Preemptive Antiviral Treatment Research Articles

Implementation of CMV-T-Track® in Clinical Routine to Guide Management of CMV Reactivation

Background: Despite Letermovir prophylaxis, reactivation of cytomegalovirus (CMV), requiring close monitoring and preemptive antiviral treatment, remains to be an issue after allogeneic hematopoietic stem cell transplantation (HSCT). Monitoring CMV-specific cellular immunity can help to identify patients at risk and may guide monitoring intervals and therapeutic decisions. CMV T-Track®, a standardized IFN-γ ELISpot assay, conducted after the end of treatment of a first CMV reactivation was shown to identify patients at risk of recurrent reactivation with a positive predictive value (patients with a negative test after the first CMV reactivation had a subsequent recurrent CMV reactivation) of 80%. As these results originate from a clinical trial with a distinct patient population, we analyzed its usefulness and value within the clinical routine. Here we describe the results within the clinical routine in an unselected patient cohort and the influence of different GvHD prophylaxis on T-Track® outcome, as well as factors promoting CMV reactivation despite positive test results. Methods: In total, 169 patients were monitored for CMV reactivation with CMV-PCR for 365 days after HSCT and CMV immunity was measured using CMV T-Track® at d+100. CMV T-Track® was repeated at d+200 and+ 300 in case of a negative first test result d+100. Patient characteristics: 125 patients received ATG, 24 Alemtuzumab i.v. and 12 ptCy. 8 patients were transplanted from an HLA-identical sibling and received no T cell depleting (TCD) agent. CMV-serostatus: Donor(D)+/recipient(R)+ in 123, D+/R- in 9, D-/R+ in 34 and D-/R- in 3 patients. All CMVpos recipients received Letermovir prophylaxis until d+100. Results: At d+100 164/169 tests produced a robust result, only 5 tests were invalid. 110 patients had a positive T-Track® at d+100, with a higher percentage in patients with a CMVpos donor (99/132 (75%) vs. (10/37 (27%)). After Alemtuzumab we observed the lowest rate of positive T-Track® 10/24 (42%) at d+100, followed by ATG 83/125 (66%), whereas pTCy showed a good response 11/12 (92%). Only 5/8 (63%) patients without TCD had a positive test result. 9/10 (90%) of patients with a positive T-Track® d+100 despite a CMVneg donor had a positive CMV-PCR before d+100, whereas only 3/27 (11%) CMVireamias were detected in those without CMV immunity. In patients with a CMVpos donor 59/108 (55%) had a documented reactivation leading to a positive T Track®, in contrast to 9/33 (27%) with a negative T-Track®. 18/20 (90%) patients developed a positive T-Track® at d+200 after CMViraemia between d+100 and d+200. 24 patients were persistently negative at d+300. Despite a positive T-Track® at d+100, 28/110 (25%) patients needed treatment for CMV reactivation. In most of them immunosuppressive treatment for GvHD was initiated after d+100: 20/28 (71%) high dose corticosteroids, 1/28 (4%) Ruxolitinib. Excluding patients, that received additional immunosuppression after d+100 only 7/89 (8%) developed a CMV reactivation despite a positive d+100 T-Track®. This yields a negative predictive value of 0,921 for the result of T-Track® at d+100. 25/59 (42%) patients with a negative T-Track® at d+100 subsequently developed a treatment requiring CMV reactivation. Discussion/Conclusion: CMV T-Track® is feasible in clinical routine and can help identify patients at risk for CMV reactivation. In our cohort 110/169 (65%) patients showed a cellular immune response against CMV at day +100. Excluding patients that received additional immunosuppression in the later course, only 7/89 (8%) developed a CMV reactivation after a positive d+100 T-Track®. With this T-Track® result at d+100 has a negative predictive value of 0,921. CMV negative donor was the strongest predictor for a negative test result. Alemtuzumab was the only TCD associated with a negative impact. CMVireamia increases CMV immune response and is mandatory in patients with a CMV negative donor to establish CMV-immunity. We therefore consider CMV T-Track® a useful tool in clinical routine to identify patients with sufficient CMV-immunity at d+100. This could help to guide monitoring intervals or therapeutic decisions such as prolonged prophylaxis or need for preemptive treatment.

Impact of Cytomegalovirus Replication in Patients with Aggressive B Cell Lymphoma Treated with Chimeric Antigen Receptor T Cell Therapy

Data are scarce on cytomegalovirus (CMV) replication in patients receiving CD19-directed chimeric antigen receptor (CAR) T cell treatment. Here we describe the incidence, severity, and management of CMV infection in patients with aggressive B cell lymphoma treated with CAR T cell therapy. In this retrospective observational study, we analyzed CMV viral load and its clinical impact in patients with aggressive B cell lymphoma receiving CAR T cell therapy between July 2018 and December 2021 at a single center. Patients with a negative baseline CMV IgG or a previous allogeneic stem cell transplantation were excluded. CMV replication was determined in whole blood. Overall, 105 patients met the study's inclusion criteria. Ten patients presented with CMV replication before CAR T cell infusion and were analyzed separately. Forty-two of the remaining 95 patients (44%) had at least 1 positive CMV determination, with a viral load ≥1000 IU/mL in 21 patients (22%). Four patients in the main cohort (N=95) and 4 patients in the preinfusion replication group (N=10) achieved a viral load >10,000 IU/mL. Only 7 patients received preemptive antiviral treatment. No CMV end-organ disease was reported. The sole independent risk factor associated with CMV viremia ≥1000 IU/mL was dexamethasone treatment (odds ratio, 8.4; 95% confidence interval, 2.4 to 36.6; P=.002). Based on our findings, we designed an algorithm for CMV management in this setting. CMV replication is relatively frequent in patients with aggressive B cell lymphoma receiving CAR T cell therapy. It is usually self-limited and not associated with end-organ disease. Patients receiving dexamethasone or harboring CMV replication before infusion might benefit from active surveillance and preemptive treatment strategies.

Prevention of hepatitis B reactivation in patients requiring chemotherapy and immunosuppressive therapy.

Hepatitis B virus (HBV) reactivation can lead to severe acute hepatic failure and death in patients with HBV infection. HBV reactivation (HBVr) most commonly develops in patients undergoing cancer chemotherapy, especially B cell-depleting agent therapy such as rituximab and ofatumumab for hematological or solid organ malignancies and that receiving hematopoietic stem cell transplantation without antiviral prophylaxis. In addition, the potential consequences of HBVr is particularly a concern when patients are exposed to either immunosuppressive or biologic therapies for the management of rheumatologic diseases, inflammatory bowel disease and dermatologic diseases. Thus, screening with HBV serological markers and prophylactic or pre-emptive antiviral treatment with nucleos(t)ide analogues should be considered in these patients to diminish the risk of HBVr. This review discusses the clinical manifestation, prognosis and management of HBVr, risk stratifications of cancer chemotherapy and immunosuppressive therapy and international guideline recommendations for the prevention of HBVr in patients with HBV infection and resolved hepatitis B.

Cytomegalovirus Prophylaxis versus Pre-emptive Strategy: Different CD4+ and CD8+ T Cell Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation

Reconstitution of T cells after transplantation is a determinant of the long-term success of the procedure, and the correlation with T cell recovery and cytomegalovirus reactivation and disease is well known. We evaluated 110 patients who underwent transplantation: 55 received pre-emptive antiviral treatment, and in the other 55 patients, prophylaxis with letermovir was employed. A progressive statistically significant difference in T cell reconstitution between the 2 groups was observed, starting from day +60 with faster recovery in the pre-emptive group. Moreover, a higher incidence of cytomegalovirus reactivation was observed in prophylactic group after discontinuation of letermovir, and subsequent antiviral treatment has been necessary. Our findings confirm, as previously reported, that cytomegalovirus reactivation is a potent stimulator of T cell function.

Management of Hepatitis B Virus in Allogeneic Hematopoietic Stem Cell Transplantation.

The high morbidity of HBV reactivation following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is partially due to the intense immunologic potency of complex therapeutic regimens, the use of antithymocyte globulin and calcineurin inhibitors to prevent graft versus-host disease (GVHD), prolonged immune reconstitution, and hematological malignancies infected with hepatitis B virus (HBV). Immunosuppression results in the reactivation of HBV replication from covalently closed circular DNA (cccDNA) residing in hepatocytes. However, the role of viral mutations during HBV reactivation needs to be validated. All individuals scheduled to receive allo-HSCT or wish to donate stem cells should be screened for hepatitis B surface antigen (HBsAg), antibodies to hepatitis B core (anti-HBc), and HBV-DNA. HBsAg-positive recipients of allo-HSCT have a high risk of HBV reactivation; thus, they should receive prophylactic antiviral therapy. The high barrier to resistance nucleos(t)-ide analogs (NAs) seems to be superior to the low barrier agents. Resolved-HBV recipients have a lower risk of HBV reactivation than HBsAg-positive recipients. Although prophylactic antiviral therapy remains controversial, regular monitoring of alanine transaminase (ALT) and HBV-DNA combined with preemptive antiviral treatment may be an optimized strategy. However, optimal antiviral therapy duration and time intervals for monitoring remain to be established. Accepting stem cells from HBsAg-positive donors is associated with a risk of developing HBV-related hepatitis. The overall intervention strategy, including donors and recipients, may decrease the risk of HBV-related hepatitis following HSCT from HBsAg positive stem cells. In this review, we summarize the issues of HBV in allo-HSCT, including HBV reactivation mechanism, HBsAg-positive recipients, HBV-resolved infection recipients, and donor-related factors, and discuss their significance.

Vaccination of Hematopoietic Stem Cell (HCT) Donors with Triplex, a Novel Cytomegalovirus Vaccine: Safety, Feasibility and Adoptive Transfer of Protective CMV-Specific T Cells in HCT Recipients

An innovative approach to protect hematopoietic cell transplant (HCT) recipients from cytomegalovirus (CMV) viremia early after transplant is vaccinating the donor prior to stem cell harvest, before the recipient can achieve adequate immune responses. Triplex vaccine, a recombinant modified vaccinia Ankara expressing immunodominant CMV antigens (pp65, IE1 and IE2), is being evaluated in a Phase 1 trial (NCT03560752) to immunize donors of CMV seropositive (CMV+) recipients. Triplex, developed to elicit and enhance protective CMV-specific T cells, is a promising vaccine that demonstrated excellent tolerability and immunogenicity in healthy adults (La Rosa et al., Blood 2017), and in HCT CMV seropositive recipients, who had a 50% reduction in CMV reactivation requiring preemptive antiviral therapy, and significantly enhanced CMV-specific immune responses (Aldoss et al. AIM, 2020). Aim of the current Phase I trial is to assess a proof of concept and preliminary results of safety, feasibility and transfer of CMV-specific immunity, in recipients receiving an HCT from a matched related donor (MRD), vaccinated with Triplex. After obtaining informed consent, 18-75 year old HCT recipients (CMV seropositive) with matched related donors underwent T cell replete HCT. Donors received one Triplex injection 10-60 days prior to start of stem cell mobilization, and recipients underwent HCT within 9 weeks of donor vaccination. As per standard of care, Triplex vaccinated donors were mobilized with granulocyte colony-stimulating factor, prior to apheresis. The study has a target of 18 HCT donor/recipient pairs. All HCT recipients are followed until day 365 post-HCT for safety, virologic and immunologic assessment. All donors are monitored for vaccine induced adverse events. Antiviral treatment for viremia is considered a failure of donor vaccination to provide protection to the recipient. As of July 2020, we have safely vaccinated 9 MRD with Triplex, and infused mobilized peripheral blood stem cells, with T cells by volume approximately 10-25% to their recipients. No adverse events, possibly or likely related to the vaccine were reported. No preemptive antiviral treatment was administered to any of the HCT recipients. Six donor/recipient pairs have reached study end, and immune monitoring has been completed. Two donor/recipient pairs have been evaluated immunologically for up to 6 months and one to day 100 post-HCT. The flow cytometry panel of cellular immune assays included measuring concentrations of CMV-specific T cells expressing the 4-1BB (CD137) activation marker, and assessing the memory phenotype profiles (performed as detailed in La Rosa et al., Blood 2017). Peripheral blood mononuclear cells (PBMC) were stimulated for 24 hours with either pp65, IE1 and IE2 overlapping 15mer peptide libraries and then stained with fluorescently tagged antibodies against CD137, CD3, CD8, CD4, combined with CD28 and CD45RA memory markers by using a Beckman-Coulter Gallios cytometer with Kaluza software. Early post-HCT development of robust and long-lasting frequency of pp65-, IE1- and IE2-specific CD4 and CD8 T cells was observed in all recipients (Figure 1A). Memory profiles of CMV specific T cells had marked prevalence of effector memory phenotype early post-HCT, which persisted over time. Interestingly, on day 28 post-HCT, pp65-specific CD8 T cell levels were significantly higher in the 9 recipients who received an HCT from a Triplex vaccinated MRD compared to a control cohort of consecutively enrolled MRD HCT recipients (Figure 1B). In summary, this is the first clinical trial to assess the possible benefit of vaccinating MRD, to elicit early CMV immune recovery in CMV seropositive HCT recipients, at high risk for developing CMV serious complication after HCT. The approach is feasible and highly tolerable, with promising evidence of efficacy, indicating that Triplex vaccination of the MRD confers early protective anti-CMV immunity to the HCT recipient. Clinical and immunological outcomes from the ongoing study indicate that this novel immune therapeutic strategy provides a safer alternative to antivirals, including letermovir prophylaxis and may find application in higher CMV risk patients, such as haploidentical HCT recipients. Figure 1 Disclosures Nakamura: Viracor: Consultancy; Celgene: Other: Support on seminar; Kyowa-Kirin: Other: Support on a meeting presentation; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; Magenta Therapeutics: Other: Advisory board meeting; NapaJen Pharma: Consultancy; Kadmon Corporation: Other: Advisory board meeting. Diamond:Helocyte: Consultancy.

Assessing Anti-HCMV Cell Mediated Immune Responses in Transplant Recipients and Healthy Controls Using a Novel Functional Assay.

HCMV infection, reinfection or reactivation occurs in 60% of untreated solid organ transplant (SOT) recipients. Current clinical approaches to HCMV management include pre-emptive and prophylactic antiviral treatment strategies. The introduction of immune monitoring to better stratify patients at risk of viraemia and HCMV mediated disease could improve clinical management. Current approaches quantify T cell IFNγ responses specific for predominantly IE and pp65 proteins ex vivo, as a proxy for functional control of HCMV in vivo. However, these approaches have only a limited predictive ability. We measured the IFNγ T cell responses to an expanded panel of overlapping peptide pools specific for immunodominant HCMV proteins IE1/2, pp65, pp71, gB, UL144, and US3 in a cohort of D+R– kidney transplant recipients in a longitudinal analysis. Even with this increased antigen diversity, the results show that while all patients had detectable T cell responses, this did not correlate with control of HCMV replication in some. We wished to develop an assay that could directly measure anti-HCMV cell-mediated immunity. We evaluated three approaches, stimulation of PBMC with (i) whole HCMV lysate or (ii) a defined panel of immunodominant HCMV peptides, or (iii) fully autologous infected cells co-cultured with PBMC or isolated CD8+ T cells or NK cells. Stimulation with HCMV lysate often generated non-specific antiviral responses while stimulation with immunodominant HCMV peptide pools produced responses which were not necessarily antiviral despite strong IFNγ production. We demonstrated that IFNγ was only a minor component of secreted antiviral activity. Finally, we used an antiviral assay system to measure the effect of whole PBMC, and isolated CD8+ T cells and NK cells to control HCMV in infected autologous dermal fibroblasts. The results show that both PBMC and especially CD8+ T cells from HCMV seropositive donors have highly specific antiviral activity against HCMV. In addition, we were able to show that NK cells were also antiviral, but the level of this control was highly variable between donors and not dependant on HCMV seropositivity. Using this approach, we show that non-viraemic D+R+ SOT recipients had significant and specific antiviral activity against HCMV.

Ultra-high sensitivity HBsAg assay can diagnose HBV reactivation following rituximab-based therapy in patients with lymphoma

HBV reactivation is a risk in patients receiving anti-CD20 antibodies for the treatment of lymphoma. The purpose of this post hoc analysis was to evaluate the efficacy of an ultra-high sensitivity HBsAg assay to guide preemptive antiviral treatment in patients with lymphoma and resolved HBVinfectionsusing prospectively stored samples from an HBV DNA monitoring study. HBV reactivation (defined as HBV DNA levels of ≥11IU/ml) was confirmed in 22 of 252 patients. A conventional HBsAg assay (ARCHITECT, cut-off value: 0.05 IU/ml) and an ultra-high sensitivity HBsAg assay employing a semi-automated immune complex transfer chemiluminescence enzyme technique (ICT-CLEIA, cut-off value: 0.0005 IU/ml) were performed at baseline, at confirmed HBV reactivation and monitored after HBV reactivation. Baseline HBsAg was detected using ICT-CLEIA in 4 patients; in all of whom precore mutants with high replication capacity were reactivated. Of the 6 patients with HBV DNA detected below the level of quantification at baseline, 5 showed HBV reactivation and 3 of the 5 had precore mutations. Sensitivity for detection by ARCHITECT and ICT-CLEIA HBsAg assays at HBV reactivation or the next sampling after HBV reactivation was 18.2% (4 of 22) and 77.3% (17 of 22), respectively. Of the 5 patients undetectable by ICT-CLEIA, HBV reactivation resolved spontaneously in 2 patients. All 6 patients reactivated with precore mutations including preS deletion could be diagnosed by ICT-CLEIA HBsAg assay at an early stage of HBV reactivation. Multivariate analysis showed that an anti-HBs titer of less than 10 mIU/ml, HBV DNA detected but below the level of quantification, and HBsAg detected by ICT-CLEIA at baseline were independent risk factors for HBV reactivation (adjusted hazard ratios, 15.4, 31.2 and 8.7, respectively; p <0.05). A novel ICT-CLEIA HBsAg assay is an alternative method to diagnose HBV reactivation. UMIN000001299. Hepatitis B virus can be reactivated in lymphoma patients receiving anti-CD20 antibodies such as rituximab. Currently, reactivation requires the monitoring of HBV DNA, but monitoring of the surface antigen (HBsAg) could provide a relatively inexpensive, quick and easy alternative. We assessed the performance of an ultra-high sensitivity HBsAg assay and showed that it could be effective for the diagnosis and monitoring of HBV reactivation.

Cytomegalovirus reactivation after bortezomib treatment for multiple myeloma and light chain amyloidosis

Cytomegalovirus (CMV) is an opportunistic herpesvirus, and reactivation of infection is possible in immunocompromised patients. Historically, the risk for haematology patients is restricted to those treated with an allogeneic transplant or T-cell depleting agents. Bortezomib is a highly efficacious proteasome inhibitor widely used to treat multiple myeloma and light chain (AL) amyloidosis patients. The objective of this small prospective study was to quantify the risk of CMV reactivation associated with bortezomib treatment. Fifty-seven consecutive multiple myeloma or AL amyloidosis patients commencing bortezomib-based therapy were included. Viral copy numbers were established at baseline and then at fortnightly intervals during treatment. Pre-emptive anti-viral treatment was initiated in patients with a viral load >7500copies/mL. Reactivation of CMV was detected in 39% (n=12/31) of seropositive bortezomib treated patients compared with 0% of CMV seronegative patients. Detectable DNAemia developed during the first two cycles of treatment in 83% (n=10/12) patients. Anti-viral treatment was initiated in 42% (n=5/12), but no cases of active CMV disease were seen. This study suggests that there is a substantial risk of CMV reactivation in CMV-seropositive plasma cell dyscrasia patients treated with bortezomib.

New considerations in hematopoietic stem cell transplantation for severe combined immunodeficiency: how did newborn screening change our field, and can we finally brake the glass ceiling for haploidentical transplantation?

Pioneered in 1968, hematopoietic stem cell transplantation (HSCT) first cured a patient with severe combined immune deficiency (SCID) transplanted from a matched sibling, bringing hope for this previously fatal disease. Since then, HSCT has become the standard of care treatment for SCID with thousands of patients transplanted successfully worldwide. Initially successful mainly in patients with a matched sibling donor and in specific easier to transplant types of SCID, nowadays, most patients with SCID undergo successful transplantation due to HSCT technique advances. These include refined human leukocyte antigen (HLA)-tissue typing, use of alternative donors, availability of new stem cell sources such as umbilical cord blood, less toxic chemotherapeutic conditioning, as well as improved graft-versus-host disease (GvHD) prophylaxis. Other factors contributing to the success of transplantation include the improvement of supportive care by molecular detection of viral infections, enabling preemptive antiviral treatment before organ damage occurs. Increased awareness for primary immunodeficiency disorders (PID), leading to earlier diagnosis and referral to specialist centers, has been another important factor in successfully transplanting SCID patients. A major game changer in the last decade has been the implementation of neonatal screening for SCID. This increased early diagnosis, allowing for this disease to be almost universally diagnosed soon after birth in countries which included this test in their newborn screening program. As a result, early and optimal transplant timing and conditions could be achieved. However, very early diagnosis also raised new questions regarding SCID patients with a “leaky” phenotype, as well as dilemmas regarding transplant and conditioning regimens in very young infants. With improved diagnosis and treatment options, overall survival has increased to over 90% for SCID babies with a genoidentical donor and similar results are emerging for matched unrelated donor HSCT. Due to new advances, we hope to achieve similar results for those given HSCT from haploidentical donors as well. This review will focus on the new considerations in HSCT seen in recent years, and examines the effect they have had on treatment options and outcomes for SCID patients. Statement of novelty: The field of HSCT has advanced considerably since the first successful SCID bone marrow transplant in 1968. However, success rates have been limited due to delayed diagnosis and poor outcome of patients for which a HLA-matched donor could not be found. This review will discuss recent advances occurring in the last decade in HSCT for SCID, and our hopes to bring cure to this once fatal disease.

Unmet need in chronic hepatitis B management.

Despite all these exciting developments, there remain some unmet needs in the management for patients with chronic hepatitis B (CHB). As majority of CHB patients are going to use oral nucleos(t)ide analogues (NAs) for decades, Safety profile of NAs is of no doubt an important issue. The newest nucleotide analogue tenofovir alafenamide is potent in terms of viral suppression, together with favourable renal and bone safety profile. Biochemical response as reflected by alanine aminotransferase (ALT) normalization is recently found to be prognostically important. Patients who achieved ALT normalization have reduced the risk of hepatic events by 49%. Functional cure as reflected by hepatitis B surface antigen seroclearance not only implies patients may stop NA treatment, it also confers to a reduced risk of hepatocellular carcinoma and other hepatic events. Hence functional cure should be the ultimate treatment goal in CHB patients. Preemptive antiviral treatment may reduce mother-to-child transmission of hepatitis B virus, especially if birth dose of vaccination cannot be given in the first two hours after delivery. Lastly, despite the currently first-line NAs have high-genetic barrier to drug resistance mutations, there are still are many patients who were previously treated with low barrier of resistance including lamivudine, telbivudine or adefovir dipivoxil which could lead to antiviral resistance and affecting the choice of NAs.

1732. Adenovirus Load Dynamics Are Consistently Correlated With Risk of Mortality in Pediatric Allogeneic Hematopoietic Cell Transplant Recipients: Findings From the Landmark AdVance Study

BackgroundAdenovirus (AdV) infection is an important cause of mortality among allogeneic hematopoietic cell transplant (allo-HCT) recipients. Current European Conference of Infections in Leukemia (ECIL-4) guidelines support weekly AdV screening for those at-risk and pre-emptive antiviral treatment with off-label cidofovir when adenoviremia is detected. However, there is limited understanding of the relative prognostic strength of different dynamic AdV viral load measures. We examined the association between adenovirus viral load dynamics and mortality in pediatric allo-HCT recipients managed under the current standard of care.MethodsAdVance was a multinational, multicenter study characterizing the current screening and treatment practices for AdV infection in allo-HCT recipients between January 2013 and September 2015. This analysis focused on pediatric (<18 years) patients who experienced AdV viremia ≥1,000 copies/mL within 6 months of HCT. Multivariate Cox Proportional Hazard models, controlling for factors including immune reconstitution, were used to examine the relationship between AdV viral load dynamics (Figure 1) and all-cause mortality in the 6 months after first AdV viremia ≥1,000 copies/mL.ResultsA total of 241 pediatric allo-HCT recipients had AdV viremia ≥1,000 copies/mL in the 6 months following allo-HCT. Among these, 43/241 (18%) died within 6 months of first AdV ≥1,000 copies/mL. AdV viral load dynamics; whether measured by AdV AAUC0–16, peak viremia, 2-week change in viremia, or days of viremia >1,000 copies/mL, were consistently correlated with all-cause mortality (Figure 2; hazard ratio [HR] range: 1.3–2.3). Most notably, patients with AdV AAUC0–16 in the highest quartile had an HR of 11.6 relative to those in the lowest (confidence interval: 4.7–24.0; Figure 3).ConclusionAdV infection is a significant risk for allo-HCT recipients. The AdVance study has identified several dynamic measures of AdV viral load that correlate with the risk of mortality in pediatric allo-HCT recipients. Results show for the first time, that AdV AAUC0–16 provides the optimal correlation with mortality in this population and serves as a clinically useful indicator of outcome in patients with AdV infection. Disclosures F. Galaverna, Chimerix, Inc.: Investigator, Research support. R. Wynn, Chimerix, Inc.: Scientific Advisor, Grant recipient and Speaker honorarium. Orchard Therapeutics: Scientific Advisor and Shareholder, Consulting fee and Licensing agreement or royalty. Genzyme: Scientific Advisor, Speaker honorarium. P. Comoli, Chimerix, Inc.: Investigator, Research support. A. Chandak, Chimerix, Inc.: Research Contractor, Research support. Analytica Laser: Employee, Salary. E. Vainorius, Chimerix, Inc.: Employee and Shareholder, Salary. T. Brundage, Chimerix, Inc.: Employee and Shareholder, Salary. E. Mozaffari, Chimerix, Inc.: Employee and Shareholder, Salary. G. Nichols, Chimerix, Inc.: Employee and Shareholder, Salary.

Liver transplantation for hepatitis C virus (HCV) non-viremic recipients with HCV viremic donors.

In the context of organ shortage, the opioid epidemic, and effective direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV), more HCV-infected donor organs may be used for liver transplantation. Current data regarding outcomes after donor-derived HCV in previously non-viremic liver transplant recipients are limited. Clinical data for adult liver transplant recipients with donor-derived HCV infection from March 2017 to January 2018 at our institution were extracted from the medical record. Ten patients received livers from donors known to be infected with HCV based on positive nucleic acid testing. Seven had a prior diagnosis of HCV and were treated before liver transplantation. All recipients were non-viremic at the time of transplantation. All 10 recipients derived hepatitis C infection from their donor and achieved sustained virologic response at 12weeks posttreatment with DAA-based regimens, with a median time from transplant to treatment initiation of 43days (IQR 20-59). There have been no instances of graft loss or death, with median follow-up of 380days (IQR 263-434) posttransplant. Transplantation of HCV-viremic livers into non-viremic recipients results in acceptable short-term outcomes. Such strategies may be used to expand the donor pool and increase access to liver transplantation.

The clinical and economic impact of cytomegalovirus infection in recipients of hematopoietic stem cell transplantation

CMV infection (CMV-I) remains an important complication of hematopoietic stem cell transplantation (HSCT). This was a retrospective, single-center cohort study in HSCT recipients. Primary outcomes were adjusted cost and all-cause mortality. Secondary analyses investigated CMV risk factors and the effect of serostatus. Overall, 690 transplant episodes were included (allogeneic [n=310]; autologous [n=380]). All received preemptive CMV antiviral therapy at first detectable DNAemia. CMV-I occurred in 34.8% of allogeneic and 2.1% of autologous transplants; median time to onset was 45days. In allogeneic HSCT recipients, the primary risk factor for CMV-I was CMV donor/recipient (D/R) serostatus. In a Markov multi-state model for allogeneic HSCT recipients, the hazard ratio for CMV-I and relapse was 1.5 (95% CI 0.8-2.8) and for CMV-I and mortality 2.4 (95% CI 0.9-6.5). In a multivariable model for all patients, CMV-I was associated with increased total cost (coefficient=0.21, estimated incremental daily cost USD $500; P=0.02). Cost was attenuated in allogeneic HSCT recipients (coefficient=0.13, USD $699 vs $613, or $24892 per transplant episode; P=0.23). CMV disease (CMV-D) complicated 29.6% of CMV-I events in allogeneic HSCT recipients, but was not associated with an incrementally increased adjusted risk of mortality compared with CMV-I alone. CMV-I (56.4%) and CMV-D (19.8%) were significantly overrepresented in D-/R+ serostatus HSCT recipients, and mortality was higher in R+ HSCT recipients. Despite early preemptive antiviral treatment, CMV-I impacts clinical outcomes and cost after HSCT, but the impact on cost is less pronounced in allogeneic HSCT recipients compared with autologous HSCT recipients.

Risk-Guided Strategy to Prevent Cytomegalovirus Associated Complications After Liver Transplantation

Aim: We evaluated a risk-guided strategy to prevent cytomegalovirus-associated complications (CMV-ac) after liver transplantation (LT). Patients &amp; methods: Forty liver graft recipients were stratified according to their CMV risk status to prophylactic (high risk, HR and group) or pre-emptive antiviral treatment (intermediate, IR, and low risk, LR and group). A detailed analysis of clinical and virological data was performed. Results: 8/40 patients were classified within the HR, 28/40 within the IR and 4/40 within the LR group. Incidence of CMV viremia was 3/8 (38%) in the HR, 9/28 (32%) in the IR and 0/5 in the LR group. Mortality rate of CMV-ac was 0%. Conclusion: A risk-guided antiviral strategy is effective to prevent severe CMV-ac up to 1 year after LT.

Transplanting hepatitis C virus-positive livers into hepatitis C virus-negative patients with preemptive antiviral treatment: A modeling study.

Transplanting HCV-positive livers into HCV-negative patients with preemptive DAA therapy could improve patient survival on the LT waiting list. Our analysis can help inform clinical trials and minimize patient harm. (Hepatology 2018;67:2085-2095).

Cytomegalovirus infection management in solid organ transplant recipients across European centers in the time of molecular diagnostics: An ESGICH survey.

Scant information is available about how transplant centers are managing their use of quantitative molecular testing (QNAT) assays for active cytomegalovirus (CMV) infection monitoring in solid organ transplant (SOT) recipients. The current study was aimed at gathering information on current practices in the management of CMV infection across European centers in the era of molecular testing assays. A questionnaire-based cross-sectional survey study was conducted by the European Study Group of Infections in Immunocompromised Hosts (ESGICH) of the Society of Clinical Microbiology and Infectious Diseases (ESCMID). The invitation and a weekly reminder with a personal link to an Internet service provider (https://es.surveymonkey.com/) was sent to transplant physicians, transplant infectious diseases specialists, and clinical virologists working at 340 European transplant centers. Of the 1181 specialists surveyed, a total of 173 responded (14.8%): 73 transplant physicians, 57 transplant infectious diseases specialists, and 43 virologists from 173 institutions located at 23 different countries. The majority of centers used QNAT assays for active CMV infection monitoring. Most centers preferred commercially available real-time polymerase chain reaction (RT-PCR) assays over laboratory-developed procedures for quantifying CMV DNA load in whole blood or plasma. Use of a wide variety of DNA extraction platforms and RT-PCR assays was reported. All programs used antiviral prophylaxis, preemptive therapy, or both, according to current guidelines. However, the centers used different criteria for starting preemptive antiviral treatment, for monitoring systemic CMV DNA load, and for requesting genotypic assays to detect emerging CMV-resistant variants. Significant variation in CMV infection management in SOT recipients still remains across European centers in the era of molecular testing. International multicenter studies are required to achieve commutability of CMV testing and antiviral management procedures.

Preemptive antiviral therapy with entecavir can reduce acute deterioration of hepatic function following transarterial chemoembolization.

Background/AimsHepatic damage during transarterial chemoembolization (TACE) is a critical complication in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Apart from its role in preventing HBV reactivation, there is some evidence for the benefits of preemptive antiviral therapy in TACE. This study evaluated the effect of preemptive antiviral therapy on acute hepatic deterioration following TACE.MethodsThis retrospective observational study included a prospectively collected cohort of 108 patients with HBV-related HCC who underwent TACE between January 2007 and January 2013. Acute hepatic deterioration following TACE was evaluated. Treatment-related hepatic decompensation was defined as newly developed encephalopathy, ascites, variceal bleeding, elevation of the bilirubin level, prolongation of prothrombin time, or elevation of the Child-Pugh score by ≥2 within 2 weeks following TACE. Univariate and multivariate analyses were conducted to identify factors influencing treatment-related decompensation. Preemptive antiviral therapy involves directing prophylaxis only toward high-risk chronic hepatitis B patients in an attempt to prevent the progression of liver disease. We regarded at least 6 months as a significant duration of preemptive antiviral treatment before diagnosis of HCC.ResultsOf the 108 patients, 30 (27.8%) patients received preemptive antiviral therapy. Treatment-related decompensation was observed in 25 (23.1%) patients during the follow-up period. Treatment-related decompensation following TACE was observed more frequently in the nonpreemptive group than in the preemptive group (29.5% vs. 6.7%, P=0.008). In the multivariate analysis, higher serum total bilirubin (Hazard ratio [HR] =3.425, P=0.013), hypoalbuminemia (HR=3.990, P=0.015), and absence of antiviral therapy (HR=7.597, P=0.006) were significantly associated with treatment-related hepatic decompensation.ConclusionOur findings suggest that preemptive antiviral therapy significantly reduces the risk of acute hepatic deterioration. Preventing hepatic deterioration during TACE by applying such a preemptive approach may facilitate the continuation of anticancer therapy and thus improve long-term outcomes.

Hepatitis B virus reactivation in patients with solid tumors receiving systemic anticancer treatment

Hepatitis B virus (HBV) reactivation is a well-known risk during chemotherapy for hematological malignancies with reported rates ranging between 14% and 72%. However, there is a paucity of data regarding HBV infection management and reactivation risk in patients receiving systemic treatments for solid tumors. We conducted a PubMed search for publications from January 1990 until May 2016 related to HBV reactivation. The search terms were 'hepatitis B reactivation', cross-referenced with 'chemotherapy', then 'hepatitis B' cross-referenced with International Non-proprietary Name of each of the most used chemotherapy drugs in solid tumors. From these data, a grading of HBV reactivation risk and recommendations for management are given for most frequently used anticancer drugs in solid tumors. Most drugs used for the treatment of solid tumors can induce hepatitis B reactivation in HBs antigen-positive patients. HBV screening can be recommended before systemic treatment initiation. Pre-emptive antiviral treatment can reduce the risk of HBV reactivation and prevent chemotherapy disruption.

HBV reactivation risk factors in patients with chronic HBV infection with low replicative state and resolved HBV infection undergoing hematopoietic stem cell transplantation in Korea.

To elucidate the rate and risk factors of HBV reactivation in patients with chronic HBV infection with low replicative state and resolved HBV infection undergoing allogenic/autologous hematopoietic stem-cell transplantation (HSCT) in Korea. The medical charts of 506 patients who underwent allogenic/autologous HSCT from January 2008 to December 2013 were analyzed retrospectively. We examined the reactivation rate and variables related to the risk of HBV reactivation, with a median follow-up period of 41.8 (1-245)months. Univariate analysis was used to identify any factors associated with HBV reactivation. Factors that were significant in the univariate analysis were entered into a stepwise multivariate analysis to find the most significant risk factors associated with HBV reactivation. The reactivation rate of HBV in patients who underwent HSCT was 4.2% (21/506). In subgroup analysis, the HBV reactivation rate (14.3%) was the highest among HBsAg(+) patients (5/35). The reactivation rate of HBV in patients with resolved HBV infection [HBsAg(-)/HBcAb(+) with or without anti-HBs antibody] was 5.9% (10/171). In univariate analysis for risk factors of HBV reactivation in patients who underwent HSCT, initial detectable HBV DNA (p=0.004), age (≥60years) (p=0.012), recipient hepatitis B surface antigen-positive (HbsAg)(+) before HSCT (p=0.004), recipient hepatitis B surface antibody-negative (HBsAb)(-) before HSCT (p=0.005), recipient hepatitis B core antibody-positive (HbcAb)(+) before HSCT (p=0.013), and donor HBsAg(+) (p<0.001) were associated with reactivation of HBV. In multivariate analysis, significant risk factors of HBV reactivation in patients who underwent HSCT were old age (≥60years) (p=0.032) and donor HBsAg(+) (p=0.026). Old age (≥60years) and donor HBsAg(+) were risk factors for HBV reactivation in HSCT patients. Preemptive antiviral treatment should be considered in these patients.