Guy W. Neff, MD, MBA, Christopher W. Duncan, MD, MPP, and Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF
Dr. Neff is Chief of Hepatology at Tampa General Medical Group in Tampa, Florida. Dr. Duncan is affiliated with Highline Gastroenterology in Seattle, Washington. Dr. Schiff is a Professor of Medicine and Director of the Schiff Liver Institute and the Center for Liver Diseases at the University of Miami’s Miller School of Medicine in Miami, Florida.
Address correspondence to:
Dr. Guy W. Neff, Chief of Hepatology, Tampa General Medical Group, 409 Bayshore Blvd., Tampa, FL 33606; Tel: 813-844-8686; E-mail: gneff@tgh.org
Abstract: Cirrhosis is a worldwide problem that is associated with a substantial economic burden. Hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, and alcoholic liver disease are the main causes of cirrhosis, but cost-effective preventive strategies are only available for HBV infection. Treatment algorithms for HBV infection and HCV infection are numerous and may be economically advantageous, depending on the regimen utilized; however, effective treatment for alcoholic liver disease is lacking, with abstinence from alcohol consumption continuing to be the main treatment strategy. In addition, liver transplantation (the only cure for cirrhosis) continues to consume substantial economic resources despite a recent reduction in overall cost. More sensitive predictors of post–liver transplantation disability could reduce this cost by allowing interventions that would promote productivity and increase health-related quality of life after liver transplantation. This paper highlights recent publications that evaluate the cost-effectiveness of strategies that prevent or treat the main causes of cirrhosis as well as publications that assess the impact of quality of life on the overall cost burden of the disease.
Cirrhosis is a chronic liver disorder caused by a variety of diseases, with the most common being hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, and alcoholic liver disease.1 These diseases attack the liver, leading to progressive liver damage and, ultimately, liver failure and death. For example, 1–46% of patients with chronic HCV infection will likely develop cirrhosis during a 30-year period.2 Cirrhosis, the twelfth leading cause of death in the United States in 2007, represents a large economic burden, with the national cost for treatment in 2008 ranging from $14 million to $2 billion, depending on disease etiology.3,4 This burden is expected to rise over the next 20 years, given that the percentage of patients with HCV-related cirrhosis is predicted to almost double.5
The overall cost of cirrhosis includes direct costs (drug and hospitalization costs) and indirect costs (due to loss of work productivity and reduction in health-related quality of life [HRQOL]). In 2004, the direct costs of cirrhosis and chronic liver disease in the United States (excluding patients with HCV infection) were estimated to be $2.5 billion, whereas indirect costs were estimated to be $10.6 billion.6 Because cirrhosis is a progressive disorder, preventing or arresting its causes may substantially reduce the monetary burden of the disease. Furthermore, effectively managing underlying diseases in order to slow the progression of cirrhosis to liver failure would be beneficial, assuming that such measures would not incur undue medical expenditures. However, even with management, cirrhosis may progress to liver failure, in which case liver transplantation will be required for the patient’s survival.
Given that liver transplantation entails a large economic outlay for relatively few individuals, the cost-effectiveness of the procedure, particularly in terms of the allocation of available livers and patients’ HRQOL post-transplantation, may be questionable. This paper examines the overall economic burden of cirrhosis, including the cost-effectiveness of preventive and therapeutic strategies, liver transplantation, and overall societal impact of cirrhosis.
Prevention of Cirrhosis
Hepatitis B Virus Infection
In the 1990s, the World Health Organization (WHO) recommended that all countries incorporate HBV vaccination into their national immunization programs. Many nations (such as the United States) heeded this advice and routinely require immunization (either 2 or 3 doses) for infants (at birth), children, adolescents (≤19 years of age), and adults (who have never previously been vaccinated).7-9 Numerous studies have reported on the long-term efficacy of HBV vaccination, and various cost analyses support the economic efficacy of this practice (Table 1).10-21 Nevertheless, several countries (such as Canada) delay immunization until adolescence, while other countries (such as the United Kingdom and Ireland) do not have universal vaccination programs, even though such programs may be economical.19,21,22 In general, the most cost-effective vaccination strategy for a nation is determined by its level of HBV endemicity, the ease of implementing a widespread vaccination program, the duration of protection offered by vaccination, and the infection risk per age group.23 The overall cost of a vaccination program also depends on the dosing regimen used (ie, 2 vs 3 doses) and whether it includes the administration of booster doses. Because 3-dose regimens and booster doses incur additional costs with uncertain efficacy, debate continues regarding the cost-effectiveness of these practices; further studies are necessary to determine the impact of these practices on the overall economic burden.10-12,14,24,25 Regardless of the specific regimen used, the incidence of HBV infection significantly declined in several countries after the implementation of widespread vaccination, indicating that this practice is beneficial at least in terms of morbidity.26-28
Hepatitis C Virus Infection
Unlike HBV infection, there is currently no vaccine available for HCV, despite ongoing research. Thus, prevention of HCV infection focuses mainly on controlling nosocomial exposure (ie, blood screening, safe injection, and infection control) and reducing high-risk behaviors (ie, intravenous drug use).29 Implementation of safe nosocomial practices may reduce HCV transmission, but these practices are often costly and exceed the economic ability of low-income countries.29,30 In these cases, cooperation with and monetary subsidization by local and international agencies are essential.
Collaboration between healthcare providers and patients at high risk for HCV infection (ie, intravenous drug users and incarcerated individuals) is also paramount.29,31,32 Intravenous drug users contract the largest number of new HCV infections per year because of needle sharing.32 Concerted efforts to educate this population and provide methods by which they can procure sterile injection equipment are indispensable and relatively economical, particularly in countries where prevention and support programs for substance abusers are already in place.29,32 Screening populations at high risk for HCV infection may also reduce the overall economic burden of the disease by identifying patients with HCV infection and providing early treatment, thus potentially preventing progression to more serious and costly complications (eg, cirrhosis).31-33
Alcoholic Liver Disease
It is well established that alcohol consumption has a relationship with cirrhosis as well as with cirrhosis-related mortality, suggesting that policies and procedures intended to curtail alcohol intake and alcoholism may also reduce cirrhosis.34-37 Such policies include school-based and public education campaigns on alcohol-associated disease, brief advice on alcohol consumption for individuals at risk for alcoholism, stringent alcohol purchase laws, government monopolies on alcohol, limitations on alcohol marketing campaigns, and taxes on alcohol.38,39 A 2009 analysis by Anderson and associates on the economic benefit of each of these policies revealed that restriction of alcohol sales and a tax increase on retail alcohol purchases were generally cost-effective, whereas educational programs and counseling were not cost-effective.38 Additionally, Alcoholics Anonymous intervention may impact the progression of liver disease and the overall outcome in patients with chronic alcoholism, although this finding has not been statistically or experimentally verified.40 Pharmacologic treatment of alcoholism may also prevent cirrhosis, but only one study has evaluated the cost of such interventions.41 This investigation revealed that increased spending on alcoholism treatment correlated with reductions in cirrhosis-related death rates. It would be beneficial to conduct additional investigations regarding the cost advantages of different therapeutic treatments for alcoholism as they relate to cirrhosis.
Treatment of Underlying Causes of Cirrhosis
Hepatitis B Virus Infection
HBV infection is a global concern, requiring large expenditures for healthcare and prevention. Although guidelines for the prevention and treatment of HBV infection have been published by the WHO, adoption of and adherence to these recommendations vary among countries.42,43 Therefore, it is difficult to compare healthcare costs and the economic burden of HBV infection among countries, particularly given the diverse economic conditions worldwide. Nonetheless, progression of HBV infection to cirrhosis has been shown to increase healthcare costs in several countries, and economic analyses of standard treatment regimens in some of these nations indicate an economic benefit associated with stopping the progression of chronic HBV infection.44-48 For example, the average yearly disease cost for an individual with chronic HBV infection without cirrhosis (€1,158–1,271) is lower than the average cost for patients with HBV infection and compensated cirrhosis (€1,254–1,512) or decompensated cirrhosis (€1,512–3,016), although the exact cost estimates may vary according to the treatment paradigms and drugs utilized.49
In the United States, 7 treatments are available for chronic HBV infection: interferon α-2b, peginterferon α-2a, lamivudine, adefovir (Hepsera, Gilead), entecavir (Baraclude, Bristol-Myers Squibb), telbivudine (Tyzeka, Novartis), and tenofovir (Viread, Gilead).50 Recommended first-line therapies include entecavir, peginterferon α-2a, and tenofovir. These recommendations are based on efficacy, tolerability, and favorable resistance profiles in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients; however, these recommendations do not take cost-effectiveness into account. Numerous studies in several countries have evaluated the cost-effectiveness of HBV treatments, although these studies have varied in population data utilized, specific regimens compared, and overall data reported (ie, quality-adjusted life year [QALY] vs incremental cost-effectiveness ratio [ICER]).49,51-58 In general, adefovir, entecavir, peginterferon α-2a, and tenofovir have been shown to be cost-effective, but there is little evidence supporting the cost-effectiveness of lamivudine (Table 2).
Hepatitis C Virus Infection
Treatment for chronic HCV infection focuses on viral suppression to an undetectable level, thereby deterring disease progression and preventing related complications such as cirrhosis and hepatic carcinoma.59 The viral suppression is essential, as patients who do not achieve long-term viral suppression (ie, sustained virologic response) are more likely to have greater liver-related morbidity and mortality.60 Five treatment options for HCV infection are available in the United States (interferon monotherapy, interferon plus ribavirin, peginterferon plus ribavirin, peginterferon plus ribavirin and telaprevir [Incivek, Vertex], and peginterferon plus ribavirin and boceprevir [Victrelis, Merck]). Published guidelines recommend the use of peginterferon combined with ribavirin plus 1 of the 2 direct-acting antiviral agents as first-line therapy in most chronic HCV genotype 1 infection patient populations. Treatment duration with peginterferon α plus ribavirin therapy varies with the patient’s HCV genotype (ie, 24–48 weeks for HCV genotype 1 infection and 24 weeks for HCV genotypes 2 and 3 infection). Thus, genotype testing before treatment initiation is recommended in the United States.
The recent US Food and Drug Administration approval and inclusion of telaprevir and boceprevir combined with pegylated interferon and ribavirin as standard-of-care therapy in HCV genotype 1 infection patients will change the economic modeling for this disease. The increased sustained virologic response rates achieved with these new agents will require in-depth analysis involving cost analyses and treatment outcomes.
Overall cost evaluations of these therapies have been examined in a number of countries and suggest that interferon monotherapy is more cost-effective than no treatment, interferon plus ribavirin is more economically sound than interferon alone, and peginterferon plus ribavirin is more cost-effective than interferon plus ribavirin (Table 3).61 Even in HCV patients who have a low risk of progression to cirrhosis, treatment with peginterferon combination therapy may be cost-effective because of the resulting improvement in quality of life. For example, in a 2003 cost-effectiveness analysis, peginterferon plus ribavirin therapy saved $15,000–55,000 per QALY, depending on HCV genotype, versus interferon monotherapy.2 These savings were thought to be the result of improved HRQOL, as these patients were not likely to require substantial HCV-related healthcare costs during their lifetime.2 Peginterferon plus ribavirin therapy may also be cost-beneficial in patients who are co-infected with HIV or who have chronic liver disease and persistently normal alanine aminotransferase levels.62,63 In addition, compared to standard 24- and 48-week treatment regimens, it may be cost-effective to reduce the duration of treatment to 12 weeks in patients with HCV genotype 2 or 3 infection or to increase the duration of therapy to 72 weeks in HCV-infected patients who have a reduction in HCV RNA level of less than 2 log10 by Week 24 of therapy.64,65
Furthermore, although peginterferon α-2a plus ribavirin has been shown to be economically satisfactory when administered without regard to HCV genotype, adjusting treatment duration based on HCV genotype is cost-effective even in populations with a low prevalence of HCV genotype 2 or 3 infection, despite the additional cost of genotyping.66,67 Cost analyses of the effect of adjusting peginterferon α-2a plus ribavirin treatment based on race and alanine aminotransferase level are not currently available but would be beneficial for determining the overall economic benefit of HCV therapies.
Given these data, treatment of patients with HCV infection is economically advantageous compared to do-nothing strategies. Using a multicohort, natural history model, treatment of 25% of patients with HCV infection reduces the incidence of cirrhosis by 1%.5 In comparison, if 50% or 100% of HCV-infected patients received therapy, the expected reduction in the incidence of cirrhosis would be 8% or 16%, respectively. Overall, data involving direct–acting antiviral agents reveal impressive response rates, and these drugs have changed the management of chronic HCV infection. However, the therapeutic cost of these alterations requires further investigation.
Alcoholic Liver Disease
Alcoholic liver disease can present in several stages, including fatty liver disease, alcoholic hepatitis, and chronic hepatitis with cirrhosis.68 Although these stages may overlap, therapeutic strategies to reverse and prevent progression of this disease to cirrhosis would likely be cost-effective, given that end-stage liver disease caused by this disorder can only be treated with liver transplantation. Reversal of fatty liver disease is possible within weeks of abstaining from alcohol; thus, the primary treatment recommendation is abstinence from alcohol. However, many patients continue to consume alcohol. Therapeutic agents to aid alcoholic abstinence are generally ineffective, although naltrexone or acamprosate (Campral, Forest Laboratories) may be used to reduce the likelihood of relapse in patients who abstain from alcohol. A cost-effectiveness analysis examined the use of acamprosate for 48 weeks in patients with fatty liver disease, cirrhosis, pancreatitis, or alcoholic cardiomyopathy and found that acamprosate was cost-effective compared to no treatment and resulted in a life-year gain of 1.2 years.69 Although the cost of acamprosate (2,177 German marks in 1996) was greater than no treatment, this acquisition cost was insignificant compared to the cost of liver complications resulting from continued abuse of alcohol. Other treatment options, such as prednisolone and pentoxifylline, are also available for patients with alcoholic hepatitis, and although published cost-effectiveness analyses are not yet available, these interventions are likely cost-effective given their efficacy for deterring progression to liver failure.68
Liver Transplantation
Liver transplantation is the only effective treatment for the end-stage liver disease caused by chronic liver damage, and this procedure is associated with excellent survival rates.70,71 Although both deceased and living donor transplantations are performed in the United States, an overall higher cost has been reported with living donor transplantations.70,72 Despite the excellent survival rates associated with liver transplantation, its high expense and benefit to only a small number of individuals have brought its cost-effectiveness into question.73 Indeed, the cost of liver transplantation in the United States is approximately 34% higher than in other countries in the Organization for Economic Cooperation and Development (OECD), although survival rates among these countries are similar (Figure 1). The higher cost of liver transplantation in the United States compared to other OECD countries is due to several factors, including a higher daily price of hospital stays (despite a reduction in their duration), administrative complexity, and malpractice litigation. Differences in the allocation procedures for liver transplantation may also contribute to these cost differences.
In 2006, the United States began using Model for End-Stage Liver Disease (MELD) scores to allocate organs for liver transplantation, whereas other countries in the OECD have yet to adopt the MELD system.73 There is substantial debate about whether MELD scores represent the most reliable evaluation of liver disease to designate hierarchy for liver transplantation and how the use of MELD scores may impact cost.74-80 Patients with high MELD scores receive priority for liver transplantation over patients with low MELD scores, in an attempt to reduce mortality and healthcare utilization by these patients.81 However, this policy results in increased waiting time for patients with mild liver dysfunction. This increase in waiting time may incur additional hospital costs for patients with minimal liver dysfunction as the disease progresses to a decompensated state. Furthermore, patients with higher MELD scores (ie, 28–40) incur significantly higher pretransplantation and total costs versus patients with lower MELD scores (ie, 6–27).82 In addition, patients with better overall health are more likely to survive surgery than patients with comorbidities. Given these observations, it is possible that liver transplantation in patients with less severe liver function may be cost-effective because of these patients’ decreased use of additional healthcare resources. Further studies examining the relationships among MELD score designation, cost, and successful liver transplantation are necessary to examine this possibility.
The cost of liver transplantation includes postsurgical management of patients to prevent complications, which should be taken into account when determining patients’ fitness and the cost-effectiveness of liver transplantation. For example, patients’ MELD scores have been associated with post-transplantation peritonitis, pneumonia, and Clostridium difficile colitis, which increase total hospital costs by a median of $75,433, $50,572, and $29,031, respectively.83 In addition, underlying diseases such as HBV infection and HCV infection must also be controlled to prevent the recurrence of cirrhosis. For patients with HBV infection, standard-of-care treatment involves post-transplantation prophylaxis with lamivudine and/or adefovir and hepatitis B immunoglobulin, which have been shown to be efficacious and cost-effective.50,84 Post-transplantation HCV prevention is more difficult because of patients’ intolerance to standard prophylactic antiviral regimens; however, these treatments have been shown to be cost-effective, resulting in an ICER of $29,100 per life year saved versus no prophylactic therapy.85,86
Societal Impact of Cirrhosis
As mentioned, the total cost of cirrhosis encompasses direct costs (medical costs) and indirect costs (due to reduced HRQOL and lost productivity). Because liver transplantation is the ultimate treatment for cirrhosis, substantial attention has been given to the HRQOL and productivity of liver transplantation recipients. Reduced HRQOL in patients before liver transplantation has been reported, but improvement of HRQOL after transplant-ation remains debatable, with several studies demonstrat-ing improvement and other studies reporting continued impairment.87-93 In studies that report continued reductions in post-transplantation HRQOL compared to the HRQOL of the general population, post-transplantation HRQOL correlated with employment, suggesting that employment may be reduced in patients even after transplantation compared to the general population.91,93 Overall, 55% of patients report employment after transplantation, although the number of unemployed patients was greatly increased post-transplantation in one study (Figure 2).90,94 The main causes of unemployment or reduction in employment were poor physical functioning and poor health, although some patients were reluctant to return to the workplace for fear of losing government-sponsored health insurance and disability income.89,90,94,95 These observations suggest that liver transplantation may not fully restore HRQOL and workplace productivity to patients and, thus, may not alleviate monetary expenditures from government-sponsored programs such as Medicaid. Therefore, establishing effective indicators of reduced post-transplantation HRQOL and work productivity would be beneficial. The most intuitive indicator for such an assessment is MELD score; however, conflicting data make its use as an adequate predictor questionable.87,96-99
Summary
Prevention and treatment of chronic liver diseases (ie, HBV infection, HCV infection, and alcoholic liver disease) may lessen the economic impact of these diseases by reducing comorbidities associated with cirrhosis and the need for liver transplantation. The preventive measures for HBV infection that are currently available may be economically advantageous in some countries, but prevention of HCV infection and alcoholic liver disease remains challenging. There are several effective treatment strategies for reducing symptoms of HBV infection and HCV infection, and some of these strategies may be cost-effective compared to do-nothing strategies. In contrast, treatment of alcoholic liver disease remains difficult, with the primary therapy consisting of abstinence from alcohol. More effective therapies for maintaining alcoholic abstinence would be beneficial and could greatly reduce the need for liver transplantation and retransplantation. Liver transplantation costs have decreased in recent years; however, this procedure remains costly and has questionable economic benefit, given that patients who receive a liver transplant may not regain adequate HRQOL and/or rejoin the workforce. Additional cost-effective preventive and treatment strategies, along with more reliable pretransplantation predictors of post-transplantation work productivity, are essential before the economic burden of cirrhosis can be sufficiently reduced.
Dr. Neff was assisted by Medthink Communications in pulling references for review. The authors have no competing interests or financial support for research to declare.
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