HepatitisC:aclinicalreview INVITEDREVIEW

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INVITED REVIEW

Hepatitis C: a clinical review

AA Modi, TJ Liang

The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

Hepatitis C is a major cause of chronic liver disease. It has been recognized as a global health problem because of the progression to cirrhosis and hepatocellular cancer.

Chronic hepatitis C is usually asymptomatic but can cause considerable liver damage before its recognition.

This review discusses the natural history, clinical features, diagnosis, therapy, treatment responses and the side effects associated with the treatment of hepatitis C.

Oral Diseases (2008) 14, 10–14

Keywords: natural history; therapy; genotype; peginterferon;

ribavirin

Introduction

About 170 million people in the world are infected with hepatitis C virus (HCV). Since the discovery of HCV in 1989 (Alter et al, 1999), the number of acute HCV cases has fallen by more than 80% (Wasley and Alter, 2000).

However, hepatitis C is still a major health burden because 60–80% of infected people progress to chronic infection (Di Bisceglie, 2000). HCV is a single-stranded RNA virus belonging to the Flaviviridae family (Lin- denbach and Rice, 2005). The major routes of trans- mission are injection drug use, blood transfusion, hemodialysis, organ transplantation and less frequently sexual intercourse. Six major genotypes (1–6) of HCV have been identiﬁed, and they have varying geographical distribution. Genotypes 1, 2 and 3 are distributed worldwide with genotype 1 accounting for 40–80% of all cases. Genotype 4 is found in the Middle East and Egypt, genotype 5 in South Africa and genotype 6 in South East Asia (Wasley and Alter, 2000).

Natural history

Hepatitis C virus infection can present as acute or chronic hepatitis. Acute hepatitis usually is asymptomatic and rarely leads to hepatic failure. Symptomatic

acute HCV has a mild clinical course with <25% of patients presenting with jaundice. About 60–80% people with acute infection develop chronic infection (Hoofna- gle, 2002). The rate of spontaneous viral clearance in patients with chronic HCV is very low. Approximately one ﬁfth (20–30%) of patients with chronic HCV develop cirrhosis over a time period of 10–30 years (Thomas and Seeﬀ, 2005). Several factors may deter- mine the rapidity of disease progression. Some of the well-characterized factors are HCV acquisition at an advanced age (>40–55 years), male sex, HIV co-infection, higher body mass index, presence of hepatic steatosis and consumption of alcohol. Patients with cirrhosis can decompensate with complications. Decom- pensated cirrhosis results in portal hypertension, which can lead to ascites, spontaneous bacterial peritonitis, esophageal varices, neurological complications such as hepatic encephalopathy and hepatic coma, and hepato- renal syndrome leading to renal failure. Chronic infection can also be associated with extra-hepatic manifestations such as cryoglobulinemia, porphyria cutanea tarda, arthralgia, membranoproliferative glomerulonephritis, Sjogren’s syndrome, Raynaud’s syndrome, idiopathic thrombocytopenic purpura and non-Hodgkin’s lymphoma (Liang et al, 2000). Among those with cirrhosis, 1–4% per year develop hepatocellular carcinoma (Fattovich et al, 2004). Deaths associated with chronic HCV are usually a result of the complications of decompensated cirrhosis and hepatocellular carcinoma. Survival rates decline rapidly with the onset of decompensation. The 5-year survival rate for patients with compensated cirrhosis is as high as 90% as compared to 50% for those with decompensated cirrhosis (Fattovich et al, 1997; Hu and Tong, 1999).

Clinical features and diagnostic evaluation Most patients with chronic HCV are asymptomatic or may present with nonspeciﬁc symptoms such as fatigue or malaise. Some of them may have arthralgia and myalgia. Patients with decompensated disease may display peripheral manifestations of cirrhosis, such as palmar erythema, spider nevi, Dupuytren’s contracture, gynaecomastia, parotid enlargement, temporal muscle wasting, ascites, hepatosplenomegaly or testicular

Correspondence: T Jake Liang, MD, NIDDK, NIH, 10 Center Drive, Room 9B-16, Bethesda, MD 20892, USA. Tel: +1 301 496 1721, Fax: +1 301 402 0991, E-mail: Jakel@bdg10.niddk.nih.gov

Received 09 September 2007; accepted 10 September 2007

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atrophy. The diagnosis of HCV is made by the presence of anti-HCV antibody and HCV RNA in the blood.

Further evaluation includes genotyping and quantifying HCV viral level, which usually is in the range of 0.2)5 million IU ml⁾¹. Basic laboratory tests like liver function tests, prothrombin time and hepatitis B as well as HIV serologies should be performed. Liver biopsy is often useful in making the correct diagnosis and determining the severity of inﬂammation and stage of ﬁbrosis (Kleiner, 2005).

Treatment

Treatment considerations for hepatitis C are based on the presentation of the disease (acute vs chronic), genotype, laboratory values, presence of co-infection (HIV, hepatitis B) and co-morbidities. The main goal of treatment of HCV is to achieve sustained virologic response (SVR), deﬁned as the absence of HCV RNA in serum at least 6 months after the discontinuation of therapy. The cost of a 48-week treatment ranges from

$30 000 to $40 000 not including the clinic visits during ongoing treatment (Hoofnagle and Seeﬀ, 2006; Shah and Wong, 2006). Hence, every patient should be carefully evaluated with respect to treatment indica- tions, associated co-morbidities, adherence to treatment and reliability of follow-up.

Chronic hepatitis C

Treatment of chronic hepatitis C in adults is recommended for those who have detectable HCV RNA levels, elevated aminotransferase (ALT) levels, liver biopsy ﬁndings suggestive of progressive liver disease and the absence of any serious co-morbid conditions or contraindications as listed in Table 1 (Strader et al, 2004; Dienstag and McHutchison, 2006). ALT levels however, do not always correlate with disease severity and hence, treatment should not be denied in those with normal ALT levels (Bacon, 2002).

The therapy of hepatitis C has improved substantially over the years (Figure 1). The current recommended treatment of chronic HCV is the combination of

peginterferon and ribavirin. a-Interferon was first shown to have a benefit in chronic hepatitis C infection in 1986 (Di Bisceglie and Hoofnagle, 2002). Five to fifteen percent of patients achieved SVR after a 6- to 12-month course of IFN-a. The overall response rates were substantially increased by the addition of the oral nucleoside analog ribavirin. IFN-a, by activating a variety of antiviral pathways, is active against many RNA viruses including HCV. The mechanism of action of ribavirin is not well understood. It has no direct antiviral activity and appears to enhance the antiviral effect of IFN-a in the treatment of hepatitis C, possible by a combination of mechanisms (Feld and Hoofnagle, 2005).

Another signiﬁcant advance in HCV therapy came with the development of long-acting pegylated interferon (peginterferon). A polyethylene glycol moiety is covalently attached to the IFN-a molecule resulting in a product that is still biologically active, but has a larger molecular mass, improved distribution and increased half-life. The combination of peginterferon and ribavirin has been shown to yield the highest response rates in three pivotal trials (Manns et al, 2001; Fried et al, 2002;

Hadziyannis et al, 2004). With peginterferon and ribavirin, 70–80% of patients with genotype 2 or 3 infection and 42–45% of those with genotype 1 infection can achieve a SVR. These results were signiﬁcantly better than those achieved with standard combination therapy or peginterferon monotherapy. The current recommended regimen is summarized in Table 2. There is no current established treatment for patients with genotype 4, 5 or 6. These patients are usually treated with the same regimen used for genotype 1 patients (El-Zayadi et al, 2005).

Acute hepatitis C

An optimal treatment regimen for acute hepatitis C has not yet been established. Genotype and HCV RNA levels do not seem to play a role in determining treatment outcomes (Alberti et al, 2002). Up to 50%

of patients with acute HCV spontaneously clear the virus (Gerlach et al, 2003; Hofer et al, 2003). Hence, a delay of treatment for 8–12 weeks after the onset of acute hepatitis C has been suggested. A recent trial

Table 1 Contraindications to treatment with peginterferon and ribavirin

Absolute contraindications 1. Pregnancy

2. Breast feeding

3. Allergic reaction to either drug Relative contraindications

1. Decompensated liver disease as deﬁned by bilirubin >1.5 mg dl⁾¹, prothrombin

time >15 s or INR‡1.7, albumin <3.4 g dl⁾¹, ascites, bleeding esophageal varices, hepatic encephalopathy 2. Neuropsychiatric diseases

3. Coronary artery disease 4. Cerebrovascular disease 5. Renal failure

6. Previous organ transplantation

Close monitoring and dose adjustment might be required in patients with anemia, thrombocytopenia or leucopenia. Patients with renal dysfunction might need adjustment of ribavirin dose.

6%

16%

34%

42% 39%

54%

61%

0 20 40 60 80 100

IFN 6 m IFN 12 m IFN/R 6 m IFN/R 12 m PegIFN 12 m Peg/R low 12 m

Peg/R std 12 m

Sustained response (%)

1980s 1990s 2000s

Figure 1 Progress in therapy of hepatitis C. IFN, interferon; PegIFN, peginterferon; R, ribavirin; R low, low-dose ribavirin; R std, standard- dose ribavirin

AA Modi and TJ Liang

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demonstrated >90% SVR rates in individuals with acute HCV when treatment with peginterferon was started within 12 weeks after onset of disease. Both IFN and peginterferon with or without the combination of ribavirin have been used in various studies with promising results. Studies with IFN-a have reported SVR rates of as high as 95% when patients are treated for 24 weeks (Kamal et al, 2006). Similarly, studies of peginterferon with or without ribavirin have reported SVR rates of 80–89% with 24 weeks of treatment (Kamal et al, 2004; Wiegand et al, 2006).

Treatment response

There are three types of response to therapy: SVR, relapse or breakthrough, and non-response. In patients with SVR, HCV RNA levels become undetectable in 4–

24 weeks and remain negative for the entire duration of follow-up. ALT levels return to normal and liver histology shows improvement. In those with relapse (20%), the HCV RNA levels reappear after therapy is stopped, usually within a few weeks of the end of treatment. In those with breakthrough (10%), HCV RNA levels initially become undetectable but reappear during therapy. In patients with non-response, HCV RNA levels never become undetectable during treatment. In genotype 1 patients, it is unlikely to achieve SVR if they do not become HCV RNA negative by 24 weeks of therapy (Manns et al, 2001; Hadziyannis et al, 2004). Moreover, if HCV RNA levels do not decrease by 2 log10IU ml⁾¹ or more by 12 weeks of therapy, SVR is unlikely in >98% of cases and therefore therapy should be stopped (Davis, 2002;

McHutchison et al, 2002).

Predictors of treatment response

Various factors have been associated with lower response rates in patients undergoing treatment with peginterferon and ribavirin. They are genotype 1, African American race, pretreatment HCV RNA levels of >800 000 IU ml⁾¹, male sex, higher body mass index and advanced ﬁbrosis (Feld and Hoofnagle, 2005;

Hoofnagle and Seeﬀ, 2006). Hence, these factors should be reviewed when considering therapy.

Adverse effects of treatment

Treatment with peginterferon and ribavirin is associated with numerous adverse eﬀects (Table 3). Most patients

undergoing treatment experience side effects ranging from mild to severe. As a result, patient education of potential side effects as well as monthly visits for monitoring blood counts and symptoms should be emphasized before the initiation of therapy. The most common side effects of peginterferon are fatigue, muscle aches and psychological side effects such as depression, anxiety, irritability and sleep disturbance. These side effects are usually managed in an outpatient setting with patient education, antidepressants⁄anxiolytics, referral to a psychiatrist and the use of erythropoietin or granulocyte macrophage colony stimulating factor if needed. If side effects are not well controlled, dose reduction from 180 lg week⁾¹ to 135 or 90 lg week⁾¹ for peginterferon alfa-2a, and from 1.5 to 1.0 lg kg⁾¹week⁾¹for peginterferon alfa-2b as well as drug discontinuation should be considered (Fried, 2002).

Table 2 Current recommended therapy for chronic hepatitis C

Genotype

Peginterferon dose (SQ)

Ribavirin dose (PO)

Duration of treatment

(weeks) 1 Peginterferon a-2a:

180 lg week⁾¹ Peginterferon a- 2b:

1.5 lg kg⁾¹week⁾¹

1000 mg day⁾¹for body wt.£ 75 kg 1200 mg day⁾¹for body wt. > 75 kg

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2 or 3 Same as above 800 mg day⁾¹ 24

Table 3 Adverse eﬀects Adverse eﬀects of

peginterferon Comments

Inﬂuenza like symptoms:

Fever

Typically after the ﬁrst injection.

Gastrointestinal symptoms:

Nausea

Hair loss: 20–25% of patients,

usually temporary.

Bone marrow suppression:

Leucopenia, thrombocytopenia

Typically 30–50% reduction in counts, may treat with G-CSF.

CNS toxicity: headache, depression, irritability, psychological changes

10% of patients, use of anti-depressants, dose reduction if severe.

Seizures 1–2% of patients,

dose discontinuation.

Autoimmune thyroid disease:

Hypothyroidism, hyperthyroidism

1–2% of patients, treat if symptomatic.

Others: cardiac side eﬀects, interstitial nephritis,

vision and hearing disturbances, elevation in serum aminotransferases Adverse effects of

Ribavirin Comments

Hemolytic anemia Dose reduction if

symptomatic or Hct <30%, dose discontinuation if Hct drops further, may use erythropoietin.

Lymphopenia Lymphocyte counts may

decrease by 10–15%.

Gout: Increase in uric acid Discontinue if attack severe⁄prolonged.

Pruritis 20% of patients,

discontinue if severe.

Nasal stuﬃness, sinusitis 20% of patients, treat if symptomatic.

Teratogenicity Discontinue if pregnancy

test positive.

Others: Hepatic iron accumulation, cholelithiasis, retinal changes

Hct, hematocrit; G-CSF, granulocyte-colony stimulating factor.

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The most common side eﬀect of ribavirin is hemolytic anemia, which usually warrants dose reduction. Around 1–2% of patients on combination therapy experience serious side eﬀects such as myo- cardial infarction in patients with underlying coronary artery disease or stroke in patients with atherosclerotic disease. About 30–40% of patients on 48 weeks of treatment require dose reductions with early discontinuation in up to 20% of patients (Fried et al, 2002; Hadziyannis et al, 2004). Temporary discontinuation of ribavirin should also be considered in patients with severe anemia until the hematocrit returns to >30 either with or without the institution of erythropoietin.

Future advances in therapy

Many new approaches to therapy of chronic hepatitis C are being studied in clinical trials. Some of the recent advances have been made in the modiﬁcation of the dose and duration of current recommended combination therapy. Ribavirin in high doses (1400–

2400 mg) has been shown to achieve higher SVR rates in a small trial at the expense of a higher toxicity proﬁle (Lindahl et al, 2005). New forms of IFN are being tested clinically. A new generation of small molecule inhibitors targeting the viral-encoded en- zymes, such as the proteases and polymerases is being developed. Many of them are in late phase clinical trials (Pawlotsky, 2007). Although some of them are quite promising in suppressing HCV levels in HCV- infected people, drug resistant mutants emerge rapidly after the initiation of therapy. Therefore they would have to be used in combination with IFN-based therapy.

Conclusion

Treatment of hepatitis C has improved substantially in response rates across all genotypes. However, progress remains to be made to improve the SVR rates for genotype 1 patients as well as relapsers and non- responders. Until the above-discussed new agents pass rigorous scrutiny in clinical trials, the current combination therapy of peginterferon and ribavirin will remain the mainstay treatment of hepatitis C for the next 3–

5 years.

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