Prophylactic Antiviral Treatment Research Articles

Long-term Follow-up Results after Prophylactic Antiviral Administration in Patients with Herpes Simplex Keratitis

Purpose: We analyzed the effectiveness of prophylactic oral antivirals in preventing herpes simplex keratitis (HSK) and the clinical manifestations of recurrence.Methods: A retrospective analysis was conducted on 30 eyes of 30 patients diagnosed with HSK who received prophylactic oral antiviral agents for > 6 months. We analyzed the initial and recurrent clinical features of HSK, the recurrence rate, and the relationship between recurrence and the duration of oral antivirals.Results: The mean age of the patients was 64.5 ± 14.0 years, and the mean follow-up duration was 72.4 ± 40.3 months. Of the 30 eyes, 21 (70%) experienced HSK recurrence. The initial clinical features of recurrent cases included herpetic epithelial keratitis (14.3%), stromal keratitis (47.6%), and endotheliitis (38.1%). Notably, no significant associations were observed between the initial clinical features of HSK or the duration of oral antivirals and HSK recurrence. However, male patients exhibited a significantly higher recurrence rate. Epithelial keratitis (47.6%) was the most common HSK type observed during recurrence.Conclusions: A recurrence rate of 70% was observed in patients who received prophylactic oral antiviral treatment for > 6 months. Herpetic epithelial keratitis was the most common clinical phenotype after recurrence. Notably, long-term clinical monitoring could assist in predicting and preventing recurrence.

Evaluation of the frequency of hepatitis b virus reactivation and the importance of hepatitis b prophylaxis in hematology patients receiving immunosuppressive therapy: a single-center study

Aims: The aim of this study was to evaluate the rate of hepatitis B virus reactivation (HBVr) in hematology patients receiving immunosuppressive therapy in our center and the clinical characteristics of patients with HBVr. We will also investigate the importance of effective prevention of this potentially life-threatening event and management of hepatitis B virus (HBV) prophylaxis. Methods: In this study, hepatitis B prophylaxis and its effects on patients over 18 years of age receiving immunosuppressive therapy in the hematology clinic were analyzed. 122 patients were included in the study. The HBV markers of the patients were determined by the chemiluminescence method. In the study, HbsAg(+) and isolated antiHbc IgG-positive patients received prophylactic antiviral treatment. The differential diagnosis of HBV reactivation and the criteria determined to define HBV reactivation were performed. Clinical characteristics and descriptive information of patients receiving HBV prophylaxis were analyzed using SPSS 25.0. Results: The median age of 122 patients (59.8% male) was 58 years. It was determined that five HbsAg-positive patients had no prior follow-up and did not receive antiviral treatment. 117 patients had isolated anti-HBc IgG positivity. The median duration of prophylaxis was 15 (9- 21.25) months, and the total follow-up period was 19.5 (11.75- 30.25) months. 81.1% of the patients received regular HBV prophylaxis treatment; 59% of them received entecavir, and the rest received tenofovir disoproxil. Bone marrow transplantation was performed in 25 patients. HBV reactivation was detected in only 4 patients (3.3%); one of these patients had received allogeneic and one autologous bone marrow transplantation; and three patients had received chemoimmunotherapy including Rituximab. The diagnoses of the patients with HBVr were acute myeloid leukemia, lymphoma, and chronic lymphocytic leukemia. During the follow-up period, 29 patients (23.8%) died due to their primary disease, but there were no deaths due to HBV reactivation. Conclusion: The data obtained in this study show that effective hepatitis B prophylaxis treatment is successful in preventing HBV reactivation in hematology patients. HBVr was observed in four patients who did not take HBV prophylaxis medication regularly.

A predictive model of herpes zoster after allogeneic hematopoietic stem cell transplantation: VZV reactivation following antiviral prophylaxis discontinuation.

Herpes zoster (HZ) refers to the rash appearing on dermatomes due to varicella zoster virus (VZV) reactivation. The incidence of HZ is significantly higher in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients than in non-HSCT recipients. Although acyclovir prophylaxis is routinely administered to every allo-HSCT recipient for 1 year after transplantation, some individuals eventually develop late-onset HZ after completing prophylaxis. Little information is known about the clinical features of HZ after prophylactic antiviral treatment discontinuation, and an effective predictive model of late-onset HZ needs to be established. A total of 3366 patients who had received allo-HSCT from 2012 to 2017 were included in our study, among whom 201 developed HZ after 1 year (late-onset HZ). We designed a nested case-control study to identify potential predictors of late-onset HZ. Finally, we established a predictive model using binary logistic regression analysis. Age (p < .001), use of immunosuppressants at +1 year (p < .001), CD4-CD8 ratio at +1 year (p < .001), certain mental disorders (depression, anxiety, insomnia and adjustment disorder) (p < .001), engraftment time of neutrophils (p < .001), and CD8+ cell count at +30 days (p < .001) were independent predictors of late-onset HZ. A risk grading system was established based on regression coefficients. Discrimination and calibration analysis indicated that the model had good performance. We also identified several predictive factors of the incidence of HZ-related complications. This is the first scoring system for predicting the incidence of late-onset HZ after allo-HSCT. This model can be applied to identify individuals at high risk of late-onset HZ in the early period after receiving allo-HSCT.

P11.78.A BIUXX

Abstract BACKGROUND Glioblastoma (GBM) is a tumor with dismal prognosis and the definition of novel therapeutic targets is a pressing matter in neuro-oncology. Several groups reported the presence of Cytomegalovirus (CMV) in GBM. This virus establish a life-long infection in the host and is able to induce the hallmarks of cancer. Thus, antiviral therapy targeting CMV may represent a valid therapeutic option for patients with GBM. Over the last 15 years we treated more than 150 patients with GBM at Karolinska Universiy Hospital with the antiviral drug valganciclovir as an add-on to standard therapy. We compared retrospectively survival of these patients with contemporary controls with similar clinical and demographic characteristics treated only with standard therapy and found that patients receiving the antiviral seemed to survive longer. In addition to the direct oncomodulatory effect of CMV in GBM cells, its reactivation may affect negatively fragile individuals such as patients with GBM. Indeed patients serologically positive for CMV survives shorter time compared to serologically negative patients. Also Goerig et al. showed that CMV may also be reactivated during irradiation of the brain and cause life threating encephalitis in as many as 48% IgG positive patients with brain tumors. This was linked to encephalopathy and to early mortality risk. Thus, a successful therapeutic strategy would be to start antiviral therapy before or concomitantly radio-chemotherapy since antiviral drugs could prevent CMV reactivation before the virus would be able to cause neurologic deterioration. MATERIAL AND METHODS we analyzed by prospectively collected serological data (IgG and IgM) for CMV of 42 patients with GBM treated with valganciclovir (n=22) or placebo (n=20) in a double blind setting before, during and after radio-chemotherapy and at 6 and 12 months follow ups. We built contingency table and performed Fisher´s exact test. RESULTS At the end of radiation therapy, 5 of 12 (41.6%) IgG positive patients in the placebo group were also IgM positive, showing an active/recent infection, while none of the 16 patients were IgM positive in the valganciclovir treated group (p=0.0067). Three of the 5 patients with CMV reactivation in the placebo group experienced also neurological deterioration and developed an early recurrence at just 3 months while none developed early recurrence in VGCV group. CONCLUSION Valgancicovir prevented CMV reactivation in patients with GBM undergoing chemo-radiotherapy in a prospective, randomize setting. Prophylactic antiviral treatment may therefore be used to prevent encephalopathy and to early mortality risk linked to CMV reactivation. The clinical value of these results will need to be confirmed in larger studies. In this regard, a randomized trial evaluating anti-CMV therapy in 220 patients with GBM (the VIGAS 2, NCT04116411) is currently ongoing at our institution.

Low incidence of hepatitis B virus reactivation in patients with hematological malignancies receiving novel anticancer drugs: A report from a high epidemic area and literature review.

More and more novel anticancer drugs have been approved for patients with hematological malignancies in recent years, but HBV reactivation (HBV-R) data in this population is very scarce. This study aimed to evaluated HBV-R risk in patients with hematological malignancies receiving novel anticancer drugs. HBV markers and serum HBV DNA levels of patients with hematological malignancies receiving novel anticancer drugs in a tertiary cancer hospital were retrospectively collected. HBV-R risk in the whole cohort and subgroups was described. The relevant literature was reviewed to make a pooled analysis. Of 845 patients receiving novel anticancer drugs, 258 (30.5%) were considered at risk for HBV-R. The median duration of exposure to novel drugs was 5.6 (0.1-67.6) months. The incidence of HBV-R was 2.1% in patients with past HBV infection without prophylactic antiviral treatment (PAT) and 1.2% in all patients at risk of HBV-R. In a pooled analysis of 11 studies with 464 patients, the incidence of HBV-R was 2.4% (95% CI: 1.3-4.2) in all at-risk patients receiving novel anticancer drugs and 0.6% (95% CI: 0.03-3.5) in patients with anticancer drugs plus PAT. The incidence of death due to HBV-R was 0.4% (95% CI: 0.1-1.6) in all at-risk patients and 18.2% (95% CI: 3.2-47.7) in patients with HBV-R. Most episodes of HBV-R are preventable, and most cases with HBV-R are manageable. We recommend that novel anticancer drugs should not be intentionally avoided when treating cancer patients with HBV infection.

Loss of SFXN1 mitigates lipotoxicity and predicts poor outcome in non-viral hepatocellular carcinoma

Hepatocellular carcinoma (HCC) imposes a huge global burden, arising from various etiological factors such as hepatitis virus infection and metabolic syndrome. While prophylactic vaccination and antiviral treatment have decreased the incidence of viral HCC, the growing prevalence of metabolic syndrome has led to an increase in non-viral HCC. To identify genes downregulated and specifically associated with unfavorable outcome in non-viral HCC cases, screening analysis was conducted using publically available transcriptome data. Among top 500 genes meeting the criteria, which were involved in lipid metabolism and mitochondrial function, a serine transporter located on inner mitochondrial membrane SFXN1 was highlighted. SFXN1 protein expression was significantly reduced in 33 of 105 HCC tissue samples, and correlated to recurrence-free and overall survival only in non-viral HCC. Human HCC cells with SFXN1 knockout (KO) displayed higher cell viability, lower fat intake and diminished reactive oxygen species (ROS) production in response to palmitate administration. In a subcutaneous transplantation mouse model, high-fat diet feeding attenuated tumorigenic potential in the control cells, but not in the SFXN1-KO cells. In summary, loss of SFXN1 expression suppresses lipid accumulation and ROS generation, preventing toxic effects from fat overload in non-viral HCC, and predicts clinical outcome of non-viral HCC patients.

HBV reactivation and its effect on survival in HBV-related hepatocarcinoma patients undergoing transarterial chemoembolization combined with tyrosine kinase inhibitors plus immune checkpoint inhibitors.

This study aimed to access hepatitis B virus (HBV) reactivation and its effect on survival in HBV-related hepatocarcinoma (HCC) patients who underwent transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs). In this single-center retrospective study, we enrolled 119 HBV-related unresectable advanced HCC patients receiving TACE combined with TKIs plus ICIs. Risk factors for HBV reactivation were analyzed by logistic regression. Kaplan-Meier method was applied to draw the survival curve, and log-rank test was used to compare survival between patients with and without HBV reactivation. A total of 12 patients (10.1%) encountered HBV reactivation in our study, of which only 4 patients received antiviral prophylaxis. The incidence of HBV reactivation was 1.8% (1/57) in patients with detectable baseline HBV DNA and 4.2% (4/95) in patients with antiviral prophylaxis respectively. Lack of prophylactic antiviral treatment (OR=0.047, 95%CI 0.008-0.273, P=0.001) and undetectable HBV DNA (OR=0.073, 95%CI 0.007-0.727, P=0.026) were independent risk factors for HBV reactivation. The median survival time (MST) for all patients was 22.4 months. No survival difference was observed in patients with or without HBV reactivation. (MST: undefined vs 22.4 months, log-rank test: P=0.614). HBV reactivation could occur in HBV-related HCC patients who treated with TACE in combination with TKIs plus ICIs. Before and during the combination treatment, it is necessary to routinely monitor HBV DNA and to take effective prophylactic antiviral therapy.

Clinical Features of Pediatric Age Herpes Simplex Virus Keratitis.

The objective of this study is to evaluate the clinical features of pediatric herpes simplex virus keratitis, its recurrence rates, and its effects on visual acuity. In this retrospective case series, records of pediatric patients (0-16 years) who presented with herpes simplex virus keratitis between January 2012 and September 2021 were evaluated. Data including age, gender, additional systemic diseases, the number of recurrences, recurrence time, treatment protocol, follow-up period, and presence of amblyopia were reviewed. Twenty-four patients (16 females and 8 males) with a mean age of 6.6 ± 4 (1.1-15) years were included in the study. The mean follow-up time was 21 ± 19.9 (7-94) months. Four patients (16.6%) had bilateral keratitis. Including all 4 patients with bilateral involvement, a total of 10 (41.6%) patients had additional systemic diseases that cause immunodeficiency. After prophylactic antiviral treatment for at least 6 months (except for isolated epithelial keratitis), recurrence was detected in 5 (22.7%) patients, who were all immunodeficient. Among immunodeficient individuals, the recurrence rate was found to be 50%. Keratitis recurrence was significantly associated with immunodeficiency ( P = 0.03). However, type of keratitis ( P = 0.42), gender ( P = 0.47), and bilaterality ( P = 0.54) were not related with recurrence. 66.7% of the patients younger than 10 years developed amblyopia during follow-up. In childhood, the most frequent corneal manifestation of herpes simplex virus is stromal keratitis that mostly progresses with corneal scarring, residual astigmatism, and amblyopia. The recurrence rate increases in the presence of immunosuppression. Close follow-up, rapid diagnosis, and treatment are critical for battling against amblyopia and achieving good visual prognosis.

Factors Associated with Severe Outcomes Among Immunocompromised Adults Hospitalized for COVID-19 - COVID-NET, 10 States, March 2020-February 2022.

Immunocompromised persons are at increased risk for severe COVID-19-related outcomes, including intensive care unit (ICU) admission and death (1). Data on adults aged ≥18 years hospitalized with laboratory-confirmed COVID-19 from 10 U.S. states in the COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) were analyzed to assess associations between immunocompromise and ICU admission and in-hospital death during March 1, 2020-February 28, 2022. Associations of COVID-19 vaccination status with ICU admission and in-hospital death were also examined during March 1, 2021-February 28, 2022. During March 1, 2020-February 28, 2022, among a sample of 22,345 adults hospitalized for COVID-19, 12.2% were immunocompromised. Among unvaccinated patients, those with immunocompromise had higher odds of ICU admission (adjusted odds ratio [aOR]=1.26; 95% CI=1.08-1.49) and in-hospital death (aOR=1.34; 95% CI=1.05-1.70) than did nonimmunocompromised patients. Among vaccinated patients,* those with immunocompromise had higher odds of ICU admission (aOR=1.40; 95% CI=1.01-1.92) and in-hospital death (aOR = 1.87; 95% CI=1.28-2.75) than did nonimmunocompromised patients. During March 1, 2021-February 28, 2022, among nonimmunocompromised patients, patients who were vaccinated had lower odds of death (aOR=0.58; 95% CI=0.39-0.86) than did unvaccinated patients; among immunocompromised patients, odds of death between vaccinated and unvaccinated patients did not differ. Immunocompromised persons need additional protection from COVID-19 and using multiple known COVID-19 prevention strategies,† including nonpharmaceutical interventions, up-to-date vaccination of immunocompromised persons and their close contacts,§ early testing, and COVID-19 prophylactic (Evusheld) and early antiviral treatment,¶ can help prevent hospitalization and subsequent severe COVID-19 outcomes among immunocompromised persons.

Manifestation of Herpetic Eye Disease after COVID-19 Vaccine: A UK Case Series

ABSTRACT Purpose To highlight the potential risk of herpetic eye disease (HED) reactivation following COVID-19 vaccine. Methods Retrospective analysis of all patients who presented with HED within 28 days post-first dose COVID-19 vaccination. Results Eleven eyes (n = 10 patients) were included. The mean interval between COVID-19 vaccination and ocular symptoms/signs was 12.3 ± 10.3 days. Four (40%) patients presented with HSV keratitis, and six (60%) patients presented with VZV keratitis (five had concurrent other signs of herpes zoster ophthalmicus). Common ocular signs included multiple scattered dendritic/pseudodendritic corneal epitheliopathy (90.9%), anterior uveitis (63.6%), and endothelitis (27.3%). All cases were successfully treated with topical and systemic antiviral treatment and/or topical corticosteroids (mean healing time = 3.9 ± 1.6 weeks). Conclusions Our case series highlights the potential temporal association between HED and COVID-19 vaccine. Prophylactic antiviral treatment is recommended in patients with a history of HED prior to COVID-19 vaccination.

Effectiveness of Antiviral Therapy in Highly-Transmissible Variants of SARS-CoV-2: A Modeling and Simulation Study.

As of October 2021, neither established agents (e.g., hydroxychloroquine) nor experimental drugs have lived up to their initial promise as antiviral treatment against SARS-CoV-2 infection. While vaccines are being globally deployed, variants of concern (VOCs) are emerging with the potential for vaccine escape. VOCs are characterized by a higher within-host transmissibility, and this may alter their susceptibility to antiviral treatment. Here we describe a model to understand the effect of changes in within-host reproduction number R0, as proxy for transmissibility, of VOCs on the effectiveness of antiviral therapy with molnupiravir through modeling and simulation. Molnupiravir (EIDD-2801 or MK 4482) is an orally bioavailable antiviral drug inhibiting viral replication through lethal mutagenesis, ultimately leading to viral extinction. We simulated 800 mg molnupiravir treatment every 12 h for 5 days, with treatment initiated at different time points before and after infection. Modeled viral mutations range from 1.25 to 2-fold greater transmissibility than wild type, but also include putative co-adapted variants with lower transmissibility (0.75-fold). Antiviral efficacy was correlated with R0, making highly transmissible VOCs more sensitive to antiviral therapy. Total viral load was reduced by up to 70% in highly transmissible variants compared to 30% in wild type if treatment was started in the first 1–3 days post inoculation. Less transmissible variants appear less susceptible. Our findings suggest there may be a role for pre- or post-exposure prophylactic antiviral treatment in areas with presence of highly transmissible SARS-CoV-2 variants. Furthermore, clinical trials with borderline efficacious results should consider identifying VOCs and examine their impact in post-hoc analysis.

Effectiveness of prophylactic antiviral therapy in reducing HBV reactivation for HBsAg-positive recipients following allogeneic hematopoietic stem cell transplantation: a multi-institutional experience from an HBV endemic area.

Hepatitis B virus reactivation (HBVr) is not uncommon in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Hepatitis B surface antigen (HBsAg)-positive patients receiving allo-HSCT have a very high risk of HBVr. However, the validity of prophylactic antiviral treatment in HBsAg-positive allo-HSCT recipients has not been well studied. We aimed to add experience in dealing with HBsAg-positive patients following allo-HSCT. We conducted a cohort study that included 11 years of data of HBsAg-positive allo-HSCT patients in multiple centers. The cumulative incidence of HBVr with antiviral prophylaxis at 60 months following transplantation was 8.9%. Both lamivudine (LAM) and entecavir (ETV) effectively reduced the incidence of HBVr. Patients with absent-mild cGVHD had a lower HBVr rate than that of patients with moderate-severe cGVHD (HR = 0.201, P = 0.020). The incidence of HBsAg seroclearance at 60 months following transplantation was 34.3%. Recipients accepting from anti-HBs-negative donors were associated with a lower HBsAg seroclearance rate than that of those accepting from anti-HBs-positive donors (HR=0.255, P < 0.001). The peripheral blood stem cell (PBSC) donor source had a higher HBsAg seroclearance rates than that of the PBSC plus bone marrow stem cell source (HR = 4.700, P = 0.047). The prophylactic antiviral treatment effectively reduced HBVr in HBsAg-positive recipients receiving allo-HSCT. HBsAg-positive recipients accept anti-HBs-positive PBSC donor sources may facilitate the acquisition of HBsAg seroclearance after transplantation.

Hepatitis B Seropositive Status in Recipients or Donors Is Not Related to Worse Outcomes after Haploidentical Hematopoietic Stem Cell Transplantation

Hepatitis B virus (HBV) has a high rate of chronic infection in Asian populations, and only limited studies have been performed to analyze the impact of HBV-seropositive haploidentical hematopoietic stem cell transplantation (haplo-HSCT) recipients and donors. The present study aimed to evaluate the effect on clinical outcomes in those patients. We conducted a retrospective study enrolling 237 consecutive patients undergoing first haplo-HSCT. The patients were classified into 3 groups: recipient HBV-positive group (R+D-; n=62), donor HBV-positive group (D+; n=83), and HBV-negative group (R-D-; n=92). Corresponding prophylactic antiviral treatment was given in the R+D- and D+ groups. The results were compared among the 3 groups using the Kruskal-Wallis test for continuous variables, Pearson's chi-square test for categorical variables, the competing-risk method to evaluate cumulative incidence, Kaplan-Meier curves to estimate overall survival (OS) and disease-free survival (DFS), and a Cox proportional hazard model to analyze multivariable influences. The 3-year cumulative HBV reactivation rate was 4.2%. The median time to HBV reactivation was 845 days (range, 545 to 1439 days) after haplo-HSCT. The R+D- group tended to have a higher cumulative incidence of HBV reactivation compared with the D+ group (11.8% versus 3.1%; P=.080). Significant differences in the causes of hepatic damage were observed among the 3 groups (P=.017), and all patients with acute hepatitis B after haplo-HSCT were from the R+D- group. Multivariate analysis showed that pretransplantation HBV status was associated with cytomegalovirus reactivation (R+D- versus R-D-: hazard ratio, 1.514; 95% confidence interval, 1.060 to 2.163; P=.023). The 3-year OS and DFS, 3-year cumulative incidence of nonrelapse mortality (NRM), rates of relapse and graft-versus-host disease (GVHD), and causes of death were comparable among the 3 groups. Pretransplantation HBV serostatus had no significant effect on OS, DFS, NRM, relapse, or GVHD in the multivariate analysis. Based on our data, seropositivity for hepatitis B surface antigen (HbsAg) or core antibody (HBcAb) in donors or recipients before transplantation did not negatively affect the overall outcome after haplo-HSCT under the premise of proper antiviral prophylaxis along with regular post-transplantation surveillance, and HBV seropositivity should not be considered a contraindication to haplo-HSCT.

Among CMV-positive renal transplant patients receiving non-T-cell depleting induction, the absence of CMV disease prevention is a safe strategy: A retrospective cohort of 372 patients.

Cytomegalovirus (CMV) is the most common opportunistic pathogen affecting renal transplant recipients, especially in the first months. CMV-seropositive renal transplant recipients (CMV R+) are at intermediate risk for CMV disease, but this risk is enhanced among CMV R+ receiving T-cell depleting induction, compared to CMV R+ receiving non-depleting induction. In this second group, data in favor of prophylactic antiviral treatment with valganciclovir to reduce CMV disease is sparse. In this retrospective and multicentric trial, we included 372 CMV R+ transplanted between January 2012 and April 2015 and receiving non-depleting induction. During the first year following transplantation, CMV disease occurred in 5/222 patients (2.25%) in the prophylaxis group and 9/150 (6%) in the no-prophylaxis group (difference +3.7; 95% CI: 0.5-8; P=.002 for non-inferiority). The incidence of allograft rejection and other infectious diseases was similar between the two groups. Graft and patient survival were similar at the end of follow-up. In conclusion, the absence of prophylaxis did not appear to have a deleterious effect for CMV diseases among CMV R+ receiving non-depleting induction.

Epidemiological characteristics of de novo hepatitis B infection in liver transplant recipients-An experience from a tertiary care centre in Qatar.

The emergence of hepatitis B surface antigen in a patient with previously negative hepatitis B virus (HBV) serology post-orthotropic liver transplant (OTLX) is known as de novo hepatitis B (DNHB). As there are no data on patients with DNHB available from Qatar, we aim to do a pioneer study indexing their clinical profile and epidemiology of patients with DNHB in Qatar. This descriptive epidemiological study was done by retrospectively reviewing records of 159 post-OTLX patients. HBV serology of these patients post-OTLX was reviewed, and 17 were identified as DNHB cases. Baseline epidemiological characteristics were defined and compared between DNHB cases and the rest. DNHB cases were analyzed statistically using the chi-square test and Kaplan-Meier curve. The majority of the subjects were men (65%) and Qataris (40%). Mean age was 57.4±12.5years. Bulk of them underwent OTLX in China (44%). The overall incidence of DNHB was 10.7%, with transplants in China having significantly higher incidence than transplants from all other countries. The mortality rate was 23.5% in DNHB cases compared to 2.8% in non-DNHB. 67% of patients survived at least 64months after the diagnosis of DNHB. Five-year survival did not vary significantly between those with DNHB and those without. Orthotropic liver transplant in centers selecting donors liberally without screening for HBV poses the risk of DNHB. We recommend having protective levels of HBs antibodies before OTLX. Prophylactic antiviral treatment should be considered until peri-operative HBV transmission has been excluded by screening hepatic tissue for HBV DNA.

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.

A Novel Strategy for the Prevention of Hepatitis B Virus-Related Hepatitis Following Allogeneic Hematopoietic Stem Cell Transplantation from Hepatitis B Surface Antigen-Positive Donors

Hematopoietic stem cell transplantation (HSCT) is increasingly being applied globally. Cases in which healthy HSCT donors are chronically infected with hepatitis B virus (HBV) are relatively common in areas where HBV is endemic. Recipients of stem cells from such hepatitis B surface antigen (HBsAg)-positive donors are at risk of viral infection, and thus may develop HBV-related hepatitis. Given the lack of standardized approach to minimizing the risk of such infections from HBsAg+ donors during HSCT, we conducted this study with the aim of developing an efficient strategy to address this challenge. A strategy comprising antiviral treatment for detectable HBV-DNA in HBsAg+ donors, hepatitis B immune globulin (HBIG) administration in HBsAg- recipients with passive immunity, and prophylactic antiviral treatment for HBsAg+ recipients was developed. The strategy was validated using a case-control study of 40 recipients who received stem cells from HBsAg+ donors (group A) and 40 pair-matched controls who received stem cells from HBsAg- donors (group B). The cumulative incidence of HBV-related hepatitis was relatively similar in the 2 groups (group A: 8.5%; 95% confidence interval [CI], -.9% to 17.9%; group B: 7.9%; 95% CI, -.9% to 16.7%; P=.939). In HBsAg- recipients who received passive immunity from HBIG treatment, a significant negative linear correlation was observed between HBsAb titer in vivo and time in the first year after allo-HSCT (R2=.23; P < .001). This method was cost-effective, with a median cost of all HBV management of USD 332.1 (range, 172.7 to 1985.3), compared with USD 1464.9 (range 409.9 to 1985.3) for conventional strategies (P < .001). The novel strategy presented in here is robust in preventing HBV-related hepatitis after allo-HSCT with stem cells from HBsAg+ donors. This is important for the effective application of allo-HSCT in HBV-endemic areas without precluding the use of HBsAg+ donors.

Cytomegalovirus: A Troll in the ICU? Overview of the Literature and Perspectives for the Future.

Cytomegalovirus (CMV) is one of the most pathogenic viruses in human. After a primary infection, CMV resides in the host for life as a latent infection. When immunity is reduced, CMV can escape the suppressive effects of the immune system and lead to viremia and antigenemia. This reactivation, first seen in transplant patients, has also been documented in non-immunocompromised CMV-seropositive critically ill patients and is associated with higher morbidity and mortality. In the latter, it is not clear whether CMV reactivation is an innocent bystander or the cause of this observed worse outcome. Two studies showed no difference in the outcome of CMV-seropositive and seronegative patients. In addition, proof-of-concept studies investigating prophylactic antiviral treatment to prevent CMV reactivation during critical illness, failed to show a beneficial effect on interleukin levels or clinical outcome. Further research is necessary to resolve the question whether CMV replication impairs the prognosis in non-immunocompromised critically ill patients. We here give a concise overview on the available data and propose strategies to further unravel this question. First, post-mortem investigation may be useful to evaluate the effect of viral replication on organ inflammation and function. Second, further research should focus on the question whether the level of viremia needs to exceed a threshold to be associated with worse outcome. Third, clinical and biochemical assessments may help to identify patients at high risk for reactivation. Fourth, preemptive treatment based upon early detection of the virus is currently under investigation. Finally, immune-stimulating biologicals may be beneficial in high-risk groups.

Determining Whether Prophylactic Antiviral Treatment Is Necessary in HBsAg-Negative/HBcAb-Positive Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

The incidence of hepatitis B virus (HBV) infection is high in the Asian population. Increasing attention is being given to the risk of HBV reactivation in hepatitis B core antibody-positive [HBcAb(+)] patients during immunosuppressive therapy. Knowledge of HBV reactivation in hematopoietic stem cell transplantation (HSCT) is limited. Moreover, the effect of hepatitis B surface antibody (HBsAb) on HBV reactivation in HBcAb(+) patients during HSCT remains uncertain. We sought to investigate the role of HBsAb and the need for prophylactic antiviral treatment in hepatitis B surface antigen-negative [HBsAg(-)]/HBcAb(+) patients during HSCT. We classified 665 HBsAg(-) HSCT recipients into 4 groups: HBcAb(-)HBsAb(-) (n=189), HBcAb(-)HBsAb(+) (n=176), HBcAb(+)HBsAb(-) (n=49), and HBcAb(+)HBsAb(+) (n=251). HBV reactivation was identified in 16 patients after HSCT. The median time to HBV reactivation was 645 days (range, 455 to 1957 days) after transplantation. The cumulative HBV reactivation rate was significantly higher in the HBcAb(+)HBsAb(-) group compared with the HBcAb(+)HBsAb(+), HBcAb(-)HBsAb(-), and HBcAb(-)HBsAb(+) groups, respectively (P< .001). Notably, the risk of HBV reactivation was significantly higher in the HBcAb(+)HBsAb(-) group compared with the HBcAb(+)HBsAb(+) group (P= .007; hazard ratio, 4.750; 95% confidence interval, 1.531 to 14.737). Our results point to a protective role of HBsAb in HBV-resolved patients undergoing HSCT and indicate that prophylactic anti-HBV treatment might not be mandatory for HBsAg(-), HBcAb(+)HBsAb(+) patients following HSCT. The surveillance protocol of intense follow-up early (HBV DNA and HBsAg monthly) might not be necessary.

Reactivation of hepatitis B virus infection in rheumatic diseases: risk and management considerations.

In patients with rheumatic diseases undergoing immunosuppressive treatment, hepatitis B virus reactivation (HBVr) has been long recognized as a major treatment-related adverse event with substantial morbidity and mortality. Because HBVr is easily preventable with appropriate screening and monitoring strategies, and, when indicated, prophylactic antiviral treatment, awareness of this complication is of the utmost importance, especially in the era of biologic treatments. As a condition, it continues to be topical, in view of the emergence of novel classes of immunosuppressive drugs (i.e. Janus kinase inhibitors) acquiring licenses for a variety of rheumatic diseases. The class-specific risk of these agents for HBVr has not yet been determined. Moreover, ambiguity still exists for the management of patients planned to be treated with traditional agents, such as cyclophosphamide and glucocorticoids, particularly in the setting of resolved HBV infection. Clinicians in the field of rheumatic diseases should be tailoring their practice according to the host’s profile and treatment-specific risk for HBVr. In this review, the authors attempt to critically review the existing literature and provide practical advice on these issues.