CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

and 4.8±0.9, 3.8±0.7, 6.3±0.7 log units higher, respectively, in CR. Heterogeneous drug exposure was seen by MSI, with highest accumulation for FTC, TFV, and RAL in the mucosa and lamina propria of the IL and CR, corresponding to high density of CD3+, CD4+, and CD8+ T cells. Only TFV was detected in BLT (IL: 2.5±1.5; CR: 3.0±1.9) and hu-HSC-Rag (IL: 11.4±10.3; CR: 60.0±26.2). IL and CR concentrations were 2.8±0.9 and 3.0±1.9 log units higher than plasma, respectively, for BLT and were 4.4±0.9 and 6.4±0.5 log units higher than plasma for hu-HSC-Rag. MSI quantitative response was similar to LC-MS/MS. Conclusions: This study is the first to map the biodistribution of multiple ARVs across intestinal tissue from different animal models. Observed differences in tissue concentrations cannot be extrapolated solely from plasma. By differentiating and quantifying ARV exposure within and across compartments, IR-MALDESI MSI can provide key information to evaluate ARV penetration into putative reservoir tissues and guide selection of optimal interspecies scaling of therapy.

448 Single-Dose Maraviroc Provides High Drug Levels in All Sites: No Gender Differences

Julie Fox 1 ; JuanManuelTiraboschi 1 ; Laura J. Else 2 ; Carolina Herrera 3 ; Deidre Egan 2 ; Alieu Amara 2 ; Akil Jackson 4 ; Robin Shattock 3 ; David J. Back 2 ; Saye Khoo 2 ; Marta Boffito 4 1 Guys and St Thomas’ NHS Fndn Trust, London, UK; 2 Univ of Liverpool, Liverpool, UK; 3 Imperial Coll London, London, UK; 4 Chelsea and Westminster Hosp NHS Fndn Trust, London, UK

Background: Oral pre-exposure prophylaxis (PrEP) is an effective prevention strategy against HIV-1 transmission. All completed PrEP clinical trials have tested ARV acting post-viral entry in the target cell. Maraviroc (MVC) showed no protection ex vivo following stat dosing [CROI 2105] and daily dosing studies are ongoing. Understanding the drugs levels achieved by stat dosing which failed to show ex vivo protection will help to inform future clinical trials of daily or “on demand” MVC PrEP. We present results of a PK dosing study of single oral dose MVC 300mg in all HIV exposure compartments and compare men and women, in a phase 2, multi-site, open label, randomised controlled clinical trial. Methods: 56 healthy adult female (n=26) and male participants (n=30) were randomized to a control arm (Arm A n=6 with tissue samples taken at two time points one month apart) or to one of 4 intervention arms (n=12 per arm) where a single oral MVC 300 mg dose was taken at two time points prior to sampling, one month apart (Arm B: first sampling 2 h post first dose and second sampling 24 h post second dose; Arm C: 4 h and 36 h; Arm D: 6 h and 48 h; Arm E: 12 h and 72 h). Sampling to determine MVC concentrations included blood, saliva and rectal fluid (RF) for all subjects. In addition, men provided a urethral swab and rectal tissue (RT) and women provided cervico-vaginal fluid (VF) and vaginal tissue (VT). MVC drug concentrations were measured by validated LC-MS/MS.

Table 1: Drug levels over a 72h duration following single oral dosing of Maraviroc 300mg

Correlation with plasma R 2

72h level compared to plasma

Cmax compared to plasma

Duration levels above MEC (hours)

Cmax (4hr) compartment-­‐ to-­‐ plasma ratio

AUC Ratio

Compartment to plasma

Plasma

-­‐

8

-­‐

-­‐

4.6x lower

Saliva (Males)

0.8149

0

0.2

0.22

0.7687

4

0.17

5.8x lower

1.3x higher

0.2

Saliva (Females)

Poster Abstracts

urethra

0.2442

60

116

116x higher 1.7x higher 157.7

VF (Swab)

0.2955

12

2.6

2.6x higher 24x higher 3.6

VF (Aspirate) 0.0927

6

0.4

2.5x lower

12x higher 1.24

VT

0.66

24

3.6

3.6x higher 26x higher 4.55

99x higher

718x higher

RF (Males)

0.0058 (NS)

72

99

427.1

RF (Females)

0.00007(NS)

72

102

102x higher

13754x higher

470.2

RT (Males) 0.114 Results: MVC Cmax was reached within 4 hours in all compartments, and exceeded suggested MEC (25 ng/ml). The highest Cmax level was in urethra (median 4 hr compartment-to-plasma ratio =116), RF (99 males and 102 females), RT (9.7 males), VT (3.6) and vaginal fluid (2.6): only saliva (0.22 males and 0.17 females) levels were lower than plasma at Cmax. MVC concentrations remained above the MEC of 25ng/ml until the following times: saliva (2h ), VF 12h, plasma 8h, VT 24h, urethra 60h, RF >72h, RT >72h. All drug levels were above EC90 of 0.5ng/ml for 72 h except saliva; most samples were <0.4 ng/ml at 72 h). At 72 h drug concentrations in compartments were higher than plasma: saliva (males 2 0.617) correlated in males and VF swab and VT (0.182) correlated in females. Conclusions: MVC concentrations greater than the EC90 occurred in multiple sites of HIV acquisition after single oral 300mg MVC. This suggests that MVC may be a suitable candidate for PrEP. However, the lack of inhibition in rectal and vaginal tissue previously reported suggests that either the ex 72 9.7 9.7x higher 60x higher 31.8

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CROI 2016