Abstract
Chronic hepatitis C virus (HCV) infection is a major cause of cirrhosis and hepatocellular carcinoma worldwide1 and the leading indication for liver transplantation in the adult United States population.2 Although the incidence of chronic HCV infection is declining, the number of deaths is projected to rise over the next decade.3 Hence, the major reason for treating chronic HCV infection is to mitigate the morbidity and mortality associated with the infection but also to alleviate patient symptoms and to prevent person-to-person transmission. Successful eradication or virological cure is possible and a reduction in liver-related outcomes has been demonstrated in patients with advanced liver disease who achieve this desirable endpoint.4–6
Keywords: Hepatitis C Virus, Natural History, Cost, Treatment
Despite these facts, only 7% to 11% of patients are treated based on an analysis conducted by the Division of Viral Hepatitis at the Centers for Disease Control and Prevention of two large datasets containing more than 18,000 subjects.7 This is partly because treatment of chronic HCV infection has been challenging for both the patient and healthcare provider. Available regimens were complex to administer, of long duration, associated with substantial toxicity and moderately effective in that only ~50% of patients with the most common genotype of the virus-HCV genotype 1 responded. Patients had to be carefully selected for therapy. Only those with more advanced liver disease based on a liver biopsy with a reasonable likelihood of responding to treatment, with limited comorbid conditions and who could be expected to tolerate treatment were recommended for therapy.8 All others, particularly those with mild disease, were advised to be followed perhaps with a repeat liver biopsy every five years to reassess the need for treatment. Consequently, many infected individuals were ineligible to receive therapy due to contraindications or if treated, had to prematurely discontinue therapy due to intolerance or opted not to receive therapy preferring to wait for the promise of safer, more effective treatment.
The other reason for the low treatment rate was related to our understanding of the natural history of chronic HCV infection. Liver disease is thought to progress slowly in the majority of patients, particularly if certain factors that can accelerate fibrosis progression are absent such as older age at infection, male sex, heavy alcohol consumption, obesity, insulin resistance and co-infection with HIV or HBV.9–11 It is estimated that approximately 25% of individuals will progress to cirrhosis or decompensated liver disease over a period of 25–30 years.9 Therefore, treating a patient early in the course of their disease would expose them to unnecessary toxicity and complications from treatment with unproven benefit on outcome of their liver disease.
In this issue of JAMA, Butt and Colleagues report rather provocative results from an analysis of a VA database which suggests that after infection with HCV, patients may experience a more rapid progression of liver fibrosis and accelerated time to development of cirrhosis than previously thought. However, once cirrhosis develops, the disease appears to stabilize and the development of hepatic decompensation in the first 10 years is infrequent.
Does this mean that we should change our approach to treatment and recommend therapy for patients earlier in the course of their disease? Before addressing this question, we need to revisit the current state of therapy. Therapy of chronic HCV infection is at a watershed moment. Multiple oral agents have been developed that specifically target key viral proteins necessary for the viral lifecycle and tested in different combinations for variable durations ranging from 12 to 24 weeks.12–17 These new regimens are highly effective and increase the response rate from approximately 50% to >90%. More importantly, these new treatment regimens have become much simpler to administer, safer and more tolerable with minimal side effects.
So given this interesting data on natural history coupled with the prospect for more effective and safer therapies, effectively removing many of the previous barriers to therapy, one may make a strong argument for treating everyone. Why delay therapy when we are unsure how best to monitor untreated patients and accurately identify patients who are at risk for disease progression thereby allowing the disease to advance which may adversely affect future response rates and increase the risk of complications from the disease? In response, there are several epidemiological studies indicating that most individuals with hepatitis C will die with rather than from their infection.18–20 Furthermore, evidence of the benefits of treating patients with mild disease is lacking and the new impediment to treatment is now the cost of therapy. The recently approved oral agents sofosbuvir, a HCV polymerase inhibitor, costs $84,000 dollars for a 12-week course equating to about $1,000.00 per pill21 and simeprevir, a HCV protease inhibitor, $66,000 for 12 weeks or approximately $786.00 per pill.22 The price of these new drugs has not escaped the attention of policy makers or insurers. A recent analysis conducted for the Pharmaceutical Care Management Association estimated that the cost of new HCV drug therapies will increase 2015 federal spending on the individual Medicare Part D program by approximately $2.9 billion to $5.8 billion.23 This is equivalent to a 6% to 11% increase in federal Part D spending or approximately $100 to $200 per Medicare Part D beneficiary per year.23 Officials for the State Medicaid plans have cautioned that the cost of the new treatments will place substantial financial burden on Medicaid budgets.24 Major news organizations reported that three states Colorado, Illinois and Pennsylvania, have already implemented specific criteria to permit use of the drugs only in patients with the most advanced stage of liver disease while limiting treatments for patients with a history of drug use and alcohol abuse.25,26 So the bottom line is even if we wanted to treat everyone we simply could not afford to.
It is somewhat ironic that with more effective and safer therapy we are still debating who to treat but this is the current state of affairs surrounding treatment of hepatitis C. So clinicians are faced yet again with the situation of having to prioritize who should receive treatment but for different reasons. Who are the patients that are most likely to benefit from therapy? Patients with the greatest risk for disease progression i.e. those with advanced liver disease, patients co-infected with HIV or HBV and patients who have received a liver transplant who are at risk for recurrent cirrhosis or graft failure should be given priority.27 Not many would argue with this list. A somewhat more controversial group are individuals who have a high risk of transmitting the infection these include men who have sex with men, active injection drug users, incarcerated persons and persons on long-term hemodialysis.27 Treatment in this case serves a dual purpose; it benefits the individual as well as society. Practitioners have been reluctant to treat these persons because of their high risk for re-infection. For the time being the decision to treat other patients should be individualized. Patients who are not treated should be closely monitored for disease progression using liver biopsy, non-invasive testing or a combination of the two. However, this is not an exact science and it is possible some patients may progress despite our best intentions. Until the issue of cost associated with these new treatments is resolved, the debate on who should receive treatment will rage on.
Acknowledgements:
This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.
References:
- 1.Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. December 15 2012;380(9859):2095–2128. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.2009 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1999–2008. U.S. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation; 2010. [Google Scholar]
- 3.Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. February 2010;138(2):513–521, 521 e511–516. [DOI] [PubMed] [Google Scholar]
- 4.van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA : the journal of the American Medical Association. December 26 2012;308(24):2584–2593. [DOI] [PubMed] [Google Scholar]
- 5.Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of internal medicine. November 20 2007;147(10):677–684. [DOI] [PubMed] [Google Scholar]
- 6.Bruno S, Stroffolini T, Colombo M, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology. March 2007;45(3):579–587. [DOI] [PubMed] [Google Scholar]
- 7.Holmberg SD, Spradling PR, Moorman AC, Denniston MM. Hepatitis C in the United States. The New England journal of medicine. May 16 2013;368(20):1859–1861. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Ghany MG, Strader DB, Thomas DL, Seeff LB, American Association for the Study of Liver D. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. April 2009;49(4):1335–1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Seeff LB. Natural history of chronic hepatitis C. Hepatology. November 2002;36(5 Suppl 1):S35–46. [DOI] [PubMed] [Google Scholar]
- 10.Kenny-Walsh E Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. The New England journal of medicine. April 22 1999;340(16):1228–1233. [DOI] [PubMed] [Google Scholar]
- 11.Wiese M, Fischer J, Lobermann M, et al. Evaluation of liver disease progression in the German hepatitis C virus (1b)-contaminated anti-D cohort at 35 years after infection. Hepatology. January 2014;59(1):49–57. [DOI] [PubMed] [Google Scholar]
- 12.Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. The New England journal of medicine. May 15 2014;370(20):1889–1898. [DOI] [PubMed] [Google Scholar]
- 13.Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. The New England journal of medicine. April 17 2014;370(16):1483–1493. [DOI] [PubMed] [Google Scholar]
- 14.Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. The New England journal of medicine. May 22 2014;370(21):1983–1992. [DOI] [PubMed] [Google Scholar]
- 15.Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. The New England journal of medicine. April 24 2014;370(17):1604–1614. [DOI] [PubMed] [Google Scholar]
- 16.Manns M, Pol S, Jacobson IM, et al. All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet. July 26 2014. [DOI] [PubMed] [Google Scholar]
- 17.Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet. July 26 2014. [DOI] [PubMed] [Google Scholar]
- 18.Guiltinan AM, Kaidarova Z, Custer B, et al. Increased all-cause, liver, and cardiac mortality among hepatitis C virus-seropositive blood donors. American journal of epidemiology. March 15 2008;167(6):743–750. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Seeff LB, Miller RN, Rabkin CS, et al. 45-year follow-up of hepatitis C virus infection in healthy young adults. Annals of internal medicine. January 18 2000;132(2):105–111. [DOI] [PubMed] [Google Scholar]
- 20.Just SA, Grau K, Georgsen J, et al. Long-term follow-up among Danish transfusion recipients identified in the national hepatitis C lookback. Transfusion. March 2012;52(3):582–588. [DOI] [PubMed] [Google Scholar]
- 21.Sofosbuvir (Sovaldi) for chronic hepatitis C. The Medical letter on drugs and therapeutics. January 20 2014;56(1434):5–6. [PubMed] [Google Scholar]
- 22.Simeprevir (Olysio) for chronic hepatitis C. The Medical letter on drugs and therapeutics. January 6 2014;56(1433):1–3. [PubMed] [Google Scholar]
- 23.http://us.milliman.com/uploadedFiles/insight/2013/healthcare-reform-hepatitis-c.pdf. Accessed August 4th, 2014.
- 24.http://www.washingtonpost.com/blogs/wonkblog/wp/2014/04/28/an-84000-hepatitis-drug-is-giving-states-and-insurers-a-major-headache/. Accessed August 4th, 2014.
- 25.http://www.bloomberg.com/news/2014-03-05/hepatitis-c-drug-price-limiting-state-medicaid-approvals.html. Accessed Auguts 4th, 2014.
- 26.http://online.wsj.com/articles/how-illinois-allocates-84-000-drug-for-hepatitis-c-1407114940. Accessed August 4th, 2014.
- 27.http://www.hcvguidelines.org/. Accessed August 8th, 2014.