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Pharmacotherapy of hepatitis C virus infection: a brief review.

Hepatitis C virus (HCV) is a viral pandemic, with an estimated 170 million persons infected worldwide. In the United States, over 3 million persons are infected, making it the most common blood borne infection in America (Armstrong et al., 2006; Wasley, Grytdal, & Gallagher, 2008).

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).

Treatment

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

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

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

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 (Zadaxin[R])

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 (VX-950)

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 (Viramidine[R])

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.

Summary

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.

References

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
Article Type:Report
Geographic Code:1USA
Date:May 1, 2009
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