Universal Antiviral Prophylaxis Research Articles

Meet in the middle: Could cell mediated-immunity assays be the answer for ideal Cytomegalovirus prophylaxis after lung transplantation? Observational study from a single center with intermittent antiviral prophylaxis.

Cytomegalovirus (CMV) can cause tissue-invasive disease and indirect effects after lung transplantation (LTx) such as acute rejection episodes and chronic lung allograft dysfunction. Monitoring CMV-specific cell immune recovery (CMV-CIR) after LTx can individualize CMV risks and establish better antiviral approach. This study evaluated the dynamics of CMV-CIR, using QuantiFERON-CMV assay (Qiagen Group), in the first year after LTx. Prospective observational cohort study included lung transplant recipients from December/2015 to December/2016. Universal antiviral prophylaxis with intravenous ganciclovir 5mg/kg/day 3 days/week for 3 months was given for CMV-seropositive recipients (R+) and only CMV-seropositive donor and negative recipient (D+/R-) received a 6-month-prophylaxis with ganciclovir and valganciclovir, on alternate days, in the first 3 months and then, 3 more months of valganciclovir. QuantiFERON-CMV was measured at the same time points of surveillance bronchoscopies. CMV infection was defined as any DNAemia detected and CMV disease with proven biopsy or antigenemia pp65 above 10 cells/300.000 neutrophils. Thirty-eight patients were included. On days 45, 90, and 365 days post-LTx, 60%, 72%, and 81% QuantiFERON-CMV were reactive, respectively. Eleven patients (28.9%) presented CMV-disease and 27 DNAemia/CMV infections. Reactive tests were able to predict CMV disease only at 90 days after LTx (p=.027) but failed on DNAemia/CMV infection (p=.148). Daily prophylaxis, for D+/R- patients (13.2%), remained as an independently associated factor for not achieving reactive QuantiFERON-CMV (adjusted OR .27, 95%CI .12-.60, p=.02). QuantiFERON-CMV may be another diagnostic tool to help stratify CMV-disease risk and individualized antiviral prophylaxis after LTx.

Cytomegalovirus Disease as a Risk Factor for Invasive Fungal Infections in Liver Transplant Recipients under Targeted Antiviral and Antimycotic Prophylaxis.

We retrospectively analyzed the medical records of 214 adult liver transplant recipients (LTRs). Universal antiviral prophylaxis was utilized in recipients with CMV mismatch; intermediate- and low-risk patients received pre-emptive treatment. Six percent of patients developed CMV disease independent of their serostatus. The occurrence of CMV disease was associated with elevated virus load and increased incidence of leucopenia and IFIs. Furthermore, CMV disease was associated with higher one-year mortality and increased relapse rates within the first year of OLT. CMV disease causes significant morbidity and mortality in LTRs, directly affecting transplant outcomes. Due to the increased risk of IFIs, antifungal prophylaxis for CMV disease may be appropriate. Postoperative CMV monitoring should be considered after massive transfusion, even in low-risk serostatus constellations. In case of biliary complications, biliary CMV monitoring may be appropriate in the case of CMV-DNA blood-negative patients.

Effective CMV prophylaxis with high-dose valaciclovir in allogeneic hematopoietic stem-cell recipients at a high risk of CMV infection.

Cytomegalovirus (CMV) infection increases mortality and morbidity following allogeneic hematopoietic stem-cell transplantation (alloHSCT). Universal antiviral prophylaxis with letermovir is effective but unsubsidized in Australia. Valaciclovir demonstrates anti-CMV activity in high doses, but few current real-world studies explore its use as primary prophylaxis in high-risk patients post-alloHSCT. We performed a retrospective analysis of alloHSCT recipients at high risk of clinically significant CMV infection (cs-CMVi), defined as a plasma CMV DNA viral load of >400IU/ml requiring preemptive therapy, or CMV disease. High-risk recipients were CMV seropositive and underwent T-cell depleted, haploidentical or umbilical cord stem-cell transplants. Consecutive patients transplanted from July 2018 to January 2020, treated with valaciclovir 2g TDS from day +7 to +100 (HD-VALA), were compared to a historical cohort (July 2017-June 2018) who only received preemptive CMV therapy, and standard valaciclovir (SD-VALA) for varicella/herpes prophylaxis. We compared incidence of and time to cs-CMVi. In the SD-VALA cohort (n=27, median CMV follow-up duration 259 days), 23/27 (85%) developed cs-CMVi at a median of 39 days. For the HD-VALA cohort (n=35, median CMV follow-up duration 216 days), 19/35 (54%) developed cs-CMVi, at a median of 68 days. Time to cs-CMVi was significantly longer in HD-VALA cohort (p<.0001). On multivariate analysis, HD VALA reduced the risk of cs-CMVi (HR 0.32, p=.0005). In alloHSCT recipients at high risk for cs-CMVi, HD-VALA resulted in lower cumulative reactivation, and delayed reactivation, reducing requirement for preemptive CMV therapy in the early post-engraftment period.

Common Viral Infections In Children After Kidney Transplantation

Viral infection is a common complication among pediatric kidney transplant recipients, causing significant morbidity and mortality. Sources of viral infection in pediatric transplant recipients include donor allografts, blood products, and latent virus reactivation. Major risks of viral infection include kidney donor-derived, nosocomial and community-acquired infections as well as the immunosuppressive status of recipients. Clinical presentations are variable, ranging from no symptoms to severe disease. Preventive strategies such as immunization and pretransplant-specific viral screening in both donors and recipients are performed before kidney transplantation to identify high-risk recipients. Posttransplant prophylactic strategies include universal prophylaxis and preemptive therapy. Universal antiviral prophylaxis is required for high-risk cytomegalovirus (CMV)-mismatch pediatric recipients. Preemptive therapy requires the administration of sensitive viral surveillance tests to detect subclinical viral infections to optimize individualized immunosuppressive drugs and initiate antiviral therapy. This review summarizes current knowledge regarding common viral infections in children after kidney transplantation, including CMV, BK polyomavirus, Epstein-Barr virus (EBV), and coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

High Dose Valaciclovir As CMV Prophylaxis in Allogeneic Hematopoietic Stem Cell Recipients at High Risk of CMV Reactivation

Background Cytomegalovirus (CMV) is a common, potentially devastating complication of allogeneic haematopoietic stem cell transplantation (alloHSCT). Universal antiviral prophylaxis strategies including letermovir are effective, but unsubsidised in Australia. Prophylactic ganciclovir or valganciclovir are challenging due to myelotoxicity. Valaciclovir demonstrates anti-CMV activity in high doses, but little current data explore prophylaxis in the alloHSCT setting, particularly in haploidentical transplantation. We aimed to evaluate the clinical efficacy and tolerability of high dose valaciclovir (high dose VALA) as CMV prophylaxis in high risk patients undergoing alloHSCT. Methods This study was completed at the Royal Melbourne Hospital, Melbourne Australia. We performed a retrospective analysis of alloHSCT recipients at high risk of CMV reactivation (defined as recipient and/or donor CMV seropositivity, and undergoing T-cell depletion, haploidentical or umbilical cord stem cell transplantation). Patients transplanted between July 2018 - June 2019, treated with high dose VALA (2g TDS) from day +7 to +100 and beyond were compared to a historical cohort (transplanted between July 2017 - June 2018) on standard dose valaciclovir (std dose VALA) (500mg BD until engraftment then 500mg daily). We compared the rates and time to reach a CMV threshold of 400 IU/ml, at which point pre-emptive CMV therapy was commenced. Tolerability was also evaluated. Results Patient demographics are described in Table 1. Of the standard dose VALA cohort, (median follow-up 259 days), 23/31 (74%) developed a viral load &amp;gt;400 IU/mL, requiring pre-emptive CMV therapy. None had CMV disease. Median time to viral load &amp;gt;400 IU/mL was 39 days (range 13 - 68). Of the high dose VALA cohort (median follow-up 209 days), 11/25 (44%) developed a viral load &amp;gt;400 IU/mL, requiring pre-emptive CMV therapy. Of these 11 cases, 7 patients had viral load &amp;gt;400 IU/mL while on high dose VALA prior to D+100, 3 patients had ceased high dose VALA prior to D+100 due to intolerance and in 1 patient this occurred post D+100 while on high dose VALA. One patient developed CMV (gut) disease following early cessation of high dose VALA, whilst on standard dose VALA. Median time to reactivation &amp;gt;400 IU/mL was 64 days (range 26-170). Time to reactivation &amp;gt;400 IU/ml was significantly different between the standard vs high dose VALA cohorts (mean ± SEM; 37.9 ± 2.7 vs 67.8 ± 11.3 days, **p=0.0015). Median duration of high dose VALA prophylaxis was 50 days (range 11-288). Seven (28%) patients continued high dose VALA to day +100 and beyond. Intolerance led to early cessation in 10 (40%) patients (acute kidney injury, n=6; cytopenia, n=3; both, n=1). Other patients ceased due to requirement for definitive CMV therapy (n=6) and unclear reasons (n=2). Conclusions In high risk alloHSCT recipients, high dose VALA is an effective CMV prophylactic strategy resulting in lower CMV reactivation rates, and delays CMV reactivation. This may reduce requirements for myelotoxic CMV treatment during the early post-engraftment period and need for inpatient admission. CMV infection following high dose VALA cessation remains a risk, particularly when dose reductions have occurred due to toxicity, and intolerance and ongoing monitoring is required. Treatment tolerability remains a limitation. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Valaciclovir, for CMV prophylaxis

Varicella Zoster Virus Infection in Children with Autologous Hematopoietic Cell Transplantation: A Retrospective, Single-Center Study in Korea

Although long-term antiviral prophylaxis is recommended to prevent varicella zoster virus (VZV) infection in seropositive recipients of allogeneic and autologous (auto-) hematopoietic cell transplantation (HCT), studies of VZV infections in pediatric auto-HCT recipients are rare. This study aimed to investigate the incidence and characteristics of VZV infection in pediatric auto-HCT recipients and explore the risk factors of VZV infection and its effect on survival outcomes. This study included all pediatric patients who underwent auto-HCT at Samsung Medical Center, Seoul, Korea, between January 1998 and December 2013. Before 2006, short-term acyclovir prophylaxis was provided until neutrophil engraftment; thereafter, routine prophylaxis was not provided. Patients who developed either herpes zoster or chickenpox within 2 years from transplantation were identified, and a chart review was performed. A total of 413 recipients and 698 auto-HCTs were included. Sixty-one episodes of VZV infections were identified in 54 patients. Fourteen cases of VZV infection (23%; 14 of 61) occurred within 30 days after auto-HCT. The cumulative incidence of the first episode of VZV infection at 2 years after transplantation was 14% (95% confidence interval [CI], 7.9% to 22.8%) in all recipients and 9% (95% CI, 1.0 to 26.6) in VZV-seronegative patients. Notably, the VZV infection rate increased with age and the VZV infection rate in patients age 15 to 19 years was almost three times higher than in patients age 0 to 4 years (28% versus 10%; P=.003). However, there was no difference in the VZV infection rate between recipients of single auto-HCT and recipients of tandem auto-HCT. Two patients died of disseminated VZV infection. VZV infection is a considerable risk in auto-HCT recipients with or without short-term prophylaxis. Universal antiviral prophylaxis might be considered, particularly in older children, regardless of VZV serologic results. To our knowledge, this is the largest study of VZV infection in pediatric auto-HCT recipients reported to date.

Epidemiology of Post-Transplant Lymphoproliferative Disorders in Children with Solid Organ Transplant over 34 Years of a Single Center Experience

Background Post-Transplant lymphoproliferative disorders (PTLD) are a heterogeneous group of lymphoid neoplasms following solid organ transplantation (SOT) caused by uncontrolled lymphoproliferation often induced by Epstein Barr Virus (EBV) due to the lack of cytotoxic T cell response resulting from immunosuppression. A pre-emptive intervention strategy for PTLD prevention was implemented in our center in 2002 for all EBV-mismatched SOT recipients consisting in close monitoring of the viral load and consideration for early intervention (Ex; reduction of immunosuppression) in addition to universal antiviral prophylaxis (implemented in 1990). We aim to describe the incidence and risk factors for PTLD in children with SOT, including all transplant types, at a single center over 34 years. We also aim to analyze the impact of a pre-emptive PTLD prevention program. Material and methods All patients younger than 18 years of age who received SOT at the University of Alberta Hospital/Stollery Children's Hospital from January 1st, 1984 to December 31st, 2018 were included. Donor and recipient baseline data (age, sex, donor living status, date and type of transplant, EBV and cytomegalovirus serostatus) were extracted from a prospective database. Retrospective chart review was performed for PTLD cases along with expert pathology review (when tissue available). Local Ethics Board was obtained. Statistical analyses were performed using SPSS software version 25 and R version 3.3.3. Results Characteristics of the study population, immunosuppression regimen used by transplant program and specific immunosuppression for PTLD cases are summarized in table 1, 2 and 3 respectively. PTLD characteristics were compared based on the time of presentation of PTLD ≤1 year, 1 to 5 years and &amp;gt;5 years (table 4). Most of the cases with PTLD presented with primary involvement in multiple sites followed by lymph nodes, gastro-intestinal tract, allograft, tonsils/adenoids and other sites. Advance staging (III-IV) was present in 71% of cases. The incidence rate of PTLD for the whole group was 0.82/100 Person-year (Figure 1 A). The incidence rate peaked at 1-year post-transplant and had a decreasing trend in the following years post-transplant, with no cases beyond 12 years post-transplant (Figure 1 B). The cumulative incidence was the highest for the multi-visceral transplants followed by thoracic, liver and kidney transplants (Figure 1C). Univariate analysis showed children younger than 5 years at transplant had 5-fold higher risk of PTLD compared to children ≥ 10 years of age at transplant. Donors ≤ 5 years of age at transplant, showed 3-fold higher risk PTLD comparing to older donors. Liver transplant had 2.8-fold and thoracic transplants had 5-fold higher risk of PTLD comparing to kidney transplants, no significant risk was associated with multi-visceral group (only 1 case in the cohort). EBV seronegative recipient was associated with 2.6-fold higher risk of PTLD comparing to EBV seropositive recipient. Era prior to implementation of pre-emptive intervention had 3-fold risk of PTLD comparing to era post implementation. Patients transplanted at 1.1 - 5 years of age was an independent risk factor associated with PTLD in multivariate analysis (table 3) SOT recipients showed EBV seroconversion with age (Figure 3A). PTLD based on EBV Donor Recipient (DR) serostatus showed more cases D positive R negative (D+R-) in the first-year comparing to D negative Recipient negative (D-R-), D-R- cases increased between 1-5 years equivalent to D+R-, beyond 5 years D+R- decreased with no D-R- cases (Figure 3B). D-R- serostatus had the highest probability of PTLD followed by D+R- (Figure 3 C). Eleven (24%) out of 45 patients with PTLD presented with PTLD relapse. Seven (5.6%) out of 125 deaths of SOT were secondary to PTLD. PTLD was the most common cause of death in the PTLD group (50%) followed by graft failure/rejection. Conclusions Incidence of PTLD peaked in the first-year post-transplant and decreased overtime with increase incidence in thoracic and multi-visceral transplants. Risk factors for PTLD included patients transplanted at younger age, younger donors, thoracic and liver transplants and EBV seronegativity in the recipient. A pre-emptive intervention strategy for PTLD prevention implemented in 2002 decreased the risk of PTLD. Disclosures No relevant conflicts of interest to declare.

Current Perspectives on Cytomegalovirus in Heart Transplantation

Cytomegalovirus (CMV) is the most common infectious agent in heart transplantation. Its peculiar features, including a complex interplay with host’s immune system and lifelong latency, have been associated with reduced graft survival by the development of manifestations of graft rejection, such as cardiac allograft vasculopathy. Modern antiviral agents have been effective in reducing the clinical impact of acute CMV syndromes, thus questioning the current role of the virus on chronic graft dysfunction. In this setting, prolonged universal antiviral prophylaxis may appear an easy and effective strategy to abolish the CMV issue in clinical practice. Nevertheless, several unanswered questions are still open: is CMV still involved in CAV development despite ganciclovir use? Do we have evidence that benefits from universal antiviral prophylaxis overcome costs and toxicities? Do we have anything new in the pipeline? In this article, we review the latest evidences unraveling the answers to these burning questions.

Safety of Abatacept in Rheumatoid Arthritis With Serologic Evidence of Past or Present Hepatitis B Virus Infection.

Rheumatoid arthritis (RA) with concomitant hepatitis B virus (HBV) infection represents a therapeutic challenge due to the risk of HBV reactivation under immunosuppressive treatment. To date there are few data coming from anecdotal case reports that concern HBV reactivation following treatment with abatacept. This observational retrospective study was aimed to assess the safety profile of abatacept in this particular clinical setting. Eleven Italian rheumatologic centers provided data from patients with RA and positive HBV serology treated with intravenous abatacept. HBV markers and clinical and laboratory data were checked at followup visits every 3 months. In total, 72 patients were included in the study: 47 inactive carriers, 21 occult carriers, and 4 chronic active carriers for HBV. At baseline all of the patients had normal liver function tests and low or undetectable HBV DNA levels, except for those with chronic active hepatitis. Thirteen patients received prophylaxis with lamivudine, and 4 received treatment with adefovir or tenofovir. At the end of the 24-month followup period, 49 patients were being treated. Data from 316 followup visits showed that abatacept was safe. No patients experienced reactivation of hepatitis B. Treatment withdrawals (23 patients) were due to lack of efficacy, subject decision/lost at followup, or adverse events not related to HBV infection. Our study provides reassuring data about the safety profile of abatacept in RA with concomitant HBV infection without universal antiviral prophylaxis. Further prospective studies are needed to confirm these preliminary results.

Incidence and risk factors of herpes zoster among adult renal transplant recipients receiving universal antiviral prophylaxis.

BackgroundHerpes zoster (HZ) is a significant cause of morbidity and complications in adult renal transplant recipients. We determined the incidence, complications and risk factors for the development of HZ after renal transplantation in a setting using universal antiviral prophylaxis.MethodsThe medical files of all adult renal transplants, performed between 2004 and 2008, were retrospectively reviewed to assess the clinical characteristics and risk factors of HZ. Incident cases of HZ were determined and the probability of developing post-transplant HZ for all subjects was calculated using the Kaplan Meier method. A multivariable Cox proportional hazards model was applied to assess the risk factors associated with the development of HZ.ResultsA total of 450 patients were eligible with a median follow up of 38 months. Twenty nine subjects (6.4 %) developed HZ, the median time to onset was 18 months, only three of them (10.3 %) required hospitalization, and none developed disseminated or visceral disease and death directly attributed to zoster. However, high rates of post-herpetic neuralgia (48.7 %) were observed. Overall incidence was calculated at 20.6 cases per 1000 patient-years of follow-up. Following multivariate analysis, increased age ≥ 60 years old, positive pre-transplant history of varicella related disease and administration of rejection treatment conferred an increased risk of 4.00-fold (CI: 1.79- 8.92), 16.00-fold (CI: 4.62- 55.52), and 5.57-fold (CI: 1.56- 19.84) respectively, for the development of post-transplant zoster.ConclusionsHZ remains a common complication after renal transplantation in adults under current immunosuppession protocols and universal antiviral prophylaxis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-015-1038-1) contains supplementary material, which is available to authorized users.

Cytomegalovirus infection in liver transplant recipients: Updates on clinical management

Cytomegalovirus (CMV) infection is a common complication after liver transplantation, and it is associated with multiple direct and indirect effects. Management of CMV infection and disease has evolved over the years, and clinical guidelines have been recently updated. Universal antiviral prophylaxis and a pre-emptive treatment strategy are options for prevention. A currently-recruiting randomized clinical trial is comparing the efficacy and safety of the two prevention strategies in the highest risk D+R- liver recipients. Drug-resistant CMV infection remains uncommon but is now increasing in incidence. This highlights the currently limited therapeutic options, and the need for novel drug discoveries. Immunotherapy and antiviral drugs with novel mechanisms of action are being investigated, including letermovir (AIC246) and brincidofovir (CMX001). This article reviews the current state of CMV management after liver transplantation, including the updated practice guidelines, and summarizes the data on investigational drugs and vaccines in clinical development.

Cost analysis in favor of a combined approach for cytomegalovirus after kidney transplantation: a single‐center experience

In kidney transplant recipients, cytomegalovirus (CMV) can cause significant morbidity, mortality, and costs, which can be prevented by universal antiviral prophylaxis or preemptive therapy. With the aim to improve our understanding of the advantages and disadvantages of these interventions, we documented resource use for 101 consecutive kidney transplant recipients in our center receiving preemptive therapy and estimated resource use for 2 alternative scenarios. At 100 days after transplantation, the mean total costs of our preemptive strategy including monitoring and treatment with intravenous ganciclovir was €2545 per patient. At €4853 per patient, these costs were highest for the CMV-positive donor/CMV-negative recipient (D+/R-) patient subgroup (n = 28), who frequently require recurrent treatment. A treatment scenario with valganciclovir prophylaxis for D+/R- and R+ patients, in which we ignored late-onset disease after discontinuation of prophylaxis, resulted in an estimated cost of €1892 per patient. A combined approach using valganciclovir prophylaxis in the D+/R- group and a preemptive strategy in the R+ groups would result in the lowest mean and median costs per patient (€1701). Our study suggests that a combined approach, using valganciclovir prophylaxis in D+/R- patients and preemptive treatment in R+ patients, may result in the lowest cost. This approach seems reasonable as it restricts expensive prophylactic drug therapy to those who would benefit the most, whereas it limits the risk for drug toxicity and late-onset disease in those at lower risk for CMV.

Long-Term Outcomes of Pre-emptive Valganciclovir Compared with Valacyclovir Prophylaxis for Prevention of Cytomegalovirus in Renal Transplantation

Prevention of cytomegalovirus (CMV) is essential in organ transplantation. The two main strategies are pre-emptive therapy, in which one screens for and treats asymptomatic CMV viremia, and universal antiviral prophylaxis. We compared these strategies and examined long-term outcomes in a randomized, open-label, single-center trial. We randomly assigned 70 renal transplant recipients (CMV-seropositive recipient or donor) to 3-month prophylaxis with valacyclovir (n=34) or pre-emptive valganciclovir for significant CMV viremia detected at predefined assessments through month 12 (n=36). Among the 55 patients who had a protocol biopsy specimen available at 3 years to allow assessment of the primary outcome, 9 (38%) of 24 patients in the prophylaxis group and 6 (19%) of 31 patients in the pre-emptive therapy group had moderate to severe interstitial fibrosis and tubular atrophy (odds ratio, 2.50; 95% confidence interval, 0.74-8.43; P=0.22). The prophylaxis group had significantly higher intrarenal mRNA expression of genes involved in fibrogenesis. The occurrence of CMV disease was similar in both groups, but pre-emptive therapy improved 4-year graft survival (92% versus 74%; P=0.049) as a result of worse outcomes in patients with late-onset CMV viremia. In conclusion, compared with valacyclovir prophylaxis, pre-emptive valganciclovir therapy may lead to less severe interstitial fibrosis and tubular atrophy and to significantly better graft survival.