Extensive fibrotic deposition in advanced hepatitis C virus (HCV) liver disease is the histopathological hallmark of a chronic necro-inflammatory process that involves parenchymal cells. Progressive derangement of normal liver architecture correlates with a reduction in liver synthetic function and brings to its late clinical expressions of decompensation, such as intractable ascites, hepatic synthetic failure, encephalopathy, jaundice, variceal bleeding, and hepatocellular carcinoma. Once cirrhosis is present, the process is generally considered as irreversible and predisposing to high mortality risk with a survival rate of 50% at 5 years[ ¹]. A mathematical model of the natural history of chronic hepatitis C projected number of cases with cirrhosis to increase by more than 50% by 2010[ ²]. As a result, there will be a dramatic increase in the number of cases with complications of liver failure throughout the next three decades.

Once decompensation complicates liver cirrhosis, liver transplantation is the only successful therapeutic option. However, the limited number of organ donors as well as impairment in age-related cardiovascular, renal, and pulmonary functions, renders this option unlikely for the majority of patients. In addition, age over 65 years is commonly considered as an exclusion criterion to enlist patients for liver transplant. Exploring new therapeutic options to offer patients with HCV end-stage liver cirrhosis is a critical need, as cirrhotics who are never listed for liver transplant could still potentially benefit from non-surgical therapy.

Compensated cirrhosis is defined by the absence of clinical complications and presence of both preserved hepatic synthetic function and adequate bone marrow reserve. Post-hoc analyses of patients with bridging fibrosis or compensated cirrhosis included in two international, registrative trials on the efficacy of Peg-IFN and ribavirin, produced a 43% rate of sustained viral clearance (SVR) by 48 wk administration of once weekly Peg-IFN alpha 2a 180 μg plus ribavirin 1000-1200 mg/d[ ³]: a similar rate of 44% was seen in those treated with Peg-IFN alpha-2b 1.5 μg/kg weekly plus ribavirin 800 mg/d for 48 wk[ ⁴]. From previous trials, data on cirrhotic patients could not be retrieved separately from those with bridging fibrosis, so that exact figures of SVR rate in cirrhotics remain to be determined. Moreover, cirrhotics enrolled in these studies were commonly in a Child-Pugh-Turcotte (CPT) class A, had as a rule a compensated disease, and slightly abnormal hematological parameters; moreover, no information was usually given on the degree of portal hypertension.

The first study proving the benefits of antiviral therapy in cirrhotics with signs of portal hypertension, a subset of patients with more advanced cirrhosis than the cohort of cirrhotics enrolled in registrative trials, was the one published by Di Marco et al[ ⁵]. In the study, a branch of 51 cirrhotics received 1 μg/kg per week of Pegylated-interferon alpha-2b plus oral ribavirin at a fixed dose of 800 mg/d for 52 wk. By intention-to-treat analysis, a sustained virologic response (SVR) was achieved by 11 patients (21.6%), with a therapeutical efficacy poorest in those infected with genotype 1 and 4 (6 of 45, 13.3%) than in those with genotypes 2 and 3 (5 of 6, 83.3%). All responders achieved negative HCV-RNA during the first 12 wk of treatment, and no subject still positive at this time evaluation became negative later despite continued treatment. The median WBC count decreased from baseline, particularly during the first two months of treatment. Five patients stopped PEG-IFN due to neutrophil counts < 0.75 × 10 ³/dL, but none of them developed infections. Cumulative incidence of events was significantly higher in patients without an SVR: disease deterioration occurred only in 6% of patients with SVR as compared to 38% of non-responders. This study established the effectiveness of antiviral therapy in the subgroup of patients with severe portal hypertension, although it must be emphasized that entry criteria for the trial excluded patients with clinical, biochemical, or hematological decompensation of the liver disease.

Safety of combination therapy in cirrhotics is a major concern. Bone marrow suppression by administration of both standard or Peg-IFN-alpha leads to significant decrease in all 3 lineages of the hematopoietic system, whereas anemia through haemolysis is more a sequela of ribavirin therapy[ ⁶]. Absolute neutrophil and lymphocyte counts typically decrease by 30% to 50% of baseline values during therapy[ ⁷]. In a recent analysis of patients treated at a single referral center, where basal neutropenia was not an exclusion criterion, therapy was safely accomplished despite decreases in neutrophils below the usual levels that lead to dose reduction or drug interruption[ ⁸]. No patients who developed infections had a pre-existing neutropenia (below 1500 cells/mL), and none developed neutropenia of less than 750 cells/mL at any point during treatment. Although the use of interferon in cirrhotics with neutropenia is usually not recommended, there is no evidence, up to now, of a significantly higher risk of severe infections or death correlated with interferon therapy in cirrhotics, a concern supported by the studies of Heathcote and Di Marco, where none of the cirrhotics with interferon-induced neutropenia of less than 750 cells/mL developed serious infection or sepsis[ ^{4 , 5}].

It is currently recommended that development of leucopenia during antiviral therapy, an event that develops in 15%-20% of cases[ ⁹], to be managed by modification or withdrawal of drugs. This recommendation may potentially affect achieving an SVR, being the therapeutic outcome dependent on both dose and duration of currently administered drugs[ ¹⁰]. Hematopoietic cytokines, such as granulocyte colony-stimulating factor (G-CSF), at the weekly dosage of 300 μg, can reverse neutropenia, enabling patients to remain on full dosage and duration of therapy[ ^{11 , 12}]. However, G-CSF is prescribed less frequently than erythropoietin, likely for two reasons: First, ribavirin-induced anaemia is more common than IFN-induced neutropenia and, secondly, practitioners are probably less responsive to neutropenia than to anaemia being the latter more often symptomatic than neutropenia. As regards to chronic hepatitis C, no official guidelines have been set for the use of G-CSF, probably because of the absence of firm data of the benefit of the cytokine administration in increasing SVR while reducing infections.

Treatment of HCV-infected patients induces hemoglobin drop in the majority of patients[ ¹³]. The anemia is of “mixed” type: Ribavirin induces a dose-dependent hemolytic anaemia, whereas IFN alpha suppresses erythroid progenitor cell and red blood cell production[ ⁷]. The mean maximal hemoglobin decrease, reached within the first 12 wk of therapy, is a relevant point as a reduction in ribavirin dosage in the initial 12 wk of therapy below 80% of the starting dose lowers the chance of early virologic response (EVR)[ ¹⁴] and compromise treatment success[ ^{15 , 16}]. The management of anemia recommends ribavirin dose reduction untill 600 mg/d if hemoglobin decreases to < 10 g/dL in a patient without cardiac risk factors, and discontinuation of ribavirin if hemoglobin becomes < 8.5 g/dL[ ¹⁷]. A decrease in hemoglobin levels is normally accompanied by an increase in the serum erythropoietin (sEPO) level, an endogenous hormone that acts in the bone marrow to increase the number of erythroid progenitor cells[ ¹⁸], which will ultimately normalize the hemoglobin level[ ¹⁹]. In HCV-infected patients treated with PEG-IFN/RBV, although increased levels of sEPO, the hemoglobin level did not return to normal, suggesting that the physiological increase in sEPO is not sufficient to fully compensate for the degree of anemia. Administration of recombinant human erythropoietin at a dosage of 40 to 60 U once weekly, may constitute an alternative: 88% of patients receiving erythropoietin versus 60% of controls could maintain the assigned ribavirin doses[ ²⁰].

Antiviral therapy is commonly deferred in cirrhotics with signs of liver decompensation, due to even more compelling concerns over treatment-induced side effects. Along with the progression of liver disease, a reduction in the capability to remove endotoxin and bacteria from the bloodstream, due an acquired immunodeficiency state, is observed in these patients[ ²⁹]. However, the majority of cirrhotics with HCV infection have reasonably stable hepatic function after a successful treatment of a decompensated event and, therefore, might be suitable candidates for antiviral therapy. It seems conceivable that tolerance of antiviral therapy in this particular setting of patients might be extremely poor due to their advanced age, as adherence to combination therapy is negatively influenced by increasing patient’s age[ ³⁰]. In addition, impaired age-related cardiovascular and pulmonary functions may reduce tolerance of ribavirin-induced anemia, while impaired renal function by increasing blood levels of ribavirin (primarily cleared by kidney) may worsen anemia. Finally, insulin resistance secondary to HCV infection may further impair response to combination therapy[ ³¹].

Several reports on antiviral therapy in HCV-infected cirrhotic patients who sustained one or more episodes of liver decompensation are available in the literature[ ^{32 - 36}] (Table 1): The results indicate that these patients might tolerate current antiviral regimens. However, unstandardized dosages of antiviral drugs that have been administered for a variable and different treatment length may have underestimated and differentiated outcomes and virologic response rates in previous reports. After reviewing existing experience, the International Liver Transplantation Society Expert Panel issued guidelines, in 2003, for the use of interferon-based therapy in patients with cirrhosis, strongly considering therapy in those with a CTP score ≤ 7, and possibly in those with a score of 8 to 11 (Table 2). In the low-accelerating dosage regimen, starting doses were 1.5 MU thrice weekly for conventional interferon, 0.5 μg/kg per week for Peg-IFN alpha 2b, or 90 μg/wk for Peg-IFN alpha 2a, given alone or in combination with a ribavirin dose of 400 mg/dL[ ³²]. Dose adjustments for each of the two drugs were made every 2 wk as tolerated to achieve optimal effective doses. Using an initially low, accelerating regimen of non-pegylated interferon plus ribavirin, 39% of 102 patients experienced clearance of HCV-RNA on treatment, and 21% attained an SVR, 11% with genotype 1, and 50% with genotypes 2 and 3[ ³⁶]. Moreover, of patients with SVR, none relapsed after liver transplantation[ ³⁷]. By including Peg-IFNs, further improvement in efficacy can be expected. In our initial investigation, Peg-IFN alpha 2b (1.0 μg/kg) plus standard dose of ribavirin were administered for a short treatment duration (24 wk for all genotypes) to decompensated cirrhotic patients[ ³³]: The overall SVR rate attained with this suboptimal regimen of therapy amounted to 19.7% (13 of 66 treated cases), higher efficacy (43.5% of SVR) being found in genotype 2 and 3 infection than in genotype 1 and 4 (7%). Therapy was tolerated by patients, at a remarkable exception of individuals with very advanced liver disease (CTP score > 10) who experienced severe life-threatening side effects.

Based on our initial investigation, we went further to determine whether currently recommended dosages of Peg-IFN and ribavirin for the standard length of treatment could be safely tolerated in decompensated cirrhotic patients. An ongoing protocol has been set up at our institution where all cirrhotic patients with a CTP score ≤ 9 and a decompensated event that abated with common management are offered therapy with Peg-IFN alpha-2b (1.5 μg/kg) and ribavirin (800-1000 mg for genotypes 2 and 3, and 1000-1200 mg for genotypes 1 and 4) for the recommended treatment duration (48 and 24 wk for genotype 1 and non-1, respectively) (submitted, unpublished data). In this program, at the end of the 24 wk follow-up period off therapy, 35% of our end-staged cirrhotics cleared the HCV infection, 16% of patients with genotype 1 and 4, and 59% of patients with genotype 2 and 3. Almost 60% of patients tolerated full dosage and duration of treatment, whilst 18 (19.1%) patients discontinued treatment and among these 4 developed severe infections.