Risk Of Viral Reactivation Research Articles

Pharmacological considerations in pharmacotherapy of rheumatology patients with liver disease: a brief narrative review.

The presence of chronic liver diseases such as metabolic dysfunction-associated steatosis liver disease, viral hepatitis, and cirrhosis may affect the treatment plan in patients with rheumatologic disorders, with concern about the adverse effects of the rheumatic medications on the course of liver disease. Advanced liver disease can change the elimination and activation of many drugs. In addition, there are concerns about the risk of viral reactivation after using biologics and immunosuppressants in patients with chronic viral hepatitis. This narrative review will assess the considerations that should be made before starting the most frequently used drugs in all common rheumatic diseases and patients with chronic liver diseases including chronic viral hepatitis.

The importance of triple panel testing for hepatitis B and the burden of isolated anti-hepatitis B core antibodies within a community sample

Within the United States (US), 2.4 million individuals are living with chronic hepatitis B, but less than 20% are diagnosed. Isolated anti-hepatitis B core (iAHBc) antibodies indicate serology in an individual that is positive for anti-HBc antibodies, while negative for surface antigen (HBsAg) and surface antibodies (anti-HBs). A result of iAHBc could indicate a chronic occult bloodstream infection, necessitating further testing. This study assesses the prevalence and risk factors associated with anti-HBc and iAHBc within community high-risk screening in Greater Philadelphia. Participants (n = 177) were screened for HBsAg, anti-HBs, and anti-HBc during community screening events in 2022. Chi-square tables and Firth logistic regression were used to describe the data and to assess the odds of iAHBc. The findings indicate that there was an iAHBc prevalence of 7.3% (n = 13) within our study. The odds of anti-HBc were increased for immigrants from the Western Pacific (4.5%) and Africa (11.9%). Individuals born in Africa had 7.93 greater odds for iAHBc than those born in the Americas, and these odds are multiplied by 1.01 for every 1-year increase in age. Our data show a high burden of iAHBc within high-risk and often hard-to-reach communities. Triple panel screening should be incorporated into all HBV screening programs, in accordance with current Centers for Disease Control and Prevention (CDC) universal screening recommendations, to ensure a comprehensive picture of the disease burden and reduce the risk of missing people with occult hepatitis B and those at risk for viral reactivation or liver complications.

Management of autoimmune and viral hepatitis in immunotherapy: a narrative review.

Cancer immunotherapy has firmly established itself as a pillar of cancer care due to its advantages over traditional anti-tumor therapy but also carries limitations due to potential for severe adverse reactions. This review highlights the current understanding and management of patients with autoimmune and viral hepatitis immune in the setting of immune checkpoint inhibitor (ICI) therapy. A literature search was conducted on PubMed, Scopus, Google Scholar SEER*Stat databases (from inception to December 2022) using search terms: "immune checkpoint inhibitor", "autoimmune hepatitis", "viral hepatitis", "HBV pathogenesis", "HCV pathogenesis", "HBV reactivation", "HCV reactivation", "cancer immunotherapy", "immune related adverse events", "immune related hepatitis". Pre-existing autoimmune disease (AD), whether active or inactive, can predispose patients receiving ICI therapy to develop autoimmune disease flares or immune-related adverse events (irAEs). Thus, patients with AD have routinely been excluded from clinical trials and data on safety of ICI therapy are limited. Hepatic irAE can be seen in ICI therapy and is a distinct entity from autoimmune hepatitis (AIH). ICI therapy alters the immune environment in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Patients who had prior exposure to HBV are at risk for viral reactivation. However, the prevalence of viral hepatitis in patients receiving immunotherapy is underrecognized and can lead to increases in liver biochemical tests as well as deterioration of liver function ultimately limiting treatment. The high morbidity and mortality associated with immune-related hepatitis emphasizes the need for screening of underlying diseases, including autoimmune and viral hepatitis, prior to initiation of ICI. Presence of AIH or chronic viral hepatitis is the most important risk factor for hepatic adverse events in ICI therapy. Screening for AIH, HBV and HCV is paramount in patients who will undergo ICI therapy.

Absolute lymphocyte counts (ALC) recovery and risk of viral reactivation in the setting of haploidentical hematopoietic stem cell transplant.

e19065 Background: The impact of early absolute lymphocyte repopulation after allogeneic hematopoietic stem cell transplant has historically been shown to predict the risk of post-transplant infection, and subsequently, non-relapse mortality (NRM). Previous studies have shown that ALC recovery after allogeneic stem cell transplant is associated with risk of viral reactivation and survival. In this study we aim to investigate the role of ALC recovery in the contemporary era with myeloablative haploidentical hematopoietic stem cell transplant (HI-HSCT). Methods: We retrospectively analyzed adult patients at University of Southern California (USC) Norris Cancer Hospital who received myeloablative conditioning haplo-HSCT (Fludarabine with 12 Gy of radiation) from 2014 to 2020. The primary endpoint was correlation between ALC recovery day 21 and risk of viral reactivation including cytomegalovirus (CMV), Epstein-Barr Virus (EBV) and BK virus. ALC recovery cut off was chosen to be 175/uL on day +21 and 500/uL on day +60 based on prior reports. Results: 58 patients were identified as recipients of MAC haploidentical-HSCT. 17 had ALC recovery at day +21. Mean age was 49 years, 31 (53.4%) were males and 27 (46.6%) were females. 41 (70%) patients were Hispanic, 12 (20%) were non-Hispanic White, and the majority had AML (51%). 76% received > 5*106/kg CD34+ cell dose and 78% received CD3 + cell dose < 3*108/kg. Serum CMV, EBV and urine BK virus were detected in 38 (65.5%), 8 (15.7%) and 11 (32.4%) respectively. Clinically significant CMV reactivation (required treatment with antiviral therapy) was detected in 26 (44.8%) patients. Lack of ALC recovery on day +21 did not show correlation with CMV, EBV and BK virus reactivation. Also, the risk of CMV reactivation was not related to day +60 ALC recovery (p-value = 0.469). On univariate analysis, ALC recovery day +21, day +60, and CMV reactivation did not show correlation with overall survival. In multivariate analysis when adjusted for age and pre-transplant CMV status, higher CD 3+ cell dose of > 3*108/kg was associated with reduced risk of CMV reactivation HR = 0.35 (0.15-0.85) p-value = 0.02. Conclusions: Previous studies have established ALC recovery as a predictor of better outcome. This has not been established in patients undertaking myeloablative HI-HSCT. Our study shows that lack of ALC recovery on day +21 does not affect CMV, EBV and BK virus reactivation and risk of CMV reactivation does not correlate with day +60 ALC recovery. Also, ALC recovery and CMV reactivation does not impact overall survival. The use of Letermovir, effective CMV therapies and close viral surveillance in contemporary practice is likely responsible for mitigating poor outcomes with CMV reactivation. Graft composition needs to be studied prospectively, as higher CD3+ cell dose may present an opportunity to reduce CMV reactivation in HI-HSCT.

Hepatic Events and Viral Kinetics in Hepatocellular Carcinoma Patients Treated with Atezolizumab plus Bevacizumab

Introduction: In the Phase 3 IMbrave150 trial (NCT03434379), atezolizumab + bevacizumab demonstrated a clinically meaningful survival benefit over sorafenib in patients with unresectable hepatocellular carcinoma (HCC), including those with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. We used IMbrave150 data to investigate the safety and risk of viral reactivation or flare in infected patients treated with atezolizumab + bevacizumab or sorafenib. Methods: Patients with unresectable HCC not previously treated with systemic therapy were randomized 2:1 to atezolizumab + bevacizumab or sorafenib. In this exploratory analysis, safety was continually evaluated, including for hepatic adverse events. Patients were monitored for HBV and HCV reactivation and flare at screening, the beginning of Cycles 5 and 9, and at treatment discontinuation. Results: Of 501 enrolled patients, 485 were included in the safety population; 329 (68%) received atezolizumab + bevacizumab, and 156 (32%) received sorafenib. Overall, 150 (31%) and 58 (12%) patients had HBV and HCV infections, respectively. The safety profiles of atezolizumab + bevacizumab and sorafenib were consistent across patients, regardless of viral infection. Overall, hepatic serious adverse events occurred in 11% of patients receiving atezolizumab + bevacizumab and 8% receiving sorafenib. HBV or HCV reactivation occurred in 2% or 16% of atezolizumab + bevacizumab-treated patients, respectively, versus 7% or 14% with sorafenib. There were no instances of hepatitis flare with atezolizumab + bevacizumab. Conclusions: Atezolizumab + bevacizumab had a similar hepatic safety profile in patients with and without HBV or HCV infection. Viral reactivation rates were similar between arms. Overall, these data support the use of atezolizumab + bevacizumab in patients with HCC and HBV or HCV infection without any special precaution.

Hepatitis B screening to reduce the risk of viral reactivation in gynecologic oncology patients receiving chemotherapy at a regional tertiary cancer center: A quality improvement initiative.

e18628 Background: In 2020, ASCO released a Provisional Clinical Opinion recommending universal hepatitis B virus (HBV) screening prior to systemic chemotherapy to reduce the risk of reactivation and associated morbidities. There is limited data for HBV prevalence and risk factors in gynecologic oncology. In gynecologic oncology patients at the Juravinski Cancer Centre, median baseline screening rate over 6 months was 0%. Our aim was to increase the rate of HBV screening to 70% in gynecologic oncology patients initiating chemotherapy over 6 months and compare real-world efficacy of risk factor-based vs. universal screening. Methods: We performed an interrupted time series study using the Model for Improvement methodology. Four interventions were introduced to address identified screening barriers: provider education, standardization of a testing protocol, integration with existing clinical workflow, and biweekly feedback reports. These were modified in response to outcomes and stakeholder feedback in Plan-Do-Study-Act cycles. Process and outcome measures data were collected by chart review and analyzed on statistical process control and run charts. Retrospective chart review collected demographic and disease data including Centers for Disease Control (CDC) hepatitis risk factors. Results: From Dec 1/20 to Nov 30/21, there were 381 new chemotherapy initiations in gynecology patients. The proportion of physicians screening increased significantly from 0% to 85%, and HBV monthly screening rates increased significantly from 0% to 72.2% by month 8 and were sustained for 4 months at last analysis. The integrated clinic screening protocol and feedback report interventions were each associated with increased screening rates. Of 330 unique patients initiating chemotherapy, 175 were screened (53%). Although ≥95% lacked data for 4 CDC hepatitis risk factors, 60.9% had ≥1 risk factor, and 11.2% had ≥2. HBV surface antigen (HBSAg) was non-reactive in all screened patients, but anti-HBV core (HBc) antibody was reactive in 5 (2.9%), indicative of prior infection. Real world risk factor-based screening in those with ≥1 CDC risk factor would have only identified 3/5 seropositive patients. In the screened population, risk-factor based screening had sensitivity 60%, specificity 38.8%, PPV 2.8%, NPV 97.1%. There were no HBV reactivations. Conclusions: Implementation of 4 interventions to increase HBV screening in gynecologic oncology patients receiving chemotherapy significantly improved screening rates, achieving our target at 8 months with sustained improvement. Risk-factor based screening lacks sensitivity compared to universal screening which may impact management. Lessons learned from this initiative may be applicable to other interventions to reduce infectious morbidity in oncologic populations.

Prevalence of hepatitis B virus infection and risk of reactivation in rheumatic population undergoing biological therapy

Hepatitis B (HBV) is a common comorbidity among rheumatic patients. The prevalence of HBV infection and the rate of reactivation remain unclear. The literature data suggested a higher risk in chronic than in past infection. Currently, the literature data are mostly focused on anti-TNF and rituximab. This retrospective observational study aimed to analyse the prevalence of HBV infection and the risk of viral reactivation in a population of rheumatic patients undergoing anti-TNF and non-anti-TNF agents. We analysed 1216 rheumatic patients, treated with both csDMARDs and bDMARDs between 2006 and 2017. Serologic markers for HBV (HBsAg, anti-HBs, anti-HBc) were performed prior and during biologic treatment. Patients with chronic or resolved infection were monitored every 3 months. The prevalence of HBV in our cohort was 15.7% (chronic infection: 0.4%, resolved infection: 12.6%, anti-HBc positivity alone: 2.6%). 12 (6.2%) out of 191 HBV infected patients experienced a reactivation. All of them showed markers of past infection. One patient experienced HBV reactivation despite lamivudine. Only one patient experienced acute hepatitis, probably due to the interruption of immunosuppressors in anticipation of surgery, not preceded by any HBV prophylactic treatment. HBV reactivation is a rare event in patients treated with a bDMARD and it can also occur while taking lamivudine, not only in chronic carriers (as per the literature data) but also in inactive ones. Regular screening followed by prompt treatment can prevent symptoms or complications. Due to the risk of hepatitis following the immune reconstitution, an antiviral therapy should be considered in the case of sudden discontinuation of csDMARDs or bDMARD.

Hematopoietic Stem Cell Transplant (HSCT) Utilizing Reduced Intensity Conditioning without Radiation Is an Effective Treatment for Children with Sickle Cell Disease Using Alternative Donors

Sickle cell disease can be cured with allogeneic HSCT. However, graft rejection and treatment related morbidity remains an obstacle in treating these patients with HSCT. Consequently, the intensity of the preparative regimen is crucial in establishing a balance between low treatment related morbidity and durable engraftment. <b>Methods and Materials:</b> This is a single center retrospective analysis of pediatric HSCT recipients that received non-radiation containing reduced intensity conditioning from September, 2016, to present. The patients were all conditioned with distal alemtuzumab (d-23 thru d-20), fludarabine (d-7 thru d-2), thiotepa (d-3) and melphalan (d-2). GvHD prophylaxis consisted of MMF and tacrolimus for all patients. Haploidentical transplants received posttransplant cyclophosphamide, and mismatched sibling donors received prednisone. Bone marrow was the preferred graft source. G-CSF was given to donors with a significant weight discrepancy to recipient. <b>Results:</b> Three patients with sickle cell disease received this non-radiation containing reduced intensity regimen utilizing distal alemtuzumab. Neutrophil and platelet engraftment were timely. No life threatening complications were incurred posttransplant. Acute GvHD (grade I skin) occurred in one patient, and there has been no chronic GvHD in 2 evaluable patients. Donor engraftment has been 100% in whole blood and CD3+ compartments in all 3 patients. All 3 patients remain transfusion free with serum hemoglobin near normal range. <b>Conclusion:</b> Reduced intensity conditioning utilizing distal alemtuzumab and no radiation results in durable engraftment with no significant GvHD in this small number of patients with sickle cell disease with complications. Risk of viral reactivation, especially CMV, remains high in patients receiving alemtuzumab containing conditioning.

A Cost-Effectiveness Analysis of Performing Hepatitis B Screening Before Solid-Tumor Chemotherapy

Currently, routine screening for hepatitis B virus (HBV) infection is recommended for patients at risk for viral reactivation, including those

Fast CMV and EBV Reactivations after Ruxolitinib for Graft-Versus-Host Disease Treatment

Introduction: Corticosteroid-refractory graft-versus-host disease (GVHD) remains a serious complication of hematopoietic stem cell transplantation (HSCT) with high morbidity and mortality rates. Unfortunately, no standard therapy exists for this setting. Ruxolitinib (ruxo), an oral selective Janus-associated kinase (JAK) inhibitor, achieved good results for corticoresistant acute and chronic GVHD in preclinical and clinical studies, with 80% overall response rates. Recent studies showed an increased risk of infections in patients treated with ruxo, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivations. Patients and methods: In order to assess the efficacy and the safety of ruxo, we reviewed here the outcome of 57 patients who received ruxo for corticosteroid-refractory GVHD (in case of digestive tract involvement or in the absence of available ongoing clinical trials) or as a steroids-sparing medication. EBV and CMV reactivation risks were also assessed in the 137 consecutive patients received HSCT between January 1, 2012 and December 31, 2017 and who presented acute or chonic GVHD (57 of whom received ruxo). For this purpose, each reactivation were analyzed separately as a competing risk with death in a cause specific Cox model of survival after the first GVHD occurrence and the onset of ruxo therapy was coded as time dependent covariate. Results: The median age of 57 patients with ruxo was 55 years (range, 49 to 61). Indication for HSCT was acute myeloid leukemia for 25% patients, lymphoma for 30%, acute lymphoblastic leukemia for 11%, myeloproliferative neoplasm for 14% and myelodysplastic syndrome for 7%. Only 9% of this patients received ruxo before HSCT. Unrelated donor was used for 60% patients and main source of hematopoietic stem cells was peripheral stem cells (93%). T cell depletion with polyclonal anti-thymocyte globulin was performed for 89% of patients. Conditioning with high doses cyclophosphamide was used for 21% patients. A lymphopenia &lt;1G/L persisted at day 100 for 42/51 patients evaluated. In these 57 patients, ruxo was given for 62 episode of GVHD (acute: 21 [which 95% for an acute grade III-IV GVHD]; chronic: 36; overlap syndrome: 5). Response rates to ruxo were 48% for acute GVHD, 60% for overlap syndrom and 58% for chronic GVHD. The overall GVHD related-death rate was 33% (19% for acute GVHD and 14% for chronic GVHD). Our median follow-up was 30 months (range, 9 to 42) after HSCT. Main non-infectious adverse events were cytopenias (17/57) and hepatic cytolysis (6/57) leading to discontinuation or tapering of ruxo in 12 patients. EBV reactivation (&gt; 4 log or increasing viral charge of 0.5 log) occurred in 19 patients after ruxo with a 6-weeks cumulative incidence (6WCuI) of 22% (95CI [95% confidence interval]: 15-34). It was the first reactivation in 13 patients. CMV reactivation (&gt; 3 log) occurred in 8 patients after ruxo with a 6WCuI of 4% (95CI: 7-25). It was the first reactivation in 3 patients (Figure 1). The distribution of first reactivation before ruxo and in the remaining 80 patients is shown in Table 1. Thus, 6WCuI of first EBV and CMV reactivation after the first episode of GVHD was 24% (95CI: 19-31) and 20% (95CI: 15-25) respectively. Finally, onset of ruxo coded as time dependent covariates retained a significant adverse prognostic value for the competing risks of death and first episode of EBV reactivation (HR [Hazard Ratio]: 2,657, p&lt;0,05) as well as first episode of CMV reactivation (HR: 1,747, p&lt;0,05) after first episode of GVHD. Discussion /Conclusion: Ruxo initiation coded as a time-dependent covariate was significantly associated with the overall risk of viral reactivation after the first episode of GVHD and the viral reactivations incidences after ruxo were similar with the incidence of reactivation at the onset of GVHD. Thus, it might be linked to the immuno-compromised state induced by both HSCT and GVHD. Furthermore, as we used ruxo for serious gastro intestinal GVHD, we could have selected patients with a more severe GVHD, requiring multiple immunosuppressive therapy, worsening immune reconstitution. To our knowledge it is the first study to assess the competing risk of CMV and EBV reactivation during ruxo treatment for GVHD. Given its effectiveness in corticoresistant GVHD, ruxo use must not be limited by the fear of viral reactivation at the light of our data, conditioned upon a close monitoring of viral loads in the first weeks. Disclosures No relevant conflicts of interest to declare.

Hepatitis B virus and hepatitis C virus infection in immunocompromised patients.

To provide an update on recent studies of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in cancer patients with an emphasis on viral reactivation after cancer treatment, new antiviral therapies, and safety concerns. The diagnostic criteria for HBV reactivation in patients receiving cancer therapy were revised in 2018. HBV reactivation in these patients is preventable, even with the use of new cancer therapies. HCV reactivation also has been reported in cancer patients, particularly those with hematologic malignancies, and is not a virologic condition usually associated with poor outcome. Prophylaxis to prevent HCV reactivation is not recommended because therapy with direct-acting antivirals eradicates the infection in the majority of cancer patients. Cancer patients with HBV or HCV infection are at risk for viral reactivation, with many similarities between these two infections. Patients at high risk for reactivation will benefit significantly from taking oral antivirals, which will reduce the risk of HBV reactivation or prevent development of HCV reactivation following its virologic cure.

Particulate matter exposure increases JC polyomavirus replication in the human host

BackgroundHuman polyomaviruses (HPyVs) asymptomatically infect the human population during childhood and establish latency in the host. Viral reactivation and urinary excretion can occur when the immune system is impaired. Exposure to particulate air pollution, including the PM10/PM2.5 components, is a public health problem and has been linked to several disorders. Studies assessing the relationship between PM10/PM2.5 exposure and viral replication are lacking. ObjectivesTo investigate the relationship between HPyVs viruria and PM10/PM2.5 exposures. MethodsIndividual environmental exposure was assessed in 50 healthy adult volunteers using a chemical transport model (CTM) with a municipality resolution for daily PM10 and monitoring stations data for daily PM2.5 exposures. For each subject, a urine sample was collected, and HPyVs (JCPyV, BKPyV, MCPyV, HPyV6, HPyV7 and HPyV9) loads were determined. Zero-inflated negative binomial (ZINB) regression was used to model the count data, as it contained excessive zeros. Covariates were chosen by stepwise selection. ResultsHPyVs DNA was detected in 54% (median:87.6*105 copies/ml) of the urine samples. JCPyV was the prevalent (48%, (median viral load:126*105 copies/ml). Considering the load of the most frequently measured HPyVs, JCPyV, in the count-part of the ZINB model, every unitary in PM measured 2 days before urine collection (PM Day −2) was associated with an increase in JCPyV load (PM10: +4.0%, p-value = 0.002; PM2.5: +3.6%, p-value = 0.005). In the zero-part, the significant predictor was the PM10 measured 5 days before urine collection (+3%, p-value = 0.03). ConclusionsThe environmental levels of PM10/PM2.5 increase the JCPyV viruria. Our findings emphasize the need for studies assessing the influence of air pollution exposure on the risk of viral reactivation.

Viral Hepatitis B during Chronic Inflammatory Bowel Diseases at Fez University Hospital: Prevalence and Risk Factors

Patients with chronic inflammatory bowel diseases (IBD) have long been considered at risk for viral hepatitis B. However, recent epidemiological studies have found similar prevalence, or even lower than in the general population. The objective of this work is to determine the prevalence of viral hepatitis B (HVB) during IBD, to determine the risk factors in the service of Hepato-gastroenterology of university hospital Hassan II-Fez, and of evaluate the impact on therapeutic management. PATIENTS AND METHODS: This is a retrospective study, spread over a period of 17 years and a half (January 2001-June 2017). All patients treated for IBD who are tested for Hbs Ag and anti Hbcwere included. The HVB DNA levels were tested in case of positivity of HbsAgor anti Hbc. Results: Over the study period, 755 patients were included. The average age of our patients was 35 years [14 - 87] with a sex-ratio H/F of 0.67. We had 391 cases (51.8%) of Crohn’s disease (CD) and 364 cases (48.2%) of ulcerative colitis (UC). Anti HBctest was positive in 1.98% of cases (N = 15). In these patients, HBsAg was positive in 1.19% of cases (N = 9). The prevalence of HVB was 2.55% in CD (N = 10) versus 1.37% in UC (N = 5). In our work, no history of surgery, digestive endoscopy or transfusion has been shown to be a risk factor for viral transmission. CONCLUSION: The prevalence of HVB in IBD is similar to that of the general population. The safety of blood transfusions and the improvement of asepsis probably explain these results. However, the risk of viral reactivation during HVB, sometimes fatal under immunosuppressive treatment, requires systematic screening.

Using clinical databases to verify the impact of Japanese regulatory agency alerts: Hepatitis B testing behavior after an alert regarding risk of viral reactivation

Using clinical databases to verify the impact of Japanese regulatory agency alerts: Hepatitis B testing behavior after an alert regarding risk of viral reactivation

Reactivation of hepatitis B virus after withdrawal of erlotinib.

Reactivation of hepatitis B virus (hbv) is a reported complication for patients undergoing chemotherapy, particularly immunochemotherapy with anti-CD20 agents such as rituximab. However, as the use of molecularly targeted agents increases, the risk of viral reactivation is less clearly defined. Here, we present the case of a 62-year-old woman with newly diagnosed EGFR mutation-positive metastatic non-small-cell lung cancer (nsclc). Per interview, our patient had a remote history of hbv infection. She was started on erlotinib and developed profound diarrhea leading to renal failure that required hospital admission and temporary discontinuation of erlotinib. At 8 days after erlotinib cessation, she had a marked spike in her liver function tests, with viral serologies that were consistent with hbv reactivation. Although erlotinib and other tyrosine kinase inhibitors (tkis) are not classically associated with hbv reactivation, hbv reactivation can occur even in the setting of tki withdrawal. Before tki initiation, careful patient screening in those at risk for hbv should be performed to attenuate preventable hepatotoxicity and to differentiate between other causes of hepatotoxicity (for example, drug-induced toxicity).

The hepatitis B virus reactivation after transarterial chemoembolization in Chinese hepatocellular carcinoma patients with low serum hepatitis B virus DNA level.

ObjectiveTo investigate the reactivation of the hepatitis B virus (HBV) following transarterial chemoembolization (TACE) in Chinese hepatocellular carcinoma (HCC) patients with low serum HBV DNA level, and to analyze the factors related to HBV reactivation in HCC patients with low serum HBV DNA level.MethodsFrom November 2011 to January 2014, 109 patients newly diagnosed with HCC with an HBV DNA level less than 2,000 IU/mL were enrolled in the study. These patients underwent at least two TACE procedures and were followed-up for at least 3 months to assess the reactivation of HBV DNA. Ten variables were compared in patients with and without HBV reactivation to evaluate the factors related to HBV reactivation in HCC patients with low serum HBV DNA level.ResultsOf 109 HCC patients with low level HBV DNA, nine patients were HBeAg-positive, the other 100 patients were HBeAg-negative. Twenty-three of 109 (21.1%) patients developed HBV reactivation after TACE. Of nine HBeAg-positive patients, 55.6% (5/9) developed HBV reactivation, while in 100 HBeAg-negative patients, the rate of HBV reactivation was 18% (18/100) (P=0.019). Of ten variables of patients with low level HBV DNA, the levels of AFP and HBeAg status were found to be significantly correlated with HBV reactivation. Nevertheless, on binary logistic regression analysis, only HBeAg-positive status was the independent predictor of HBV reactivation in HCC patients with low serum HBV DNA level (odds ratio, 7.41; P=0.013).ConclusionHCC patients with low serum HBV DNA level still remain associated with risk of viral reactivation after TACE, and HBeAg-positive HCC patients have a higher risk than patients with HBeAg-negative status.

Using Clinical Databases to Verify the Impact of Regulatory Agency Alerts in Japan: Hepatitis B Testing Behavior After an Alert Regarding Risk of Viral Reactivation.

BackgroundMeasures of the effectiveness of risk minimization activities are necessary for the appropriate use of drugs, and clinical databases are a low-cost method of quickly producing such results.ObjectiveThe aim of this study was to explore the secondary application of clinical databases in verifying the impact of risk minimization activities; specifically, whether such databases could be used to identify changes in hepatitis B virus testing behavior after an alert from the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan.MethodsPatient data from December 1, 2010 to November 30, 2012 were extracted from the Medical Data Vision clinical database. The percentages of patients tested for hepatitis B virus DNA (HBV-DNA), hepatitis B surface antigen (HBsAg), and hepatitis B surface antibody (HBsAb)/hepatitis B core antibody (HBcAb) were compared 1 year before (consecutive 6-month periods A and B) and 1 year after (consecutive 6-month periods C and D) a PMDA alert regarding viral reactivation in patients receiving immunosuppressive agents.ResultsData for 9866 patients in the clinical database were analyzed. After the PMDA alert, the percentage of patients tested for HBV-DNA linearly increased in periods A to D: 4.70 % (n = 262/5571), 5.78 % (n = 330/5710), 6.52 % (n = 398/6101), and 7.59 % (n = 479/6315). However, no changes were observed in the rates of HBsAg and HBcAb/HBsAb testing (around 50 and 70 %, respectively). Overall testing rates appeared to differ depending on disease and drug type.ConclusionThese findings suggest that the PMDA alert was effective at recommending HBV-DNA testing. This secondary application of clinical databases may be effective for verifying the impact of risk minimization activities.

The Impact of Donor HLA Type on Characteristics of CMV-Specific T Cell Products: Experience from Two UK Randomized Trials

ObjectiveInvestigator-led Phase I/II studies have shown that adoptive transfer of donor virus-specific cytotoxic T cell lymphocytes (CTL) can reconstitute immunity on a long-lasting basis in patients at risk for viral reactivation following allogeneic hematopoietic stem cell transplantation (allo HSCT). In an effort to provide a consistent high-purity product, it is critical to detect patterns of donor material which may predict final product quality and consequently CMV protection.MethodsWe performed two prospective studies of cytomegalovirus-specific (CMV) CTL in the UK, using a proprietary technology for direct selection of CTL based on MHC class I-multimer (Streptamer®) binding (STAGE Cell Therapeutics GmbH). Eligible donors were pre-screened for the presence of selectable CMV-specific cells by immunophenotyping with flow cytometry. Eligible HLA alleles for this selection procedure are A*0101, A*0201 (two epitopes, IE-1 and PP65), A*2402, B*0702 and B*0801. In our experience, a minimum threshold of 0.1% CD8+Streptamer+ cells of total CD3+ T cells ensures a successful selection.The table summarizes the manufacturing data from 39 products, showing that despite a large variety of donor material, these cells can be significantly enriched to produce a viable, CMV-specific T cell product. Table(n=39)MeanRange% CMV + cells in donor starting material (of CD8+)1.63%0.12 – 13.3 %% CMV+ cells in final product (of CD3+)78.59%4.48 – 99.56 %% CD3+ cells in final product62.16%10.20 – 98.51 %% viability in final product94.41%76.86 – 98.88 %T cell dose /kg infused2.45x1047.23x102 – 5.35x104Total number of T cells infused1.79x1065.63x104 – 4.20x106ResultsPre-screen results have been analyzed from 56 eligible donors. Of these donors, 40 were screened for more than one eligible HLA type. In the presence of more than one eligible allele, selection was based on the most abundant population of CD8+Streptamer+ cells.The majority of donors screened were confirmed as eligible HLA type A02 (33/56), closely followed by A01 and B07 (both 22/56). However the alleles found to be the most dominant for Streptamer binding (giving the highest percentage of positive cells in these pre-screens) were A01 and B07 (both 11/20). Thus while A02 is a more frequent allele in the studied donor population, it is often subdominant in the presence of another Streptamer-eligible allele. Where A01 is present in combination with one other allele, A01 is more frequently dominant.We also investigated whether the allele chosen for the selection procedure was predictive of the purity (CD3+Streptamer+) of the final CMV CTL product. We examined 39 selections. The majority of selections (22/39) were performed on A02-PP65. The selections produced a varying product with a purity range of 4.48% - 99.56% (SD 30.9%). Our data suggests that A01 and B07 are more indicative of a high purity CMV selection, however this was not demonstrated beyond statistical significance when compared to A02-PP65 (A01, p-value=0.34, B07, p-value=0.15).Other factors were observed that influence product purity. The percentage of CD3+ cells and the total number of Streptamer positive cells in the starting material were also key variables for predicting the purity of the selection. Pre-screen results were not found to have a direct correlation with product purity. We investigated whether a successful pre-screen can be predicted on the presence of a single HLA type, regardless of other alleles present. A donor is least likely to have a selectable population for A24 or A02-IE-1. A01(median pre-screen 0.61%) and B07 (median pre-screen 0.53%) donors are more likely to have a positive pre-screen compared to the other alleles.ConclusionCell Medica is developing a model for centralized production and delivery of CMV-specific CTL for transplant centers across Europe. Interrogation of historical data demonstrates important patterns for donor selection and effective pre-screen methods to ensure a consistent and high quality cell product. Further investigation is required to determine the impact of donor selection and product purity on CMV protection in patients. In addition, functional analysis of the specific cells may also be an important factor to consider in the donor and selectable epitope screening process. DisclosuresSkulte:Cell Medica: Employment. Mitra:Cell Medica: Employment. Thomas:Cell Medica Ltd: Employment. Cobb:Cell Medica Ltd: Employment. Stansfield:Cell Medica: Employment. Newton:Cell Medica Ltd: Employment.

Detection of different virus-specific CD8+ T cells after kidney transplantation.

The early diagnosis of viral reactivation after kidney transplantation (KTX) is an unsolved problem. Survey of virus-specific T-cell responses may identify patients at risk for viral reactivation. We therefore quantified virus-specific CD8+ T-cells to evaluate their potential predictive value for viral reactivation and infection in KTX patients. We quantified the virus-specific responses of CD8+ T-cells for CMV, EBV, HPV and HHV in 23 patients undergoing KTX for 6 mo after transplantation. We enumerated T-cells for 36 virus-specific binding peptides and five different human leukocyte antigen (HLA) alleles through the binding of Class I iTAg major histocompatibility complex (MHC) tetramers. The patients' pre-operative serologic status for CMV and CMV-specific CD8+ T-cell numbers were correlated with one another (p=0.0046). Three patients had clinical CMV disease and all three remained or became CMV-tetramer-positive for at least one HLA allele during follow-up. Three of the four patients with viral infections caused by or reactivations of viruses other than CMV were initially negative for CMV-specific CD8+ T-cells but became CMV-positive. Most of the patients who were initially CMV-tetramer positive also had tetramer-positive T-cells specific for Epstein-Barr virus (EBV); human papillomavirus (HPV)-6b, -11, -16, or -18; or human herpesvirus (HHV)-8. All of the patients who developed viral disease other than that caused by CMV remained or became positive for at least one binding peptide that was specific for a virus not directly related to the clinical features of a viral disease. Patients who were positive for any virus had a significantly greater risk of developing complications of viral disease during the 6-mo follow-up period in the study (p=0.026), suggesting a general susceptibility to viral reactivation. The evaluation of virus-specific CD8+ T-cells may prospectively help to identify patients at risk for viral reactivation after KTX.

Reactivation of human polyomaviruses in immunocompromised states

Infection with various human polyomaviruses (HPyVs) is prevalent, with rates as high as 80 % within the general population. Primary infection occurs during childhood through respiratory or urino-oral transmission. While the majority of individuals exhibit asymptomatic latent infection, those immunocompromised persons are at risk for viral reactivation and disease progression resulting in conditions such as progressive multifocal leukoencephalopathy (PML), trichodysplasia spinulosa, Merkel cell carcinoma, and polyomavirus associated nephropathy. Individuals with altered immune systems due to HIV, organ transplantation, lymphoproliferative diseases, and monoclonal antibody therapy are particularly susceptible to reactivation of various HPyVs. While the specific factors that induce lytic infection have yet to be defined, it is evident that dysfunctional host cellular immune responses allow active infection to occur. Immunosuppressant conditions, such as in chronic alcohol abuse, may serve as added risk factors for reactivation of HPyVs. Since the human HPyV family is rapidly expanding, continuing studies are needed to characterize the role that known and newly discovered HPyVs play in human disease.