Persistent immune ac activation an and depression am among Ugan - PowerPoint PPT Presentation

Persistent immune ac activation an and depression am among Ugan andan ans in init itia iatin ing ART Jonathan L. Chang, Nicholas Musinguzi, Alexander C. Tsai, Conrad Muzoora, Mwebesa Bwana, Yap Boum, Russell Tracy, Jeff N. Martin, Jessica E. Haberer, David R. Bangsberg, Peter W. Hunt, Mark J. Siedner

Disclosures and Acknowledgement • No disclosures • I would like to acknowledge persons living with HIV in Uganda and elsewhere for contributing generously to this research

Bac Background und and and Metho hods ds • Chronic inflammation, even after effective ART, has been associated with numerous comorbidities and mortality • Relationship between inflammation and depression less clear • 453 Ugandan adults initiating ART from 2005-2013 followed 3-4 times/year for 2 years Byakwaga H et al. , JID 2014; Siedner MJ et al., JID 2017; Lee S et al. , JID 2017; Martinez P et al. , JAIDS 2014

Bac Background und and and Metho hods ds • Chronic inflammation, even after effective ART, has been associated with numerous comorbidities and mortality • Relationship between inflammation and depression less clear • 453 Ugandan adults initiating ART from 2005-2013 followed 3-4 times/year for 2 years Byakwaga H et al. , JID 2014; Siedner MJ et al., JID 2017; Lee S et al. , JID 2017; Martinez P et al. , JAIDS 2014

Bac Background und and and Metho hods ds • Chronic inflammation, even after effective ART, has been associated with numerous comorbidities and mortality • Relationship between inflammation and depression less clear • 453 Ugandan adults initiating ART from 2005-2013 followed 3-4 times/year for 2 years EXPOSURE IL-6 0.6 Log 10 marker level D-dimer Δ sCD14 0.3 sCD163 KT ratio 0.0 0 6 Month since ART start Byakwaga H et al. , JID 2014; Siedner MJ et al., JID 2017; Lee S et al. , JID 2017; Martinez P et al. , JAIDS 2014

Bac Background und and and Metho hods ds • Chronic inflammation, even after effective ART, has been associated with numerous comorbidities and mortality • Relationship between inflammation and depression less clear • 453 Ugandan adults initiating ART from 2005-2013 followed 3-4 times/year for 2 years OUTCOME EXPOSURE IL-6 0.6 Log 10 marker level D-dimer Depressive symptom severity during first 2 years of ART use Δ sCD14 0.3 sCD163 Binary probable Continuous KT ratio 0.0 depression 0 6 Month since ART start Byakwaga H et al. , JID 2014; Siedner MJ et al., JID 2017; Lee S et al. , JID 2017; Martinez P et al. , JAIDS 2014

Bac Background und and and Metho hods ds • Chronic inflammation, even after effective ART, has been associated with numerous comorbidities and mortality • Relationship between inflammation and depression less clear • 453 Ugandan adults initiating ART from 2005-2013 followed 3-4 times/year for 2 years OUTCOME EXPOSURE IL-6 0.6 Log 10 marker level D-dimer Depressive symptom severity during first 2 years of ART use Δ sCD14 0.3 sCD163 Binary probable Continuous KT ratio 0.0 depression 0 6 Month since ART start GEE regression models, adjusted for demographic and clinical • characteristics Byakwaga H et al. , JID 2014; Siedner MJ et al., JID 2017; Lee S et al. , JID 2017; Martinez P et al. , JAIDS 2014

1. Depressive symptom score: continuous outcome p < 0.001 p = 0.006 p = 0.007 p = 0.019 0.1 Adjusted beta (95% CI) * * * * * * * 0.0 -0.1 -0.2 sCD14 KT ratio IL-6 D-dimer sCD163 sCD14, adjusted KT ratio, adjusted for KT ratio for sCD14 6-month change in marker level (in quartiles *Lowest quartile used as reference from smallest to largest decreases) • Models adjusted for age, sex, BMI, marital status, education, asset index, baseline depressive symptom score, CD4+ count, viral load suppression, tuberculosis co-infection, time on ART, year of enrollment, heavy drinking, and smoking.

1. Depressive symptom score: continuous outcome p < 0.001 p = 0.006 p = 0.007 p = 0.019 0.1 Adjusted beta (95% CI) * * * * * * * 0.0 -0.1 -0.2 sCD14 KT ratio IL-6 D-dimer sCD163 sCD14, adjusted KT ratio, adjusted for KT ratio for sCD14 6-month change in marker level (in quartiles *Lowest quartile used as reference from smallest to largest decreases) • Models adjusted for age, sex, BMI, marital status, education, asset index, baseline depressive symptom score, CD4+ count, viral load suppression, tuberculosis co-infection, time on ART, year of enrollment, heavy drinking, and smoking.

1. Depressive symptom score: continuous outcome p < 0.001 p = 0.006 p = 0.007 p = 0.019 0.1 Adjusted beta (95% CI) * * * * * * * 0.0 -0.1 -0.2 sCD14 KT ratio IL-6 D-dimer sCD163 sCD14, adjusted KT ratio, adjusted for KT ratio for sCD14 6-month change in marker level (in quartiles *Lowest quartile used as reference from smallest to largest decreases) 2. Probable depression: binary outcome • Models adjusted for age, sex, BMI, marital status, education, asset index, baseline depressive symptom score, CD4+ count, viral load suppression, tuberculosis co-infection, time on ART, year of enrollment, heavy drinking, and smoking.

1. Depressive symptom score: continuous outcome p < 0.001 p = 0.006 p = 0.007 p = 0.019 0.1 Adjusted beta (95% CI) * * * * * * * 0.0 -0.1 -0.2 sCD14 KT ratio IL-6 D-dimer sCD163 sCD14, adjusted KT ratio, adjusted for KT ratio for sCD14 6-month change in marker level (in quartiles *Lowest quartile used as reference from smallest to largest decreases) 2. Probable depression: binary outcome • Models adjusted for age, sex, BMI, marital status, education, asset index, baseline depressive symptom score, CD4+ count, viral load suppression, tuberculosis co-infection, time on ART, year of enrollment, heavy drinking, and smoking.

Di Discus ussion • Greater decreases in inflammatory biomarkers, particularly sCD14 and KT ratio, were associated with lower future depressive symptoms after ART initiation • Additional measures, beyond suppressive ART, may be necessary to reduce mental health disturbances in persons living with HIV • Measures that target macrophage activation and tryptophan metabolism may be effective

Re References 1. Byakwaga H, Boum Y, Huang Y, et al. The kynurenine pathway of tryptophan catabolism, CD4+ T-cell recovery, and mortality among HIV-infected Ugandans initiating antiretroviral therapy. J Infect Dis. 2014;210(3):383-391. 2. Lee S, Byakwaga H, Boum Y, et al. Immunologic pathways that predict mortality in HIV- infected Ugandans initiating antiretroviral therapy. J Infect Dis. 2017;215(8):1270-1274. 3. Siedner MJ, Kim JH, Nakku RS, et al. Persistent immune activation and carotid atherosclerosis in HIV-infected Ugandans receiving antiretroviral therapy. J Infect Dis. 2016;213(3):370-378. 4. Martinez P, Tsai AC, Muzoora C, et al. Reversal of the Kynurenine pathway of tryptophan catabolism may improve depression in ART-treated HIV-infected Ugandans. J Acquir Immune Defic Syndr . 2014;65(4):456-462.