We studied unselected, hepatitis B surface antigen (HBsAg)-positive parenteral drug abusers for antibody to hepatitis D virus (anti-HD) and antibody to human immunodeficiency virus (HIV). The prevalences of anti-HD and antibody to HIV were 67% and 58%, respectively, and there was no association between positivity for these two markers. In a logistic regression model, anti-HD was associated with older age (P = .001), longer duration of drug abuse (P = .045), and the presence of liver disease (P = .002). Antibody to HIV was associated with a younger age (P = .003) and increased serum globulin levels (P less than .001). In patients infected with HIV, the severity of hepatic dysfunction remained correlated with anti-HD. In anti-HD-positive patients, most indices of hepatic dysfunction were similar whether or not antibody to HIV was present, but serum aspartate aminotransferase levels were significantly higher in patients with both anti-HD and antibody to HIV. (124 +/- 16 vs. 74 +/- 11, P less than .05).

Infection with hepatitis B virus (HBV) can result in spontaneous resolution or chronic infection, which can remain asymptomatic or can progress to cirrhosis and/or hepatocellular carcinoma. The host immune response is thought to be a major determinant of the outcome of HBV infection and virus-specific cytotoxic T lymphocytes (CTL) can mediate immunity against the virus and cause liver pathology. Antigen-nonspecific innate lymphocytes may also contribute to HBV infection and liver disease, therefore, we examined the frequencies, phenotypes, cytolytic activities and cytokine profiles of circulating natural killer (NK) cells, CD1d-restricted invariant natural killer T (iNKT) cells and CD56(+) T cells in 102 asymptomatic HBV-infected patients and compared them with those in 66 uninfected control subjects. NK cells expressing low levels of CD56 (CD56(dim)) and CD56(+) T cells were significantly expanded in the circulation of HBV-infected patients compared with control subjects. CD1d expression and iNKT cell frequencies were similar in both groups. Despite these expansions, we did not detect augmented natural or cytokine-induced cytotoxicity in the HBV-infected subjects. All lymphocyte populations studied produced interferon-γ (IFN-γ) significantly more frequently when taken from HBV-infected patients compared with when taken from healthy controls. Additionally, NK cells from the patients more frequently produced interleukin-10. As our HBV-infected cohort consisted of asymptomatic patients with low viral loads, we propose that CD56(dim) NK cells and CD56(+) T cells control HBV infection by noncytolytic mechanisms.

Background: CLL is a B-cell malignancy characterized by profound immune dysregulation, including dysfunctional T cells. Ibrutinib (ibr), a first-in-class, once-daily BTK inhibitor, is approved in the US for the treatment of CLL/SLL, and has been reported to additionally inhibit ITK in T cells. Previous studies showed that ibr has a positive impact on T-cell compartments by decreasing abnormally elevated regulatory T cells and pseudo-exhausted effector T cells, while preserving naive T-cell counts post 1 year of treatment (Solman ASH Lymphoma 2016; Solman ASCO 2017). Moreover, lower infection rates have been reported following 6 months of ibr treatment, suggesting that ibr might restore T-cell functions over time (Long JCI 2017). To further assess the effects of ibr on T-cell function, we evaluated the ability of cells to proliferate, degranulate, and release cytokines upon stimulation. Methods: Samples for this study were derived from patients (pts) with relapsed/refractory CLL enrolled in the RESONATE™ trial (Byrd NEJM 2014). In the 2 treatment arms, ibr and ofatumumab (ofa), we compared responders (PR) and non-responders (SD) per investigator assessment at week (wk) 24 - end of ofa treatment - to isolate the treatment effect on T cells. In total, we selected 19 pts wk1 through wk48 from ibr arm (420 mg once daily; 12 PR & 7 SD at wk24) and 21 pts wk1 through wk24 from ofa arm (300 mg once followed by weekly 2000 mg; 10 PR & 11 SD at wk24). Also included in the study for reference were 18 untreated, age-matched healthy donors. Cryopreserved PBMCs were immunophenotyped before and after 4-day in vitro stimulation with anti-CD3/CD28. T-cell proliferation was measured with CFSE staining, while secreted lytic proteins and cytokines were measured by bead-based immunoassays. Unless specified otherwise, median changes at wk24 relative to baseline (wk1) are reported. Results: Compared to reference range (ref) of healthy donors, all CLL samples were found to have higher percentage of apoptotic T cells. We further evaluated the fraction of apoptotic T cells in each treatment arm. In the treated CLL patients, a larger decrease in the apoptotic fraction was observed in vivo with ibr (46%) compared to ofa (24%). To evaluate how well T cells were able to respond to stimulation, we assessed T-cell death post in vitro stimulation. In vitro, both treatments were found to reduce cell death, with ofa exerting an earlier effect on apoptosis (57% for ofa vs 17% for ibr at wk24, down to 37% at wk48), and ibr having a larger effect on non-apoptotic cell death (53% for ibr at wk12-48 vs no change for ofa). T-cell proliferative ability improved significantly with ibr (+28%, P=0.001), while it decreased with ofa (-49%, P=0.003). In both arms, T-cell proliferation was higher in pts with PR compared to SD (+39% vs +6% for ibr and -20% vs -96% for ofa), and for CD8+ cells compared to CD4+ (14% for ibr and 52% for ofa). We confirmed degranulation impairment in CLL pts at baseline with a lower ability to release perforin, granzyme-A, granzyme-B, and granulysin upon stimulation. Lytic protein secretion was improved by both treatments, with a greater overall effect observed in ibr (5-fold) vs ofa pts (3-fold) at wk24. In particular, granulysin increased up to 11-fold at wk48 with ibr treatment, leading to full restoration according to ref. Relative to healthy donors, CLL pts at baseline secreted less IL-4, IL-6, IL-10, and IL-17. Each of these cytokines was increased by 3-4-fold and maintained near ref through treatment with ibr, while maximum 2-fold improvement was observed in ofa pts. IL-2 and TNF-α were elevated in CLL pts, and their secretion remained high with both treatments. Further analyses showed that degranulation and cytokine secretion changes were likely not a direct result of cell counts or disease resolution. Conclusions: Together, these data suggest ibr has a positive impact on T-cell proliferation and effector functions including degranulation and cytokine release. T-cell proliferative ability was found to be associated with treatment response, but improvement was significantly higher in ibr-treated pts, indicating a unique immune reconstitution effect of ibr beyond the effect of disease resolution. Improvement in effector T-cell function at wk24 and beyond may lead to lower infection rates in later cycles of therapy and/or support an adaptive anti-CLL immune response. Disclosures Solman: AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie company: Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Taylor:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Other: Travel, accomodations, expenses. You:Pharmacyclics LLC, an AbbVie Company: Employment, Other: Travel, accomodations, expenses; AbbVie: Equity Ownership. O'Brien:Acerta: Research Funding; Regeneron: Research Funding; Kite Pharma: Research Funding; Vaniam Group LLC: Consultancy; TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Aptose Biosciences Inc.: Consultancy; GlaxoSmithKline: Consultancy; Astellas: Consultancy; Alexion: Consultancy; Sunesis: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. Dean:CTI BioPharma Corp.: Employment, Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. James:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership, Other: Spouse's employment and stocks, Patents & Royalties: AbbVie Patent Applications. Mongan:Thermo Fisher Scientific: Patents & Royalties: Patents; AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Other: Travel, accommodations, expenses.

7524 Background: Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is indicated by FDA for treatment (Tx) of patients (pts) with CLL. Following the outcome of the RESONATE-2 trial, ibr was approved as the first chemotherapy-free Tx option for treatment-naïve (TN) pts. In this study, ibr reduced the risk of progression or death by 84% compared with chlorambucil (chl). To assess the impact of ibrutinib vs this traditional chemotherapeutic agent on the immune system, quantitative changes in circulating cells were studied throughout the first year of Tx. Methods: Immunophenotypic analyses were performed by flow cytometry on peripheral blood to assess lymphoid and myeloid cells of TN CLL pts who received 420 mg ibr once daily (n=50) or 0.5-0.8 mg/kg chl twice a month (n=30). Medians of statistically significant changes (p<0.05, Wilcoxon test) in absolute counts of 1-year paired samples (pre-dose vs 1-year) are reported. Results: Chl progressively reduced circulating B, T, NK, NKT cells, myeloid derived suppressor cells (MDSC), and monocytes by 69%-99%. All development stages of CD4+ and CD8+ T cells, except stem cell memory T cells (TSCM), decreased by 51%-90%. Regulatory T cells (Treg) and PD1+ T cells also decreased similarly; however, long-term activated T cells (TLA) were not impacted. On the other hand, ibr mainly reduced B cells (90%), MDSC (61%) and some T cells, specifically TLA, PD1+ T cells, Treg and effector T cells (27-52%). Naïve T cells, TSCM, central memory T cells and NK cells were spared throughout the full year of Tx. Classical monocytes were increased (+187%), while non-classical monocytes and intermediate monocytes remained relatively steady. Conclusions: Chl, a traditional chemotherapy, affected non-specifically most immune cell subsets in circulation, although surprisingly it did not affect TLA which have been reported as dysfunctional in CLL. Ibr represents a more targeted Tx approach than cytotoxic chemotherapy; essentially B cells, abnormal T subsets (TLA, PD1+T, Treg) and pro-tumor MDSCs were reduced. However, ibr preserved naïve T cells, NK cells and monocytes, which are important for mounting anti-tumor responses. Clinical trial information: NCT01722487.