Prophylactic azithromycin does not improve lung function in paediatric HIV-related lung disease

A once-weekly prophylactic dose of azithromycin does not improve lung function in children with HIV-associated chronic lung disease (HCLD), according to results of the BREATHE* trial. However, azithromycin was associated with a reduction in acute respiratory exacerbations (AREs).

“We hypothesized that azithromycin would reduce systemic inflammation, which would translate into improvement of lung function, and/or have an antibiotic effect … but there was no evidence of improvement of pulmonary function in our trial,” the researchers pointed out.

Study participants were 347 children aged 6–19 years (median age 15.3 years, 51 percent boys, mean baseline FEV₁** z score -2.00) with perinatally-acquired HIV treated with antiretroviral therapy (ART) for ≥6 months and HCLD*** who attended outpatient HIV clinics at two public hospitals in Malawi and Zimbabwe in 2016–2019. They were randomized 1:1 to receive either oral azithromycin (weight-based dose) or placebo once weekly for 48 weeks.

At 48 weeks, FEV₁ z score – an assessment of lung function – did not significantly differ between patients who received azithromycin and placebo (adjusted mean difference [AMD], 0.06 higher with azithromycin, 95 percent confidence interval [CI], -0.10 to 0.21; p=0.48). [JAMA Network Open 2020;3:e2028484]

However, AREs occurred at a significantly lower rate among azithromycin than placebo recipients (12.1 vs 24.7 per 100 person-years; hazard ratio [HR], 0.50, 95 percent CI, 0.27–0.93; p=0.03).

All-cause hospitalization rate was numerically, but not significantly, lower among azithromycin vs placebo recipients (1.3 vs 7.1 events per 100 person-years [two and nine recipients, respectively]; HR, 0.24, 95 percent CI, 0.06–1.07; p=0.06).

No drug-related severe adverse events were reported. The three deaths that occurred were among placebo recipients. There were no incidents of Salmonella typhi or Clostridium difficile infection. Gastroenteritis and malaria each affected one patient in the azithromycin and two in the placebo group. Gastrointestinal symptoms were more common in the azithromycin group but were minor and spontaneously resolved.

Weight-for-age z score was numerically but not significantly higher in the azithromycin than placebo group (mean 0.03 higher; p=0.56).

“Our trial found no difference in the primary outcome of lung function but showed that azithromycin is an effective intervention in reducing ARE events associated with HCLD in children and adolescents,” said the researchers.

Azithromycin may have also reduced incidents of diarrhoea and malaria which are common causes of death in HIV-positive children, though further research is warranted to establish this, they continued. 

“Despite being common, there is no evidence base to guide management of childhood HCLD, often resulting in presumptive treatment for tuberculosis,” the researchers pointed out. “Therefore, the present findings potentially have substantial implications in terms of reduced antimicrobial use.”

They recommended that future studies look into identifying which patients would most benefit from prophylactic azithromycin as well as the optimal duration of treatment. This would ensure maximum benefit and reduce antimicrobial resistance. Other avenues for research include the impact of the intervention on quality of life, school attendance, and economic burden, they said.