CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

related physiological changes may alter ARV exposure. As limited data are available on PK of DTG during pregnancy, we present data on 3rd trimester DTG exposure in HIV-positive pregnant women. Methods: Multi-centre phase IV study in HIV infected pregnant women recruited in European HIV treatment centers. Patients treated with DTG 50mg QD during pregnancy had 24-hour PK profiling in the 3rd trimester (T3) and 3-7 weeks postpartum (PP). Paired cord (CB) and maternal (MB) blood samples were taken at delivery. Safety and virological data were collected. DTG plasma concentrations were determined with a validated LC-MS/MS method (LLOQ of 0.01mg/L). Geometric mean ratio (GMR) T3 PK versus PP with 90% confidence interval (CI) was calculated for AUC0-24h, Cmax and Ctrough. Results: 14 patients (10 black, 4 white/other), median (range) age 32 (21-42) yrs were included. 5 patients did not attend at postpartum, 1 patient was excluded from PK analysis because of invalid plasma concentrations. Median (range) GA at delivery was 39 wks (34-40); birth weight was 3258 gr (2120- 4040). Peri-delivery all patients had HIV VL<50cps/mL. 10 children were HIV un-infected (4 unknown status).One intrauterine fetal death (34 weeks GA) occurred due to cholestasis pregnancy syndrome, 1 infant had hypospadia, 1 had polydactily (as other members of her family). Two maternal hospital admissions occurred to exclude pre-eclampsia. Ratios T3/PP (GMR (90%CI), n=8) were: 0.88 (0.67-1.16) for AUC0-24h; 0.94 (0.75-1.18) for Cmax; 0.74 (0.50- 1.09) for Ctrough. One patient had a subtherapeutic Ctrough (<0.3 mg/L) in the T3 of pregnancy. Median (range) CB:MB ratio was 1.4 (1.1-1.8; n=8). Conclusion: Although variability is high, DTG AUC0-24h seems similar in pregnancy and postpartum. In T3 DTG plasma Ctrough was above the efficacy level of 0.3 mg/L in all but one patient. These findings, coupled with the undetectable viral loads at delivery, support standard dosing of DTG during pregnancy. 759 PREGNANCY ASSOCIATED WITH DECREASED SERUM ISONIAZID LEVELS IN WOMEN LIVING WITH HIV Kamunkhwala Gausi 1 , Paolo Denti 1 , Lubbe Wiesner 1 , Carole Wallis 2 , Carolyne Onyango-Makumbi 3 , Tsungai Chipato 4 , Gerhard Theron 5 , Sarah Bradford 6 , Diane Costello 7 , Renee Browning 8 , Nahida Chakhtoura 9 , Adriana Weinberg 10 , Grace Montepiedra 11 , Amita Gupta 12 , for the IMPAACT P1078 (TB APPRISE) Study Group Team 1 University of Cape Town, Cape Town, South Africa, 2 Lancet Laboratories, Johannesburg, South Africa, 3 Makerere University–Johns Hopkins University Research Collaboration, Kampala, Uganda, 4 University of Zimbabwe, Harare, Zimbabwe, 5 Stellenbosch University, Stellenbosch, South Africa, 6 FHI 360, Durham, NC, USA, 7 University of California Los Angeles, Los Angeles, CA, USA, 8 National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA, 9 NIH, Bethesda, MD, USA, 10 University of Colorado, Aurora, CO, USA, 11 Harvard T. H. Chan School of Public Health, Boston, MA, USA, 12 Johns Hopkins University School of Medicine, Baltimore, MD, USA Background: World Health Organization guidelines recommend that all people living with HIV from low- and middle-income countries (LMIC) where TB is endemic receive > 6 months of isoniazid (INH) preventive therapy, including pregnant women. INH plasma concentrations during pregnancy have not been well described. Methods: Pregnant women living with HIV infection (WLWH) at 14 to 34 weeks of gestation and on or starting ART were recruited from 8 LMIC into a phase IV randomized double-blind placebo-controlled multicenter international trial (IMPAACT P1078). The study had two arms: Arm A (immediately started on INH 300 mg daily for 28 weeks, then placebo) and Arm B (started on placebo, then switched to INH 300 mg daily at 12 weeks postpartum). A subset of women underwent intensive PK sampling (before INH dosing,1, 2, 4, 6, 8 and 12 h after), while the remaining women underwent sparse PK sampling (approximately 2 h after dose). Sampling occurred once at ≥ 2 weeks after recruitment and again at 12-21 weeks after delivery. NAT2 acetylator status was determined. INH PK was described by a two-compartment disposition model and elimination with a well-stirred liver model. Allometric scaling based on total body weight was applied on clearance, volume parameters, and hepatic plasma flow. Results: INH concentrations from 32 intensively and 752 sparsely-sampled women were included. 748 WLWH were on efavirenz-based ART. The median weight, age, and gestation at study entry were 67 (range 38,166) kg, 29 (18, 45) years, and 28 (14-34) weeks, respectively. After including NAT2 genotype, the model predicted a 67-kg woman to have clearance of 13.5, 38.3, and 71.3 L/h if slow, intermediate, or fast acetylator, respectively. After adjusting for

these factors, pregnancy was found to increase INH clearance by 23% (p<0.001) compared with postpartum, i.e. a 67-kg NAT2 intermediate acetylator would have an area under the time-concentration curve of 6.70 h.mg/L during pregnancy and 7.84 to during postpartum. Conclusion: INH exposure was decreased during pregnancy, likely due to increased clearance. Overall, INH clearance in all three NAT2 acetylator groups was higher compared to historical nonpregnant ranges, regardless of pregnancy. The consequences of this reduction in exposure on the safety and effectiveness of INH preventive therapy is being further investigated.

Poster Abstracts

760 VIROLOGICAL RESPONSE OF RAL-BASED REGIMEN AMONG HIV- INFECTED PREGNANT WOMEN IN BRAZIL Ana R. Pati Pascom , Mariana V. Meireles, Fernanda Rick, Filipe d. Perini,

Fernanda F. Fonseca, Adele Benzaken Ministry of Health, Brasilia (DF), Brazil

Background: Antiretroviral therapy (ART) led to important declines in the likelihood of HIV perinatal transmission. In 2017, Brazil implemented 3TC- TDF-RAL as the preferred regimen for HIV-infected pregnant women (HIPW), replacing 3TC-TDF-EFV. Our study aims to identify treatment-related factors associated with the virological response of RAL-based regimens compared with other regimens in HIPW on ART in Brazil, from January/2016 to June/2018. Methods: We analyzed programmatic data from HIPW aged 15 and over who had at least one antiretroviral prescription between January/2016 and June/2018, and had at least one viral load (VL) measurement between 60-180 days after this prescription. Logistic regression models were used to assess the likelihood of achieving viral load suppression (VLS), defined as last viral load (VL) count <50copies/mL within 60-180 days after first prescription during pregnancy. Results: A total 8,539 HIPW aged 15+ were included - median age 29 (IQR: 23–34) - of whom 948 (11%) were using TDF+3TC+RAL. Approximately 38% of HIPWwere treatment naïve (63% among HIPW using RAL-based and 49% among those on EFV-based regimen) and 42%were on ART for over two years. Overall VLS after 60-180 days after first prescription during pregnancy was 77% (82% among HIPW using TDF+3TC+RAL, 81% among those using TDF+3TC+EFV and 71% among those using TDF+3TC+LPV/r; p-value<0.001). In multivariable analysis, compared to HIPW using TDF+3TC+EFV, odds of VLS were 36% (aOR=1.358; CI95%: 1.105-1.668) higher among those using TDF+3TC+RAL and 49% lower among those using TDF+3TC+LPV/r (aOR=0.516; CI95%: 0.401-0.664). Other factors that increased the odds of achieving VLS were higher baseline CD4, lower baseline VL, lower time on ART, older age, and higher educational level. Conclusion: This study revealed the significant superiority of TDF+3TC+RAL compared to other regimens in suppressing viral load among HIPW. This superiority remains after controlling for certain sociodemographic and clinical characteristics, such as age and baseline CD4. Therefore, RAL-containing regimens are an important tool for the reduction of mother-to-child transmission.Interestingly, lower time on ART showed higher odds of achieving VLS, suggesting that non-naïve HIPWmay have been on suboptimal ART before or during pregnancy. Further research is needed to elucidate these findings.

CROI 2019 293