Hepatitis C (HCV) treatment is not a "one size fits all".
|Abstract:||During the past ten years, there has been a remarkable increase in the number and spectrum of medications used for the treatment of viral hepatitis infections including the hepatitis C virus infection (HCV). Still there is considerable variability among physicians in the use and duration of treatment of the currently available medications. Therefore, the current literature on the HCV therapy will be reviewed and summarized.|
(Care and treatment)
Hepatitis C (Genetic aspects)
Hepatitis C (Risk factors)
Drug therapy, Combination (Usage)
Drug therapy, Combination (Health aspects)
Peginterferon alfa-2a (Usage)
Peginterferon alfa-2a (Health aspects)
Ribavirin (Health aspects)
Bukeirat, Faisal A.
Bukeirat, Mimi M.
|Publication:||Name: West Virginia Medical Journal Publisher: West Virginia State Medical Association Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2012 West Virginia State Medical Association ISSN: 0043-3284|
|Issue:||Date: March-April, 2012 Source Volume: 108 Source Issue: 2|
|Geographic:||Geographic Scope: United States Geographic Code: 1USA United States|
The hepatitis C virus is a major public health problem, and a leading cause of chronic liver disease. (1) With more than 180 million people infected worldwide, and more than 4.5 million Americans infected with the hepatitis C virus; it is no wonder that chronic Hepatitis C viral (HCV) infection is a significant public health issue not only in the USA but worldwide. (2)
The Hepatitis C virus is a RNA virus which is transmitted via infected blood and body fluids (examples of exposure risk would be: blood transfusion or organ transplant before 1992, intravenous drug use, snorting drugs, sexual exposure, and tattooing); as such there is no need for HCV-infected persons to limit ordinary household activities except for those that might result in blood exposure, such sharing a razor, nail-clipper, or toothbrush. The hepatitis C virus is not transmitted by hugging, kissing, sharing of eating utensils or breastfeeding.
Infection with the hepatitis C virus (HCV) can result in both acute and chronic hepatitis. Acute HCV is usually asymptomatic and rarely causes liver failure. On the other hand, chronic HCV is the aftermath of an acute infection, with eighty to one hundred percent of patients remaining HCV-RNA positive, and sixty to eighty percent developing chronic HCV with persistently abnormal liver enzymes [elevated AST and ALT]. The current recommended therapy for chronic HCV infection is the dual therapy consisting of the combination of pegylated interferon alfa and ribavirin.
A literature search was performed from 2000 to December 2009, using the computerized PubMed database, looking for English publications regarding Hepatitis C viral (HCV) infection and its available medications and treatment options. The most up to date treatment and recommendations were reviewed and the results are hereby summarized. In addition the most recent practice guidelines set forth by the American Association for the Study of Liver Diseases (AASLD) were reviewed.
Whom to treat?
All individuals with chronic hepatitis C (HCV) infection should be offered therapy, if there are no contraindications for it (Table 1). Therefore, all patients presenting to their doctor with abnormal LFT who are HCV-RNA positive by PCR should be offered therapy.
Infection with evidence of active liver inflammation should be confirmed by liver biopsy (Bx); as all other tests including ALT levels and viral titers are not reflective of the actual inflammation in the liver or presence of liver fibrosis/cirrhosis.
There are certain contraindications to treatment; Table 1 below shows conditions or situations where therapy is currently contraindicated: 2
What determines patient's response to treatment?
Response to treatment is dependent on a number of host (patient) factors and viral factors. (3)
Patient factors include age, gender, alanine aminotransferase (ALT) levels, amounts of iron deposits in the liver, stage of fibrosis, insulin resistance, and the patient's genetics. Recent work by Ge et al. shows that a specific polymorphism located close to the gene, which codes for interleukin 28B [IL-28B], was demonstrated to strongly influence SVR with the cure rate being twice as high if you have the CC allele. (4)
Viral factors include HCV genotype, and viral load namely serum concentrations of HCV RNA at the time of initiation of antiviral therapy.
There are three terms that are frequently used when referring to the results of HCV therapy; these are RVR, EVR, and SVR. RVR is Rapid Virologic Response at 4 weeks of therapy; EVR is Early Virologic Response at 12 weeks of therapy, and SVR which is Sustained Virologic Response at 6 months after therapy.
Response is determined by testing the patient at four, twelve, and 24 weeks by ordering both hepatitis C PCR qualitative as well as hepatitis C quantitative viral load by PCR. If the qualitative test is negative, that would be a positive response, and if there was a 2-log drop in the viral load, that would constitute a positive response as well (meaning that patient is responding to therapy).
Is one product better than the other?
Current treatment for hepatitis C infection consists of combination therapy using pegulated interferon plus ribavirin.
Both available peg-Interferon products [Pegasys: peginterferon alfa-2a; Pegintron: peginterferon alfa-2b] that are available on the market are equally efficacious with similar side effects. (2-5)
The most common side-effects that we should look for are: neuropsychiatric side-effects including anxiety and depression, flu-like symptoms, fatigue and muscle aches, skin rashes and irritation (which respond very well to topical steroids), thyroid derangement (both hyper--and hypo-thyrodism), hemolysis with ribavirin, and bone marrow suppression with interferon.
The dose of interferon can be adjusted according to the degree of bone marrow suppression, but once the platelet count has dropped below 50,000 or the absolute neutrophilic count [ANC] has dropped below 500, then treatment should be withheld. The medication insert that comes with each of these drugs has a detailed schedule that can help guide the dose adjustments of these medications and/or a call to your gastroenterology colleague.
Duration of therapy?
The initial determinant factor for the tentative duration of treatment is the viral genotype: whether HCV genotype 1,2,3,4,5, or 6.
[FIGURE 1 OMITTED]
After treatment has been initiated the factor that predicts long term response (sustained virologic response "SVR") is the initial response to treatment (the Rapid Virologic Response "RVR").
HCV viral genotypes 2 and 3 are treated with peg-interferon plus ribavirin (800 mg daily) for 24 weeks. If there is a RVR at 4 weeks of therapy, then shortening the duration of therapy to 12 weeks can be considered. If the treatment is well tolerated, recommend the full course for 24 weeks.
For HCV genotypes 1, 4, 5, and 6, it is recommended that ribavirin is dosed based on patient's weight (kg): if patient weighs less than 75kg, then 800mg/daily as 400 bid is utilized; however, if the patient weighs more than 75kg, then 1000mg should be used daily, given in two divided doses: 400 in the morning and 600 at night. If the patient weighs more than 100kg, the maximum dose of ribavirin of 1200mg/daily could be attempted with careful monitoring of the CBC.
For HCV genotype 1 (most common in the US); if there is a RVR, the duration of therapy can be shortened to 24 weeks instead of 48 weeks. If there is a slow viral response (meaning that the qualitative PCR becomes negative at 24 weeks rather than 12 weeks, or if there is a two-log drop in the viral titer but the qualitative test is still positive at 12 weeks) then it is recommended that the duration of treatment be extended to 72 weeks (Figure 1).
Preceding therapy, patients, both male and female should be counseled to prevent pregnancy during and up to six months after therapy. Furthermore, all patients should have a baseline evaluation that includes the following:
a) Psychiatric evaluation and clearance. If patient is taking anti-depressants, require four weekly follow-ups to their psychiatrist for the duration of therapy.
b) Baseline retinal examination by an ophthalmologist, due to the effects of interferon.
c) Blood work should include CBC with differential, LFT, KFT, and TSH.
During therapy, a weekly CBC for the first month and every four weeks thereafter should be maintained. Any change in the dosage of either ribavirin or interferon should revert patient to a weekly cycle until blood counts are stable.
What new therapies are coming?
The investigational agents for HCV infection can be divided into three areas:
a) Treatments targeting HCV-encoded proteins.
b) Treatments targeting host-encoded proteins.
c) Therapeutic and preventive vaccines.
In addition, there are ongoing discussions among the liver experts about triple therapy rather than dual therapy. There are some promising reports with triple therapy using interferon, ribavirin, plus nitazoxanide "an anti-protozoal drug" or triple therapy with interferon, ribavirin, plus one of the protease inhibitors such as Telaprevir or Boceprevir; and or the addition of the antiviral agent Silibinin. (6-15)
Telaprevir and Boceprevir are protease inhibitors which belong to a class of agents known as DAA's (Direct-Acting Anti-virals), and are the two products currently in phase three development. Hopefully, these medications will soon be available on the market. (16) Once these products are readily available, they will be used in conjunction with ribavirin and peginterferon for the initial 8 to 12 weeks of therapy followed by another 12 weeks of ribavirin and peginterferon if necessary. Due to their excellent anti-viral effects, many physicians are withholding therapy for newly diagnosed HCV patients till these drugs are available on the market.
The take home message is that it is our duty as treating physicians to keep people on therapy by eliminating drop-outs, keeping in mind that it is no longer acceptable to think of genotype 1 and 4 as "difficult to treat" or that genotype 2 and 3 are "easy to treat". Treatment should be tailored to the specific patient and to the specific virus that infected that particular patient.
Although the genotype is an important driver of response and is useful in designing the initial treatment plan, it is clear that once treatment is initiated, RVR is the most important and powerful predictor of SVR. (3)
It is our opinion that HCV is a potentially treatable disease, but treatment is not a "one size fits all", but rather should be tailored and individualized for each patient. However, if there is a response at week four of therapy [RVR], treat the patient for 24 weeks only, regardless of the genotype. If there is a response at week 12 of therapy [EVR], treat for 48 weeks, regardless of the genotype. If there is a response at 24 weeks of therapy [Slow Virologic Response], treat for 72 weeks regardless of the genotype.
Chronic HCV is a potentially treatable disease with the following response rates "Sustained Virologic Response":
a) SVR of approximately 70-75% if RVR is achieved
b) SVR of approximately 55-63% if EVR is achieved
c) SVR of approximately 30-33% if there was a Slow Viral Response
The most recent and detailed recommendations about treatment of HCV can be found in the American Association for the Study of Liver Diseases (AASLD) practice guidelines that were published in the Hepatology Journal in April 2009, (2); or at their web site: www.aasld.org/practiceguidelines.
Since the preparation of this manuscript, Incivek [Telaprevir] and Victrelis [Boceprevir] have become available on the market for the treatment of Hepatitis C Genotype 1 as triple therapy using one of them in addition to ribavirin and pigulated interferon.
(1.) Williams R. Global challenges in liver disease. Hepatology 2006; 44:521-526.
(2.) Ghany et al. Diagnosis, management, and treatment of Hepatitis C: An update. Hepatology 2009; 49:1355-1374.
(3.) Berg T. Tailored treatment for hepatitis C. MD Consult 2010; at www.mdconsult.com/das/article/body/185458161-2/jorg.
(4.) Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance, Nature 2009; 461: 798-801.
(5.) Lindahl K, Stahle L, Bruchfeld A, Schvarcz R. High dose ribavirin in combination with standard dose peg-interferon for treatment of patients with chronic hepatitis C. Hepatology 2005; 41: 275-279.
(6.) Jiang D, Guo H, Xu C, et al. Identification of three interferon inducible cellular enzymes that inhibit the replication of hepatitis C virus. J Virol 2008; 82:1665.
(7.) Rossignol JF, Kabil SM, El-Gohary Y, et al. Clinical trial: randomized double-blinded placebo-controlled study of nitazoxanide monotherapy for the treatment of patients with chronic hepatitis C genotype 4. Aliment Pharmacol Ther2008; 28:574.
(8.) Rossignol JF, Elfert A, El-Gohary Y, Keefe EB. Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. Gastroenterology 2009; 136:856.
(9.) Salberg M, Frelin L, Diepolder H, et al. A first clinical trial of therapeutic vaccination using naked DNA delivered in vivo electroporation shows antiviral effects in patients with chronic hepatitis C. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver, Copenhagen, Denmark; April 22-26, 2009; abstract # 43.
(10.) Folori A, Capone S, Ruggeri L, et al. A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees. Nat Med 2006; 12:190.
(11.) Elmowalid GA, Qiao M, Jeong SH, et al. Immunization with hepatitis C virus-like particles results in control of hepatitis C virus infection in chimpanzees. Proc Natl Acad Sci U S A 2007; 104:8427.
(12.) Seeff LB, Curto TM, Szabo G, et al. Herbal product use by persons enrolled in the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) Trial. Hepatology 2008; 47:605.
(13.) Liu J, Manheimer E, Tsutani K, Gluud C. Medicinal herbs for hepatitis C virus infection: a Cochrane hepatobiliary systematic review of randomized trials. Am J Gastroenterol 2003; 98: 538.
(14.) Polyak SJ, Morishima C, Shuhart H, et al. Inhibition of T-cell inflammatory cytokines, hepatocyte NF-KappaB signaling, and HCV infection by standardized Silymarin. Gastroenterology 2007; 132: 1925.
(15.) Ferenci P, Screzer TM, Kerschner H, et al. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology 2008; 135:1561.
(16.) Herrera J. Treatment of Hepatitis C in the Pre-DAA's Era: treat Now or wait for New Medications? Practical gastroenterology 2010; 6: 13-19.
Faisal A. Bukeirat, MD, FACG
Consultant in Digestive Diseases
Governor of the WV Chapter of American College of
Gastroenterology (ACG), Morgantown
Mimi M. Bukeirat
Senior at University High School (UHS), Morgantown
Table 1: Contraindications for HCV Therapy 1. Known hypersensitivity to drugs used to treat HCV 2. Age less than 2 years 3. Major depression or uncontrolled psychiatric health issues 4. Autoimmune hepatitis or other autoimmune conditions known to be exacerbated by HCV therapy 5. Untreated thyroid disease 6. Pregnancy or unwillingness to comply with adequate contraception 7. Solid organ transplant (lung, heart, or kidney) 8. Severe concurrent medical disease such as severe hypertension, heart failure, significant coronary artery disease, poorly controlled diabetes, chronic obstructive pulmonary disease (COPD)
|Gale Copyright:||Copyright 2012 Gale, Cengage Learning. All rights reserved.|