Curing Chronic Hepatitis C With Sofosbuvir-Based Regimens

Since the hepatitis C virus (HCV) was first identified more than 3 decades ago, this potentially deadly disease has grown into a major global public health concern, with 180

million people worldwide chronically infected. But during this same time period, 3 important advances in the fight against this serious liver disease have had an immense impact.

First, we have gained a better understanding of the total burden of HCV. We now know that HCV causes not only significant liver disease and its associated complications, but also a number of extrahepatic manifestations—all of which lead to mortality and morbidity, and have a tremendous economic impact on society. Rheumatologic diseases, such as chronic fatigue, arthritis, and vasculitis, are other well-known complications of HCV, as are insulin resistance and type 2 diabetes mellitus.¹

Over the past few years, predictions of the future clinical burden of HCV have grown increasingly dire. In the United States, 36,000 deaths from HCV are expected each year through 2030, and 1 million patients are expected to develop cirrhosis by 2020.^2,3 Approximately 150,000 and 14,000 patients will develop liver decompensation and liver cancer, respectively.³ Due to this burden of advancing disease, chronic HCV infection is now the leading indication for liver transplantation, with some 5500 Americans awaiting a liver.⁴

As well, we now better understand the economic burden of HCV. It is estimated that total direct medical expenditures attributable to chronic HCV in the United States will reach $10.7 billion between 2010 and 2019. Over this same period, it is projected that decompensated cirrhosis and hepatocellular carcinoma will lead to $21.3 billion in related societal costs, and that the indirect costs attributable to HCV-related deaths in persons younger than 65 years will total $54.2 billion.⁵

The second advancement has been in terms of the treatment of HCV. Over the past decade, treatment of HCV has improved tremendously, with higher response rates and improved tolerability. Although initial treatments with interferon-based regimens did result in sustained virologic response (SVR) for some HCV-infected patients, the regimens were plagued with substantial side effects that negatively affected patients’ well-being. These treatment-related side effects were associated with substantial

direct costs (cost of medications and side effect management) as well as indirect costs related to the loss of work productivity, and other important patient- reported outcomes (PROs).⁶

Third, over the years, we have developed a greater appreciation for the benefits of achieving sustained virologic response 12 weeks following treatment (SVR12). In fact, we now know that SVR12 really represents a cure for HCV. Achieving this outcome in HCV patients lowers their risk of developing complications of cirrhosis, can reduce mortality, improves PROs, and offers economic benefits to society.^7,8 These benefits of SVR12 have become more obvious as better treatment regimens, free of interferon and ribavirin, have emerged with higher efficacy, excellent tolerability, simpler administration schedules, and shorter duration of treatment. The latter 3 will

certainly contribute to the improvement of patients’ adherence to these regimens and will potentially close the gap between efficacy (cure rates from clinical trials) and effectiveness (cure rates reported in the community practices) of anti-HCV treatment. One of these regimens is based on sofosbuvir. With its favorable efficacy and safety profile, sofosbuvir is rapidly becoming the new “backbone” of HCV treatment, replacing the old backbone, interferon, along with its associated toxicity and low efficacy.

The development of sofosbuvir and its use in combination with other drugs has provided new opportunities to eradicate HCV, leading members of the FDA panel that approved the drug to term it a “game changer.” It is currently being combined with other agents in a number of interferon- and ribavirin-free regimens, all with excellent preliminary efficacy and safety.^9-11

Sofosbuvir represents the culmination of decades of innovation and collaboration among industry, clinicians, and thousands of patients who have participated in clinical trials. While the opportunity to cure chronic HCV has existed for some time, it is with the availability of these new regimens that we can now imagine curing patients in large numbers with a well-tolerated short course of therapy. Additionally, these regimens have been shown to improve extrahepatic manifestations of HCV, such as

fatigue and other important PROs. Finally, from a societal perspective, these regimens have been shown to be costeffective and are now widely adopted in clinical guidelines from important international societies and the Department of Veterans Affairs.¹²

Because of these 3 major advances, I believe we are witnessing the golden age of HCV treatment. With efficacy rates approaching 100%, lack of substantial side effects, and no need for extensive laboratory testing and monitoring, we have the potential to eradicate HCV. I believe the barriers to eradication will be a lack of effort made to identify these patients through effective screening programs; our lack of willingness to accept HCV as an important cause of a “systemic disease” with both hepatic

and extrahepatic manifestations; our incomplete appreciation of the total burden of disease (clinical burden, economic burden, and PRO burden), and finally, our reluctance to invest in treatment now rather than wait until the disease becomes more advanced and the benefits are potentially diluted.

In healthcare we often see preventive care ignored, avoided, or deemed too costly, only to have patients suffer the long-term consequences and exponentially more expensive treatments and hospital care later on. No situation better illustrates this thinking than the current debate over whether patients infected with HCV should receive a recently approved sofosbuvir-based regimen that can prevent the need for much costlier care.

Despite the evidence that sofosbuvirbased regimens offer a cost-effective cure for chronic HCV, many payers in the United States have pushed back aggressively on the price of the drug. Some have called for physicians to delay treating patients with sofosbuvir until they progress to later-stage disease. This approach ignores a number of important issues. First, treating a patient with HCV and advanced fibrosis does not eliminate their risk for liver cancer. By rationing treatment to those with advanced liver disease we compromise the most optimal benefit to all HCV patients. Second, this approach ignores the fact that HCV has a number of important extrahepatic manifestations that can negatively impact patients (fatigue and quality of life), their families (stigma of HCV infection), and society (lower worker productivity). Third, it ignores the fact that most HCV-infected patients are baby boomers who account for a large number of HCV-related complications and liver transplantations. This could

have a tremendous negative economic impact on our society over the next 1 to 2 decades. Setting aside the moral implications of these demands, as a hepatologist who studies questions important from patients’ perspective and issues related to cost-effectiveness, my work shows that this approach would likely cost more than curing patients now. Nevertheless, these regimens have been shown to be cost-effective, with incremental cost- effectiveness ratios well within the accepted range.¹³ Therefore, I believe there is significant value in initiating treatment at an early stage of HCV.

To address the ongoing debate on the downstream costs and sequelae associated with waiting to treat, I and some colleagues created a model to assess the long-term health outcomes associated with treating patients early (in the noncirrhotic stage) and later (in the cirrhotic stage). We found that the number of cases of liver disease complications in the cohort of patients with cirrhosis was more than triple that in the cohort without cirrhosis.¹⁴ In fact, this model underestimates the total benefit of treatment and achieving cure in early stages of liver disease. In addition to the benefits of reducing liver disease complications, one must add the benefit of reducing the extrahepatic manifestations such as fatigue, arthritis, and even type 2 diabetes mellitus. By considering the total burden of HCV and by accounting for “total benefit” of HCV cure, the resultant benefit to the individuals, communities, and the society could be tremendous.

It is clear that earlier treatment with more effective therapies such as sofosbuvir-based regimens will curb future liver disease and HCV-related extrahepatic diseases, as well as the long-term costs associated with advancing disease. It is only with a complete understanding of HCV disease and the total benefit that a cure can bring that all stakeholders—patients, clinicians, payers, and policy makers—can come together to eradicate this virus once and for all.

In a relatively simple analysis, the cost of an anti-HCV regimen must not only include the cost of the drug but also the duration of treatment, number of laboratory tests required for side effects or efficacy monitoring, and additional doctors’ office visits for the management of side effects—depression, anemia, leukopenia—and their tremendously expensive treatments (growth factors and antidepressants, among others). In addition, the cost of treatment side effects negatively impacting worker productivity are real to patients, their families, and employees. Finally, if one considers the so-called “cost per cure,” the fact that more than half of patients who are treated but not cured needs to be part of the equation. In the interferon-as-backbone era, patients were treated multiple times. If you factor in all these costs and consider them from the perspectives of patients, families, clinicians, and society, there is no doubt that a regimen with close to a 100% cure rate will be cost-effective.

EBIID

I believe treatment of HCV with these new regimens, including sofosbuvir-based regimens, is a good deal for patients and the society. Sofosbuvir-based regimens provide a meaningful breakthrough that represents a rare, and perhaps unprecedented, achievement in medicine. Recognizing that healthcare resources are scarce and that we must get maximum value from each dollar spent, we should find ways to embrace and deliver cost-effective cures for our patients with HCV. We should all embrace the notion that what is true for individuals and families is also true for society: sometimes you have to spend money to save money.