CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Methods: All HIV-infected children diagnosed before 2 years of age, and confirmed by DNA-PCR were enrolled in an initial therapeutic cohort offering a cART with cotrimoxazole prophylaxis (TMP/SMX: 200/40/day once daily) in Ouagadougou (Burkina Faso), and Abidjan (Ivory Coast). Quantification of TMP and SMX in human plasma collected 6 months after cART initiation was performed using a validated liquid chromatography method with UV detector. Plasma concentrations collected from HIV-infected children aged from 6 months to 2.5 years were analyzed using a nonlinear mixed effects modeling, with NONMEM software. Estimated individual PK parameters were used to calculate individual exposures (Area under curves : AUC) to TMP and SMX. Pharmacogenetic studies are underway. Results: Overall, 114 children with a median age of 1.6 years, a median weight of 9 kg, and a sex ratio (M/F) of 0.88 were analysed. TMP’s and SMX’s PK were described by a one- compartment model with first-order absorption and elimination. A very large interindividual variability in cotrimoxazole concentrations was pointed out. With the dosing regimen currently recommended exposure are much lower in one third of the children than those found in adults. In order to maintain a comparable exposure as in adults in this population, an increase of the dose should be considered. In addition, a trend was observed between cotrimoxazole lower exposure and infection with malaria (p=0.08). Conclusions: With the dosing regimen currently recommended one third of the children are underexposed compared to adults. Moreover, a trend to more malaria infection has been suggested in children with low SMX exposure. 513 ART Choice Impacts Antimalarial Exposure and Treatment Outcomes in Ugandan Children Background: Treatment guidelines for HIV and malaria co-infected children are not developed despite concern that drug interactions impact malaria outcomes. Artemether- lumefantrine (AR-LR), contains long-acting LR with a predominant impact on reinfection rates. Previously, HIV infected children, managed with lopinavir/ritonavir (LPV/r)-based ART, had lower risk for malaria compared to those on efavirenz (EFV) or nevirapine (NVP)-based ART. The pharmacological basis for these distinctions has not been fully addressed. Methods: Using intensive and population methods, we investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of AR-LR as treatment, in the context of varying ART in HIV infected children 0.5 to 8yrs in the highly endemic region of Tororo. HIV-uninfected children served as controls (C). Intensive (area under the concentration-time curve, AUC) and sparse PK were done over 21d with clinical and parasitological response followed for 42 d. AR, active dihydroartemisinin (DHA), and LR were measured by LC tandemMS. Results: 130 children had intensive PK (n=30LPV/r; 19EFV; 30NVP and 51C); 89 children had sparse PK (n=26LPV/r; 7EFV; 18NVP and 38C). Lower AR AUC was seen with EFV and NVP compared with C [GMR; EFV:0.41 (p=0.0003); NVP:0.36 (p<0.001)]; DHA was reduced only with EFV [GMR 0.29 (p<0.0001)]. Notably, LPV/r and EFV had dramatic and converse effects on LR AUC; LPV/r and EFV resulted in 2 fold highe r and 3 fold lower AUC, respectively. Nearly all EFV children exhibited undetectable LR day 14 and 21 levels (Table). Cumulative 28d risk of parasitologic failure was 11, 44 and 32%, for children on LPV/r, EFV and NVP, respectively. Children on EFV vs. LPV/r had a 4.4 fold higher risk of parasitologic failure at 28d (p=0.007). Recurrent parasitemia risk at 28d was linked with LR AUC (p=0.03) and day 7 levels (HR 0.55, p=0.001). Day 7 <175 ng/mL, a key threshold for clinical outcomes, was linked with 2.5-fold higher risk of recurrent parasitemia (p=0.012) with 9, 89, and 10% of LPV/r, EFV and NVP children below this threshold. Sunil Parikh 2 ; Norah Mwebaza 3 ; Richard Kajubi 3 ; Joshua Ssebuliba 3 ; Sylvia Kiconco 3 ; Liusheng Huang 1 ; Qin Gao 1 ; Abel Kakuru 3 ; Jane Achan 3 ; Francesca T. Aweeka 1 1 University of California, San Francisco, San Francisco, CA, US; 2 Yale University, New Haven, CT, US; 3 Makerere University College of Health Sciences, Kampala, Uganda

Poster Abstracts

Conclusions: Based on PK for 219 malaria episodes, EFV-based ART results in clinically significant reductions in AR and LR exposure. LR exposure is strongly linked to parasitological failure and 89% of EFV children had day 7 LR <175 ng/mL. In the face of emerging resistance, optimum AR-LR dosing is critical. Low exposure to both AR and LR with EFV-based ART suggests need for improved dosing guidelines in children. 514 Exploring Long-Term Adherence Markers Using Hair and Dried Blood Spots in iPrEX OLE Monica Gandhi 1 ; DavidV. Glidden 1 ; Albert Liu 2 ; Peter L. Anderson 7 ; Howard Horng 1 ; Juan Guanira 3 ; Beatriz Grinsztejn 4 ; Suwat Chariyalertsak 5 ; Linda-Gail Bekker 6 ; Robert M. Grant 1 iPrEX OLE 1 University of California San Francisco, San Francisco, CA, US; 2 San Francisco Department of Public Health, San Francisco, CA, US; 3 Investigaciones Medicas en Salud, Lima, Peru; 4 Instituto de Pesquisa Clinica Evandro Chagas, Rio de Janeiro, Brazil; 5 Chiang Mai University, Chiang Mai, Thailand; 6 University of Cape Town, Cape Town, South Africa; 7 University of Colorado, Denver, CO, US Background: Adherence to tenofovir/emtricitabine (TFV/FTC)-based PrEP is critical to efficacy. The limitations of self-reported adherence in reliably capturing TFV/FTC exposure are well-known, raising interest in pharmacologic measures where drug levels are assessed in a biomatrix (e.g. plasma, peripheral blood mononuclear cells (PBMCs), dried blood spots (DBS), hair). Plasma and PBMC collection can be challenging, require refrigeration and biohazard precautions, and represent short-term exposure. Hair and DBS collection provide feasibility advantages in resource-limited settings and levels in these matrices represent longer-term exposure, although correlation between these measures is unknown. We report for the first time the correlation of drug levels and concordance of drug detection in hair and DBS in PrEP. Methods: The iPrEX Open Label Extension (OLE) enrolled 1603 HIV-negative MSM and transwomen who previously enrolled in PrEP trials, of which 1225 initiated PrEP. DBS were collected at 4 and 8 weeks following PrEP initiation and then every 12 weeks. Hair samples were collected on an opt-in basis every 12 weeks. Hair and DBS levels of drugs were measured via liquid chromatography/ tandemmass spectrometry. Spearman’s correlation coefficients assessed relationships between TFV and FTC levels in hair and TFV- disphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) concentrations in red blood cells measured with DBS. Results: 806 paired hair-DBS samples were available for comparison in iPrEX OLE. TFV levels in hair and TFV-DP levels in DBS were strongly correlated (r 0.734, p <0.001), as were TFV in hair and FTC-TP in DBS (r 0.781, p<0.001) and FTC in hair and TFV-DP in DBS (r 0.742, p <0.001); FTC in hair and FTC-TP in DBS were more modestly correlated (r 0.587, p <0.001). A comparison of the levels of detection for the relevant antiretroviral or metabolite in the two matrices are shown in the Table. Concentrations of drugs in either matrix were mostly concordant in terms of detectability.

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CROI 2015