Over 180 million people are infected with hepatitis C virus (HCV) worldwide. Despite significant advances in therapy, an alarmingly high number of patents remain both undiagnosed and untreated. Linkage to care is a significant barrier to HCV treatment due to ineffective risk-based screening and the asymptomatic nature of HCV until it reaches advanced stages of disease. Increasing complexity of HCV therapy, largely due to individualization of treatment, has led to improvements in efficacy but also threatens to propagate and maintain a disparity in access to care. Personalized, or individualized, medicine has been touted as the future of pharmaceutical innovation; however, in a global epidemic such as HCV, deconstructing and reversing this trend may be essential to more effectively combat this disease.
hepatitis C virus
standard of care
World Health Organization.
Evolution of HCV Therapy
In 1989, HCV therapy was simplistic and relatively ineffective. Interferon monotherapy given three times a week for 6 months yielded very few patients with sustained virologic response. As our understanding of the hepatitis C virus improved, HCV therapy became “individualized” as viral and host characteristics were both used to risk stratify patients and optimize response to therapy. These characteristics included patient weight, histologic stage of disease, race, viral genotype, IL28b genetic polymorphism status, and on-treatment viral kinetics. In May 2011, the first direct-acting antiviral (DAA) agents, boceprevir and telaprevir, became available to be used in combination with peginterferon (PEG) and ribavirin (RBV). DAA-based triple therapy has boosted sustained virologic response (SVR) rates to ∼75% in genotype 1 patients; however, it requires detailed pretreatment evaluation and complex on-treatment monitoring.[2, 3] Duration of treatment and stopping rules are largely based on close monitoring of viral kinetics. In two decades, HCV treatment was transformed from a “one size fits all” approach to a complex, individualized therapy that is tailored to optimize outcomes for specific subsets of patients and responses.
Price Tag of Individualized Medicine
HCV therapy comes at a cost. The total medication cost of current protease inhibitor-based therapy generally ranges from $52,600 to $89,700 depending on agents used and duration of therapy required. However, the true cost of HCV care goes far beyond pricing of drugs. It is the opportunity cost of care that threatens widespread availability of treatment. Extensive evaluation and monitoring that is required for standard of care (SOC) HCV therapy threatens to become impossibly time-consuming for many providers to continue treating HCV patients. For example, SOC therapy for a genotype 1 treatment-naïve patient may require 6 to 8 clinic visits and 50 to 66 separate laboratory tests that must be drawn and interpreted. Patent education, laboratory monitoring, and clinic visits are more extensive with current therapy, and are often under-reimbursed and poorly incentivized in many healthcare systems. HCV treatment currently requires more expertise than ever to deliver safe and effective care. In evidence, DAA-based triple therapy requires more comprehensive understanding of potential drug-drug interactions, viral kinetics, risk factors for generating viral resistance, and side effect management of patients who are vulnerable to rash, anemia, and decompensated liver disease. These factors threaten to alienate many providers and may shrink an already limited workforce equipped to deliver HCV care. Age-based screening of U.S. patients born between 1945 and 1965 has recently been recommended by the Centers for Disease Control and Prevention (CDC) to better identify up to 800,000 previously undiagnosed and untreated individuals. In our current system, complexity of care has created an imbalance of increasing efficacy with diminishing access to HCV therapy. The next generations of DAAs have the potential to significantly reduce the burden of on-treatment evaluation and monitoring; however, it will be crucial that a primary focus in development is to cure disease on a population scale rather than an individualized approach. Advances in treatment, especially in a global epidemic, are only useful if they have practical, useful, and widespread applications.
Need to Simplify Care
The HCV pipeline of new therapeutic agents is robust and moving forward at high speed. New antiviral agents such as newer NS3/4A protease inhibitors, NS4B inhibitors, NS5A inhibitors, NS5B polymerase inhibitors, lambda interferons, and cyclophilin inhibitors are currently under development and hold promise for safer, simpler, and more effective therapy. However, as long as HCV therapy remains complex, SVR rates that approach 100% are less impressive unless a plan is in place that allows for widespread use. A utilitarian approach is needed, where complex regimens that benefit relatively few individuals are replaced with therapy that has the potential to reach the most patients. Simplifying treatment and streamlining pathways of care will be essential in reducing the global burden of HCV.
Ongoing HCV development programs should aim to devise treatment regimens that limit the need for extensive evaluation, both before and during therapy. Features of a simplified HCV therapy can be defined as: interferon-free or all oral medications; pan-genotypic coverage; fixed duration of therapy; reduced daily pill burden: limited (if any) requirement of on-treatment monitoring of viral kinetics; good tolerability and efficacy in patients with extensive comorbidities including cirrhosis; and ease of storage and administration. Although this may seem like an unattainable “wish list,” combinations of DAAs with many of these features are currently under investigation, with initial data reporting SVR rates over 90%. Efficacy will soon be at an acceptable level; therefore, the emphasis of development should shift to simplification and standardization of treatment. Although simplicity is a goal, the cost of developing and administering these regimens must also be taken into account. Extremely simple, but expensive, therapy may not be as effective in reducing overall burden of disease as treatment that is slightly more complex and less costly. Balancing cost of therapy with ease of administration will be critical in effectively expanding access to care.
Expansion of Providers
In many parts of the world, including those with more extensive resources such as the U.S., patients with HCV face significant barriers to care. These barriers include effective screening and identification of patients with HCV as well as access to providers who offer HCV care and therapy. Improved methods for screening at-risk populations should be linked with efforts to expand the number of providers who are able to treat HCV. Unless patterns change, even if new diagnoses of HCV are made, referral for treatment to subspecialists and tertiary care centers will remain impractical, expensive, and inefficient. A key element will be to recruit trained, mid-level providers and primary care physicians as new treaters, in addition to expanding the capacity of gastroenterologists, hepatologists, and infectious disease specialists. The World Health Organization (WHO) defines task shifting as a “process whereby specific tasks are moved, where appropriate, to health workers with shorter training and fewer qualifications. By reorganizing the workforce in this way, task shifting can make more efficient use of existing human resources and ease bottlenecks in service delivery.” Task shifting has been endorsed by the WHO in human immunodeficiency virus (HIV) care, and has been shown to provide less costly and noninferior treatment outcomes in resource-limited regions when compared to a traditional physician-based model. In addition, extending HCV care into the primary care setting has been shown to be successful by using telemedicine to equip local physicians with the expertise needed to manage HCV therapy. Similar programs could be implemented globally especially where subspecialty referral is impossible. Broadening the scope to new HCV providers will be dependent on a simpler algorithm of care, which seems highly likely in the near future. Efforts should be made to create policy not only to educate nonspecialist providers in HCV care, but also to incentivize these physicians to treat patients infected with HCV as more efficient therapies evolve.
In conclusion, there has been considerable enthusiasm regarding the use of DAAs to treat HCV. Efforts are being made through increased awareness and recommendations for age-based screening to identify more patients with HCV. However, the current complexity of treatment is a significant therapeutic barrier. Directing resources to support drug development plans to simplify treatment algorithms, even at the expense of optimized SVR rates, in addition to taking creative approaches to expand HCV care into a primary care setting are essential steps in ultimate viral eradication. Complex, individualized care is not the solution for control of the HCV epidemic. True evolution of therapy will likely require broadly available, simple, and accessible treatment.
Andrew Aronsohn, M.D.Donald Jensen, M.D.
University of Chicago Medical Center
Department of Medicine
Section of Gastroenterology, Hepatology and Nutrition
Center for Liver Diseases