CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

are ongoing). Median age (range) was 31yrs (24-55), 1 was male, 4 self-reported as white and 5 as black African/Caribbean. DTG geometric mean ratios (GMR, DTG+DRV/c versus DTG alone) and 90% confidence intervals (CI) Cmax, AUC, C24h were 0.89 (0.79-1.02), 0.84 (0.73-0.96), 0.81 (0.66-0.98). DRV GMR (DRV/ c+DTG versus DRV/c alone, 90%CI) of DRV Cmax, AUC, C24h were 0.79 (0.71- 0.89), 0.87 (0.78-0.96), 0.82 (0.67-1.00), and of c Cmax, AUC, C24h were 0.86 (0.77-0.96), 0.88 (0.78-1.00) 0.98 (0.74-1.28), No grade 3 or 4 adverse events or laboratory abnormalities were observed. Conclusion: Concentrations of DTG during co-administration with DRV/c decreased by <20% and those of DRV with DTG by <21%, suggesting this combination can be prescribed safely in the treatment of HIV-1, including in patients harbouring resistance that benefit from optimal antiretroviral exposures. 469 PHARMACOKINETICS (PK) OF ETHINYLESTRADIOL/LEVONORGESTREL WITH ATAZANAVIR/COBICISTAT Emilie R. Elliot 1 , Elisa Bisdomini 1 , Laura Else 2 , Sujan Dilly Penchala 2 , Saye Khoo 2 , Graeme Moyle 1 , Nneka Nwokolo 1 , Marta Boffito 1 1 Chelsea and Westminster Hospital, London, UK, 2 University of Liverpool, Liverpool, UK Background: The combined oral contraceptive pill is the preferred method of contraception for many women. However, women living with HIV often need to dose adjust their contraception due to drug drug interactions with antiretrovirals. The concentration of ethinyloestradiol (EE) is increased by unboosted atazanavir (ATV), and decreased by ATV/ritonavir (r) (while progestin exposure is increased and may lead to side effects). Therefore, if an oral contraceptive is administered with ATV/r, it must contain at least 30μg of EE and strict compliance is necessary. However, data on ATV boosted by cobicistat (c) are not yet available. Methods: This phase 1, open label, 57 day, cross over, PK study, enrolled healthy female volunteers aged 18-35years, who were randomized to: i) group 1 received EE/levonogestrel (LNG, Microgynon) alone on days 1-21, EE/LNG (21 days) + ATV/c (14 days) in the co-administration phase (days 22-43) and ATV/c alone on days 43-56; ii) group 2 received ATV/c alone on days 1-21, EE/LNG (21 days) + ATV/c (14 days) in the co-administration phase (days 22-43) and EE/LNG alone on days 43-56. Each group underwent intensive PK sampling on days 14, 35 and 56, and EE/LNG concentrations were measured by LC/MS. Results: Of 14 healthy female volunteers screened, 11 were enrolled (1 was not eligible and 2 withdrew consent for personal reasons) and 6 completed all PK phases (5 withdrew consent because of gastrointestinal adverse events, fatigue or rash). Geometric mean ratios (GMR, with vs without ATV/c) and 90% confidence intervals (CI) of EE Cmax, AUC, C24h were 1.05 (0.92-1.19), 1.01 (0.83-1.22), 0.75 (0.60-0.93). GMR and CI (90%) of LNG Cmax, AUC, C24h were 0.83 (0.68-1.02), 0.92 (0.71-1.18), 1.01 (0.73-1.38). No grade 3 or 4 adverse events or laboratory abnormalities were observed in the women who completed the study. Conclusion: Our findings show that EE C24h decreased by only 25%with ATV/c (versus 37%with ATV/r in previous studies). For the first time LNG PK was investigated during co-administration with cobicistat and no significant changes in its concentrations were measured. 470 THE EFFECT OF ANTACIDS AND MULTIVITAMINS ON RALTEGRAVIR Helen Reynolds 1 , Joseph Lewis 1 , Deidre Egan 2 , Mas Chaponda 1 , Laura Else 2 , Justin Chiong 2 , Darren M. Moss 2 , David Back 2 , Andrew Owen 2 , Saye Khoo 2 1 Royal Liverpool University Hospital, Liverpool, UK, 2 University of Liverpool, Liverpool, UK Background: Raltegravir (RAL) absorption is influenced by antacids and gastrointestinal pH but it is unclear which of these mechanisms has the predominant effect on pharmacokinetic (PK) variability. We sought to characterise the effect of separate metals on the PK of RAL in healthy volunteers, and to determine the role of intestinal pH in this interaction. Methods: Open label, randomised, 3 arm, 5 phased controlled healthy volunteer study. Participants received a single dose (sd) of RAL (400 mg tablet), followed by RAL plus Maalox Plus (30 ml), sodium bicarbonate (1 g), Forceval (1tablet) or Maalox Plus (30 ml) 2 h prior to dosing without food, for 4 study days. The Heidelberg pH diagnostic systemwas used to collect gastrointestinal pH data. Blood samples and pH measurements were collected at 0, 1, 2, 3, 4, 6, 8, 10 and 12 h post dose. Plasma RAL concentrations were determined by validated LC-MS/MS, and PK parameters were estimated (WinNonLin). The primary

endpoint was a change in AUC, C12h, CMAX, or TMAX. Secondary endpoints were safety and tolerability of combinations, and correlation of pH with RAL PK. Results: Of fifteen participants randomised, three withdrew due to adverse events and two withdrew consent. All combinations were well-tolerated with one serious clinical event reported. A significant increase in RAL GMR (90 % CI) AUC0-12 (1.96; 1.04 – 3.72) and CMAX (2.07; 1.00 – 4.30) when RAL was administered with sodium bicarbonate was observed. A significant decrease in TMAX (GMR 0.58; 90 % CI 0.43 – 0.78) was seen when Maalox Plus was administered at the same time as RAL which was not observed when the antacid was taken 2 h prior to RAL. The multivitamin, Forceval, did not significantly affect the PK of RAL. PK data shown below are in keeping with previous studies. Optimal pH (6 to 8) for RAL solubility was achieved on administration of sodium bicarbonate or Maalox Plus (+/- 2 h). Conclusion: A significant increase in absorption of RAL in the presence of antacid lacking divalent cations (sodium bicarbonate) was observed which is likely to relate to the unopposed ‘boosting’ effect of a raised pH upon absorption and the known pH-dependent solubility of RAL. In conclusion, not all antacids influence the PK of RAL in the same way. RAL exposure was approximately doubled by sodium bicarbonate, whereas aluminium/magnesium hydroxide did not exhibit this effect.

Poster Abstracts

471 RAVIDASVIR PHARMACOKINETICS AND ARV DRUGS INTERACTIONS IN HCV+/-HIV INFECTED ADULTS Tim R. Cressey 1 , Soek-Siam Tan 2 , Hajjah Rosaida Hj Mohd Said 3 , Muhammad Radzi Abu Hassan 4 , Haniza Omar 2 , Tee Hoi Poh 5 , Chan Wah Kheong 6 , Suresh Kumar 7 , Satawat Thongsawat 8 , Kanawee Thetket 9 , Suparat Khemnark 10 , Anchalee Avihingsanon 11 , François Simon 12 , Isabelle Andrieux-Meyer 12 , Marc Lallemant 12 1 Program for HIV Prevention and Treatment, Chiang Mai, Thailand, 2 Selayang Hospital, Selayang, Malaysia, 3 Hospital Ampang, Ampang, Malaysia, 4 Hospital Sultanah Bahiyah, Alor Setar, Malaysia, 5 Hospital Tengku Ampuan Afzan, Kuantan, Malaysia, 6 University of Malaya Medical Centre, Kuala Lumpur, Malaysia, 7 Sungai Buloh Hospital, Sungai Buloh, Malaysia, 8 Chiang Mai University, Chiang Mai, Thailand, 9 Nakornping Hosp, Chiang Mai, Thailand, 10 Bamrasnaradura Infectious Diseases Institute, Bangkok, Thailand, 11 HIV–NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand, 12 Drug for Neglected Diseases Initiative, Geneva, Switzerland Background: Ravidasvir is a NS5A inhibitor that exhibits potent pan-genotypic inhibition of Hepatitis C virus (HCV) replication in vitro. Sofosbuvir plus ravidasvir (SOF/RDV) has shown excellent efficacy and safety in genotype 4 HCV-infected adults in Egypt. SOF/RDV is currently under study in HCV patients (+/- HIV) from South East Asia, where prevalent genotypes are 3, 1 and 6. We assessed the pharmacokinetics (PK) of RDV in this population and the impact of SOF/RDV treatment on the concentrations of commonly prescribed antiretrovirals (ARV) in HIV/HCV co-infected adults. Methods: Data were analyzed within the ongoing phase II/III trial assessing the efficacy, safety, tolerance, and PK of SOF/RDV in HCV (+/- HIV)-infected adults in Thailand and Malaysia (NCT01671982). To determine the PK of RDV in Asian adults, 25 HCV mono-infected patients had intensive steady-state 24-hour blood sampling. RDV PK parameters were calculated using non- compartmental analysis. To assess possible drug-drug interactions in HIV/ HCV co-infected patients, mid-dose or trough ARV drug concentrations were measured before (week 0) and after SOF/RDV treatment initiation (Week 4), and compared with Wilcoxon signed-rank tests.

CROI 2018 168