CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

818 Pharmacokinetics, Safety, and Efficacy of Maraviroc in Pediatric Patients With R5 HIV Carlo Giaquinto 1 ; Muthuhadini P. Mawela 2 ; Kulkanya Chokephaibulkit 3 ; Annie Fang 4 ; Elna van der Ryst 5 ; Srinivas RaoValluri 4 ; ManoliVourvahis 4 ; Rebecca Zhang-Roper 6 ; Lynn McFadyen 7 ; Jayvant Heera 8 1 Univ of Padova, Padova, Italy; 2 Sefako Makgatho Hlth Scis Univ, Pretoria, South Africa; 3 Siriraj Hosp, Mahidol Univ, Bangkok, Thailand; 4 Pfizer, Inc, New York, NY, USA; 5 Pfizer Inc, The Rsr Network, Sandwich, UK; 6 GSK, Stockley Park, UK; 7 Pfizer, Inc, Sandwich, UK; 8 Pfizer, Inc, Groton, CT, USA Background: Maraviroc (MVC) is a CCR5 antagonist approved to treat adults infected with CCR5-tropic (R5) HIV-1. Study A4001031 was conducted to evaluate the pharmacokinetics (PK), safety and efficacy of MVC in treatment-experienced (TE) pediatric patients. Methods: This is an open-label, two-stage (stage 1: dose-finding; stage 2: safety/efficacy), age-stratified, non-comparative, multicenter study to evaluate the PK, safety and efficacy of MVC plus optimized background therapy (OBT) in TE children infected with R5 HIV-1. A total of 103 participants were enrolled into one of four age/formulation cohorts (Table) and dosed twice daily. Initial doses were determined by body surface area (BSA) and OBT, based on interactions with MVC in adults. Dose adjustment and PK re-evaluation occurred if average concentrations (C avg ) at Week 2 were <100 ng/mL (stage 1). Results: The majority of participants (90/103) included in the Week 48 primary analysis received OBT containing potent CYP3A4 inhibitors. The dosing strategy resulted in 49/50 stage 1 participants rolling over into stage 2 achieving C avg concentrations ≥100 ng/mL irrespective of age, BSA or OBT, and an exposure range similar to that seen in adults. MVC was well-tolerated with a safety profile comparable to that of adults. The majority of treatment-emergent adverse events (TEAEs) were of Grade 1 severity. There were no deaths. None of the Grade 3 or 4 TEAEs or serious adverse events was considered to be related to MVC. Fourteen subjects had Grade 3 or 4 laboratory abnormalities with Grade 3 neutropenia the most common (n=8). All cohorts had a median decrease from baseline in HIV-1 RNA of >1 log 10 , while 67/103 subjects (65.0%) achieved HIV-1 RNA <400 copies/ mL using the FDA snapshot (MSDF) algorithm, and 49/103 (47.5%) achieved HIV-1 RNA <48 copies/ml. An increase from baseline in median CD4+ cell count and percentage was seen for all age-groups. A total of 23 (22.3%) patients experienced protocol-defined virologic failure with few instances of non-R5 tropism (n=5), MVC resistance (n=1) or clinically , with exposure ranges similar to that observed in adults. MVC’s safety profile in this population was comparable to that seen in adults with no new safety concerns identified. Virologic efficacy was comparable to what was reported in a similarly treatment-experienced adult population. These data support dosing recommendations for TE patients 2-<18 years old. relevant resistance-associated mutations (n=3). Conclusions: Participants achieved the target C avg

819 Safety of Tenofovir on Bone Mineral Density in HIV-Infected Youths: A 10-Year Study

Poster Abstracts

Vania Giacomet 1 ; Katia Maruca 2 ; Paola Erba 1 ; Maria Puzzovio 2 ; Pilar Nannini 3 ; Silvia Capelli 2 ; Alessandro Ambrosi 2 ; Gianvincenzo Zuccotti 4 ; Stefano Mora 2 1 Luigi Sacco Hosp, Univ of Milan, Milan, Italy; 2 San Raffaele Scientific Inst, Milan, Italy; 3 Univ of Milan, Milan, Italy; 4 Ospedale Buzzi, Univ of Milan, Milan, Italy Background: HIV-infected adults receiving highly active antiretroviral therapy (HAART) containing tenofovir DF (TDF) have decreased bone mineral density (BMD) measurements. Data in children are conflicting. The aim of this study was to assess the long-term safety of a TDF-containing HAART on BMD in a cohort of pediatric patients. Methods: This was a single-site, longitudinal, controlled, observational study. We enrolled 26 vertically HIV-infected Caucasian youths (13 girls), aged 4.9 to 17.9 years, with undetectable viral load, receiving HAART containing lamivudine, stavudine (d4T) and a protease inhibitor (PI). At enrollment, all subjects replaced d4T with TDF and PI with efavirenz (EFV). We measured BMD at the lumbar spine and in the whole skeleton by dual-energy x-ray absorptiometry yearly for 10 years. BMD measurements were compared to those obtained in 201 healthy youths (90 girls), aged 3 to 25 years. To investigate the natural patterns of the variables over the time, the trend of each variable observed on healthy subjects as function of age was analyzed fitting quantile regression models based on natural spline with knots chosen on quartiles. Analyses were performed by non-linear mixed effect regression models for longitudinal data Results: During the study period, patients did not differ from healthy subjects in anthropometric measurements, and maintained HIV-RNA < 50 cp/ml and stable CD4+ count: mean values (range) at baseline vs 10-year were 842 (236-1518) and 854 (314-1526) cells/μL, respectively. The BMD regression curves of patients were significantly lower than those built for healthy subjects at the lumbar spine both when data were expressed as absolute values (P=0.017) or as z-scores (P=0.012) Similarly, BMD regression curves of the whole skeleton were significantly lower in patients (P<0.001 both for absolute values and z-scores). The difference between patients and control subjects did not change over time, and the longitudinal analyses did not show differences between patients and control subjects, thus indicating that bone mineral acquisition was not impaired. Conclusions: Our long-term study on BMD measurements demonstrate that switching d4T to TDF and PI to EFV in HIV-infected youths, guarantees an optimal control of infection, does not normalize bone mineral density, but is not associated with a further impairment of bone mass 820 HIV Encephalopathy Despite Prolonged Viral SuppressionWith Slow Spontaneous Recovery Steve Innes ; Barbara Laughton; Ronald vanToorn; Els Dobbels; Mark F. Cotton Stellenbosch Univ and Tygerberg Children’s Hosp, Cape Town, South Africa Background: Early antiretroviral therapy (ART) dramatically reduces risk of HIV encephalopathy (HIVE) in children. Neurological deterioration, despite successful viral suppression in blood, has previously been attributed to HIV relapse within the central nervous system, a known sanctuary site. We describe four children with new onset HIVE despite long- standing viral suppression in blood and undetectable HIV DNA and RNA PCR in cerebrospinal fluid (CSF). Methods: Four CHER (Children with HIV Early antiRetroviral therapy) trial participants were followed up clinically 3-monthly for 7 years. Blood HIV viral load and CD4 levels were measured at 6-12 monthly intervals. HIVE diagnosis required two of: (i) Acquired cortical motor deficit manifesting as pathological upper motor neuron (UMN) signs; (ii) Impaired brain growth manifesting as acquired microcephaly or generalized brain atrophy on imaging; (iii) Failure to attain or loss of developmental milestones.

342

CROI 2016