, respiratory, and quality-of-life measurements, and microbiology. This trial was registered with the Australian/New Zealand Registry (ACTRN12612000010897).FindingsWe screened 604 children and enrolled 236. 179 children had an exacerbation and were assigned to treatment: 97 to amoxicillin-clavulanate, 82 to azithromycin). By day 21, 61 (84%) of 73 exacerbations had resolved in the azithromycin group versus 73 (84%) of 87 in the amoxicillin-clavulanate group. The risk difference showed non-inferiority (-0·3%, 95% CI -11·8 to 11·1). Exacerbations were significantly shorter in the amoxicillin-clavulanate group than in the azithromycin group (median 10 days [IQR 6-15] vs 14 days [8-16]; p=0·014). Adverse events were attributed to the trial medication in 17 (21%) of 82 children in the azithromycin group versus 23 (24%) of 97 in the amoxicillin-clavulanate group (relative risk 0·9, 95% CI 0·5 to 1·5).InterpretationBy 21 days of treatment, azithromycin is non-inferior to amoxicillin-clavulanate for resolving exacerbations in children with non-severe bronchiectasis. In some patients, such as those with penicillin hypersensitivity or those likely to have poor adherence, azithromycin provides another option for treating exacerbations, but must be balanced with risk of treatment failure (within a 20% margin), longer exacerbation duration, and the risk of inducing macrolide resistance.FundingAustralian National Health and Medical Research Council.

Dataset Information

Effect of azithromycin on incidence of acute respiratory exacerbations in children with HIV taking antiretroviral therapy and co-morbid chronic lung disease: a secondary analysis of the BREATHE trial.

Background

Methods

Findings

Interpretation

Funding

Publications

Effect of azithromycin on incidence of acute respiratory exacerbations in children with HIV taking antiretroviral therapy and co-morbid chronic lung disease: a secondary analysis of the BREATHE trial.

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