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Background Treatment of chronic hepatitis C virus infection with direct acting antiviral therapy results in viral elimination in over 90% of cases. The duration of treatment required to achieve cure differs between individuals and relapse can occur. We asked whether cellular and transcriptional profiling of peripheral blood collected during treatment could identify biomarkers predictive of treatment outcome. Methods We analyzed peripheral blood collected during treatment of genotype 1 HCV with 24 weeks of sofosbuvir and weight-based or low dose ribavirin in a trial in which 29% of patients relapsed. Changes in host immunity during treatment were assessed by flow cytometry and whole blood gene expression profiling. Differences in expression of immune-relevant transcripts based on treatment outcome were analyzed using the Nanostring Human Immunology V2 panel. Results Multiple cellular populations changed during treatment, but pre-treatment neutrophil counts were lower and natural post-treatment killer cell counts were higher in patients who relapsed. Pre-treatment expression of genes associated with interferon-signaling, T-cell dysfunction, and T-cell co-stimulation differed by treatment outcome. We identified a pre- and post-treatment gene expression signature with high predictive capacity for distinguishing treatment outcome, but neither signature was sufficiently robust to suggest viability for clinical use. Conclusions Patients who relapse after hepatitis C virus therapy differ immunologically from non-relapsers based on expression of transcripts related to interferon signaling and T-cell dysfunction, as well as by peripheral neutrophil and NK-cell concentrations. These data provide insight into the host immunologic basis of relapse after DAA therapy for HCV and suggests mechanisms which may be relevant for understanding outcomes with currently approved regimens.

Treatment of chronic hepatitis C virus (HCV) infection with direct acting antivirals (DAAs) results in a sustained virologic response (SVR) in most patients. While highly efficacious, ~3–5% of patients do not achieve SVR despite having virus that appears susceptible. It is unclear whether host factors contribute to treatment failures, although innate and adaptive immunity may play a role. Previous studies showed that after DAA treatment, the composition of intrahepatic immune cells does not normalize relative to healthy volunteers, even in cases where SVR is achieved. We used paired pre- and post-treatment liver biopsies from 13 patients treated with sofosbuvir and ribavirin, 4 of whom relapsed, to analyze intracellular immune changes during DAA treatment and explore correlations with inflammation and treatment outcome. We performed single marker immunohistochemistry followed by electronic image capture, manual annotation of parenchymal and non-parenchymal regions, and quantitative image analysis. The predominant cellular change during treatment was a decrease in CD8+ cellular density in both parenchymal and non-parenchymal regions. CD68+ Kupffer cell density correlated with hepatic inflammation (AST, ALT) pre-treatment, but did not change during treatment. CD4+ cellular density decreased in non-parenchymal regions and, intriguingly, was lower pre-treatment in subjects who eventually relapsed. Other cellular markers (CD56, CD20), as well as markers of apoptosis (TIA-1) and activated stellate cells, did not change significantly during treatment or differ by treatment outcome. CONCLUSION: The predominant intrahepatic cellular change during DAA treatment of chronic HCV infection is a reduction in CD8+ cellular density, but this did not correlate with treatment outcome.

To identify immunologic correlates of hepatitis C virus (HCV) relapse after direct-acting antiviral (DAA) therapy, we quantified select immune transcripts in whole blood from noncirrhotic HCV subjects treated with 4–6 weeks of DAAs. We identified specific markers of natural killer-cell and CD8+ T-cell function (GZMB, PRF1, NKp46) with higher expression in subjects who relapsed. These findings suggest a role for host immunity in HCV eradication with ultrashort DAA therapy. We quantified whole blood immune transcripts in noncirrhotic HCV subjects treated with shortcourse antiviral therapy. Markers of natural killer-cell and CD8+ T-cell function had higher expression in virologic relapsers, suggesting a role for host immunity in HCV eradication.

Background and aims Most patients with cirrhosis induced by chronic HBV infection experience fibrosis regression after long-term antiviral treatment, while some remain cirrhotic. Fibrosis regression is associated with lower odds of developing hepatic decompensation and hepatocellular carcinoma, but mechanisms impacting differential fibrosis regression between individuals are unclear. We asked whether soluble molecules, including serum microRNAs, could serve as biomarkers of fibrosis regression. Methods We analysed cryopreserved sera from clinical trials in which cirrhotic HBV-infected patients (baseline Ishak fibrosis score of 5-6) received 240 weeks of nucleotide analogue treatment. Liver biopsies at week 240 in these trials showed 71/96 patients (74%) had fibrosis regression (Ishak ≤ 4) while 25/96 (26%) remained cirrhotic (Ishak 5-6). We quantified inflammatory markers (CXCL10, soluble CD163) and miRNAs (n = 179) from serum at baseline, week 48 and week 240 of treatment in a sub-cohort of patients with (n = 14) or without (n = 14) fibrosis regression. Results CXCL10, sCD163 and miRNAs previously associated with HBV replication and inflammation decreased during treatment but did not differ based on fibrosis regression. Two miRNAs (miR-421 and miR-454-3p) had lower baseline expression in patients with subsequent fibrosis regression. In all, 27 miRNAs differed at week 240 and had higher expression in patients with fibrosis regression (eg miR-199a-3p, miR-423-3p, miR-142-3p, miR-let-7d-5p). Several miRNAs (miR-141-3p, let-7d-5p) that correlated with regression have previously been implicated in the pathophysiology of non-alcoholic steatohepatitis. Conclusions In cirrhotic patients with chronic HBV infection treated with antiviral therapy, serum miRNAs have differential expression based on fibrosis regression, suggesting potential utility as biomarkers.

Objectives The opioid epidemic has resulted in rising rates of hepatitis C virus (HCV) infection in women of childbearing age. With this changing epidemiology in mind, the Infectious Diseases Society of America/American Association for the Study of Liver Diseases guidelines were updated in 2018 to recommend screening all pregnant women for HCV infection, irrespective of risk factors. Because HCV infection can affect maternal-fetal health and result in vertical transmission, presentation for pregnancy-related medical care represents an opportunity to diagnose and manage HCV infection, as well as prepare for treatment postpartum. Methods We performed a retrospective chart review spanning 2007-2016 to examine the epidemiology of HCV infection and opioid use disorder in a southern academic obstetrical clinic and to explore the impact of new screening guidelines if implemented. Composite data from the electronic health record and individual chart review were used to determine rates of HCV infection and opioid use disorder in obstetrics, explore patient demographics, and examine perinatal outcomes. Results Rates of both opioid use disorder and chronic HCV infection increased significantly during the 10-year period of analysis. Patients diagnosed as having chronic HCV infection were primarily white (95%) and there was no observed impact of HCV on perinatal outcomes. HCV testing in pregnancy, even when patients had documented opioid use disorder, was infrequent (0.7% of all pregnancies). Documented follow-up for HCV postpartum for both mothers and infants was incomplete, with only one-third of identified HCV-exposed infants referred and only 9% receiving HCV testing at our institution. Conclusions HCV prevalence increased between 2007 and 2016, but screening and treatment of HCV in this southern obstetrical cohort was infrequent. The implementation of universal screening in pregnancy will likely identify additional cases, and an improved cascade of care will be necessary to address the HCV epidemic.