CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

n=9). The patients in this cohort have been immunized annually and had sero-protective antibody titers at T0; R were defined as having hemagluttination inhibition titers >1:40, and >4-fold increase above T0 4 wks post-vaccination. Results: There were no observed differences in frequencies of pTfh between the groups before or after in vitro stimulation ( p=0.9, ANOVA). However, t ranscriptomic analysis of pTfh from HC and R demonstrated a response to H1N1 stimulation which was marked by increased or stable expression of Tfh-related genes ( MAF, IL21, BCL6 , ICOS ) and TCR signaling genes ( CD3D , MAPK3 , FYN , PKC A ), while in NR they were significantly downregulated after stimulation. Interestingly, pTfh from NR displayed higher levels of the inhibitory receptor CTLA4 ( p=0.01 , student’s t test) compared to R suggesting a possible mechanism for reduced responses to vaccination. Conclusions: Targeted molecular profiling of pTfh in previously vaccinated HIV-infected children, before influenza vaccination revealed antigen-driven favorable gene expression selectively in R. These results suggest that quality rather than quantity of pTfh in the periphery is controlling responses to vaccination. 948 The Potential of BCG and HIV-TB Vaccines to Exacerbate HIV-1 Pathogenesis in Infants Kara Jensen 1 ; Koen K.Van Rompay 2 ;William R. Jacobs 3 ; Glenn Fennelly 3 ; Katie Mollan 1 ; Michael G. Hudgens 1 ; Mike Piatak 4 ; Michelle H. Larsen 3 ; Kristina De Paris 1 1 University of North Carolina, Chapel Hill, NC, US; 2 California National Primate Research Center, University of California, Davis, CA, US; 3 Albert Einstein College of Medicine, New York, NY, US; 4 Frederick National Laboratory, Frederick, MD, US Background: The only licensed vaccine to prevent tuberculosis infection, Bacille Calmette Guérin (BCG), can cause Mycobacterium bovis dissemination in HIV-1 infected infants . We previously demonstrated that a double-auxotroph M. tuberculosis strain (A Mtb ), expressing SIV genes to potentially protect against both TB and SIV/HIV infections, is immunogenic and safe in SIV-infected neonatal macaques. Here, we tested vaccine efficacy against repeated low-dose oral SIV challenge to mimic breast milk HIV-1 transmission in human infants. Methods: Infant rhesus macaques were orally immunized at birth with A Mtb -SIV and boosted ID with A Mtb -SIV at week 3 (n=6), IM with MVA-SIV at weeks 3 and 6 (n=8) or not boosted (n=5). BCG (n=7) or mock (n=11) groups were also included. Weekly low-dose oral SIV challenges were started at week 9. Plasma viremia was measured by RT-PCR and immune activation by flow cytometry and ELISA. The number of challenges until SIV infection were compared with an exact log-rank test, and viremia and immune activation outcomes with Kruskal-Wallis or Mann Whitney tests. Results: A Mtb -SIV, A Mtb , and BCG versus mock vaccinated infants appeared to require fewer SIV exposures for infection. Although the risk of SIV infection per exposure was not statistically different, BCG recipients had higher peak viremia compared to A Mtb or A Mtb -SIV (p=0.001), or mock infants (p=0.009). Further, BCG and combined A Mtb vaccinated infants had significantly higher acute phase viremia AUC compared to mock animals (p=0.037 and 0.029, respectively). The frequency of potential SIV target cells, CCR5 + CD4 + T cells, was significantly higher in all vaccinated compared to mock infants at the time of SIV exposure. Mycobacteria vaccine-induced CD4 + T cell activation was supported also by elevated levels of CD69 (p<0.0001), HLA-DR (p=0.025), and Ki-67 (p=0.007) in vaccinated versus mock animals. Furthermore, plasma levels of IFN-g (p=0.028), sCD14 (p=0.0015) and sCD163 (p=0.0016) were increased in vaccinated compared to mock infants. Conclusions: A single dose of live attenuated A Mtb or BCG at birth induced persistent immune activation in infant macaques that was unresolved nine weeks later. Novel TB vaccine candidates under development include highly replication-attenuated auxotroph strains of BCG that are similar to our A Mtb vaccines. To avoid potentially enhanced morbidity in HIV-1 infected infants, TB vaccine candidates should be thoroughly evaluated for their risk of inducing persistent immune activation.

TUESDAY, FEBRUARY 24, 2015 Session P-U10 Poster Session

Poster Hall

2:30 pm– 4:00 pm Pharmacokinetics, Safety, and Efficacy of ART in Children and Youth 949 Prediction of ARV Drug Clearance in Children Frantz Foissac ; Naïm Bouazza; ElodieValade; Mailys De Sousa; Floris Fauchet; Sihem Benaboud; Deborah Hirt; Stéphane Blanche; Saïk Urien; Jean-MarcTreluyer EA 08 Université Paris Descartes, Sorbonne Paris Cité, Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, France, Paris, France

Poster Abstracts

Background: Ethical difficulties to conduct clinical trials in pediatric populations lead to insufficient pharmacokinetics data especially in HIV-1 infected children. Several antiretroviral (ARV) drugs are thus still not recommended in young children which may result in use of “off-label” prescriptions. However, the pharmacokinetic profile differs widely from birth to adolescence as compared to adult and to predict accurate clearance values in children, especially in neonates and infants, could improve the rational in dosing decisions. Methods: A systematic review of pharmacokinetic reports in pediatric populations was performed to gather drugs clearances from birth to adulthood. A single equation to describe the clearances maturation process was then developed. The analysis was performed using the nonlinear mixed-effect modeling program NONMEM. The model accuracy was evaluated on ARV drugs for which pediatric pharmacokinetic studies were previously published (i.e., abacavir, atazanavir, emtricitabine, efavirenz, enfuvirtide, lamivudine, lopinavir, nelfinavir, nevirapine, stavudine, tenofovir and zidovudine). Prediction errors were also compared to those obtained fromweight-based allometric scaling. Results: The maturation of clearances was best described by a model based on both weight and age and taking into account drug adult clearance value. Age-related maturation of clearance reached 90% of adult value within 1.5 years of life. For children aged more than 2 years both allometry and age/weight based model provided accurate predictions (prediction error < 15%). However, contrary to allometry, the prediction error of the age/weight based model stay accurate from 6 months to 2 years old. Indeed, for children aged less than 2 years, allometric scaling alone systematically overestimated clearances. Accounting for age improved the clearance prediction. A high uncertainty remained regarding the predicted ARV drugs clearance in children aged less than 6 months: 352% and 83% respectively for allometry and the age/weight based model. Conclusions: This analysis established a single equation using adult clearance value as well as age and weight to predict ARV drug clearance in children older than 6 months.To accurately predict drug clearance in children aged less than 6 months where the enzyme maturation process are not fully mature, a more complex physiologically based model including the maturation of active-transporters and specific enzymes involved in absorption and/or metabolism should be investigated.

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CROI 2015