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Hepatitis C Treatment

Disease is curable with antiviral therapy in majority of treated patients.

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Learning Scope #400
1 contact hour
Expires Sept. 24, 2014

You can earn 1 contact hour of continuing education credit in three ways: 1) Grade and certificate are available immediately after taking the online test. 2) Send the answer sheet (or a photocopy) to ADVANCE for Nurses, Learning Scope, 2900 Horizon Dr., King of Prussia, PA 19406. 3) Fax the answer sheet to 610-278-1426. If faxing or mailing, allow 30 days to receive certificate or notice of failure. A certificate of credit will be awarded to participants who achieve a passing grade of 70 percent or better.

Merion Matters is an approved provider of continuing nursing education by the Pennsylvania State Nurses Association (No. 221-3-O-09), an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation.Merion Matters is also approved as a provider by the California Board of Registered Nursing (No. 13230) and by the Florida Board of Nursing (No. 3298).

The goal of this continuing education offering is to provide nurses with current information on hepatitis C. After reading this article, you will be able to:

1. Recognize people at risk for hepatitis C infection and understand hepatitis C diagnostic testing.
2. Recommend the approved hepatitis C therapies for naïve patients and treatment-experienced patients.
3. Understand the endpoints of therapy and at what time points to stop therapy due to treatment futility.

The author serves in research, speaking and consultant roles for Merck, Vertex, Genentech, BMS, Gilead and Abbott.


The hepatitis C virus is the most common cause of chronic viral liver disease in the U.S. and the leading indication for liver transplantation. It is estimated more than 6 million Americans have chronic hepatitis C infection. The majority of people exposed to this disease will develop chronic infection and the virus commonly leads to liver fibrosis, cirrhosis and liver cancer.1 The hepatitis C virus, unlike the hepatitis B and human immunodeficiency viruses, is curable with antiviral therapy in the majority of treated patients.

Risk Factors

Hepatitis C is transmitted in a parenteral fashion. The most common risk factor for hepatitis C is intravenous drug use.1 Prior to 1992, transfusion of blood or plasma-derived products was associated with significant risk of transmission of hepatitis C.2 Other potential risk factors for hepatitis C include intranasal cocaine use, tattooing, body piercing, accidental needlestick injury and the sharing of household items.3 Sexual transmission of the hepatitis C virus is uncommon.

Perinatal transmission of hepatitis C may occur in approximately 3-5 percent infants born to mothers infected with hepatitis C.4 Perinatal transmission is associated with two independent risk factors: high viral load at time of delivery and a mother who is HIV-positive. Breastfeeding by mothers with hepatitis C appears to be safe with no reported cases of viral transmission to newborns.5

Other high risk groups for hepatitis C infection include people who received clotting factor concentrates prior to 1987, people on hemodialysis, hemophiliacs, and people who received either a solid organ tumor or a bone marrow transplant prior to 1992.1

The CDC has recently recommended all people born between 1945 and 1965 be screened for hepatitis C infection.6

Natural History

Chronicity is the hallmark of hepatitis C infection. Approximately 15-30 percent of patients exposed to the hepatitis C virus recover spontaneously while the remaining 70-85 percent developed chronic infection. Most patients with chronic hepatitis C infection appear to have mild-to-moderate histological disease. Cirrhosis may develop in as many as 15-30 percent of infected patients. Although fulminant disease is rare in hepatitis C, its occurrence has been reported.7

Presentation & Diagnosis

Most patients with hepatitis C are asymptomatic. If symptoms do occur, the most common complaints are fatigue, abdominal pain, poor appetite, weight loss and pruritus.

The diagnosis of hepatitis C is made when specific testing is requested. The primary care physician generally performs this testing if risk factors are determined or abnormal liver chemistries are noted. Blood banks and life insurance companies routinely test blood donors and applicants for hepatitis C.

The initial test used to evaluate for hepatitis C infection is an anti-hepatitis C antibody (anti-HCV Ab). The antibody test will yield a positive result in current and resolved disease and may not become positive for 3-6 months after exposure, causing a delay in the diagnosis of acute hepatitis C.

A positive anti-HCV Ab requires a polymerase chain reaction for the presence of the hepatitis C virus in the serum (HCV-RNA) test to be obtained.1 A positive HCV-RNA by PCR confirms the diagnosis of chronic hepatitis C infection, regardless of the viral level. Once HCV-RNA is found to be positive, hepatitis C genotyping must be performed.

Eleven major genotypes have been identified and these genotypes can be further subdivided into more than 100 subtypes.8 Genotype distribution is worldwide. However, genotypes 1a and 1b are the most common genotypes in the U.S., accounting for more than 75 percent of all infections.

Genotype 3, less common in the U.S. except in younger intravenous drug users, is highly prevalent on the Indian subcontinent. Genotype 4a accounts for the majority of infection in Egypt. Genotype 4 and 5 are common in South Africa where genotype 5 accounts for more than 50 percent of cases. Genotypes 6-11 are found primarily in Southeast Asia.

Hepatitis C genotype does not appear to affect the rate of disease progression. Genotype is, however, a predictor of response to therapy. Genotype does determine antiviral treatment selection.

Treatment

The primary aim of therapy in hepatitis C is to achieve a sustained viral response, which is defined as an undetectable HCV-RNA 6 months after stopping antiviral therapy. Secondary goals of antiviral therapy include improvement in histology, quality of life and prevention of hepatocellular carcinoma.

Therapy for chronic hepatitis C is selected based upon numerous factors. The two most important factors are the perceived ability of the patient to successfully tolerate therapy and the determination of hepatitis C genotype, which guides treatment selection.

The current FDA-approved regimens for the treatment of hepatitis C genotype 1 are a triple combination therapy of pegylated interferon, ribavirin and a protease inhibitor (boceprevir or telaprevir) or dual therapy with pegylated interferon and ribavirin. Protease inhibitors are not approved for the treatment of genotype 2 and 3 disease. The treatment of choice for genotype 2 and 3 disease is a combination of pegylated interferon and ribavirin for 24 weeks.

Antiviral therapy containing either telaprevir or boceprevir is not FDA-approved for use in patients with decompensated cirrhosis, post-transplantation patients, patients with HIV or children.

Patients being considered for therapy are further categorized into subclasses. By definition, naïve patients have not received previous hepatitis C treatments.

Previously treated patients or treatment-experienced patients are divided into relapsers, partial responders and null responders. Relapse patients are those who had a negative virus at the end of therapy and whose virus recurred after cessation of therapy. Partial responders are those who had at least a 2-log drop in viral load but virus never became undetectable on therapy. Null responders are the group of patients who had less than a 2-log drop in viral load while on therapy. These classifications do not take into account underlying histology. In general, decompensated cirrhotic patients with chronic hepatitis C infection should not be treated with current antiviral therapy.

Boceprevir-Based Therapy

The FDA approved the combination of pegylated interferon, ribavirin and the protease inhibitor boceprevir in May 2011. This therapy was approved for use in patients 18 years of age or older with compensated liver disease, including cirrhosis. The SPRINT-2 trial reported sustained viral response rates of 68 percent in non-black patients and 53 percent in black patients.9

The treatment duration is dependent upon on-treatment response. Patients who have an undetectable HCV-RNA at treatment weeks 8 and 24 are eligible for a 28-week treatment course. Patients with an HCV-RNA level less than 100 IU/mL at week 12 and undetectable HCV-RNA at week 24 should be treated for a total duration of 48 weeks. Any patient with an HCV-RNA level of greater than 100 IU/mL at week 12 or with a positive HCV-RNA at week 24 should be considered a treatment failure and therapy should be discontinued. Continuation of therapy after treatment failure may lead to the development of resistant strains of the hepatitis C virus. All patients with cirrhosis are treated for a total of 48 weeks and are not eligible for a shortened course of therapy.10

All patients started on this regimen are started on a 4-week lead-in phase of either pegylated interferon alfa 2a or 2b given subcutaneously and ribavirin given orally twice a day at a total daily dose of 800-1,200 mg. At the start of week 5, boceprevir is added to the regimen at a dose of 800 mg 3 times a day. Boceprevir should be taken with a light meal or snack. In patients with undetectable HCV-RNA at treatment weeks 12 and 24, this triple therapy is continued to treatment week 28 and all three medications are discontinued. In those patients who had a positive HCV-RNA at week 12 and are undetectable at week 24, triple therapy is continued up to week 36. At week 36, boceprevir is discontinued and pegylated interferon and ribavirin are continued for 12 more weeks and these medications are stopped at week 48.

In patients with cirrhosis, the regimen of therapy is a 4-week lead-in of pegylated interferon and ribavirin followed by 36 weeks of triple therapy with pegylated interferon, ribavirin and boceprevir.

The most common side effects seen with this regimen are anemia, neuropsychiatric symptoms, fatigue, headache and dysgeusia.

Telaprevir-Based Therapy

In May 2011, the FDA also approved the triple combination therapy of pegylated interferon, ribavirin and the protease inhibitor telaprevir for the treatment of adults, including those with compensated cirrhosis with chronic hepatitis C, genotype 1. The ADVANCE trial published in the New England Journal of Medicine reported a 75 percent sustained viral response rate in naïve patients treated with this triple regimen.11

Sustained viral response was reported by race and ethnicity in the Illuminate trial: 74 percent for Caucasians, 60 percent for blacks and 67 percent for Hispanics.12

The treatment duration is dependent upon on-treatment response. Patients who have an undetectable HCV-RNA level at 4 and 12 weeks of therapy are eligible for a 24-week treatment course. Those that have an HCV-RNA level of less than 1,000 IU/mL at weeks 4 and 12 and have an undetectable viral load at 24 weeks are treated for a total duration of 48 weeks. All cirrhotic patients are treated for 48 weeks and do not qualify for a shortened course of treatment. Patients with an HCV-RNA level of greater than 1,000 IU/mL at either week 4 or 12 of treatment or who have detectable HCV-RNA at week 24 of therapy are considered treatment failures and therapy must be discontinued. Continuation of therapy once treatment has been a failure and considered futile may result in the development of viral mutations, making further therapy more complex.13

The treatment regimen of this triple therapy is as follows: For the first 3 months of therapy, pegylated interferon alfa 2a or 2b is given as a subcutaneous injection once a week, ribavirin is given orally twice daily at a dose of 800-1,200 mg, and telaprevir is given orally at a dose of 750 mg every 8 hours. Telaprevir must be taken with a 20 g fat meal for adequate absorption. At the end of the first 3 months of therapy, telaprevir is stopped and the pegylated interferon is continued for the remainder of the treatment course.13

The most common side effects of this regimen are anemia, neuropsychiatric symptoms, rash, pruritus, nausea, anorectal discomfort and fatigue.

Boceprevir

The combination of pegylated interferon, ribavirin and boceprevir is approved for use in treatment-experienced patients. The RESPOND-2 trial reported sustained viral response rates for relapsers and non-responders as 75 percent and 52 percent, respectively.14 The presence of bridging fibrosis or cirrhosis was associated with a decreased sustained viral response rate in this study.15

Relapse and partial-responder patients treated with this regimen may be eligible for a shorter duration of therapy than 48 weeks. All patients start treatment with a 4-week lead-in of pegylated interferon and ribavirin. At the start of week 5, boceprevir is added to the regimen. The triple therapy is then continued for 32 weeks. In those patients with undetectable HCV-RNA at weeks 12 and 24, therapy is stopped at week 36. Patients whose HCV-RNA was positive at week 12 but less than 100 IU/mL and who were HCV-RNA undetectable at week 24, boceprevir is stopped at week 36 and pegylated interferon and ribavirin are continued for another 12 weeks to complete at 48-week course of therapy.10

As in naïve patients, treatment-experienced patients with cirrhosis are treated with a 4-week lead in phase followed by 44 weeks of triple therapy. In all treatment-experienced patients, the futility rules for stopping are the same as the naïve patient population.

Telaprevir

The combination therapy of pegylated interferon, ribavirin and telaprevir is approved for use in treatment-experienced patients. The REALIZE trial reported sustained viral response rates for relapsers, partial responders and null responders as 83 percent, 59 percent and 29 percent, respectively.16 Histology appeared to not influence response rates in previous relapse patients as patients with mild disease and cirrhosis had similar sustained viral response rates. Histology did influence response rates in both the partial responder and null responder groups.15

Partial responders with F0-1 disease, F2-3 disease and F4 disease (cirrhosis) had sustained viral response rates of 72 percent, 56 percent and 34 percent, respectively. Null responders with F0-1 disease, F2-3 disease and F4 disease (cirrhosis) had sustained viral response rates of 41 percent, 39 percent and 14 percent, respectively. This data questions the utility of this triple therapy in cirrhotic, previous null responder patients. As in treatment naïve patients, the treatment course is with three medications for the first 3 months followed by the remainder of therapy with pegylated interferon and ribavirin.

The duration of therapy for relapse patients is similar to naïve patients and may be 24 or 48 weeks depending upon on-treatment response. Partial responders, null responders and all cirrhotic patients require 48 weeks of therapy. Futility rules, medication dosages and side effects are similar to the naïve patient population.

Treatment of Genotype 2 & 3

The treatment of genotype 2 and 3 disease is with either pegylated interferon alfa 2a or alfa 2b plus and ribavirin 800 mg a day for 24 weeks.1 The sustained virologic response ranges from 96 to 82 percent with 6 months of therapy. Protease inhibitor therapy is not approved for use in genotypes 2 and 3.

Alternative Medicines

Researchers estimate the use of complementary medicine by hepatitis C patients dissatisfied with conventional medications to be as high as 60 percent.17 Many different types of agents are used, including milk thistle, vitamin therapies, Chinese herbal therapies, acupuncture and lifestyle modification techniques. Despite the widespread use of these modalities, few if any well-designed clinical trials have been published to evaluate the efficacy of these therapies in hepatitis C.

Silymarin or milk thistle is the most common alternative medication used by patients with hepatitis. Silymarin, which exhibits certain antioxidant properties and may function as a free radical scavenger, has been used to treat all forms of liver disease for more than 2,000 years. It appears to be a safe for use in liver disease. Recently, a controlled trial found no benefit of silymarin in patients with hepatitis C.18

Patient dissatisfaction with conventional therapies has fueled the growth of alternative medicines in hepatology. Healthcare providers must keep an open mind and familiarize themselves with the purported efficacy and potential toxicities of alternative medications to provide effective counsel to their patients. Patients must inform their healthcare providers of all their medications, alternative or conventional.

References

1. Ghany, M.G., Strader, D.B., Thomas, D.L., et al. (2009). Diagnosis, management and treatment of hepatitis C: an update. Hepatology, 49(4), 1335-1374.

2. Conry-Cantelena, C., Vanraden, M., Gibble, J., et al. (1996). Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection. New England Journal of Medicine. 334(26), 1691-1696.

3. Ridzon, R., Gallagher, K., Ciesielski, C., et al. (1997). Simultaneous transmission of human immunodeficiency virus and hepatitis C from a needle stick injury. New England Journal of Medicine, 336(13), 919-922.

4. Ohto, H., Terazawa, S., Sasaki, N., et al. (1994). Transmission of hepatitis C virus from mothers to infants. New England Journal of Medicine, 330(11), 744-750.

5. Lin, H.H., Kao, J.H., Hsu, H.Y., et al. (1995). Absence of infection in breast fed infants born to hepatitis C virus infected mothers. Journal of Pediatrics, 126(4), 589-591.

6. CDC. (2012). Proposed recommendations for the identification of HCV chronic infection among persons born during 1945 through 1965. Retrieved Aug. 5, 2012 from the World Wide Web: http://www.cdc.gov/hepatitis/HCV/birthcohorttesting.htm

7. Chen, S.L., & Morgan, T.R. (2006). Natural history of hepatitis C infection. International Journal of Medical Sciences, 3(2), 47-52.

8. Forns, X., & Bukh, J. (1999). The molecular biology of hepatitis C virus: genotypes and quasispecies. Clinics in Liver Disease, 3(4), 693-716.

9. Poordad, F.F., McCone, J., Bacon, B.R., et al. (2011). Boceprevir for untreated chronic HCV genotype 1 infection. New England Journal of Medicine, 364(13), 1195-1206.

10. Boceprevir capsules [package insert]. (2011). Whitehouse Station, NJ: Merck & Co. Inc.

11. Jacobson, I.M., McHutchison, J.G., Dusheiko, G.M., et al. (2011). Telaprevir for previously untreated chronic hepatitis C infection. New England Journal of Medicine, 364(25), 2405-2416.

12. Sherman, K.E., Flamm, S.L., Afdahl, N., et al. (2011). Response-guided telaprevir combination treatment for hepatitis C virus infection. New England Journal of Medicine. 365(11), 1014-1024.

13. Telaprevir tablets [package insert]. (2011). Cambridge, MA: Vertex Pharmaceuticals Inc.

14. Bacon, B.R., Gordon, S.C., Lawitz, E., et al. (2011). Boceprevir for previously treated chronic HCV genotype 1 infection. New England Journal of Medicine. 364(13), 1207-1217.

15. Bruno, S., Vierling, J.M., Esteban, R., et al. (2011). Boceprevir in addition to standard of care enhanced SVR in patients with hepatitis C genotype 1 with advanced fibrosis/cirrhosis: subgroup analysis of SPRINT-2 and RESPOND-2 studies. Journal of Hepatology. 54(suppl 1), S4.

16. Zeuzem, S., Andreone, P., Pol, S., et al. (2011). Telaprevir for retreatment of HCV infection. New England Journal of Medicine, 364(25), 2417-2428.

17. Eisenberg, D.M., Davis, R.B., Ettner, S.L., et al. (1998). Trends in alternative medicine use in the United States, 1990-1997: Results of a follow-up national survey. JAMA, 280(18), 1569-1575.

18. Fried, M.W., Navarro, V.J., Afdhal, N., et al. (2012). Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. JAMA, 308(3), 274-282.

David Bernstein is chief of the division of hepatology at North Shore University Hospital, Manhasset, NY.




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