A systematic literature review of the economic and healthcare resource burden of cytomegalovirus.

OBJECTIVE: Cytomegalovirus (CMV) can infect individuals at any age, including infants, who may contract it from infected mothers (congenital CMV [cCMV]). Whereas CMV infection is typically asymptomatic or causes mild illness in healthy individuals, infection can result in severe outcomes in immunocompromised individuals and in infants with cCMV. This systematic review aims to characterize the economic impact of CMV and cCMV infections. METHODS: Medline, Embase, and LILACS databases were searched for publications reporting the economic impact of cCMV and CMV infections across all age groups. Manuscripts published between 2010 and 2020 from Australia, Latin America, Canada, Europe, Israel, Japan, the United States, and global (international, worldwide) studies were included; congress materials were excluded. Outcomes of interest included cCMV- and CMV-attributable direct costs/charges, resource utilization, and indirect/societal costs. RESULTS: Of 751 records identified, 518 were excluded based on duplication, population, outcome, study design, or country. Overall, 55 articles were eligible for full-text review; 25 were further excluded due to population, outcome, study design, or congress abstract. Two publications were additionally identified, resulting in economic impact data compiled from 32 publications. Of these, 24 publications reported cost studies of cCMV or CMV, including evaluation of direct costs/charges, healthcare resource utilization, and indirect/societal costs, and 7 publications reported economic evaluations of interventions. The populations, methods and outcomes used across these studies varied widely. CONCLUSIONS: CMV and cCMV infections impose a considerable economic impact on different countries, populations, and outcomes. There are substantial evidence gaps where further research is warranted.

Evaluation of treatment patterns, healthcare resource utilization, and costs among patients receiving treatment for cytomegalovirus following allogeneic hematopoietic cell or solid organ transplantation.

AIM: Management of cytomegalovirus (CMV) infection/disease in transplant recipients may be complicated by toxicities and resistance to conventional antivirals, adding to the overall healthcare burden. We characterized treatment patterns, healthcare resource utilization (HCRU), and costs to elucidate the healthcare burden associated with CMV therapies post-transplant. MATERIALS AND METHODS: A retrospective, longitudinal cohort study of transplant recipients using data from a US commercial insurance claims database (2013-2017) was conducted. Patients with a claim for post-transplant CMV diagnosis and anti-CMV treatment (ganciclovir, valganciclovir, foscarnet, or cidofovir) were identified (Treated CMV cohort) and compared with patients with neither a claim for CMV diagnosis nor anti-CMV treatment (No CMV cohort) for outcomes including HCRU and associated costs. Allogeneic hematopoietic cell transplantation (HCT) or solid organ transplantation (SOT) recipients were analyzed separately. Anti-CMV treatment patterns were assessed in the Treated CMV cohort. Costs were evaluated among subgroups with myelosuppression or nephrotoxicity. RESULTS: Overall, 412 allogeneic HCT and 899 SOT patients were included in the Treated CMV cohorts, of which 41.7% and 52.5%, respectively, received multiple antiviral courses. Treated CMV cohorts compared with No CMV cohorts had higher mean monthly healthcare visits per patient (allogeneic HCT: 8.83 vs 6.61, SOT: 5.61 vs 4.45) and had an incremental adjusted mean monthly cost per patient differences of $8,157 (allogeneic HCT, p < .004) and $2,182 (SOT, p < .004). Among Treated CMV cohorts, HCRU and costs increased with additional CMV antiviral treatment courses. Mean monthly costs were higher for patients with than without myelosuppression or nephrotoxicity. LIMITATIONS: Results may not be generalizable to patients covered by government insurance or outside the USA. CONCLUSIONS: CMV post-transplant managed with conventional treatment is associated with substantial HCRU and costs. The burden remains particularly high for patients requiring multiple treatment courses for post-transplant CMV or for transplant recipients who develop myelosuppression or nephrotoxicity.

Combined Analysis of Early CD4+ T Cell Counts and CMV Serostatus May Improve CMV Risk Assessment after Allogeneic Hematopoietic Cell Transplantation.

The incidence and severity of viral complications after cellular therapy are highly variable. Recent publications describe relevant interactions between the human Cytomegalovirus (CMV) and host immunity in recipients of allogeneic hematopoietic cell transplantation (HCT). Although immune monitoring is routinely performed in HCT patients, validated cut-off levels correlating with transplant outcomes such as survival or CMV reactivation are mostly limited to day +100, which is later than the median time for CMV reactivation in the absence of medical prophylaxis. To address this gap in early risk assessment, we applied an unsupervised machine learning technique based on clustering of day +30 CD4+ helper T cell count data, and identified relevant cut-off levels within the diverse spectrum of early CD4+ reconstitution. These clusters were stratified for CMV recipient serostatus to identify early risk groups that predict clinical HCT outcome. Indeed, the new risk groups predicted subsequent clinical events such as NRM, OS, and high CMV peak titers better than the most established predictor, i.e., the positive CMV recipient serostatus (R+). More specifically, patients from the R+/low CD4+ subgroup strongly associated with high CMV peak titers and increased 3-year NRM (subdistribution hazard ratio (SHR) 10.1, 95% CI 1.38-73.8, p = 0.023), while patients from the R-/very high CD4+ subgroup showed comparable NRM risks (SHR 9.57, 95% CI 1.12-81.9, p = 0.039) without such an association. In short, our study established novel cut-off levels for early CD4+ T cells via unsupervised learning and supports the integration of host cellular immunity into clinical risk-assessment after HCT in the context of CMV reactivation.

The clinical and economic burden of cytomegalovirus management post allogeneic hematopoietic stem cell transplantation in Japan - a retrospective database study.

Introduction: Reactivation of cytomegalovirus (CMV) infection is a major threat and it causes significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). There remains, however, a paucity of evidence regarding the economic burden of current CMV management in Japan. The aim of this study is to characterize the healthcare resource utilization (HCRU) and cost incurred for CMV management post allo-HSCT, using a Japanese hospital claims database.Methods: Patients who underwent allo-HSCT between April 2010 and March 2018 were identified and followed up for 180 days.Results: In total, 916 patients were included for analysis and categorized into CMV (-) group and CMV (+) group based on the presence of a CMV episode within 100 days post allo-HSCT. A CMV episode was defined as evidence of receiving at least one dose of the following anti-CMV drugs, ganciclovir, foscarnet, or valganciclovir. The mean (± standard deviation [SD]) total length of stay was 93.6 (± 43.7) days in the CMV (+) group, which was significantly longer than 55.9 (±40.6) days in the CMV (-) group, and this trend was more pronounced in patients with multiple CMV episodes. The mean (±SD) total medical cost within 180 days post allo-HSCT was US$122,328 (±56,977) in the CMV (+) group, while the mean total medical cost was US$75,344 (±43,821) in the CMV (-) group. Moreover, transfusion and antimicrobial use was observed as the major medication cost component, which is suggestive of the indirect effect of CMV episodes.Conclusion: This study demonstrated that CMV episodes post allo-HSCT were associated with increased HCRU and cost.

The Economic Burden of Congenital Cytomegalovirus Disease in the First Year of Life: A Retrospective Analysis of Health Insurance Claims Data in the United States.

PURPOSE: Congenital cytomegalovirus (cCMV) infection is the most common congenital infection in the United States; however, limited data exist regarding the economic burden of cCMV disease (cCMVd) among newborns and infants. The purpose of this study was to compare health care resource utilization and costs between infants with cCMVd at birth and during the first year of life versus matched infants without diagnosed cCMVd. METHODS: Retrospective analyses of health insurance claims data from the MarketScan Commercial Claims and Encounters and Multi-State Medicaid databases (January 1, 2011-December 31, 2016) were conducted. Infants with cCMV diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 771.1 or 078.5; International Classification of Diseases, Tenth Revision, Clinical Modification code P35.1 or B25) were included. Two mutually exclusive periods were examined: initial hospital stay at birth ("birth" analysis) and subsequent 12 months ("postbirth" analysis). Infants with cCMVd in both periods were matched 1:1 to infants without cCMVd based on demographic and clinical characteristics. All-cause costs for cCMVd in infants versus matched control infants were reported in 2016 US dollars. Multivariable regression analyses controlled for additional confounding factors. FINDINGS: In the birth analysis, 397 of 404 newborns with cCMVd (167 vaginal deliveries, 230 cesarean deliveries) were matched to control infants; newborns with cCMVd had an additional mean (95% CI) of 9.1 (5.8-12.3) and 9.0 (4.6-13.5) inpatient days and $24,274 (10,082-38,466) and $31,770 (9911-53,630) more unadjusted inpatient costs versus control infants for vaginal and cesarean deliveries, respectively. In the postbirth analysis, 678 of 679 infants with cCMVd were matched with control infants; infants with cCMVd had an additional $58,806 (95% CI, 41,247-76,365) in unadjusted costs versus control infants, with inpatient visits accounting for 85% of the difference. Newborns with cCMVd accrued costs at birth averaging 1.5 to 2.1 times greater than control infants for cesarean and vaginal deliveries. During the first year of life, infants with cCMVd had costs averaging 7 times greater than control infants. IMPLICATIONS: cCMVd is associated with substantial economic burden from birth and during the first year of life. Our findings support the notion that developing effective prevention of cCMVd and increasing awareness of the disease among women should be a public health priority, given the economic burden of cCMVd.

Cytomegalovirus Screening in Pregnancy: A Cost-Effectiveness and Threshold Analysis.

OBJECTIVE: To determine threshold cytomegalovirus (CMV) infectious rates and treatment effectiveness to make universal prenatal CMV screening cost-effective. STUDY DESIGN: Decision analysis comparing cost-effectiveness of two strategies for the prevention and treatment of congenital CMV: universal prenatal serum screening and routine, risk-based screening. The base case assumptions were a probability of primary CMV of 1% in seronegative women, hyperimmune globulin (HIG) effectiveness of 0%, and behavioral intervention effectiveness of 85%. Screen-positive women received monthly HIG and screen-negative women received behavioral counseling to decrease CMV seroconversion. The primary outcome was the cost per maternal quality-adjusted life year (QALY) gained with a willingness to pay of $100,000 per QALY. RESULTS: In the base case, universal screening is cost-effective, costing $84,773 per maternal QALY gained. In sensitivity analyses, universal screening is cost-effective only at a primary CMV incidence of more than 0.89% and behavioral intervention effectiveness of more than 75%. If HIG is 30% effective, primary CMV incidence can be 0.82% for universal screening to be cost-effective. CONCLUSION: The cost-effectiveness of universal maternal screening for CMV is highly dependent on the incidence of primary CMV in pregnancy. If efficacious, HIG and behavioral counseling allow universal screening to be cost-effective at lower primary CMV rates.

Healthcare costs attributable to congenital cytomegalovirus infection.

OBJECTIVE: Congenital cytomegalovirus infection (cCMV) can cause symptoms at birth as well as long-term impairment. This study estimates cCMV-related healthcare costs in the Netherlands in early childhood. DESIGN, SETTING AND PATIENTS: In a nationwide retrospective cohort study, 156 children with cCMV were identified by testing 31 484 neonatal dried blood spots for cCMV. Use of healthcare resources in the first 6 years of life by children with cCMV and a matched cCMV-negative control group were analysed. Mean costs per child were calculated by multiplying healthcare resource use by its reference prices. EXPOSURE: Children with cCMV were compared with cCMV-negative children. MAIN OUTCOME MEASURES: The average total healthcare costs per child were based on the average costs for hospital admissions and consultations by healthcare providers. RESULTS: Mean healthcare costs of children with cCMV (€6113, n=133) were higher than children without cCMV (€3570, n=274), although statistically not significant, with a mean difference of €2544 (95% CI €-451 to €5538). The costs of children with long-term impairment were two times higher in children with cCMV (€17 205) compared with children without cCMV (€8332). CONCLUSIONS: Children with cCMV, especially those with long-term impairment and those symptomatic at birth, accrue higher healthcare costs than cCMV-negative children in the first 6 years of life, although this is not statistically significant. This economic impact is of importance in the evaluation of preventive measures against cCMV. TRIAL REGISTRATION NUMBER: NTR3582.

Economic burden of preemptive treatment of CMV infection after allogeneic stem cell transplantation: a retrospective study of 208 consecutive patients.

BACKGROUND: Cytomegalovirus (CMV) infection and disease (CMV episodes) are global concerns after allogeneic hematopoietic stem cell transplantation (HSCT). They affect survival, both by direct and indirect effects. Due to safety issues of current anti-CMV antivirals, long-term CMV prophylaxis is poorly tolerated and the most common strategy to decrease the incidence of CMV disease is preemptive. New, less toxic, molecules are currently being assessed for CMV prophylaxis which should replace or considerably decrease the preemptive approach. The aim of this study was to assess the economic burden of CMV episodes after HSCT with a preemptive approach. METHODS: We analyzed data from 208 consecutive adults transplanted in our institution, between 2008 and 2013. Hospital resource utilization was retrieved via the linked hospital admissions and Diagnostic Related Groups for the period of conditioning to 12 months after transplant. RESULTS: CMV episodes occurred in 70 patients (34%) over the first 12 months following HSCT, after a mean of 75 days (median: 46 (7-334)). The mean total length of stay was significantly associated with the occurrence of a CMV episode (113.9 vs. 87.5 days, p = 0.0002) but was associated neither with the pre-transplant CMV serology of donors/recipients nor with survival. The mean cost of transplant was €104,016 (SD = €37,281) after 12 months. Bivariate and multivariate analyses indicated that the occurrence of >1 CMV episode increased the costs of allogeneic HSCT by 25-30% (p < 0.0001). CONCLUSION: Our study, which is the largest, single-institution cost study of allogeneic HSCT in Europe, shows that two or more CMV episodes significantly increased the transplant cost. New prophylactic strategies to prevent CMV infection and disease should decrease transplant costs.

[Antiviral humanized and human monoclonal antibodies].

The paper considers the characteristics of monoclonal antibodies, methods for their experimental preparation, problems of their production, and possibilities of their use for the emergency prevention of viral infections and for the treatment of chronic diseases caused by human immunodeficiency virus, hepatitis B and C viruses, and herpes viruses. The future of experimentally produced or clinically trialed monoclonal antibodies is mainly determined by commercial considerations. It is possible that simplification of industrial production technologies and a reduction in the cost of evidence-based methods for evaluation of clinical effectiveness will allow monoclonal antibodies to be extensively used for the prevention and treatment of viral infections.

Screening and treating for primary cytomegalovirus infection in pregnancy: where do we stand? A decision-analytic and economic analysis.

OBJECTIVE: To estimate which 1 of 3 screening strategies for primary maternal cytomegalovirus infection, with intention to treat with hyperimmune globulin, is most cost-effective. STUDY DESIGN: A decision-analytic and cost-effectiveness model was constructed for pregnant women, comparing 3 strategies screening for primary maternal cytomegalovirus infection with intention to treat with cytomegalovirus-intravenous immune globulin: (1) serum screen all pregnant women, (2) serum screen women with risk factors for primary cytomegalovirus, (3) serum screen women with suspicious sonographic findings. Probability, use (or value), and cost estimates were derived from published literature. RESULTS: Universal screening for primary maternal cytomegalovirus was the preferred and most cost-effective strategy. However, if treatment with cytomegalovirus-intravenous immune globulin achieved less than a 47% reduction (relative risk, 0.53) in clinical disease, universal screening would no longer be cost-effective. CONCLUSION: Universal screening for primary maternal cytomegalovirus infection is cost-effective based on available evidence, highlighting the urgent need for additional study evaluating the efficacy of cytomegalovirus-intravenous immune globulin to prevent congenital cytomegalovirus.

Resource use and treatment costs after kidney transplantation: impact of demographic factors, comorbidities, and complications.

BACKGROUND: Our goal was to quantify outcomes, resource use, and treatment costs for the first 2 years after renal transplantation in a "real-life" European setting and to assess the impact of preoperative risk factors and postoperative complications on treatment costs. METHODS: Inpatient and outpatient records of all patients who received a renal transplant at Medizinische Hochschule Hannover, Germany, between January 1998 and July 2000, were evaluated. Key clinical events were recorded. Direct costs were calculated for primary hospitalization, the remainder of year 1, and year 2 after transplantation. Cost of organ procurement, pretransplant care, and transplant surgery were excluded. Cost consequences for key clinical events were determined. RESULTS: Of 204 patients undergoing transplantation, 195 and 149 completed 1 year and 2 years of follow-up, respectively. The outcomes of years 1 and 2, respectively, were as follows: graft failure, 5.4%, 0.7%; acute rejection, 35.9%, 5.4%; cytomegalovirus (CMV) infection, 29.2%, 2.0%; and delayed graft function, 30.9%. Costs for primary hospitalization, the remainder of year 1, and year 2 averaged Euro 15,380, Euro 18,636, and Euro 14,484, respectively. Cost-driving events included graft failure Euro 36,228), acute rejection (Euro 9,638), delayed graft function (Euro7,359), and CMV infection (Euro 4,149). Graft failure and acute rejection for year 1 also added significantly to the costs for year 2. CONCLUSIONS: These results show that posttransplant clinical outcomes result in a significant increase in treatment costs. Because the economic impact of primary causes of chronic rejection (acute rejection and CMV) and delayed graft function is substantial, careful selection of the most appropriate immunosuppressive regimen is essential.

Management of cytomegalovirus infection by weekly surveillance after renal transplant: analysis of cost, rejection and renal function.

BACKGROUND: Recently published guidelines recommend anti-viral prophylaxis as the best method of preventing cytomegalovirus (CMV) disease in the post-transplant period, but some authors have suggested that surveillance strategies may be as effective and less costly. The aim of the present study was to analyse the effectiveness and cost of a deferred treatment strategy using weekly CMV polymerase chain reaction (PCR) surveillance in high risk renal transplant recipients. METHODS: We used weekly surveillance for plasma CMV PCR positivity for the first 3 months in consecutive renal transplants between CMV seropositive donors and seronegative recipients, and analysed incidence of CMV infection, timing of infection, acute rejection and renal function at 1 year. RESULTS: There was evidence of CMV infection in 27/41 (65.9%) patients and of CMV disease in 20/41 (48.8%). Only 8/20 (40%) patients were PCR positive before disease onset. Patients were treated on the basis of clinical evidence of CMV disease (deferred strategy), but we used the data to compare the potential costs of a pre-emptive strategy (all patients PCR positive before the onset of clinical features of disease treated with intravenous ganciclovir) and prophylaxis (oral ganciclovir for 3 months in all patients). The deferred strategy cost pound 1159 per patient (excluding the cost of hospitalization) while a pre-emptive strategy would cost pound 1381 per patient. Prophylaxis costs pound 1500- pound 2213 per patient depending on published estimates of relative risk reduction. Mean estimated creatinine clearance at 1 year was 70.0 ml/min in patients who experienced no infection, 47.7 ml/min in patients who experienced infection but no disease, and 39.6 ml/min in patients who experienced CMV disease (P < 0.001). The incidence of acute rejection in these groups was 7.1, 14.3 and 35%, respectively (P = 0.13). CONCLUSIONS: CMV surveillance strategies may cost slightly less but may have a deleterious effect on long-term outcome compared with prophylaxis.

Modeling costs and cost-effectiveness of different CMV management strategies in liver transplant recipients as a support for current and future decision making.

OBJECTIVES: To develop a generic decision-analytic model to predict health and economic outcomes of different management options for cytomegalovirus (CMV) infection and disease in liver transplant patients. METHODS AND DATA: The model considers different CMV management strategies, thereby emphasizing the important difference between infection and disease. The first strategy starts with prophylaxis prior to transplantation, followed by preemptive treatment if infection, based on positive CMV diagnostic tests, is confirmed. The second strategy is a preemptive strategy consisting of only testing followed by preemptive treatment. Finally, in the wait-and-treat strategy, antiviral treatment is only started when clinical signs of CMV disease appear. Management and resource-use data were obtained from clinical experts in large transplant centers in France, Germany, and the United Kingdom. Cost data were collected from the health care payer's perspective. A Bayesian revision technique was applied to distinguish effectiveness of current management options for CMV infection vs. CMV disease, an aspect that is currently underreported in literature. RESULTS: CMV prophylaxis in liver transplant recipients is generally more cost-effective than preemptive and wait-and-treat strategies. In order of importance, changes in drug costs, drug efficacy, specificity of CMV testing, cost of hospitalization, probability of CMV relapse and baseline CMV risk are the most important factors influencing the cost-effectiveness. CONCLUSION: This model describes different strategies applied for management of CMV in liver transplant patients and is useful both for current decision making, optimal disease management, and assessment of future research targets.

A survey of allogeneic bone marrow transplant programs in the United States regarding cytomegalovirus prophylaxis and pre-emptive therapy.

Despite an extensive literature, no consensus has emerged regarding the optimal preventive strategy for CMV in allogeneic bone marrow transplantation (BMT). No survey of CMV prevention in BMT centers in the United States has yet been published. A questionnaire was sent to all allogeneic BMT programs in the United States, as listed in the November 1998 National Marrow Donor Program (NMDP) address roster. Questions included whether universal prophylaxis, pre-emptive therapy, or some other strategy was used for CMV prevention, and which CMV diagnostic tests were utilized. Eighty-one of 96 programs (86%) responded to the survey. Of these, 46 (56%) utilize a pre-emptive ganciclovir strategy, whereas 17 (21%) utilize universal prophylaxis, and 15 (19%) utilize a hybrid strategy based on risk stratification. The most commonly utilized CMV diagnostic tests are CMV-DNA by PCR (55 centers), shell vial centrifugation culture (52), tissue culture (42), pp65 antigenemia assay (38), and CMV-DNA by Digene hybrid capture (14). Of these, the CMV-DNA by PCR, pp65 antigenemia assay, and shell vial culture are the most frequently utilized as triggers for pre-emptive therapy. Quantitative assays are common (PCR 42%, Digene 64%). We conclude that centers currently performing allogeneic BMT in the United States employ a variety of strategies for CMV prevention, and differ in their diagnostic tests of choice for CMV monitoring. These results emphasize the need for large-scale studies to identify optimal diagnostic and management protocols. Bone Marrow Transplantation (2000) 26, 763-767.

Cytomegalovirus infection in the liver transplant recipient. Epidemiology, pathogenesis, and clinical management.

The effects of cytomegalovirus (CMV) on the liver transplant patient can be divided into two general categories: the direct infectious disease effects (e.g. CMV mononucleosis, hepatitis, pneumonitis, GI infection) and the indirect effects that are mediated by cytokines elaborated as a consequence of the infection. These indirect effects include an immunosuppressive effect that contributes to the development of superinfection with fungi, bacteria, and Pneumocystis carinii; a role in the pathogenesis of allograft injury; and a role in the development of post-transplant lymphoproliferative disease. The two key steps in the pathogenesis of CMV infection-reactivation of the virus from latency and systemic spread-are modulated by the immunosuppressive therapy administered. New antiviral programs, primarily those involving ganciclovir, have resulted in considerable progress in the prevention and treatment of CMV disease among liver transplant recipients.

Lifetime cost of treating a person with HIV infection.

A study was conducted to examine the inpatient, outpatient and drug therapy costs incurred from initial presentation with HIV infection or AIDS to death, where death occurred between 1990 and 1994. The average lifetime cost per patient was 18,729 pounds being made up of 8428 pounds for inpatient care, 2086 pounds for outpatient care and 8215 pounds for drug therapy. Sixty per cent of patients died at home. Active cytomegalovirus infection was the most common condition encountered in the high cost patients. Escalating drug costs may eventually lead to priority setting for the management of certain opportunistic infections.