CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Methods: PHIV and PHEU youth from PHACS who had ever received ≥1 dose of the HPV4 vaccine and had available repository sera drawn ≥20 days following last dose were included. Antibodies to HPV 6, 11, 16 & 18 were measured at Merck laboratories on the most-recent sample. We compared seroconversion and geometric mean titer (GMT) between PHIV and PHEU by number of HPV vaccine doses received, after correcting for age at 1st and time since last dose. We used general linear models to identify factors associated with lower GMT in PHIV. Medical records were reviewed for diagnosis of abnormal cytology (≥ASCUS; AC) and genital warts (GW). Incidence rates (IR) per 100 person-years were calculated for AC/GW among sexually active girls. There were too few cases in boys (n=1) to study. Results: For 303 PHIV and 116 PHEU youth, mean (SD) age at 1st dose was 13.4 (2.7) and 12.4 (2.1) years; mean years from last dose to specimen was 3.1 (1.6) and 2.8 (1.4), respectively. PHIV were less likely to seroconvert than PHEU after 1 dose for HPV 11 (83% vs 95%), 16 (88% vs 99%) and 18 (62% vs 87%) (p<0.01); lower seroconversion for PHIV was also observed for 2 and 3+ doses (p≥0.05). Significant differences in GMT were seen for 1 and 2 but not 3+ doses for HPV 11, 16 & 18 in youth vaccinated at the target age of ≤13 years (Figure). This was also true for all ages. In multivariable models for vaccinated PHIV (≥1 dose), higher HIV RNA and older age at 1st dose were associated with lower GMT for all 4 HPV types. For those vaccinated prior to sexual debut, the IR (95% CI) for AC/GWwas 10.1 (5.8-16.5) in PHIV and 0.0 (0-5.9) in PHEU girls. There was no difference in IR in PHIV girls vaccinated prior versus after sexual debut. Conclusion: Vaccine effectiveness was much lower in PHIV girls than expected. Lower GMT for HPV 16/18, or presence of non-vaccine types, may partly explain this. Alternatively, mother-to-infant HPV transmission may have occurred as HIV-infected mothers have high rates of HPV shedding from genital/oral fluids. Studies are needed to assess HPV type infections. HPV vaccine trials in infants should be considered to optimize protection in PHIV. 806 DOLUTEGRAVIR PHARMACOKINETICS, SAFETY AND EFFICACY IN HIV+ CHILDREN 2 TO <6 YEARS OLD Theodore Ruel 1 , Edward Acosta 2 , Rajendra P. Singh 3 , Carmelita Alvero 4 , Kathleen George 5 , Stephanie Popson 6 , Cindy Vavro 7 , Rohan Hazra 8 , AndrewWiznia 9 , for the P1093Team 1 Univ of California, San Francisco, San Francisco, CA, USA, 2 Univ of Alabama at Birmingham, Birmingham, AL, USA, 3 GlaxoSmithKline, King of Prussia, PA, USA, 4 Harvard Univ, Boston, MA, USA, 5 FHI 360, Durham, NC, USA, 6 Frontier Sci & Tech Rsr Fndn, Inc., Amherst, NY, USA, 7 ViiV Hlthcare, Rsr Triangle Park, NC, USA, 8 NICHD, Bethesda, MD, USA, 9 Albert Einstein Coll of Med, Bronx, NY, USA Background: There is an urgent need for new drugs to treat HIV-1 infected children globally. Dolutegravir (DTG; S/GSK1349572) is a first-line agent for the treatment of HIV-1 infected adults due to its potency, high barrier to resistance, and tolerability; it promises a similar role in children. IMPAACT P1093 is an ongoing phase 1/2 open-label pharmacokinetic (PK) and dose finding study of DTG in age-defined pediatric cohorts (4 weeks to <18 years of age). Pediatric doses that provide DTG exposure comparable to that observed from 50 mg once daily in adults with acceptable safety and tolerability will be selected for each age cohort. Methods: Children ≥2 and <6 years old received DTG granules-in-suspension at doses of ~0.8 mg/kg once daily. At enrollment, DTG was either started as monotherapy or added to a stable-failing regimen. Intensive PK evaluations were completed after oral administration of weight-based dose between days 5-10; background regimen was then optimized. Safety, tolerability, and plasma HIV RNA levels were assessed at 4 weeks. Based on adult data, target individual exposures were AUC24h range of 37-67 mg*hour/L (primary) and C24h range of 0.77-2.26 mg/L (secondary). Results: Ten children (5 female) with median (range) age 4 years (2-5), and weight 14.6kg (9.9-17.1) were studied. Median baseline (BL) CD4+ cell % and HIV-1 RNA levels were 28.0 (IQR: 22.0, 31.4) and 4.8 log10(c/mL) (IQR:4.7-5.3), respectively. Mean (range) DTG dose was 0.87 mg/kg (0.58 to 1.06). DTG demonstrated moderate intersubject PK variability. The geometric mean (CV%) AUC24h and C24h were 44.7 (36%) mg*hour/L and 0.51 (68%) mg/L, respectively. HIV-1 RNA levels were < 400 c/mL in 8/10 and < 50 c/ml in 6/10 after 4 weeks of treatment, with median (range) change from BL of -3.1 log10(c/mL) (-3.4 to -2.1). DTG was well tolerated with no Grade 3 or Grade 4 AEs and no discontinuations due to AEs. Conclusion: DTG granules-in-suspension administered at ~0.8 mg/kg once daily in this cohort of children ≥2 to <6 years old achieved the target AUC24h; C24h was below the target but above the pharmacodynamic threshold reported in adults. DTG was virologically potent and well tolerated through week 4. These novel data will form the basis for dosing of DTG as dispersible tablets to be studied in this and younger age cohorts. 807 PHARMACOKINETICS OF RILPIVIRINE AFTER SWITCHING FROM EFAVIRENZ IN ADOLESCENTS Watsamon Jantarabenjakul 1 , Narukjaporn Thammajaruk 2 , Torsak Bunupuradah 2 , Jiratchaya Sophonphan 2 , Tim R. Cressey 3 , Angela Colbers 4 , David M. Burger 4 , Wanatpreeya Phongsamart 5 , Thanyawee Puthanakit 1 , Chitsanu Pancharoen 1 1 Chulalongkorn Univ, Bangkok, Thailand, 2 HIV Netherlands Australia Thailand Rsr Collab,Thai Red Cross AIDS Rsr, Bangkok, Thailand, 3 Prog for HIV Prevention and Treatment, Chiang Mai, Thailand, 4 Radboud Univ, Nijmegen, Netherlands, 5 Mahidol Univ, Bangkok, Thailand Background: Rilpivirine (RPV) has become a recommended non-nucleoside reverse transcriptase inhibitor (NNRTI), replacing efavirenz (EFV) due to fewer CNS effects. RPV pharmacokinetics (PK) data are limited among HIV-infected adolescents, particularly after switching from EFV, which potentially reduces rilpivirine exposure due to fading CYP3A inducing capacity. This study aims to describe the pharmacokinetic profile of RPV after switching from EFV in HIV-infected adolescents. Methods: HIV-infected adolescents aged 12-18 years, weighing ≥ 25 kilograms, treated with EFV-based antiretroviral therapy for ≥ 3 months and HIV RNA (VL) < 50 copies/ mL were switched from EFV to RPV. RPV 25 mg was taken once daily with a meal. At week 4, a PK profile was determined at 0 (pre-dose), 1, 2, 4, 5, 6, 9, 12 and 24 hours following an observed intake of RPV with a standardized meal (525 kcal). RPV concentrations were measured using a validated liquid chromatography-mass spectrometry (LC-MS) method (lower limit of quantification (LLQ) 4 ng/mL). RPV PK parameters were calculated using a non-compartmental method (Winnonlin 6.3) and compared with published data (the PAINT and pooled ECHO/THRIVE PK substudies). The target RPV C24h was > 40 ng/mL. EFV plasma concentrations were measured at weeks 0 and 4 (LLQ 100 ng/mL). VL was measured at weeks 12 and 24. Adherence was determined by pill count. Results: From January to June 2016, 20 adolescents were enrolled; 12 adolescents were male. Median age and weight (range) were 15.7 years (13.8-18.9) and 49 kilograms (31-93) respectively. Median baseline CD4 count (range) was 726 cells/mm3 (236 - 1145). Pre-switching regimens were TDF/3TC/EFV (90%) and AZT/3TC/EFV (10%). 16 adolescents had adherence of > 95% at their PK visit. The PK parameters of RPV are shown in Table 1. All values from the present study are comparable with the PAINT and ECHO/THRIVE sub- studies. Four adolescents (20%) had RPV C24h < 40 ng/mL, of which two reported poor adherence < 95%. Mean (SD) EFV plasma concentrations at week 0 was 2030 ng/ml (1037) which median (range) post-dose were 14 hours (2-16), but none had detectable levels at week 4. All evaluable adolescents had undetectable VLs (< 50 copies/ml) at weeks 12 and 24. Conclusion: HIV-infected adolescents switching from EFV to RPV had adequate RPV pharmacokinetic profiles and there was no virological failure detected at 24 weeks following switching.

Poster and Themed Discussion Abstracts

CROI 2017 349