CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

Results: Based on an analysis of in vitro potency data, Ph1b POC efficacy, and Ph2 data, a dose of ISL 0.75 mg QD is expected to provide maximal efficacy in treatment-naïve PLWH, and also be highly efficacious in virologically suppressed and HTE participants. Based on the in vitro potency and supported by the POC data for ISL, the expected concentrations of ISL-TP after a single 0.75 mg dose are sufficient to suppress both wild-type virus and HIV-RT resistant variants. ISL-TP accumulates after multiple dosing resulting in higher IQ at steady state. Simulations show that most patients would rapidly surpass the IQ threshold for all common HIV-RT resistant variants. Conclusion: ISL 0.75 mg QD, in combination with DOR 100 mg QD, is appropriate for further evaluation in a development program consisting of treatment-naïve, virologically-suppressed, and HTE PLWH. 463 FOSTEMSAVIR EXPOSURE-RESPONSE RELATIONSHIPS IN TREATMENT- EXPERIENCED HIV PATIENTS Ridhi Parasrampuria 1 , Navin Goyal 1 , Katy Moore 2 , Peter Ackerman 3 , Cyril C. Llamoso 3 , Keith Barker 4 , Mindy Magee 1 1 GlaxoSmithKline, Collegeville, PA, USA, 2 ViiV Healthcare, Research Triangle Park, NC, USA, 3 ViiV Healthcare, Branford, CT, USA, 4 GlaxoSmithKline, Uxbridge, UK Background: Fostemsavir (FTR) is an oral prodrug of its active moiety, temsavir (TMR), an investigational HIV-1 attachment inhibitor. Phase 3 efficacy exposure- response (ER) relationships in heavily treatment-experienced (HTE; multi-drug resistant) HIV-1 patients with FTR 600 mg BID, and safety ER relationships from Phase 2b (TE) and P-3 (HTE) with FTR 400, 600, 800 mg BID and 600, 1200 mg QD were evaluated. Methods: Individual PK parameters estimated from a population PK model were used to evaluate ER relationships. Efficacy endpoints: change in plasma HIV-1 RNA from Day 1 to 8 (functional monotherapy), >0.5 and >1.0 log 10 decrease in HIV-1 RNA on Day 8 and at Week 24, proportion of subjects with HIV-1 RNA <40, <200 and <400 copies/mL. In addition, covariates of virologic (TMR IC 50 and gp120 substitutions), immunologic (CD4+ T-cell count), and demographic factors as predictors of virologic response were investigated. Simulations were conducted to predict virologic responses on Day 8 under different extrinsic and intrinsic factors. Safety endpoints included: change from baseline in AST, ALT, CPK, SCr, QTcF up to Week 24, and occurrence of rash. Following graphical exploration, linear, inhibitory Emax and logistic regression models were explored. Results: ER relationship was established between TMR C tau and change in plasma HIV-1 RNA from Day 1 to 8, however, relationship was shallow and highly variable. Baseline HIV-1 RNA and CD4+ count were covariates; the higher the baseline value, the greater the reduction. Addition of IC 50 (as C tau /PBIC 50 ) did not improve the relationship. Model predicted probability of >0.5 and >1 log 10 decrease in HIV-1 RNA on Day 8 was 80% and 58%, at plasma TMR C tau of 500 ng/mL with median baseline HIV-1 RNA (4.65 log 10 copies/mL) and CD4+ (>20 cells/mm 3 ). At Week 24, no relationship could be established between plasma TMR C tau and HIV-1 RNA or CD4+ counts. Simulations showed no clinically relevant changes in Day 8 virologic response (Table 1). There was no clear correlation seen between TMR exposure and the safety endpoints explored. Conclusion: Higher reduction in plasma HIV-1 RNA from Day 1 to 8 with increase in TMR C tau in HTE HIV-1 patients on FTR 600 mg BID was observed. Simulations showed the impact of food, co-medications, and body weight were not clinically relevant.

464LB BICTEGRAVIR DISTRIBUTION AND BICTEGRAVIR/FTC/TAF ACTIVITY IN GENITAL TRACT AND RECTUM Arkaitz Imaz 1 , Juan M. Tiraboschi 1 , Jordi Niubo 1 , Javier Martinez-Picado 2 , Mackenzie L. Cottrell 3 , Pere Domingo 4 , Ivan Chivite 5 , Eugènia Negredo 6 , Sandra Morenilla 1 , Victor Urrea 2 , Sofia Scevola 1 , Benito Garcia 1 , Angela Kashuba 3 , Daniel Podzamczer 1 1 Bellvitge University Hospital, Barcelona, Spain, 2 IrsiCaixa Institute for AIDS Research, Badalona, Spain, 3 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 4 Hospital Sant Pau, Barcelona, Spain, 5 Hospital de Sant Joan Despí Moisès Broggi, Sant Joan Despí, Spain, 6 Fundació Lluita Contra la Sida, Badalona, Spain Background: Antiretroviral distribution in the genital tract (GT) and rectum is required to suppress HIV replication within these compartments. Pharmacokinetics and HIV decay in the GT and rectum have not yet been described for the new integrase inhibitor bictegravir (BIC). Methods: Prospective study of HIV-1–infected, ART–naive males (n=15) and females (n=8) initiating BIC/F/TAF 50/200/25 mg. HIV-1 RNA was measured (Abbott RealTime HIV-1; quantification limit 40 c/mL) in blood plasma(BP) as well as in seminal plasma (SP) and rectal fluid (RF) in men, and cervicovaginal fluid (CVF) in women, at baseline (BL), days 3, 7, 14 and 28, and weeks 12 and 24. HIV-1 RNA decline between timepoints in SF and RF were compared to BP. Total BIC concentrations were quantified in BP, SP, RF, rectal tissue (RT) and CVF at 24 hours post dose (C 24h ) on day 28 and week 12 using a validated LC-MS/MS assay. Results: Median (range) BL characteristics were: age 30 (20-57) yrs; CD4 419 (9-1165) cells/μL; BP HIV-1 RNA 4.89 (3.17-6.10) log 10 c/mL. HIV-1 RNA was >40 c/mL at BL in SP, RF and CVF in 12/15, 13/15 and 4/8 individuals, with a median(range) of 3.74 (2.29-4.74), 4.29 (2.75-5.22) and 2.56 (1.61-3.56) log 10 c/ mL. HIV-1 RNA decrease was significantly lower in SP compared to BP up to day 14 with no statistically significant differences thereafter, whereas no differences were observed between RF and BP. Of those with HIV-1 RNA >40 c/mL in SP, RF and CVF at BL, 42%, 77% and 100% had undetectable HIV-1 RNA at day 14, and 92%, 92% and 100%, respectively, at day 28, whereas 47% of men and 37% of women had HIV-1 RNA >40 c/mL in BP at day 28. In men, median(range) BIC C 24h in BP, SP, RF and RT were 2640 (424-10300) ng/mL; 65.5 (20.1-923) ng/mL; 23.4 (4.5-336.9) ng/swab; and 74.1 (6.0-478.5) ng/g, respectively. In women, BIC C 24h in BP and CFV were 2320 (834-5770) ng/mL and 61.6 (14.4-1760.2) ng/mL. On average BIC C 24h in SP,CVF and RT (assuming tissue density=1g/ml) were 2.7%, 2.8% and 2.6% of BP C 24h . Total BIC concentrations exceeded the EC 50 for wild type HIV-1 (1.1 ng/mL) in all compartments. Conclusion: BIC/F/TAF resulted in rapid HIV-1 RNA decay in GT and rectum. Total BIC concentrations in these compartments exceed the EC 50 for wild-type HIV-1. 465LB SAFETY AND PHARMACOKINETICS OF INTRAVENOUS VRC01LS AND 10-1074 IN YOUNG CHILDREN Edmund V. Capparelli 1 , Gbolahan Ajibola 2 , Kenneth Maswabi 2 , Kara Bennett 3 , Michael D. Hughes 4 , Molly Pretorius Holme 4 , Kelly Seaton 5 , Adrian B. McDermott 6 , Marina Caskey 7 , Lucio Gama 6 , Patrick Jean-Philippe 8 , Joseph Makhema 2 , Daniel R. Kuritzkes 9 , Mathias Lichterfeld 10 , Roger L. Shapiro 4 1 University of California San Diego, La Jolla, CA, USA, 2 Botswana Harvard AIDS Institute Partnership, Gabarone, Botswana, 3 Bennett Statistical Consulting, Inc, New York, NY, USA, 4 Harvard T.H. Chan School of Public Health, Boston, MA, USA, 5 Duke University, Durham, NC, USA, 6 Vaccine Research Center, NIAID, Bethesda, MD, USA, 7 The Rockefeller University, New York, NY, USA, 8 NIAID, Bethesda, MD, USA, 9 Brigham and Women's Hospital, Boston, MA, USA, 10 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA Background: Early-treated HIV+ children may be ideal candidates for use of broadly neutralizing monoclonal antibodies (bNAbs) as an alternative to antiretroviral treatment (ART), but pediatric bNAb data to date has been limited to subcutaneous administration of VRC01/LS during infancy. In preparation for a trial of dual bNAb use as a treatment alternative, we evaluated the safety and pharmacokinetics (PK) of monthly VRC01LS or 10-1074 dosed intravenously among HIV+ children on suppressive ART. Methods: The PK phase of the Tatelo Study in Botswana enrolled 12 children who had received ART continuously from< 7 days through at least 96 weeks of life, and had HIV-1 RNA < 40 copies/mL for at least 24 weeks prior to entry. While continuing ART, 6 participants received VRC01LS (30 mg/kg load at day 0, then 10mg/kg at days 28 and 56) and 6 participants received 10-1074 (30 mg/kg on days 0, 28 and 56). bNAb concentrations were tested 18 times over 12 weeks using murine anti-VRC01 and anti-10-1074 antibodies.

Poster Abstracts

CROI 2020 163