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Hepatitis C

The high cost of effective treatment presents ethical dilemmas

Learning Objectives:
1. Understand the six genotypes related to hepatitis C virus (HCV).
2. List the medications and treatment options for the 6 genotypes of HCV.
3. Describe the testing for HCV and requirements for treatment.  

In 2015, an estimated 3.5 million people in the United States were diagnosed with the hepatitis C virus (HCV). Between 15% and 25% of people infected with HCV clear the virus without treatment, while 75% to 85% become chronically ill.1 However, patients can have chronic HCV for decades without experiencing signs and symptoms. Chronic HCV eventually results in liver damage and cirrhosis.

The CDC recommends HCV screening for all patients who:

  • were born between 1945 and 1965
  • injected illegal drugs at any time
  • received clotting factors before 1987
  • received blood transfusions or solid organ transplants before July 1992
  • received long-term hemodialysis treatment
  • have been diagnosed with HIV
  • are healthcare workers who experienced a needle stick involving an HCV-positive patient
  • have signs and symptoms of liver disease
  • are children of HCV
  • positive mothers (tested after age 18 months).

People born between 1945 and 1965 are five times more likely to be infected with HCV than anyone else.2 Adults born in this time frame make up 75% of people with HCV. Experts predict that one-time testing of everyone born in these years could prevent more than 120,000 deaths and would identify approximately 800,000 undiagnosed cases of HCV.2

Genotypes

HCV has six genotypes that have evolved over many years. A genotype is the strain of HCV a person was exposed to when he or she became infected, and it is possible to be infected with more than one genotype. Genotypes are of clinical importance for treatment but not a significant influence on liver disease progression. Genotype can be confirmed with a simple blood test.

Approximately 75% of infected people in the United States have HCV genotype 1, 20% to 25% have genotype 2 or 3, and a small percentage has genotype 4, 5 or 6.3 Genotype 4 is more prevalent in Africa and the Middle East, but it is emerging in Europe among injection drug users and men having sex with men.3 Genotype 5 is more prevalent in South Africa, and genotype 6 is more common in Southeast Asia. Patients with genotypes 2 and 3 are at least two times as likely as patients with genotype 1 to achieve a sustained virologic response (SVR) to previous treatment therapy.³ SVR is used more than any other efficacy endpoint in clinical studies of HCV, and signifies the elimination of HCV from the body.

New HCV Treatments

The HCV treatments that have become available in the past 5 years are second-generation direct-acting antiviral (DAA) agent therapies. These treatments are highly effective, safer and better tolerated than prior therapies. In premarket clinical trials, they have achieved an SVR of 90% or greater.3 The regimen for DAA treatment ranges from 12 weeks to 24 weeks. Dosing does not need to be continued once the regimen is complete and the SVR goal is achieved. This improved HCV therapy could potentially reduce the public health burden of chronic liver disease by eradicating chronic HCV and subsequent cirrhosis.4,5

The DAAs available in September 2016 are ribavirin, sofosbuvir, ledipasvir, daclatasvir, simeprevir, paritaprevar, grazoprevir, velpatasvir, ombitasvir, ritonavir, and elbasvir used alone or in combination.4,5

Treatment Options Based on Genotype           

This section summarizes the treatment approaches recommended by American Association for the Study of Liver Disease (AASLD) and the Infectious Diseases Society of America (IDSA).

Treatment options for genotype 1 treatment-naïve patients:

  • Ledipasvir-sofosbuvir (Harvoni) 90 mg/400 mg fixed-dose treatment for 8 weeks for patients without cirrhosis, 12 weeks for patients with cirrhosis. SVR 94% to 100% with or without cirrhosis.5-9
  • Ombitasvir-paritaprevir-ritonavir plus dasabuvir fixed-dose treatment with weight-based ribavirin (≤ 75 kg to 1,000 mg and ≥ 75 kg to 1,200 mg) for subtype 1a without cirrhosis for 12 weeks, and 24 weeks for subtype 1a with cirrhosis. Subtype 1b should be treated for 12 weeks without ribavirin regardless of the presence of cirrhosis. SVR > 95%.5,7,10
  • Simeprevir plus sofosbuvir 150 mg/400 mg combination treatment for 12 weeks without cirrhosis, 24 weeks with cirrhosis. SVR exceeds 90%.5,7,11,12
  • Daclatasvir plus sofosburvir 60 mg/400 mg for 12 weeks without cirrhosis. The with cirrhosis regimen has not been studied.5,7,13
  • Elbasvir plus grazoprevir 50 mg/100 mg fixed dose combination treatment for 12 weeks for patients with or without cirrhosis. SVR < 95%.5,7
  • Sofosbuvir plus velpatasvir 400 mg/100 mg fixed dose combination treatment for 12 weeks for patients with or without cirrhosis. SVR 98% to 99%.5,7

Treatment options for genotype 1 treatment-experienced (prior peginterferon and ribavirin failure) patients:

  • Ledipasvir-sofosbuvir (Harvoni) 90 mg/400 mg fixed-dose treatment for 12 weeks without cirrhosis, 24 weeks with cirrhosis. SVR 94%.5-9
  • Ombitasvir-paritaprevir-ritonavir plus dasabuvir fixed-dose treatment with weight-based ribavirin (≤ 75 kg to 1,000 mg and ≥ 75 kg to 1,200 mg) subtype 1a without cirrhosis for 12 weeks; 24 weeks with cirrhosis. Subtype 1b without ribavirin regardless of the presence of cirrhosis for 12 weeks. SVR > 94%.5,7,10
  • Simeprevir plus sofosbuvir 150 mg/400 mg combination treatment for 12 weeks without cirrhosis, 24 weeks with cirrhosis. SVR exceeds 90%.5,7,11,12
  • Daclatasvir plus sofosburvir 60 mg/400 mg for 12 weeks without cirrhosis. The with cirrhosis regimen has not been studied.5,7,13
  • Elbasvir plus grazoprevir 50 mg/100 mg fixed-dose combination treatment for 12 weeks for patients with or without cirrhosis. SVR < 95%.5,7
  • Sofosbuvir plus velpatasvir 400 mg/100 mg fixed-dose combination treatment for 12 weeks for patients with or without cirrhosis. SVR 98% to 99%.5,7

Treatment options for genotype 2:

  • Sofosbuvir and weight-based ribavirin is the preferred treatment for most patients with genotype 2, regardless of whether the patient is treatment-naïve or treatment-experienced. SVR 97%.5,12,14

Treatment options for genotype 3 treatment-naïve patients:

  • Daclatasvir plus sofosbuvir for 12 weeks without cirrhosis. SVR 98%.5,13,14
  • Daclatasvir plus sofosbuvir plus weight-based ribavirin for 12 weeks with cirrhosis. SVR unknown.5,13,14

Treatment options for genotype 3 treatment-experienced patients:

  • Daclatasvir plus sofosbuvir for 12 weeks without cirrhosis. SVR 92%.5,13,14
  • Daclatasvir plus sofosbuvir plus weight based ribavirin for 12 weeks with cirrhosis. SVR unknown.5,13,14

Treatment options for genotype 4 treatment-naïve patients:

  • Ledipasvir-sofosbuvir (Harvoni) 90 mg/400 mg fixed-dose treatment for 12 weeks without or with cirrhosis. SVR 96%.5,8,15
  • Ombitasvir-paritaprevir-ritonavir fixed-dose treatment with weight-based ribavirin (≤ 75 kg to 1,000 mg and ≥ 75 kg to 1,200 mg) without cirrhosis for 12 weeks. With cirrhosis has not been tested. SVR is 100% without cirrhosis.5,10,15
  • Sofosbuvir and weight-based ribavirin (≤ 75 kg to 1,000 mg and ≥ 75 kg to 1,200 mg) for 24 weeks regardless of presence of cirrhosis. SVR 100%.5,12,15
  • Sofosbuvir plus velpatasvir 400 mg/100 mg fixed-dose combination treatment for 12 weeks for patients with or without cirrhosis. SVR 98% to 99%.5,7

Treatment options for genotype 4 treatment-experienced patients:

  • Ledipasvir-sofosbuvir (Harvoni) 90 mg/400 mg fixed-dose treatment for 12 weeks without or with cirrhosis with a 91% SVR.5,8,15
  • Ombitasvir-paritaprevir-ritonavir fixed-dose treatment with weight-based ribavirin (≤ 75 kg to 1,000 mg and ≥ 75 kg to 1,200 mg) without cirrhosis for 12 weeks. With cirrhosis has not been tested. SVR is 100% without cirrhosis.5,10,15
  • Sofosbuvir and weight-based ribavirin (≤ 75 kg to 1,000 mg and ≥ 75 kg to 1,200 mg) for 24 weeks regardless of presence of cirrhosis. SVR 87%.5,12,15
  • Sofosbuvir plus velpatasvir 400 mg/100 mg fixed dose combination treatment for 12 weeks for patients with or without cirrhosis. SVR 98% to 99%.5,7

Treatment options for genotype 5 and 6:

  • Ledipasvir-sofosbuvir (Harvoni) 90 mg/400 mg fixed-dose treatment for 12 weeks for treatment-naïve and treatment-experienced patients without or with cirrhosis. SVR 95%.5,8,15 algo
  • Sofosbuvir plus velpatasvir 400 mg/100 mg fixed-dose combination treatment for 12 weeks for patients with or without cirrhosis. SVR 98% to 99%.5,7

Cost of DAA Treatment

The cost of DAA treatment for HCV is high. Without insurance to cover most or all of the costs involved, the majority of HCV patients could not afford the new treatments. Six companies are active in the development of HCV medications: AbbVie, Bristol-Myers Squibb, Gilead, Johnson & Johnson, Merck and Co, and Roche. It is the responsibility of government agencies, insurers, multilateral agencies and nongovernment organizations to ensure accessibility to effective treatments for HCV.16

Pharmaceutical companies could help improve accessibility to DAA medications by ensuring affordability. The guidelines by AASLD and IDSA state that "Although the wholesale acquisition costs of HCV drugs often make treatment appear unaffordable, the reality is that insurers, pharmacy benefit managers and government agencies negotiate pricing and few actually pay the much-publicized retail price. However, the negotiated pricing and cost structure for pharmaceutical products in the United States are not transparent, and it is therefore difficult to estimate the true cost and cost-effectiveness of HCV drugs. Whatever the actual current cost of HCV DAAs, competition and negotiated pricing have not improved access to care for many persons with HCV infection and continue to limit the public health impact of these new therapies. Insurers, government and pharmaceutical companies should work together to bring medication prices to the point where all of those in need of treatment are able to afford and readily access it."5

The current high prices for DAAs could deter donors, health insurers and governments from providing enough funds to curb the HCV epidemic. Out-of-pocket affordability is critical to patients. Manufacturers can formulate generic medications to generate competition for the current DAA manufacturers and drive costs down.6

The price for a 12-week course of sofosbuvir in the United States is $84,000.6 A higher-volume/lower-priced approach is in the works, due to expanding competition. Current U.S. production of the drug costs $68 to $136 for a 12-week course.6

The Centers for Medicare and Medicaid Services (CMS) requires all states to provide 100% coverage for DAA drugs, as stated in section 1927 (d)(4) and 1927(d)(4)(C) of the Social Security Act. Each state has individual stipulations on coverage approval. The requirement for abstinence from illegal drugs and/or alcohol can range from none to 12 months.17,18 Some states have limited the availability of treatment to patients with liver damage stage F3; others only cover F4 liver damage. Another restriction on Medicare/Medicaid coverage is that prescriptions are to be prescribed by a gastroenterologist, hepatologist, liver transplant specialist or an infectious disease specialist, or in consultation with one (and this must be documented).16

If a pharmaceutical manufacturer offers a rebate on DAA medication, by law the drug must be available in state Medicaid programs. This raises the issue of whether current state restrictions are violating the federal Medicaid law.17

The cost breakdown for current HCV DAA treatments is as follows (as of 2016):

  • Ledipasvir-sofosbuvir: 12 weeks for $94,500 and 24 weeks for $189,000. Gilead offers a patient and prescriber assistance program for patients with no insurance or Medicaid or Medicare coverage.8 
  • Ombitasvir-pavitaprevir-ritonavir plus dasabuvir: 12 weeks for $83,319 and 24 weeks for $166,638. AbbVie has an assistance program.10
  • Daclatasvir plus sofosbuvir: 12 weeks for $147,000. Bristol-Myers Squibb and Gilead offer patient assistance programs.13
  • Simeprevir plus sofosbuvir: 12 weeks for $150,000. Janssen offers a prescription assistance program.11
  • Daclatasvir plus sofsbuvir plus ribavirin: $147,550 for 12 weeks. Bristol-Myers Squibb, Gilead, Copegus, Rebetol and Ribasphere offer prescription assistance.13
  • Sofosbuvir plus ribavirin: 12 weeks for $84,850. Gilead, Copegus, Rebetol and Ribasphere offer assistance programs.12
  • Elbasvir plus grazoprevir: 12 weeks for $54,600. Merck offerx assistance programs.18

The differences in costs for HCV treatment around the world are dramatic. For example, a 12-week regimen of sofosbuvir in the United States is $84,000, while in Egypt the same regimen costs 900 U.S. dollars. A patent for the branded drug was not approved in India by Gilead, so the manufacturer of a generic sofosbuvir allows India to sell the treatment for 250 U.S. dollars. Gilead estimated that the cost to research and develop sofosbuvir ranged from $100 million to $11 billion. The price of $84,000 for sofosbuvir is based on the lifetime cost to treat a patient with chronic hepatitis C. At that price, Gilead will generate a $200 billion profit.19

Testing and Requirements for Treatment

Although Medicaid has provisions to pay for the new HCV treatments, patients must meet strict stipulations for coverage. Some states have a sobriety requirement, while others may pay only for treatment of the most severe presentations.17 Each insurance plan must be researched on an individual basis. It is a difficult task for providers to know which reimbursements are available through private insurance, Medicaid or Medicare.

With this in mind, ethical issues arise when deciding to test patients for HCV (see figure for a testing algorithm). If a clinician tests a patient and the result is positive for HCV, how will the patient pay for treatment? Does the clinician choose not to recommend testing for HCV in an at-risk patient if it is clear that the patient could never pay for treatments? Making these critical and important decisions is difficult, and the provider and patient must work side by side to determine if testing for HCV is worth the cost of treatment. An asymptomatic patient may decide that HCV testing is not justified, and it is the partnership between patient and clinician that will produce an educated decision that is right for the patient.

 Informed Decision Making

HCV is a potentially life-threatening disease that affects millions of people globally. New DAA treatment options are available that have an SVR > 95%. The cost of these treatments is high. Based on a patient's situation, testing may be recommended as outlined by the CDC. If a patient is tested, the results of the HCV test can determine the need for treatment.

If the results of an HCV test are positive, a decision must be made to treat or not treat. Thorough patient education is necessary to assist in this decision. It is the role of the provider to allow the patient time to absorb the new knowledge, think rationally about the situation and its ramifications, and make an informed decision.

Medicaid, Medicare and many private insurance companies require that treatment is prescribed for the sickest of patients. Medicaid and the prison system argue that patients often move out of the poverty status, and that neither Medicaid nor the prison system should sustain the cost of treating patients with HCV. Private insurance companies argue that patients switch insurance providers often, and that they, too, should not incur the cost of HCV treatment.

Another argument is that approximately 70% of people with HCV will not develop advanced liver cirrhosis or liver cancer, so billions of dollars should not be spent on patients for whom the therapy will not make a difference. This brings an ethical and moral dilemma before healthcare providers, including nurse practitioners. Thus, the motivation of providers to test a population for HCV is slowed tremendously.20

The ethically skewed belief that patients with HCV are of low socioeconomic status and that their behavior somehow excludes them from the right to the resources that could restore their health status is as medically and ethically perverse as the pharmaceutical companies that produce the DAAs and the insurance providers that deny coverage.20

Providers are in a difficult spot when it comes to HCV today. They know that screening and treating patients with HCV could prevent spread of the virus, but they also know that screening can lead to high costs that patients cannot afford.20 Being a partner to patients is crucial when major medical decisions are to be made. Building trust and demonstrating empathy are essential to the formation of the patient-practitioner team. Providers have a moral and ethical responsibility to advocate and represent these patients when insurance and Medicaid place almost impossible stipulations on healthcare and treatment of HCV. Such teams and advocacy result in quality patient-centered care for patients with HCV.

 References

1. Centers for Disease Control and Prevention. Hepatitis C FAQs for health professionals. http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm
2. Centers for Disease Control and Prevention. Hepatitis C testing for anyone born during1945-1965: new CDC recommendations. http://www.cdc.gov/Features/HepatitisCTesting/index.html
3. Chopra S. Characteristics of the hepatitis C virus. UpToDate. 2015. http://www.uptodate.com/contents/characteristics-of-the-hepatitis-c-virus
4. Gurusamy K, et al. Pharmacological treatments for chronic hepatitis C liver disease: a network meta-analysis (protocol). The Cochrane Collaboration. 2015;4. doi:10.1002/14651858.CD011641
5. American Association for the Study of Liver Disease, Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis c. HCV Guidance. 2016. http://www.hcvguidelines.org6 
6. Haley SJ, Kreek MJ. A window of opportunity: maximizing the effectiveness of new HCV regimens in the United States with the expansion of the affordable care act. Am J Pub Health. 2015;105(3):457-463.
7. Edwards DJ, et al. Access to hepatitis c medicines. Bull World Health Org. 2015;93:799-805.
Chopra S, Muir AJ. Treatment regimens for chronic hepatitis c virus genotype 1. UpToDate. 2015. http://www.uptodate.com/contents/treatment-regimens-for-chronic-hepatitis-c-virus-genoptype-1
8. Hepatitis C Online. Ledipasvir-sofosbuvir. http://hepatitisc.uw.edu/page/treatment/drugs/ledipasvir-sofosbuvir
9. U.S. Food and Drug Administration. FDA approves first combination pill to treat hepatitis C 2014. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418365.htm
10. Hepatitis C Online. Ombitasvir-paritaprevir-ritonavir and dasabuvir. http://hepatitisc.uw.edu/page/treatment/drugs/3d  
11.  Hepatitis C Online. Simeprevir. http://hepatitisc.uw.edu/page/treatment/drugs/simeprevir-drug
12. Hepatitis C Online. Sofosbuvir. http://hepatitisc.uw.edu/page/treatment/drugs/sofobuvir-drug
13. Hepatitis C Online. Daclatasvir. http://hepatitisc.uw.edu/page/treatment/drugs/daclatasvir  
14. Chopra S, Graham CS. Treatment regimens for chronic hepatitis c virus genotype 2 and 3. UpToDate. 2015. http://www.uptodate.com/contents/treatment-regimens-for-chronic-hepatitis-c-virus-genoptype-2-and-3
15. Chopra S, Muir AJ. Treatment regimens for chronic hepatitis c virus genotype 4, 5, and 6. UpToDate. 2015. http://www.uptodate.com/contents/treatment-regimens-for-chronic-hepatitis-c-virus-genoptype-4-5-and-6
16. Center for Medicare and Medicaid Services. Assuring Medicaid beneficiaries access to Hepatitis C (HCV) drugs. 2015. https://www.medicaid.gov/Medicaid-CHIP-Program-Information/By-Topics/Benefits/Prescription-Drugs/Downloads/Rx-Releases/State-Releases/state-rel-172.pdf
17. Barua S, et al. Restrictions for Medicaid reimbursement of sofosbuvir for the treatment of hepatitis C virus infection in the United States. Ann Intern Med. 2015;163(3):215-223. 18. Hepatitis C Online. Elbasvir-Grazoprevir. http://www.hepatitisc.uw.edu/page/treatment/drugs/elbasvir-grazoprevir
19. Trooskin SB, et al. Access to costly new hepatitis C drugs: medicine, money, and advocacy. Clin Infect Dis. 2015;61(12):1825-1830.
20. Fleck, L. The ethical challenges raised by hepatitis c drugs. MSU Bioethics. 2014. https://msubioethics.com/2014/10/23/hepatitis-c/

Gretta Langley is a student in the DNP/FNP program at the University of North Florida. She has completed a disclosure statement and reports no relationships related to this article.




 
 

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