Browsing by Author "Sax, Paul E."

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    Changes in proteinuria and albuminuria with initiation of antiretroviral therapy: data from a randomized trial comparing tenofovir disoproxil fumarate/emtricitabine versus abacavir/lamivudine
    (Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2014-09-01) Wyatt, Christina M.; Kitch, Douglas; Gupta, Samir K.; Tierney, Camlin; Daar, Eric S.; Sax, Paul E.; Ha, Belinda; Melbourne, Kathleen; McComsey, Grace A.; AIDS Clinical Trials Group Study A5224s Team; Department of Medicine, IU School of Medicine
    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.
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    Cystatin C-Based Renal Function Changes After Antiretroviral Initiation: A Substudy of a Randomized Trial
    (Oxford University Press, 2014-04-16) Gupta, Samir K.; Kitch, Douglas; Tierney, Camlin; Daar, Eric S.; Sax, Paul E.; Melbourne, Kathleen; Ha, Belinda; McComsey, Grace A.; Department of Medicine, IU School of Medicine
    Background.  The effects of antiretrovirals on cystatin C-based renal function estimates are unknown. Methods.  We analyzed changes in renal function using creatinine and cystatin C-based estimating equations in 269 patients in A5224s, a substudy of study A5202, in which treatment-naive patients were randomized to abacavir/lamivudine or tenofovir/emtricitabine with open-label atazanavir/ritonavir or efavirenz. Results.  Changes in renal function significantly improved (or declined less) with abacavir/lamivudine treatment compared with tenofovir/emtricitabine using the Cockcroft-Gault formula (P = .016) and 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI; P = .030) and 2012 CKD-EPI cystatin C-creatinine (P = .025). Renal function changes significantly improved (or declined less) with efavirenz compared with atazanavir/ritonavir (P < .001 for all equations). Mean (95% confidence interval) renal function changes specifically for tenofovir/emtricitabine combined with atazanavir/ritonavir were −8.3 (−14.0, −2.6) mL/min with Cockcroft-Gault; −14.9 (−19.7, −10.1) mL/min per 1.732 with Modification of Diet in Renal Disease; −12.8 (−16.5, −9.0) mL/min per 1.732 with 2009 CKD-EPI; +8.9 (4.2, 13.7) mL/min per 1.732 with 2012 CKD-EPI cystatin C; and −1.2 (−5.1, 2.6) mL/min per 1.732 with 2012 CKD-EPI cystatin C-creatinine. Renal function changes for the other treatment arms were more favorable but similarly varied by estimating equation. Conclusions.  Antiretroviral-associated changes in renal function vary in magnitude and direction based on the estimating equation used.
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    Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens for initial treatment of HIV-1 infection: week 144 results from two randomised, double-blind, multicentre, phase 3, non-inferiority trials
    (Elsevier, 2020-06) Orkin, Chloe; DeJesus, Edwin; Sax, Paul E.; Arribas, Jose R.; Gupta, Samir K.; Martorell, Claudia; Stephens, Jeffrey L.; Stellbrink, Hans-Jurgen; Wohl, David; Maggiolo, Franco; Thompson, Melanie A.; Podzamczer, Daniel; Hagins, Debbie; Flamm, Jason A.; Brinson, Cynthia; Clarke, Amanda; Huang, Hailin; Acosta, Rima; Brainard, Diana M.; Collins, Sean E.; Martin, Hal; Medicine, School of Medicine
    Background In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. We report week-144 efficacy and safety results from these studies. Methods We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, and tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were registered with ClinicalTrials.gov, NCT02607930 and NCT02607956. Findings 629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, emtricitabine, and tenofovir alafenamide, 325 to dolutegravir, emtricitabine, tenofovir alafenamide). At week 144, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and lamivudine group (difference −2·6%, 95% CI −8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 273 (84%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (difference −1·9%, −7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug discontinuation were reported for no participants in the bictegravir, emtricitabine, and tenofovir alafenamide group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in the bictegravir, emtricitabine, and tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (−0·1 vs −0·3; p=0·007) at week 144; no differences were observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study. Interpretation These long-term data support the use of bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people with HIV, with no emergent resistance. Funding Gilead Sciences.
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    Renal Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate: A Pooled Analysis of 26 Clinical Trials
    (Wolters Kluwer, 2019-03) Gupta, Samir K.; Post, Frank A.; Arribas, José R.; Eron, Joseph J., Jr.; Wohl, David A.; Clarke, Amanda E.; Sax, Paul E.; Stellbrink, Hans-Jürgen; Esser, Stefan; Pozniak, Anton L.; Podzamczer, Daniel; Waters, Laura; Orkin, Chloe; Rockstroh, Jürgen K.; Mudrikova, Tatiana; Negredo, Eugenia; Elion, Richard A.; Guo, Susan; Zhong, Lijie; Carter, Christoph; Martin, Hal; Brainard, Diana; Sengupta, Devi; Das, Moupali; Medicine, School of Medicine
    Objective: Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has been associated with improvement in markers of renal dysfunction in individual randomised trials; however the comparative incidence of clinically significant renal events remains unclear. Design: We used a pooled data approach to increase the person-years of drug exposure analysed, maximizing our ability to detect differences in clinically significant outcomes. Methods: We pooled clinical renal safety data across 26 treatment naïve and antiretroviral switch studies in order to compare the incidence of proximal renal tubulopathy (PRT) and discontinuation due to renal adverse events (AEs) between participants taking TAF-containing regimens versus those taking TDF-containing regimens. We performed secondary analyses from seven large randomised studies (two treatment-naïve and five switch studies) to compare incidence of renal AEs, treatment-emergent proteinuria, changes in serum creatinine, creatinine clearance, and urinary biomarkers (albumin, beta-2-microglobulin, and retinol binding protein to creatinine ratios). Results: Our integrated analysis included 9,322 adults and children with HIV (n = 6360 TAF, n = 2962 TDF) with exposure of 12,519 person-years to TAF and 5947 to TDF. There were no cases of PRT in participants receiving TAF versus 10 cases in those receiving TDF (p < 0.001), and fewer individuals on TAF (3/6360) versus TDF (14/2962) (p < 0.001) discontinued due to a renal AE. Participants initiating TAF- vs. TDF-based regimens had more favourable changes in renal biomarkers through 96 weeks of therapy. Conclusion: These pooled data from 26 studies, with over 12,500 person-years of follow-up in children and adults, support the comparative renal safety of TAF over TDF.