CME

EARN CATEGORY I CME CREDIT by reading this article and the article beginning on page 42 and successfully completing the posttest on page 49. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of October 2007.

LEARNING OBJECTIVES
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Outline the epidemiology of hepatitis C, how it is transmitted, and what can be done to prevent it Describe the natural history, clinical presentation, and diagnosis of hepatitis C Discuss the standard of care for hepatitis C, how the disease is monitored, and what other therapeutic options might become available

Hepatitis C virus infection: A current review
The standard therapy for hepatitis C cures 40% to 50% of infections, but new treatments now being studied in clinical trials may improve these numbers.
Douglas L. Senecal, PA-C; Joseph Morelli, MD

epatitis C—the disease caused by infection with the hepatitis C virus (HCV)—is the number one indication for liver transplantation and one of the most common causes of chronic liver disease worldwide.1,2 HCV is a positive, single-stranded RNA virus in the Flaviviridae family that is transmitted through parenteral exposure. The virus directly infects the hepatocyte yet is proposed to be noncytopathic; hepatic parenchymal damage occurs as a consequence of the host’s immune response and subsequent development of an inflammatory infiltrate, as seen in Figure 1. HCV was first isolated in 1989; before this occurred, serologic evaluation for the virus was impossible, leaving people exposed to blood products at risk for infection. Fortunately, testing techniques have now evolved to the point that even very small levels of virus can be detected. Eleven HCV genotypes have been identified, with prevalence depending on geographic location. In the United States, genotypes 1, 2, 3, and 4 are most common, with genotype 1 comprising 75% of US infections.2,3 Today’s standard therapy, pegylated interferon combined with ribavirin, offers an overall cure rate of approximately 40% to 50%.4,5 However, specifically targeted antiviral therapies, such as the protease and polymerase inhibitors now in clinical trials, may improve on the current standard of care. Because hepatitis C is being diagnosed more frequently and the treatment regimens are complex, PAs play an integral role in providing care.

H

active chronic HCV infection.2,3 An estimated 26,000 infections are acquired each year, and the 10,000 to 12,000 yearly deaths occur in those whose infections progress to cirrhosis or hepatocellular carcinoma (HCC).2,3 Risk factors for HCV transmission that should prompt screening at the primary care level are listed in Table 1 (page 22). As with all infectious diseases, prevention of viral transmission is key. Some experts have suggested that sharing toothbrushes and razors poses greater risk than does monoga-

EPIDEMIOLOGY AND PREVENTION

The CDC has estimated that 3.9 million Americans have been exposed to HCV and that 2.7 million Americans have

FIGURE 1. This liver biopsy specimen from a patient with chronic hepatitis C shows an inflammatory infiltrate around the portal tract.

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CME Hepatitis C
TABLE 1. Risk factors for hepatitis C Birth to a mother with positive antibodies for HCV Blood transfusion before 1992 Hemodialysis History of cocaine use History of tattoos IV drug use Multiple sexual partners Needlestick or mucosal exposure (in a health care worker) Organ transplant before 1992 Sex with an HCV-infected patient Treatment with clotting factor for hemophilia before 1987 Unexplained elevations of liver enzymes

much as one log in a day’s time, making this marker an unreliable gauge of disease progression.9 Serial testing of quantitative HCV RNA is not recommended outside of the treatment setting. The natural history of patients with HCV-induced cirrhosis is quite alarming. Once this condition has been diagnosed, the risk is as high as 3.9% per year that decompensation of underlying cirrhosis will occur and be accompanied by HCC, ascites, bleeding from varices, jaundice, hepatic encephalopathy, or renal/pulmonary dysfunction.10 Fortunately, only 20% to 25% of all patients with cirrhosis will ever decompensate and require transplantation.10 When decompensation does occur, the overall 5-year survival is approximately 50%, and recent studies show the major cause of death in this population to be HCC.10 Because the risk for HCC is relatively high, screening patients with cirrhosis every 6 to 12 months with abdominal imaging and alphafetoprotein levels is recommended.11,12
CLINICAL PRESENTATION AND DIAGNOSIS

mous heterosexual intercourse. Sexual transmission has undergone much scrutiny, however, as studies have quoted anywhere from 2% to 22% infection rates, depending on sexual practices.6,7 The American Association for the Study of Liver Diseases (AASLD) states that sexual practices need not be altered in monogamous heterosexual couples, as the risk of infection is minimal.6 However, advising couples to use barrier protection is reasonable.
NATURAL HISTORY

The natural history of HCV infection guides patient education and influences the decision of whether a patient should undergo therapy. In patients infected with HCV, 10% to 20% will have spontaneous clearance and chronic infection will develop in the other 80% to 90%.8 The chronic infection will progress to cirrhosis (over a period of 20 to 30 years), in approximately 20% to 30% of patients.8 The progression of fibrosis is more rapid in patients who are older at the time of infection, nonwhite, infected with HIV, have hepatic steatosis, or consume alcohol.9 Studies have shown that viral load does not predict disease progression and can fluctuate as

Hepatitis C has historically been a silent disease, and most patients with acute infection do not present with the symptoms or extrahepatic effects listed in Table 2. Patients who have established cirrhosis are more commonly symptomatic because of the manifestations of advanced liver disease.13 Acute hepatitis C The incubation period of HCV is 2 to 26 weeks, and only about 20% of patients with acute HCV infection develop clinical signs and symptoms.14 Serum HCV RNA has been found to be the most sensitive marker of acute infection, and the level will be positive 7 days to 8 weeks after infection (often well before antibody production begins, which occurs approximately 50 days after infection).14 Nevertheless, an HCV antibody test should be ordered along with testing for HCV RNA to ensure that the patient did not have pre-existing chronic hepatitis with another acute hepatitis superimposed. Acute HCV infection is defined by a positive result on HCV polymerase chain reaction (PCR) testing two times in a row.15 Spontaneous clearance is represented by a negative result on PCR testing performed monthly for 3 months, along with formation of HCV antibodies.15

KEY POINTS
■ Hepatitis C is the number one indication for liver transplantation and one of the most com-

COMPETENCIES
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mon causes of chronic liver disease worldwide.
■ Understanding the natural history of HCV infection is paramount because this understanding

Medical knowledge Interpersonal & communication skills Patient care Professionalism Practice-based learning and improvement Systems-based practice

guides patient education and influences therapy.
■ Most acute HCV infections go unnoticed; the viral incubation period is between 2 and 26 weeks,

and only about 20% of patients with acute infection develop clinical signs and symptoms.
■ The standard definition of chronic HCV infection is the persistence of HCV RNA in the serum

for longer than 6 months.
■ Therapy with pegylated interferon combined with ribavirin offers an overall cure rate of

approximately 40% to 50%; rates are higher for some genotypes of HCV. Specifically targeted antiviral therapies, now in clinical trials, may improve on the current standard of care.

22 JAAPA • OCTOBER 2007 • 20(10) • www.jaapa.com

Chronic hepatitis C The standard definition of chronic HCV infection is the persistence of HCV RNA in the serum for longer than 6 months. Initial HCV antibody testing is usually prompted by a history of risk factors or elevated liver enzymes. Unfortunately, false-negative results are often seen in patients undergoing hemodialysis or in immunocompromised patients; furthermore, those who spontaneously clear the virus will still produce antibodies to HCV.14 In either case, confirmatory testing with quantitative HCV RNA would be preferred over a qualitative test because response to therapy can be predicted based on viral load along with other factors such as HCV genotype.16 MANAGEMENT

TABLE 2. Signs and symptoms of hepatitis C Anorexia Arthralgia Autoimmune thyroiditis Essential mixed cryoglobulinemia Fatigue Leukocytoclastic vasculitis Membranoglomerulonephritis Myalgia Nausea Polyarteritis nodosa Porphyria cutanea tarda Right upper quadrant pain

In patients with acute infection, the benefits of treatment almost always outweigh the risk, but patients with confirmed HCV infection should be assessed for the relative barriers to treatment noted in Table 3. Next, the HCV genotype and potential duration of infection should be determined; this information will indicate whether obtaining a liver biopsy will yield information that will affect the decision to treat. Several subgroups of patients, such as those infected with genotypes 2 or 3 and patients with clinical findings of cirrhosis, may not require liver biopsy as it will rarely influence management. Most would agree that patients infected with HCV genotypes 2 and 3 should undergo therapy unless there are major barriers to treatment. On the other hand, patients infected with HCV genotype 1 with relative barriers to therapy may benefit from liver biopsy, which allows the provider to tailor the decision to treat based on the histologic findings. For instance, a patient with advanced fibrosis on biopsy should have aggressive therapy to halt disease progression, whereas a patient with minimal disease has the option of awaiting more efficacious therapies with fewer side effects. Some investigators are looking into the efficacy of measuring fibrosis using noninvasive methods. Serologic assays have been found to be helpful only when fibrosis is either minimal or advanced; their predictive value for patients with middlestage fibrosis is poor.17 Ultrasound elastography is currently being investigated as another assessment tool, but factors such as body mass index and ascites appear to limit its sensitivity and specificity.18 Once the appropriate data have been considered and the decision to treat has been made, patients should be counseled on treatment side effects and be reassured that all side effects will regress once medications are withdrawn. The side effects associated with pegylated interferon are fatigue, lowgrade fever, myalgia, arthralgia, headache, hair loss, diarrhea, and weight loss. The side effects associated with ribavirin are headache, pruritus, rash, and cough. These side effects can often be minimized if the patient is premedicated with acetaminophen and/or diphenhydramine and remains well hydrated throughout therapy. The potential adverse events noted in Table 4 should be emphasized so the patient is aware of associated risks before committing to therapy.
Continued on page 24

TABLE 3. Relative barriers to treatment Active substance abuse Adherence issues Baseline hematologic abnormalities Established cirrhosis Financial issues Pre-existing autoimmune disease Social support concerns Uncontrolled psychiatric disease Uncontrolled thyroid disease

TABLE 4. Adverse events associated with therapy Anemia Cardiac decompensation Decompensation of underlying cirrhosis Exacerbation of autoimmune disease Exacerbation of thyroid disease Neutropenia Pancreatitis Pulmonary toxicity Retinal disease Thrombocytopenia Worsening psychiatric disease

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CME Hepatitis C
Therapy Pegylated interferon is available in two forms, peginterferon alfa-2a, which is initiated at a fixed dosage of 180 mcg/wk SC, and peginterferon alfa-2b, which is dosed at 1.5 mcg/kg/wk SC. Contraindications to these agents include decompensated cirrhosis, an absolute neutrophil count less than 1,000 cells/µL, a platelet count less than 50,000 cells/µL, severe depression, active substance abuse, retinopathy, and untreated autoimmune or thyroid disease. For patients infected with HCV genotypes 1, 4, 5, or 6, ribavirin is dosed at 1,000 mg/d for those weighing less than 75 kg and at 1,200 mg/d for those weighing more than 75 kg. For patients infected with HCV genotypes 2 or 3, ribavirin is dosed at 800 mg/d regardless of weight. Contraindications to ribavirin are a hemoglogin less than 10 g/dL, coronary artery disease, renal insufficiency, and active or potential pregnancy. If pregnancy might occur during or 6 months following therapy, two modes of contraception should be used. The current AASLD guidelines for acute HCV infection suggest treatment with full-dose pegylated interferon monotherapy for 6 months after the patient has been given 2 to 4 months to spontaneously clear the virus and has not done so.19,20 With this therapy, rates of cure—called a sustained virologic response (SVR)—have been cited at 81% to 91%.19,20 The current therapeutic regimen for chronic HCV infection is derived based on genotype. For infection with HCV
ALGORITHM. Treatment of hepatitis C

genotypes 1, 4, 5, or 6, the current regimen consists of pegylated interferon and weight-based ribavirin for 12 weeks, at which time HCV RNA should be measured to assess for early virologic response (EVR) (EVR is defined as a two-log drop from baseline). Should the patient achieve an EVR, then therapy should be continued for a total of 48 weeks.4,5 Those who have not achieved an EVR at 12 weeks have a less than 3% chance of achieving SVR and should be taken off therapy.4,5 Once therapy is complete, HCV RNA testing is done to assess whether an end-of-treatment (EOT) response has been achieved; this is defined by a negative HCV RNA at the end of therapy. Lastly, HCV RNA should be measured 24 weeks later to assess for SVR. After 48 weeks of therapy, the estimated SVR for genotype 1 patients is approximately 50%4,5 (see the algorithm). For infections with HCV genotypes 2 or 3, the current standard of care is 24 weeks of pegylated interferon and nonweight-based ribavirin. HCV RNA is measured at EOT and 24 weeks after EOT to assess for SVR, which is achieved in approximately 76% to 81% of patients.4,5 For treatment of patients with both hepatitis C and HIV infection, the same regimens are used, bearing in mind that these patients have a lower SVR.21-23 Before treatment is started, HIV disease must be well-controlled, as evidenced by suppressed viremia and a CD4+ cell count of greater

HCV infection confirmed with HCV RNA

Determine HCV genotype and viral load

Genotypes 1, 4, 5, 6

Genotypes 2, 3

Treat for 12 wk with pegylated interferon and weight-based ribavirin

Treat for 24 wk with pegylated interferon and ribavirin, 800 mg/d

<2 log drop

≥2 log drop

Check HCV RNA at EOT and 24 weeks after therapy to assess for SVR

Discontinue therapy

Continue therapy to 48 wk

Check HCV RNA at EOT and 24 wk after therapy to assess for SVR
Key: EOT, end of treatment; HCV, hepatitis C virus; SVR, sustained virologic response.

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than 250 cells/µL. In patients receiving highly active antiretroviral therapy, screening for drug interactions before treatment and monitoring during treatment are essential. Monitoring Baseline studies prior to therapy should include a CBC with differential, AST, ALT, alkaline phosphatase, total bilirubin, albumin, thyroid-stimulating hormone, free thyroxine, prothrombin time/international normalized ratio, beta-human chorionic gonadotropin in women, and quantitative HCV RNA with HCV genotyping. Once baseline values are established and therapy is initiated, patients should have blood drawn for a CBC twice a week for the first 8 weeks; if no cytopenia is noted, a monthly CBC should suffice. Every 3 months, liver and thyroid function should be assessed. Patients who experience aggressive cytopenia should be considered for dose reduction or treatment with epoetin alfa or filgrastim. A dose reduction of pegylated interferon is recommended when the WBC count drops to less than 1,500 cells/µL or the absolute neutrophil count drops to less than 750 cells/µL. Bone marrow stimulation with filgrastim is initiated when the WBC count drops to less than 1,000 cells/µL or the absolute neutrophil count drops to less than 500 cells/µL. The dosage of filgrastim is 300 mcg 1 to 3 times weekly, depending on hematologic response, with a goal of an absolute neutrophil count greater than 1,000 cells/µL. Dose reduction of ribavirin is recommended when the hemoglobin drops more than 2 g/dL in a 4-week period. Bone marrow stimulation with epoetin alfa is initiated at 40,000 units and titrated up to 60,000 units every 7 to 10 days, depending on response. Therapy is initiated if the hemoglobin drops to less than 11 g/dL or falls more than 3 g/dL from baseline. The target hemoglobin is in the range of 10 to 12 g/dL.
POTENTIAL NEW THERAPIES

DRUGS MENTIONED Acetaminophen Albumin-interferon alpha (Albuferon)* Diphenhydramine Epoetin alfa (Epogen, Procrit) Filgrastim (Neupogen)

Peginterferon alfa-2a (Pegasys) Peginterferon alfa-2b (PEG-Intron) Ribavirin (Copegus, Rebetol) Taribavirin (Viramidine)* *Investigational agent

The most promising new therapies for hepatitis C are the protease/polymerase inhibitors, which are currently undergoing clinical trials. Additional compounds being studied include a ribavirin analog, taribavirin, to address the hemolytic anemia associated with standard ribavirin and longer-acting interferon; and albumin-interferon alpha, which will offer biweekly as opposed to weekly dosing of interferon.24,25 Although supporting data are limited, the clinician may sometimes find it appropriate to tailor therapy based on rapid virologic response (RVR), defined as a negative HCV RNA after 4 weeks of therapy.26 Some clinicians are using longer courses of therapy in patients with genotype 3 HCV infection and a high viral load, or in patients with genotypes 1 or 3 HCV infection who do not obtain an RVR. Studies to support this have been done for genotype 1, but there are no data for genotype 3.26 Additionally, shortening therapy in genotype 2 and 3 patients who have an RVR has been examined, but the data have yet to be evaluated and confirmed in large, controlled trials.27 JAAPA
Douglas Senecal and Joseph Morelli practice in the Department of Hepatology, University of Florida College of Medicine, Gainesville. They have indicated no relationships to disclose relating the content of this article.

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The natural history of compensated cirrhosis due to hepatitis C virus: a 17-year cohort study of 214 patients. Hepatology. 2006;43(6):1303-1310. 11. Tanaka H, Nouso K, Kobashi H, et al. Surveillance of hepatocellular carcinoma in patients with hepatitis C virus infection may improve survival. Liver Int. 2006;26(5):543-551. 12. Fattovich G, Llovet JM. Risk factors for hepatocellular carcinoma in HCV-cirrhosis: what we know and what is missing. J Hepatol. 2006;44(6):1013-1016. 13. Tong MJ, el-Farra NS, Reikes AR, Co RL. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med. 1995;332(22):1463-1466. 14. Alter MJ. The detection, transmission, and outcome of hepatitis C virus infection. Infect Agents Dis. 1993;2(3):155-166. 15. Gerlach JT, Diepolder HM, Zachoval R, et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology. 2003;125(1):80-88. 16. EASL International Consensus Conference on Hepatitis C. Paris, 26-28 February 1999. Consensus statement. European Association for the Study of the Liver. J Hepatol. 1999;30(5):956-961. 17. Imbert-Bismut F, Ratziu V, Pieroni L, et al; MULTIVIRC Group. Biochemical markers of liver fibrosis in patients with chronic hepatitis C virus infection: a prospective study. Lancet. 2001; 357(9262):1069-1075. 18. Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology. 2005;41(1):48-54. 19. Kamal SM, Fouly AE, Kamel RR, et al. Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response. Gastroenterology. 2006;130(3):632-638. 20. Hwang SJ, Lee SD, Chan CY, et al. A randomized controlled trial of recombinant interferon alpha-2b in the treatment of Chinese patients with acute post-transfusion hepatitis C. J Hepatol. 1994;21(5):831-836. 21. Thomas DL. Hepatitis C and human immunodeficiency virus infection. Hepatology. 2002;36(5) (suppl 1):S201-S209. 22. Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001;33(4):562-569. 23. Chung RT, Anderson J, Volberding P, et al. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004; 351(5):451-459. 24. Bain VG, Kaita KD, Yoshida EM, et al. 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. J Hepatol. 2006;44(4):671-678. 25. Balan V, Nelson DR, Sulkowski MS, et al. A Phase I/II study evaluating escalating doses of recombinant human albumin-interferon-alpha fusion protein in chronic hepatitis C patients who have failed previous interferon-alpha-based therapy. Antivir Ther. 2006;11(1):35-45. 26. Sánchez-Tapias JM, Diago M, Escartín P, et al; TeraViC-4 Study Group. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology. 2006;131(2):451-460. 27. Andriulli A, Dalgard O, Bjoro K, Mangia A. Short-term treatment duration for HCV-2 and HCV-3 infected patients. Dig Liver Dis. 2006;38(10):741-748.

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