BackgroundIn the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.Methods and FindingsStored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case–control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0–4.1; p = 0.05), 8.3 (95% CI, 3.3–20.8; p < 0.0001), and 12.4 (95% CI, 4.2–37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case–control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1–3.1; p = 0.02) to 1.5 (95% CI, 0.8–2.8) and 1.4 (95% CI, 0.8–2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively.ConclusionsIL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation. Trial Registration: ClinicalTrials.gov (NCT00027352).

sCD14, a marker of monocyte response to LPS, is an independent predictor of mortality in HIV infection. Therapeutic attenuation of innate immune activation may improve survival in patients with HIV infection.

BackgroundThe SMART study was a trial of intermittent use of antiretroviral therapy (ART) (drug conservation [DC]) versus continuous use of ART (viral suppression [VS]) as a strategy to reduce toxicities, including cardiovascular disease (CVD) risk. We studied the predictive value of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and D-dimer with CVD morbidity and mortality in HIV-infected patients who were enrolled in SMART beyond other measured CVD risk factors.MethodsA blood sample was available in 5098 participants who were enrolled in the SMART study for the measurement of IL-6, hsCRP and D-dimer. Hazard ratios (HR) with 95% CI for CVD events were estimated for each quartile (Q) for each biomarker vs the 1st quartile and for 1 SD higher levels. For both treatment groups combined, unadjusted and adjusted HRs were determined using Cox regression models.ResultsThere were 252 participants who had a CVD event over a median follow-up of 29 months. Adjusted HRs (95% CI) for CVD for Q4 vs Q1 were 4.65 (2.61, 8.29), 2.10 (1.40, 3.16), and 2.14 (1.38, 3.33) for IL-6, hsCRP and D-dimer, respectively. Associations were similar for the DC and VS treatment groups (interaction p-values were >0.30). The addition of the three biomarkers to a model that included baseline covariates significantly improved model fit (p<0.001). Area under the curve (AUC) estimates improved with inclusion of the three biomarkers in a model that included baseline covariates corresponding to other CVD risk factors and HIV factors (0.741 to 0.771; p<0.001 for difference).ConclusionsIn HIV-infected individuals, IL-6, hsCRP and D-dimer are associated with an increased risk of CVD independent of other CVD risk factors. Further research is needed to determine whether these biomarkers can be used to improve CVD risk prediction among HIV positive individuals.

Purpose of review HIV infection is characterized by chronic immune system activation and inflammatory cytokine production. This review will highlight recent developments using plasma and cellular biomarkers of immune system activation and dysfunction to predict mortality and opportunistic disease in HIV-infected individuals. Recent findings HIV infection results in features characteristic of early aging of the immune system or ‘immune senescence’, driven by chronic antigen exposure and immune system activation. Microbial translocation of gut bacterial components is associated with chronic immune activation and possibly systemic inflammation. Antiretroviral therapy may not fully normalize this condition. Baseline elevations of certain biomarkers of inflammation or coagulopathy, notably interleukin-6 (IL-6), C-reactive protein (CRP), and d-dimer, have been associated with mortality or opportunistic disease, after adjustment for appropriate variables, in several large randomized clinical trials. It is not known if elevated IL-6 or CRP causes this morbidity and mortality or if they are simply surrogate markers of a global inflammatory state. Summary Several inflammatory biomarkers appear to add to our ability to predict mortality or opportunistic disease in HIV-infected individuals. Before biomarkers will be useful, it will be necessary to identify interventions that moderate biomarker levels, and then determine if this moderation attenuates disease outcomes.

Mild-moderate increased liver enzymes are common in HIV patients without HCV/HBV and absence of PI use is independently associated with elevations in both AST and ALT, while features typical of hepatic steatosis (DM and BMI) are only associated with increased ALP.