June 6, 2013

Basic Answers to Complicated Questions for the Course of Chronic Hepatitis C Treatment

Expert Review of Gastroenterology and Hepatology

Necati Örmeci, Hakan Erdem

Expert Rev Gastroenterol Hepatol. 2012;6(3):371-382.

Abstract and Introduction
Abstract

Hepatitis C virus infection is a long-lasting disease, which causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma, thus leading to liver-related death. Currently, the optimal treatment for chronic hepatitis C infection is the combination of pegylated interferon and ribavirin. The aim of this review is to assess the long-term clinical outcomes of interferons alone or in combination with ribavirin in the management of chronic hepatitis C.

Introduction

Hepatitis C virus (HCV), discovered in 1989, is an enveloped virus, with a 9600 bases in length, single-stranded RNA genome contained in a capsid, itself enveloped by a lipid bilayer in which two different glycoproteins are combined. The genome encodes a polyprotein of approximately 3000 amino acid residues that is processed post-translationally by host and viral proteases into ten structural and nonstructural proteins. The nonstructural proteins encode several enzymes required for protein processing and replication. The HCV RNA genome serves as a template for viral replication and as a viral messenger RNA for viral production. There are six genotypes. Genotypes 1 and 4 are associated with a lower rate of therapeutic response.[1]

Overall, 2–3% of the human population, reaching approximately up to 170 million people around the world, is infected with HCV.[2] HCV infection is the leading cause of chronic hepatitis (55–85% per year), liver cirrhosis (2–5% per year) and hepatocellular carcinoma (HCC; 1–3% per year) in the world.[3] After the acquisition of HCV, 15–35% of patients resolve spontaneously, the serum is cleared from HCV-RNA and antibodies for HCV are detected. Accordingly, the remainder of the patients (65–85%) appear to experience a chronic course.[3–5] The natural history of the disease is largely modulated by cofactors – for example, progression to cirrhosis is high in HIV/HCV coinfection, or concomitant, even moderate, alcohol consumption combined with hepatitis C infection. This unfavorable natural course can be substantially improved when cofactors are removed – that is, by constant effective antiretroviral therapy or abstinence from alcohol consumption.[6–8] The approximate time intervals between infection and the occurrence of chronic hepatitis, liver cirrhosis or hepatocellular carcinoma (HCC) are approximately 6 months to 10, 20 and 30 years, respectively. Among the patients with chronic hepatitis C (CHC), progression of fibrosis is either minimal or absent in 15–33% of cases during the following 1–2 decades, and those cases do not usually experience liver cirrhosis. However, 75% of the patients with CHC may progress and develop cirrhosis. Among those patients with liver cirrhosis, three-quarters of the patients remain stable, whereas the remaining cases may develop liver decompensation, leading to life-threatening complications such as ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy, liver cancer and death within 5 years. Moreover, the most common indication for liver transplantation is HCV-induced cirrhosis in the USA, Japan, Europe and Australia.[4]

Since its discovery in 1989, treatment of HCV has evolved from conventional interferon (IFN) monotherapy to the currently recommended combination of pegylated IFN (PEG-IFN)-α and ribavirin (RBV).[9–12] IFN has been shown to have immune-modulating, antiviral, antifibrotic and antiproliferative effects in CHC. RBV is a guanosine nucleoside analog that has been shown to have antiviral activity by various means. The drug blocks viral replication via RNA polymerase, enhances the host-adaptive antiviral immune response and increases the mutational frequency by the mutagens, thus leading to lethal mutagenesis.[13] In fact, higher RBV serum concentrations are known to correlate with improved treatment outcomes.[14,15] However, it is still not clear how RBV works synergistically with IFN to improve sustained virological response (SVR) rates.[16]

SVR is defined as the loss of HCV-RNA with a sensitive PCR method for a minimum of 6 months after the end of treatment in CHC.[17] The liver is the main site of HCV replication, although the process can take place in extrahepatic locations, such as in peripheral blood mononuclear cells and monocyte-derived dendritic cells. It may be assumed that reactivation from those reservoirs may occur easily on some occasions, particularly in patients with immune suppression and advanced fibrosis or those infected with genotype 1 HCV.[18–20]

A number of studies reported that the SVR rate of IFN-α monotherapy varies between 5 and 15% of patients.[4,21] By contrast, RBV has been demonstrated to be unable to maintain the SVR alone. However, adding RBV to IFN significantly improved treatment outcomes so that SVR rates increased up to 54–56%,[22–24] and this approach has been accepted as the mainstay of CHC management. This combination has been well tolerated even in thalassemia major patients, except for an increase in blood transfusion requirements because of RBV side effects.[25]

Approximately 70–75% of patients who are infected with HCV in the USA are infected with genotype 1, which is associated with a lower rate of response. Currently, standard treatment with PEG-IFN and RBV results in less than 50% SVR rates in these patients. Recently, several molecular targets, such as NS3 protease and NS4A protein, which cleave the viral gene products and are necessary for the life cycle of the virus, have been identified. The combinations of NS3 protease and NS4A protein inhibitors, together with PEG-IFN and RBV, improved SVR in naive patients, and also in relapsers and nonresponders.[1]

The combination of telaprevir, a protease inhibitor specific to the HCV NS 3/4A serine protease, together with PEG-IFN and RBV for 24 weeks in naive patients who had genotype 1 HCV infection, resulted in 75% SVR in a Phase II trial.[26] Similarly, the combination of telaprevir and PEG-IFN plus RBV for 12 weeks in previously treated patients led to an-SVR of 88%.[27]

The combination of bocepravir, another potent HCV protease inhibitor, and PEG-IFN plus RBV for 24 or 44 weeks in naive non-black patients with HCV genotype 1 achieved a 67 or 68% SVR in Phase II studies. However, the same combination at 24 or 44 weeks had a 42 or 53% SVR in HCV-naive black patients.[28] Similarly, the combination of bocepravir and PEG-IFN plus RBV for 44 weeks in previously treated patients with HCV genotype 1 had an 88% SVR if the patients had undetectable HCV-RNA after the first 8 weeks of treatment.[29]

In terms of health-related quality of life, eradication of HCV with PEG-IFN plus RBV results in better quality of life and decreased fatigue, even in normal alanine aminotransferase (ALT) patients.[30] Treatment of patients with PEG-IFN-α2a was associated with less disabling fatigue and less impairment in patient functioning compared with IFN-α2a in patients with CHC as well.[31–33] In the literature, there are numerous reports using different methodologies and patient populations in the treatment and course of CHC. This multifaceted accumulation of the data in the literature habitually prevents meta-analysis of the current knowledge. Thus, the aim of this review is to project the long-term outcomes of IFN or PEG-IFN and their combinations with RBV in terms of durability of SVR, regression of liver fibrosis and cirrhosis, mortality and morbidity, and improving survival and quality of life. These tricky issues are summarized by basic answers to complicated questions for CHC in this paper.

The Place of the Virological Response in CHC Treatment
Does SVR Maintained With IFN Administration Point to HCV Eradication?

Long-term follow-up studies have shown that the risk of virological recurrence is very low (1–8%) when the patient had successfully established SVR.[18,34–40] In a large cohort study, 344 patients with CHC were treated with IFN-based regimens, and the patients were followed up for a median duration of 3.27 years. HCV-RNA was controlled in the sera (n = 1300), post-treatment liver tissue samples (n = 114) and peripheral blood mononuclear cells (n = 156). Serum HCV-RNA remained undetectable in all of the patients, and in none of the specimens of peripheral blood mononuclear cells. But, in just two out of 114 (1.7%) liver tissue specimens, HCV-RNA was detectable. Histological analyses of 126 paired liver biopsies revealed that the stage of fibrosis improved in 56%, was stable in 32% and deteriorated in 12%. Regression of cirrhosis was observed in 64% of cases while decompensation was seen in none. Three patients had HCC. The authors of the study concluded that these results strongly suggest that SVR may be considered as indicative eradication of HCV infection.[18]

Giannini et al. evaluated a cohort of 231 patients with CHC, who had at least 48 weeks of follow-up after SVR to PEG-IFN and RBV treatment. Median duration of follow-up after SVR was 164 weeks and exceeded 5 years in 30% of the cohort. SVR was pertinent in 211 patients (91%) while HCV-RNA became positive in two patients (less than 1%) within 1 year after SVR, and in 18 patients (8%) serum HCV-RNA was transiently positive in at least one follow-up evaluation. Clinical outcome was not significantly different between patients with persistently negative and transiently positive serum HCV-RNA.[40]

Do Human Genetic Factors Influence HCV Treatment Responses?

Polymorphism in the region of the IL-28B gene located at chromosome 19 has been associated with prediction of SVR in genotype 1 HCV and rapid virological response in genotype 2 and 3 HCV.[41,42] In patients of European ancestry, as well as in African–American and Hispanic patients, the CC genotype was associated with a twofold greater SVR rate than the TT genotype, with CT being closer to TT than to CC.[42]

Does SVR Prevent Liver Failure?

Veldt et al. reported a retrospective cohort study in which SVR was achieved in 29.6% of 479 patients with CHC after IFN-based treatment.[43] One hundred and thirty-one patients (27%) received IFN monotherapy, 130 (27%) received IFN and RBV, ten (2.1%) received PEG-IFN monotherapy, and 208 (43%) received PEG-IFN and RBV. Follow-up time was 2.1 (0.8–4.9) years for all patients. They concluded that SVR was associated with a reduction in liver failure (unadjusted hazard ratio: 0.03 [95% CI: 0.00–0.91]).[43]

Why are Virological or Biochemical Responses Important in CHC Therapy?

Veldt et al. reported a meta-analysis of 286 CHC patients with SVR and 50 biochemical responders (detectable virus but normal ALT levels).[38] Before the treatment, 5.2% of patients with SVR had liver cirrhosis and 39% were genotype 1. Those patients were followed up for a mean period of 59 months. The late virological relapse rate in cases with SVR after 5 years of follow-up was 4.7% (95% CI: 2.0–7.4). In this group, decompensation was detected in only 1.0% (95% CI: 0.0–2.3) and HCC was not detected during the follow-up time. SVR was found to be associated with the improvement of liver fibrosis. For biochemical responders, the rates of development of decompensation and HCC during long-term follow-up were 9.1% (95% CI: 0.5–17.7) and 7.1% (95% CI: 0–15.0), respectively. SVR was found to be a better prognostic factor than biochemical response.[38]

Is there any Difference in Mortality Between the Normal Population & the CHC Patients With SVR?

The standard mortality rate in patients with SVR was 1.4% (95% CI: 0.3–2.5) and 5.6% in biochemical responders (95% CI: 0.0–12.6). The survival in patients with SVR was compatible with the general population. On the other hand, there was a trend to a higher standard mortality ratio in biochemical responders after 5 years of follow-up. However, the difference did not reach statistical significance.[38]

Does the Establishment of SVR Have an Effect on Mortality in Cirrhotic Patients?

In a prospective study of 352 patients with compensated liver cirrhosis as a result of CHC, the patients were followed up for a median of 14.4 years (range: 0.9–19.5 years) in terms of annual decompensation, occurrence of HCC and liver-related mortality. One hundred and ninety-four patients were treated with a single course of IFN or a combination of PEG-IFN plus RBV. At the end, 131 had decompensation, HCC occurred in 109 patients, nine had liver transplants and 158 patients died. There was no difference in annual rates of decompensation, HCC and liver-related mortality between the patients with non-SVR and the untreated patients. The overall liver-related mortality rate was significantly reduced in patients with SVR compared with the nonresponders and the untreated group (p = 0.03). Multivariate analysis revealed the beneficial effect of SVR on mortality and survival ( ).[44]

Table 1.  The place of the virological response in chronic hepatitis C treatment.

Questions Answers
Does SVR maintained with IFN administration point to HCV eradication? Most likely
Do human genetic factors influence HCV treatment responses? Apparently yes
Does SVR prevent liver failure? Most likely
Why are virological or biochemical responses important in CHC therapy? They improve outcomes, SVR being the better one
Is there any difference in mortality between the normal population and the CHC patients with SVR? Not much
Does the establishment of SVR have a positive effect on mortality in cirrhotic patients? Obviously yes

CHC: Chronic hepatitis C; HCV: Hepatitis C virus; IFN: Interferon; SVR: Sustained virological response.

The Course of the Fibrotic Process
What are the Factors Influencing the Progression of Fibrosis?

Advanced age on admission in patients with CHC is one of the influencing factors on the progression of fibrosis. Other factors are the therapeutic modality, immune suppression, severe inflammation of the liver, Aspartat–Platelet Ratio Index (APRI), high ALT levels, hepatic steatosis, ongoing alcohol consumption and coinfection of the liver with another virus, constant antiretroviral treatment, male gender, and genetic and environmental factors.[4,8,45–48]

How Does Perinatally Acquired HCV Infection Progress?

Casiraghi et al. followed up 31 patients who had perinatally acquired HCV infection 35 years ago. They concluded that in just a small group of patients who acquired HCV infection early in life, slow progression and mild outcomes were detected.[49] Similarly, in another study by Rerksuppaphol et al., HCV infections acquired during infancy were found to be asymptomatic and slowly progressive.[50] It is reported that the progression of liver fibrosis from stage 0 to 4 occurs as 0.10–0.15 fibrosis units per decade.[47,51]

How do CHC Patients With Mild Fibrosis Progress in the Long Term?

In a large cohort study, 282 patients who had mild fibrosis (Ishak stage F0 or F1) were evaluated in terms of progression of liver fibrosis stage over a median interval of 52.5 months. Progression of liver fibrosis stage was detected in 118 patients (42%). Thirteen (5%) of 282 progressed to Ishak stage 4 or more. The age at initial biopsy and mean ALT levels were the independent factors for the progression of liver fibrosis. Apparently, CHC with initially mild fibrosis does progress in a substantial proportion of patients and thus should not be viewed as a benign disease.[52]

How do CHC Patients With Normal ALT Levels Progress?

Approximately 30% of patients with CHC show persistently normal ALT levels. In all studies, liver histology was, on average, significantly less severe in subjects with persistently normal ALT than in those with abnormal ALT. Although the majority of data seem to show that HCV carriers with normal ALT have mild and stable disease, with favorable prognoses, several studies reported a significant progression of fibrosis in approximately 20–30% of the patients with ALT normality, and the development of HCC in some cases has been described, despite persistent ALT normality. Sudden worsening of disease with ALT increase and histological deterioration has been described in the literature.[53] For example, Okanoue et al. performed liver biopsies on 129 HCV carriers with normal ALT. Sixty-nine patients were followed for more than 5 years and 35 underwent serial liver biopsies. Approximately 90% of HCV carriers with normal initial ALT had normal to mild liver histology. Subsequently, 30% developed symptomatic CHC within 5 years. Approximately as many as a third of HCV-infected patients with normal ALT became candidates for antiviral therapy within 5 years.[54]

Is There any Difference Between PEG-IFN & Conventional IFN for SVR in Treatment of HCV?

A meta-analysis, which evaluated three randomized multicentric trials, was performed in 1013 naive CHC patients with or without cirrhosis. The patients were treated with PEG-IFN or IFN and were evaluated in terms of beneficial effects on liver histology. PEG-IFN reduced the risk of fibrosis more than IFN (standardized mean differences: -0.14; 95% CI: -0.27 to -0.01; p = 0.04). A decrease in fibrosis occurred mainly in the patients with SVR (standardized mean differences; -0.59; 95% CI: -0.89 to -0.30; p < 0.0001) and relapsers (standardized mean differences; -0.34; 95% CI: -0.54 to 0.14; p = 0.0007). However, there was no significant reduction among the nonresponders (p = 0.15).[55]

What are the Reduction Rates in Fibrosis & Inflammation in Patients With CHC Treated With PEG-IFN & RBV?

George et al. assessed the clinical, virologic, histologic and biochemical outcomes after successful HCV therapy.[56] Among 150 patients with SVR after PEG-IFN and RBV combination therapy, those who had fibrosis stage F2 and F3 were followed up for 5 years. Fibrosis score decreased in 40 (82%) patients. Accordingly, hepatic inflammation score decreased in 45 (92%) patients. HCC occurred in two patients who had liver cirrhosis preceding the treatment. All the other patients with pretreatment cirrhosis or advanced fibrosis had improved fibrosis scores on long-term follow-up biopsy. No patient had conclusive evidence of virological relapse.[56]

Does the Low-dose Maintenance Therapy Contribute to Improvement in Patients With CHC?

In a study by Shiffman et al., viral suppression with full-dose PEG-IFN and RBV was associated with a significant reduction in clinical outcomes. However, continuing with low-dose PEG-IFN (90 µg/kg/week) for a long-term maintenance therapy (3.5 years) could not lead to further improvement or decline in clinical outcomes ( ).[57]

Table 2.  The course of the fibrotic process.

Questions Answers
What are the factors influencing the progression of fibrosis? Advanced age

Therapy

Immune suppression

Severe inflammation of the liver

High ALT levels

Hepatic steatosis

Alcohol consumption

Coinfection
How does perinatally acquired HCV infection progress? Quite slowly
How do CHC patients with mild fibrosis progress in the long term? Rapidly in the substantial portion
How do CHC patients with normal ALT levels progress? A third becomes candidates for therapy in 5 years
Is there any difference between PEG-IFN and conventional IFN for SVR in treatment of CHC? Seemingly PEG-IFN is better
Is there any difference between PEG-IFN and conventional IFN on fibrosis? Weekly PEG-IFN is better than three-times weekly IFN
What is the reduction rate in fibrosis and inflammation in CHC patients treated with PEG-IFN and RBV? Up to half
Does low-dose maintenance therapy contribute to improvement in CHC patients? Apparently no

ALT: Alanine aminotransferase; CHC: Chronic hepatitis C; HCV: Hepatitis C virus; PEG-INF: Pegylated interferon; RBV: Ribavirin; SVR: Sustained virological response.

Approach to CHC-related Cirrhosis
Does the IFN/PEG-IFN Plus RBV Combination Delay the Development of Esophageal Varices in CHC?

D'Ambrosio et al. prospectively assessed 127 patients who received weight-based RBV combined with either IFN-α2b 3 million units three-times per week (n = 36), or weekly PEG-IFN-α2b 1.5 µg/kg (n = 68) or weekly PEG-IFN-α2a 180 µg (n = 23). Patients were followed up endoscopically for median endoscopic follow-ups of 68 months for the 62 patients with SVR and 57 months for the 65 non-SVR patients (p = 0.3). De novo esophageal varices (EVs) developed in ten (9.1%) patients including two out of 57 SVR and eight out of 53 non-SVR (3.5 vs 15.1%; p = 0.047), whereas EV progressed in size in three patients, including one out of five SVR and two out of 12 non-SVR (p = 0.87). Two non-SVR patients bled from EV and one died. Apparently, successful therapy prevents or delays the de novo onset of EV in patients with compensated cirrhosis because of HCV, but does not abrogate the need for continued endoscopic surveillance.[58]

What is the Therapeutic Approach to the Patients With Cirrhosis?

Among 3010 patients who were enrolled into four randomized clinical trials, 153 decompensated cirrhotic patients due to CHC were treated with full-dose PEG-IFN and RBV combination. Overall and genotype 1–4 SVRs were found in 35 and 16% of patients, respectively. Liver fibrosis improved in 49% (75 out of 153) of the patients after the treatment. The authors of this study, Iacobellis et al., concluded that in the case of a Child-Pugh score of less than seven or Model for End-Stage Liver Disease (MELD), a scoring system for assessing the severity of chronic liver disease, score of less than 18, cirrhotic patients due to HCV infection should be treated. When Child-Pugh score is between 8 and 11 or MELD score is in the range of 18–25, the patients can be treated carefully. However, if Child-Pugh score is over 11 or MELD score is over 25, patients should not be treated. Although the response rate appears to be lower in cirrhotic patients, successful therapy may potentially improve survival and can be life saving.[59]

Can the Use of Conventional IFN Alone Contribute to Long-term Outcomes in Compensated HCV-related Cirrhosis?

Valla et al. conducted a randomized controlled multicentric study to evaluate the effect of IFN-α2b (3 million units, three-times weekly for 48 weeks) in patients with compensated HCV-related cirrhosis.[59] The treatment group was compared with untreated patients as the control group in terms of SVR, improvement of histological activity and occurrence of HCC. Overall, 99 patients with biopsy-proven cirrhosis were included in the study, and they were followed up for 160 ± 57 weeks. At the end of follow-up, 48 weeks of IFN therapy did not significantly improve the 3-year outcome.[60]

In another study, Fattovich et al. conducted a multicentric cohort of 384 European cirrhotic patients due to HCV infection. Two hundred and five patients were treated with IFN. All patients were followed up for a mean period of 5 years in terms of the risk of HCC, decompensation and liver-related deaths. The 5-year risk of HCC development was 7%, and that of decompensation was 18%. Deaths occurred in 51 patients (13%) and 70% of these fatalities were related to the liver. The survival rate was 91 and 79% at 5 and 10 years, respectively. There was no significant difference in terms of estimated 5-year survival in the treated versus the untreated group (96 vs 95%; ).[61]

Table 3.  Approach to chronic hepatitis C-related cirrhosis.

Questions Answers
Does IFN/PEG-IFN plus RBV combination delay the development of esophageal varices in CHC? Obviously yes
What is the therapeutic approach to HCV infection with cirrhosis? Child-Pugh <7, MELD >18: treat

Child-Pugh 8–11, MELD 18–25: treat carefully

Child-Pugh >11, MELD >25: do not treat
Can the use of IFN alone contribute to long-term outcomes in compensated cirrhosis? Apparently no

CHC: Chronic hepatitis C; HCV: Hepatitis C virus; PEG-IFN: Pegylated interferon; RBV: Ribavirin.

Interrelations Between CHC-related Liver Disease & HCC
Which Factors Facilitate the Progression to HCC in Patients With CHC?

Among 32,806 patients with CHC, HCC occurred in 262 patients. HCC was 12-fold more frequent in the case of liver cirrhosis (p < 0.001), threefold more frequent heavy alcohol consumption (p < 0.001) and 1.4-fold more frequent for diabetes mellitus (p = 0.04). Moreover, Asian ethnicity male sex, advancing age and hemodialysis were also associated with increased risk for HCC.[62]

In a study by Akuta et al., 454 noncirrhotic patients with CHC were treated with IFN and were followed up for 11.3 years.[63] Data for overall patients disclosed that fibrosis at stage 3, absence of treatment (group B) and age over 50 years were associated with increased risk for HCC. The patients with high ALT levels (17.6%) in group C were also associated with a significant risk of HCC.[63]

In the study by Okanoue et al., 1246 patients with CHC who previously received IFN therapy were included and followed-up for a mean of 7.7 years. The progression rate of fibrosis was faster in CHC patients with elevated serum ALT levels. HCC was noted in 157 patients with CHC after IFN therapy. However, the development of HCC was significantly reduced in both sustained responders and transient biochemical responders compared with nonresponders. In sustained responders, HCC developed primarily in male patients older than 55 years of age with advanced-stage liver histology on admission.[54]

Does Therapy Decrease the Development of HCC?

Ikeda et al. conducted a study to evaluate the effect of IFN on CHC in terms of HCC development.[64] In total, 1643 patients were enrolled in the study, in which 1191 patients were treated with IFN and 452 were enrolled as untreated controls. The risk of HCC in the treated and untreated groups was 2.1 and 4.8% at the end of 5 years, and 7.6 and 12.4% at the end of 10 years, respectively (p = 0.0036).[64]

In a retrospective cohort study by Tanaka et al., 594 patients with CHC who were treated with IFN-α were enrolled and 144 untreated patients were included as the control group.[65] In this study, 175 patients had SVR, 165 were temporary responders and 254 were nonresponders. IFN and control groups were followed up for a mean of 57.2 ± 13.9 months and 67.7 ± 28.7 months, respectively. The risk of HCC was reduced by 48% in the IFN group compared with the control group (p = 0.064). Hazards ratios for the development of HCC were 0.16 (95% CI: 0.04–0.62) in the patients with SVR, 0.27 (95% CI: 0.09–0.79) in the temporary responders group and 0.74 (95% CI: 0.37–1.48) in the nonresponders.[65]

Three randomized controlled trials and 15 nonrandomized controlled trials, including 4614 patients, were evaluated in a meta-analysis to disclose whether IFN reduces the risk ratio of HCC in patients with chronic hepatitis B and CHC. The rate of HCC development in CHC was lower in patients with SVR (overall risk difference -12.8%; 95% CI: -8.3 to -17.2%; p < 0.0001) and also in nonresponders compared with untreated patients (overall risk difference -11.8%; 95% CI: -6.4 to -19.1%; p < 0.0001).[66]

Does the Low-dose Maintenance Therapy Contribute to the Prevention of HCC in Nonresponders?

However, 1048 patients with chronic HCV who did not respond to PEG-IFN plus RBV treatment continued the same therapy at a half dose for 3.5 years. They were followed up for a period of 6.5 years. Extended analysis of the HALT-C cohort showed that long-term PEG-IFN did not reduce the incidence of HCC among patients with advanced hepatitis C who did not achieve SVR. Patients with cirrhosis who received PEG-IFN treatment had a lower risk of HCC than controls.[67]

Is the Efficacy of PEG-IFN Plus RBV Combination Better Than IFN Alone in the Prevention of HCC?

Twenty studies involving 4700 patients with HCV-related cirrhosis who were treated with IFN alone or with RBV combination were evaluated in terms of reducing the risk of HCC and were followed up for more than 5 years. Pooled data showed reduced HCC risk in the treatment group compared with untreated patients (relative risk: 0.43; 95% CI: 0.33–0.56). The maximum benefit was observed in patients treated with RBV-based regimens.[12]

Does SVR Always Mean the Prevention of HCC?

An interesting and alarming paper came from Scherzer et al., who reported five cases of CHC without cirrhosis. The patients developed HCC after SVR due to IFN-based therapies. Consequently, successful antiviral treatment in CHC may not always prevent the development of HCC, and long-term surveillance should be carried out for HCC.[68]

Does the Multicourse Treatment of Nonresponders Contribute to the Prevention of HCC?

In a study by Akuta et al., 454 noncirrhotic patients with CHC were treated with IFN and were followed up for 11.3 years. A hundred and fifty-two patients (33.5%) had SVR (group A). Among 302 nonresponders, 130 (28.6%) patients were followed up without any treatment (group B) and 172 patients (37.9%) had multicourse IFN treatment (group C). Groups A and C have shown significantly better clinical outcomes compared with group B.[63]

Are Herbal Medicines Better Than IFN for the Prevention of HCC?

Since there is a need to develop better antiviral agents, both by synthetic chemistry and from herbal sources, there are some in vitro studies showing the efficacy of herbal medications on HCV. Glycyrrhizin,[69] San-Huang-Xie-Xin-Tang, a Chinese herbal formula,[70] and Phyllanthus amarus [71] are a few examples.

In one study, 120 elderly patients over 60 years of age with biopsy-proven CHC or liver cirrhosis were treated with IFN-α. Another 240 patients treated with herbal medicines were accepted as controls. The risk of HCC at 5 and 10 years in both groups was 5.9 and 13.7% and 17.1 and 32.8%, respectively. The patients with advanced fibrosis (F3–F4), the herbal medicine group and those with an α-fetoprotein (AFP) level over 10 ng/ml were associated with an increased risk of HCC.[72]

A Phase II trial of saiko-ko-to in hepatitis C patients who were not candidates for IFN-based therapies was performed. In this study, 24 patients with CHC received sho-sai-ko-to at 2.5 g orally three-times daily for 12 months. Liver function, HCV viral load and liver biopsy histology were assessed before and after the intervention. Improvement of aspartate aminotransferase was observed in 67% of study participants. Improvement of ALT was seen in 75% of patients. Viral load response was mixed, with seven patients showing reductions, ten showing increases and seven indeterminate due to assay limitations. Among the nine (38%) subjects who showed improvement in histology activity in a paired comparison of pre- and post-treatment liver biopsy, five (21%) showed an improvement of two points or greater, meeting the predefined criteria for 'response'.[73] The formulation was accepted to be promising.

Do the Biochemical Hepatic Markers Correlate With the Development of HCC?

Kobayashi et al. studied CHC in the older population, and found that CHC patients with persistently elevated ALT levels had a higher risk of HCC. Thus, the authors of the study recommended that the patients should be treated as early as possible.[74]

Tai et al. studied clinical parameters such as age, hepatic inflammation score, ALT levels, platelet counts and AFP. They found that the prevalence of elevated AFP (>15 ng/ml) was found in 23.9% of patients with CHC without cirrhosis. Multivariate analysis revealed that age over 55 years, hepatic activity index inflammation score over 7, ALT level over 150 U/l and platelet count less than 150 × 109 cells/l were associated with elevated AFP levels. Multivariate analysis also revealed that HCV genotype 1b, platelet count ≤150 × 109 cells/l, aspartate aminotransferase >80 U/l and AFP over 6 ng/ml were associated with advanced fibrosis.[75]

Takata et al. compared liver function and background factors of HCC in 1096 patients with HCV. They found that HCV-related HCC in patients older than 75 years occurred in mild hepatic inflammation with a slight elevation of ALT, higher serum albuminemia, normal international normalized ratio and mild fibrosis.[76]

The aspartate–platelet ratio index (APRI) assessed 6 months after the end of treatment (APRI–6 months) was found to be an important predictive factor for the development of HCC in liver cirrhotic patients. Thus, AFP and APRI–6 months levels together with ultrasonographic examination should be controlled every 3–6 months in cirrhotic patients.[48]

Kumada et al. identified the independent risk factors involved in the development of HCC in 519 patients with chronic HCV infection who have normal ALT levels (< 40 IU/ml).[77] They found that high ALT levels (>20 IU/ml), low platelet count <15.0 × 104/m3, high bilirubinemia >1.2 mg/ml and total albuminemia <3.5 g/dl were closely associated with the development of hepatocarcinogenesis. Early treatment should be recommended with these clinical characteristics.[77]

In a study by Ikeda et al., 461 out of 1643 patients had SVR and 145 patients had biochemical response without losing HCV-RNA. The patients with SVR and biochemical responders had a lower risk of HCC compared with untreated patients (hazard ratio: 0.32; p = 0.012) and that of the elevated ALT group.[64]

Can Combining RBV & IFN Confer Additional Benefits in the Prevention of HCC?

Twenty studies evaluating 4700 patients with cirrhosis due to CHC were analyzed. They were treated with IFN alone or with RBV and the risk reduction for HCC was followed up for more than 5 years. Pooled data showed reduced HCC risk in the treatment group compared with untreated patients (relative risk: 0.43; 95% CI: 0.33–0.56). The maximum benefit was observed in patients treated with RBV-based regimens.[12]

Does Advanced Age Facilitate the Development of HCC?

In a study by Akuta et al., age over 50 years was associated with an increased risk of HCC among the nonresponders to IFN therapy, either in the absence of retreatment or in the retreated patients with IFN.[63]

What are the Determinants of the Efficacy of IFN Treatment in the Prevention of HCC in the Older Population?

Arase et al. studied the incidence of HCC and survival probability after the initiation of IFN therapy in 500 patients with CHC older than 60 years of age. The mean follow-up time was 7.4 years. SVR occurred in 28% of patients. Seventy-one out of 500 patients had HCC during the follow-up. The cumulative incidence of HCC was 9.6, 17.4 and 31.3% at 5, 10 and 15 years, respectively. The risk of HCC increased in the patients without SVR (p < 0.0001), in male patients (p < 0.0001) and in those patients with advanced stages of liver fibrosis (p = 0.008). The cumulative survival probability was 95, 86.4 and 78% at 5, 10 and 15 years, respectively. Long-term survival was associated with initially mild fibrosis (p < 0.0001), SVR (p = 0.034) and being female (p = 0.015).[78]

A meta-analysis, from three randomized multicentric studies, was performed in 1013 naive patients with HCV with or without cirrhosis. The patients were treated with PEG-IFN or IFN and were evaluated in terms of beneficial effect on liver histology. PEG-IFN reduced the risk of fibrosis compared with IFN (standardized mean difference: -0.14; 95% CI: -0.27 to -0.01; p = 0.040). A decrease in fibrosis mainly occurred in the patients with SVR (standardized mean difference: -0.59; 95% CI: -0.89 to -0.30; p < 0.0001) and relapsers (standardized mean difference: -0.34; 95% CI: -0.54 to -0.14; p = 0.0007). However there was no significant reduction among the nonresponders (p = 0.15) ( ).[55]

Table 4.  Interrelationships between chronic hepatitis C-related liver disease and hepatocellular carcinoma.

Questions Answers
Which factors facilitate the progression to HCC in patients with CHC? Liver cirrhosis

Heavy alcohol consumption

Diabetes mellitus

Asian ethnicity

Male sex

Older age

Hemodialysis

Fibrosis at stage 3

Absence of treatment

Unresponsive to treatment
Does therapy decrease the development of HCC? Apparently yes
Does the low-dose maintenance therapy contribute to the prevention of HCC in nonresponders? Seemingly no
Is the efficacy of PEG-IFN plus RBV combination better than IFN alone in the prevention of HCC? Apparently yes
Does SVR always mean the prevention of HCC? No
Does the multicourse treatment of nonresponders contribute to the prevention of HCC? Seemingly yes
Are herbal medicines better than IFN in the prevention of HCC? Obviously no
Do the biochemical hepatic markers correlate with the development of HCC? Increased ALT levels, yes

Hepatic inflammation score >7, yes

Platelet count <150,000, yes
Can combining RBV and IFN confer additional benefits in the prevention of HCC? Obviously yes
Does advanced age facilitate the development of HCC? Apparently yes
What are the determinants of the efficacy of IFN treatment in the prevention of HCC in the older population? Initial mild fibrosis

SVR

Female sex

CHC: Chronic hepatitis C; HCC: Hepatocellular carcinoma; PEG-IFN: Pegylated interferon; RBV: Ribavirin; SVR: Sustained virological response.

CHC-related Liver Disease & Crude Mortality
Does Treating CHC Decrease Mortality?

Imazeki et al. evaluated the effect of IFN therapy on survival in a cohort study, which enrolled 459 patients with biopsy-proven CHC for 8.2 ± 2.9 years. Fifteen (14%) out of 104 untreated and 33 (9%) out of 355 IFN-treated patients died during the follow-up. Liver-related deaths were seen in 32 (67%) patients, 25 (52%) of whom died of HCC. IFN treatment decreased the risk ratio for overall death to 0.521 (95% CI: 0.263–1.034) and liver-related deaths to 0.208 (95% CI: 0.088–0.495) compared with untreated patients. The patients with SVR were seen to decrease the risk ratios of both overall deaths to 0.219 (95% CI: 0.068–0.710) and liver-related deaths to 0.030 (95% CI: 0.003–0.267).[79]

Yoshida et al. conducted a large multicentric cohort study to evaluate the effect of IFN on survival in CHC patients. In total, 2889 patients (2430 treated with IFN median dose 480 million units for 137 days, and 459 untreated controls) were enrolled into the study. All patients were followed up for 5.4 years. A total of 86 patients died (30 out of 459 untreated, seven out of 817 with SVR and 49 out of 1613 nonresponders) and 58 of those patients lost their lives because of liver-related disease. The overall mortality rate was higher in the untreated patients (standard mortality rate: 0.9; 95% CI: 0.7–1.1). The risk of death was reduced in the IFN-treated group compared with the untreated group (risk ratio for overall deaths: 0.367 [95% CI: 0.236–0.596]; risk ratio for liver-related deaths: 0.284 [95% CI: 0.164–0.494]). The risk ratio for SVR was found to be 0.148 (95% CI: 0.064–0.343) and 0.050 (95% CI: 0.012–0.216) for the IFN-treated and untreated groups, respectively.[80]

Which Factors are the Determinants of Mortality in CHC?

Niederau et al. prospectively followed up 838 patients with CHC for a mean of 50.2 months (standard deviation: ±26.9 months). During the follow-up, 62 patients died (31 related to and 31 unrelated to liver disease). Twelve patients had liver transplantation. Multivariate regression analysis revealed that survival was decreased with the presence of cirrhosis, long duration of disease, history of intravenous drug abuse and excessive alcohol consumption. On the other hand, IFN therapy apparently improved the survival.[81]

Which Factors are the Determinants of Mortality in HCV-related Cirrhosis?

In a study by Bruno et al., the predictors for the liver-related and overall mortality were found to be old age at admission, male gender, genotype 1 as the infecting strain, EV, elevated AFP levels and baseline MELD score over 10.[44]

Does IFN Treatment Affect Overall Death Rates in Patients With CHC?

Imazeki et al. evaluated the efficacy of IFN on survival in a cohort study that enrolled 459 patients with biopsy-proven CHC for 8.2 ± 2.9 years (range: 7–183 months). Fifteen (14%) out of 104 untreated and 33 (9%) out of 355 IFN-treated patients died during the follow-up. Four (3%) out of 116 patients with SVR versus 29 (12%) out of 239 patients without SVR died. Liver-related deaths were seen in 32 (67%) patients, and 25 (52%) of these died of HCC. IFN treatment decreased the risk ratio for overall death to 0.521 (95% CI: 0.263–1.034) and liver-related deaths to 0.208 (95% CI: 0.088–0.495) compared with untreated patients. Presence of SVR showed a decrease in the risk ratio for overall death to 0.219 (95% CI: 0.068–0.710) and for liver-related death to 0.030 (95% CI: 0.003–0.267).[79]

Yoshida et al. conducted a large multicentric cohort study with a retrospective design to evaluate the value of IFN on survival in patients with CHC. A total of 2889 patients (2430 treated with IFN and 459 untreated controls) were enrolled in the study. The median dose and duration of IFN administration were 480 million units and 137 days, respectively. All patients were followed up for 5.4 years. In total, 86 patients died (30 out of 459 untreated, seven out of 817 with SVRs and 49 out of 1613 nonresponders) and 58 of these patients died due to of liver-related causes. Compared with the general population, overall mortality was high among untreated patients (standardized mortality ratio [SMR]: 1.9; 95% CI: 1.3–2.8) but not among IFN-treated patients (SMR: 0.9; 95% CI: 0.7–1.1). Compared with untreated patients, the risk of death was reduced among IFN-treated patients (risk ratio for overall death: 0.367; 95% CI: 0.236–0.596; risk ratio for liver-related death: 0.284; 95% CI: 0.164–0.494) and among sustained responders (risk ratios: 0.148 [95% CI: 0.064–0.343] and 0.050 [95% CI: 0.012–0.216 ] for overall and liver-related deaths, respectively). The risk of liver-unrelated deaths remained unchanged.[80]

What is the Long-term Survival Rate in CHC?

In a retrospective cohort study including 594 patients with CHC, expectations for 8-year survival in the treatment and control groups were 97 and 81%, which differed significantly.[65]

Is There Any Difference Between the Cause of Mortality Spectra in Young Adults & Older CHC patients?

In Denmark, a cohort of 10.991 HCV-infected patients were followed up. The 10-year survival rate decreased from 84.1% among HCV-infected patients aged 20–29 years to 21.1% among those aged 70 years or older. Most deaths among younger patients were from unnatural causes and most deaths among older patients were from non-liver-related natural causes ( ).[82]

Table 5.  Chronic hepatitis C-related liver disease and crude mortality.

Questions Answers
Does treating CHC decrease mortality? Obviously yes
Which factors are the determinants of mortality in CHC? Presence of cirrhosis

Long duration of disease

Intravenous drug abuse

Excessive alcohol consumption
Which factors are the determinants of mortality in HCV-related cirrhosis? Old age on admission

Male gender

Genotype 1

Esophageal varices

High α-fetoprotein

MELD score >10
Does IFN treatment affect overall death rates in CHC patients? Yes
What is the long-term (8-year) survival rate in CHC? Treated patients: 97%

Untreated patients: 81%
Is there any difference between the cause of mortality spectra in young adult and elder CHC patients? Older patients are more likely to die of liver-related causes

CHC: Chronic hepatitis C; HCV: Hepatitis C virus; IFN: Interferon.

Expert Commentary & Five-year View

Although the studies reviewed here differ in methodologies and assumptions about the efficacy of therapeutic modalities, their results are reasonably consistent with each other. In conclusion, using IFN/PEG-IFN or combination with RBV in the treatment of CHC patients with or without cirrhosis results in a long durable response, improved fibrosis and cirrhosis, decreased risk of liver decompensation, decreased mortality and morbidity rates, and increased survival and quality of life, especially in patients with SVR and in biochemical responders compared with nonresponders or untreated controls. On the other hand, the development of new and potent drugs for common resistance mutations and all HCV genotypes is under consideration. In these studies, IFN modifications, immune modulators, RNA interference, antisense oligonucleotides, cyclophilin inhibitors, host lipid biosynthesis inhibitors and natural products have been evaluated. Moreover, the development of new antivirals has focused on some particular areas such as RBV analogs, protease inhibitors, NS5B polymerase inhibitors, NS5A and helicase inhibitors. Finally, the US FDA approved telaprevir, a protease inhibitor, in May 2011, and new drugs are under development.

Sidebar
Key Issues
  • Chronic hepatitis C (CHC) is a worldwide disease and is the leading cause of liver cirrhosis and hepatocellular carcinoma.
  • In the management of the disease, interferon (IFN) plus ribavirin combination is the current therapeutic modality.
  • Sustained virological response achieved with therapy is likely to represent the eradication of the disease.
  • Weekly pegylated IFN is seemingly better than three-times weekly conventional IFN for achieving a sustained virological response in the treatment of CHC.
  • Seemingly, low-dose and long-term maintenance therapy does not contribute to improvement in patients with CHC.
  • Treatment of CHC seems to delay the development of cirrhosis.
  • Therapy seems to decrease the development of hepatocellular carcinoma in patients with CHC.
  • Treating CHC seems to decrease mortality.
  • Development of new drugs in the management of CHC has long been considered. Hence, telaprevir was approved for CHC in May 2011, and new drugs are in the pipeline.
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    Papers of special note have been highlighted as:
    • of interest
    •• of considerable interest

Expert Rev Gastroenterol Hepatol. 2012;6(3):371-382. © 2012  Expert Reviews Ltd.

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