The Alaska Native/American Indian experience of hepatitis C treatment with sofosbuvir-based direct-acting antivirals.

BACKGROUND: Direct-acting antiviral (DAA) drugs have been effective in the treatment of chronic hepatitis C virus (HCV) infection. Limited data are available on safety, tolerability, and efficacy in American Indian or Alaska Native people. We aim to evaluate the treatment outcomes of sofosbuvir- based regimens for treatment of HCV in a real life setting in Alaska Native/American Indian (AN/AI) people. METHODS: AN/AI patients within the Alaska Tribal Health System with confirmed positive anti-HCV and HCV RNA, who were 18 years of age and older were included in the study. Pretreatment baseline patient characteristics, treatment efficacy based on sustained virologic response (SVR) 12 weeks after treatment completion, and adverse effects were assessed. The following treatments were given according to the American Association for the Study of Liver Diseases/Infectious Disease Society of America (AASLD/IDSA) HCV Guidance: ledipasvir/sofosbuvir, sofosbuvir plus weight-based ribavirin, and sofosbuvir/velpatasvir. RESULTS: We included 501 patients with a mean age of 54.3 (range 21.3-78.3) in the study. Overall SVR was achieved in 95.2% of patients who received one of the three DAA regimens. For those with cirrhosis, overall SVR was 92.8% and for those with genotype 3 91.1% achieved SVR. The most common symptom experienced during treatment was headache. Joint pain was found to decrease during treatment. One person discontinued sofosbuvir plus ribavirin due to myocardial infarction and one discontinued sofosbuvir/velpatasvir due to urticaria. CONCLUSIONS: In the real-world setting, sofosbuvir-based treatment is safe, effective, and well tolerated in AN/AI patients. Sustained virologic response was high regardless of HCV genotype or cirrhosis status.

Cascade of Care for Alaska Native People With Chronic Hepatitis C Virus Infection: Statewide Program With High Linkage to Care.

Most persons with chronic hepatitis C virus (HCV) infection in the United States are undiagnosed or linked to care. We describe a program for the management of Alaska Native patients infection utilizing a computerized registry and statewide liver clinics resulting in higher linkage to care (86%) than national estimates (~25%).

Observed Changes in Natural Killer and T cell Phenotypes with Evaluation of Immune Outcome in a Longitudinal Cohort Following Sofosbuvir-Based Therapy for Chronic Hepatitis C Infection.

BACKGROUND: Chronic hepatitis C virus (HCV) infection diminishes immune function through cell exhaustion and repertoire alteration. Direct acting antiviral (DAA)-based therapy can restore immune cell subset function and reduce exhaustion states. However, the extent of immune modulation following DAA-based therapy and the role that clinical and demographic factors play remain unknown. METHODS: We examined natural killer (NK) cell, CD4+, and CD8+ T cell subsets along with activation and exhaustion phenotypes across an observational study of sofosbuvir-based treatment for chronic HCV infection. Additionally, we examined the ability of clinical variables and duration of infection to predict 12 weeks of sustained virologic response (SVR12) immune marker outcomes. RESULTS: We show that sofosbuvir-based therapy restores NK cell subset distributions and reduces chronic activation by SVR12. Likewise, T cell subsets, including HCV-specific CD8+ T cells, show reductions in chronic exhaustion markers by SVR12. Immunosuppressive CD4+ regulatory T cells decrease at 4-weeks treatment and SVR12. We observe the magnitude and direction of change in immune marker values from pretreatment to SVR12 varies greatly among participants. Although we observed associations between the estimated date of infection, HCV diagnosis date, and extent of immune marker outcome at SVR12, our regression analyses did not indicate any factors as strong SVR12 outcome predictors. CONCLUSION: Our study lends further evidence of immune changes following sofosbuvir-based therapy. Further investigation beyond SVR12 and into factors that may predict posttreatment outcome is warranted.

Diet affects arctic ground squirrel gut microbial metatranscriptome independent of community structure.

We examined the effect of diet on pre-hibernation fattening and the gut microbiota of captive arctic ground squirrels (Urocitellus parryii). We measured body composition across time and gut microbiota density, diversity and function prior to and after five-weeks on control, high-fat, low-fat (18%, 40% and 10% energy from fat, respectively), or restricted calorie (50% of control) diets. Squirrels fattened at the same rate and to the same degree on all diets. Additionally, we found no differences in gut microbiota diversity or short chain fatty acid production across time or with diet. Analysis of the gut microbial transcriptome indicated differences in community function among diet groups, but not across time, and revealed shifts in the relative contribution of function at a taxonomic level. Our results demonstrate that pre-hibernation fattening of arctic ground squirrels is robust to changes in diet and is accomplished by more than increased food intake. Although our analyses did not uncover a definitive link between host fattening and the gut microbiota, and suggest the squirrels may possess a gut microbial community structure that is unresponsive to dietary changes, studies manipulating diet earlier in the active season may yet uncover a relationship between host diet, fattening and gut microbiota.

Field degradation of aminopyralid and clopyralid and microbial community response to application in Alaskan soils.

High-latitude regions experience unique conditions that affect the degradation rate of agrochemicals in the environment. In the present study, data collected from 2 field sites in Alaska, USA (Palmer and Delta) were used to generate a kinetic model for aminopyralid and clopyralid degradation and to describe the microbial community response to herbicide exposure. Field plots were sprayed with herbicides and sampled over the summer of 2013. Quantification was performed via liquid chromatrography/tandem mass spectrometry, and microbial diversity was assessed via next-generation sequencing of bacterial 16S ribosomal ribonucleic acid (rRNA) genes. Both compounds degraded rapidly via pseudo-first-order degradation kinetics between 0 d and 28 d (t1/2 = 9.1-23.0 d), and then degradation slowed thereafter through 90 d. Aminopyralid concentration was 0.048 µg/g to 0.120 µg/g at 90 d post application, whereas clopyralid degraded rapidly at the Palmer site but was recovered in Delta soil at a concentraction of 0.046 µg/g. Microbial community diversity was moderately impacted by herbicide treatment, with the effect more pronounced at Delta. These data predict reductions in crop yield when sensitive plants (potatoes, tomatoes, marigolds, etc.) are rotated onto treated fields. Agricultural operations in high-latitude regions, both commercial and residential, rely heavily on cultivation of such crops and care must be taken when rotating.

Effects of season and host physiological state on the diversity, density, and activity of the arctic ground squirrel cecal microbiota.

We examined the seasonal changes of the cecal microbiota of captive arctic ground squirrels (Urocitellus parryii) by measuring microbial diversity and composition, total bacterial density and viability, and short-chain fatty acid concentrations at four sample periods (summer, torpor, interbout arousal, and posthibernation). Abundance of Firmicutes was lower, whereas abundances of Bacteroidetes, Verrucomicrobia, and Proteobacteria were higher during torpor and interbout arousal than in summer. Bacterial densities and percentages of live bacteria were significantly higher in summer than during torpor and interbout arousal. Likewise, total short-chain fatty acid concentrations were significantly greater during summer than during torpor and interbout arousal. Concentrations of individual short-chain fatty acids varied across sample periods, with butyrate concentrations higher and acetate concentrations lower during summer than at all other sample periods. Characteristics of the gut community posthibernation were more similar to those during torpor and interbout arousal than to those during summer. However, higher abundances of the genera Bacteroides and Akkermansia occurred during posthibernation than during interbout arousal and torpor. Collectively, our results clearly demonstrate that seasonal changes in physiology associated with hibernation and activity affect the gut microbial community in the arctic ground squirrel. Importantly, similarities between the gut microbiota of arctic ground squirrels and thirteen-lined ground squirrels suggest the potential for a core microbiota during hibernation.

Temporal dynamics of the cecal gut microbiota of juvenile arctic ground squirrels: a strong litter effect across the first active season.

Arctic ground squirrels (Urocitellus parryii) are active for a scant 3 to 5 months of the year. During the active season, adult squirrels compete for mates, reproduce, and fatten in preparation for hibernation, while juvenile squirrels, weaned in early July, must grow and acquire sufficient fat to survive their first hibernation season. During hibernation, the gut microbial community is altered in diversity, abundance, and activity. To date, no studies have examined the gut microbiota of hibernators across the truncated active season. We characterized trends in diversity (454 pyrosequencing), density (flow cytometry), viability (flow cytometry), and metabolism (short-chain fatty acid analysis) of the gut microbial community of juvenile arctic ground squirrels across their first active season at weaning and at 4, 6, 8, and 10 weeks postweaning. At 8 weeks postweaning, the mean bacterial density was significantly higher than that at weaning, and the mean percentage of live bacteria was significantly higher than that at either weaning or 4 weeks postweaning. No significant differences in microbial diversity, total short-chain fatty acid concentrations, or molar proportions of individual short-chain fatty acids were observed among sample periods. The level of variability in gut microbial diversity among squirrels was high across the active season but was most similar among littermates, except at weaning, indicating strong maternal or genetic influences across development. Our results indicate that genetic or maternal influences exert profound effects on the gut microbial community of juvenile arctic ground squirrels. We did not find a correlation between host adiposity and gut microbial diversity during prehibernation fattening, likely due to a high level of variability among squirrels.