Effect of Once-Weekly Azithromycin vs Placebo in Children With HIV-Associated Chronic Lung Disease The BREATHE Randomized Clinical Trial

被引:23
作者
Ferrand, Rashida A. [1 ,2 ]
McHugh, Grace [2 ]
Rehman, Andrea M. [3 ]
Mujuru, Hilda [4 ]
Simms, Victoria [2 ,3 ]
Majonga, Edith D. [2 ]
Nicol, Mark P. [5 ,6 ]
Flaegstad, Trond [7 ,8 ]
Gutteberg, Tore J. [7 ,9 ]
Gonzalez-Martinez, Carmen [10 ,11 ]
Corbett, Elizabeth L. [1 ,10 ]
Rowland-Jones, Sarah L. [12 ]
Kranzer, Katharina [1 ,2 ]
Weiss, Helen A. [3 ]
Odland, Jon O. [7 ,13 ]
机构
[1] London Sch Hyg & Trop Med, Dept Clin Res, Keppel St, London WC1E 7HT, England
[2] Biomed Res & Training Inst, Harare, Zimbabwe
[3] London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, MRC Int Stat & Epidemiol Grp, London, England
[4] Univ Zimbabwe, Dept Paediat, Harare, Zimbabwe
[5] Univ Cape Town, Div Clin Microbiol, Cape Town, South Africa
[6] Univ Western Australia, Sch Biomed Sci, Perth, WA, Australia
[7] Arctic Univ Norway, UiT, Fac Hlth Sci, Tromso, Norway
[8] Univ Hosp North Norway, Dept Paediat, Tromso, Norway
[9] Univ Hosp North Norway, Dept Microbiol & Infect Control, Tromso, Norway
[10] Malawi Liverpool Wellcome Trust Clin Res Programm, Blantyre, Malawi
[11] Univ Malawi, Coll Med, Dept Paediat & Child Hlth, Blantyre, Malawi
[12] Univ Oxford, Nuffield Dept Med, Oxford, England
[13] Univ Pretoria, Fac Hlth Sci, Sch Hlth Syst & Publ Hlth, Pretoria, South Africa
基金
英国惠康基金; 英国医学研究理事会;
关键词
HUMAN-IMMUNODEFICIENCY-VIRUS; VERTICALLY-ACQUIRED HIV; INFECTED CHILDREN; ANTIRETROVIRAL THERAPY; LONG-TERM; ADOLESCENTS; BRONCHIECTASIS; EXACERBATIONS; BRONCHIOLITIS; INFLAMMATION;
D O I
10.1001/jamanetworkopen.2020.28484
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 taking ART. 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 weight-for-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 adverse events. 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.
引用
收藏
页数:14
相关论文
共 43 条
[1]   Azithromycin for Prevention of Exacerbations of COPD [J].
Albert, Richard K. ;
Connett, John ;
Bailey, William C. ;
Casaburi, Richard ;
Cooper, J. Allen D., Jr. ;
Criner, Gerard J. ;
Curtis, Jeffrey L. ;
Dransfield, Mark T. ;
Han, MeiLan K. ;
Lazarus, Stephen C. ;
Make, Barry ;
Marchetti, Nathaniel ;
Martinez, Fernando J. ;
Madinger, Nancy E. ;
McEvoy, Charlene ;
Niewoehner, Dennis E. ;
Porsasz, Janos ;
Price, Connie S. ;
Reilly, John ;
Scanlon, Paul D. ;
Sciurba, Frank C. ;
Scharf, Steven M. ;
Washko, George R. ;
Woodruff, Prescott G. ;
Anthonisen, Nicholas R. .
NEW ENGLAND JOURNAL OF MEDICINE, 2011, 365 (08) :689-698
[2]   Immunomodulatory Effects of Macrolide Antibiotics - Part 2: Advantages and Disadvantages of Long-Term, Low-Dose Macrolide Therapy [J].
Altenburg, J. ;
de Graaff, C. S. ;
van der Werf, T. S. ;
Boersma, W. G. .
RESPIRATION, 2011, 81 (01) :75-87
[3]   Effect of Azithromycin Maintenance Treatment on Infectious Exacerbations Among Patients With Non-Cystic Fibrosis Bronchiectasis The BAT Randomized Controlled Trial [J].
Altenburg, Josje ;
de Graaff, Casper S. ;
Stienstra, Ymkje ;
Sloos, Jacobus H. ;
van Haren, Eric H. J. ;
Koppers, Ralph J. H. ;
van der Werf, Tjip S. ;
Boersma, Wim G. .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2013, 309 (12) :1251-1259
[4]   Serum and WBC pharmacokinetics of 1500 mg of azithromycin when given either as a single dose or over a 3 day period in healthy volunteers [J].
Amsden, GW ;
Gray, CL .
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 2001, 47 (01) :61-66
[5]  
[Anonymous], 2019, UNAIDS DAT 2019
[6]  
Attia EF, 2017, PEDIATR INFECT DIS J, V36, pE93, DOI [10.1097/INF.0000000000001453, 10.1097/inf.0000000000001453]
[7]   Bronchiectasis and other chronic lung diseases in adolescents living with HIV [J].
Attia, Engi F. ;
Miller, Robert F. ;
Ferrand, Rashida A. .
CURRENT OPINION IN INFECTIOUS DISEASES, 2017, 30 (01) :21-30
[8]   Incidence and Prevalence of Opportunistic and Other Infections and the Impact of Antiretroviral Therapy Among HIV-infected Children in Low- and Middle-income Countries: A Systematic Review and Meta-analysis [J].
B-Lajoie, Marie-Renee ;
Drouin, Olivier ;
Bartlett, Gillian ;
Quynh Nguyen ;
Low, Andrea ;
Gavriilidis, Georgios ;
Easterbrook, Philippa ;
Muhe, Lulu .
CLINICAL INFECTIOUS DISEASES, 2016, 62 (12) :1586-1594
[9]   Quantitative CT analysis for bronchiolitis obliterans in perinatally HIV-infected adolescents-comparison with controls and lung function data [J].
Barrera, Christian A. ;
Du Plessis, Anne-Marie ;
Otero, Hansel J. ;
Mahtab, Sana ;
Githinji, Leah N. ;
Zar, Heather J. ;
Zhu, Xiaowei ;
Andronikou, Savvas .
EUROPEAN RADIOLOGY, 2020, 30 (08) :4358-4368
[10]   Long-term macrolide antibiotics for the treatment of bronchiectasis in adults: an individual participant data meta-analysis [J].
Chalmers, James D. ;
Boersma, Wim ;
Lonergan, Mike ;
Jayaram, Lata ;
Crichton, Megan L. ;
Karalus, Noel ;
Taylor, Steven L. ;
Martin, Megan L. ;
Burr, Lucy D. ;
Wong, Conroy ;
Altenburg, Josje .
LANCET RESPIRATORY MEDICINE, 2019, 7 (10) :845-854