CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

1 University of California San Francisco, San Francisco, CA, USA, 2 University of Alabama at Birmingham, Birmingham, AL, USA, 3 GlaxoSmithKline, King of Prussia, PA, USA, 4 Harvard T.H. Chan School of Public Health, Boston, MA, USA, 5 FHI 360, Durham, NC, USA, 6 Frontier Science & Technology Research Foundation, Inc, Amherst, NY, USA, 7 ViiV Healthcare, Research Triangle Park, NC, USA, 8 Walter Reed Project– Kericho, Kericho, Kenya, 9 University of Zimbabwe, Harare, Zimbabwe, 10 National Institute of Child Health and Human Development, Bethesda, MD, USA, 11 NIAID, Bethesda, MD, USA, 12 Albert Einstein College of Medicine, Bronx, NY, USA Background: Dolutegravir (DTG, S/GSK1349572) is recommended as first- line treatment for HIV-infected adults and children 6 yrs and older due to its potency, high barrier to resistance, convenience and tolerability. A 5mg dispersible tablet (DTG-DT) formulation for children is being evaluated in IMPAACT P1093 (NCT01302847), an ongoing phase I/II open-label dose-finding study. The first DTG-DT dosing tested did not meet target drug exposures. Here we present the intensive pharmacokinetic (PK), 4-week safety and efficacy data of higher dosing for DTG-DT in children ages 6 mo to <6 yr. Methods: Enrollment was stratified into two age cohorts of 10 children (≥6 mo to <2 yr and ≥2 to <6 yr). DTG-DT was dosed once daily by WHO weight-band (6 to <10kg: 15mg, 10 to <14kg: 20mg, 14 to <20kg: 25mg). Children received DTG-DT alone or added to stable-failing or empiric initial background regimens. PK sampling was completed between days 5-10 under fasting conditions. Background regimens were optimized based on enrollment HIV genotypes. Safety, tolerability, and plasma HIV-1 RNA levels were assessed through 4 weeks. Based on adult data, exposure targets were geometric mean (GM) (range) AUC24h of 46 (37-134) mg.h/L and C24h of 995 (697-2260) ng/mL. Results: Twenty children (10 female) with median (range) age 22 months (6, 71), and weight 9.4 kg (6.5, 17.5) were studied. Median baseline CD4+ cell % and HIV-1 RNA levels were 27.3 (IQR: 22.0, 36.9) and 4.3log10 (c/mL) (IQR: 3.3, 5.3). For age cohorts of ≥6 mo to <2 yr and ≥2 to <6 yr, the GM(CV%) AUC24h(CV%) was 70.2 (49.6) mg.h/L and 59.0 (62.2) mg.h/L, C24h was 1094(70.4) ng/mL and 791 (105) ng/mL, and Cmax was 5702(37) ng/mL and 5181 (44) ng/mL, respectively. C24h levels varied from 104 to 4579 ng/mL (figure). DTG was well tolerated, with no drug-related Grade 3 or 4 AEs or discontinuations. HIV-1 RNA levels were <400 c/mL in 16/20 and <50 c/ml in 8/20 participants after 4 weeks of treatment, with median decrease from BL of 2.38 log10 (c/mL) (IQR: 1.36, 3.11). Conclusion: The tested dosing of DTG-DT met pre-specified AUC24h and C24h targets for age-cohorts children 6 mo to <6 yr old, even with moderate intra- participant variability. DTG was virologically potent and well tolerated through week 4. With the additional PK, long-term safety and efficacy data currently being collected, these novel results will form the basis of safe and efficacious WHO weight-band dosing recommendations for DTG-DT in children.

1 Radboud University Medical Center, Nijmegen, Netherlands, 2 MRC Clinical Trials Unit at UCL, London, UK, 3 University of Zimbabwe, Harare, Zimbabwe, 4 Joint Clinical Research Centre, Kampala, Uganda, 5 Joint Clinical Research Center, Lubowa, Uganda, 6 Baylor College of Medicine Children’s Foundation, Kampala, Uganda Background: Weight band pharmacokinetic (PK) substudies within the ongoing phase III ODYSSEY-trial evaluate PK and safety of simplified weight band-based dosing of dolutegravir (DTG) for children on first-line and second- line antiretroviral therapy (ART). This substudy assessed PK and safety of DTG adult film-coated tablets (FCT) and pediatric dispersible tablets (DT) in children weighing 20 to <25kg who make up a high proportion of children living with HIV. DT have higher bioavailability compared to FCT in adults (ratio 1.5-1.8). Methods: Steady state 24h DTG PK profiles in fasted children taking once- daily DTG 50mg FCT or 30mg DT (6x5mg) were recorded ≥7 days after switch from DTG 25mg FCT. Blood was sampled at t=0, 1, 2, 3, 4, 6 and 24h and DTG plasma concentrations were measured with a validated UPLC-MS/MS method. Non-compartmental PK analysis was performed to calculate PK parameters (WinNonlin 8.1). Results were compared to those in HIV-positive adults taking DTG 50mg FCT once/twice daily, and children 20 to <25kg on 25mg FCT once daily (Table). Safety was evaluated at 2, 4, 12, and then every 12 weeks. Results: 15 African children were enrolled in Zimbabwe and Uganda (Table). The 50mg FCT (n=7) and 30mg DT (n=8) doses both resulted in geometric mean (GM) C trough values comparable to adults on DTG 50mg FCT once-daily and were higher compared to children 20 to <25kg on 25mg FCT. GM AUC 0-24h for both doses was in-between values observed in adults taking DTG 50mg once daily and 50mg twice daily. GM C max on both doses exceeded adult GM values for DTG 50mg once and twice daily. DTG 50mg FCT in this weight band provided a lower GM C max compared to 30mg DT. After median (IQR) follow-up of 11.9 (4.0-11.9) and 5.1 (3.0-11.8) weeks on 50mg FCT and 30mg DT respectively, no children experienced grade 3/4, serious adverse events or discontinued DTG. Conclusion: Daily DTG 50mg FCT and 30mg DT provide similar and appropriate PK profiles for children 20 to <25kg. Short-term safety data are reassuring and, provided ongoing longer-term safety is acceptable, these results support use of either 50mg FCT or DTG 30mg DT in this weight band. Adult DTG 50mg FCT could offer a practical and accessible dosing strategy for children weighing 20 to <25kg allowing rapid alignment of WHO-preferred ART regimens for adults and children ≥20kg in low- and middle-income countries.

Poster Abstracts

831 RECENT HIV INFECTION SURVEILLANCE AMONG ADOLESCENT GIRLS AND YOUNG WOMEN IN MALAWI Danielle Payne 1 , Andrew D. Maher 2 , Kathryn Curran 3 , Elfriede Agyemang 3 , Evelyn Kim 1 , Franklin Kilembe 4 , Trudy Dobbs 3 , Innocent Zungu 1 , Bharat S. Parekh 3 , Suzie Welty 2 , Dalitso Midiani 5 , Andrew F. Auld 1 , Rose Nyirenda 5 , George Rutherford 2 , Andrea A. Kim 3 1 CDC Malawi, Lilongwe, Malawi, 2 University of California San Francisco, San Francisco, CA, USA, 3 CDC, Atlanta, GA, USA, 4 Global AIDS Interfaith Alliance, Blantyre, Malawi, 5 Malawi Department of HIV and AIDS, Lilongwe, Malawi Background: Tests for recent infection can distinguish recent (in the last 12 months) from long-term HIV infection, and have been used to estimate HIV incidence in population-based surveys but have had limited application in programmatic settings. We implemented a novel surveillance system to detect

830LB ADULT DOLUTEGRAVIR 50MG TABLETS IN CHILDREN LIVING WITH HIV WEIGHING 20 TO <25KG Pauline Bollen 1 , Anna Turkova 2 , Hilda Mujuru 3 , Elizabeth Kaudha 4 , Abbas Lugemwa 5 , Pauline Amuge 6 , Angela Colbers 1 , Cecilia Moore 2 , Anna Parker 2 , Victor Musiime 4 , James G. Hakim 3 , Deborah Ford 2 , Diana Gibb 2 , David M. Burger 1 , for the ODYSSEY trial team

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