CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

sought to determine an EFV dose and study its safety and efficacy in HIV+ children from TB-endemic countries. Here we present the data for HIV+/TB+ infants 3 months to two years. Methods: IMPAACT P1070 is a prospective, Phase I/II open-label 24 wk trial of EFV in HIV+ children 3-<36 months with or without TB. Using CYP2B6 genotype-directed, weight- band dosing subjects initiated EFV & 2 NRTIs at EFV doses of ~65mg/kg as opened capsules once-daily. These dosages are ~ 30% greater than those used in TB-uninfected infants (results not shown). CYP2B6 genotype was drawn at baseline and intensive PK was performed at wk 2. Doses were adjusted if outside the target AUC (35 -180 mcg*hr/mL). HIV-1 RNA and toxicity labs were drawn every 4-8 wks. Results: 8 subjects 3 to <24 months receiving ATT (5 males, med age 13 months (10-17.5 IQR)) enrolled with median follow up of 24wk (18-25 IQR). All 8 were CYP2B6 GG/GT and initiated EFV at a median dose of 64.9 mg/kg (57.7-67.7 IQR). The median EFV AUC was 92.87 mcg*h/mL ( 40.9-160.14 IQR). 6/8 subjects met the wk 2 AUC target, 1 was below (due to non-adherence) and 1 above (achieved the target range after dose reduction). Possibly treatment-related toxicities ≥ gr 3 occurred in 1 subject (gr 4 SGPT/SGOT) at wk24. This resolved after discontinuing EFV, TMP/SMX and ATT and did not recur when EFV was restarted. 2 subjects discontinued EFV before wk24; 1 due to difficulty administering EFV and 1 for poor adherence. Baseline median RNA was 5.9 log10 copies(cps) /ml (5.5-6.1 IQR) and 8/8 (100% ITT; 95%CI 63-100%) achieved either ≥1 log 10 drop from baseline RNA or <400 cps/ml by week 8; 5/6 subjects who completed 24 wks had RNA <400 cps/ml and 1/6 had 404 cps/ml. Conclusions: Amplified dosing (~65.9 mg/kg) in co-infected HIV+/TB+ children with CYP2B6 GG/GT genotype produced therapeutic EFV concentrations in most children <2 yrs with excellent safety and virological outcomes. However, a lower dose is likely to be needed in this age group taking ATT with slow CYP2B6 metabolism, as is required in young children without ATT. Optimal exposure of EFV can be achieved in HIV+/TB+ children <2yrs but requires pretreatment genotyping. 459 Interaction of Darunavir/Ritonavir and Darunavir/Cobicistat With Rifampicin In Vitro Owain Roberts ; David J. Back; Saye Khoo; Andrew Owen; Marco Siccardi Univ of Liverpool, Liverpool, UK Background: Clinical management of HIV patients co-infected with tuberculosis (TB) is hampered by drug-drug interactions (DDIs) that limit therapeutic options. Rifampicin (RIF), an important component of anti-TB treatment regimens, is a strong inducer of key metabolic enzymes, and thus can negatively affect antiretroviral bioavailability, clearance and efficacy. The aim of this study was to quantify DDIs between RIF and cobicistat (COBI)-boosted darunavir (DRV), and to compare this with DDIs between RIF and ritonavir (RTV)- boosted DRV (DRV/r) using an in vitro approach. Methods: Cryopreserved primary human hepatocytes plated on collagen-coated cell culture plates were overlaid with Geltrex™ matrix and were treated with RIF (10 µM) alone, or together with RTV (0.1–10 µM) or COBI (0.13–12.76 µM) in Williams’ Medium E incubation medium, or were left untreated. Test compounds were replenished each day for a total of 72 hours, after which cells were treated with test compounds together with DRV (5 μM) for one hour. Resultant DRV concentrations were quantified using HPLC-UV. Apparent intrinsic clearance (CL int.app. ) of DRV was calculated, and expressed as the mean ± SD (μl/min/10 6 hepatocytes) of a total of three biological replicates, using cells obtained from three separate donors. Results: Under control conditions where cells treated with DRV alone, DRV CL int.app. was 13.2 ± 1.5 μl/min, while following incubation with 10 μM RIF, DRV CL int.app. increased to 20.5 ± 4.7 μl/min (+55% compared to control). Inclusion of 1 μM RTV, or 1.28 μM COBI, was sufficient to overcome the effect of 10 μM RIF , reducing DRV CL int.app. by -15% and -3% compared to control, respectively. Using regression analysis, log 10 RTV and COBI concentrations were found to be associated with percentage inhibition of DRV CL int.app. (β = 20.7, p = 0.001 and β = 11.3, p = 0.001, respectively; Figure 1 ). Conclusions: DDIs between RIF and both DRV/r and DRV/COBI were quantified using an in vitro human hepatocyte model. RIF-induced elevations in DRV CL int.app. were overcome by co-incubation with RTV or COBI. RTV- and COBI-mediated attenuation of RIF-enhanced DRV CL int.app. occurred in a concentration-dependent manner, but RTV reversed RIF induction more strongly than COBI. These results provide an insight into the relative effect of RTV and COBI as pharmacoenhancers in the presence of RIF, and can be used to inform pharmacokinetic models for optimising regimens in patients receiving concurrent antiretroviral and anti-TB therapy.

Poster Abstracts

460 HIV-1 Attachment Inhibitor Prodrug BMS-663068: PK Assessment With Rosuvastatin Ishani Landry; BlisseVakkalagadda; Susan Lubin; Michael Hesney; JianWang; Frank LaCreta; Timothy Eley Bristol-Myers Squibb, Princeton, NJ, USA

Background: BMS-663068 is a prodrug of BMS-626529, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+ T cells. In the HIV-infected population, hypercholesterolemia is a prevalent comorbidity and increases the risk of cardiovascular disease. Thus, BMS-663068 may be coadministered with statins. In vitro, BMS-626529 inhibits proteins that transport statins, specifically OATP1B1, OATP1B3, and BCRP (IC 50 values of 32μM, 16.0μM, and 12.4μM, respectively), suggesting that BMS-626529 has the potential to affect the pharmacokinetics (PK) of statins. This study assessed the effect of multiple doses of BMS-663068 on the PK of rosuvastatin, a probe substrate for OATP and BCRP.

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CROI 2016