Effect of Treatment Assignment in Participants With Significant Proteinuria or Albuminuria
At baseline, 18% of included participants had clinically significant proteinuria (UPCR ≥200 mg/g) and 11% had clinically significant albuminuria (UACR ≥30 mg/g) (Table 1). Only 4 participants had a baseline UPCR ≥1 g/g, consistent with overt proteinuria of more than 1 g/24 hours. These 4 participants and 1 additional participant had a baseline UACR ≥300 mg/g, signifying macroalbuminuria; by chance, all 5 of these participants with overt proteinuria and/or macroalbuminuria were randomized to open-label ATV/r. Overall, there was a decrease in the prevalence of clinically relevant proteinuria and albuminuria from baseline to week 96 in all treatment groups. Among participants with data available at baseline and at week 96, the prevalence of UPCR ≥200 mg/g decreased from 18.0% to 9.6%, and the prevalence of UACR ≥30 mg/g decreased from 11.2% to 5.1% (exact McNemar test P = 0.013 for both comparisons).
In 21 of 30 participants with baseline UPCR ≥200 mg/g, the week 96 UPCR was <200 mg/g. These 21 cases were balanced across the 4 treatment arms. New onset proteinuria ≥200 mg/g was observed in 7 of 137 participants with baseline UPCR <200 mg/g. Five of these participants were randomized to TDF/FTC (2 with EFV and 3 with ATV/r) and 2 were randomized to ABC/3TC (1 in each NNRTI/PI arm). In 14 of 20 participants with baseline UACR ≥30 mg/g, the week 96 UACR was normal. Five of these participants were randomized to TDF/FTC (4 with EFV and 1 with ATV/r) and 9 were randomized to ABC/3TC (3 with EFV and 6 with ATV/r). New onset albuminuria ≥30 mg/g was observed in 3 of 158 participants with normal baseline UACR, all of whom were randomized to TDF/FTC (2 with EFV and 1 with ATV/r). The numbers of participants with clinically significant proteinuria and albuminuria were too small to allow statistical comparisons.
In this prespecified secondary analysis of the metabolic substudy of a randomized clinical trial, we observed significantly greater improvements in proteinuria and albuminuria over 96 weeks among ART-naive adults randomized to ART containing ABC/3TC versus TDF/FTC. This effect remained significant after adjusting for potential imbalances in randomization. Assignment to open-label ATV/r versus EFV was not associated with a significant difference in proteinuria or albuminuria over 96 weeks of treatment.
These results are consistent with previous clinical trials demonstrating improvements in markers of CKD with the initiation of ART,6–8 even with regimens that include TDF, and it is reassuring that the prevalence of clinically significant proteinuria and albuminuria decreased in all treatment arms. Although observational studies have demonstrated an association between cumulative exposure to TDF and increased incidence of proteinuria,10 the change in albuminuria over 48 weeks did not differ significantly between participants randomized to TDF/FTC versus ABC/3TC in the ASSERT study.13 Although we did not observe an increase in the prevalence or level of proteinuria or albuminuria over 96 weeks of therapy with TDF/FTC, the pattern of change in UACR suggests that an early improvement with ART initiation was followed by a rebound in albuminuria with longer exposure to TDF/FTC (Fig. 1C). This result is consistent with the previously reported association between cumulative exposure to TDF and increased incidence of proteinuria as assessed by dipstick urinalysis, which largely detects albuminuria.10 Although it is possible that our results reflect an initial improvement in HIV-related kidney injury with virologic suppression, followed by the development of proximal tubular injury or dysfunction in the setting of TDF/FTC, the current study was not designed to evaluate potential mechanisms. Similarly, we cannot explain the apparent differences in pattern and magnitude of change in proteinuria and albuminuria, which may indicate different types of kidney injury. Future studies should include additional biomarkers that can help to distinguish between HIV-related and ART-related kidney injury. Finally, it is notable that clinically significant proteinuria and albuminuria were observed in fewer than 20% of participants at baseline. Nonetheless, even small elevations in proteinuria and albuminuria, such as those observed in this study, have been associated with clinically significant differences in cardiovascular disease and all-cause mortality.2–5
Although recent studies have suggested that cumulative exposure to ATV/r is associated with decreased eGFR,9–11 we did not observe a differential effect of ATV/r versus EFV on changes in proteinuria or albuminuria, other indicators of CKD. It is possible that this lack of difference reflects a deleterious effect of EFV, consistent with a previously reported association between NNRTI use and higher albuminuria.19 Of note, by chance, all subjects with high levels of proteinuria and albuminuria were randomized to the ATV/r arm. We have previously reported greater improvements in albuminuria in individuals with higher baseline levels.20 It is possible that imbalance in baseline proteinuria and albuminuria could have masked a true benefit of EFV over ATV/r. Nonetheless, the number of participants with high levels of proteinuria or albuminuria was small, and the effect of outliers should be minimized by the log transformation of UPCR and UACR data. Of note, the distribution of proteinuria and albuminuria was similar between the NRTI treatment arms, the primary focus of this analysis.
Although this is the first study to demonstrate differential effects of TDF/FTC and ABC/3TC on proteinuria and albuminuria using data from a randomized trial, several additional limitations should be acknowledged. First, although UPCR and UACR measurements were centralized, our analysis was based on a single measurement of proteinuria and albuminuria at each time point. It is reassuring that the observed effects of NRTI component were in the same direction, albeit less significant, at 48 weeks. Second, the study was not specifically powered for this secondary analysis, and missing data at week 96 further limited our sample size for the primary intention-to-treat analyses. Although there were no statistically significant differences with respect to baseline characteristics, it is also possible that participants with missing data at week 96 differed from participants who were included in the primary analysis. Third, our analysis was complicated by the unblinding of the NRTI component and switches from ABC/3TC to TDF/FTC in participants with high screening HIV-RNA following the DSMB report in February 2008. Results of the as-treated analyses with data censored after a change in NRTI were qualitatively similar, although the differences in albuminuria reduction were no longer statistically significant. Fourth, although it is reassuring that proteinuria and albuminuria did not worsen in participants randomized to TDF/FTC, our results are short term when viewed in the context of lifelong ART. By design, follow-up of study participants ended when the last enrolled participant reached week 96; as a result, there is a decreasing sample size on visits after this time point. Particularly, given the low baseline prevalence of clinically significant proteinuria/albuminuria or decreased eGFR, these short-term results do not exclude the possibility of worsening proteinuria or albuminuria with more prolonged exposure. We did observe a more significant effect of NRTI assignment at week 96 than at week 48, which could suggest a cumulative effect of treatment; unfortunately, the small sample size after week 96 did not allow us to explore this further. Fifth, although we did not detect a significant interaction between NRTI and NNRTI/PI component, the current analysis likely only had adequate power to detect large treatment interactions. Finally, our results may not be generalizable to patients with baseline creatinine clearance <60 mL/minute or with uncontrolled diabetes, who were excluded from the current study and who are at greatest risk for adverse renal and cardiovascular outcomes. In contrast, more than one-third of participants were of self-reported black race, another important risk factor for CKD. There were no significant interactions between NRTI component and race, age, or blood pressure, suggesting that the observed NRTI effects were not significantly influenced by these traditional CKD risk factors.
Our data are consistent with previous studies demonstrating improvements in proteinuria or albuminuria after the initiation of ART.6–8 These are the first data from a randomized clinical trial to suggest that the initiation of TDF/FTC in ART-naive individuals may not be associated with the same degree of improvements in proteinuria and albuminuria that are observed with ABC/3TC. Future studies should consider the long-term clinical significance of these differences, particularly among individuals with pre-existing CKD or CKD risk factors.
The authors thank the study participants for their generous donation of time and effort in the successful completion of this trial. The authors also thank the following participating sites and site investigators: Sadia Shaik, MD and Ruben Lopez, MD, Harbor-UCLA Medical Center (Site 603) CTU Grant AI0694241, UL1RR033176, CTSI Grant UL1TR000124; Susan L. Koletar, MD and Diane Gochnour, RN, The Ohio State University Medical Center (Site 2301) CTU Grant AI069474; Geyoul Kim, RN and Mark Rodriguez, RN, Washington University (Site 2101) CTU Grant U01AI069495, GCRC Grant UL1 RR024992; Elizabeth Lindsey, RN and Tamara James, BS, Alabama Therapeutics CRS (Site 5801) CTU Grant U01 AI069452; Ann C. Collier, MD and Jeffrey Schouten, MD, JD University of Washington (Site 1401) CTU Grant AI069434, UL1 RR025014; Jorge L. Santana Bagur, MD and Santiago Marrero, MD, Puerto Rico-AIDS Clinical Trials Unit (Site 5401) CTU Grant 5 U0I AI069415-03; Jenifer Baer, RN, BSN and Carl Fichtenbaum, MD, University of Cincinnati (Site 2401) CTU Grant AI069513; Patricia Walton, BSN, RN and Barbara Philpotts, BSN, RN, Case Western Reserve (Site 2501) CTU Grant AI69501; Princy Kumar, MD and Joseph Timpone, MD, Georgetown University (Site 1008) CTU Grant AIDS Clinical Trials Group Grant 5U01AI069494; Donna Pittard, RN, BSN and David Curri, RN, University of North Carolina (Site 3201) CTU Grant 5-U01 AI069423–03, UNC CFAR P30 AI050410 (-11), UNC CTRC UL 1RR 025747; Julie Hoffman, RN and Edward Seefried, RN, San Diego Medical Center UC (Site 701) CTU Grant AI69432; Susan Swindells, MBBS and Frances Van Meter, APRN-University of Nebraska (Site 1505) CTU Grant AI 27661; Deborah McMahon, MD and Barbara Rutecki, MSN, MPH, CRNP, University of Pittsburgh (Site 1001) CTU Grant 1 U01 AI069494-01; Michael P. Dube, MD and Martha Greenwald, RN, MSN, Indiana University (Site 2601) CTU Grant 5U01AI025859, GCRC M01 RR00750; Ilene Wiggins, RN, and Eric Zimmerman, RN, Johns Hopkins University (Site 201) CTU Grant AI27668, CTSA Grant UL1 RR025005; Judith Aberg, MD and Margarita Vasquez RN, New York University/NYC HHC at Bellevue Hospital Center (Site 401) CTU Grant AI27665, New Grant AI069532 10; Martin McCarter and M. Graham Ray, RN, MSN, Colorado AIDS Clinical Trials Unit (Site 6101) CTU Grant AI69450, RR025780; Mamta Jain, MD and Tianna Petersen, MS, University of Texas Southwestern Medical Center (Site 3751) CTU Grant 3U01AI046376–05S4; Emily Stumm, BS and Pablo Tebas MD, University of Pennsylvania, Philadelphia (Site 6201) CTU Grant P30-AI0450008–11, CFAR Grant UO1-AI069467-04; Mary Albrecht, MD and Neah Kim, NP, Beth Israel Deaconess (Partners/Harvard) CRS (Site 103) CTU Grant U01 AI069472-04; Paul Edward Sax, MD and Joanne Delaney RN, Brigham and Women's Hospital (Site 107) CTU Grant UOI AI 069472; Christine Hurley, RN and Roberto Corales, DO, AIDS Care (Site 1108) CTU Grant U01AI069511–02 (as of 2/12/08), GCRC UL1 RR 024160; Keith Henry, MD and Bette Bordenave, RN, Hennepin County Medical Center (Site 1502) CTU Grant N01 AI72626; Wendy Armstrong, MD and Ericka R. Patrick, RN, MSN, CCRC, Emory University HIV/AIDS Clinical Trials Unit (Site 5802) CTU Grant UO1Al69418–01/CFAR Grant Number: P30Al050409; Jane Reid, RNC, MS and Mary Adams, RN, MPH, University of Rochester (Site 1101) CTU Grant U01AI069511–02 (as of 2/12/08), GCRC: UL1RR 024160; Gene D. Morse, PharmD, FCCP, BCPS-SUNY, Buffalo, Erie County Medical Center (Site 1102) CTU Grant AI27658; Kimberly Y. Smith, MD, MPH and Joan A. Swiatek, APN, Rush University Medical Center (Site 2702) CTU Grant U01 AI069471; Nancy Hanks, RN and Debra Ogata-Arakaki, RN, University of Hawaii at Manoa, Leahi Hospital (Site 5201) CTU Grant AI34853; Ardis Moe, MD and Maria Palmer, PA-C, UCLA Medical Center (Site 601) CTU Grant 1U01AI069424-01; Jeffery Meier, MD and Jack T. Stapleton, MD, University of Iowa Hospitals and Clinics (Site 1504) CTU Grant UL1RR024979; Gary Matthew Cox, MD and Martha Silberman, RN, Duke University Medical Center Adult CRS (Site 1601) CTU Grant 5U01 AI069 484-02 2705; Gerianne Casey, RN and William O'Brien, MD, University of Texas, Galveston (Site 6301) CTU Grant AI32782; Valery Hughes, FNP and Todd Stroberg, RN, Cornell CRS (Sites 7803 and 7804) CTU Grant U01 AI069419, CTSC UL1 RR024996; Nyef El-Daher, MD, McCree McCuller Wellness Center at the Connection (Site 1107) CTU Grant U01AI069511–02 (as of 2/12/08), GCRC: UL1 RR 024160; Rebecca J. Basham, BS and Husamettin Erdem, MD, Vanderbilt Therapeutics CRS (Site 3652) CTU Grant AI46339–01; MO1 RR 00095.
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Keywords:© 2014 by Lippincott Williams & Wilkins
HIV; antiretroviral therapy; kidney disease