In recent years, each edition of HEPATOLOGY has included a viewpoint article written by a member of the Editorial team. This month Dr Michael Charlton has offered his turn at the microphone to Dr. Donald Jensen and Dr Andrew Aronsohn from the University of Chicago, in order that they can address a pressing issue that will emerge in tandem with the likely approval by the U.S. Food and Drug Administration of boceprevir and/or telaprevir.
More than 120 million people are infected with hepatitis C worldwide.1 Hepatitis C virus (HCV) is a leading cause of liver-related mortality and is the most common indication for liver transplantation in the United States.2 Since the introduction of pegylated interferon and ribavirin nearly 10 years ago, response rates have been relatively stagnant, with less than half of treated patients achieving a sustained virological response.2 Data from the first direct-acting antiviral (DAA) agent, BILN 2061, was initially presented at the American Association for the Study of Liver Diseases annual meeting in 2002, which sparked enthusiasm over improving therapeutic efficacy.3 Nearly a decade later, we find ourselves on the brink of a new era of HCV therapy. Telaprevir and boceprevir will likely receive U.S. Food and Drug Administration approval by mid-2011, and based on phase 2 and 3 data, will significantly improve rates of sustained virological response in patients infected with HCV genotype 1 when compared to current standard-of-care therapy.4-7 This improved efficacy has been well-publicized for years, and anticipation of DAA availability has already become part of the HCV treatment algorithm. Greater understanding of the natural history of HCV and identification of risk factors for progression to advanced liver disease has allowed many physicians to recommend deferral of standard-of-care therapy in favor of waiting for DAA availability for patients who are at low risk to progress to significant liver disease in the near future. This was demonstrated in a large VA-based study of 4084 patients evaluated for HCV therapy with interferon and ribavirin.8 Of the eligible patients who declined therapy, 50.3% stated they had deferred treatment in anticipation of more effective medications.8 Treatment-naive patients who have deferred standard-of-care therapy, in addition to patients who have failed previous regimens of HCV treatment, will likely create a surge of requests to initiate therapy in mid-2011.
The influx of patients requesting HCV therapy will present a significant problem. HCV therapy is becoming increasingly complex, and the addition of DAAs will only add to the time needed to effectively educate and appropriately monitor patients while they are receiving treatment. This may be partially offset by response-guided therapy that shortens treatment duration. We recently performed a time analysis study at our institution to gain understanding of time allotment needed for each new DAA-treated patient and to estimate the maximum patient capacity of a health care provider. On average, a health care provider can reasonably initiate therapy on only three patients each week before exceeding their work capacity. Because we anticipate at least 500 requests for evaluation for HCV therapy within the first few weeks of DAA availability, current staffing will be unable to meet the demands of all patients with HCV who are expected to request treatment.
Resource scarcity will be a prominent issue once DAA therapy becomes available. Historically, enthusiasm over a scientific breakthrough has caused the medical community to lose sight of the importance of prediction and resolution of problems of scarcity.9 In 1922, Frederick Banting and Charles Best discovered how to produce and use insulin to treat diabetes mellitus. Word of this life-saving medication traveled quickly, creating a deluge of requests for insulin that could not possibly be fulfilled due to limitations of production capacity.10 Unprepared to handle this dilemma, Dr. Banting created a somewhat arbitrary and subjective plan where Banting himself decided whom to treat first, which resulted in friends and politically well-connected individuals unfairly receiving priority over others.9 Twenty years later, penicillin was discovered, and efforts were made to avoid the injustices seen with insulin allocation. From 1942 to 1944, the Committee on Chemotherapeutic and Other Agents was responsible for rationing penicillin to civilians.11 Although efforts were made to prioritize clinical need over political and social worth, penicillin allocation became subject to intense scrutiny due to a double standard in rationing for civilian and military personnel. Penicillin was carefully allocated to civilians based on severity of disease; however, it was liberally given to military personnel to treat gonorrhea, a less serious illness, because it was highly effective and allowed soldiers to quickly return to their duties.9 In 1960, Belding Scribner developed a shunt that allowed patients with chronic kidney disease to safely undergo dialysis.12 Given the paucity of dialysis machines compared to the number of patients with chronic kidney disease, physicians were once again forced to allocate scarce, life-saving technology. A nine-member committee consisting of two physicians and seven lay persons was formed in 1961 to determine who would receive dialysis services. Because most patients with chronic kidney disease had similar medical needs for dialysis, the committee made decisions in part based on a patient's “social worth.”9 Not surprisingly, this criterion was widely criticized and eventually led to approval of legislation in 1972 to allow federal funding for hemodialysis to all Americans with chronic kidney disease.
In 2011, nearly a century after the discovery of insulin, we continue to struggle with issues of resource scarcity. Equitable distribution of antiretroviral medication to patients with human immunodeficiency virus worldwide and organ allocation for transplantation illustrate that despite major advances in medical technology, our underlying moral dilemmas remain unchanged. History has taught us that failure to preemptively develop a moral framework to deal with problems of scarcity can lead to injustices to patients in need. Distributive justice is a moral principle that emphasizes “fair, equitable, and appropriate distribution” of scarce resources.13 Equality for all patients should be paramount, yet this should be carefully balanced with appropriate emphasis on medical need. With the arrival of DAA therapy, we will be unable to initially treat all patients requesting therapy, and we will once again be forced to allocate a scarce resource. Critical analysis of this problem has yielded two potential solutions for this allocation dilemma: a first-come, first-served approach and a needs-based approach.
A conventional first-come, first-served approach, as the name implies, offers therapy, when appropriate, to patients in the order in which they are seen in the clinic after DAA launch. If (and when) the health care team becomes saturated, a waiting list will form, and patients on that list will be offered therapy when the health care team has more capacity. This approach has some advantages. It is the simplest plan and requires no planning prior to DAA availability. In fact, this approach will likely be a default system used by any center that has not enacted a preconceived DAA allocation system. First-come, first-served strictly adheres to the principle of justice, because all patients have an equal claim to therapy, and specific prioritizations are not made. However, it is inadequate because it ignores the importance of medical need where the workforce available to treat is limited in relation to the need.
We propose a needs-based allocation system. Much like the Model for End-Stage Liver Disease system, priority would be given to the sickest patients first in an effort to optimize outcomes for all patients with HCV. Prior to the launch of DAA therapy, treatment-eligible patients with HCV could be provided with an educational symposium outlining the natural progression of HCV and describing an allocation system, which would stress the importance of expediting treatment for the sickest patients and the safety of waiting for therapy in patients with early stages of disease. Then, patients who have previously deferred therapy and new patients will be prioritized on the basis of need, with patients with cirrhosis at one end of the spectrum and asymptomatic patients with F0-F2 fibrosis at the other end of the spectrum. This system satisfies the principle of justice while placing appropriate emphasis on medical need.
There will be inherent difficulties in this prioritization system. First, many patients with early stage disease have been eagerly awaiting the launch of DAA therapy and may be disappointed to find out that they may have to wait even longer to initiate therapy. Although it is anticipated that educational sessions will help these patients understand the reasoning behind their increased wait time, some patients will still choose not to wait and will seek more expedited treatment elsewhere. In addition, the choice to treat patients with more advanced liver disease first will likely result in poorer initial outcomes and more complications related to therapy. Finally, there may be medical legal implications to treating patients who are outside of approved indications for therapy. However, the benefit of a morally sound allocation system should outweigh these legal risks, and by ensuring that health care providers have adequate time with each patient, adverse outcomes can be greatly diminished.
The availability of DAA therapy will forever change the landscape of HCV, in that we will be able to cure patients of disease who we were unable to cure in the past. Unfortunately, this medical breakthrough will be coupled with resource scarcity. Historically, some of the greatest scientific discoveries in medicine have failed to provide a distribution system that appropriately emphasized not only justice and equality but also medical need. We hope to learn from the past by proposing a preconceived plan that would both educate patients and allocate therapy to the neediest patients first, thereby fulfilling the moral framework of distributive justice.