When is it appropriate to delay a potentially lifesaving treatment? Should treatment decisions be based purely on economic grounds? In the United States, these questions confront payers and government programs covering patients with hepatitis C virus (HCV) infection. New, highly effective oral treatments for this serious infection have recently received food and drug administration (FDA) approval in the U.S. but their list prices make immediate treatment of all infected patients infeasible. In response, many payers have instituted coverage policies that authorize treatment only for the sickest patients, putting off therapy for less severely ill patients. However, new data suggests that this approach may constitute a suboptimal policy, if not carefully executed. While not all patients require immediate treatment, an optimal strategy should treat patients before they progress too far towards end-stage disease; beyond the point when even highly effective treatments can confer only diminished benefit. Minimally invasive clinical markers of disease progression should be monitored to help guide when treatment should be initiated.
Hepatitis C is an infection of the liver caused by the HCV, which is generally transmitted by blood-to-blood contact. Historically, HCV was spread through blood transfusions but thanks to universal screening the current most frequent mode of infection relates to drug abuse and dirty needles [
1- Denniston Maxine M.
- et al.
Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010.
,
2Centers for Disease Control and Prevention. Viral hepatitis: hepatitis C FAQs for health professionals [Internet]. Atlanta (GA): CDC; [last updated 2015 May 31; accessed 2015 Jul 10]. Available from: http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm.
,
,
4- Yaphe S.
- Bozinoff N.
- Kyle R.
- Shivkumar S.
- Pai N.P.
- Klein M.
Incidence of acute hepatitis C virus infection among men who have sex with men with and without HIV infection: a systematic review.
,
5- Suryaprasad A.G.
- White J.Z.
- Xu F.
- Eichler B.A.
- Hamilton J.
- Patel A.
- et al.
Emerging epidemic of hepatitis C virus infections among young nonurban persons who inject drugs in the United States, 2006–2012.
]. HCV affects approximately 130–170 million persons worldwide [
[6]The global burden of hepatitis C.
] and roughly 2.7 million Americans [
1- Denniston Maxine M.
- et al.
Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010.
,
7Evolving epidemiology of hepatitis C virus in the United States.
,
8The changing epidemiology of hepatitis C virus infection in the United States: National Health and Nutrition Examination Survey 2001 through 2010.
].
Patients with chronic hepatitis C (CHC) are generally asymptomatic and so remain unaware of their illness until a diagnosis is made incidentally, or severe liver disease develops [
9- Denniston M.M.
- Klevens R.M.
- McQuillan G.M.
- Jiles R.B.
Awareness of infection, knowledge of hepatitis C, and medical follow-up among individuals testing positive for hepatitis C: National Health and Nutrition Examination Survey 2001–2008.
,
10- Smith B.D.
- Morgan R.L.
- Beckett G.A.
- Falck-Ytter Y.
- Holtzman D.
- Teo C.G.
- et al.
Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965.
]. Approximately 20–30% of infected patients will develop cirrhosis after 20 years [
[6]The global burden of hepatitis C.
]. Once cirrhosis occurs, hepatocellular carcinoma (HCC) develops in approximately 4% of these patients per year [
[11]Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease.
]. Overall, liver complications represent a substantial public health burden. Although screening of the blood supply and drug abuse prevention efforts have helped to dramatically reduce the incidence of new hepatitis C infections, the aging population of already infected patients steadily experiences severe HCV complications such as cirrhosis, liver failure, hepatocellular carcinoma, and death [
12The natural history of hepatitis C virus (HCV) infection.
,
13The history of the “natural history” of hepatitis C (1968–2009).
,
14- Butt A.A.
- Wang X.
- Moore C.G.
Effect of hepatitis C virus and its treatment on survival.
,
15Risk factors for the rising rates of primary liver cancer in the United Stats.
,
16- Davis G.L.
- Albright J.E.
- Cook S.F.
- et al.
Projecting future complications of chronic hepatitis C in the United States.
,
17- Rein D.B.
- Wittenborn J.S.
- Weinbaum C.M.
- et al.
Forecasting the morbidity and mortality associated with prevalent cases of pre-cirrhotic chronic hepatitis C in the United States.
,
18- Lee M.H.
- Yang H.I.
- Lu S.N.
- et al.
Chronic hepatitic C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study.
].
Until 2014, treatment for HCV relied on interferon-alpha (IFN-α) based regimens, ordinarily including ribavirin and (more recently) a protease inhibitor – either boceprevir or telaprevir [
[19]Di Bisceglie A, Kuo A, Rustgi V, Sulkowski M. Virological Outcomes and Adherence to Treatment Algorithms in a Longitudinal Study of Patients with Chronic Hepatitis C Treated with Boceprevir or Telaprevir in the U.S. (HCV-TARGET). In: 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), November 1–5; 2013; Washington, DC.
]. Those regimens had numerous unsatisfactory characteristics, including a long duration of treatment (often 24–48 weeks), and severe, nearly universal side effects such as fatigue, flu-like symptoms, and depression [
20- McHutchison J.G.
- Gordon S.C.
- Schiff E.R.
- et al.
Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis.
,
21- Fried M.W.
- Shiffman M.L.
- Reddy R.
- et al.
Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
,
22- Manns M.P.
- McHutchison J.G.
- Gordon S.C.
- et al.
Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial.
]. Needless to say, treatment completion rates were poor, with both dose reduction (35–42%) and discontinuation (14–19%) common [
21- Fried M.W.
- Shiffman M.L.
- Reddy R.
- et al.
Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
,
22- Manns M.P.
- McHutchison J.G.
- Gordon S.C.
- et al.
Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial.
]. Of those that did complete treatment, less than 50% achieved a sustained virologic response (SVR) [
[23]- McHutchison J.G.
- Lawitz E.J.
- Shiffman M.L.
- Muir A.J.
- Galler G.W.
- McCone J.
- et al.
Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection.
]. Our recent analysis of data from the US Veterans Affairs health care system found that only 25% of HCV patients initiated therapy and only 16% of the treated patients achieved any viral response [
[24]McCombs JS, Tonnu-MiHara I, Matsuda T, McGinnis J, Fox S. Can hepatitis C treatment be safely delayed? Evidence from the veterans administration healthcare system. In: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). April 22–26, 2015;S191; Vienna, Austria.
].
Beginning in 2014, novel oral treatment regimens with vastly superior characteristics became available. Unlike the IFN-α regimens, which rely on upregulating the patients’ own immune system, these direct acting agents block various key stages of viral replication. Currently approved drugs include Harvoni (sofosbuvir/ledipasvir), Daklinza (daclatasvir), Olysio (simeprevir), Sovaldi (sofosbuvir), Technivie (ombitasvir, paritaprevir and ritonavir) and Viekira Pak (ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir tablets) [
]. Specific treatment regimens vary, depending on factors such as HCV genotype, and may incorporate multiple drugs (potentially including ribavirin) [
[26]Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus.
]. Recommended treatment intervals are generally 12 weeks for patients without cirrhosis, and 24 weeks for cirrhotic patients. Side effects are much less common, and generally less severe [
27- Jacobson I.M.
- McHutchison J.G.
- Dusheiko G.
- Di Bisceglie A.M.
- et al.
ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection.
,
28- Poordad F.
- McCone Jr, J.
- Bacon B.R.
- et al.
SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection.
]. Treatment success rates are also much higher: SVR rates achieved in FDA Stage 3 clinical trials generally exceeded 90%, although real-world rates may be somewhat lower [
,
30Effectiveness of sofosbuvir-based regimens in genotype 1 and 2 hepatitis C virus infection in 4026 US Veterans.
]. Our previous study using VA data clearly documents that merely attaining an initial viral load response is associated with reduced risk of complications associated with chronic HCV infection, such as cirrhosis, HCC, liver transplant, or death [
[31]The risk of long-term morbidity and mortality in patients with chronic hepatitis C: results from an analysis of data from a Department of Veterans Affairs Clinical Registry.
].
Unfortunately, the cost of these new drugs, at their U.S. Wholesale Acquisition Cost (i.e., list prices), creates both an affordability challenge, and a “value for money” dilemma. While the cost per treated patient remains roughly the same as with the previous interferon based regimens, demand for them is many times higher. The undiscounted price for a 12 week course of Solvaldi is $84,000; for Harvoni it is $95,000. Some regimens also require drug combinations that drive the price still higher. Even if we assume a discounted treatment cost, after price re-negotiation, of $50,000 per patient, treating every HCV positive patient in the U.S. would cost in the order of $200 Billion. This compares to total annual U.S. spending on all prescription drugs of around $300 Billion [
[32]Projecting future drug expenditures-2012.
]. Of course, successful treatment should avert many late HCV complications, but even if treatment actually proves cost saving in the long run, it remains simply too expensive to treat all patients immediately.
This high upfront cost of treatment represents a key barrier, despite the fact that recent studies suggest treatment is generally quite cost-effective. Benefits also include an up to 80% reduction in progression to end-stage complications, such as liver failure, liver cancer, or liver transplantation [
[33]Infectious Diseases Society of America (IDSA)/American Association for the Study of Liver Diseases (AASLD). Published on recommendations for testing, managing, and treating hepatitis C: when, and in whom to initiate HCV Therapy. Available Online at: http://hcvguidelines.org/printpdf/91; 2015a [accessed 10.30.2105. Last updated 8.22.2015].
]. Cost effectiveness studies suggest that for treatment naive patients with genotype 1 infections (the most common genotype), incremental cost effectiveness ratios (ICERs) range from cost saving (i.e., $0/per Quality Adjusted Life-Year (QALY)) up to $31,453/per QALY. Treatment for other genotypes and more complicated treatment scenarios appears less cost-effective, with ICERs often well in excess of $100,000/QALY. However, those ratios improve significantly when price discounts are incorporated [
[34]Infectious Diseases Society of America (IDSA)/American Association for the Study of Liver Diseases (AASLD). Published on recommendations for testing, managing, and treating hepatitis C: overview of cost, reimbursement, and cost-effectiveness considerations for hepatitis C treatment regimens. Available Online at: http://hcvguidelines.org/printpdf/184; 2015b [accessed 10.08.2105. Last updated 8.20.2015].
]. In addition to the direct benefits, large scale HCV treatment should also significantly reduce the incidence of both new infections and re-infections by shrinking the pool of infectious persons who can transmit the disease through needle sharing or other blood-borne contact. One recent modeling study that considered both disease progression and transmission suggested that treating all diagnosed patients (assumed to be 50% of the total HCV infected population) provides the most net economic and health benefits over ten years – significantly exceeding the costs of treatment. Only treating the most severely affected patients, by comparison, generated negative net economic and health benefits. [
[35]Broad hepatitis C treatment scenarios return substantial health gains, but capacity is a concern.
]
Both economic questions – treatment affordability and cost effectiveness – hinge on drug price. This cost conundrum is certainly not unique to HCV drugs. For example, a similar debate is now beginning over coverage for the new PCSK9 inhibitors for elevated cholesterol [
]. The issue is particularly acute in the United States, compared with Europe, given the decentralized structure of our drug markets, and higher average drug prices. The U.S. pricing market is neither transparent, nor efficient: In the U.S., healthcare payers represent a patchwork of private, not for profit, and various governmental entities. Each entity, or their contracted pharmacy benefits manager, must negotiate price discounts with pharmaceutical companies separately. Those price agreements are generally subject to confidentiality clauses. Equally significant, negotiations on price usually require granting that drug ‘preferred’ status, limiting the ability of payers to offer unrestricted access to more than one treatment option. A further complication is that some government entities, especially the Medicare program, are barred from any innovation which restricts open access to services including the implementation of competitive bidding systems. Fortunately, most Medicare part D plans which cover more than 37 million beneficiaries, can negotiate price individually, leading to significant variation in prices paid among the over 1,000 part D plans [
]. In short, while Europe has opted for more global price controls, the U.S. system constitutes a more piecemeal approach to negotiating prices and access. Since demand for drugs is generally quite inelastic (insensitive) to pricing, resulting U.S. drug prices are roughly double those in Europe [
[38]D. Squires and C. Anderson, U.S. Health care from a global perspective: spending, use of services, prices, and health in 13 countries, the commonwealth fund; 2015.
].
Numerous solutions to the U.S. price issue have been proposed. For example, Schulman and colleagues [
[39]- Schulman Kevin A.
- Balu Suresh
- Reed Shelby D.
Specialty pharmaceuticals for hyperlipidemia—impact on insurance premiums.
], when considering the a potential impact on annual drug spending, suggest several options: mandating greater patient cost sharing; instituting direct government negotiation of prices; restricting the indications for covering a drug to only those patients most likely to benefit; adopting international reference (i.e., average) pricing; and promoting re-importation of drugs from lower cost countries. While space precludes a full discussion of each option, implementing any of them in the U.S. would require overcoming significant financial, regulatory, and political challenges.
The issue of when to treat is still further complicated by U.S. payers’ incentives to ‘cost shift’. This is driven by the fact that while the treatment costs needed to ‘cure’ a patient’s HCV infection are incurred immediately, the health and economic benefits accrue much later. Patients often switch between health plans, driven by changes in employment, residence, and program eligibility [
[40]Few Americans switch employer health plans for better quality, lower costs.
]. This creates an incentive for payers to delay treatment for low risk patients – essentially betting that many will dis-enroll before becoming seriously ill. This is a common economic problem, not unique to drug treatment decisions, known by game theorists as the Prisoner’s Dilemma variant of a Nash equilibrium. The solution that has emerged from game theory is to impose a uniform policy on all players, so that while each must pay now, overall they also all receive the large later benefits from that investment. While imposing such a uniform policy on all U.S. healthcare payers for all possible services is neither feasible nor necessary, developing one for HCV treatment certainly merits investigation.
What should such a policy look like? We believe that such a policy should be based on the characteristics both of the disease and of the new but expensive therapies now available. First, not all infected patients require immediate treatment, since many patients will never develop any significant complications, such as cirrhosis of the liver. Second, achieving SVR significantly reduces the risk of serious and costly HCV related events and deaths, especially for patients that have already demonstrated early disease progression. Third, treatment and initial viral response can come too late. Our research using Veterans Affairs (VA) data clearly demonstrated that treatment effectiveness and the risk reductions associated with achieving an initial viral response are diminished if treatment is delayed beyond some point [McCombs
et al., in submission]. Our research also established that a simple index, known as FIB4 [
[41]- Vallet-Pichard A.
- Mallet V.
- Nalpas B.
- et al.
FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and fibrotest.
], which is based on common blood tests, can be used to monitor patient progression, reducing the need for more invasive diagnostic tests, such as liver biopsy. However, establishing the optimal level of the FIB4 at which to initiate therapy remains unresolved. Based on VA data, we estimate that patients with FIB4+ evidence of any significant disease progression represent 45% of the total HCV infected population.
Considering all of these factors, we propose a treatment strategy as follows: If it is not feasible to treat all infected patients, then prioritize treatment for all patients with any evidence of significant disease progression – aiming to treat them all over a 3–5 year period. Start with the most severely ill [i.e., patients with the highest FIB4 scores], then lower the critical FIB4 value over time until all patients with evidence of progression have been treated – down to an appropriate a minimum FIB4 value. From that point forward, screen all known and newly diagnosed HCV cases, and then treat once each patient exceeds this minimum FIB4 value. Using FIB4 is not the only possible minimally invasive screening strategy, but it is evidence based, straightforward to implement, and potentially quite effective.
What seems clear is that we need a policy, now, that expands eligibility beyond just the sickest – offering patients treatment before their liver damage becomes irreversible. While it may be financially infeasible to treat all HCV patients immediately, adopting this proposed strategy appears likely to optimize patient health outcomes, while limiting overall cost. Put most succinctly, the approach is this: Treat everyone who needs treatment, as soon as they need treatment, but not before they need it.
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Article info
Publication history
Published online: February 11, 2016
Accepted:
February 4,
2016
Received in revised form:
January 28,
2016
Received:
November 14,
2015
Copyright
© 2016 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
