Kathleen Melbourne

Bone Mineral Density and Fractures in Antiretroviral-Naive Persons Randomized to Receive Abacavir-Lamivudine or Tenofovir Disoproxil Fumarate-Emtricitabine Along With Efavirenz or Atazanavir-Ritonavir: AIDS Clinical Trials Group A5224s, a Substudy of ACTG A5202

BACKGROUND Long-term effects of abacavir (ABC)-lamivudine (3TC), compared with tenofovir (TDF)-emtricitabine (FTC) with efavirenz (EFV) or atazanavir plus ritonavir (ATV/r), on bone mineral density (BMD) have not been analyzed. METHODS A5224s was a substudy of A5202, in which HIV-infected treatment-naive participants were randomized and blinded to receive ABC-3TC or TDF-FTC with open-label EFV or ATV/r. Primary bone end points included Dual-emission X-ray absorbtiometry (DXA)-measured percent changes in spine and hip BMD at week 96. Primary analyses were intent-to-treat. Statistical tests used the factorial design and included linear regression, 2-sample t, log-rank, and Fishers exact tests. RESULTS Two hundred sixty-nine persons randomized to 4 arms of ABC-3TC or TDF-FTC with EFV or ATV/r. At baseline, 85% were male, and 47% were white non-Hispanic; the median HIV-1 RNA load was 4.6 log(10) copies/mL, the median age was 38 years, the median weight was 76 kg, and the median CD4 cell count was 233 cells/μL. At week 96, the mean percentage changes from baseline in spine and hip BMD for ABC-3TC versus TDF-FTC were -1.3% and -3.3% (P = .004) and -2.6% and -4.0% (P = .024), respectively; and for EFV versus ATV/r were -1.7% and -3.1% (P = .035) and -3.1% and -3.4% (P = .61), respectively. Bone fracture was observed in 5.6% of participants. The probability of bone fractures and time to first fracture were not different across components. CONCLUSIONS Compared with ABC-3TC, TDF-FTC-treated participants had significantly greater decreases in spine and hip BMD, whereas ATV/r led to more significant losses in spine, but not hip, BMD than EFV. Clinical Trials Registration. NCT00118898.

Peripheral and Central Fat Changes in Subjects Randomized to Abacavir-Lamivudine or Tenofovir-Emtricitabine With Atazanavir-Ritonavir or Efavirenz: ACTG Study A5224s

BACKGROUND We compare the effect of 4 different antiretroviral regimens on limb and visceral fat. METHODS A5224s was a substudy of A5202, a trial of human immunodeficiency virus type 1 (HIV-1)-infected, treatment-naive subjects randomized to blinded abacavir-lamivudine (ABC-3TC) or tenofovir DF-emtricitabine (TDF-FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV-r). The primary endpoint was the presence of lipoatrophy (≥ 10% loss of limb fat) at week 96 by intent-to-treat (ITT) analysis. Secondary endpoints included changes in limb and visceral fat. Statistical tests included linear regression, binomial, two-sample t test, and Fishers exact test. RESULTS A5224s enrolled 269 subjects; 85% were male, and 47% were white non-Hispanic. The subjects had a median baseline HIV-1 RNA level of 4.6 log(10) copies/mL, a median age of 38 years, a median CD4+ cell count of 233 cells/μL, median limb fat of 7.4 kg, median visceral adipose tissue (VAT) of 84.1 cm(2), and VAT: total adipose tissue (TAT) ratio of 0.31. At week 96, estimated prevalence of lipoatrophy (upper 95% confidence interval [CI]) was 18% (25%) for ABC-3TC and 15% (22%) for TDF-FTC (P = .70); this was not significantly less than the hypothesized 15% for both (P ≥ .55 for both). The secondary as-treated (AT) analysis showed similar results. At week 96, the estimated mean percentage change from baseline in VAT was higher for the ATV-r group than for the EFV group (26.6% vs 12.4%; P = .090 in ITT analysis and 30.0% vs 14.5%; P = .10 in AT analysis); however, the percentage change in VAT:TAT was similar by ITT and AT analysis (P ≥ .60 for both). Results were similar for absolute changes in VAT and VAT:TAT. CONCLUSIONS ABC-3TC- and TDF-FTC-based regimens increased limb and visceral fat at week 96, with a similar prevalence of lipoatrophy. Compared to the EFV group, subjects assigned to ATV-r had a trend towards higher mean percentage increase in VAT. CLINICAL TRIALS REGISTRATION NCT00118898.

Inflammation markers after randomization to abacavir/lamivudine or tenofovir/emtricitabine with efavirenz or atazanavir/ritonavir

Background:The effect of specific antiretrovirals on inflammation is unclear. Methods:A5224s was a substudy of A5202, which randomized HIV-infected treatment-naïve patients to blinded abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in a factorial design. Our analysis compared changes in inflammation markers from baseline to week 24 between ABC/3TC and TDF/FTC. Secondary analyses included changes at week 96 and comparisons of EFV vs. ATV/r. Results:Analyses included 244 patients (85% male, 48% white non-Hispanic), median age 39 years, HIV-1 RNA 4.6 log10 copies/ml, CD4 240 cells/&mgr;l. TNF-&agr;, soluble receptors of TNF-&agr; (sTNFR)-I and II, soluble vascular cellular adhesion molecule (sVCAM)-1 and soluble intercellular adhesion molecule (sICAM)-1 decreased significantly at weeks 24 and 96, without significant differences between components (P ≥ 0.44). At week 24, ABC/3TC had a greater high-sensitivity C-reactive protein (hsCRP) mean fold change than TDF/FTC {1.43 vs. 0.88, estimated mean fold change percentage difference [&Dgr;] 61.5% [95% confidence interval (CI) 13.6%, 129.5%]; P = 0.008}. Similar results were seen at week 96 (P = 0.021). At week 24 (but not 96), EFV had a greater hsCRP mean fold change than ATV/r [1.41 vs. 0.88; &Dgr; = 60.2% (12.6%, 127.7%); P = 0.009]. IL-6 decreased significantly at week 24 with TDF/FTC but not with ABC/3TC (between-components P = 0.019). At week 96, IL-6 decreased significantly in both nucleoside reverse transcriptase inhibitor components (between-components P = 0.11). IL-6 changes were not significantly different between ATV/r and EFV at either time point (P ≥ 0.89). Conclusions:Soluble TNF-receptors and adhesion molecules decreased following treatment initiation and did not differ by regimens. Differences were seen on hsCRP and IL-6 changes with ABC/3TC vs. TDF/FTC and on hsCRP with EFV vs. ATV/r.

Vitamin D and Calcium Attenuate Bone Loss With Antiretroviral Therapy Initiation: A Randomized Trial

Background Antiretroviral therapy (ART) initiation for HIV-1 infection is associated with 2-6% loss in bone mineral density (BMD).Context Patients with HIV who initiate antiretroviral therapy (ART) lose bone mineral density (BMD). The role of supplementation with vitamin D and calcium in preventing such loss is unknown. Contribution In a randomized clinical trial of patients with HIV who were initiating ART, BMD, 25-hydroxyvitamin D, parathyroid hormone, phosphate metabolism, and markers of bone turnover were measured at baseline. Patients who then received vitamin D3 plus calcium along with ART had smaller declines in BMD of the hip and spine than those who received placebo along with ART. Caution Nearly all of the patients were men. Implication Supplementation with vitamin D and calcium may prevent bone loss in patients with HIV initiating ART. Antiretroviral therapy (ART) has transformed HIV infection from a terminal disease to a manageable chronic illness. Although incidence of AIDS-defining conditions has decreased, it has increased for other comorbid conditions (1), including osteoporosis and fragility fractures (27). Both viral and host factorsHIV infection mediated by certain viral proteins, HIV-associated inflammation, lifestyle and behavioral factors, underlying genetic predisposition, comorbid conditions, and ARTprobably contribute to bone loss and fracture risk (814). Studies of ART initiation have confirmed that 2% to 6% of hip and spine BMD is lost over the first 24 to 48 weeks after initiation, with subsequent stabilization (1518). The magnitude of bone loss is similar to that seen with glucocorticoids or during the first year of menopausal transition (19, 20). Initial loss is marked by an increase in serum bone resorption markers followed by a delayed compensatory increase in bone formation markers (21); therefore, this catabolic window, a high bone turnover state with excess resorption, may be a central mechanism of bone loss with ART initiation. Tenofovir disoproxil fumarate (TDF), a nucleotide analogue reverse transcriptase inhibitor, has been associated with greater bone loss than other reverse transcriptase inhibitors (15, 16). Use of TDF is associated with increased parathyroid hormone (PTH), elevated vitamin D binding protein, and reduced free 1,25-dihydroxyvitamin D [1,25-(OH)2D3] levels (22, 23), suggesting that functional vitamin D deficiency with TDF use potentially contributes to excess bone loss. Initiation of efavirenz (EFV), a nonnucleoside reverse transcriptase inhibitor, is associated with a 6.2- to 12.5-nmol/L decrease in 25-hydroxyvitamin D [25-(OH)D] levels (24, 25). Efavirenz induces cytochrome P450 enzymes involved in vitamin D metabolism and may accelerate the catabolism of 25-(OH)D and 1,25-(OH)2D3, the latter being the active vitamin D metabolite (26). These ART agents are combined with emtricitabine (FTC), a nucleoside analogue reverse transcriptase inhibitor, into a fixed-dose combination, once-a-day pill (EFV/FTC/TDF) that is highly effective for treating HIV (27). Beyond effects on bone metabolism, vitamin D has immunomodulatory effects mediated through the vitamin D receptor present on cells in both the innate and the adaptive immune system (28, 29). Vitamin D increases monocyte expression of CD14 and cathelicidin, molecules involved in innate immune responses (30, 31); down-regulates cytokine expression in activated T cells; and suppresses T-cell proliferation and production of interferon- and interleukin (IL)-2, thus reducing the net state of inflammation (32, 33). These pathways are particularly relevant in HIV infection, in which excess monocyte and T-cell activation are important drivers of morbidity and mortality (3437). We hypothesized that high-dose vitamin D and calcium supplementation would attenuate bone loss associated with initiation of EFV/FTC/TDF. In addition, we evaluated immunomodulatory effects of vitamin D in the setting of HIV treatment. We report the results of the AIDS Clinical Trials Group A5280 trial, a multicenter, randomized, double-blind, placebo-controlled study assessing the effect of daily oral doses of 4000 IU of vitamin D3 and 1000 mg of calcium carbonate in adults with HIV initiating their first ART regimen with EFV/FTC/TDF. Methods Patients with ART-naive HIV without evidence of resistance to the antiretrovirals in the regimen and with HIV-1 RNA levels greater than 1000 copies/mL were eligible if they met the following criteria: screening 25-(OH)D level between 25 and 188 nmol/L; creatinine clearance of 60 mL/min/1.73 m2 or greater, estimated by the CockcroftGault formula; and serum calcium level less than 2.6 mmol/L. We excluded patients with daily calcium supplementation greater than 500 mg, daily vitamin D supplementation greater than 800 IU, any bisphosphonate use, recent steroid or chemotherapy treatments, clinically active thyroid disease, active substance or alcohol abuse, history of fragility fracture, documented osteoporosis, nephrolithiasis, or weight greater than 136 kg (limit of the dual-energy x-ray absorptiometry [DXA] scanner). Pregnant and breastfeeding women were also excluded. We did 3-day dietary recalls at entry to estimate vitamin D and calcium intake. Patients were randomly assigned to 4000 IU of cholecalciferol (vitamin D3) daily plus 500 mg of calcium carbonate twice daily or identically matching placebos (Tishcon) and were counseled to take with food to facilitate absorption. Some experts consider the current upper U.S. Dietary Reference Intake of 2000 IU to be below actual physiologic requirements; therefore, we tested the highest supplementation without risk for toxicity (3840). A dose of 4000 IU of vitamin D3 is the highest daily dose considered safe for adults by the Institute of Medicine (41) and has previously been evaluated in persons with HIV with excellent tolerability and safety data (42). Patients were randomly assigned in a 1:1 ratio using permuted blocks stratified by screening serum 25-(OH)D levels (50 and >50 nmol/L). Randomization was done using Web-based access to a central computer system maintained by the Frontier Science & Technology Research Foundation (Buffalo, New York). The institutional review boards of all participating sites approved the study, and all patients provided written informed consent. The primary end point was percentage of change in total hip BMD from baseline to 48 weeks. Secondary end points included percentage of change in lumbar spine BMD at 48 weeks, change in plasma 25-(OH)D and PTH levels, markers of bone turnover, soluble inflammatory biomarkers, and CD4 cell counts at 24 and 48 weeks. Incidence of hypercalcemia and nephrolithiasis was monitored. All DXA scans were read in a blinded fashion at the Body Composition Analysis Center at Tufts Medical Center (Boston, Massachusetts) using a standardized protocol. Biomarker Assays Screening was done at local laboratories certified by the Clinical Laboratory Improvement Amendments. Serum samples were stored at 70C at the Irving Institute Biomarkers Core Laboratory at Columbia University Medical Center (New York, New York) and underwent batched analysis. We measured 25-(OH)D2 and 25-(OH)D3 by liquid chromatographymass spectrometry, intact PTH by a radioimmunoassay (Scantibodies), procollagen-1 N-terminal peptide (P1NP) by a radioimmunoassay (Immunodiagnostic Systems), C-terminal telopeptide of type 1 collagen (CTX) by an enzyme-linked immunosorbent assay [ELISA] (Immunodiagnostic Systems), IL-6 by an ELISA (R&D Systems), soluble tumor necrosis factor receptor (sTNFR) by an ELISA (R&D Systems), and soluble CD14 by an ELISA (R&D Systems). Inflammatory biomarkers were chosen based on association with relevant end points (4346). All biomarkers, except for 25-(OH)D, were measured in duplicate, and values were averaged for analysis. Statistical Analysis To provide an intention-to-treat analysis, evaluations were done regardless of treatment change or discontinuation. Two patients who did not have the correct vitamin D test done at baseline were excluded from the efficacy analyses. Stratified Wilcoxon rank-sum tests were used to evaluate for distribution shifts between the treatment groups, which were stratified by screening vitamin D levels. Fisher exact tests and Wilcoxon rank-sum tests were used to evaluate for differences between groups for categorical and continuous secondary outcomes, respectively. Wilcoxon signed-rank tests were used to evaluate change within a treatment group. The 95% CIs for median changes within a group were estimated using a distribution-free method via percentiles. For the BMD outcomes, modification of the treatment effect by screening vitamin D stratum was evaluated by means of linear regression. Analyses of the primary outcomes of change in hip and spine BMD from baseline to 48 weeks used a multiple-imputation approach to fill in missing data with a Markov-chain Monte Carlo method. A prespecified complete-case approach was used for analyses by stratum and to assess interactions. Five imputations were used, based on screening 25-(OH)D strata, age, sex, and race/ethnicity. All statistical tests were 2-sided and interpreted at the 5% nominal level of significance without adjustment for multiple comparisons. Analyses were done using the FREQ, UNIVARIATE, REG, MI, and MIANALYZE procedures in SAS, version 9.2 (SAS Institute), and STRATIFY and PAIRED procedures in Proc-StatXact, version 9 (Cytel). Role of the Funding Source The National Institute of Allergy and Infectious Diseases funded the study. Industry sponsors (Bristol-Myers Squibb, Gilead Science, and Tishcon) provided antiretrovirals, vitamin D, calcium, and matching placebos, and additional funding was provided for completion of DXA scans and laboratory assays. The National Institute of Allergy and Infectious Diseases had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. The manuscript was reviewed by ind

Associations of inflammatory markers with AIDS and non-AIDS clinical events after initiation of antiretroviral therapy: AIDS clinical trials group A5224s, a substudy of ACTG A5202.

Background:The association of inflammatory biomarkers with clinical events after antiretroviral therapy initiation is unclear. Methods:A5202 randomized 1857 treatment-naive subjects to abacavir/lamivudine or tenofovir-DF/emtricitabine with efavirenz or atazanavir/ritonavir. Substudy A5224s measured inflammatory biomarkers on subjects with available plasma from baseline and week 24 or 96. An exploratory analysis of the association of high-sensitivity C-reactive protein, interleukin-6 (IL-6), soluble receptors of tumor necrosis factor &agr; (sTNF)-RI, sTNF-RII, TNF-&agr;, soluble vascular cellular adhesion molecules (sVCAM-1), and soluble intercellular adhesion molecules (sICAM-1) with times to AIDS and to non-AIDS events used Cox proportional hazards models. Results:Analysis included 244 subjects; 85% men and 48% white non-Hispanic with median age 39 years, HIV-1 RNA of 4.6 log10 copies per milliliter, and CD4 of 240 cells per microliter. Overall, 13 AIDS events (9 opportunistic infections, 3 AIDS-cancers, and 1 recurrent bacterial pneumonia) and 18 non-AIDS events (6 diabetes, 4 cancers, 3 cardiovascular, and 5 pneumonias) occurred. Higher baseline IL-6, sTNF-RI, sTNF-RII, and sICAM-1 were significantly associated with increased risk of AIDS-defining events. Adjustment for baseline HIV-1 RNA did not change results, whereas adjusting for baseline CD4 count left only sTNF-RI and sICAM-1 significantly associated with increased risk. Time-updated values of IL-6, sTNFR-I and II, and sICAM-1 were also associated with an increased risk. For non-AIDS events, only higher baseline high-sensitivity C-reactive protein was significantly associated with increased risk, whereas higher IL-6 was marginally associated with higher risk. Analyses of time-updated biomarker values showed tumor necrosis factor &agr; to be significantly associated with increased risk, even after adjustment for antiretroviral therapy, and CD4 count or HIV-1 RNA. Conclusions:Higher levels of several inflammatory biomarkers were independently associated with increased risk of AIDS and non-AIDS events.

The Safety and Efficacy of Granulocyte-Macrophage Colony-Stimulating Factor (Sargramostim) Added to Indinavir- or Ritonavir-Based Antiretroviral Therapy: A Randomized Double-Blind, Placebo-Controlled Trial

Sargramostim is a yeast-derived, recombinant human granulocyte-macrophage colony-stimulating factor with therapeutic potential in human immunodeficiency virus (HIV) infection. Its safety and activity when used in combination with protease inhibitors were evaluated in a randomized, double-blind trial in which 20 HIV-infected subjects on stable antiretroviral regimens, including indinavir or ritonavir, received sargramostim or placebo 3 times a week for 8 weeks. Analysis of HIV virus load excluded any 0. 5 log10 increase due to sargramostim (95% confidence interval, -0.68 to 0.44). Sargramostim was well tolerated, and inflammatory cytokines and surrogate markers of disease progression, such as serum levels of interleukin-10 and soluble tumor necrosis factor receptors types Iota and IotaIota, remained stable in subjects receiving sargramostim. Sargramostim treatment was associated with a trend toward decreased HIV RNA (>0.5 log10) and increased CD4+ cell count (>30%). These results became statistically significant only when subjects with baseline virus loads within the limits of detection or baseline CD4 cell count >50 were analyzed. No difference in indinavir pharmacokinetics was observed before or after sargramostim therapy.

Weight and lean body mass change with antiretroviral initiation and impact on bone mineral density.

Objective:To compare the effect that initiating different antiretroviral therapy (ART) regimens has on weight, BMI, and lean body mass (LBM) and explore how changes in body composition are associated with bone mineral density (BMD). Methods:A5224s was a sub-study of A5202, a prospective trial of 1857 ART-naive participants randomized to blinded abacavir–lamivudine (ABC/3TC) or tenofovir DF–emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir–ritonavir (ATV/r). All participants underwent dual-energy absorptiometry (DXA) and abdominal computed tomography for body composition. Analyses used two-sample t-tests and linear regression. Results:A5224s included 269 participants: 85% men, 47% white non-Hispanic, median age 38 years, HIV-1 RNA 4.6 log10 copies/ml, and CD4+ cell count 233 cells/&mgr;l. Overall, significant gains occurred in weight, BMI, and LBM at 96 weeks postrandomization (all P < 0.001). Assignment to ATV/r (vs. EFV) resulted in significantly greater weight (mean difference 3.35 kg) and BMI gain (0.88 kg/m2; both P = 0.02), but not LBM (0.67 kg; P = 0.15), whereas ABC/3TC and TDF/FTC were not significantly different (P ≥ 0.10). In multivariable analysis, only lower baseline CD4+ cell count and higher HIV-1 RNA were associated with greater increase in weight, BMI, or LBM. In multivariable analyses, increased LBM was associated with an increased hip BMD. Conclusion:ABC/3TC vs. TDF/FTC did not differ in change in weight, BMI, or LBM; ATV/r vs. EFV resulted in greater weight and BMI gain but not LBM. A positive association between increased LBM and increased hip BMD should be further investigated through prospective interventional studies to verify the impact of increased LBM on hip BMD.

Impact of randomized antiretroviral therapy initiation on glucose metabolism.

Objective:Prior studies have found that early HIV protease inhibitors contribute to glucose dysregulation. Few randomized trials have evaluated glucose indices in antiretroviral-naive individuals on newer antiretroviral therapy (ART). Methods:A5224s was a substudy of A5202, a prospective trial of 1857 ART-naive participants randomized to blinded abacavir-lamivudine (ABC/3TC) or tenofovir DF-emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV/r). Analyses used two-sample t-tests, Spearman correlation coefficients and linear regression. Results:A5224s included 269 nondiabetic individuals: 85% men, 47% white non-Hispanic, baseline median age 38 years, HIV-1 RNA 4.6 log10 copies/ml and CD4+ cell count 233 cells/&mgr;l. Overall, significant 96-week increases occurred in fasting glucose, insulin and the homeostatic model assessment of insulin resistance (HOMA-IR), P ⩽ 0.004. Assignment to EFV (versus ATV/r) resulted in significantly greater glucose increase [mean difference 4.4; 95% confidence interval (CI) 1.3, 7.5 mg/dl; P = 0.006] but not insulin or HOMA-IR (P ≥ 0.72). Glucose indices were not significantly different between ABC/3TC and TDF/FTC arms, P ≥ 0.18. Significant correlations were detected between changes in glucose indices and changes in BMI; all r ≥ 0.23, P ⩽ 0.001. In multivariable analyses, in addition to the EFV effect, higher baseline HIV-1 RNA and greater BMI change were significant independent factors associated with greater glucose increase. Conclusion:Changes in glucose metabolism were not significantly different between TDF/FTC and ABC/3TC-based regimens. A small but significantly greater increase in glucose was observed in those assigned to EFV. As glucose dysregulation may increase with time on ART, longer term studies will be needed to further clarify the clinical significance of these findings.

Markers of renal disease and function are associated with systemic inflammation in HIV infection

Both renal disease and systemic inflammation predict non‐AIDS‐defining events and overall mortality in HIV‐infected patients. Here, we sought to determine the relationships between renal disease and circulating inflammation markers.

Changes in proteinuria and albuminuria with initiation of antiretroviral therapy: data from a randomized trial comparing tenofovir disoproxil fumarate/emtricitabine versus abacavir/lamivudine.

Background:Antiretroviral therapy (ART) is associated with improved kidney function; however, the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF) has been associated with decreased kidney function and proteinuria. Methods:We examined changes in urine protein:creatinine (UPCR) and urine albumin:creatinine (UACR) ratios in 245 ART-naive participants in A5202 randomized in a substudy to blinded NRTI (abacavir/lamivudine, ABC/3TC, n = 124 or TDF/emtricitabine, TDF/FTC, n = 121) with open-label protease inhibitor (PI) atazanavir/ritonavir or nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz. Results:At baseline, 18% of participants had clinically significant proteinuria (UPCR ≥200 mg/g), and 11% had clinically significant albuminuria (UACR ≥30 mg/g). The prevalence of clinically significant proteinuria and albuminuria decreased from baseline to week 96 in all treatment groups. In intention-to-treat analyses, there was a significant effect of NRTI component on fold change in UPCR (P = 0.011) and UACR (P = 0.018) from baseline to week 96, with greater improvements in participants randomized to ABC/3TC. There was no significant effect of NNRTI/PI component on fold change in UPCR (P = 0.23) or UACR (P = 0.88), and no significant interactions between NRTI and NNRTI/PI components. Conclusions:In this prespecified secondary analysis, ART initiation was associated with improvements in proteinuria and albuminuria, with significantly greater improvements in participants randomized to ABC/3TC versus TDF/FTC. These are the first data from a randomized trial to suggest that initiation of TDF/FTC may not be associated with the same degree of improvement in proteinuria and albuminuria that have been reported with other regimens. Future studies should consider the long-term clinical significance of these findings.