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Changes in Inflammation and Endothelial Activation Markers in ARV-naïve Subjects Randomized to Abacavir/Lamivudine or Tenofovir/Emtricitabine along with Efavirenz or Atazanavir/ritonavir: AIDS Clinical Trials Group A5224s, a Sub-study of ACTG A5202
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Reported by Jules Levin
CROI 2012 March 5-8 Seattle, WA
Grace McComsey1, D Kitch2, E Daar3, C Tierney2, N Jahed4, K Melbourne5, B Ha6, T Brown7, A Bloom8, and P Sax9
1Case Western Reserve Univ, Cleveland, OH, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Los Angeles Biomed Res Inst at Harbor-UCLA Med Ctr, Torrance, CA, US; 4Social & Sci Systems, Inc, Silver Spring, MD, US; 5Gilead Sci, Foster City, CA, US; 6GlaxoSmithKline, Res Triangle Park, NC, US; 7Johns Hopkins Univ, Baltimore, MD, US; 8Frontier Sci and Tech Res Fndn, Amherst, NY, US; and 9Brigham and Women`s Hosp and Harvard Med Sch, Boston, MA, US
BACKGROUND: The effect of initiation of different antiretroviral regimens on inflammation markers has not been fully assessed.
METHODS: A5202 randomized 1857 treatment-naive subjects to blinded ABC/3TC or TDF/FTC with open-label EFV or ATV/r in a factorial design. Substudy A5224s compared changes in inflammation markers from baseline to week 24 in ABC/3TC vs. TDF/FTC- containing arms. Secondary endpoints included changes from baseline to week 96 and comparisons of EFV vs. ATV/r-containing arms. Primary analyses were intent-to-treat. Statistical tests used 2- sample t-tests and linear regression. All analyses were prespecified.
RESULTS: A5224s included 244 A5202 subjects; 85% male, 48% white non-Hispanic, median age 39 years, HIV-1 RNA 4.6 log10 copies/mL, CD4 240 cells/μL, high-sensitivity C-reactive protein (hsCRP) 1.70 mg/L, and interleukin-6 (IL-6) 0.79 pg/mL. There were no significant interactions between the NRTIs and the EFV and ATV/r components for any of the inflammation markers at weeks 24 or 96 (all p≥0.23). Soluble TNF receptors (sTNFR-I and -II), TNF-α, and the adhesion molecules sVCAM-1 and sICAM-1 decreased significantly at weeks 24 and 96, without significant differences between regimen components at either time point (p ≥0.44). At week 24, ABC/3TC- containing arms had a greater mean fold change in hsCRP than TDF/FTC (1.43 vs. 0.88); estimated mean fold change percent difference (D) 61.5% [95% CI 13.6%, 129.5%]; p=0.008, which remained significant at week 96 (p=0.02). A post-hoc analysis did not detect a differential NRTI effect between subjects with (n=168) and without (n=68) HIV-1 RNA <50 copies/mL at week 24 (p=0.7). At week 24 (but not week 96), EFV-containing arms had a greater mean fold change in hsCRP than ATV/r (1.41 vs. 0.88); D= 60.2% [12.6%, 127.7%]; p=0.009. IL-6 decreased significantly at week 24 in the TDF/FTC arms, but not in the ABC/3TC arms (p= 0.02 for between- arms differences). At week 96, however, similar decreases were seen in both NRTI arms (p= 0.11 for between-arms differences). Changes in IL-6 were not significantly different between ATV/r and EFV arms at either time point (p ≥0.9).
CONCLUSIONS: Soluble TNF receptors and adhesion molecules decreased following treatment initiation and did not significantly differ by regimens. Less favorable effects are seen on hsCRP and IL-6 when initiating ABC/3TC vs. TDF/FTC and on hsCRP with EFV vs. ATV/r. Further work is ongoing to define the clinical significance of these findings.
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