Cost-Effectiveness of Rifaximin Treatment in Patients with Hepatic Encephalopathy.

BACKGROUND: Hepatic encephalopathy (HE) is a complication of cirrhosis of the liver causing neuropsychiatric abnormalities. Clinical manifestations of overt HE result in increased health care resource utilization and effects on patient quality of life. While lactulose has historically been the mainstay of treatment for acute HE and maintenance of remission, there is an unmet need for additional therapeutic options with a favorable adverse event profile. Compared with lactulose alone, rifaximin has demonstrated proven efficacy in complete reversal of HE and reduction in the incidence of HE recurrence, mortality, and hospitalizations. Evidence suggests the benefit of long-term prophylactic therapy with rifaximin; however, there is a need to assess the economic impact of rifaximin treatment in patients with HE. OBJECTIVE: To assess the incremental cost-effectiveness of rifaximin ± lactulose versus lactulose monotherapy in patients with overt HE. METHODS: A Markov model was developed in Excel with 4 health states (remission, overt HE, liver transplantation, and death) to predict costs and outcomes of patients with HE after initiation of maintenance therapy with rifaximin ± lactulose to avoid recurrent HE episodes. Cost-effectiveness of rifaximin was evaluated through estimation of incremental cost per quality-adjusted life-year (QALY) or life-year (LY) gained. Analyses were conducted over a lifetime horizon. One-way deterministic and probabilistic sensitivity analyses were conducted to assess uncertainty in results. RESULTS: The rifaximin ± lactulose regimen provided added health benefits despite an additional cost versus lactulose monotherapy. Model results showed an incremental benefit of $29,161 per QALY gained and $27,762 per LY gained with rifaximin ± lactulose versus lactulose monotherapy. Probabilistic sensitivity analyses demonstrated that the rifaximin ± lactulose regimen was cost-effective ~99% of the time at a threshold of $50,000 per QALY/LY gained, which falls within the commonly accepted threshold for incremental cost-effectiveness. CONCLUSIONS: The clinical benefit of rifaximin, combined with an acceptable economic profile, demonstrates the advantages of rifaximin maintenance therapy as an important option to consider for patients at risk of recurrent HE. DISCLOSURES: This analysis was funded by Salix Pharmaceuticals, a division of Bausch Health US. Salix and Xcenda collaborated on the methods, and Salix, Xcenda, Jesudian, and Ahmad collaborated on the writing of the manuscript and interpretation of results. Bozkaya and Migliaccio-Walle are employees of Xcenda. Ahmad reports speaker fees from Salix Pharmaceuticals, unrelated to this study. Jesudian reports consulting and speaker fees from Salix Pharmaceuticals, unrelated to this study. The results from this model were presented at AASLD: The Liver Meeting 2014; November 7-11; Boston, MA.

Economic Implications of Hepatocellular Carcinoma Surveillance and Treatment: A Guide for Clinicians.

The incidence of hepatocellular carcinoma (HCC) is increasing worldwide, with significant morbidity and associated costs. Treatment allocation depends on the stage of diagnosis; however, resource utilization can be significant across all stages. We aimed to summarize the available data on the cost effectiveness of surveillance of and treatments for HCC in the context of current treatment guidelines. We performed a focused review of studies investigating the economic burden and cost effectiveness of HCC surveillance treatment modalities published between January 2000 and January 2019. The overall economic burden of HCC is increasing in the USA and in several countries worldwide due to its rising incidence and the proliferation of therapies. Liver transplantation is a cost-effective strategy for early-stage HCC treatment in selected patients. In settings where liver transplantation is not available or in patients awaiting transplant, ablative or locoregional therapies are cost effective with increases in quality-adjusted life-years. First-line therapy with sorafenib for advanced stage HCC is cost effective in the treatment of compensated cirrhosis. The cost effectiveness of recently approved systemic therapies for advanced HCC require further investigation. Existing studies have shown that guideline-recommended surveillance techniques and several available therapies for the treatment of HCC are cost effective; however, there are limitations in the literature, including reliance on suboptimal modeling with incomplete/simplified model structure or inadequate inputs. With increasing therapeutic options in patients with HCC, understanding their relative value is critical in designing HCC treatment algorithms.

Comparing Simultaneous Liver-Kidney Transplant Strategies: A Modified Cost-Effectiveness Analysis.

BACKGROUND: The proportion of patients with kidney failure at time of liver transplantation is at a historic high in the United States. The optimal timing of kidney transplantation with respect to the liver transplant is unknown. METHODS: We used a modified cost-effectiveness analysis to compare 4 strategies: the old system ("pre-OPTN"), the new Organ Procurement Transplant Network (OPTN) system since August 10, 2017 ("OPTN"), and 2 strategies which restrict simultaneous liver-kidney transplants ("safety net" and "stringent"). We measured "cost" by deployment of deceased donor kidneys (DDKs) to liver transplant recipients and effectiveness by life years (LYs) and quality-adjusted life years (QALYs) in liver transplant recipients. We validated our model against Scientific Registry for Transplant Recipients data. RESULTS: The OPTN, safety net and stringent strategies were on the efficiency frontier. By rank order, OPTN > safety net > stringent strategy in terms of LY, QALY, and DDK deployment. The pre-OPTN system was dominated, or outperformed, by all alternative strategies. The incremental LY per DDK between the strategies ranged from 1.30 to 1.85. The incremental QALY per DDK ranged from 1.11 to 2.03. CONCLUSIONS: These estimates quantify the "organ"-effectiveness of various kidney allocation strategies for liver transplant candidates. The OPTN system will likely deliver better liver transplant outcomes at the expense of more frequent deployment of DDKs to liver transplant recipients.

Utility-based criteria for selecting patients with hepatocellular carcinoma for liver transplantation: A multicenter cohort study using the alpha-fetoprotein model as a survival predictor.

The lifetime utility of liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) is still controversial. The aim of this study was to ascertain when LT is cost-effective for HCC patients, with a view to proposing new transplant selection criteria. The study involved a real cohort of potentially transplantable Italian HCC patients (n = 2419 selected from the Italian Liver Cancer group database) who received nontransplant therapies. A non-LT survival analysis was conducted, the direct costs of therapies were calculated, and a Markov model was used to compute the cost utility of LT over non-LT therapies in Italian and US cost scenarios. Post-LT survival was calculated using the alpha-fetoprotein (AFP) model on the basis of AFP values and radiological size and number of nodules. The primary endpoint was the net health benefit (NHB), defined as LT survival benefit in quality-adjusted life years minus incremental costs (US $)/willingness to pay. The calculated median cost of non-LT therapies per patient was US $53,042 in Italy and US $62,827 in the United States. On Monte Carlo simulation, the NHB of LT was always positive for AFP model values ≤ 3 and always negative for values > 7 in both countries. A multivariate model showed that nontumor variables (patient's age, Child-Turcotte-Pugh [CTP] class, and alternative therapies) had the potential to shift the AFP model threshold of LT cost-ineffectiveness from 3 to 7. LT proved always cost-effective for HCC patients with AFP model values ≤ 3, whereas the cost-ineffectiveness threshold ranged between 3 and 7 using nontumor variables.

Cost-effectiveness of liver transplantation in methylmalonic and propionic acidemias.

Propionic acidemia (PA) and classical methylmalonic acidemia (MMA) are rare inborn errors of metabolism that can cause early mortality and significant morbidity. The mainstay of disease management is lifelong protein restriction. As an alternative, liver transplantation (LT) may improve survival, quality of life, and prevent further neurological deterioration. The aim of our study was to estimate the incremental costs and outcomes of LT versus nutritional support in patients with early-onset MMA or PA. We constructed a Markov model to simulate and compare life expectancies, quality-adjusted life years (QALYs), and lifetime direct and indirect costs for a cohort of newborns with MMA or PA who could either receive LT or be maintained on conventional nutritional support. We conducted a series of 1-way and probabilistic sensitivity analyses. In the base case, LT on average resulted in 1.5 more life years lived, 7.9 more QALYs, and a savings of $582,369 for lifetime societal cost per individual compared to nutritional support. LT remained more effective and less costly in all 1-way sensitivity analyses. In the probabilistic sensitivity analysis, LT was cost-effective at the $100,000/QALY threshold in more than 90% of the simulations and cost-saving in over half of the simulations. LT is likely a dominant treatment strategy compared to nutritional support in newborns with classical MMA or PA.

Evaluation of clinical and safety outcomes associated with conversion from brand-name to generic tacrolimus in transplant recipients enrolled in an integrated health care system.

STUDY OBJECTIVE: To evaluate clinical and safety outcomes among transplant recipients whose tacrolimus was converted from the brand-name formulation to a generic formulation. DESIGN: Retrospective analysis. DATA SOURCE: Clinical databases and electronic records from a large, integrated health care system in California. PATIENTS: A total of 234 clinically stable, adult transplant recipients (renal, liver, and heart) whose tacrolimus was converted from the brand-name formulation to a generic formulation between October 1, 2010, and December 31, 2010, according to a physician-approved protocol. MEASUREMENTS AND MAIN RESULTS: For each patient, pre- and postconversion tacrolimus trough concentrations and serum creatinine concentrations were analyzed. Data were also collected on the percentage of patients who required dosage titration, drug cost savings, and rates of reversion to brand-name tacrolimus, biopsy-proved acute allograft rejections, and mortality. No significant differences were noted in mean ± SD pre- and postconversion tacrolimus trough levels (6.74 ± 1.61 vs 6.96 ± 2.31 ng/ml, p=0.137) or serum creatinine concentrations (1.33 ± 0.48 vs 1.36 ± 0.82 mg/dl, p=0.302). The mean ± SD percent change in tacrolimus trough concentration was 5.63 ± 32.95%. Thirty-six patients (15.4%) required dosage titration. Six patients (2.6%) reverted back to brand-name tacrolimus. No deaths or acute rejections occurred. Use of the generic product saved each patient an average of $45/month in drug acquisition cost and $26/prescription copayment. CONCLUSION: Clinical experience as well as research data show that use of generic tacrolimus results in trough concentrations that are comparable to the brand-name drug. Given the lack of adverse events reported and the cost savings recognized, conversion from brand-name tacrolimus to generic tacrolimus should be encouraged. Since dosage titration may be required, close therapeutic drug monitoring is recommended.

Critical issues in the treatment of hepatitis C virus infection in methadone maintenance patients.

AIMS: Hepatitis C virus (HCV) infection is a common chronic complication of injection drug use. Methadone maintenance programs contain large numbers of patients infected with HCV. This paper reviews HCV infection with emphasis on the medical care of HCV-infected, or HCV and human immunodeficiency virus co-infected, patients on methadone or buprenorphine maintenance. METHODS: Literature searches using PubMed, PsycINFO and SocINDEX were used to identify papers from 1990-present on antiviral therapy for HCV in methadone maintenance patients and on liver transplantation in methadone maintenance patients. RESULTS: Injection drug use is the most significant risk factor for HCV infection in most western countries. The prevalence of HCV antibody is high in injection drug users (53-96%) and in patients enrolled in methadone maintenance programs (67-96%). Studies of antiviral therapy for HCV in methadone maintenance patients show rates of sustained virological response (SVR), defined as negative HCV-RNA 24 weeks after the end of treatment, of 28-94%. In studies with contrast groups, no significant differences in SVR between methadone and contrast groups were found. Excellent completion rates of antiviral therapy (72-100%) were found in five of six studies. There are many barriers to methadone maintenance patients' receiving antiviral therapy, and research on overcoming barriers is discussed. Liver transplantation has been successful in methadone maintenance patients but has not been utilized widely. CONCLUSION: High quality medical care for all aspects of HCV infection can be provided to methadone maintenance patients. The literature supports the effectiveness of such services, but the reality is that most patients do not receive them.

A prospective study investigating the cost effectiveness of intraoperative blood salvage during liver transplantation.

BACKGROUND: Adult orthotopic liver transplantation is associated with significant use of allogenic blood products, which places considerable demands on finite resources. This could be reduced by autologous red cell salvage use, and we evaluated its cost effectiveness in this prospective study. METHODS: Intraoperative autotransfusion was used in 660 adult liver transplant patients between January 1997 and July 2002. These included 134 with acute liver failure, 62 retransplants, 90 alcohol-related, 183 viral, 98 cholestatic chronic liver diseases, and 93 with other etiologies. RESULTS: The total volume of red blood cells transfused was 3641+/-315 ml, 2805+/-234 ml, 2603+/-443 ml, and 2785+/-337 ml for alcohol-related, viral, cholestatic, and others, respectively. Low preoperative hemoglobin was significantly associated with higher intraoperative transfusion requirements. Blood volumes transfused at retransplantation were significantly higher (7077+/-1110 ml vs. 2864+/-138 ml; P<0.001) than for acute liver failure and chronic liver disease. Autologous blood volumes transfused were similar in all diagnostic groups, but were significantly greater in retransplantation (2754+/-541 ml vs. 1524+/-77 ml; P<0.01). Venovenous bypass was significantly associated with higher transfusion requirements. Total savings per case were similar for all diagnostic groups but were greater in cases of retransplantation (864+/-222 pounds (1235+/-317 US dollars) vs. 238+/-24 pounds (340+/-34 US dollars; P<0.001). With the use of autologous transfusion over the study period, a cost saving of 131,901 pounds (188,618 US dollars) was achieved. CONCLUSIONS: Intraoperative red blood cell salvage and autologous transfusion is cost effective in adult liver transplantation. Currently, where optimum resource utilization and fiscal constraint are paramount in healthcare delivery, autologous transfusion is an important adjunct in liver transplantation.

Ability to pay and geographical proximity influence access to liver transplantation even in a system with universal access.

Ireland, in common with many countries, has a mixed private and public health care system. Concern has been expressed that this system may lead to inequity in access to medical treatment. To investigate this concern, all contacts and first admissions to the national liver transplant unit were identified between April 1, 2000, and March 31, 2002. The effects of private health insurance and area of residence on the likelihood of receiving a liver transplant were assessed. A total of 202 patients were admitted. Forty-three patients from this cohort received a liver transplant (21.3%). Of patients with private health insurance, 17 of 50 (34.0%) were transplanted, compared with 26 of 152 (17.1%) without private health insurance (relative risk [RR] = 1.99; 95% CI, 1.18-3.35; P = .01). For residents of the Eastern (close to the liver transplant unit), patients with private health insurance were no more likely to be transplanted (RR = 0.95; 95% CI, 0.35-2.54; P = 1.0), whereas for residents of other areas, patients with private insurance were 3 times more likely to receive a transplant than those without health insurance (RR = 3.11; 95% CI, 1.59-6.08; P = .001). Patients living outside the Eastern region without private health insurance were only half as likely as all other patient types combined to receive a transplant (RR = 0.52; 95% CI, 0.29-0.92; P = .02). In this study the possession of private health insurance appeared to increase the chances of receiving a liver transplant. Patients without private health insurance living distant from the liver transplant unit appeared particularly disadvantaged. In conclusion, these findings suggest significant inequity in liver transplant allocation in Ireland and deserve further assessment.

Bayesian estimation, simulation and uncertainty analysis: the cost-effectiveness of ganciclovir prophylaxis in liver transplantation.

This paper demonstrates the usefulness of combining simulation with Bayesian estimation methods in analysis of cost-effectiveness data collected alongside a clinical trial. Specifically, we use Markov Chain Monte Carlo (MCMC) to estimate a system of generalized linear models relating costs and outcomes to a disease process affected by treatment under alternative therapies. The MCMC draws are used as parameters in simulations which yield inference about the relative cost-effectiveness of the novel therapy under a variety of scenarios. Total parametric uncertainty is assessed directly by examining the joint distribution of simulated average incremental cost and effectiveness. The approach allows flexibility in assessing treatment in various counterfactual premises and quantifies the global effect of parametric uncertainty on a decision-maker's confidence in adopting one therapy over the other.

The transplant experience of liver recipients: ethical issues and practice implications.

The transplant experience of 20 liver organ transplant recipients was investigated in a longitudinal study. Five primary themes were identified from analysis of recipients' interviews including concerns about: (1) quality of life, (2) quality of health care, (3) economic factors, (4) social support factors, and (5) psychological factors. These findings are analyzed within the current context of social work in health care characterized by three interactive trends: advances in medical technology, changing health care economics, and a shift in the locus of health care delivery from institutions to the community. All five themes reflect the impact of these trends and give rise to ethical issues with practice implications.

Cost analysis of intraoperative blood salvage during orthotopic liver transplantation.

Approximately 6,000 to 7,000 orthotopic liver transplantation (OLT) procedures are performed annually, which require the administration of large volumes of blood products. Thus liver transplantation can significantly strain local and regional blood resources at a time when transfusion practices are changing dramatically, in large part because of anxiety caused by the human immunodeficiency virus. Intraoperative autologous transfusion has been proposed as a means of both reducing transfusion demands and lessening the hazards of allogeneic transfusion. However, the cost effectiveness of intraoperative blood salvage has not been unequivocally determined. We retrospectively examined the cost of intraoperative autologous transfusion during OLT for a 2-year period at the University of Cincinnati Hospital. A direct comparison was made between the charge for autologous transfusion and the calculated cost of allogeneic transfusion. Seventy OLT procedures were performed during the years 1993-1994. The average charge for autologous transfusion was $1,048.73 per case. Cell-salvage volumes for all cases were added, and the calculated conservation of allogeneic packed red blood cells totaled 359.6 units, worth $30,026.60 or $428.95 per case. The break-even point is approximately 12.6 units, and most patient do not receive this volume of salvaged blood. In fact, cell salvage reached cost equivalence in only three cases (4.8%). Moreover, the cost deficit of autologous transfusion during this 2-year period averaged $586.56 per case.

Pediatric liver transplantation in Georgia: a paradigm for the health care crisis in the United States?

The United States health care system, felt by many to be the most technologically advanced program in the world, has many critics. Two indisputable facts that drive such criticism are 1) inequitable access and 2) rising costs out of proportion to other countries. Although Georgia is a poor state and ranks nationally near the bottom in most measures of child and adolescent care, we decided to start a pediatric liver transplant program at Egleston Children's Hospital at Emory, Atlanta. Over the past 2 1/2 years, 18 transplants have been performed in 14 patients; 10 children are presently surviving. Looking carefully at the expenses of the first 10 patients, the average cost of orthotopic liver transplantation for the eight survivors was $206,375. The hospital costs for providing care to these 10 children were over $2 million. In a state that ranks 49th out of 50 states in infant mortality and with nearly one-third of its pre-school children not immunized against preventable diseases, is this a fair and equitable distribution of our resources?