Health care reform: How personalized medicine could help bundling of care for liver diseases
Authors: Lopa Mishra
Journal: Hepatology (2011)

The National Health Care Acts in 2010 support bundling of care for certain procedures, a well-known concept from the mid 1980s, defined as a single payment for all costs incurred for treatment of a disease. Bundling of care has been instituted by many including The Texas Heart Institute's charging a flat fee for coronary artery bypass surgery ($13,800 versus the average Medicare payment of $24,588 at that time).1-3 Predicted to decrease national health care spending by 5.4% between 2010 and 2019, bundling has the potential for maintaining high quality care while reducing financial risk to patients.4, 5 Disadvantages of bundling include lack of scientific evidence demonstrating improved health outcomes and its relevance to academic health centers, where innovation in care and education are not factored in with bundled payments.6-10 These uncertainties notwithstanding, bundling is an evolving concept that could help overall healthcare, and concurrently determine cost for a specific disease process at the time of diagnosis. Abbreviations: ALD, alcohol-induced liver disease; HBV, hepatitis B virus; HCC, hepatocellular cancer; HCV, hepatitis C virus; HER2, human epidermalgrowth factor receptor 2; HCGC, The Hepatocellular Cancer Global Consortium; HIV, human immunodeficiency virus; iPS, induced pluripotent stem cell; OR, odds ratio; PARP, poly (ADP-ribose) polymerase; STIC, stem-like tumor initiating cell; TGF, transforming growth factor. How does bundled care affect us hepatologists? Taking a look at our current scenario: total charges for hospitalizations for the hepatitis C virus (HCV) were $514 million and alcohol-induced liver disease (ALD) $1.8 billion in 1985 in the U.S.11 Furthermore, human immunodeficiency virus (HIV) infection (odds ratio [OR], 4.5), complications of cirrhosis, such as variceal bleeding, encephalopathy, and hepatorenal syndrome, sociodemographic factors, such as race and health insurance were all associated with an increased risk of death among these patients with cost of care greatest in the later stages of almost all illnesses. Early and effective intervention has the potential to greatly attenuate these complications and costs. Approximately 2.7 to 3.9 million people have chronic HCV liver disease, 20% of whom will progress to cirrhosis over 20 to 30 years with 5% dying of hepatocellular cancer (HCC) in the United States.12 Chronic hepatitis B virus (HBV) is associated with a 15% to 25% risk of cirrhosis and HCC, and accounts for 600,000 deaths worldwide.3 Other disorders such as nonalcoholic fatty liver disease — arising from single or combination of factors including insulin resistance, hypertension, dyslipidemia, and obesity, termed “metabolic syndrome,”13 and hemochromatosis (relative risk of 200 times the normal population) are each significant risk factors for HCC; collectively responsible for the rise in HCC incidence that has tripled in the United States from 1975 through 2005.14, 15 Indeed HCC, the third most common cancer worldwide, accounts for a 47% increase in liver cancer deaths in males and 23% increase in females over the last 5-8 years (HCC is the 8th most common cancer in males in Texas). Chronic HCV infection in 2008 affected 2.94 million patients with a mortality rate from HCC of 86%. The cost of HCC is over $50,000-$115,000/person. Based on the current 3-4 fold increase in HCC in the United States, the projected increase in HCC cost could be astronomical, at the rate of 69,000-92,000 cases per year in the United States, carrying a potential annual burden of cost of $8-10.5 billion!16 Clearly, a cost benefit analysis of bundled care in hepatology could prove it to be a more efficient form of care. Specific burden cost measures are needed for the field of hepatology and include: (1) early detection when it is easier to treat disease effectively; (2) identification of high risk patients; (3) stratification of care; (4) development of low, cost high yield markers and imaging modalities; and (5) low toxicity targeted therapeutics. There is reason to conclude that these modalities will improve survival and health outcomes that could ultimately become the leading determinate of high-quality care in patients with chronic liver disease which otherwise has a high risk of progressing to HCC.17 Fundamentally, the subsequent decrease in the burden of cost-evidence could be realized based on personalized medicine.18, 19 In many ways physicians have always practiced personalized medicine using their clinical observations to switch drugs, adjust dosages to optimize treatment or avoid harmful side effects. It is only recently that a patient's molecular information such as protein biomarkers in the blood have been incorporated into clinical care. Detection of differences within a disease category can lead to optimal care as exemplified in breast cancer, where about 30 percent of breast cancers have an increased expression of a cell surface protein called human epidermalgrowth factor receptor 2 (HER2). Inhibition of the HER2 receptor by an antibody drug — Herceptin® (trastuzumab) markedly improves survival in this subgroup.2, 20, 21 I envision that partial or full cancer genomes will routinely be sequenced as part of the clinical evaluation of cancer patients. The first human genome project, which sequenced half a dozen people, cost 1.5 billion dollars and took 15 years. The same amount of data can now be processed in a week at a fraction of the cost. Understanding the genetic aberrations enables us to target molecular aberrations with drugs and detect disease at an earlier stage when it is easier to treat effectively. Other benefits include ability to select optimal therapy, reduce trial-and-error prescribing, decrease reduce adverse drug reactions, and improve patient compliance with therapy. Improving the selection of targets for drug discovery will reduce the time, cost, and failure rate of clinical trials, revive drugs that failed clinical trials or were withdrawn from the market, avoid withdrawal of marketed drugs, and shift the emphasis in medicine from reaction to prevention, all of which will reduce the overall cost of health care. This “pharmacogenomic” approach could reduce the time and cost of drug development. Identifying subgroups of patients most likely to respond to therapy could reduce the size, time, and expense of clinical trials. Potentially a savings of $335 million per drug could be realized by this approach and has been successful in a recent phase III clinical trial for the drug Tykerb (lapatinib). This study was terminated early due to the drug's remarkable success in treating a genetically defined subset of patients with breast cancer.22-24 We need a global collaborative program that addresses key pharmacogenomics and applies current innovations if we are going to lead a change in course for HCC, and lead the field of bundled care in hepatology, for one of the most common and lethal cancers worldwide. The Hepatocellular Cancer Global Consortium (HCGC) currently at 55 Investigators, was established informally in 2003 and recently more formally. The HCGC is one group that is able to address specific goals: prevention, detection, and treatment leading to elimination of HCC.25 Clearly clinicians, scientists, and collaborative research in hepatology needs to bring new insights from innovative fields of science to ours, and apply these to the large patient population of 2,993 HCCs in the United States. All of these resources are important elements to this process. This HCGC program proposes five potentially paradigm shifting translational projects, that include the first HCC genome-wide study in a U.S.-based population of 2,993 HCC cases, new and potentially effective therapeutics, taking advantage of a large patient population and meeting the challenge of the alarmingly rising incidence of hepatocellular cancer in the United States. Although the risk factors are well defined, the molecular mechanisms of hepatocarcinogenesis are unclear. It is known that up to 40% of HCC are clonal in origin and potentially arise from stem-like tumor initiating cells (STICs). These concepts have drawn attention to pathways that control stem-cell proliferation. Among these, genetics have revealed modulation of the transforming growth factor-β (TGF-β) pathway as a key functional pathway to STIC and HCC suppression. Moreover, E3 ligases and poly(ADP-ribose)polymerases (PARPs), are dramatically over-expressed in HCC with inactivation of TGF-β signaling, suggesting these as attractive targets for new therapeutics.26 These findings have led HCGC to deploy small-molecule compounds targeting the intracellular and nuclear oncogenic pathways that are specifically and highly activated only when the TGF-β pathway is inactivated. Such therapeutics are aimed at E3 ligases, PARP inhibition and histone deacetylase (HDAC) inhibition, that are now in Phase I trials in the United States. The combined programs take advantage of international collaborations in induced pluripotent stem cells (iPS), STIC suppression, promising to yield future replacement strategies. The proposed projects include: genetic variations in the TGF-β pathway as predictors of HCC; identification of effective agents for the prevention of HCC in high-risk individuals; targeting E3 ligases in HCC; targeting DNA damage repair in HCC in partnership from pharmaceuticals; new therapeutics targeting interleukin-30 in STICs: determining safety for liver tumor prevention and treatment. The goals are effective prevention, detection and treatment of HCC, eliminating this common cancer. The HCGC aims to achieve this goal by assembling a highly talented group of clinicians and scientists committed to expedicious translation of HCC findings from the laboratory to the clinic as well as from the clinic to the laboratory. In order to prioritize the elimination of HCC as a health risk, the HCGC program is now a multi-institutional, multidisciplinary research program in HCC, that supports treatment and research beyond traditional boundaries. The program will provide a framework as well as crucial resources to allow further advances alongside state-of-the-art translational work and provide an unprecedented opportunity to effectively alter the course of this lethal and rising cancer, leading the path for cost saving bundling of care for hepatocellular cancer through personalized medicine. Currently, bundled payments are to be paid to hospitals for a single admission for inpatient care. Planning hospital admissions for focused appropriate care and avoiding unplanned visits should help hospitals and physicians control costs. Perhaps the future is now. The author would like to acknowledge Dr. Bibhuti Mishra, Dr. John Stroehlein, Dr. Gottumukkala Raju, Ms. Lisa Hafemeister and Ms. Anabel Morales for their time and assistance with this commentary. Science is organized knowledge. Wisdom is organized life. Immanuel Kant German philosopher (1724-1804).