Management Of Antiretroviral Therapy Trial Research Articles

Relationship between inflammatory and coagulation biomarkers and cardiac autonomic function in HIV-infected individuals.

To examine the relationship between inflammatory and coagulation biomarkers and cardiac autonomic function (CAF) as measured by heart rate variability in persons with HIV. This analysis included 4073 HIV-infected persons from the Strategies for Management of Antiretroviral Therapy study. We examined the association between IL-6, high-sensitivity C-reactive protein (hsCRP) and D-dimer with heart rate variability measures (SDNN and rMSSD), both cross-sectionally and longitudinally. Cross-sectional analysis revealed significant inverse associations between IL-6, hsCRP and d-dimer with SDNN and rMSSD (p < 0.01 for all comparisons). However, longitudinal analysis failed to show a significant association between baseline IL-6, hsCRP and d-dimer with change in CAF over time. Cross-sectionally, higher levels of inflammatory and coagulation biomarkers were associated with lower levels of CAF in the Strategies for Management of Antiretroviral Therapy trial. Although deterioration in CAF was observed during followup, baseline levels of inflammatory and coagulation markers were not predictive of the decline in CAF over time.

Improved neurocognitive test performance in both arms of the SMART study: impact of practice effect.

We evaluated factors associated with improvement in neurocognitive performance in 258 HIV-infected adults with baseline CD4 lymphocyte counts above 350 cells/mm³ randomized to intermittent, CD4-guided antiretroviral therapy (ART) (128 participants) versus continuous therapy (130) in the Neurology substudy of the Strategies for Management of Antiretroviral Therapy trial. Participants were enrolled in Australia, North America, Brazil, and Thailand, and neurocognitive performance was assessed by a five-test battery at baseline and month 6. The primary outcome was change in the quantitative neurocognitive performance z score (QNPZ-5), the average of the z scores of the five tests. Associations of the 6-month change in test scores with ART use, CD4 cell counts, HIV RNA levels, and other factors were determined using multiple regression models. At baseline, median age was 40 years, median CD4 cell count was 513 cells/mm³, 88 % had plasma HIV RNA ≤ 400 copies/mL, and mean QNPZ-5 was -0.68. Neurocognitive performance improved in both treatment groups by 6 months; QNPZ-5 scores increased by 0.20 and 0.13 in the intermittent and continuous ART groups, respectively (both P < 0.001 for increase and P = 0.26 for difference). ART was used on average for 3.6 and 5.9 out of the 6 months in the intermittent and continuous ART groups, respectively, but the increase in neurocognitive test scores could not be explained by ART use, changes in CD4, or plasma HIV RNA, which suggests a practice effect. The impact of a practice effect after 6 months emphasizes the need for a control group in HIV studies that measure intervention effects using neurocognitive tests similar to ours.

Biomarkers and Bacterial Pneumonia Risk in Patients with Treated HIV Infection: A Case-Control Study

BackgroundDespite advances in HIV treatment, bacterial pneumonia continues to cause considerable morbidity and mortality in patients with HIV infection. Studies of biomarker associations with bacterial pneumonia risk in treated HIV-infected patients do not currently exist.MethodsWe performed a nested, matched, case-control study among participants randomized to continuous combination antiretroviral therapy (cART) in the Strategies for Management of Antiretroviral Therapy trial. Patients who developed bacterial pneumonia (cases) and patients without bacterial pneumonia (controls) were matched 1∶1 on clinical center, smoking status, age, and baseline cART use. Baseline levels of Club Cell Secretory Protein 16 (CC16), Surfactant Protein D (SP-D), C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer were compared between cases and controls.ResultsCases (n = 72) and controls (n = 72) were 25.7% female, 51.4% black, 65.3% current smokers, 9.7% diabetic, 36.1% co-infected with Hepatitis B/C, and 75.0% were on cART at baseline. Median (IQR) age was 45 (41, 51) years with CD4+ count of 553 (436, 690) cells/mm3. Baseline CC16 and SP-D were similar between cases and controls, but hsCRP was significantly higher in cases than controls (2.94 µg/mL in cases vs. 1.93 µg/mL in controls; p = 0.02). IL-6 and d-dimer levels were also higher in cases compared to controls, though differences were not statistically significant (p-value 0.06 and 0.10, respectively).ConclusionsIn patients with cART-treated HIV infection, higher levels of systemic inflammatory markers were associated with increased bacterial pneumonia risk, while two pulmonary-specific inflammatory biomarkers, CC16 and SP-D, were not associated with bacterial pneumonia risk.

Biomarkers and Electrocardiographic Evidence of Myocardial Ischemia in Patients With Human Immunodeficiency Virus Infection

We assessed the relation of inflammatory and coagulation biomarkers with electrocardiographic (ECG) evidence of myocardial ischemia. High-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer levels were measured at study entry for 3,085 human immunodeficiency virus-infected participants (mean age 44 years; 26.4% women; 24.6% black) in the Strategies for Management of Antiretroviral Therapy trial. Logistic regression models were used to examine the associations of these biomarkers with prevalent and incident myocardial ischemia. The latter analyses were performed for 1,411 participants who were randomly assigned to receive continuous antiretroviral therapy during follow-up to suppress the human immunodeficiency virus viral load and had ≥1 ECG reading during the follow-up period. The median hsCRP, IL-6, and D-dimer level was 1.65 μg/ml (interquartile range 0.69 to 4.11), 1.60 pg/ml (interquartile range 1.00 to 2.75), and 0.18 μg/ml (interquartile range 0.11 to 0.32), respectively. At baseline, the prevalence of major or minor Q-QS or ST-T ECG abnormalities was 18.6%. The biomarker levels were associated with prevalent major or minor ischemic abnormalities on the univariate analyses; however, adjustment for traditional risk factors attenuated these associations. The adjusted odds ratio for major or minor ischemic abnormalities and 95% confidence intervals for the greatest versus lowest quartiles was 1.3 (95% confidence interval 0.9 to 1.7) for hsCRP, 1.0 (95% confidence interval 0.7 to 1.3) for IL-6, and 1.1 (95% confidence interval 0.9 to 1.5) for D-dimer. During a median follow-up of 2.3 years, new definite or probable ischemic ECG abnormalities developed in 11.7% of participants receiving continuous antiretroviral therapy. Biomarker levels were not associated with incident abnormalities on unadjusted or adjusted analyses. In conclusion, higher levels of hsCRP, IL-6, and D-dimer were not associated with ischemic ECG abnormalities. Elevated biomarker levels and ECG abnormalities indicating myocardial ischemia might reflect different risk pathways for cardiovascular disease.

Interruption of antiretroviral therapy is associated with increased plasma cystatin C

Cystatin C has been proposed as an alternative marker of renal function. We sought to determine whether participants randomized to episodic use of antiretroviral therapy guided by CD4 cell count (drug conservation) had altered cystatin C levels compared with those randomized to continuous antiretroviral therapy (viral suppression) in the Strategies for Management of Antiretroviral Therapy trial, and to identify factors associated with increased cystatin C. Cystatin C was measured in plasma collected at randomization, 1, 2, 4, 8 and 12 months after randomization in a random sample of 249 and 250 participants in the drug conservation and viral suppression groups, respectively. Logistic regression was used to model the odds of at least 0.15 mg/dl increase in cystatin C (1 SD) in the first month after randomization, adjusting for demographic and clinical characteristics. At randomization, mean (SD) cystatin C level was 0.99 (0.26 mg/dl) and 1.01 (0.28 mg/dl) in the drug conservation and viral suppression arms, respectively (P = 0.29). In the first month after randomization, 21.8 and 10.6% had at least 0.15 mg/dl increase in cystatin C in the drug conservation and viral suppression arms, respectively (P = 0.0008). The difference in cystatin C between the treatment arms was maintained through 1 year after randomization. After adjustment, participants in the viral suppression arm had significantly reduced odds of at least 0.15 mg/dl increase in cystatin C in the first month (odds ratio 0.42; 95% confidence interval 0.23-0.74, P = 0.0023). These results demonstrate that interruption of antiretroviral therapy is associated with an increase in cystatin C, which may reflect worsened renal function.

Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV Infection

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).