Changes in Inflammation and Endothelial Activation Markers in ARV-naļve 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
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 ARV regimens on inflammation markers has not been fully assessed.
Methods: A5202 randomized 1857 treatment-naļve subjects to blinded abacavir/lamivudine (ABC/3TC) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in a factorial design. Sub-study 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 pre-specified.
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 NRTI and the EFV and ATV/r components for any of the inflammation markers at weeks 24 or 96 (all p ≥0.23). Soluble tumor necrosis factor receptors (sTNFR-I and -II), TNF-a, 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 percentage difference (D) 61.5% (95%CI 13.6% to 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% to 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.