D-Dimer Levels before HIV Seroconversion Remain Elevated Even after Viral Suppression and Are Associated with an Increased Risk of Non-AIDS Events

Abstract

The mechanism underlying the excess risk of non-AIDS diseases among HIV infected people is unclear. HIV associated inflammation/hypercoagulability likely plays a role. While antiretroviral therapy (ART) may return this process to pre-HIV levels, this has not been directly demonstrated. We analyzed data/specimens on 249 HIV+ participants from the US Military HIV Natural History Study, a prospective, multicenter observational cohort of >5600 active duty military personnel and beneficiaries living with HIV. We used stored blood specimens to measure D-dimer and Interleukin-6 (IL-6) at three time points: pre-HIV seroconversion, ≥6 months post-HIV seroconversion but prior to ART initiation, and ≥6 months post-ART with documented HIV viral suppression on two successive evaluations. We evaluated the changes in biomarker levels between time points, and the association between these biomarker changes and future non-AIDS events. During a median follow-up of 3.7 years, there were 28 incident non-AIDS diseases. At ART initiation, the median CD4 count was 361cells/mm3; median duration of documented HIV infection 392 days; median time on ART was 354 days. Adjusted mean percent increase in D-dimer levels from pre-seroconversion to post-ART was 75.1% (95% confidence interval 24.6–148.0, p = 0.002). This increase in D-dimer was associated with a significant 22% increase risk of future non-AIDS events (p = 0.03). Changes in IL-6 levels across time points were small and not associated with future non-AIDS events. In conclusion, ART initiation and HIV viral suppression does not eliminate HIV associated elevation in D-dimer levels. This residual pathology is associated with an increased risk of future non-AIDS diseases.

Association Between HIV Infection and the Risk of Heart Failure With Reduced Ejection Fraction and Preserved Ejection Fraction in the Antiretroviral Therapy Era

“…36 Most important, our data also suggest that even HIV-infected individuals with high CD4 cell counts are likely still at risk for HF compared with uninfected individuals, in part because HIV-infected individuals with high CD4 cell counts who are rapidly diagnosed, treated, and virally suppressed do not return to their pre-HIV levels of inflammation. 37 Moreover, this residual inflammation is associated with an increased risk of future non-AIDS diseases. 37 In contrast, time-updated elevated HIV-1 RNA viral load was only significantly associated with HFrEF.…”

“…37 Moreover, this residual inflammation is associated with an increased risk of future non-AIDS diseases. 37 In contrast, time-updated elevated HIV-1 RNA viral load was only significantly associated with HFrEF. These findings are consistent with reports before the ART era in which unsuppressed HIV viremia, perhaps through direct infection of cardiac myocytes 38,39 or cardiac autoantibodies, 40 results in a cardiomyopathy consistent with HFrEF.…”

Epidemiology of ischemic heart disease in HIV

“…Recent data have shown increased mortality with increasing levels of IL-6, soluble CD14 (sCD14), and d-dimer, 69 increased risk of serious non-AIDS conditions or death with increased IL-6 and d-dimer, 70 greater cIMT and higher mortality with higher IL-6, 71 increased risk of non-AIDS events with higher d-dimer, 72 increased microvascular dysfunction with elevated markers of inflammation, coagulation, and T-cell activation, 73 and greater prevalence of severe coronary stenosis and coronary artery calcification score with increased tumor necrosis factor α (TNFα). 74 Inflammation also impacts outcomes following CVD events.…”

Revisiting a quarter of a century of simian immunodeficiency virus (SIV)-associated cardiovascular diseases at the German Primate Center

“…In addition, an association between HIV infection and hematological changes has been found; e.g., HIV infection causes a hypercoagulable state (Shen and Frenkel, 2004). Furthermore, the increase of soluble hypercoagulation biomarkers such as D-dimer has been found to be associated with an increased risk of non-AIDS events (Freiberg et al, 2016). Elevated D-dimer and interleukin (IL)-6 levels have been found to be linked to an increased incidence of CV disease (Duprez et al, 2012) and even associated with an enhanced all-cause mortality in HIV-infected patients.…”