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Changes in Inflammatory and Coagulation Biomarkers: A Randomized Comparison of Immediate versus Deferred Antiretroviral Therapy in Patients With HIV Infection - published pdf attached
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"Cumulatively, these data (from SMART) suggest ART-associated viral suppression is not going to normalize inflammation, and studies that evaluate anti-inflammatory treatments used in addition to ART should be an active research priority." see JAIDS publication
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-- Findings from additional studies support that inflammatory markers remain upregulated despite treatment with ART.
-- The cause(s) of persistent inflammation despite HIV viral suppression is an area of active research. One explanation is residual immune activation, whether related to low-level HIV replication or other mechanisms.30,38,39 In addition, adverse lipid and metabolic changes associated with HIV infection or ART exposure may be important proinflammatory factors.36,40,41 The potential benefits of ART with respect to reducing inflammation and thrombotic activity may also differ by specific class or drug.42-45 Cumulatively, these data suggest ART-associated viral suppression is not going to normalize inflammation, and studies that evaluate anti-inflammatory treatments used in addition to ART should be an active research priority.
-- Nonsmokers demonstrated greater improvement in hsCRP (-36%
-- A lower BMI was associated with a greater decline in hsCRP levels (-28%
-- The degree of improvement (ie, decrease) in D-dimer, but not hsCRP and IL-6, levels were inversely associated with HIV RNA levels at 6 months (Fig. 3).
-- Among participants in VS who achieved HIV RNA levels 400 copies/mL or less, median (IQR) and mean percent (on loge scale) change in biomarker levels at month 6 were: 0.00 (-0.47 to 0.70) mg/mL and -28% for hsCRP; -0.34 (-1.41 to 0.32) pg/mL and -26% for IL-6; and -0.10 (-0.31 to 0.00) mg/mL and -51% for D-dimer. These changes represent a significant within participant decline in all three biomarkers from baseline to Month 6 among VS participants who achieved an undetectable viral load at Month 6 (Fig. 3)
-- In SMART, levels of all three biomarkers in HIV-infected individuals at baseline predicted risk for both short- and long-term mortality and were more strongly related to risk for non-AIDS-related conditions than for AIDS
-- Chronic inflammation among persons with HIV in- fection may be, in part, a consequence of activation of lymphocytes and dendritic cells, damage to the mucosal barrier, injury to endothelial surfaces, and other factors related to HIV replication.
-- among SMART participants with viral suppression on ART, hsCRP levels were 38% to 40% higher and IL-6 levels were 39% to 60% higher, respectively, when compared with HIV-uninfected control subjects from the Coronary Artery Risk Development In Young Adults (CARDIA) study and the Multi-Ethnic Study of Atheroscelerosis (MESA).
JAIDS Oct 2010 Ahead of Print
Jason V. Baker, MD, MS,* Jacqueline Neuhaus, PhD,* Daniel Duprez, MD, PhD,* Lewis H. Kuller, MD, PhD, Russell Tracy, PhD, Waldo H. Belloso, MD,k Stephane De Wit, MD, PhD, Fraser Drummond, MBChB,** H. Clifford Lane, MD, Bruno Ledergerber, PhD, Jens Lundgren, MD, Daniel E. Nixon, MD,kk Nicholas I. Paton, MD and James D. Neaton, PhD* for the INSIGHT SMART Study Group
Objectives: Among a subgroup of participants in the Strategies for Management of Antiretroviral Therapy (SMART) Trial that were naive to antiretroviral therapy (ART) or off ART (6 months or longer) at study entry, risk of AIDS and serious non-AIDS events were increased for participants who deferred ART compared with those randomized to (re)initiate ART immediately. Our objective was to determine whether ART initiation in this group reduced markers of inflammation and coagulation that have been associated with increased mortality risk in SMART. Changes in these biomarkers have been described after stopping ART, but not after starting ART in SMART.
Methods: Stored specimens for 254 participants (126 drug conservation [DC] and 128 viral suppression [VS]) who were naive to ART or off ART (6 months or longer) were analyzed for interleukin-6, high sensitivity C-reactive protein, and D-dimer at baseline and Months 2 and 6.
Results: At Month 6, 62% of the VS group had HIV RNA less than 400 copies/mL and median CD4 count was 190 cells/mm3 higher than for the DC group (590 versus 400 cells/mm3). Compared with DC, the VS group had 32% (95% confidence interval, 19%-43%) lower D-dimer levels at Month 6 (P , 0.001); differences were not significant for high sensitivity C-reactive protein or interleukin-6 levels.
Conclusions: In this randomized comparison of immediate versus delayed ART initiation, D-dimer, but not interleukin-6 and high sensitivity C-reactive protein, declined significantly after starting ART. Further studies are needed to determine whether improvements in D-dimer are associated with reduced risk of clinical disease and whether adjunct treatments used in combination with ART can reduce inflammation among individuals with HIV infection.
Conclusions: In this randomized comparison of immediate versus delayed ART initiation, D-dimer, but not interleukin-6 and high sensitivity C-reactive protein, declined significantly after starting ART. Further studies are needed to determine whether improvements in D-dimer are associated with reduced risk of clinical disease and whether adjunct treatments used in combination with ART can reduce inflammation among individuals with HIV infection.
DISCUSSION
We analyzed stored specimens in a unique subset of SMART trial participants to carry out a randomized compar- ison of immediate versus delayed initiation of ART on inflammatory and coagulation biomarkers among a small subgroup of participants and found that initiating ART reduces levels of D-dimer. For those who initiated ART after randomization (VS group), D-dimer levels declined by 2 months, the decline persisted through 6 months, and the decline was greater for participants who achieved viral suppression. Differences between the DC and VS groups for changes in hsCRP and IL-6 were more modest and did not reach statistical significance in this randomized comparison.
A large body of epidemiologic data support the importance of inflammation and thrombotic activity for CVD risk and mortality from any cause.15 In the general population, higher levels of hsCRP, IL-6, and D-dimer have all been associated with risk for CVD.4-7,16-18 In SMART, levels of all three biomarkers in HIV-infected individuals at baseline predicted risk for both short- and long-term mortality and were more strongly related to risk for non-AIDS-related conditions than for AIDS.2,19,20 Non-AIDS-related conditions are now more common than AIDS events for persons with HIV infection receiving ART at higher CD4 counts.1,21-25 Thus, reducing inflammation and thrombotic activity may represent an additional therapeutic goal in the clinical management of HIV infection in the current era.
HIV replication has been shown to be an important factor in the upregulation of coagulation pathways and thrombotic activity.2,10,12,26-28 In the Swiss-Thai-Australia Treatment In- terruption Trial (STACCATO), D-dimer levels were associated with HIV RNA levels before and after (median 8 months) starting ART.10 In another study of 41 participants, D-dimer levels improved after 5 to 13 months of treatment with ART.12 In SMART, D-dimer increased markedly 1 month after stopping ART among persons with suppressed virus at baseline, and the increase was strongly correlated with HIV RNA levels.2 Here we show that the D-dimer levels declined 6 months after starting ART by an amount (-32%) similar to the increase 1 month after ART interruption that we previously reported.2 However, D-dimer levels among SMART partic- ipants with suppressed HIV viral loads are still 49% higher than uninfected controls, suggesting residual thrombotic activity persists despite effective HIV treatment with ART.29
Chronic inflammation among persons with HIV in- fection may be, in part, a consequence of activation of lymphocytes and dendritic cells, damage to the mucosal barrier, injury to endothelial surfaces, and other factors related to HIV replication.12,30-34 In STACCATO, initiating ART was associated with declines in markers of endothelial activation (P-selectin and soluble vascular cell adhesion molecule-1).10 However, in this and another report, hsCRP levels did not decline after treatment with ART.10,11 Similarly, we did not observe significant improvement in hsCRP or IL-6 levels after ART initiation when compared with those who deferred ART. Given that not all participants achieved an HIV RNA level less than 400 copies/mL by Month 6, it is possible that ART associated declines in hsCRP and IL-6 may have been apparent with a greater degree of viral suppression. However, baseline levels of IL-6 and hsCRP were not associated with baseline HIV RNA levels, and ART-related changes in D- dimer levels were poorly correlated with changes in the two inflammatory markers in this study. The findings for IL-6 were surprising given the rapid increase in IL-6 that we saw after ART interruption in SMART and the relationship of that increase with loss of virologic control.2 One other explanation may be that an improvement in inflammatory markers associated with starting ART takes longer than 6 months. However, among SMART participants with viral suppression on ART, hsCRP levels were 38% to 40% higher and IL-6 levels were 39% to 60% higher, respectively, when compared with HIV-uninfected control subjects from the Coronary Artery Risk Development In Young Adults (CARDIA) study and the Multi-Ethnic Study of Atheroscelerosis (MESA).29
Findings from additional studies support that inflam- matory markers remain upregulated despite treatment with ART. Fibrinogen (men and women) and CRP (men only) levels were elevated in 1131 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV infection (FRAM) when compared with 281 general pop- ulation control subjects (from CARDIA).35,36 In another cross- sectional comparison of 494 persons, hsCRP levels were higher among persons with HIV infection, compared with HIV-negative control subjects, even among ''HIV controllers'' with undetectable HIV RNA levels in the absence of ART.37
The cause(s) of persistent inflammation despite HIV viral suppression is an area of active research. One explanation is residual immune activation, whether related to low-level HIV replication or other mechanisms.30,38,39 In addition, adverse lipid and metabolic changes associated with HIV infection or ART exposure may be important proinflammatory factors.36,40,41 The potential benefits of ART with respect to reducing inflammation and thrombotic activity may also differ by specific class or drug.42-45 Cumulatively, these data suggest ART-associated viral suppression is not going to normalize inflammation, and studies that evaluate anti-inflammatory treatments used in addition to ART should be an active research priority.
Limitations of this study include the small sample size, short follow-up duration, and that not all participants in the VS group achieved an undetectable viral load. The variability in biomarker levels, and CRP in particular, over time in this cohort also limits the ability to detect significant changes. The ongoing Strategic Timing of Antiretroviral Therapy (START) trial will be able to explore the influence of ART-related HIV suppression on inflammatory markers in a much larger data set. Another limitation is that current data are lacking to quantify the clinical event risk associated with absolute changes in these biomarkers among HIV-infected persons. START will also provide valuable insight into whether these biomarkers are useful for risk stratification by assessing the effects of treatment-related changes on AIDS and non-AIDS-related events. Finally, the ART treatment used in SMART was chosen by the investigator and patient and was not randomized. The effects of different treatments on these biomarkers will require larger randomized studies of different ART regimens.
In summary, the initiation of ART resulted in a rapid decline in D-dimer levels that are associated with suppression of HIV replication. Larger studies, with longer follow-up, are needed to determine if these treatment-related changes are clinically relevant.
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