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TELOMERE LENGTH, TELOMERASE ACTIVITY, AND AGE-RELATED DISEASE: ACTG NWCS 422
Chad J. Achenbach1, Drew Nannini1, Isabelle Clerc1, Hannah Hudson1, Brian Joyce1, Kunling Wu2, Katherine Tassiopoulos2, Peter W. Hunt3, Babafemi Taiwo1, Richard D'Aquila1, Sudhir Penugonda1, Lifang Hou1, Frank J. Palella1
1Northwestern University, Chicago, IL, USA,2Harvard University, Boston, MA, USA,3University of California San Francisco, San Francisco, CA, USA
Telomere length (TL) and telomerase activity (TA) require further study as biomarkers of age-related disease among persons with HIV (PWH). We assessed factors associated with short TL and associations between TL, TA and age-related co-morbidities among PWH on suppressive ART.
A nested case-control study using clinical data and banked PBMCs from ACTG Longitudinal Linked Randomized Trials (ALLRT). Cases had: (1) sustained plasma HIV RNA (VL) suppression to <200 copies/mL within 24 weeks of ART initiation and for ≥96 weeks; (2) non-accidental death or confirmed diagnosis of cancer, cardiovascular, liver, renal, neurocognitive, or pulmonary disease, bone fractures or diabetes; (3) banked PBMC pre-ART, week 48 and pre-event. For each case, there were 2 controls matched for sex, age and duration of NRTI. TL was determined using qPCR with relative TL measured by quantifying a telomere repeat copy versus single copy reference gene ratio (T/S ratio). TA was determined using a real-time quantitative telomerase repeats amplification protocol (RQ-TRAP). TA data were log[sub]10[/sub] transformed. Univariable and multivariable conditional logistic regression evaluated associations between TL, TA and disease.
We studied 351 participants (117 cases, 234 controls); 23% female, 53% non-white, 8% IDU and 56% smokers. Pre-ART, median age was 42 years, CD4 cells/µl 253, CD8 cells/µl 766, CD4/CD8 ratio 0.25, VL 4.7 log10 copies/mL, TL 0.41 and TA 1.9 log10. Among incident cases, 14 (35%) were diabetes, 33 (28%) renal disease, 18 (15%) cancer, 14 (12%) CVD, 7 (6%) death and 4 (4%) bone fractures. Short pre-ART TL (<0.4 T/S ratio) was associated with pre-ART VL >105 copies/mL (OR=1.9; 95% CI 1.2-3.0) and pre-ART TA in the lowest quartile (OR 1.8; 95% CI 1.0-3.2). We found no associations between short pre-ART TL and age, smoking, CD4 or CD4/CD8 ratio. Factors positively associated with age-related disease were earlier calendar study entry year, pre-ART CD4<200 cells/µl, higher pre-ART VL, initial ART regimen without TDF, lower CD4/CD8 ratio at 96 weeks and smoking. Neither pre-ART TL nor TA were associated with age-related disease in univariable or multivariable analyses.
Pre-ART telomeres were significantly shorter among PWH with higher VL levels; however, pre-ART TL and TA were not associated with age-related disease. Longitudinal data of changes in TL and TA during ART and associations with disease events are forthcoming.