Pharmacotherapy of hepatitis C virus infection: a brief review.
HCV is an RNA virus that belongs to the flavivirus family. There are at least six different HCV genotypes (genotypes 1 to 6) and more than 50 subtypes. In the United States, HCV genotype 1 is the most common form. There is little difference in severity of disease or outcomes between genotypes. However, genotypes 2 and 3 are more likely to respond to interferon therapy than genotype 1. HCV infects hepatocytes, leading to liver disease. About 15% to 25% of persons infected will spontaneously clear infection without treatment; however, approximately 75% to 85% will remain chronically infected. Of those patients with chronic infection, 60% to 70% will develop chronic liver disease, 5% to 50% will go on to develop cirrhosis over the course of 20 to 30 years, and 1% to 5% will die from liver disease (cirrhosis or cancer). Other medical conditions, such as glomerulonephritis, essential mixed cryoglobulinemia, porphyria cutanea tarda, diabetes, and non-Hodgkins lymphoma, are more common in HCV-infected persons (National Digestive Diseases Information Clearinghouse, 2006).
Hepatitis C is usually diagnosed when serum aminotransferases are elevated and anti-HCV antibodies are found in the serum. The diagnosis is confirmed by detecting HCV RNA in the serum. A liver biopsy is not necessary for diagnosis, but may be useful in grading the severity of the disease and staging the degree of fibrosis. Chronic hepatitis C is defined as a positive anti-HCV antibody and elevated serum aminotransferases for more than 6 months (National Institutes of Health [NIH], 2002).
The goal of therapy is to prevent complications associated with HCV infection, which can be achieved by eradicating the virus. Eradication of the virus is considered when there is a sustained virologic response (SVR) as defined by the absence of detectable HCV RNA at the end of treatment and 6 months later (see Table 1) (Strader, Wright, Thomas, & Seeff, 2004). The SVR is the most reliable endpoint for the evaluation of therapy, and has been associated with long-term beneficial clinical outcomes, such as improved quality of life, decrease in liver inflammation/fibrosis, and prevention of the development of hepatocellular carcinoma. There are currently two types of therapeutic modalities available: the immunomodulators (interferons) and ribavirin, an antiviral drug (see Table 2).
Interferons are biological response modifiers that have antiviral, antiproliferative, and immunomodulatory effects. There are two types of interferon preparations approved for the treatment of chronic hepatitis C infection. The standard or non-pegylated interferons include interferon alfa2a and -2b, and alfacon-1, and the peginterferons alfa-2a and -2b.
Interferon alfa-2a and -2b have a short elimination half-life of approximately 2 to 8 hours, therefore requiring three times a week administration. Interferon alfacon-1, also known as consensus interferon, is bioengineered to have a different amino acid sequence than interferon alfa2a and -2b. As a result, there is a higher binding affinity to the interferon receptor and increased biologic activity (Blatt, Davis, Klein, & Taylor, 1996; Keeffe & Hollinger, 1997). Treatment with interferon alone is effective in about 10% to 20% of patients.
Peginterferon is made by attaching a polyethylene glycol (PEG) moiety to the interferon molecule, giving it a higher molecular weight. Pegylation decreases the clearance of the drug, prolonging the time it remains in the body, therefore permitting once weekly dosing. There are two peginterferons currently available. Peginterferon alfa-2a (Pegasys[R]) has a 40KD branched chain PEG while peginterferon alfa-2b (PegIntron[R]) has a 12KD linear PEG molecule attached to the interferon molecule. In patients with renal dysfunction, the dose should be reduced (see Table 3) (Roche, 2008; Schering, 2008a).
The interferons are associated with many serious adverse effects. Flu-like symptoms (fever, chills, myalgias, and arthralgias), bone marrow suppression (leucopenia, thrombocytopenia), and depression can be significant and dose-limiting (see Table 4). Adverse effects tend to be more severe during the initial weeks of treatment and can be managed with an analgesic, such as acetaminophen (less than 2 grams/day). Exacerbation of hepatitis (flare) can occur with treatment. Treatment with interferon/ peginterferon should be stopped if hepatic decompensation occurs (see Table 5). Depression can be managed with serotonin reuptake inhibitors (SSRIs) (Strader et al., 2004).
Ribavirin is a nucleoside analog that has antiviral activity against HCV, respiratory syncytial virus (RSV). Ribavirin has direct antiviral effects by inhibiting HCV polymerase, thereby decreasing viral replication. Ribavirin also has indirect antiviral effects by modulating cytokine responses and immunosuppressive effects. It is believed that liver damage occurs when the immune system reacts to HCV infected cells. By suppressing the immune system, this inflammatory response will be inhibited (Tam, Lau, & Hong, 2001). The addition of ribavirin to interferon therapy significantly improves virologic response rates to about 30% to 50%.
One of the most significant adverse effects of ribavirin is hemolytic anemia, which is correlated with elevated plasma and erythrocyte levels (Martin & Jensen, 2008). Ribavirin is primarily removed by the kidneys; thus, it can accumulate in the presence of renal dysfunction and is not removed by hemodialysis (see Table 3). Ribavirin is associated with teratogenic and embryocidal effects, and is contraindicated in women who are pregnant and in male partners of women who are pregnant. A negative pregnancy test should be confirmed immediately prior to initiation of therapy, and at least two forms of contraception should be used (see Table 4).
In randomized clinical trials, peginterferon plus ribavirin have resulted in the highest SVR rates and represents the current standard of care. The likelihood of achieving SVR can be predicted by patient characteristics and early virologic response (EVR). Patients with genotype-2 or -3 HCV infection, lower pre-treatment HCV RNA levels, younger age, lower body weight, and absence of bridging fibrosis and cirrhosis have a higher SVR rate. In patients with genotype 1 infection, SVR was highest with higher ribavirin dose and who were treated for 48 weeks (Strader et al., 2004). Therefore, the treatment duration and ribavirin dose will vary depending on the HCV genotype. Practice guidelines for the diagnosis, management, and treatment of hepatitis C infection have been published (Strader et al., 2004). The reader is encouraged to review the guidelines for a comprehensive overview on the management of HCV infection.
Treatment in Patients with Renal Dysfunction
Infection with HCV is a major cause of liver disease in patients with chronic kidney disease. Mortality is increased in patients on hemodialysis and graft loss in kidney transplant recipients (Fabrizi, Poordad, & Martin, 2002). There are limited data on the use of interferon therapy in patients on chronic dialysis. A recent meta-analysis not only found that interferon-based treatment resulted greater efficacy in achieving a sustained virologic response in 41% of patients, but it discovered a higher rate of adverse effects as well. There is a greater exposure to interferon (increased elimination half-life and area-under-the-curve) in patients undergoing hemodialysis (Gordon et al., 2008). Elevated interferon plasma levels may account for increased efficacy as well as more frequent adverse effects. Ribavirin can accumulate in the setting of renal dysfunction, resulting in significant hemolysis. Ribavirin should not be used in those with a creatinine clearance less than 50 mL/minute (Schering, 2008b).
Drugs Currently Under Investigation
Given the limited efficacy and significant adverse effects of the available treatment options, there are many drugs currently being investigated for the management of chronic HCV infection. The following are some brief descriptions of investigational drugs in the latter stages of development.
Albinterferon alfa-2b (Albuferon[R])
Recombinant human albumin-interferon alfa (alb-IFN) is an 85 kilodalton recombinant fusion protein consisting of human serum albumin genetically fused to interferon alfa-2b. Fusing albumin to the interferon molecule increases the elimination half-life and extends the therapeutic activity. The prolonged activity may potentially improve efficacy and tolerability, and allow for dosing every 2 to 4 weeks (Bain et al., 2006). Albumin-interferon alfa is currently undergoing phase III clinical trials.
Thymalfasin is a synthetic 28 amino acid peptide that is based on a natural substance isolated from thymus tissues. Thymalfasin works by modulating immunological responsiveness and has direct effects on viral infected cells (Rustgi, 2005). Thymalfasin has been studied in combination with peginterferon and ribavirin (Poo et al., 2004; Sherman et al., 1998). Thymalfasin is approved for use in the treatment of chronic hepatitis B infection in China, and is currently undergoing clinical trials in Europe and the United States for the treatment of HCV infection.
Telaprevir is an oral protease inhibitor being studied for the treatment of HCV infection. Telaprevir selectively inhibits HCV NS3.4A protease, which is necessary for HCV replication (Lin, Kwong, & Perni, 2006; Perni et al., 2006). Telaprevir is being studied in combination with peginterferon and ribavirin. The most common adverse effects observed were rash and gastrointestinal events.
Boeeprevir (SCH 503034)
Boceprevir is a potent HCV NS3 oral protease inhibitor that has been studied in combination with peginterferon alfa-2b (Sarrazin et al., 2007). Boceprevir by itself and in combination with peginterferon was generally well tolerated, with headache, myalgia, rigor, and fever being the most common reported adverse events.
Taribavirin is a synthetic nucleoside analog. Following oral administration, it is extensively taken up by the liver and converted to the active metabolite, ribavirin. This increases exposure to the liver while minimizing exposure to red blood cells. Taribavirin is currently in phase 2b studies (Gish et al., 2007).
More information about chronic hepatitis C clinical trials can be found at www.clinicaltrials.gov. Other useful internet resources on liver disease and hepatitis C are listed in Table 6.
HCV is a major cause of hepatitis and chronic liver disease. While no vaccine is currently available to prevent HCV infection, there have been significant improvements in the treatment of HCV infection. The drugs used to treat HCV infection are fairly effective; however, they are associated with significant adverse effects and are costly. Efforts focusing on reducing the risk of HCV transmission from nosocomial exposure (such as blood transfusions) and high risk-behaviors (such as injection drugs) will likely have an impact on hepatitis C disease burden.
Armstrong, G.L., Wasley, A., Simard, E.P., McQuillan, G.M., Kuhnert, W.L., & Alter, M.J. (2006). The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Annals of Internal Medicine, 144(10), 705-714.
Bain, V.G., Kaita, K.D., Yoshida, E.M., Swain, M.G., Heathcote, E.J., Neumann, A.U., et al. (2006). A phase 2 study to evaluate the antiviral activity, safety, and pharmacokinetics of recombinant human albumin-interferon alfa fusion protein in genotype 1 chronic hepatitis C patients. Journal of Hepatology, 44(4), 671-678.
Blatt, L.M., Davis, J.M., Klein, S.B., & Taylor, M.W. (1996). The biologic activity and molecular characterization of a novel synthetic interferon-alpha species, consensus interferon. Journal of Interferon Cytokine Research, 16(7), 489-499.
Fabrizi, F., Poordad, F.F., & Martin, P. (2002). Hepatitis C infection and the patient with end-stage renal disease. Hepatology, 36(1), 3-10.
Gish, R.G., Arora, S., Rajender Reddy, K., Nelson, D.R., O'Brien, C., Xu, Y., et al. (2007). Virological response and safety outcomes in therapy-naive patients treated for chronic hepatitis C with taribavirin or ribavirin in combination with pegylated interferon alfa-2a: A randomized, phase 2 study. Journal of Hepatology, 47(1), 51-59.
Gordon, C.E., Uhlig, K., Lau, J., Schmid, C.H., Levey, A.S., & Wong, J.B. (2008). Interferon treatment in hemodialysis patients with chronic hepatitis C virus infection: A systematic review of the literature and meta-analysis of treatment efficacy and harms. American Journal of Kidney Diseases, 51(2), 263-277.
Keeffe, E.B., & Hollinger, F.B. (1997). Therapy of hepatitis C: Consensus interferon trials. Consensus Interferon Study Group. Hepatology, 26(3, Suppl 1), 101S-107S.
Lin, C., Kwong, A.D., & Perni, R.B. (2006). Discovery and development of VX-950, a novel, covalent, and reversible inhibitor of hepatitis C virus NS3.4A serine protease.
Infectious Disorders--Drug Targets, 6(1), 3-16. Martin, P., & Jensen, D.M. (2008). Ribavirin in the treatment of chronic hepatitis C. Journal of Gastroenterology and Hepatology, 23(6), 844-855.
National Digestive Diseases Information Clearinghouse. (2006). Chronic hepatitis C: Current disease management Retrieved May 26, 2009, from http://digestive.niddk.nih.gov/ddiseases/pubs/chronichepc/
National Institutes of Health (NIH). (2002). Consensus statement on management of hepatitis C: 2002. NIH Consensus State-of-the-Science Statements, 19(3), 1-46.
Perni, R.B., Almquist, S.J., Byrn, R.A., Chandorkar, G., Chaturvedi, P.R., Courtney, L.F., et al. (2006). Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrobial Agents and Chemotherapy, 50(3), 899-909.
Poo, J.L., Sanchez-Avila, E, Kershenobich, D., Garcia-Samper, X., Gongora, J., & Uribe, M. (2004). Triple combination of thymalfasin, peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior interferon and ribavirin treatment: 24-week interim results of a pilot study. Journal of Gastroenterology and Hepatology, 19(12), S79-81.
Roche. (2008). Pegasys[R] package insert. Nutley, NJ: Author.
Rustgi, V.K. (2005). Thymalfasin for the treatment of chronic hepatitis C infection. Expert Review of Anti-Infective Therapy, 3(6), 885-892.
Sarrazin, C., Rouzier, R., Wagner, F., Forestier, N., Larrey, D., Gupta, S.K., et al. (2007). SCH 503034, A novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders. Gastroenterology, 132(4), 1270-1278.
Schering. (2008a). PegIntron[R] package insert. Kenliworth, NJ: Author.
Schering. (2008b). Rebetol[R] package insert. Kenliworth, NJ: Author.
Sherman, K.E., Sjogren, M., Creager, R.L., Damiano, M.A., Freeman, S., Lewey, S., et al. (1998). Combination therapy with thymosin alphal and interferon for the treatment of chronic hepatitis C infection: A randomized, placebo-controlled double-blind trial. Hepatology, 27(4), 1128-1135.
Strader, D.B., Wright, T., Thomas, D.L., & Seeff, L.B. (2004). Diagnosis, management, and treatment of hepatitis C. Hepatology, 39(4), 1147-1171.
Tam, R.C., Lau, J.Y., & Hong, Z. (2001). Mechanisms of action of ribavirin in antiviral therapies. Antiviral Chemistry & Chemotherapy, 12(5), 261-272.
Wasley, A., Grytdal, S., & Gallagher, K. (2008). Surveillance for acute viral hepatitis--United States, 2006. MMWR Surveillance Summaries, 57(2), 1-24.
David J. Quan, Contributing Editor
David J. Quan, PharmD, BCPS, is a Clinical Pharmacist, UCSF Medical Center, and a Health Sciences Associate Clinical Professor, Department of Clinical Pharmacy, School of Pharmacy, University of California San Francisco, San Francisco, CA.
Table 1 Definition of Treatment Responses Early virologic 2-log decrease or loss of HCV response (EVR) RNA after 12 weeks of therapy End of treatment Absence of detectable virus at response (ETR) termination of treatment Sustained virologic Absence of HCV RNA at the end response (SVR) of treatment and 6 months later Nonresponder Stable HCV RNA levels while on therapy Partial responder Greater than 2-log decrease but not undetectable Source: Strader et al., 2004. Table 2 Drugs for the Treatment of Chronic Hepatitis C Immunomodulators Interferon alfa-2a (Roferon[R], Roche Pharmaceuticals) interferon alfa-2b (Intron A[R], Schering Corporation) Interferon alfacon-1 (Infergen[R], Valeant Pharmaceuticals) Peginterferon alfa-2a (Pegasys[R], Roche Pharmaceuticals) Peginterferon alfa-2b (PegIntron[R], Schering Corporation) Antiviral Ribavirin (Copegus, Rebetol, Ribasphere, and other manufacturers) Drugs Currently in Advanced Stages of Development * Albinterferon alfa-2b (Albuferon[R], Human Genome Sciences, Inc.) Boceprevir (Schering-Plough) Telaprevir (Vertex[R] Pharmaceuticals) Taribavirin (Viramidine[R], Valeant Pharmaceuticals) Thymalfasin (Zadaxin[R], Sciclone Pharmaceuticals) * For other drugs currently under investigation, visit www.clinicaltrials.gov Table 3 Drugs Used for the Treatment of Chronic HCV Infection Combination Peginterferon and Ribavirin Regimens Peginterferon alfa-2a * 180 mcg SQ once a week (Pegasys[R]) Peginterferon alfa-2b * 1.5 mcg/kg SQ once a week (PegIntron[R]) Ribavirin * 800 to 1200 mg PO daily (in 2 divided doses), depending on genotype and patient weight Interferon Interferon alfa-2a 3 Million Units SQ three times a (Roferon A[R]) week Interferon alfa-2b 3 Million Units SQ three times a (Intron[R]) week Interferon alfacon-1 9 mcg SQ three times a week (Infergen[R]) 15 mcg SQ three times a week (nonresponders) Regimens used in certain situations Peginterferon alfa-2a * 180 mcg SO once a week (Pegasys[R]) monotherapy Peginterferon alfa-2b * 1 mcg SQ once a week (PegIntron[R]) monotherapy Interferon alfa-2b and 3 Million Units SQ three times a Ribavirin * week and 1000 to 1200 mg/day Drug Dosing in Patients with Renal Dysfunction Mild to moderate renal Reduce peginterferon alfa-2b dysfunction (Creatinine dose by 25%. clearance 30 to 50mL/min) Do not use ribavirin. Severe renal dysfunction Reduce peginterferon alfa-2b (Creatinine clearance dose by 50%. 10 to 29mL/min) Do not use ribavirin. Hemodialysis Peginterferon alfa-2a 135 mcg SQ weekly. Reduce peginterferon alfa-2b dose by 50%. Do not use ribavirin. * Dose requires adjustment in the setting of renal dysfunction. Table 4 Adverse Effects Interferon/Peginterferon Flu-Like Symptoms Neurological Fatigue/Asthenia Headache Fever Dizziness Rigors Memory impairment Pain Paresthesia Chills Gastrointestinal Psychiatric Nausea/Vomiting Irritability/anxiety/ nervousness Diarrhea Insomnia Abdominal pain Depression Taste alteration Impaired concentration Hematologic Respiratory Lymphopenia Dyspnea Neutropenia Cough Thrombocytopenia Anemia Musculoskeletal Skin Arthralgia Alopecia Myalgia Pruritus Back pain Dermatitis Dry skin Rash Increased sweating Metabolic Ophthalmologic Anorexia Blurred vision Hypothyroidism Retinopathy Injection Site Reactions Ribavirin Birth defects Hyperuricemia (teratogenic) Fatigue Loss of bone mineral density Gout Rash Hemolytic anemia Sinusitis Hyperbilirubinemia Sources: Roche, 2008; Schering, 2008a, 2008b; Strader et al., 2004. Table 5 Contraindications to Therapy Interferon/peginterferon is contraindicated in patients with: Autoimmune hepatitis Hepatic decompensation (Child class B or C [Child, Pugh score greater than 6]) in patients with cirrhosis before or during treatment Hypersensitivity Interferon/peginterferon and ribavirin combinations therapy is c Also contraindicated in patients with: Women who are pregnant Men whose female partners are pregnant Patients with hemoglobinopathies (e.g. thalassemia major, sickle-cell anemia) Sources: Roche, 2008; Schering, 2008a, 2008b; Strader et al., 2004. Table 6 Hepatitis and Liver Disease Resources www.liverfoundation.org American Liver Foundation www.cdc.gov/hepatitis/HCV.htm Centers for Disease Control and Prevention: Viral Hepatitis www.hepatitis.va.gov United States Department of Veterans Affairs National Hepatitis C Program www.aasld.org American Association for the Study of Liver Diseases www.clinicaltrials.gov Searchable registry of clinical trials www.nlm.nih.gov/medlineplus/ MedlinePlus health information hepatitisc.html from the U.S. National Library of Medicine and the National Institutes of Health
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|Title Annotation:||Pharmacology Review|
|Author:||Quan, David J.|
|Publication:||Nephrology Nursing Journal|
|Date:||May 1, 2009|
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