CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

682 Longer-Term Renal Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate Bart J. Rijnders 1 ; Frank A. Post 2 ; Armin Rieger 3 ; EugenioTeofilo 4 ; DavidWohl 5 ; Paul E. Sax 6 ; Susan Guo 7 ; Andrew Cheng 7 ; Moupali Das 7 ; Marshall Fordyce 7

1 Erasmus Univ Med Cntr, Rotterdam, Netherlands; 2 King’s Coll Hosp NHS Fndn Trust, London, UK; 3 Med Univ of Vienna, Vienna, Austria; 4 Hosp dos Capuchos, Centro Hospar de Lisboa Central, Lisbon, Portugal; 5 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 6 Brigham and Women’s Hosp, Harvard Med Sch, Boston, MA, USA; 7 Gilead Scis, Inc, Foster City, CA, USA Background: Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) results in a 91% reduction in plasma tenofovir (TFV) exposure and has demonstrated less impact on surrogate markers of renal and bone health in multiple populations, but the clinical impact of these differences has not been fully characterized. Methods: Treatment naïve HIV-1 + adults were randomized 1:1 to a single tablet regimen coformulating elvitegravir, cobicistat, emtricitabine, with TAF (E/C/F/TAF) or TDF (E/C/F/ TDF) once daily in two double blind studies. Assessments of renal function included serum creatinine and estimated GFR by Cockcroft-Gault (eGFR CG ), and 4 measures of proteinuria: urine protein:creatinine (UPCR), urine albumin:creatinine (UACR), retinol binding protein:creatinine (RBP:Cr), and beta-2-microglobulin:creatinine (β-2-Mg:Cr). A post-hoc analysis of renal events in both studies through 96 weeks is described. Results: Combined, the two studies randomized and treated 1,733 participants. Through 96 weeks, change from baseline eGFR CG , UPCR, UACR, RBP:Cr, and β-2-Mg:Cr, all favored E/C/F/TAF (p<0.001). There were no discontinuations for renal adverse events (AE) or cases of proximal tubulopathy in the E/C/F/TAF arm, while 6 participants discontinued due to a renal AE and 1 participant had subclinical tubulopathy in the E/C/F/TDF arm. Fewer participants in the E/C/F/TAF arm had clinical events of new onset chronic kidney disease (CKD) and acute kidney injury (AKI, 50% decrease in eGFR CG ), though differences were not statistically significant, while the differences in participants with significant proteinuria (UPCR >200 mg/g) and albuminuria (UACR >30 mg/g) were statistically significant (Table). Conclusions: Through 96 weeks, biomarker analysis indicated that renal tubular function was less affected by E/C/F/TAF and that clinically significant renal events were less frequent in subjects receiving E/C/F/TAF compared with those treated with E/C/F/TDF. These data provide further support for the improved renal safety profile of TAF.

Table Participants, n (%)

E/C/F/TAF (N=866)

E/C/F/TDF (N=867)

p-­‐value

Renal Events leading to Discontinuation

0

6*

0.03

Subclinical tubulopathy

0

1**

NS

New onset CKD***

24 (2.8%)

32 (3.7%)

0.34

Acute Kidney Injury (AKI)****

3 (0.3%)

11 (1.3%)

0.06

UPCR >200 mg/g

27

42

0.030

UACR >30 mg/g

37

54

0.001

Medical History

Diabetes mellitus

25 (3%)

40 (5%)

-­‐

Hypertension

119 (14%)

147 (17%)

-­‐

Cardiovascular disease

10 (1%)

14 (1%)

-­‐

Hyperlipidemia -­‐ *blood creatinine increased, glomerular filtration rate decreased, renal failure, nephropathy, renal failure, fanconi syndrome acquired/glycosuria; **continued study drug at the Week 96 visit, but had confirmed abnormality in any 2 of the following at 2 consecutive post-­‐baseline visits: serum creatinine increase ≥0.4 mg/dL, ≥1 grade decrease in phosphatemia, normoglycemic glycosuria, or ≥2 grade increase in proteinuria; *** Chronic kidney disease is defined as subjects who have maintained low eGFR measured by CG (< 60 mL/min) or high UACR (urine albumin to creatinine ratio > 30 mg/g) for at least 90 days; **** 50% decline in eGFR CKD-­‐EPI 91 (11%) 104 (12%)

683

Clinical Risk Factors for Severe Tenofovir (TDF) Associated Renal Tubulopathy Lisa Hamzah 1 ; Sophie Jose 2 ; Aseel Hegazi 3 ; Angela Bailey 4 ; David Chadwick 5 ; DeborahWilliams 6 ; Margaret Johnson 7 ; Rachael Jones 8 ; Caroline Sabin 2 ; Frank A. Post 9 1 King’s Coll London, London, UK; 2 Univ Coll London, London, UK; 3 St Georges’ Hosp NHS Trust, London, UK; 4 Imperial Coll Hlthcare NHS Trust, London, UK; 5 South Tees Hosp NHS Fndn Trust, Middlesbrough, UK; 6 Brighton and Sussex Hosps NHS Trust, Brighton, UK; 7 Royal Free London NHS Fndn Trust, London, UK; 8 Chelsea and Westminster Hosp NHS Fndn Trust, London, UK; 9 King’s Coll Hosp NHS Fndn Trust, London, UK Background: Tenofovir (TDF) is associated with treatment-limiting renal tubulopathy (RT) which may manifest as proximal tubulopathy (PT) and/or acute tubular injury (ATI) on renal biopsy. The risk factors for RT remain poorly defined. Methods: Cases of TDF treatment limiting PT (≥2 of normoglycaemic glycosuria, hypophosphataemia <2 mg/dL, protein-creatinine ratio >300 mg/g) and/or ATI were identified retrospectively in 7 major HIV treatment centres contributing to the UK CHIC cohort. Poisson regression was used to investigate factors associated with RT; age; ethnicity; calendar year of TDF start (fixed covariates); hepatitis B/C status; CD4 cell count; HIV RNA; time on TDF and protease inhibitor (PI) based regimes (time-updated covariates) were considered for inclusion in the model. Results: 15983 subjects received TDF for >4 weeks, of whom 69 (0.4%) were diagnosed with treatment limiting RT between Oct 2002-July 2013 (PT: n=52; ATI: n=17) after a median (IQR) of 43 (26, 67) months of TDF exposure. At presentation, RT was characterised by normoglycaemic glycosuria (83%), hypophosphataemia (67%) and proteinuria (94%); eGFR decline >25% from baseline (start of TDF-containing regimen) was present in 54% of cases and exposure to ritonavir-boosted PI (44% lopinavir, 35% atazanavir, 16% darunavir, 5% other) in 83% of cases. Compared to subjects without RT, those with RT were older (mean age 45.7 vs. 40.7 years), more likely to be white (91% vs. 74%), male (90% vs. 80%), have a prior AIDS diagnosis (41% vs. 26%) and lower nadir CD4 cell count (median 129 vs. 190 cells/mm 3 ) (p<0.01 for all). No differences in baseline HBV/HCV status, HIV RNA and eGFR (95 vs. 96 mL/min/1.73m 2 ) were observed. In multivariable analysis, older age, ethnicity, time on TDF, CD4 cell count and PI based regimes remained independently associated with the development of RT (Table 1). Conclusions: Severe TDF-associated RT was uncommon in this cohort and accompanied by significant eGFR decline in only half of all cases. Age and PI co-administration were risk factor for the development of RT, and black ethnicity was protective. Baseline eGFR did not identify subjects at increased risk of treatment-limiting RT.

Poster Abstracts

282

CROI 2016