Chronic obstructive pulmonary disease (COPD) in a large international cohort of HIV- infected adults with CD4+ >500 cells/mm 3 Ken Kunisaki, M.D., M.S. Co-authors: Dennis Niewoehner, Gary Collins, Daniel Nixon, Ellen Tedaldi, Christopher Akolo, Cissy Kityo, Hartwig Klinker, Alberto La Rosa, John Connett, and the INSIGHT START Study Team

Conflicts of Interest I have no conflicts of interest to report

COPD: Chronic Obstructive Pulmonary Disease Niewoehner DE. N Engl J Med 2010;362:1407

Global Burden of Disease Study. Lancet 2012;380:

HIV Increases COPD Risk Main COPD risk factor is cigarette smoking HIV is also a COPD risk factor Kuhlman 1989, Gelman 1999, Diaz 2000, Morris 2000, Crothers 2006, Crothers 2011, Drummond 2011, Drummond 2013, Nakamura 2014 COPD prevalence in PLWH varies from 3%-23% George 2009, Cui 2010, Gingo 2010, Hirani 2011, Kristoffersen 2012, Drummond 2013, Madeddu 2013, Samperiz 2013, Nakamura 2014 We aimed to assess COPD prevalence in a large, multi-site, multi-national sample of PLWH.

START Pulmonary Substudy Strategic Timing of Antiretroviral Treatment (START) Trial –Infected with HIV-1, naïve to ART –CD4 >500 cells/mm 3 –Age ≥18 –Not currently pregnant Pulmonary Substudy –Age ≥25 –No asthma medication use –No contraindications to post-bronchodilator spirometry Unstable heart disease, surgery within 6 months, respiratory illness within 6 weeks, allergy to albuterol/salbutamol

Methods Post-bronchodilator spirometry –FEV 1 –FVC –FEV 1 /FVC ratio FEV 1 /FVC <5 th %tile

Enrollment

Demographics Total AfricaAsiaEUR / ISR / AUS MEX / S. America USA n (32.0%) 103 (10.0%)313 (30.5%)191 (18.6%)91 (8.9%) Age (years) (32, 44)36 (30, 41)38 (31, 45)34 (29, 40)36 (29, 47) Female 29.1% 211 (64.3%) 27 (26.2%)26 (8.3%)26 (13.6%)9 (9.9%) Years of HIV dx 1.2 (0.4, 3.5) 1.5 (0.5, 4.8) 0.8 (0.2, 3.4)1.2 (0.5, 3.5)0.6 (0.3, 2.2)1.5 (0.4, 4.6) CD4 cells/mm (583, 767) 695 (603, 814) 618 (561, 728)634 (581, 738)632 (574, 718)674 (582, 773) Log HIV copies/mL 4.2 (3.5, 4.7) 3.8 (3.0, 4.6) 4.5 (3.9, 4.9)4.3 (3.8, 4.7)4.4 (3.9, 4.8)3.9 (3.3, 4.5) VL ≤ 400 copies/mL 9.5% 62 (19.0%)6 (5.9%)9 (2.9%)9 (4.7%)11 (12.1%) Current smoker 28.2% 46 (14.0%)20 (19.4%)140 (44.7%)53 (28.0%)30 (33.0%) Former smoker 10.8% 19 (5.8%)11 (10.7%)42 (13.4%)27 (14.3%)12 (13.2%) Never smoker 60.9% 263 (80.2%) 72 (69.9%)131 (41.9%)109 (57.7%)49 (53.8%)

Regional Demographics TotalAfricaAsiaEUR / ISR / AUS MEX / S. America USA n Age (years) Female 29.1%64.3%26.2%8.3%13.6%9.9% Years of HIV dx CD4 cells/mm Log HIV copies/mL VL ≤ 400 copies/mL 9.5%19.0%5.9%2.9%4.7%12.1% Current smoker 28.2%14.0%19.4%44.7%28.0%33.0% Former smoker 10.8%5.8%10.7%13.4%14.3%13.2% Never smoker 60.9%80.2%69.9%41.9%57.7%53.8%

COPD Prevalence Overall COPD prevalence 6.8% (95% CI: 5.3% - 8.5%) TotalAfricaAsiaEUR / ISR / AUS MEX / S. AMER USAp- value n=988n=322n=102n=298n=181n=85 FEV 1 /FVC <LLN 6.8% 7.8%2.0%9.1%3.3%8.2%p=0.03 COPD Severity, FEV 1 : ≥80% pred 52.2% 40.0%100.0%66.7% 14.3% 50%-79% pred 43.3% 60.0%0.0%25.9%33.3%71.4% 30%-49% pred 4.5% 0.0% 7.4%0.0%14.3% <30% pred 0.0%

COPD Prevalence – Region TotalAfricaAsiaEUR / ISR / AUS MEX / S. AMER USAp- value FEV 1 /FVC <LLN 6.8%7.8%2.0%9.1%3.3%8.2% p=0.03 COPD Severity --FEV 1 ≥80% pred. 52.2%40.0%100.0%66.7% 14.3% --FEV 1 50%-79% pred. 43.3%60.0%0.0%25.9%33.3%71.4% --FEV 1 30%-49% pred. 4.5%0.0% 7.4%0.0%14.3% --FEV 1 <30% pred. 0.0%

COPD by Age & Smoking TotalFEV 1 /FVC <LLN Overall cohort988 (100%)67 (6.8%) Smoking status Current27.5%11.8% Former11.1%2.7% Never61.3%5.3% p-value-<0.001 Age (years) quartile 25 – %3.9% 31 – %6.7% 37 – %7.6% >4423.2%9.2% p-value-0.13

Spirometry Regression Analysis Multivariate linear regression Lower FEV 1 /FVC ratio associated with: –Older age (p<0.0001) –Increased smoking pack-years (p<0.0001) –Differed by region (p=0.01)

Conclusions Successfully enrolled 1,026 adult PLWH (CD4>500, naïve to ART) from 80 sites and 20 countries COPD: –is not uncommon (6.8%) –appears to relate strongest to smoking and aging –varies by global region

Clinical Implications Smoking cessation COPD as PLWH age Need to familiarize PLWH providers with tools for COPD screening, diagnosis, management

Future Directions Prospective data –Kristoffersen 2012: n=63 (Denmark); 9.5% COPD prevalence at baseline; 19.0% at 4.4 year follow-up. ART effect on lung function decline –Conflicting data on ART as COPD risk factor –Randomized allocation will address this

Acknowledgements 80 sites around the world University of Minnesota (USA) –Gary Collins, Mollie Roediger- Poelhman, Carol Miller, John Connett, Dennis Niewoehner The Kirby Institute (Australia) –Cate Carey, Simone Jacoby, Vida Shahamat, Megan Clewett Copenhagen HIV Programme (Denmark) –Bitten Aagaard, Mary Pearson, Per Jansson, Daniella Gey Thank you to each of the 1,026 substudy participants MRC Clinical Trials Unit (UK) –Nafisah Braimah, Fleur Hudson, Michelle Gabriel, Nicki Doyle CPCRA (USA) –Betsy Finley, Adriana Sanchez Ellen Tedaldi (Temple Univ, USA) Daniel Nixon (VCU, USA) Jorgen Vestbo (Manchester Univ, UK) Study funded by R01 HL096453

Multivariate Linear Regression