IMPORTANCE: HIV-associated chronic lung disease (HCLD) in children is associated with small
airways disease, is common despite antiretroviral therapy (ART), and is associated with substantial
morbidity. Azithromycin has antibiotic and immunomodulatory activity and may be effective in
treating HCLD through reducing respiratory tract infections and inflammation.
OBJECTIVE: To determine whether prophylactic azithromycin is effective in preventing worsening
of lung function and in reducing acute respiratory exacerbations (AREs) in children with HCLD
DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled, randomized clinical
trial (BREATHE) was conducted between 2016 and 2019, including 12 months of follow-up, at
outpatient HIV clinics in 2 public sector hospitals in Malawi and Zimbabwe. Participants were
randomized 1:1 to intervention or placebo, and participants and study personnel were blinded to
treatment allocation. Participants included children aged 6 to 19 years with perinatally acquired HIV
and HCLD (defined as forced expiratory volume in 1 second [FEV1
] z score < −1) who were taking ART
for 6 months or longer. Data analysis was performed from September 2019 to April 2020.
INTERVENTION: Once-weekly oral azithromycin with weight-based dosing, for 48 weeks.
MAIN OUTCOMES AND MEASURES: All outcomes were prespecified. The primary outcome was the
mean difference in FEV1 z score using intention-to-treat analysis for participants seen at end line.
Secondary outcomes included AREs, all-cause hospitalizations, mortality, and weight-for-age z score.
RESULTS: A total of 347 individuals (median [interquartile range] age, 15.3 [12.7-17.7] years; 177 boys
[51.0%]) were randomized, 174 to the azithromycin group and 173 to the placebo group; 162
participants in the azithromycin group and 146 placebo group participants had a primary outcome
available and were analyzed. The mean difference in FEV1 z score was 0.06 (95% CI, −0.10 to 0.21;
P = .48) higher in the azithromycin group than in the placebo group, a nonsignificant difference. The
rate of AREs was 12.1 events per 100 person-years in the azithromycin group and 24.7 events per 100
person-years in the placebo groups (hazard ratio, 0.50; 95% CI, 0.27 to 0.93; P = .03). The
hospitalization rate was 1.3 events per 100 person-years in the azithromycin group and 7.1 events per
100 person-years in the placebo groups, but the difference was not significant (hazard ratio, 0.24;
95% CI, 0.06 to 1.07; P = .06). Three deaths occurred, all in the placebo group. The mean weightfor-age z score was 0.03 (95% CI, −0.08 to 0.14; P = .56) higher in the azithromycin group than in the
placebo group, although the difference was not significant. There were no drug-related severe
CONCLUSIONS AND RELEVANCE: In this randomized clinical trial specifically addressing childhood
HCLD, once-weekly azithromycin did not improve lung function or growth but was associated with
reduced AREs; the number of hospitalizations was also lower in the azithromycin group but the
difference was not significant. Future research should identify patient groups who would benefit
most from this intervention and optimum treatment length, to maximize benefits while reducing the
risk of antimicrobial resistance.
SUPPLEMENT 1. Trial Protocol
eAppendix. Multiple Imputation Models;
eTable 1. Baseline Characteristics by Arm for Participants Analyzed for the Primary Outcome;
eTable 2. Baseline Characteristics Comparing Participants With and Without Primary Outcome;
eTable 3. Number of Adverse Events;
eTable 4. Intervention Effect (Adjusted Mean Difference) in Post Hoc Subgroup Analysis by Recruitment Date;