Chronic hepatitis C (CHC) is a global healthcare problem affecting more than 300 million persons worldwide . Approximately 15-20% of patients chronically infected with hepatitis C virus (HCV) may develop cirrhosis, resulting in an increased risk of progressive liver failure and hepatocellular carcinoma (HCC) . Cirrhosis of the liver and HCC are life-threatening complications, and it is estimated that 4% of patients with HCV-related cirrhosis will develop HCC .
Treatment regimens for CHC have improved in the past two decades [4-6]. The combination of pegylated (peg) interferon alfa plus ribavirin is the standard of care for naïve CHC patients, achieving a rate of 50% to 90% sustained virological response (SVR) depending on the HCV genotype [7-11]. Nevertheless, a significant number of CHC patients relapse (i.e., their HCV RNA status changes from undetectable at the end of treatment to detectable after treatment follow-up) or are non-responders (i.e., they never attain undetectable HCV RNA during therapy). Liver damage among these patients may progress to cirrhosis and they are at risk of developing HCC. There are many ongoing studies aimed at investigating whether antiviral combination therapy with peginterferon-alfa plus ribavirin is able to improve the SVR rate. Factors associated with non-response have been reported and include HCV genotype 1 infection, cirrhosis, African-American ethnicity, and high baseline viral load [6,12].
In order to re-treat patients who have failed prior regimens, it is important to identify the initial virological response during their failed treatment, as well as the compliance and type of prior therapy. The optimal management strategy for the peginterferon-alfa plus ribavirin non-responder remains to be determined. Moreover, non-responders represent a very heterogeneous population; therefore, it is important to adequately classify them.
DEFINITIONS OF RESPONSE TO PRIOR TREATMENT
- Rapid virological response (RVR): negativization of HCV RNA at week 4.
- Early virological response (EVR): complete EVR (cEVR) is defined as negativization of viral load at week 12; partial EVR (pEVR) is defined as a ≥2-log decrease of HCV RNA after 12 weeks of treatment.
- Sustained virological response (SVR): patients who present with undetectable HCV RNA at the end of treatment and maintain HCV RNA negativity after 6 months of follow-up.
- Relapsers: patients who attained an undetectable HCV RNA at the end of treatment but during the follow-up months their HCV RNA became detectable again. This group has a greater possibility of achieving SVR with re-treatment.
- Breakthrough: patients who initially present with an undetectable viral load, but in whom, while still on treatment, HCV RNA becomes detectable again; in general, this situation is brought on by reduction or discontinuation of antiviral therapy (peginterferon alfa or ribavirin).
- Non-responders: these patients can be divided into two groups: null responders are those who present a small (<2 log) decline in HCV RNA after 12 weeks of therapy, with respect to basal HCV RNA, whereas partial or slow responders are those who have a >2 log decline of HCV RNA at 12 weeks, but whose viral load is no longer detectable at 24 weeks of antiviral therapy.
MECHANISMS OF NON-RESPONSE
Viral load is an important factor in the re-treatment of CHC patients. Patients with high pretreatment viral load are less likely to attain SVR [13-15]. Nevertheless, some debate regarding the definition of high viral load exists .
HCV dynamics also play an important role during antiviral combination treatment: EVR has a negative predictive value for SVR of 97%; 97% of CHC patients without EVR will not achieve SVR [5,16]. In CHC patients infected by genotype 1, those who attain cEVR are twice as likely to achieve SVR as patients who attain pEVR .
HCV genotype has been identified in several clinical trials as an important predictive factor for SVR: patients infected by HCV genotype 1 present lower SVR rates than patients infected by genotype 2 or 3 [4-6]. According to the currently accepted management strategy, CHC patients with genotype 1 or 4 should be treated with peginterferon alfa plus ribavirin for 48 weeks, and patients infected by HCV genotype 2 or 3 should be treated for 24 weeks. Nevertheless, shorter or longer regimens based on viral genotype, basal viral load, and achievement of RVR at week 4 also exist. For example, CHC patients infected by genotype 1 who achieve RVR could be treated for only 24 weeks [18,19]; on the other hand, CHC patients infected by genotype 3 and who have a high basal viral load and are slow responders, might be treated for 48 weeks . Finally, data from CHC genotype 2 or 3 patients treated for 12, 14 or 16 weeks with peginterferon-alfa plus ribavirin attained SVR rates similar to those of patients treated for the standard 24 weeks [21-23].
The host’s immune response against HCV determines whether the virus will persist or be eradicated. SVR rate is associated with several host factors, including age, ethnicity, presence of liver fibrosis/cirrhosis, obesity, comorbidities such as coinfection by human immunodeficiency virus (HIV), and liver transplantation. Several studies have demonstrated genetic characteristics of patients that may predict the response to peginterferon alfa; these include variants of genes involved in the interferon alpha (IFN-α) pathway, or in insulin resistance (e.g., SOCS-3) [24-27], and more recent studies have shown an important role for interleukin-28B polymorphisms in affecting the virological response [28-31].
The majority of clinical trials have included patients <65 years, and the studies demonstrate that SVR rates are higher in younger patients (age <40 years) than in older ones [5,6]. Two studies [32,33] have been conducted on elderly subjects (age >65 years), confirming a lower SVR rate to antiviral therapy in this age group. Ethnicity is another host factor that influences the response to antiviral therapy. African Americans show a reduced likelihood of SVR when compared with Caucasian Americans [34-37]. This lower SVR rate could be related to a putative immune difficulty that African Americans have for inhibiting viral replication . On the other hand, Asians attain higher SVR rates when compared with Caucasians . Recently, Rodriguez-Torres et al  published data on CHC patients treated with peginterferon alfa plus ribavirin in Latino and non-Latino populations, showing a lower SVR rate in the Latino population, and that this ethnicity is an independent predictor of response.
Advanced liver fibrosis and cirrhosis appear to be other host factors that decrease the SVR rate, both in naïve patients and in non-responders to previous therapy [4,6,41]. In the HALT-C trial, the presence of cirrhosis or advanced fibrosis was a major independent predictor of non-response to antiviral treatment, independent of age, ethnicity, and HCV genotype .
Obesity is an independent risk factor for fatty liver disease . It has also been demonstrated that liver steatosis is present in approximately 60% of HCV-infected patients , and that those infected by HCV genotype 3 present a higher prevalence of liver steatosis than patients with other genotypes [35,44]. CHC patients with both obesity and insulin resistance present lower SVR rates [43,45-48]. Thus, the SVR rate in genotype-1-infected patients treated with peginterferon alfa plus ribavirin was 60% in those without insulin resistance and 20% in patients with insulin resistance . Weight loss and weight-based dosing antiviral treatment must be taken into account in CHC patients with increased body mass index before the initiation of combination antiviral therapy .
HIV coinfection is associated with higher morbidity and mortality . Some studies have corroborated that HIV coinfection impairs CHC antiviral therapy, with a higher prevalence of adverse events due to peginterferon alfa and ribavirin. In addition to lower SVR rates, rapid progression to end-stage liver disease has been observed [51,52]. Liver transplantation is another clinical situation where re-treatment must be considered. Liver-transplanted patients attain lower SVR rates (near 20-30%) when compared to naïve patients [53-55]. Moreover, transplanted patients present a higher prevalence of adverse events which, in many cases, do not allow therapy continuation .
Antiviral therapy-related factors
Patient response is clearly related to the type of interferon (standard or pegylated), whether it is combined with ribavirin or not, the doses of peginterferon alfa and ribavirin, and the length of therapy [7,9].
Adherence to antiviral treatment is another important factor that can modify response rates. Poor compliance is the most frequent factor contributing to non-response to combination therapy. In clinical practice, patients who satisfy the 80/80/80 rule—receive at least 80% of the dose of peginterferon alfa and 80% of the dose of ribavirin for 80% of the time—achieve higher SVR rates, and this is a key consideration when approaching CHC patient therapy . It is also important to control other comorbidities (e.g., thyroid dysfunction or diabetes) or adverse events (e.g., cytopenias, psychiatric disorders) in order to avoid early treatment discontinuation and maintain full-dose therapy [57,58].
MANAGEMENT STRATEGIES FOR NON-RESPONDERS
Treatment for non-responders is currently an interesting challenge. There are several clinical trials in which non-responders have been re-treated, and the results have led to extension of peginterferon alfa-2b therapy to previous non-responders. Non-responders may be categorized as: non-responders to interferon alfa monotherapy, non-responders to conventional interferon alfa plus ribavirin, or non-responders to peginterferon alfa plus ribavirin.
Interferon monotherapy or consensus interferon in non-responders to interferon alfa monotherapy
Several randomized clinical trials and cohort studies with conventional interferon alfa at standard doses [59-62], high doses of conventional interferon alfa [63-65], consensus interferon (CIFN) [66-68], or lymphoblastoid interferon  in previous interferon alfa monotherapy non-responders have reported achieving SVR rates of between 0% and 5%. Tolerability and adherence were similar to those of previous treatments. Therefore, due to the low SVR rate, it is not recommended to re-treat patients who failed interferon alfa monotherapy with a second cycle of interferon monotherapy.
Evidence level: I, II. Grade of recommendation: A-B.
Interferon alfa plus ribavirin in non-responders to interferon alfa monotherapy
The majority of studies dealing with interferon alfa monotherapy of non-responders have been conducted as clinical trials for 48 weeks and with a good control bias. The SVR rates were 15-20%, but these response rates are still very low. In four studies [64,70-72], CHC patients were re-treated with interferon alfa (3 MU thrice weekly) and weight-based ribavirin (1-1.2 g/day). Other trials have been conducted with the combination of CIFN and ribavirin [66-68,73]. Taken together, the SVR rates ranged from 13% to 40%.
Three important meta-analyses have been done: 1) Cheng et al  included 18 controlled studies and 62 non-controlled studies, reporting SVR rates of 13.2% and 14.6%, respectively; 2) San Miguel et al  included only randomized clinical trials, finding an SVR rate of 12.6%; and 3) Cammá et al  included individual data of 581 CHC non-responders and reported an SVR rate of 15.7%. Overall, re-treatment with interferon alfa plus ribavirin in non-responders achieves a 15% to 20% SVR rate . Several studies have suggested different predictive factors for SVR such as HCV genotype non-1, higher dosages of interferon alfa, and a normal gamma-glutamyltranspeptidase (GGT) level [70-72,78,79].
Evidence level: I, II. Grade of recommendation: B.
Peginterferon alfa plus ribavirin in non-responders to interferon alfa plus ribavirin
Many observational studies and a few clinical trials have been conducted in order to establish the efficacy, safety and tolerability of re-treatment with peginterferon alfa plus ribavirin in patients who failed prior therapy with interferon alfa plus ribavirin [57,80-90].
In a multicenter clinical trial [91,92], CHC patients who were non-responders to interferon alfa monotherapy or combined interferon alfa plus ribavirin for 48 weeks were re-treated with peginterferon alfa plus ribavirin. As in the HALT-C trial, SVR rates varied, depending on the previous therapy: non-responders to interferon alfa monotherapy attained 35% SVR, whereas non-responders to combination therapy attained an SVR rate of only 10%. Moreover, patients with HCV genotype 2 or 3 achieved an SVR rate of 37%, and genotype-1 patients achieved a rate of 0%. No cirrhotic patients attained SVR, whereas non-cirrhotic patients achieved an SVR rate of 32%.
There are several studies involving fewer patients and lower evidence levels due to heterogeneity in the type of peginterferon alfa, dosage changes, induction regimens, or patient characteristics (non-responders or relapsers). Overall, the SVR rates were between 20% and 36% for non-responders to previous recombinant interferon alfa plus ribavirin [83,93-99].
The EPIC trial  included 2293 patients: 1430 had previously failed therapy with interferon alfa plus ribavirin and 863 had failed treatment with peginterferon alfa plus ribavirin. These patients were re-treated with peginterferon alfa-2b (1.5 μg/kg/wk) plus ribavirin (0.8-1.4 g/day) for 12 weeks. At that timepoint, if HCV RNA was undetectable, then a complete course of treatment was given for 48 weeks; in contrast, if HCV RNA was detectable, the patient continued treatment with a low dose of peginterferon alfa-2b (0.5 μg/kg/wk) for 3 or 5 years. Analysis of EVR at week 12 showed that 40% of patients with an EVR achieved an SVR. Analysis of EVR as a function of HCV genotype revealed that patients with genotype 1 attained an SVR rate of 31% versus 82% for genotypes 2 and 3. Overall, SVR was achieved by 22% of patients; that is, 38% among relapsers and 14% among non-responders. Regarding patients who had failed prior treatment with interferon alfa plus ribavirin, the SVR rate after re-treatment was 18% for prior non-responders and 43% for prior relapsers. The main predictive factors of SVR were genotype non-1, lower stage of fibrosis, low basal viral load, previous treatment, and type of previous response. Data of patients who failed to respond to peginterferon alfa plus ribavirin are presented below.
The HALT-C trial [57,80,100] was a multicenter, randomized clinical trial that included more than 1000 CHC patients with advanced fibrosis or cirrhosis (staged according to Metavir), all non-responders to conventional interferon alfa monotherapy or combined with ribavirin. Patients received peginterferon alfa-2a (180 μg/wk) plus ribavirin (1-1.2 g/day) for 20 weeks. Those with undetectable HCV RNA continued treatment for 48 weeks, whereas those with detectable HCV RNA continued for 3.5 years with low-dose peginterferon alfa-2a (90 μg/wk). SVR rates differed between patients who failed prior interferon alfa monotherapy (SVR = 28%) and patients who failed prior interferon alfa plus ribavirin (SVR = 12%). Patients with HCV genotypes 2 or 3 attained an SVR rate of 60%, compared to 14% in genotype-1-infected patients. Factors associated with SVR were: genotype non-1, low basal HCV RNA, and absence of cirrhosis.
Evidence level: I, II. Grade of recommendation: A,B.
Re-treatment with peginterferon alfa plus ribavirin for non-responders to peginterferon alfa plus ribavirin
Patients who failed peginterferon alfa plus ribavirin therapy constitute a population that is very difficult to treat. Moreover, nowadays, such non-responders could become the most prevalent population in routine clinical practice. There are two important clinical trials and only a few open-label studies targeting this population.
In the EPIC trial , as mentioned above, out of 2293 patients included in the study, 863 had previously failed to respond to peginterferon alfa plus ribavirin (375 to peginterferon alfa-2a and 488 to peginterferon alfa-2b); the remaining 1430 patients had previously failed to respond to conventional interferon alfa plus ribavirin. Patients were re-treated with peginterferon alfa-2b (1.5 μg/kg/wk) plus ribavirin (0.8-1.4 g/day); the SVR rate achieved in this population was 6%, which is lower than the 18% rate achieved in the prior non-responders to interferon alfa plus ribavirin. The type of peginterferon used in the previously failed therapy did not affect the SVR rate. Relapsers to previous peginterferon alfa plus ribavirin therapy achieved an SVR rate of 33%, versus 43% in prior relapsers to interferon alfa plus ribavirin. Non-responders to peginterferon alfa plus ribavirin, when re-treated, achieved a 6% SVR rate (4% in genotype-1 patients with advanced fibrosis and 52% in genotype-2 patients with a low stage of fibrosis). Analysis of EVR at week 12 showed that 56% of patients with undetectable HCV RNA achieved an SVR, independently of the previous therapy (interferon alfa plus ribavirin vs peginterferon alfa plus ribavirin) and the previous type of response (non-response or relapse). Predictors of response were genotype non-1, lower stage of fibrosis, and low basal HCV RNA (<600,000 IU/mL).
The REPEAT trial [101,102] analyzed the impact of an induction phase with peginterferon alfa 360 μg/kg/wk for 12 weeks and the efficacy of 72 weeks of treatment. A total of 950 CHC patients who had not responded to prior peginterferon alfa-2b plus ribavirin combination therapy were included in 4 arms: 2 of them with the induction dose of peginterferon alfa-2a (360 μg/kg/wk) plus ribavirin (1-1.2 g/day) for 12 weeks and then a standard dose of 180 μg/kg/wk plus ribavirin (1-1.2 g/day) for 48 weeks (A) or 72 weeks (B), and the other 2 arms without an induction dose and a duration of 48 weeks (C) or 72 weeks (D). Patients treated with the induction dose attained higher EVR rates than those treated with standard therapy (62% vs 45%, p <.05). Overall, the SVR rates in the 4 arms were: A: 7%, B: 16%, C: 9%, and D: 14%. The main predictive factor for SVR was duration of treatment but not the presence of the induction dose. Patients with HCV RNA <50 IU/mL at week 12 (17% of the total sample) achieved an SVR rate of 35% with the 48-week treatment, and those treated for 72 weeks achieved an SVR rate of 57%. Those patients without an EVR achieved a 4% SVR rate.
Other trials with fewer patients deserve commentary. Berg et al  conducted an open-label study in which 64 relapsers to peginterferon alfa plus ribavirin after 24 weeks of therapy were re-treated for 48 weeks with the same antiviral combination, achieving an overall SVR rate of 55%. Rustgi et al , in an open-label study, investigated patients who were non-tolerant or nonresponsive to peginterferon alfa-2b plus ribavirin at week 12, and re-treated them with peginterferon alfa-2a plus ribavirin for 48 weeks. The SVR rate for the previously non-tolerant patients was 56% versus 3% for the previous non-responders. Yoshida et al  performed a post-hoc analysis of a multicenter open-label study in 87 CHC patients who relapsed or did not respond to a first course of peginterferon-alfa-based therapy. Patients were treated with peginterferon alfa-2a plus ribavirin at a dose of 800 mg/day and later at 1000-1200 mg/day for 24 weeks to 48 weeks at the discretion of the investigator. Previous relapsers achieved an EVR of 86% and an SVR or 68%, whereas prior non-responders attained an EVR of 53% but only a 17% SVR rate.
Evidence level: I. Grade of recommendation: A.
Cammà et al  recently published a meta-analysis focused on SVR rates and factors that influence SVR rates in CHC patients who were non-responders to standard or peginterferon alfa plus ribavirin from 14 trials. The pooled estimate of the SVR rate was 16.3% (95% CI: 8.3-29.6%). As there was significant heterogeneity among the studies, the authors developed a meta-regression and found that low-baseline body mass index, infection with HCV genotype non-1, and treatment with peginterferon alfa-2a achieved higher SVR rates (>20%). These results argue against indiscriminate re-treatment of all non-responders with peginterferon alfa plus ribavirin. The authors recommend to re-treat only those patients infected with HCV genotype 2 or 3, and who are not overweight.
Re-treatment with consensus-interferon plus ribavirin or albumin-interferon plus ribavirin
Two small studies of CIFN plus ribavirin in prior non-responders to interferon alfa plus ribavirin [68,73] reported SVR rates of 22% and 35% using an induction dose of CIFN plus ribavirin. However, the main problem with this therapy was the safety profile. Recently, results from a phase 3, open-label multicenter study (DIRECT trial) have been published . In this study, 343 patients who failed peginterferon alfa plus ribavirin were re-treated with CIFN (9 μg/day one arm; 15 μg/day a second arm) plus weight-based ribavirin. SVR rates were 7% and 11%, respectively. Approximately 4% of cirrhotic patients who were re-treated with CIFN plus ribavirin achieved an SVR.
Recombinant human albumin interferon alfa-2b (albinterferon) is a novel recombinant protein produced genetically by fusion of human interferon alpha-2b and human serum albumin. Albinterferon is 2-fold larger than PEG-IFN-α2a and 4-fold larger than PEG-IFN-α2b. A phase 2 study  evaluated the efficacy and safety of albinterferon. Nelson et al  conducted a phase 2 study with 115 prior interferon alfa non-responders who were treated with different doses of albinterferon (900 μg, 1200 μg, 1500 μg, or 1800 μg every 2 weeks or 1200 μg every 4 weeks). SVR rates were 30%, 13%, 9%, 9% and 25%, respectively. Considering only patients with complete EVR, 68% attained an SVR. Overall, for genotype-1 non-responders to peginterferon alfa plus ribavirin, the SVR rate was 11%.
Triple therapy with peginterferon alfa plus ribavirin plus another drug
Several small sample-size pilot studies were undertaken with triple therapy utilizing peginterferon alfa plus ribavirin and adding amantadine or thymalfasin.
In a multicenter clinical trial, 200 non-responders to interferon alfa plus ribavirin were randomized to 48 weeks of peginterferon alfa-2b 1.5 μg/kg/wk plus ribavirin (0.8-1.2 g/day) adding amantadine (0.2 g/day) in one arm or a placebo in the other arm . The results of the study did not show statistical differences between SVR rates (24% vs 16%; p = .22). In another trial , 642 non-responders to interferon alfa or interferon alfa plus ribavirin were randomized to receive peginterferon alfa-2b 1.5 μg/kg/wk plus ribavirin (0.8-1.4 g/day) or this same combination plus amantadine (0.2 g/day) for 48 weeks. SVR rates were 23% and 32%, respectively. Other studies have reported similar results [111,112].
Evidence level: II-III. Grade of recommendation: B-C.
Three large studies were designed with 2 aims: 1) to identify SVR rates with peginterferon alfa plus ribavirin in patients who failed prior therapies, and 2) to establish the possibility of delaying or preventing the progression of liver fibrosis with lower doses of peginterferon over a long term.
The COPILOT trial [113,114] included 555 prior non-responders to interferon alfa or peginterferon alfa plus ribavirin, all with compensated liver disease. The study compared two therapeutic strategies over 4 years: low-dose peginterferon alfa-2b (0.5 μg/kg/wk) versus colchicine (0.6 mg orally, twice daily). It is important to mention that almost 50% of these patients did not complete the 4-year protocol due to noncompliance. At the end follow-up, there was no difference in event-free survival or primary end points between the two treatments, and only the event-free survival was significantly longer in patients receiving peginterferon alfa-2b versus those receiving colchicine, an effect attributable to a lower incidence of variceal bleeding in the first group.
The HALT-C trial [80,100,115] included non-responders to interferon alfa alone or combined with ribavirin, re-treating them with peginterferon alfa-2a plus ribavirin. Patients without a response at week 20 of therapy were randomized to receive low-dose peginterferon alfa-2a (90 μg/wk) for 3.5 years or no treatment. The overall SVR rate was 18% (28% in patients who had received prior interferon alfa monotherapy and 12% in those previously treated with interferon alfa plus ribavirin). More results are pending.
This clinical trial was designed for patients who did not respond to the re-treatment strategy and with liver fibrosis F2-F4. Patients enrolled in the maintenance arm received peginterferon alfa-2b 0.5 μg/kg/wk monotherapy for 3 years (F2-F3 patients) or 5 years (F4 patients), or they received no treatment. The SVR rate was 14% for non-responders and 38% for relapsers . Recent data  showed no benefit in preventing clinical events of liver decompensation, but in patients with esophageal varices the treatment significantly reduced the frequency of clinical events of hepatic decompensation.
Evidence level: II. Grade of recommendation: B.
There are a great number of ongoing trials and biomolecular studies employing new therapeutic approaches, all under the rubric specifically targeted antiviral therapies for hepatitis C (STAT-C). Protease/polymerase inhibitors appear to be a promising area of drug discovery for patients who fail peginterferon alfa plus ribavirin therapies. Currently, there are multicenter clinical trials to assess whether these new molecules, combined with peginterferon alfa plus ribavirin, achieve better SVR rates.
Boceprevir is an HCV NS3/4A serine protease inhibitor . A phase 2 study showed an SVR rate of 2% in patients re-treated with peginterferon alfa plus ribavirin without boceprevir, and 7% to 14% in those re-treated with peginterferon alfa plus ribavirin plus boceprevir .
Telaprevir is another HCV NS3/4A serine protease inhibitor [119,120]. Preliminary data are available from a phase 2 study in which patients were randomized into 4 different arms: 1) control therapy arm, with peginterferon alfa-2a (180 μg/wk) plus ribavirin (1-1.2 g/day) for 48 weeks; 2) combination of telaprevir (750 mg, 3 times daily) with peginterferon alfa-2a plus ribavirin for 12 weeks, followed by peginterferon alfa-2a plus ribavirin for another 12 weeks; 3) peginterferon alfa-2a plus ribavirin plus telaprevir for 24 weeks; and 4) telaprevir with peginterferon alfa-2a for 24 weeks. At week 12 of follow-up after the end of treatment, non-responders re-treated with peginterferon alfa-2a plus ribavirin plus telaprevir achieved an SVR rate of 41%, while non-responders re-treated with peginterferon alfa-2a plus telaprevir achieved an SVR of only 11%. Regarding previous relapsers, the SVR rates after 12 weeks of follow-up were 72% when re-treated with triple therapy versus 36% when re-treated with peginterferon alfa-2a plus telaprevir .
R7128 is a nucleoside polymerase inhibitor that has been tested in prior non-responders, achieving an RVR at week 4 of 90% in genotype-2 and -3 patients, and a decrease of >2 log at week 8 in genotype-1 patients .
Evidence level: II. Grade of recommendation: C.
Other recommendations for patients with chronic hepatitis C
Patients with chronic liver disease must be advised as to cessation of tobacco and alcohol use. An ultrasound examination of the upper abdomen and measurement of serum alpha-fetoprotein level should be performed every 6 months in cirrhotic patients. An upper gastrointestinal endoscopy should also be carried out to rule out esophageal or gastric varices in patients with suspected portal hypertension.
The available data on the management of CHC non-responders are still insufficient. Non-responders to interferon alfa monotherapy and relapsers to interferon alfa plus ribavirin could benefit from re-treatment, even for 48 weeks, with peginterferon alfa plus ribavirin. Regarding patients who failed peginterferon alfa plus ribavirin, whether to re-treat is still up for debate. Patients who had poor compliance, or who presented with advanced fibrosis at liver biopsy, or who discontinued treatment due to severe cytopenia, could perhaps benefit from another cycle of treatment, in the majority of cases, with an extended course of peginterferon alfa plus ribavirin. On the other hand, maintenance therapy is still controversial. In the future, novel approaches, including therapeutic vaccines and immunomodulatory and other drugs such as those targeting cytokine signaling pathways, should be explored.
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