Following a diagnosis of CHC, estimating the duration of infection and an assessment of disease severity may also help guide treatment decisions. The rate of fibrosis progression varies amongst CHC infected patients. Host, viral and environmental factors can all influence disease progression in CHC infection (Table 26.1). Some of these co-factors may be potentially modifiable, including alcohol consumption, smoking, metabolic factors (insulin resistance, obesity, steatosis) and HIV co-infection [17, 18]. Studies assessing fibrosis progression have mostly been cross-sectional, and based on a single liver biopsy and estimated duration of infection. Prospective studies have been based on selected cohorts attending tertiary referral centers. These estimates indicate that fibrosis progression is nonlinear and may be slow, moderate or rapid. For example, only 0–2% of younger women that acquired HCV from anti-D immune globulin progressed to cirrhosis over a 20-year period, compared to an average of 13 years for older male patients that consumed at least 50 g of alcohol daily [12]. CHC patients with compensated cirrhosis have slowly progressive disease, with an estimated annual hepatic decompensation rate of 4–5%, and 1–4% for incidence of hepatocellular carcinoma (HCC) that remains the most frequent initial complication in these patients [19,20]. Current estimates of HCC incidence rates are higher in countries such as Japan that have a longer natural history of HCV infection, but these are expected to double in the USA over the next decade.

Diagnosis and evaluation

Diagnostic tests for HCV infection comprise serologic assays for antibodies and molecular techniques for virus particle detection. Anti-HCV is typically identified using second or third generation enzyme immunoassays that detect antibodies directed against various epitopes in the core, NS3, NS4 and NS5 proteins, with a specificity of 99%. In low-risk populations, false-positive tests may occur, and recombinant immunoblot assays (RIBA) are used in some centers to confirm positive EIAs. False negative tests may occur in HIV-1 infection, renal failure and HCV-associated cryoglobulinemia. Confirmatory testing involves molecular techniques that are useful in detecting and quantifying viral genomes using target or signal amplification methods. Several reliable qualitative and quantitative assays for detection are now commercially available. The newer realtime PCR and target mediated amplification assays have lower limits of detection for HCV of below 10IU/ml. However, these tests are expensive and not recommended for low prevalence population screening. They are used for confirmatory testing in acute infection prior to development of anti-HCV, immunocompromised patients, new-borns, and in CHC patients to predict and monitor virologic responses to antiviral therapy.

Table 26.1 Host-viral factors associated with disease progression.

NAFLD: non-alcoholic fatty liver disease; ALT: alanine aminotransferase; HLA: human leucocyte antigen

All patients with confirmed CHC should have genotype testing to determine duration and likelihood of response to currently available antiviral therapy. A liver biopsy in CHC patients also provides useful baseline information in regards to necroinflammatory activity and fibrosis stage that can help determine prognosis, urgency of therapy, prediction of response to treatment, and evaluation of co-morbid states such as steatosis. In the absence of co-morbid issues that preclude treatment, patients with HCV genotype 2 and 3 infection have excellent predicted responses to antiviral therapy, and may not require a biopsy prior to therapy. However, percutaneous liver biopsy is an invasive procedure that is costly, and may be associated with a significant risk of complications that increase with age and the presence of cirrhosis. An additional concern with liver biopsy is that it samples only 1/50000^th of the liver, and thus is subject to sampling error, particularly in non-homogenously distributed chronic liver disease. Several studies have highlighted the inaccuracy of liver biopsy even for staging of advanced liver disease [21]. Some countries have adopted non-invasive serum tests of fibrosis, or imaging modalities such as transient elastography, as an alternative to liver biopsy to guide therapeutic decisions in CHC patients [22]. Despite these limitations, most experienced clinicians considering treatment for CHC infection are likely to recommend obtaining a liver biopsy, unless there are obvious contraindications.

Treatment for chronic hepatitis C

The main goal of treatment of patients with CHC infection is the prevention of progressive hepatic fibrosis through long-term eradication of HCV. The benefits of a sustained virologic response (SVR), defined as the absence of serum HCV RNA at 24 weeks after the end of treatment measured by a sensitive molecular assay, include normalization of serum alanine aminotranferase levels, improvement in hepatic necroinflammation and fibrosis, potential health-related quality-of-life benefits, reduced mortality and risk of developing complications of end-stage liver disease, in the majority of patients. Current standard-of-care therapy results in SVR rates that appear to be durable in at least 99% of patients over the subsequent five years, although 1–2% of patients may still harbor intrahepatic virus despite undetectable serum HCV RNA [23, 24]. A1b However, the presence of intrahepatic virus alone in these patients is likely to remain clinically insignificant.

Table 26.2 Contraindications to current pegylated IFN and ribavirin therapy.

Patient s election

All patients with CHC without definite contraindications to currently available IFN-based treatment should be considered as potential candidates for antiviral therapy (Table 26.2) [25]. A1a The decision to treat patients must take into account the variable natural history and rate of disease progression, associated co-morbid states, social situation and supports, risk-benefit aspects and cost-effectiveness of therapy in the individual. Patient preferences need to be considered, along with an assessment of behavioral and lifestyle aspects that may influence their ability to adhere to a prolonged duration of therapy associated with significant side effects. Patients also need to be reminded that CHC may be associated with non-specific symptoms such as fatigue, lethargy, asthenia and abdominal discomfort, which may significantly impact upon the quality of life of the individual, but do not correlate with severity of liver disease, and may not remit with successful viral eradication. Patients with significant co-morbid states that pose a relative contraindication to antiviral therapy require assessment and management in a multi-disciplinary setting with experienced health care providers. Several host and virus factors may determine successful responses to IFN-based therapy, of which the most important appear to be HCV genotype, baseline HCV RNA levels and undetectable virus at week 4 of therapy (rapid virologic response) (Table 26.3).

Table 26.3 Factors predictive of favorable virologic response to current therapy.

RVR: rapid virologic response; EVR: early virologic response.

Treatment options

The current standard-of-care treatment for CHC is a combination of pegylated interferon-alpha (PEG-IFN) and riba-virin [26–28]. A1 a Interferons (IFN) are a group of naturally occurring cytokines that exhibit a variety of immunomodu-latory, antiproliferative and antiviral effects. Pegylation refers to the covalent attachment of an inert, water soluble polymer of polyethylene glycol (PEG) to the IFN molecule in either a linear (Peginterferon alfa-2b (PEGINTRON), Schering-Plough, Kenilworth, NJ) or branch chain configuration (Peginterferon alfa-2a (PEGASYS), Hoffmann-La Roche, Basel, Switzerland) with differing molecular weights. Compared to standard interferon-alpha, the pegylated IFN compounds exhibit improved pharmacoki-netic profiles and a prolonged elimination half-life, thus allowing for increased efficacy and a convenient once-weekly subcutaneous dosing schedule (PEGINTRON, 1.5μg/kg/wk and PEGASYS, 180μg/wk). Data from a recently completed large randomized multicenter study evaluating individualized dosing efficacy in 3070 HCV genotype 1 infected patients noted similar efficacy (SVR rates 38-41%) and safety and tolerability (discontinuation rate 10-13%) for patients receiving either PEG-IFN-2a or -2b in combination with ribavrin [29]. A1a

Ribavirin is a synthetic purine nucleoside analog that likely exhibits antiviral effects through multiple pathogenic mechanisms including immunomodulation, depletion of intracellular guanosine triphosphate, and weak inhibition of HCV RNA-dependent RNA polymerase. Ribavirin acts synergistically with IFN to induce antiviral responses and reduce relapse rates, and is administered orally twice daily at weight-based doses depending on viral genotype (1000–1400mg/day for HCV genotype 1 (≤75kg = 1000mg/d, 75–105kg = 1200mg/d and >105kg = 1400 mg/d) and at a fixed dose of 800mg/day for HCV genotype 2 and 3) [30, 31]. A1c

Combination PEG-IFN and ribavirin therapy can achieve a sustained virologic response in 54–56% of patients, including 42–46% of patients with genotype 1 infection, and around 80% of those with genotype 2 and 3 infection. Most patients with genotype 1 require 48 weeks of combination therapy and those with genotypes 2 and 3 can be treated for only 24 weeks. Many of the large clinical trials have been based in Europe or North America, and there is limited treatment efficacy data available for genotypes 4–6. As a result, these patients should continue to receive treatment as for HCV genotype 1 infection [25, 32].A1c

Early response prediction

Studies of early viral kinetics in response to PEG-IFN and ribavirin indicate a rapid initial first phase decline in HCV RNA, due to virus inhibition, and a slower second phase response due to loss of HCV from infected hepatocytes. This resulted in the development of early virologic predictors in the first 12 weeks of therapy to select patients that would benefit from ongoing therapy, thereby reducing duration of treatment, cost and continued exposure to poorly tolerated drugs for non-responders. Early virologic response (EVR) is defined as a decline in HCV RNA of at least 2log₁₀ units or to undetectable levels by the first 12 weeks of treatment. Although 75–85% of patients receiving combination therapy achieve EVR, failure to achieve this early response is associated with a minimal (1.6%) chance of achieving SVR with continued treatment [33]. B2 Assessment of EVR at week 12 of combination therapy has thus been adopted into clinical practice for HCV genotype 1 patients.

Response predictors at earlier stages during treatment have also been evaluated in relation to shortening the duration of therapy for CHC patients. A study evaluating shorter 24-week duration therapy for HCV genotype 1 patients with low baseline HCV RNA (<600,000IU/mL) noted SVR rates of 89% in a subgroup of patients that achieve rapid virologic response (RVR, defined as HCV RNA < 29IU/mL by week 4). This was comparable to SVR rates of 85% observed in historical controls achieving RVR with treatment duration of 48 weeks [34] A1c Similar assessments in other study cohorts confirmed that patients with lower baseline HCV RNA and undetectable virus at week 4 of combination therapy achieve SVR rates of over 80% with 24 weeks of treatment [35]. A1c In general, 10–15% of HCV genotype 1 infected patients have a low baseline HCV RNA and achieve RVR, and thus may be theoretically considered for reducing treatment duration from 48 weeks to 24 weeks. Until further data is available, HCV genotype 1 infected patients with advanced stage disease, African-Americans, or those requiring early dose adjustments during therapy, should continue to receive the standard-of-care 48 weeks duration treatment. Furthermore, the HCV RNA threshold that defines low baseline viremia has not been clearly delineated and varies from 400,000-800,000IU/mL. In addition, a sensitive HCV RNA realtime PCR or TMA assay must be utilized to detect minimal residual viremia at week 4 that increases the likelihood of relapse with reduced duration therapy [36]. B4

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