Persistent viremia beyond 6 months of infection indicates chronic infection [10–12]. Once chronic infecti on is established, spontaneous clearance of HCV is very rare. Published estimates of fibrosis progression and time to cirrhosis are dependent on study design and the patient population, while one large systematic review of 111 studies estimated prevalence of cirrhosis at 20 years after the infection to be 14–19 % [19] (Fig. 11.1). Fibrosis progression in chronic hepatitis C is variable and depends on numerous host, viral, and environmental factors, such as age at acquisition of infection, sex, race, genetic factors, alcohol consumption, insulin resistance, and coinfection with other viruses [20] (Table 11.2). Identification of these factors is important because modifiable factors can be altered and high-risk patients should be treated promptly. For example, insulin resistance, obesity, and/or h epatic steatosis have shown to accelerate progression of fibrosis and pos sibly increase risk of HCC in patients with HCV [21]. Weigh t reduction is associated with decrease in hepatic steatosis and the rate of fibrosis progression [21].

It should be noted that serum ALT level has high visit-to-visit variability and is not a good indicator of liver disease activity or fibrosis in HCV patients [22]. Prospective data from community-based cohort of 1,235 HCV-infected persons found that ALT levels were persistently normal in 42 %, persistently elevated in 15 %, and intermittently elevated in 43 % [22]. Patients with persistently normal serum ALT levels tend to have significantly lower scores for inflammation and fibrosis, compared with patients with elevated serum ALT levels; however advanced fibrosis/cirrhosis and portal inflammation can be observed histologically in 12 and 26 % of those with persistently normal and abnormal ALT, respectively [23]. Traditionally, the gold standard for the assessment of the stage of fibrosis in HCV has been to perform percutaneous liver biopsy and then staging by METAVIR, Ishak, or Knodell scoring systems. However, in real-life practice, liver biopsy may be limited by patient’s acceptance, pain, risk of bleeding, and the possibility for sampling error. Therefore, noninvasive methods to assess liver injury and fibrosis (e.g., transient elastography, serum direct and indirect fibrotic markers) have been evaluated and are becoming increasingly available and used. Although no single noninvasive test or combination of tests developed to date can parallel the information obtained from actual histology, noninvasive methods, particularly when used in combination, can reliably differentiate between minimal and significant fibrosis or cirrhosis, and thereby avoid liver biopsy in a significant percentage of patients [24].

Among patients with HCV-induced cirrhosis, manifestations of liver failure (e.g., ascites, variceal bleeding, encephalopathy, and hepatorenal syndrome) develop in 3–5 % per year, and HCC develops in 1–4 % per year [25–27]. Once decompensation has developed, survival rate is about 50 % at 5 years and LT is the only effective therapy [25–27] (Fig. 11.1).

HCV infection can be associated with other extrahepatic conditions, such as impaired quality of life, insulin resistance, mental impairment, depression, lymphoproliferative (e.g., essential mixed cryoglobulinemia and lymphoma) and autoimmune disorders [28, 29]. Further, HCV generates a major financial burden to society. In 1997, the total cost of HCV-related illness in the USA was estimated to be $5.46 billion ($1.80 billion direct cost s and $3.66 billion indirect costs) [30]. The pr ojected annual direct medical care cost of HCV treatment from 2010 to 2019 is $6.5–$13.6 billion, with in direct costs expected to reach $75.5 billion [31].

Antiviral therapy should be considered for all patients with chronic HCV infection. In most circumstances, the decision of whether or not to proceed with treatment is based on the patient’s desire and the need for therapy. The degree of the need is a subjective assessment that is made upon considering the stage of liver disease, presence or absence of favorable factors for treatment response, safety and efficacy of the available treatment options, age and comorbid conditions.

The primary goal of treatment of HCV infection is eradication or “cure” of the virus. Sustained virologic response (SVR, undetectable HCV-RNA by sensitive assay after 12–24 weeks after completion of therapy) is known to be an excellent surrogate marker for the cure of HCV. In an extensive review of 44 long-term follow studies after treatment-induced SVR, HCV-RNA was noted to have remained undetectable in 97 % of a combined total of >4,000 HCV patients, many of whom were immunosuppressed, during their follow-up periods (range from 2 to >10 years) [32, 33]. Several studies have clearly demonstrated that SVR is associated with a substantial reduction in hepatic inflammation, reversal of fibrosis and even of cirrhosis, as well as improvement in health-related quality of life [34–38]. Hence, the risk of liver failure, at least over the short term, is virtually eliminated in patients with cirrhosis who achieve an SVR [36–38]. Notably, the risk of HCC after SVR in patients with cirrhosis is reduced by more than one half; however the risk is not eliminated and surveillance for HCC in cirrhotics must continue [37, 38]. Additional cirrhosis care, in those who achieved SVR, such as surveillance for varices is necessary although we currently do not know if the frequency of surveillance should remain the same as for those without viral clearance or those with other etiologies for cirrhosis. Successful treatment of HCV has been associated with a decrease in liver related mortali ty, need for liver transplantation, and also with a decrease in all-cause mortality [39].

Interferon-based regimen, mainly with PEG-IFN plus ribavirin (RBV), had been the standard of care of HCV therapy for more than a decade [14, 40]. Two forms of PEG-IFN are available (PEG-IFN alfa-2a and alfa-2b), and RBV should be administered according to the body weight of the patient. Although smaller trials from Europe have suggested slightly higher SVR rates with PEG-IFN alfa-2a [41, 42], a large US multicenter study did not detect any significant difference in SVR between the two PEG-IFNs plus RBV [43]. While IFN-based therapies have almost been completely replaced by IFN-free DAA-based therapies in the USA, a combination of PEG-IFN/RBV will be still widely utilized in the developing countries for quite some time because access to new drugs are restricted and delayed by policies, limited resources, and economic barriers.

PEG-IFN/RBV treatment is administered for either 48 weeks (for HCV genotypes 1, 4, 5, and 6) or for 24 weeks (for HCV genotypes 2 and 3), inducing SVR rates of 40–50 % in those with genotype 1, 50–60 % in those with genotype 4, 60–90 % in those with genotype 6, and >70–85 % in those with genotypes 2 and 3 infection [14, 40, 44]. Several host (e.g., age, race, IL-28 B genotype, obesity, metabolic, comorbidities and presence of advanced fibrosis and cirrhosis), viral (e.g., viral load and genotype), environmental (e.g., substance and alcohol abuse), and treatment-related factors (e.g., side effects, adherent to therapy) have been shown to influence the SVR rates following IFN-based therapy. It should be noted that HCV treatment outcome with PEG-IFN/RBV in Asians seems to be superior to that of non-Asian populations, and this may be due to several factors that include a favorable IL28B genotype [2, 44]. Host genetic polymorphisms located on chromosome 19 near the region coding for IL28B (or IFN lambda-3) is associated with SVR following treatment with PEG-IFN/RBV in HCV genotype 1, but also to a lesser extent for genotype 2 and 3 [45, 46]. IL28B testing is useful to predict virologic response at week 4 as a predictive marker for the success of treatment with PEG-IFN/RBV, but its role in protease inhibitor-based triple therapy is less significant, and is insignificant in IFN-free treatment regimen [45, 46]. Improvement of SVR rates with IFN-based therap y can be achievable by correction of modifiable risk factors, tr eatment adherence and response-guided adjustment of the treatment duration (response-guided therapy, RGT) [14] (Fig. 11.2).

One of the challenges in utilizing PEG-IFN/RBV therapy is management of the treatment-related side effects. The common side effects of PEG-IFN include influenza-like syndrome (fever, headache, malaise, and myalgia), cytopenia, sleep disturbance, hair loss and psychiatric effects, whereas the unusual and severe side effects include seizure, psychosis, severe depression, autoimmune reactions, bacterial infections, and thyroid dysfunction. The major side effects of RBV are hemolytic anemia, cough, rash, and teratogenicity. These side effects are generally manageable by pretreatment advice, proper clinical and laboratory monitoring, symptomatic treatment, and appropriate dose reduction of the related drugs. In cases with significant RBV-induced anemia (hemoglobin <10 g/dL), a stepwise RBV dose decrement is suggested to maintain RBV exposure during treatment in order to minimize virologic relapse [14, 47]. This strategy has been proven not to compromise the SVR rate, and erythropoiesis-stimulating agents may also be useful in select patients with difficulty in management of anemia especially in those with cirrhosis and/or multiple comorbidities [47, 48].

Therapies for chronic HCV have been evolving rapidly over the past few years, mainly due the development of new DAA targeting NS3/4A, NS5A, and NS5B HCV proteins (Table 11.3) [1, 13, 49, 50]. Accordingly, treatment-induced SVR rates have been consistently improving, and now IFN-free DAA combination regimen with short duration of treatment (<3 months), single or few pills per day, and >95 % SVR rates have become widely available. Currently, some of these all-oral combinations (such as sofosbuvir/ledipasvir with or without RBV, sofosbuvir plus simeprevir, paritaprevir/ritonavir/ombitasvir plus dasabuvir with or without RBV) have already been approved in the USA and some countries in Europe. Most recently, daclatasvir in combination with sofosbuvir with or without RBV has also been approved for use in the USA, and previously in E urope and in Japan and provides a viable option particularly for thos e with genotype 3 infection. At this evolving stage of HCV managem ent, it is suggested to continuously update the most recent recommendations for HCV treatment via the American Association for the Study of Liver Disease (AASLD), and EASL websites [1, 13]. The recent Infectious Diseases Society of America (IDSA)/AASLD guidance is summarized in Table 11.4, and with these regimens, the expected SVR rates are over 90 % for non-cirrhotic and cirrhotic patients with any of the HCV genotypes [1]. However, in real-life practice, treatment regimen for HCV may not be generalizable due to many reasons such as patient’s comorbidities, physician’s preference, availability and cost of DAA in each country, as well as the reimbursement policy. Therefore, the appropriate HCV treatment regimens should be tailored based on the risk of progressive liver disease in an individual patient, associated comorbidities, local or regional treatment guidelines and cost-effectiveness analyses.