1. For the primary endpoint, the mean eGFR (2012 CKD- EPI Cr-CC) change at 96 weeks was significantly greater for ABC/3TC vs. TDF/FTC (Figure 1). In the <100,000 c/ml stratum, the mean eGFR (2012 CKD-EPI Cr-CC) change was significantly greater for EFV vs. ATV/r with no significant difference in the ≥100,000 c/ml stratum (Figure 2); interaction p=0.045. Similar results were seen for 2009 CKD-EPI and MDRD. The mean 96 week change in eGFR (2009 CKD-EPI) was significantly greater for ABC/3TC vs. TDF/FTC within ATV/r arms with no significant difference within the EFV arms (Figure 3). Also, the mean eGFR change was significantly greater for EFV vs. ATV/r within the TDF/FTC arms but not the ABC/3TC arms (Figure 4); interaction p=0.039. Similar results were seen for Cockcroft-Gault and MDRD. The mean 96 week fold changes in A/Cr and P/Cr were significantly greater for TDF/FTC vs. ABC/3TC (Figure 5). No differences were seen for EFV vs. ATV/r. No significant 3-way interactions were found between NRTI component, NNRTI/PI component, and screening HIV-1 RNA strata. Using 2012 CKD-EPI Cr-CC, no subject developed eGFR <60 ml/min/1.73 m 2 at week 96. eGFR with all formulae increased more when baseline levels were <90 compared to ≥90, but no significant interactions were seen between baseline eGFR and either the NRTI or NNRTI/PI components. This research was supported by NIH grants U01AI068636, AI068634, AI38855, and by GlaxoSmithKline and Gilead Sciences. Long-Term Changes in Renal Parameters in ART-naïve Subjects Randomized to ABC/3TC or TDF/FTC with ATV/r or EFV: ACTG A5224s, a Sub-study of A5202 Samir K Gupta 1, Douglas Kitch 2, Camlin Tierney 2, Paul E Sax 3, Eric S Daar 4, Lynda A Szczech 5, Pablo Tebas 6, Belinda Ha 7, Kathleen Melbourne 8, and Grace A McComsey 9 1 Indiana University School of Medicine, Indianapolis, IN; 2 Harvard School of Public Health, Boston, MA; 3 Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 4 Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA; 5 PPD, LLC, Research Triangle Park, NC; 6 University of Pennsylvania, Philadelphia, PA; 7 GlaxoSmithKline, Research Triangle Park, NC; 8 Gilead Sciences, Foster City, CA; and 9 Case Western Reserve University, Cleveland, OH Results A5224s was the metabolic substudy of A5202, a trial of HIV-infected, ART-naïve subjects equally randomized to blinded ABC/3TC or TDF/FTC with open-label EFV or ATV/r. Renal function was estimated using 5 different formulae (Cockcroft-Gault, MDRD, 2009 CKD EPI, 2012 CKD-EPI CC, 2012 CKD-EPI Cr-CC). Spot urine protein/creatinine ratio (P/Cr) and albumin/creatinine ratio (A/Cr) were measured as markers of renal injury and log 10 -transformed due to their skewed distributions. All renal parameters were measured centrally (Quest Laboratories); the primary endpoint was change from baseline of eGFR (2012 CKD-EPI Cr- CC) at 96 weeks. Analyses were intent-to-treat using two-sample t- tests to compare changes from baseline between regimens; linear regression was used to test for any interactions of the NRTI and NNRTI/PI components and of the treatment component and screening HIV-1 RNA (<100,000 c/ml vs. ≥ 100,000 c/ml) or baseline renal function (<90 vs. ≥ 90); p-values <0.05 were considered statistically significant. Figures present mean and 95% CI. Methods Background: Long-term comparisons of ABC/3TC vs TDF/FTC combined with either EFV or ATV/r on renal injury and function using older creatinine (Cr)- and newer cystatin C (CC)-based estimated glomerular filtration rate (eGFR) formulae have not been performed. Methods: A5224s was a metabolic substudy of A5202, a trial of HIV-infected, treatment-naïve subjects equally randomized to blinded ABC/3TC or TDF/FTC with open- label EFV or ATV/r. We compared changes in eGFR [Cockcroft-Gault (C-G), MDRD, 2009 CKD-EPI, 2012 CKD-EPI CC, 2012 CKD-EPI Cr-CC formulae], spot urine protein/creatinine (P/Cr), and spot urine albumin/creatinine (A/Cr) at 96 weeks. Analyses were intent-to-treat using two-sample t-tests and linear regression. Results: 269 subjects were included; 203 had week 96 eGFR endpoints. Using 2012 CKD-EPI Cr-CC as the primary formula (in ml/min/1.73m2), the overall mean baseline eGFR was 103, and no subject developed an eGFR <60 at week 96. The 96 week mean eGFR change for ABC/3TC was significantly greater than for TDF/FTC (combined NNRTI/PI) [8.0 vs 3.6; P=0.025]; these differences were not found for 2012 CKD-EPI CC. Differences in eGFR changes between EFV and ATV/r (combined NRTI) depended on screening HIV-1 RNA; in those <100,000 c/ml, the mean change was significantly greater for EFV than for ATV/r [10.1 vs -0.6; P<0.001] while in those ≥100,000 c/ml, there was no significant difference [8.1 vs 5.2; P=0.34]; similarly significant differences were found in the lower but not higher HIV-1 RNA stratum using 2009 CKD-EPI and MDRD but not other formulae. With C-G, MDRD, and 2009 CKD-EPI (but not with either 2012 CC formula), ABC/3TC had a significantly greater mean change than TDF/FTC within ATV/r arms while EFV had a significantly greater mean change than ATV/r within TDF/FTC arms. Fold changes in P/Cr (0.80 vs 1.02) and A/Cr (0.69 vs 0.98) were significantly lower (both P<0.02) for ABC/3TC vs TDF/FTC; no significant fold change differences were found between ATV/r and EFV. Conclusions: At 96 weeks, compared to TDF/FTC-, ABC/3TC-treated subjects had better P/Cr and A/Cr changes and eGFR changes, which depended on concomitant ATV/r use and formula used. Compared to ATV/r-, EFV-treated subjects had better eGFR changes, which depended on concomitant TDF/FTC use, screening HIV-1 RNA, and formula used. In this trial, the 2012 CC-based formulae led to different results compared to older Cr-based formulae. The implications of these findings remain to be determined. Compared to TDF/FTC-, ABC/3TC-treated subjects at 96 weeks had better P/Cr, A/Cr changes, and eGFR changes, although the GFR changes depended on concomitant ATV/r use and formula used. The clinical implications of the relatively small changes in renal function and injury markers associated with these specific ART regimens remain to be determined. The magnitudes and directions of eGFR changes differed when using the 2012 formulae, which include CC, as opposed to those found when using older formulae, which include only Cr. The reasons for (and the clinical implications of) these differences will require further study. Contact: Samir K Gupta, MD, MS Indiana University School of Medicine Indianapolis, IN USA sgupta1@iu.edu Acknowledgements 811 Summary of Results Conclusions Abstract No. subjects (%) or median (Q1,Q3) Sex: male229 (85%) Race/ethnicity: Black non-Hispanic Hispanic White non-Hispanic Other 90 (33%) 44 (16%) 126 (47%) 9 (4%) Age (years)38 (31, 44) CD4 count (cells/mm 3 )233 (106, 334) HIV-1 RNA (log 10 c/ml)4.62 (4.24, 4.90) Hepatitis B sAg 1 : positive9 (3%) Hepatitis C Ab 2 : positive23 (9%) eGFR *,3 (ml/min/1.73 m 2 )102 (92, 115) eGFR *,3 : <90 ml/min/1.73 m 2 56 (21%) Serum creatinine 3 (mg/dl)0.9 (0.8, 1.0) Serum Cystatin C 3 (mg/l)0.88 (0.76, 0.98) Protein/creatinine ratio 4 (mg/g)95 (67, 146) Albumin/creatinine ratio 5 (mg/g)4.7 (3.2, 10.0) * eGFR estimated by 2012 CKD-EPI Cr-CC formula 1 n=267; 2 n=265; 3 n=262; 4 n=234; 5 n=242 Table 1: Baseline Characteristics of All 269 Subjects Figure 1: 2012 CKD-EPI Cr-CC Change, TDF/FTC vs. ABC/3TC Background In the HIV-infected population, renal dysfunction may occur as a result of uncontrolled viremia and, thus, can be improved by ART. However, specific ART drugs and regimens may also cause renal dysfunction. Both serum creatinine (Cr) and cystatin C (CC) are used in renal function estimating equations, but the longitudinal use of newer formulae incorporating both variables have not been examined in HIV. Comparisons of different ART regimens on quantitative proteinuria and albuminuria (markers of renal injury) have also not been fully explored. We examined the long-term changes in these various renal parameters in the A5224s substudy of ACTG A5202. Figure 2: 2012 CKD-EPI Cr-CC Change, EFV vs. ATV/r by HIV-1 RNA Stratum (interaction p=0.045) Figure 3: 2009 CKD-EPI Change, TDF/FTC vs. ABC/3TC by NNRTI/PI (interaction p=0.039) Figure 4: 2009 CKD-EPI Change, EFV vs. ATV/r by NRTI (interaction p=0.039) Figure 5: A/Cr and P/Cr Change, TDF/FTC vs. ABC/3TC