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May 2015, Vol 3, No 5 - Inside Patient Care
Lisa Cervantes, PA-C

Approximately 2 million to 4 million people in the United States, and 3% of the world’s population, are thought to be infected with the hepatitis C virus (HCV).1

The estimated number of people infected with HCV is thought to be much lower than the actual number; HCV does not usually cause symptoms, and the patient may not become aware that he or she has been infected for many years.2

HCV is transmitted through the blood, and the most common risk factor in the United States is intravenous (IV) drug use. Many patients with HCV are incarcerated or homeless, and may have poor access to healthcare. Other risk factors include intranasal drug use, blood transfusions (prior to 1992), dialysis, tattoos and body piercings with unsterile instruments, and healthcare occupations.2

Because the human immunodeficiency virus (HIV) is spread in similar ways, many patients are coinfected with HCV and HIV. However, HCV is not readily spread sexually, and only occurs in 7% to 10% of cases.

HCV Screening and Viral Load Tests

Preventive health professionals have recommended that all people with the risk factors for HCV, as well as anyone born between 1945 and 1964, be screened.2 Screening consists of drawing blood to ascertain the presence of HCV antibodies. If the results are negative, no other testing is needed, but if they are positive, the patient has been exposed to the virus,2 and an HCV RNA polymerase chain reaction (viral load) test should be conducted.3 Because HCV can be present in the blood for many years without symptoms, the damage can progress, and patients risk developing fibrosis and cirrhosis.1 Approximately 20% of patients with HCV develop cirrhosis, and, annually, about 1% of the patients with cirrhosis develop hepatocellular carcinoma.1 Because of these risks, pharmaceutical companies and healthcare researchers have been looking for effective treatments for HCV ever since the virus was discovered in 1989.4

HCV Genotypes

Until October 2014, treatment for HCV was based on subcutaneous interferon alfa. Treatment regimens were usually dictated by the patient’s HCV genotype; genotype 1—by far the most common in the United States, at roughly 70% to 75%—was the most difficult to eradicate,5 genotype 2 the easiest, and genotype 3 was somewhere in between. Genotypes 4, 5, and 6 are not seen frequently in the United States.6,7 Patients with chronic neurologic, psychiatric, cardiopulmonary, hematologic, or renal diseases were not eligible for treatment because of possible adverse effects.8 This HCV treatment was less effective in patients who were black, male, aged ≥45 years, coinfected with HIV/HCV, or obese.

Development of New Treatment Regimens

The first patients treated in the early 1990s with interferon monotherapy had a 6% chance of being successfully treated. In the late 1990s, ribavirin tablets were added to the regimen,9 and the chance of sustained virologic response (SVR; defined as no detectable HCV RNA >24 weeks after completion of the treatment10) improved to 40% to 60%.11

In 2001, a pegylated version of interferon alfa was approved by the US Food and Drug Administration (FDA), and the SVR rate improved slightly. Patient adherence improved because the new formulation afforded once- weekly dosing instead of injections 3 times a week.12 Treatment ranged from 24 to 48 weeks in length, and many side effects, such as severe fatigue, loss of appetite, depression and suicidality, muscle and joint pain, anemia, leukopenia, and thrombocytopenia, were common. These adverse events were even more pronounced with the addition of boceprevir or telaprevir, approved by the FDA in 2011.13 Patients on these medications had to be observed very closely, and many required erythropoietin and granulocyte colony-stimulating factor injections.14 Women who could become pregnant and men who could father a child had to be observed carefully because of the teratogenic potential of ribavirin.15

In November and December 2013, simeprevir and sofosbuvir, respectively, were approved by the FDA.16 For the first time, all-oral regimens were available for genotypes 2 and 3. Pegylated interferon alfa and ribavirin were still a part of the approved regimen for genotype 1, although treatment was shortened to 12 weeks instead of the original 24 to 48 weeks. SVR was achieved in >90% of patients, and patients with cirrhosis were treated in the same way as patients without cirrhosis.

At the same time, the COSMOS trial revealed very high SVR rates ranging from 79% to 93% and 93% to 100% in genotype 1 patients treated with sofosbuvir plus simeprevir, with or without ribavirin.5 Although this combination was not approved by the FDA specifically, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommended the sofosbuvir plus simeprevir regimen for genotype 1 patients. The difference between the AASLD/IDSA regimen and the indications approved by the FDA caused significant problems for getting sofosbuvir plus simeprevir approved for patients.

For a 12-week supply, both simeprevir and sofosbuvir had prices in the range of $66,000 to $84,000, respectively, and the combination treatment cost approximately $150,000.17,18 Many insurance companies, as well as Medicare and Medicaid, balked at paying these prices, and most insurers required patients to have compensated cirrhosis (ie, no hepatic encephalopathy, jaundice, ascites19) to be eligible for coverage of treatment with simeprevir or sofosbuvir.

One conclusion of the research conducted to get these medications approved was that genotype 3 was more difficult to treat than previously thought.20 In a study by Zeuzem and colleagues, criteria for SVR in patients receiving sofosbuvir and ribavirin was met in only about 85% of patients after 24 weeks of treatment.21

Harvoni Combination Therapy

In October 2014, Harvoni (ledipasvir and sofosbuvir) was approved by the FDA.22 It is thought to be 99% effective in treating genotype 1 HCV, and is only approved for use in genotype 1 patients. The Harvoni regimens provide significant advantages versus the previouslyused medications. Harvoni is dosed at 1 tablet a day for 8, 12, or 24 weeks.23 For treatment-naïve patients without cirrhosis and with a pretreatment viral load <6 million IU/mL, treatment can last for 8 weeks. In patients where previous treatment has failed and without cirrhosis, treatment lasts for 12 weeks. In patients where previous treatment failed and with cirrhosis, treatment lasts for 24 weeks.

Because there are very few side effects associated with Harvoni, patients tolerate it very well, and their compliance is high.24 Few drug interactions are associated with Harvoni. The most significant ones include several anticonvulsants, rosuvastatin, and other antivirals. Because the ledipasvir component of Harvoni can be absorbed less well in patients who are receiving proton-pump inhibitors or histamine 2 blockers, the recommendation is for the patient to take the proton-pump inhibitors or histamine 2 blockers at the same time as Harvoni, because absorption is decreased at higher gastric pH.

Viekira Pak

In December 2014, Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets packaged with dasabuvir tablets) was approved by the FDA for treating HCV genotype 1.25 This regimen is packaged with very clear instructions for how to take the tablets: 2 tablets, containing ombitasvir, paritaprevir, and ritonavir at 12.5 mg, 75 mg, and 50 mg, respectively, are taken morning and night, and 1 tablet, containing 250 mg of dasabuvir sodium monohydrate, is taken in the morning and at night as well. All of the tablets must be taken with food.26 Genotypes 1a and 1b are treated differently, with ribavirin added only for all genotype 1a patients, and for genotype 1b patients with cirrhosis. Patients with genotype 1a who have cirrhosis are treated for 24 weeks, and patients with other genotype categories receive treatment for 12 weeks.

There are drug interactions with Viekira Pak, including alanine aminotransferase elevations in patients using ethinyl estradiol–containing medications.26 Anticonvulsants and some statins and antivirals can decrease the therapeutic activity of Viekira Pak. Because some patients must receive simultaneous treatment with ribavirin, contraindications and drug interactions of ribavirin must also be noted. Women of childbearing age and their male partners must be warned about the chances for birth defects in children conceived while either parent is taking ribavirin.15 All patients should be monitored for anemia, with intervention taken as needed (ie, if hemoglobin <10.0 g/dL).

Although it is a bit more complicated to use, Viekira Pak has efficacy rates comparable to Harvoni.27 All patient groups⎯other than patients with cirrhosis⎯with genotype 1a had SVR rates of 95% to 96%, and patients with cirrhosis with genotype 1a had an SVR of 89%. Perhaps because of the additional precautions and monitoring needed, Viekira Pak is priced a little lower than Harvoni ($94,500), at about $84,000 for 12 weeks of medication.28

The Future of HCV Treatment

The approvals of Har­voni, sofosbuvir, simeprevir, and Viekira Pak have changed the landscape of HCV treatment, but there is still a lot left to do. Healthcare providers now have potent weapons with which to fight HCV; in the past, limitations to treatment included the patient’s ability to tolerate treatment. Now, the limitations for who can be treated are mostly caused by the cost of the medications. Identification of patients with HCV is essential, and having safe, effective, and affordable medications to treat them is necessary.

Although only 20% of patients with HCV will eventually develop cirrhosis, it has been challenging to predict which individuals will. These patients cost our healthcare system millions of dollars for their management, up to and including liver transplantation. With new outbreaks of IV drug use, more young people are being infected, and may, in turn, spread it to other people. The best outcome for patients, and our healthcare system, would be to consider HCV a public health problem, and eradicate it completely. As long as some individuals are infected, everyone is at risk.




References

  1. World Health Organization. Hepatitis C. Surveillance and control. www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index4.html. Accessed May 5, 2015.
  2. Centers for Disease Control and Prevention. Hepatitis C FAQs for the public. www.cdc.gov/hepatitis/C/cFAQ.htm. Updated April 15, 2015. Accessed May 5, 2015.
  3. US Department of Veterans Affairs. Laboratory tests and hepatitis C. www.hepatitis.va.gov/provider/reviews/laboratory-tests.asp. Accessed May 5, 2015.
  4. Centers for Disease Control and Prevention. Hepatitis C: 25 years since discovery. www.cdc.gov/knowmorehepatitis/media/pdfs/hepc-timeline.pdf. Updated August 22, 2014. Accessed May 5, 2015.
  5. Spach DH, Kim HN. Treatment of HCV genotype 1. www.hepatitisc.uw.edu/go/treatment-infection/treat ment-genotype-1/core-concept/all. Updated January 25, 2015. Accessed May 5, 2015.
  6. Spach DH, Kim HN. Treatment of HCV genotype 4. www.hepatitisc.uw.edu/go/treatment-infection/treat ment-genotype-4/core-concept/all. Updated February 11, 2015. Accessed May 5, 2015.
  7. Spach DH, Kim HN. Treatment of HCV genotype 5 or 6. www.hepatitisc.uw.edu/go/treatment-infection/treatment-genotype-5-or-6/core-concept/all. Updated January 18, 2015. Accessed May 5, 2015.
  8. Wilkins T, Malcolm JK, Raina D, et al. Hepatitis C: diagnosis and treatment. Am Fam Physician. 2010;81:1351-1357.
  9. Jensen DM. Advances in combination regimens in the management of HCV infection. Gastroenterol Hepatol (NY). 2014;10:134-136.
  10. Yee HS, Chang MF, Pocha C, et al. Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Am J Gastroenterol. 2012;107:669-689.
  11. World Health Organization. Pegylated interferon alpha 2a. www.who.int/selection_medicines/com mittees/expert/19/applications/Pegyinterferon_6_4_3_A_Ad.pdf. Accessed May 6, 2015.
  12. Ward RP, Kugelmas M. Using pegylated interferon and ribavirin to treat patients with chronic hepatitis C. Am Fam Physician. 2005;72:655-662.
  13. Tungol A, Rademacher K, Schafer JA. Formulary management of the protease inhibitors boceprevir and telaprevir for chronic hepatitis C virus. J Manag Care Pharm. 2011;17:685-694.
  14. Belperio PS, Backus LI, Ross D, et al. A population approach to disease management: hepatitis C direct-acting antiviral use in a large health care system. J Manag Care Pharm. 2014;20:533-540.
  15. Copegus [package insert]. San Francisco, CA: Genentech, Inc; 2002.
  16. US Food and Drug Administration. FDA approves Sovaldi for chronic hepatitis C. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm377888.htm. Updated October 1, 2014. Accessed May 6, 2015.
  17. Hepatitis C Online. Simeprevir (Olysio). www.hepatitisc.uw.edu/pdf/page/treatment/drugs/simeprevir-drug. Accessed May 6, 2015.
  18. Hepatitis C Online. Sofosbuvir (Sovaldi). www.hepatitisc.uw.edu/pdf/page/treatment/drugs/sofosbuvir-drug. Accessed May 6, 2015.
  19. Thornton K. Evaluation and prognosis of patients with cirrhosis. www.hepatitisc.uw.edu/pdf/evaluation-stag ing-monitoring/evaluation-prognosis-cirrhosis/core-concept/all. Updated February 3, 2014. Accessed May 6, 2015.
  20. Tapper EB, Afdhal NH. Is 3 the new 1: perspectives on virology, natural history and treatment for hepatitis C genotype 3. J Viral Hepat. 2013;20:669-677.
  21. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014;370:1993-2001.
  22. US Food and Drug Administration. FDA approves first combination pill to treat hepatitis C. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418365.htm. Updated October 10, 2014. Accessed May 6, 2015.
  23. Gilead Sciences Inc; Gilead Sciences Canada, Inc. Product monograph. Harvoni (ledipasvir/sofosbuvir) tablets. www.gilead.ca/pdf/ca/harvoni_pm_english.pdf. Published October 14, 2014. Accessed May 6, 2015.
  24. Gilead Sciences Inc. Application for inclusion of ledipasvir/sofosbuvir (Harvoni) tablets on the WHO Model List of Essential Medicines. www.who.int/selection_medicines/committees/expert/20/applications/LedipasvirFDC.pdf. Published November 28, 2014. Accessed May 6, 2015.
  25. US Food and Drug Administration. FDA approves Viekira Pak to treat hepatitis C. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427530.htm. Updated December 22, 2014. Accessed May 6, 2015.
  26. Viekira Pak [package insert]. North Chicago, IL: AbbVie Inc; 2014.
  27. Gritsenko D, Hughes G. Ledipasvir/sofosbuvir (Harvoni): improving options for hepatitis C virus infection. PT. 2015;40:256-276.
  28. Loftus P. FDA approves AbbVie’s hepatitis treatment. The Wall Street Journal. www.wsj.com/articles/fda-approves-abbvies-hepatitis-treatment-1419019392. Published December 19, 2014. Accessed May 6, 2015.
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