Background Leukocyte telomere length (TL) shortens with age and is associated with coronary artery disease (CAD) events in the general population. Persons living with HIV (PLWH) may have accelerated atherosclerosis and shorter TL than the general population. It is unknown whether TL is associated with CAD in PLWH. Methods We measured TL by quantitative PCR in white Swiss HIV Cohort Study participants. Cases had a first CAD event during 01.01.2000-31.12.2017. We matched 1-3 PLWH controls without CAD events on sex, age, and observation time. We obtained univariable and multivariable odds ratios (OR) for CAD from conditional logistic regression analyses. Results We included 333 cases (median age 54 years; 14% women; 83% with suppressed HIV RNA) and 745 controls. Median time (interquartile range) of TL measurement was 9.4 (5.9-13.8) years prior to CAD event. Compared to the 1st (shortest) TL quintile, participants in the 5th (longest) TL quintile had univariable and multivariable CAD event OR=0.56 (95% confidence interval, 0.35-0.91) and OR=0.54 (0.31-0.96). Multivariable OR for current smoking was 1.93 (1.27-2.92), dyslipidemia OR=1.92 (1.41-2.63), and for recent abacavir, cumulative lopinavir, indinavir, and darunavir exposure was OR=1.82 (1.27-2.59), OR=2.02 (1.34-3.04), OR=3.42 (2.14-5.45), and OR=1.66 (1.00-2.74), respectively. The TL-CAD association remained significant when adjusting only for Framingham risk score, when excluding TL outliers, and when adjusting for CMV-seropositivity, HCV-seropositivity, time spent with detectable HIV viremia, and injection drug use. Conclusion In PLWH, TL measured >9 years before, is independently associated with CAD events after adjusting for multiple traditional and HIV-related factors.

Background Coronary artery disease (CAD) is in part genetically determined. Aging is accentuated in people with HIV (PLWH). It is unknown whether genetic CAD event prediction in PLWH is improved by applying individual polygenic risk scores (PRS) and by considering genetic variants associated with successful aging and longevity. Methods In Swiss HIV Cohort Study participants of self-reported European descent, we determined univariable and multivariable odds ratios (OR) for CAD events, based on traditional CAD risk factors, adverse antiretroviral exposures, and different validated genome-wide PRS. PRS were built from CAD-associated single nucleotide polymorphisms (SNPs), longevity-associated SNPs, or both. Results We included 269 cases with CAD events between 2000-2017 (Median age 54 years, 87% male, 82% with suppressed HIV RNA) and 567 event-free controls. Clinical (i.e. traditional and HIV-related) risk factors, and PRS built from CAD-associated SNPs, longevity-associated SNPs, or both, each contributed independently to CAD events (p<0.001). Participants with the most unfavorable clinical risk factor profile (top quintile) had adjusted CAD-OR=17.82 (8.19-38.76), compared to participants in the bottom quintile. Participants with the most unfavorable CAD-PRS (top quintile) had adjusted CAD-OR=3.17 (1.74-5.79), compared to the bottom quintile. After adding longevity-associated SNPs to the CAD-PRS, participants with the most unfavorable genetic background (top quintile) had adjusted CAD-OR=3.67 (2.00-6.73), compared to the bottom quintile. Conclusions In Swiss PLWH, CAD prediction based on traditional and HIV-related risk factors was superior to genetic CAD prediction based on longevity- and CAD-associated PRS. Combining traditional, HIV-related and genetic risk factors provided the most powerful CAD prediction.

Background Telomere length (TL) shortens during aging, HIV-seroconversion and untreated chronic HIV infection. It is unknown whether early antiretroviral therapy (ART) start is associated with less TL shortening during primary HIV infection (PHI). Methods We measured TL in peripheral blood mononuclear cells by quantitative PCR in participants of the Zurich PHI Study with samples available for >6 years. We obtained uni-/multivariable estimates from mixed-effects models and evaluated the association of delaying ART start or interrupting ART with baseline and longitudinal TL. Results In 105 participants with PHI (median age 36 years, 9% women), median ART delay was 25, 42, and 60 days, respectively, in the 1 st (shortest), 2 nd, and 3 rd (longest) ART delay tertile. First ART delay tertile was associated with longer baseline TL (p for trend=0.034), and longer TL over 6 years, but only with continuous ART (p<0.001), not if ART was interrupted >12 months (p=0.408). In multivariable analysis, participants in the 2 nd and 3 rd ART delay tertile had 17.6% (5.4-29.7%; p=0.004) and 21.5% (9.4-33.5%; p<0.001) shorter TL, after adjustment for age, with limited effect modification by clinical variables. Discussion In PHI, delaying ART start for even a matter of weeks was associated with significant and sustained TL shortening.