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Similar Reductions in Markers of Inflammation and Endothelial Activation after Initiation of Abacavir/Lamivudine or Tenofovir/Emtricitabine: The HEAT Study
Grace McComsey*1, K Smith2, P Patel3, N Bellos4, L Sloan5, P Lackey6, P Kumar7, D Sutherland-Phillips3, L Yau3, and M Shaefer3
1Case Western Reserve Univ Sch of Med, Cleveland, OH, US; 2Rush Univ Med Ctr, Chicago, IL, US; 3GlaxoSmithKline, Research Triangle Park, NC, US; 4Southwest Infectious Disease Assoc, Dallas, TX, US; 5North Texas Infectious Disease Consultants, Dallas, US; 6ID Consultants, Charlotte, NC, US; and 7Georgetown Univ Sch of Med, Washington, DC, US
Background: Endothelial dysfunction and chronic
inflammation have been reported in HIV-1-infected subjects. In STACCATO, elevations
in the endothelial marker vascular cell adhesion molecule-1 (sVCAM-1) were
observed during treatment interruption. In SMART, baseline elevations in interleukin-6
(IL-6) and high-sensitivity C-reactive protein (hs-CRP) were proposed as a mechanism
for possible increased cardiovascular events in subjects taking abacavir (ABC).
This analysis compared the effects of ABC/lamivudine (3TC) and tenofovir/embricitabine
(TDF/FTC) on these biomarkers in a prospective, randomized study of ART-naïve subjects
to investigate causality.
Methods: Available samples from subjects randomized
to ABC/3TC or TDF/FTC each with lopinavir/ritonavir were analyzed at baseline
and weeks 48 and 96 for sVCAM-1, IL-6, and hsCRP. Biomarker concentrations were
measured by Quest Diagnostics using ELISA (sVCAM-1, IL-6) and fixed rate
nephelometry (hsCRP).
Results: This analysis included 476 subjects: mean age
39 years, 15% female, 45% non-white, with baseline median HIV-1 RNA and CD4+
of 4.88 log10
copies/mL and 211 cells/mm3, respectively. Mean percentage changes
from baseline in sVCAM-1 and IL-6 were statistically significant at weeks 48
and 96 in both treatment arms. Reduction in hs-CRP from baseline was
statistically significant in the TDF/FTC arm only. However, the reductions were
not significantly different between arms for any of the 3 biomarkers (p >0.05).
The low number of cardiovascular-related events (none related to study drug),
ABC/3TC:1; TDF/FTC: 2, prevented correlation with any of the biomarkers.
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|
ABC/3TC
N=243
|
TDF/FTC
N=233
|
|
|
Paired n
(baseline:48, base;ome:96)
|
Mean % change from baseline
|
Paired n
(baseline:48, baseline:96)
|
Mean % change from baseline
|
|
|
|
Week 48
|
Week 96
|
|
Week 48
|
Week 96
|
|
sVCAM-1 (ng/mL)
|
241, 211
|
-49%
|
-51%
|
228, 202
|
-48%
|
-50%
|
|
IL-6 (pg/mL)
|
220, 192
|
-26%
|
-19%
|
220, 197
|
-23%
|
-25%
|
|
Hs-CRP (mg/L)
|
235, 205
|
-12%
|
-5%
|
224, 199
|
-20%
|
-17%
|
Conclusions: Similar decreases in markers of inflammation
and endothelial activation were observed over 96 weeks of treatment with
ABC/3TC or TDF/FTC. These data do not suggest that ABC/3TC or TDF/FTC
contribute to an increase in cardiovascular risk mediated by inflammation or
worsening endothelial activation. The findings from this randomized,
prospective data do not support the hypothesis of increased inflammation
attributed to ABC from recent observational, cohort studies.
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