CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

an E

equation with an intercept, E 0

of –0.417 log

c/mL, E

of –1.334 log

10 c/mL, and EC ) was ~1.7 log 10

50 of 227ng/mL. A short-term response plateau was achieved at BMS-955176 C 24

≥500ng/

max

10

max

mL. Consistent with clinical results, predicted maximum response (E 0 + E max c/mL decline in HIV-1 RNA. Conclusions: This ER analysis from the Phase 2a POC study demonstrated maximum viral load decline at BMS-955176 C 24 informed dose selection for the ongoing Phase 2b program, which assesses BMS-955176 safety/efficacy at exposures similar to oral suspension doses ≥40 mg.

≥500ng/mL with 10 days of monotherapy. These results

426 Predicting Drug Discontinuation in TDF-Tolerant Patients: A Prospective PK/PG Study Andrea Calcagno 1 ; Jessica Cusato 1 ; Letizia Marinaro 2 ; Martina Fiumanò 1 ; Marco Simiele 1 ; Micol Ferrara 1 ; Chiara Alcantarini 1 ; Antonio D’Avolio 1 ; Giovanni Di Perri 1 ; Stefano Bonora 1 1 Univ of Torino, Torino, Italy; 2 Univ of Torino, Turin, Italy Background: Proximal tubular toxicity has been reported in tenofovir disoproxil fumarate (TDF) receiving HIV-positive patients; demographic, therapeutic, pharmacokinetic and pharmacogenetic variables might predict such toxicity. Aim of the study was to describe the prevalence of tubulopathy and the impact on risk of drug discontinuation. Methods: Adult HIV-positive patients on TDF-containing HAARTs (>6 months), with estimated creatinine clearance (eCrCl) >60 ml/min and no significant comorbidity (diabetes or urinary tract abnormalities) were included. Tenofovir (TFV) plasma and urinary concentration were measured through validated HPLC/MS-MS methods. Urinary retinol binding protein (uRBP) was measured (ELISA) and age-defined urinary creatinine corrected values were used (uRBP/uCr <130 in patients aged <50 years and <172 in older ones) to identify tubulopathy. Single nucleotide polymorphisms in the following genes were analysed through real-time PCR: ABCB1, ABCC2, ABCC4, ABCC10, SLC22A6, SLC28A2. Patients were followed prospectively and drug discontinuations were categorized as renal toxicity (eCrCl <60 ml/min, nephrolithiasis, persisting 24-hour urine abnormalities) or others. Results: 310 patients (73.2%male, 84.8% Caucasian) were enrolled. Age, BMI and eCRCL were 45.5 years (39.1-52.2), 23.5 kg/m 2 (21.7-26.2) and 90.9 ml/min (79.6-107.3). Abnormal uRBP/uCr was observed in 145/288 patients (50.3%) while 24-hour proteinuria (>300 mg) in 10/92 patients (10.9%): both were associated with low TFV urinary output (p=0.008 and p=0.005). Over a median follow up of 20.6 months (16.8-26.8) in 24 patients (out of 32, 75%) TDF was interrupted for renal toxicity: at univariate log-rank analysis it was associated with increasing age (p=0.031), male gender (p=0.004), PI use (p=0.001), eCrCl (p=0.055), tenofovir urinary/plasma ratio <350 (p=0.018), ABCB1 TT genotype (p=0.035) and SLC28A2 T allele (p=0.059). Multivariate step-wise Cox regression identified age (p=0.005), male gender (p=0.047), PI use (p=0.002) and ABCB1 TT genotype (p=0.0042) as independent predictors of tenofovir discontinuation. Conclusions: Subclinical tubular toxicity was detected in half of otherwise TDF-tolerant patients and was associated with low TFV urinary output; however, it did not predict further worsening of glomerular or tubular function requiring TDF withdrawal. Age, male gender, PI use and pharmacogenetic markers predicted TDF discontinuation for renal toxicity. 427 Random Lopinavir Concentrations Predict Resistance on Lopinavir-Based ART Richard G. Court 1 ; Michelle Gordon 2 ; Annemie Stewart 3 ; Karen Cohen 1 ; Gary Maartens 1 1 Univ of Cape Town, Cape Town, South Africa; 2 Nelson R Mandela Sch of Med, Univ of Kwazulu-Natal, Durban, South Africa; 3 Clinical Rsr Cntr, Univ of Cape Town, Cape Town, South Africa

Poster Abstracts

Background: Considering that most patients who experience virologic failure (VF) on lopinavir-based antiretroviral therapy (ART) fail due to poor adherence rather than resistance, an objective adherence measure could limit costs by rationalizing the use of genotype antiretroviral resistance testing (GART) in countries with access to third line ART. Methods: We conducted a cross-sectional study on patients at two large ART clinics in Durban, South Africa experiencing VF (HIV RNA >1000 copies/mL) on lopinavir-based ART who had GART done. An association of major protease inhibitor (PI) resistance mutations with random lopinavir concentrations was assessed. Results: 134 patients, including 31 children, were included in the analysis. The median age in years was 35.0 (IQR: 24.6 – 41.2) and the median duration on lopinavir was 24.8 months (IQR: 12.8 – 34.2). The predominantly used NRTI backbone was AZT and DDI (50.8%). The median log viral load at time of genotype was 4.6 (log 10 copies/mL). The prevalence of ≥1 major PI mutation was 21%. On

multivariate analysis, the following were associated with the presence of a major PI resistance mutation: random lopinavir concentration above the recommended minimum trough of 1mg/mL and male sex. Conclusions: Random lopinavir concentrations are strongly associated with the presence of major PI mutations. Access to costly GART could be restricted to patients with lopinavir concentrations above the recommended minimum trough.

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CROI 2016

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