Person: Alatrakchi, Nadia
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Alatrakchi
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Nadia
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Alatrakchi, Nadia
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Publication Prolonged cenicriviroc therapy reduces hepatic fibrosis despite steatohepatitis in a diet‐induced mouse model of nonalcoholic steatohepatitis(John Wiley and Sons Inc., 2018) Kruger, Annie; Fuchs, Bryan; Masia, Ricard; Holmes, Jacinta; Salloum, Shadi; Sojoodi, Mozhdeh; Ferreira, Diego S.; Rutledge, Stephanie; Caravan, Peter; Alatrakchi, Nadia; Vig, Pam; Lefebvre, Eric; Chung, RaymondNonalcoholic steatohepatitis (NASH) is a progressive liver disease projected to become the leading cause of cirrhosis and liver transplantation in the next decade. Cenicriviroc (CVC), a dual chemokine receptor 2 and 5 antagonist, prevents macrophage trafficking and is under clinical investigation for the treatment of human NASH fibrosis. We assessed the efficacy and durability of short and prolonged CVC therapy in a diet‐induced mouse model of NASH, the choline deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD) model. C57BL/6 mice received 4 or 14 weeks of standard chow or the CDAHFD. CVC (10 mg/kg/day and 30 mg/kg/day for 4 weeks and 20 mg/kg/day and 30 mg/kg/day for 14 weeks) was initiated simultaneously with the CDAHFD. At 4 and 14 weeks, livers were harvested for histology and flow cytometric analyses of intrahepatic immune cells. High‐dose CVC (30 mg/kg/day) therapy in CDAHFD mice for 4 or 14 weeks inhibited intrahepatic accumulation of Ly6Chigh bone marrow‐derived macrophages. Prolonged CVC therapy (14 weeks) yielded no significant differences in the total intrahepatic macrophage populations among treatment groups but increased the frequency of intrahepatic anti‐inflammatory macrophages in the high‐dose CVC group. Despite ongoing steatohepatitis, there was significantly less fibrosis in CDAHFD mice receiving high‐dose CVC for 14 weeks based on histologic and molecular markers, mirroring observations in human NASH CVC trials. CVC also directly inhibited the profibrotic gene signature of transforming growth factor‐β‐stimulated primary mouse hepatic stellate cells in vitro. Conclusion: CVC is a novel therapeutic agent that is associated with reduced fibrosis despite ongoing steatohepatitis. Its ability to alter intrahepatic macrophage populations and inhibit profibrogenic genes in hepatic stellate cells in NASH livers may contribute to its observed antifibrotic effect. (Hepatology Communications 2018;2:529‐545)Publication Circulating Soluble CD163 is Associated with Steatohepatitis and Advanced Fibrosis in Nonalcoholic Fatty Liver Disease(Nature Publishing Group, 2015) Mueller, Jessica L; Feeney, Eoin R; Zheng, Hui; Misdraji, Joseph; Kruger, Annie; Alatrakchi, Nadia; King, Lindsay Y; Gelrud, Louis; Corey, Kathleen; Chung, RaymondOBJECTIVES: Soluble CD163 (sCD163), a marker of Kupffer cell activation detectable in serum, correlates with inflammation and fibrosis in chronic viral hepatitis, but its role in nonalcoholic fatty liver disease is unknown. We hypothesized that sCD163 would correlate with nonalcoholic fatty liver disease activity and fibrosis. METHODS: Liver biopsies and serum were obtained from 145 obese subjects undergoing gastric bypass surgery. Subjects were divided into four groups based on fibrosis stage and nonalcoholic fatty liver disease activity score (NAS); Group 1: F0, NAS=0; Group 2: F<2, 0Publication The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial(Public Library of Science, 2010) Margolis, David M.; Read, Sarah; Kallungal, Beatrice; Palmer, Sarah; Medvik, Kathy; Lederman, Michael M.; Jacobson, Jeffrey M.; Wiegand, Ann; Kearney, Mary; Coffin, John M.; Mellors, John W.; Eron, Joseph J.; Gandhi, Rajesh; Zheng, Summer; Bosch, Ronald; Chan, Ellen; Alatrakchi, NadiaBackground: Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients. Methods and Findings: Patients receiving ART who had plasma HIV-1 RNA levels below 50 copies/mL but detectable viremia by single copy assay (SCA) were randomized to add either raltegravir or placebo to their ART regimen for 12 weeks; patients then crossed-over to the other therapy for an additional 12weeks while continuing pre-study ART. The primary endpoint was the plasma HIV-1 RNA by SCA averaged between weeks 10 and 12 (10/12) compared between treatment groups. Fifty-three patients were enrolled. The median screening HIV-1 RNA was 1.7 copies/mL. The HIV-1 RNA level at weeks 10/12 did not differ significantly between the raltegravir-intensified (n = 25) and the placebo (n= 24) groups (median 1.2 versus 1.7 copies/mL, p = 0.55, Wilcoxon rank sum test), nor did the change in HIV-1 RNA level from baseline to week 10/12 (median 20.2 and 20.1 copies/mL, p = 0.71, Wilcoxon rank sum test). There was also no significant change in HIV-1 RNA level from weeks 10/12 to weeks 22/24 after patients crossed-over. There was a greater CD4 cell count increase from baseline to week 12 in the raltegravir-intensified group compared with the placebo group (+42 versus244 cells/mm3, p= 0.082, Wilcoxon rank sum test), which reversed after the cross-over. This CD4 cell count change was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood. Conclusion: In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells. New therapeutic strategies to eliminate reservoirs that produce residual viremia will be required to eradicate HIV-1 infection.