A glass half full: Implications of screening for hepatitis C virus in the era of highly effective antiviral therapy
Authors: Glen Lutchman, W. Ray Kim
Journal: Hepatology (2015)

Potential conflict of interest: Dr. Lutchman advises Gilead and AbbVie. See Article on Page 1479 Abbreviation HCV hepatitis C virus "A pessimist sees the difficulty in every opportunity; an optimist sees the opportunity in every difficulty." ‐ Sir Winston Churchill Twenty‐five years since its discovery, hepatitis C virus (HCV) remains the leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma, frequently leading to liver transplantation or death. In an effort to reduce the public heath impact of HCV infection, the Centers for Disease Control and Prevention has updated its screening guidelines to make an additional recommendation to screen Americans born between 1945 and 1965. The rationale for the recommendation was that 75% of the 3.2 million chronically infected patients in the United States were born in this 20‐year span and that the majority of HCV‐related deaths presently occur in that birth cohort.1 Recent innovations in antiviral therapy for HCV have resulted in remarkable improvement in sustained virological response rates, better tolerability, and decreased duration of treatment compared to interferon and ribavirin‐based therapy in the previous era. As such, patients who were previously not treatment candidates due to psychiatric conditions, anemia, or autoimmune disease now have excellent treatment options.2 In fact, the advent of pan‐genotypic, highly tolerable, all‐oral antiviral therapy for HCV may make it possible to eradicate the disease altogether. In this issue of hepatology, Moorman et al.3 present their analysis of the Chronic Hepatitis C Cohort Study as it relates to the outcomes for patients who had a "late diagnosis" of chronic hepatitis C. This definition included patients with either cirrhosis, decompensated liver disease, or both at the time of initial HCV diagnosis. In this large study cohort representing a "real‐life" practice setting, a surprisingly large proportion, nearly one of every six patients with HCV infection, met the criteria for late diagnosis. In addition, the authors found that patients with late diagnosis had higher rates of hospitalization (59% versus 35%) and mortality (33% versus 9%) compared to those diagnosed at an earlier stage of liver disease. The median duration between the time of diagnosis and death was only 4.2 years. Many of these patients had been followed in the health care system prior to HCV diagnosis, with a mean gap of 6 years. Late diagnosis was more commonly seen in African American patients and in patients with Medicare insurance.3 These findings by Moorman et al. encourage optimists to advocate for broader HCV screening guidelines as they may see it as an opportunity for early intervention. Adherence to the guideline is expected to decrease the delay in detecting HCV infection and to afford early interventions to prevent cirrhosis and its complications and mortality. In contrast, pessimists would point to the fact that we do not have coherent strategies and resources with which to implement a population‐wide screening and, more importantly, to systematically care for a large number of newly diagnosed HCV patients. Figure 1 illustrates the steps needed to meaningfully reduce the public health impact of HCV infection at the population level. While screening is an essential initial step in the cascade of events, it must be followed by appropriate diagnostic evaluation, rational treatment decisions, and delivery of pharmacologic therapy and monitoring. These tasks may be performed by primary care providers, midlevel practitioners, infectious disease specialists, and hepatologists, depending on their experience with and commitment to the care of HCV patients.Figure 1: Steps needed to meaningfully reduce the public health impact of HCV infection at the population level. Abbreviation: PCP, primary care provider.With regard to the initial diagnosis, antibody‐based screening tests and confirmatory HCV RNA testing are readily available and easy to interpret, making it a suitable task for primary care or midlevel providers. Practical challenges, however, reduce adherence to the Centers for Disease Control and Prevention's screening recommendations. Regardless of the primary care provider's awareness of the need for screening, competing priorities demanded of them for preventive care reduce adherence to the screening recommendations. Potential solutions to overcome this barrier in screening have been proposed and include automatic flagging of screening candidates by the electronic health record system or delegating the screening responsibilities to nonclinician members of the health care team. The more challenging question, following screening and confirmation in HCV care for the population, is who bears the responsibility of evaluating the patient and making and executing treatment decisions for those who test positive. According to the Centers for Disease Control and Prevention's estimates, of the 3.2 million Americans with HCV infection, over 2 million belong in the baby boomer generation, approximately 1 million of whom have not been diagnosed. One of the concerns here is whether there is a sufficient number of health care providers qualified and interested in providing care for those patients. The other obvious resource needed for successful HCV care is health care funds available for diagnostic evaluation, pharmaceuticals, and monitoring during and after therapy. There have been several analyses that suggested that birth‐cohort screening is cost‐effective. They include a recent analysis that advocated treating all patients regardless of fibrosis stage.4 This obviates the need for additional testing and subsequent treatment decisions, making the treatment straightforward such that it can be delivered by a large variety of providers with minimal training in HCV. The simplicity, safety, and effectiveness of all‐oral regimens make such proposals implementable and cost‐effective.5 The immediate challenge to the "treat‐all" strategy is its budgetary impact. For example, in the first 3 months after the release of sofosbuvir, a large commercial health insurance carrier announced that it had spent over $100 million on hepatitis C prescriptions. This left a large enough impact on the company's bottom line to cause a substantial drop in its stock price.7 While $100 million is an undoubtedly large sum of money, at more than $100,000 a course, the number of patients treated would have been fewer than 1000, with an even smaller number of patients reaching sustained response. The budgetary impact of treating over 1 million HCV patients would be 1000‐fold greater. The other strategy to effectively reduce the impact of HCV is to prioritize therapy to patients who are at a higher risk of having problems in the near future. Moorman et al.3 highlight the benefits of screening to identify and treat patients prior to the development of advanced liver disease. However, not all individuals with chronic HCV infection go on to have morbidity and mortality related to the infection.8 Treating the entire population of those with HCV infection will translate to many receiving the treatment deriving little health benefit.6 In Fig. 2, several treatment scenarios are graphically summarized. In all three panels, the circle represents patients at risk of developing problems from HCV, for example, those with advanced fibrosis, in whom sustained response will have demonstrable benefits. The square represents patients who achieve sustained response. Thus, the patients in whom sustained response would make a real impact on hard endpoints in the future belong in the intersection between the circle and the square. Figure 2A depicts treatment realities in the interferon era. There was a relative minority of patients who achieved sustained response. Because patients at risk of progression were less likely to achieve sustained response (e.g., advanced fibrosis, alcohol abuse, or concomitant steatosis), the number of patients who truly benefit from sustained response was even smaller. Figure 2B represents the "treat‐all" scenario where highly effective therapy is given universally. As discussed above, this approach will cure most of the patients, potentially eradicating HCV in the population. In a large proportion of patients who receive treatment and achieve sustained response, HCV may never have caused health problems. Critics will argue that the funds used for therapy could have been directed to other needs and, thus, wasted. Figure 2C suggests that an optimal scenario may be to target treatment to those who are at risk of developing problems in the future. The tighter the square is around the circle, the more efficient the system will be made.Figure 2: Treatment scenarios. (A) Treatment reality in the interferon era. (B) Treat‐all scenario. (C) Optimal scenario, in which treatment is targeted to those at risk of developing problems in the future.While prioritizing treatment to patients who are at risk of future problems seems the optimal solution to deliver most benefits at the lowest costs, the problem lies in the identification of those patients who should be included in the target population, especially in younger patients who are in the early stages of liver injury. In principle, the strategy is consistent with the recently published recommendations form the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.9 The patient groups that will benefit in the most dramatic fashion from the newest regimens are those with clinically evident cirrhosis, those with decompensated liver disease, and those with other serious medical comorbidity. Achieving sustained virological response could potentially delay or prevent hepatic decompensation and avoid liver transplantation or death. The next group to target may include asymptomatic patients with advanced fibrosis and cirrhosis. Identifying these patients requires assessment of hepatic fibrosis, most commonly at the current time based on noninvasive diagnostic measures. It is clear that, from the public health standpoint, the targeted approach almost certainly requires hepatologists to be involved in the management of individual patients. It is impractical for other specialty physicians or generalists to be able to manage and monitor patients with cirrhosis or to incorporate treatment decisions based on assessments of the status of fibrosis. It also requires a system of health care delivery that allows tracking and monitoring of patients in whom treatment is deferred. To the extent that chronic hepatitis C is an infectious disease, eliminating the causative agent in everyone with the infection should be the ultimate goal in our public health policy. When that goal is not achievable in reality, however, the next responsible course of action for our profession may be to provide a clear vision about a disease management strategy. In such a strategy, antiviral therapy is only one, albeit very important, component of a broader range of disease management options. Screening and early diagnosis should lead to detailed assessment of the patient's status, such as fibrosis stage, comorbidity status, and extrahepatic involvement of HCV. Patients who meet the treatment criteria should be automatically accepted for therapy. Other patients who have early‐stage liver disease can be monitored with serial noninvasive fibrosis measures while preventive care is provided.10 In patients with advanced liver disease, long‐term management of their chronic liver disease is instituted, including surveillance for hepatocellular carcinoma. The data of Moorman et al.3 showing that many newly diagnosed HCV patients have advanced liver disease undoubtedly represent lost opportunities for early detection and intervention. The data emphasize the need for adherence to screening recommendations and subsequent linkage to care. On the other hand, the recent enhancement in antiviral efficacy is encouraging that patients who are diagnosed late may be as effectively treated as patients diagnosed at an earlier stage. These patients require hepatological care with management of chronic liver disease and expectant monitoring for future complications. Regardless of the health care delivery model to be employed for the care of HCV patients, major investments are needed, the least of which is an adequate number providers with appropriate expertise. Despite these obstacles that face us in our efforts to eliminate HCV and the diseases it causes, there remain many causes for optimism for those who persist in seeking opportunities given available resources.