The hepatitis C-positive patient

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Chapter 35 THE HEPATITIS C-POSITIVE PATIENT

• Hepatitis C is the leading cause for liver transplantation.

• Specific viral nucleic acid testing is available to confirm the diagnosis of acute and chronic hepatitis C virus (HCV) infection.

• Antiviral therapy should be considered for every patient with acute or chronic HCV infection with provision of counselling and support services.

• Hepatitis C genotype and viral load are useful in predicting a response to therapy; liver biopsy may be useful in providing a long-term prognosis.

• The combination of pegylated interferon and ribavirin is the international standard of therapy for patients with chronic HCV infection.

• Individualisation of antiviral therapy is possible based on genotype and virological response in the first weeks of treatment.

EPIDEMIOLOGY

Prevalence and natural history

The prevalence of hepatitis C virus (HCV) infection varies worldwide with relatively low prevalence in North America and Europe compared with higher prevalence in Asia and southern Europe. The prevalence in Australia is approximately 0.1%, making HCV infection a common cause of chronic liver disease. Recent estimates from the Hepatitis C Projections Working Group 2006 suggest that around 200,000 people were chronically infected with the virus at the end of 2005 in Australia and that the prevalence will triple over the next 20 years. Of chronically infected individuals, 10%–15% will develop liver cirrhosis over a 20-year period. Once cirrhosis is established, hepatocellular carcinoma (HCC) develops at an annual incidence of 2%. In most countries where data are available, HCV infection is the leading cause of liver transplantation. The Hepatitis C Projections Working Group concluded that the current number of people receiving treatment would need to be increased three-fold to reduce the proportion of patients living with advanced liver disease due to HCV infection.

Risk factors for acquiring HCV infection

HCV is a blood-borne virus and, therefore, a history of blood exposure can be elicited in many patients. The introduction of routine antibody screening of blood products substantially reduced the risk of transmission from blood transfusion to less than 1 in 200,000 units transfused. The implementation of nucleic acid testing has further reduced the risk to around 1 in 1,000,000 donations. There is a high prevalence of HCV infection in injecting drug users and, in Australia, the majority of patients acquired the infection through the sharing of infected needles or equipment during injecting drug use. Other less common routes of exposure include skin or mucosal penetration from tattooing or contaminated medical instruments. Sexual transmission and vertical transmission from mother to child is uncommon. Transmission following needlestick injury in a healthcare setting is also uncommon; estimates range from 0% to 6%. Post-exposure prophylaxis is not recommended.

VIROLOGY

HCV is a small, enveloped, single-stranded RNA virus of 9.5 kb that encodes a single polyprotein that is cleaved into structural and regulatory proteins. The structural region contains the core and two envelope proteins (E1 and E2). The non-structural proteins function as proteases (NS3/4) and polymerases (NS5B) and provide important targets for a new class of small molecules undergoing early phase trials for the treatment of HCV infection. Error-prone replication results in the rapid evolution of diverse quasispecies within an infected individual. It is estimated that more than 10 trillion virion particles are produced daily in both acute and chronic phases of infection.

HCV is classified on the basis of similarity of nucleotide sequence into major genetic groups designated genotypes. A recent reclassification has resulted in six major genotypes with a number of subtypes that vary geographically. Genotypes 1, 2 and 3 are common in North America, Europe, Japan and Australia; genotype 4 is common in the Middle East including Egypt, genotype 5 in South Africa and genotypes 6 and its subtypes in Asia. All major genotypes have been identified in Australia, although genotypes 1 and 3 are more common.

DIAGNOSTIC TESTING

Diagnosis of HCV exposure relies on serological assays. HCV infection is confirmed through nucleic acid testing for viral genomes (HCV RNA). Serological assays are based on the detection of specific antibodies to HCV recombinant antigens by enzyme immunoassays. The widely used second- and third-generation immunoassays can detect antibodies within 4–10 weeks after infection. False positives are common when screening low-risk populations and false negatives can occur in immunocompromised individuals, for example in HIV/HCV coinfection.

Detection of HCV RNA distinguishes previous exposure from current infection. Qualitative HCV RNA tests, based on the polymerase chain reaction (PCR), have a lower detection limit than quantitative viral load tests. Commercial tests used to quantitate HCV viraemia include a branched DNA assay (Versant™ HCV RNA 3.0, Bayer) and PCR-based assays such as the Cobas Monitor Amplicor^® HCV 2.0 and the HCV TaqMan™ (Roche Diagnostics). All systems deliver reliable, but not always directly comparable, results. While a standardised practice of expressing viral load in international units (IU/mL) has been proposed to allow comparison of different assay results, it is prudent to monitor an individual patient during treatment using only one assay to avoid inter-assay variability that may affect management decisions.

CLINICAL COURSE OF HCV INFECTION

Acute HCV infection

Acute HCV infection is commonly asymptomatic and thus infrequently recognised clinically. Systematic reviews suggest that approximately 25% of patients may spontaneously clear acute HCV infection although the exact proportion is unclear. Acute HCV may be associated with a clinical syndrome of fatigue, lethargy, low-grade fever and right upper quadrant discomfort. Serum HCV RNA typically becomes detectable 7–21 days after exposure and specific antibodies appear subsequently. Jaundice occurs in less than 20% of acute infections. Interestingly, the patients who develop clinically apparent acute hepatitis clear the virus and avoid chronic disease with greater frequency than those who have clinically silent disease (see Treatment section). The host and viral factors that influence resolution of HCV infection remain unclear.

Chronic HCV infection

The majority of persons exposed to HCV will develop chronic infection with persistence of detectable serum HCV RNA for more than 6 months. A certain proportion of these patients will have persistently normal liver function tests; in these patients the risk of progression to advanced liver diseases is low. In patients with abnormal alanine aminotransferase (ALT), the overall fibrosis progression rates are higher and some will progress through increasing stages of fibrosis to cirrhosis (Figure 35.1).

FIGURE 35.1 Hepatitis C natural history.

Complications of chronic HCV infection

Progression to cirrhosis

The primary concern for patients with chronic HCV infection is the evolution from chronic hepatitis to advanced fibrosis and cirrhosis. Estimates of progression to cirrhosis have been examined in different populations of HCV-infected patients. In studies involving liver clinic populations, rates of progression to cirrhosis have been estimated at 20%–35% at 20–30 years, which may reflect referral and selection bias. Progression to cirrhosis in community based groups, such as blood donors newly diagnosed with HCV infection, is generally lower, approximately 2%–5% after 10–20 years of infection. In the majority of community-based studies, subjects tend to be younger and a larger proportion will have normal liver function tests, which may be associated with milder disease.

Factors that affect progression to cirrhosis could be related to the virus or to the host. Interestingly, viral factors appear to play the least important role and there are no convincing data to link either HCV genotype or viral load with liver injury, although both of these factors are critical in predicting treatment outcome. Several host factors significantly influence the likelihood of progression to cirrhosis; these include age at infection (cirrhosis occurs more frequently in older compared with younger patients), gender (progression is lower among women than men) and lifetime alcohol intake. Insulin resistance (obesity, diabetes and steatohepatitis) and genetic polymorphisms in inflammatory mediators are likely to be associated with fibrosis progression.

Progression to hepatocellular carcinoma

The risk of HCC is increased 25-fold in HCV-infected patients compared with HCV-negative controls. Virtually all HCV-related HCC cases occur among patients with advanced fibrosis or cirrhosis. The annual risk of HCC development in patients with HCV cirrhosis is 1%–4% in Western populations and higher in Asian populations (up to 7%). Factors affecting progression to HCC include male gender, older age, duration of HCV infection (most cases occur after 25–30 years of chronic infection), daily alcohol intake >60 g (>6 standard alcoholic drinks/day) and coinfection with HBV.

ASSESSING LIVER INJURY

Liver function tests

Traditional ‘liver function tests’ such as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) provide a relatively insensitive indication of the degree of hepatic inflammation. These enzymes do not correlate well with either the extent of liver injury or the risk of disease progression. Serum ALT can be used to monitor treatment efficacy in addition to viral testing. However, serum ALT may be elevated even when HCV RNA is not detected because of other factors such as hepatic steatosis and hepatic iron content. Other markers such as a low albumin, elevated bilirubin and prolonged coagulation tests more accurately indicate impairment of liver function.

Histology

Histological staging provides the most reliable estimate of hepatic fibrosis and likelihood of disease progression, although it is subject to sampling error and variability in interpretation. Liver biopsy is an invasive procedure and major complications occur in 0.06%–0.3% of biopsies; however death as a direct result of liver biopsy is extremely rare. In the future, it is possible that indirect markers of fibrosis may obviate the need for a liver biopsy. Liver biopsy can provide an assessment of disease progression rate if the date of onset of infection is known; this may be helpful in counselling patients about treatment. Liver biopsy in patients with chronic hepatitis C can indicate prognosis, exclude other forms of liver disease, predict the likelihood of responding to antiviral therapy and provide baseline histology that can be factored into future management decisions.

TREATMENT

Interferon and ribavirin

Interferons are naturally occurring antiviral proteins that produce an ‘antiviral state’ to promote elimination of virally infected cells. Jay Hoofnagle and colleagues first reported using recombinant alpha interferon to treat non-A, non-B hepatitis in 1986. John McHutchison and colleagues showed in 1998 that the addition of ribavirin, a guanosine analogue, in combination with interferon reduced the relapse rate following the end of therapy, and thus improved the overall sustained response rate. The precise mechanism of ribavirin’s antiviral activity is unknown; it is ineffective against HCV when given alone. Currently the combination of pegylated interferon and ribavirin is the international standard of therapy for patients with chronic HCV infection. Addition of polyethylene glycol (pegylation) to the interferon molecule allows for weekly administration; ribavirin tablets are taken daily in divided doses.

Treatment regimens

The outcome of antiviral therapy can be defined biochemically by serum ALT normalisation and virologically by the lack of serum HCV RNA detection using a sensitive method such as PCR. A response at the completion of a treatment course is defined as an end-of-treatment response (ETR) but the desirable goal is a sustained response. A sustained virological response (SVR) is defined as undetectable HCV RNA 6 months following the completion of treatment. Non-responding patients include those who relapse (achieve an ETR but re-develop detectable serum HCV RNA) and patients with persistently detectable serum HCV RNA after adequate treatment durations.

Treatment of patients with acute symptomatic HCV infection with pegylated interferon alone may be effective in preventing chronic HCV infection in up to 90% of cases. Most studies have shown that the addition of ribavirin is not required for successful treatment. The timing of treatment remains controversial, but many studies have treated after 12 weeks’ observation in order to allow for spontaneous resolution.

For patients with chronic HCV infection, the recommended treatment duration with pegylated interferon and ribavirin varies by genotype. Patients with genotype 1 should receive treatment with either peginterferon alfa-2a (180 μg weekly) or peginterferon alfa-2b (1.5 μg/kg weekly) plus weight-based ribavirin daily for 12 months. Patients with genotypes 2 and 3 should receive the same interferon dosages plus ribavirin for 6 months; recent data suggest that a ribavirin dose of 800 mg/day is sufficient for these patients. Unfortunately, there are few data to guide therapy for patients with genotypes 4, 5 and 6, although it is generally thought that patients with genotype 4 require therapy for 12 months and patients with genotype 6 may only require treatment for 6 months. The overall SVR rate following therapy with pegylated interferon and ribavirin is approximately 55%; patients with genotype 1 have lower response rates than patients with non-1 genotypes. There is currently no consensus on the most effective treatment for patients who have either relapsed or failed to respond to pegylated interferon plus ribavirin.

Treatment with interferon may be individualised by considering genotype and, more recently, viral kinetics during therapy (see Table 35.1). Patients with genotype 1 who achieve an early virological response (EVR), generally defined as ≥2 log reduction in HCV RNA by week 12, are more likely to achieve an SVR compared with patients who do not reach this threshold. Those patients who achieve a 2 log reduction by week 12 should continue therapy until week 24; if they have undetectable HCV RNA by qualitative PCR at that time, then they should continue therapy until week 48. Patients who fail to achieve an EVR or who have detectable HCV RNA at week 24 should stop treatment, since the likelihood of achieving a SVR is less than 2%. Recent studies have looked at shortening treatment duration in genotype 1 patients with low pretreatment viral loads (Table 35.1) and prolonging treatment duration in genotype 1 patients with high viral loads.

TABLE 35.1 Virological testing during HCV antiviral therapy

Genotype 1
Week 12	Quantitative HCV RNA ≤2 log reduction → Discontinue therapy
Week 12	Quantitative HCV RNA ≥2 log reduction → Continue therapy to week 24
Week 24	Qualitative HCV RNA detectable → Discontinue therapy
Week 24	Qualitative HCV RNA undetectable → Continue therapy to week 48
Week 48	End of therapy—check HCV RNA by qualitative PCR
Week 72	End of follow-up—check HCV RNA by qualitative PCR (this determines sustained virological response or relapse)
Recent developments: • Genotype 1 patients with low viral load may only require 24 weeks total therapy if HCV RNA is undetectable by week 4 • Genotype 1 patients who achieve undetectable HCV RNA between weeks 12 and 24 may benefit from extended therapy for 72 weeks to increase the duration of HCV RNA negativity

Genotypes 2 and 3 There are no recommendations for HCV RNA testing between commencement and end of treatment Recent developments:

Patients who achieve undetectable HCV RNA by week 4 may only require 12–16 weeks total therapy to achieve a SVR

HCV = hepatitis C virus; PCR = polymerase chain reaction; RNA = ribonucleic acid; SVR = sustained virological response.

Patients with HCV genotype 2 and 3 infection are currently treated for 24 weeks with pegylated interferon and ribavirin and achieve SVR rates of 80%. Recent studies have questioned whether treatment duration could be shortened by individualising treatment based on rapid or early virological responses. Shorter treatment duration with equivalent SVR rates seems feasible only in patients who are HCV RNA negative by week 4 and some patients, for example those with genotype 3 and a high viral load, may require longer treatment durations.

Adverse events associated with treatment

Interferon

Common side effects with interferon therapy include a ‘flu-like’ syndrome of myalgias, lethargy and fatigue during the first few weeks of therapy although tachyphylaxis to these symptoms is the rule. Interferons also affect mood, and irritability and depression are common, sometimes treatment-limiting, side effects. Neutropenia and thrombocytopenia are also common but reversible events that mandate close monitoring of patients during treatment.

Ribavirin

A dose dependent haemolytic anaemia, leading to a 20–40 g/L fall in serum haemoglobin, is common in patients treated with ribavirin. Less common side effects include upper respiratory tract symptoms and skin rashes. Ribavirin is a known teratogen and both patients and their partners must undertake adequate contraception during, and for 6 months following, treatment.

Prior to commencing therapy patients should have a baseline full blood examination, urea, electrolytes, creatinine, thyroid function tests and pregnancy testing. Patients with diabetes or hypertension should have an ophthalmological examination. Counselling prior to treatment and ongoing support during treatment are important in helping patients adhere to a difficult treatment regimen; those patients who complete a course of treatment have the best chance of eradicating HCV.

Long-term benefits of antiviral therapy

The most important goal of therapy is improved survival and there are now data indicating that hepatic fibrosis may regress and that HCC may occur less often in treated patients. Histological improvement, measured as a reduction in fibrosis stage, has been noted even in patients with cirrhosis prior to treatment. Other studies have shown a significant risk reduction for developing HCC in treated patients compared with untreated patients. Generally, patients who achieve a sustained virological response show the greatest benefit, but some improvement can be seen even in patients who remain viraemic. On the basis on these observations, several, prospective, large international trials are underway examining the role of maintenance interferon therapy in viraemic, non-responding patients.

Future therapy for HCV infection

New antiviral therapy for chronic HCV infection includes modified interferons, such as albumin bound to interferon (Albuferon), which provides a longer half-life compared with pegylated interferons. A number of specifically targeted antiviral therapies have been developed against essential HCV proteins, such as the viral polymerase and protease. Phase II trials are underway with these direct small molecule inhibitors, which will likely be combined with interferon and/or ribavirin. Immune-based therapies involve stimulation of innate immunity through activation of toll-like receptors and through the development of therapeutic vaccination to stimulate adaptive immunity.

SUMMARY

The pandemic of hepatitis C remains an important public health issue and a major challenge to individual patients in regard to understanding the impact of this chronic viral infection on their health and in making a decision whether to undertake a demanding treatment regimen. The international standard therapy is a combination of pegylated interferon and ribavirin, which achieves viral eradication in 55% of patients overall, although this proportion varies with genotype and viral load. Individualisation of treatment is possible based on virological responses during therapy in different genotype groups. Treatment is associated with significant adverse effects so that ongoing medical and nursing support is required. A number of new treatment approaches, based on direct antiviral agents and immune manipulation, are likely to improve patient outcomes in the future.

FURTHER READING

De Francesco R, Migliaccio G. Challenges and successes in developing new therapies for hepatitis C. Nature. 2005;436:953-960.

Halfon P, Penaranda G, Bourliere M, et al. Assessment of early virological response to antiviral therapy by comparing four assays for HCR RNA quantitation using the international unit standard: implications for clinical management of patients with chronic hepatitis C virus infection. J Med Virol. 2006;78:208-215.

Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med. 1986;315:1575-1578.

Manns M, Wedemeyer H, Cornberg M. Treating viral hepatitis C: efficacy, side effects and complications. Gut. 2006;55:1350-1359.

McCaughan G, George J. Fibrosis progression in chronic hepatitis C virus infection. Gut. 2004;53:318-321.

McHutchison JG, Gordon SC, Schif ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1485-1492.

Micallef J, Kaldor J, Dore G. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. J Viral Hep. 2006;13:34-41.

Prati D. Transmission of hepatitis C virus by blood transfusions and other medical procedures: a global review. J Hepatol. 2006;45:607-616.

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