Estimation of lifetime costs for patients receiving a transplant: the case of liver transplantation related to hepatitis B in Italy.

Introduction: In Italy, post-liver transplant (LT) hepatitis B virus (HBV) reinfection prophylaxis is frequently based on a combined regimen of anti-HBV immunoglobulin (HBIG) and oral antivirals. However, little information is available at the national level on the cost of LT and the contribution of HBV prophylaxis. This study aimed to quantify the direct healthcare cost for adult patients undergoing LT for HBV-related disease over a lifetime horizon and from the perspective of a National Healthcare Service. Methods: A pharmaco-economic model was implemented with a 4-tiered approach consisting of 1) preliminary literature research to define the research question; 2) pragmatic literature review to retrieve existing information and inform the model; 3) micro-simulated patient cycles; and 4) validation from a panel of national experts. Results: The average lifetime healthcare cost of LT for HBV-related disease was €395,986. The greatest cost drivers were post-transplant end-stage renal failure (31.9% of the total), immunosuppression (20.6%), and acute transplant phase (15.8%). HBV reinfection prophylaxis with HBIG and antivirals accounted for 12.4% and 6.4% of the total cost, respectively; however, lifetime HBIG prophylaxis was only associated with a 6.6% increase (~€422 k). Various sensitivity analyses have shown that discount rates have the greatest impact on total costs. Conclusion: This analysis showed that the burden of LT due to HBV is not only clinical but also economic.

A systematic review of the cost and cost-effectiveness of immunoglobulin treatment in patients with hematological malignancies.

OBJECTIVES: Patients with hematological malignancies are likely to develop hypogammaglobulinemia. Immunoglobulin (Ig) is commonly given to prevent infections, but its overall costs and cost-effectiveness are unknown. METHODS: A systematic review was conducted following the PRISMA guidelines to assess the evidence on the costs and cost-effectiveness of Ig, administered intravenously (IVIg) or subcutaneously (SCIg), in adults with hematological malignancies. RESULTS: Six studies met the inclusion criteria, and only two economic evaluations were identified; one cost-utility analysis (CUA) of IVIg versus no Ig, and another comparing IVIg with SCIg. The quality of the evidence was low. Compared to no treatment, Ig reduced hospitalization rates. One study reported no significant change in hospitalizations following a program to reduce IVIg use, and an observational study comparing IVIg with SCIg suggested that there were more hospitalizations with SCIg but lower overall costs per patient. The CUA comparing IVIg versus no Ig suggested that IVIg treatment was not cost-effective, and the other CUA comparing IVIg to SCIg found that home-based SCIg was more cost-effective than IVIg, but both studies had serious limitations. CONCLUSIONS: Our review highlighted key gaps in the literature: the cost-effectiveness of Ig in patients with hematological malignancies is very uncertain. Despite increasing Ig use worldwide, there are limited data regarding the total direct and indirect costs of treatment, and the optimal use of Ig and downstream implications for healthcare resource use and costs remain unclear. Given the paucity of evidence on the costs and cost-effectiveness of Ig treatment in this population, further health economic research is warranted.

Immunoglobulin Replacement Therapy is critical and cost-effective in increasing life expectancy and quality of life in patients suffering from Common Variable Immunodeficiency Disorders (CVID): A health-economic assessment.

BACKGROUND: Common variable immunodeficiency disorders (CVID), the most common form of primary antibody deficiency, are rare conditions associated with considerable morbidity and mortality. The clinical benefit of immunoglobulin replacement therapy (IgGRT) is substantial: timely treatment with appropriate doses significantly reduces mortality and the incidence of CVID-complications such as major infections and bronchiectasis. Unfortunately, CVID-patients still face a median diagnostic delay of 4 years. Their disease burden, expressed in annual loss of disability-adjusted life years, is 3-fold higher than in the general population. Hurdles to treatment access and reimbursement by healthcare payers may exist because the value of IgGRT is poorly documented. This paper aims to demonstrate cost-effectiveness and cost-utility (on life expectancy and quality) of IgGRT in CVID. METHODS AND FINDINGS: With input from a literature search, we built a health-economic model for cost-effectiveness and cost-utility assessment of IgGRT in CVID. We compared a mean literature-based dose (≥450mg/kg/4wks) to a zero-or-low dose (0 to ≤100 mg/kg/4wks) in a simulated cohort of adult patients from time of diagnosis until death; we also estimated the economic impact of diagnostic delay in this simulated cohort. Compared to no or minimal treatment, IgGRT showed an incremental benefit of 17 life-years (LYs) and 11 quality-adjusted life-years (QALYs), resulting in an incremental cost-effectiveness ratio (ICER) of €29,296/LY and €46,717/QALY. These results were robust in a sensitivity analysis. Reducing diagnostic delay by 4 years provided an incremental benefit of six LYs and four QALYs compared to simulated patients with delayed IgGRT initiation, resulting in an ICER of €30,374/LY and €47,495/QALY. CONCLUSIONS: The health-economic model suggests that early initiation of IgGRT compared to no or delayed IgGRT is highly cost-effective. CVID-patients' access to IgGRT should be facilitated, not only because of proven clinical efficacy, but also due to the now demonstrated cost-effectiveness.

Drug costs of Medicaid-covered therapies for pemphigus vulgaris treatment.

Pemphigus vulgaris is the most common form of pemphigus affecting an estimated 30,000-40,000 people in the United States. Costs of systemic and immunoglobulin therapies for pemphigus vulgaris have remained persistently high. Herein, we address the current costs and changes in costs of immunosuppressive treatments, anti-inflammatory treatments, and immunoglobulin treatments covered by Medicaid for pemphigus vulgaris from 2013-2020.

Wound-only injection of rabies immunoglobulin (RIG) saves lives and costs less than a dollar per patient by "pooling strategy".

Since 2008, we in Himachal Pradesh have used a "pooling strategy" to help patients save money by pooling vials of antirabies vaccine at a centralized hospital and sharing them using the intradermal technique. In 2014, there was an acute shortage of rabies immunoglobulins (RIG) and two patients died after four injections of rabies vaccine were administered without RIG, which was not commercially available. After an extensive literature review and technical and ethical committee clearances, in June 2014 we started to infiltrate equine RIG (eRIG) into wound/s only without the recommended systemic intramuscular (IM) injection. WHO recommended this technique in 2018. During the four-year period June 2014 to June 2018, 7506 of 10,830 patients exposed to suspected rabid animals were injected with eRIG in and around the wounds in a single clinic at DDU Hospital Shimla without any adverse outcomes. The average volume of eRIG used per patient was 0.75 mL and cost US$ 0.75. Of the 80% of patients who were followed up, all were healthy at the end of a year, including 26 patients bitten by laboratory-confirmed rabid dogs. The reaction rate after PEP administration also declined significantly. Since February 2018, Himachal has started following the new WHO recommendations on PEP regimens of three intradermal antirabies vaccines instead of four, thereby saving hundreds of vaccine vials that became useful during shortages of rabies vaccine in India. To date, more than 700 vaccine vials have been saved in a single clinic at DDU hospital during the past 6 months alone. Not giving PEP to patients who have consumed raw milk from a suspected rabid cow has also saved 62 vials. Currently, 90 "pooling centers" have been established for sharing of vaccine and eRIG vials in Himachal State, generating huge savings that have enabled the government to provide PEP free of charge to all. The new WHO guidelines are a positive step towards a rabies-free world by 2030.

Using a modified rabies immunoglobulin protocol in a crisis of unavailability: Ethical and practical challenges.

Rabies is a dreaded disease of zoonotic origin, responsible for an estimated 55,000 deaths annually, of which 20,000 deaths are in India. Some animal bite patients need rabies immunoglobulin (RIG) for post exposure prophylaxis, in addition to the vaccine against rabies. The major reason for the high death rate in India is the high cost of RIG. Until 2017, the WHO-recommended protocol required a large amount of RIG. I describe how a cost-saving protocol for RIG was implemented in Himachal Pradesh. The published results contributed to the modification of the WHO's global recommendations on RIG use.

IgY antibodies for the immunoprophylaxis and therapy of respiratory infections.

Emergence of drug resistance among the causative organisms for respiratory tract infections represents a critical challenge to the global health care community. Further, although vaccination can prevent disease, vaccine development is impeded by several factors. Therefore, novel approaches to treat and manage respiratory infections are urgently needed. Passive immunization represents a possible alternative to meet this need. Immunoglobulin Y antibodies (IgYs) from the yolk of chicken eggs have previously been used against bacterial and viral infections in human and animals. Their advantages include lack of reaction with mammalian Fc receptors, low production cost, and ease of extraction. Compared to mammalian IgGs, they have higher target specificity and greater binding avidity. They also possess remarkable pathogen-neutralizing activity in the respiratory tract and lungs. In this review, we provide an overview of avian IgYs and describe their potential therapeutic applications for the prevention and treatment of respiratory infections.

Direct and Indirect Costs of Immunoglobulin Replacement Therapy in Patients with Common Variable Immunodeficiency (CVID) and X-Linked Agammaglobulinemia (XLA) in Italy.

BACKGROUND: In Italy, there is scarce evidence on the epidemiological and economic burden induced by primary antibody deficiencies. OBJECTIVE: The aim of this study was to elaborate the available epidemiological and cost data in order to estimate the annual expenditure induced by the management of patients affected by the common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) requiring immunoglobulin (Ig) replacement therapy. METHODS: A probabilistic cost-of-illness model was developed to estimate the number of patients with CVID and XLA, and the economic burden associated with their therapy in terms of direct or indirect costs. A systematic literature review was carried out to reveal both epidemiological and economic data. Furthermore, a probabilistic sensitivity analysis with 5000 Monte Carlo simulations was performed. RESULTS: The epidemiological model allowed us to estimate the number of prevalent patients affected by XLA and CVID in Italy in 2017, corresponding to 1885 (95% confidence interval [CI] 944-3145) and 133 (95% CI 115-152) patients, respectively. The estimated total expenditure for the treatment and management of patients with CVID and XLA requiring Ig replacement therapy amounts to €42.68 million (95% CI €14.38-€86.1 million). CONCLUSIONS: This information provides a comprehensive perspective of the economic issues, and facilitates better-informed public health decision making, in the management of CVID and XLA in Italy.

Use of chicken immunoglobulin Y in general virology.

Immunoglobulin Y (IgY), an antibody present in birds, reptiles, and amphibians, is actively transported from the serum to egg yolks, where it is stored in large quantities. The use of chicken polyclonal IgY instead of mammalian IgG antibodies for biomedical applications has ethical and economic advantages, such as the lack of a need for animal bleeding because the antibodies are extracted from eggs after hen immunization and the low cost of the production and purification methods. This article reviews the latest IgY applications in diagnostic virology and the therapeutic use of IgY in viral gastroenteritis.

Efficacy of Human Botulism Immune Globulin for the Treatment of Infant Botulism: The First 12 Years Post Licensure.

OBJECTIVES: To report the efficacy of Human Botulism Immune Globulin Intravenous (BIG-IV) in the first 12 years following its licensure in 2003 and to characterize its use nationwide in treating patients with infant botulism. STUDY DESIGN: Medical records and billing information were collected for US patients treated with BIG-IV from 2003 to 2015. Length of hospital stay (LOS) and hospital charge information for treated patients were compared with the BIG-IV Pivotal Clinical Trial Placebo Group to quantify decreases in LOS and hospital charges. RESULTS: The use of BIG-IV reduced mean LOS from 5.7 to 2.2 weeks. This shortened hospital stay resulted in a mean decrease in hospital charges of $88 900 per patient. For all US patients 2003-2015, total decreases in LOS and hospital charges were 66.9 years and $86.2 million, respectively. The decrease in mean LOS was time dependent: BIG-IV treatment on hospital days 0-3 reduced mean LOS by 3.7 weeks (P <.001 vs the BIG-IV Pivotal Clinical Trial Placebo Group), on hospital days 4-7 by 2.6 weeks (P <.001 vs the BIG-IV Pivotal Clinical Trial Placebo Group) and on hospital days 8-10 by just 1 week (P = NS). Since licensure, 1192 patients in 48 states and Washington, DC, have been treated with BIG-IV. CONCLUSIONS: The use of BIG-IV since its licensure in 2003 treated approximately 93% of US patients with laboratory-confirmed infant botulism, and prevented >65 years in hospital stay and >$85 million in hospital charges from occurring. The greatest LOS reduction was achieved when BIG-IV was administered soon after hospital admission. Effective and appropriate use of BIG-IV in the US has continued in the postlicensure period.

Limited hepatitis B immunoglobulin with potent nucleos(t)ide analogue is a cost-effective prophylaxis against hepatitis B virus after liver transplantation.

BACKGROUND: Prophylaxis against hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) includes lifelong hepatitis B immunoglobulin (HBIG) and oral antiviral agent(s). In the presence of high-genetic-barrier nucleos(t)ide analogues, the need for lifelong HBIG is questioned. We evaluated the safety and cost-effectiveness of a limited HBIG course. METHODS: OLT from 2006 to 2013 were reviewed. Patients with pre-OLT hepatitis B virus surface antigen who received HBV prophylaxis with 2 HBIG doses (anhepatic and first post-operative day; 10,000 units/dose) and potent nucleos(t)ide analogues were included. The primary end point was HBV recurrence (HBV-DNA detection). RESULTS: Thirteen patients (primary transplants) were included, median Model for End-Stage Liver Disease score was 18, and there was no fulminant failure; HBV-DNA was detected in 4 patients at OLT. After OLT, 10 patients received entecavir and/or tenofovir. Median follow-up was 23 months. One recurrence occurred (7.7%) at month 13 (HBV-DNA: 14 IU/mL); the graft maintained excellent function. This minimal viremic expression is related to hepatocellular carcinoma recurrence with neoplastic replication carrying integrated HBV-DNA; thus, there is no defined HBV viral recurrence. No graft loss or patient death was related to HBV recurrence. The 1-year patient and graft survival rate was 84.6%. Cost-savings in the first year was $178,100 per patient when compared with Food and Drug Administration-approved HBIG dosing. CONCLUSIONS: In the era of potent oral nucleos(t)ide analogues, a limited HBIG course appears to be cost-effective in preventing HBV recurrence.

Subcutaneous vs intravenous administration of immunoglobulin in chronic inflammatory demyelinating polyneuropathy: an Italian cost-minimization analysis.

Prior researches have suggested that home-based subcutaneous immunoglobulin (SCIG) is equally effective and can be less expensive than hospital-based intravenous immunoglobulin (IVIG) in treating chronic inflammatory demyelinating polyneuropathy (CIDP) patients. This economic evaluation aims at comparing costs of SCIG vs IVIG for CIDP patients in Italy. A 1-year model-based cost-minimization analysis basically populated via neurologists' opinion was undertaken from a societal perspective. Health care resources included immunoglobulin; drugs for premedication and complications (rash, headache, and hypertension) management; time of various health care professionals; pump for SCIG self-administration; infusion disposables. Non-health care resources encompassed transport and parking; losses of working and leisure time for patients and caregivers. Unit or yearly costs for resources valuation were mainly obtained from published sources. Costs were expressed in Euro () 2013. An extensive one-way sensitivity analysis (OWSA) and a scenario SA tested the robustness of the base case findings. Overall costs per patient amount to 49,534.75 (SCIG) and 50,895.73 (IVIG); saving in favour of SCIG reaches 1360.98. For both SCIG and IVIG, the cost driver was immunoglobulin (94.06 vs 86.06 % of the overall costs, respectively). Sensitivity analyses confirmed the consistency of the baseline results. SCIG may be a cost-saving therapy for Italian CIDP patients.

Subcutaneous immunoglobulin therapy for inflammatory neuropathy: current evidence base and future prospects.

Intravenous immunoglobulin therapy is of proven effect in chronic inflammatory neuropathies, including chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). In more recent years, there have been a number of anecdotal case reports and small series, followed by a few trials of variable design, of subcutaneous immunoglobulin therapy in these neuropathies. To date, limited evidence suggests that the subcutaneous route may be a more clinically effective, better-tolerated, at least cost-equivalent and a more patient-friendly option than the still more used intravenous alternative. Long-term efficacy is not as yet established in neuropathic indications by randomised controlled clinical trial evidence, and it is likely that the subcutaneous route may not be suitable in all cases with some hints to this effect appearing from the limited data available to date. Further studies are ongoing, including those of dose comparison, and more are likely to be planned in future. The literature on the use of subcutaneous immunoglobulin therapy in chronic inflammatory neuropathy is reviewed here. The current use in clinical practice, day-to-day benefits, including quality of life measures and health economics as published thus far, are evaluated. The limitations of this form of treatment in CIDP and MMN are also analysed in the light of current literature and taking into account the remaining unknowns. Future prospects and research with this mode of immunoglobulin therapy administration are discussed.

Cost-effectiveness of augmenting universal hepatitis B vaccination with immunoglobin treatment.

OBJECTIVE: To compare the cost-effectiveness of hepatitis B virus (HBV) control strategies combining universal vaccination with hepatitis B immunoglobulin (HBIG) treatment for neonates of carrier mothers. METHODS: Drawing on Taiwan's experience, we developed a decision-analytic model to estimate the clinical and economic outcomes for 4 strategies: (1) strategy V-universal vaccination; (2) strategy S-V plus screening for hepatitis B surface antigen (HBsAg) and HBIG treatment for HBsAg-positive mothers' neonates; (3) strategy E-V plus screening for hepatitis B e-antigen (HBeAg), HBIG for HBeAg-positive mothers' neonates; (4) strategy S&E-V plus screening for HBsAg then HBeAg, HBIG for all HBeAg-positive, and some HBeAg-negative/HBsAg-positive mothers' neonates. RESULTS: Strategy S averted the most infections, followed by S&E, E, and V. In most cases, the more effective strategies were also more costly. The willingness-to-pay (WTP) above which strategy S was cost-effective rose as carrier rate declined and was <$4000 per infection averted for carrier rates >5%. The WTP below which strategy V was optimal also increased as carrier rate declined, from $1400 at 30% carrier rate to $3100 at 5% carrier rate. Strategies involving E were optimal for an intermediate range of WTP that narrowed as carrier rate declined. CONCLUSIONS: HBIG treatment for neonates of HBsAg carrier mothers is likely to be a cost-effective addition to universal vaccination, particularly in settings with adequate health care infrastructure. Targeting HBIG to neonates of higher risk HBeAg-positive mothers may be preferred where WTP is moderate. However, in very resource-limited settings, universal vaccination alone is optimal.

Cost-effectiveness analysis of preventing mother-to-child transmission of hepatitis B by injecting hepatitis B immune globulin.

OBJECTIVE: Hepatitis B immune globulin (HBIG) injection during pregnancy and/or after birth is an intervention for preventing mother-to-child transmission of the hepatitis B (HB) virus. However, varying cost-effectiveness ratios among various HBIG therapies remain unclear. This study explored these differences in cost-effectiveness ratios. METHODS: Four districts in Wuhan, China, were selected for the current study using stratified random sampling. Pregnant women who were positive for HB surface antigen (HBsAg) and who received prenatal care in district-level maternal and child health hospitals were interviewed. The mothers and their children underwent follow-up visits from the time of pregnancy until the children were six-and-a-half months old. RESULTS: A total of 324 cases completed the follow-up visits on a voluntary basis. Among the 324 HBsAg-positive pregnant women investigated, 60.49% (196/324) were injected with HBIG at different trimesters. A total of 249 neonates (76.85%) received an HBIG injection within 24 h after birth. The HBsAg-positive rate in infants was 5.56% (18/324). The HBIG-injected mother and infant group had the lowest chronic infection rate among children [odds ratio=0.14, 95% confidence interval (CI) 0.02-0.90, P=0.039]. The HBIG-injected infant group exhibited the lowest HBsAb-positive rate (odds ratio=0.07, 95% CI 0.02-0.23). The cost per averted disability-adjusted life years was lowest in the infant group: USD 118.61 (95% CI 105.23-131.99). CONCLUSION: These results indicate that active and passive immunizations (HBIG and HB vaccine) entail the lowest cost in the prevention of chronic HB infection in infants. However, this programme has the lowest HBsAb-positive rate, which possibly prevents children from self-acquiring antibodies.

A novel, cost-effective and efficient chicken egg IgY purification procedure.

Chicken IgY antibodies have been touted to be a superior alternative to mammalian antibodies for use in various immunological, molecular biology and proteomics applications for several reasons. These include, but are not limited to, improved specificity due to maximum phylogenetic distance between host and recipient, cost effectiveness in maintaining commercial numbers of hens, IgY yield and the use of non-invasive methods used to isolate IgY from eggs as opposed to blood. Despite this, the routine use of IgY-based methodologies in the laboratory is not widespread. One reason for this reluctance may be derived from the difficulties and expense of isolating IgY antibodies from egg yolk in sufficient yield, with high purity at a realistic reasonable price. Here, we describe an extremely cost-effective ($5USD per egg), rapid (within 5 h), efficient and optimised technique to isolate high yields (60 mg) of high purity (~80%) chicken IgY from egg yolks using the common plant gums pectin and κ-carrageenan in the presence of calcium chloride to delipidate egg yolk mixtures whilst maintaining IgY in solution and then ammonium sulphate to subsequently precipitate the resulting IgY antibodies to higher purity. Our data demonstrates that this technique results in a high yield and purity of IgY that is comparable (if not superior to) existing commercial IgY isolation kits. The method also allows the isolation of immunologically active IgY which can be used for further downstream immunotechnological processes. Furthermore, it can also be easily implemented in a standard well equipped laboratory, and may be scaled up to commercial quantities (i.e., thousands of eggs).

Substitution of tenofovir/emtricitabine for Hepatitis B immune globulin prevents recurrence of Hepatitis B after liver transplantation.

BACKGROUND: Hepatitis B immune globulin (HBIg) with or without nucleos(t)ide analogue (NA) inhibitors has been shown to prevent recurrence of hepatitis B virus (HBV) following orthotopic liver transplantation (OLT). However, the use of HBIg has many disadvantages. AIMS: The present study was performed to determine if converting patients from HBIg ± NA to combination NA therapy could prevent recurrence of HBV. METHODS: Twenty-one recipients without evidence of HBV recurrence on HBIg ± NA for ≥ 6 months were enrolled. Patients received their last injection of HBIg at the time they initiated tenofovir disoproxil fumarate/emtricitabine (TDF/FTC; Truvada(®) ) and were followed up for 31.1 ± 9.0 [range 15-47] months. RESULTS: After 1 year, 3 patients (14%) had detectable HBsAg, one of whom was non-compliant. Two of 3 with recurrence cleared HBsAg by last follow-up on TDF/FTC; the non-compliant patient became HBV DNA-undetectable with re-institution of TDF/FTC. TDF/FTC saved $12,469/year over our standard-of-care, monthly intramuscular HBIg/lamivudine. There was no evidence of a general adverse effect of TDF/FTC on renal function. However, 3 patients developed reversible acute renal failure; on renal biopsy, 1 had possible TDF/FTC-induced acute tubular necrosis. CONCLUSIONS: Substitution of TDF/FTC for HBIg prevented recurrence of HBV DNA in 100% (20/20) of patients who were compliant with the medication and led to substantial cost savings over HBIg-containing regimens.

Cost-effectiveness of maternal treatment to prevent perinatal hepatitis B virus transmission.

OBJECTIVE: To estimate the cost-effectiveness of maternal lamivudine or hepatitis B immune globulin (HBIG) treatment, in addition to standard neonatal immunoprophylaxis, for the prevention of perinatal hepatitis B virus transmission. METHODS: A decision-tree model was created to estimate the cost-effectiveness of maternal administration of either lamivudine or HBIG in the third trimester to prevent perinatal hepatitis B transmission compared with no maternal treatment. The model was first estimated for each treatment using overall transmission rates, and then stratified by maternal hepatitis B virus DNA viral load. RESULTS: The model estimated that for each 100 hepatitis B surface antigen positive pregnant women treated with lamivudine, 9.7 cases of chronic hepatitis B virus infections are prevented, with a cost-savings of $5,184 and 1.3 life-years gained per patient treated. For HBIG, 9.5 cases of chronic hepatitis B virus infections are prevented for each 100 pregnant women treated, with a cost-savings of $5,887 and 1.2 life-years gained per patient treated. Under baseline assumptions, lamivudine remains cost-saving unless the reduction in perinatal transmission is less than 18.5%, and HBIG remains cost-saving unless the reduction in perinatal transmission is less than 9.6%. CONCLUSION: In this decision analysis, administration of lamivudine or HBIG to hepatitis B surface antigen positive pregnant women for the prevention of perinatal transmission of hepatitis B is cost-savings across a wide range of assumptions. LEVEL OF EVIDENCE: III.