Chronic infection with the hepatitis C virus (HCV) is an enormous worldwide public health problem. In 1999, the World Health Organization reported that there were 169.7 million cases of HCV worldwide, with 31.9 million in Africa, 13.1 million in the Americas, 21.3 million in the eastern Mediterranean, 8.9 million in Europe, 32.3 million in Southeast Asia (India and Indonesia included), and 62.2 million in the western Pacific (China and Japan included) . The prevalence of antibody to HCV in the United States is at least 1.8%, or 3.9 million persons, based upon an analysis of 21,241 serum samples from US citizens older than 6 years of age who participated in NHANES III . In NHANES III, 74% of those with positive HCV antibody also test positive for HCV RNA, yielding an estimated 2.7 million Americans with active infection.
Progression of chronic hepatitis C to cirrhosis occurs over several years, typically requiring two decades or more of active infection. HCV infection lacks specific symptoms, and liver disease is silent until the late stages when patients may experience biochemical deterioration or clinical complications, such as ascites, varices, or encephalopathy. In the US, the peak incidence of HCV infection occurred between 1970 and 1985. Because progression to cirrhosis requires 20 years or more of active infection, only now are large numbers of patients presenting to clinics with cirrhosis and complications of liver disease due to HCV. A recent analysis suggested that 1.7 million Americans have had hepatitis C for over 20 years, and by the year 2015 this number will swell to 3 million . Given an average rate of progression to cirrhosis of 12.5% over 20 years of infection [4-8], there are now 212,500 Americans with hepatitis C and cirrhosis, and this number will increase to 375,000 by the year 2015. If one applies the US rates for proportion of HCV RNA positivity, duration of infection, and time required for development of cirrhosis to worldwide statistics, then currently there are 7.8 million persons with cirrhosis worldwide. Projecting into the future, by 2015 there will be 13.8 million cases of cirrhosis due to HCV worldwide.
Treatment options are limited for patients with cirrhosis due to chronic hepatitis C who have undergone clinical decompensation. Medical and endoscopic therapies are useful in controlling symptoms and complications but do not improve patient survival, and liver transplantation, which does improve survival, is available to only a few HCV-infected patients with decompensated cirrhosis due to a limited supply of donor livers. Clearly the most effective strategy is halting disease progression by treatment of patients to eradicate HCV prior to onset of cirrhosis. However, many patients present to our clinics with advanced fibrosis or cirrhosis at various clinical stages of compensation or decompensation. For these reasons, the main goal of this article is delineation of the current options and outcomes of antiviral therapy for patients with advanced fibrosis and cirrhosis due to chronic hepatitis C.
Epidemiological surveys have suggested that approximately 20 years of active infection are required for development of cirrhosis and 30 years for development of hepatoma [9-11]. Cirrhosis progresses from a stage of compensation to a stage of decompensation. The term compensation defines patients with biopsy-proven cirrhosis who lack significant biochemical deterioration and have not experienced clinical complications. Patients with compensated cirrhosis are at-risk for progression of disease and clinical deterioration. Estimated rates for development of clinical deterioration (decompensation), hepatoma, and death from liver disease in patients with compensated cirrhosis are 3.6 to 6.0 %/yr, 1.4 to 3.3 %/yr, and 2.6 to 4.0 %/yr, respectively [12-15].
Goals of antiviral treatment
The main goal of therapy in compensated cirrhosis is sustained virological response (SVR), because viral clearance is associated with reduction in risk for decompensation and hepatoma. However, less than 50% of compensated cirrhotics will experience SVR when treated with current antiviral regimens. The primary aim of retreatment of nonresponders and relapsers to prior courses of antiviral therapy is still SVR. However, rates of SVR with retreatment, especially retreatment of cirrhotic patients, are very low. For this reason, the strategy of maintenance therapy to halt disease progression has been considered and is currently under investigation in large clinical trials such as HALT C .
Outcome of antiviral therapy in patients who were naïve to prior therapy
The published large, randomized, controlled trials of interferon (IFN)-based therapy include a small percentage of patients with either advanced bridging fibrosis or compensated cirrhosis [17-24]. To be enrolled, these patients had to have normal or near-normal bilirubin, prothrombin time, and albumin and absence of a history of clinical decompensation. All patients with cirrhosis in these trials were in the presymptomatic, compensated stage and classified as Child-Turcotte-Pugh class A. None had received prior therapy. Although entry criteria allowed for platelet counts as low as 90,000/µL [22,24] or 100,000/µL [17-21,23], mean platelet counts in these trials were within the normal range. The results indicate that SVR was lower in patients with advanced fibrosis or cirrhosis compared to patients with less severe stages of fibrosis. In addition, SVR improved with increased duration of therapy, addition of ribavirin (RBV), and use of pegylated interferons (PEG-IFN). SVRs were 5% to 15% for IFN monotherapy compared to 40% to 50% for the maximally effective regimen of PEG-IFN plus RBV. The most favorable report on treatment of advanced fibrotics or compensated cirrhotics was that of Hadziyannis , where 48 weeks of PEG-IFN α-2a plus RBV achieved an SVR of 50% (41% in genotype 1 and 73% in genotypes 2 and 3). However, only 35 of the 115 patients (30%) in the advanced stage group had biopsy-proven cirrhosis.
One of the more instructive reports is the study of Heathcote et al which specifically focussed on the treatment of patients with cirrhosis . Two hundred and twelve of the 271 patients (78%) in this trial had biopsy-proven cirrhosis, and the remaining 22% had bridging fibrosis. Patients were treated with either IFN α-2a, 3 mU tiw, PEG-IFN α-2a, 90 µg/wk, or PEG-IFN α-2a, 180 µg/wk. Entry criteria included absolute neutrophil count >1500/µL and platelet count >75,000/µL. Even though this trial focussed on advanced fibrosis and cirrhosis, the patients were all compensated; they had stable laboratory tests and lacked history of clinical complication.The mean absolute neutrophil counts for the three arms of the trial were 3400/µL, 3400/µL, and 3100/µL. The mean platelet counts for the three arms of the trial were 153,000/µL, 162,000/µL, and 166,000/µL. SVRs were 8%, 15%, and 30% for IFN α-2a, PEG-IFN 90 µg, and PEG-IFN 180 µg.The difficulty in treating patients with genotype 1 infection and high viral load was highlighted. None (0/32) of the latter patients treated with PEG-IFN, 90 µg/wk, and only 10% (3/29) treated with PEG-IFN, 180 µg/wk, achieved SVR.
There were two additional important findings in the Heathcote study . First, the end of treatment virological response rates (EOTR) with PEG-IFN were relatively robust, 42% for PEG-IFN, 90 µg/wk, and 44% for PEG-IFN, 180 µg/wk, and significantly better than that achieved with nonpegylated IFN (only 14%). This implies that a sizeable proportion of patients with either advanced fibrosis or cirrhosis can be rendered HCV RNA-negative during treatment with PEG-IFN monotherapy. Second, histology improved in 31%, 44%, and 54% of patients treated with IFN α-2a, PEG-IFN α-2a, 90 µg/wk, and PEG-IFN α-2a, 180 µg/wk, respectively. Histological improvement was most common in virological responders but also occurred in patients without virological response. The implication is that IFNs, especially PEG-IFNs, may have beneficial effects on hepatic fibrosis, independent of their effects on viral clearance.
Outcome of antiviral therapy in relapsers
Relapsers are more likely to respond to retreatment than nonresponders [26-29]. There have been two randomized controlled trials of IFN plus RBV in the retreatment of relapsers after IFN monotherapy, but few patients with either bridging fibrosis or cirrhosis were included [21,30]. In the Davis trial , SVRs were similar between fibrotic (46%) and nonfibrotic (49%) patients. In the Saracco trial , low fibrosis score.
No study has specifically evaluated PEG-IFN plus RBV according to stage of fibrosis in the retreatment of relapsers to IFN monotherapy. Jacobson et al  retreated 321 patients with chronic hepatitis C, 40% of whom had advanced fibrosis or cirrhosis, with PEG-IFN α-2b plus RBV, including 55 patients who had relapsed after a prior course of IFN plus RBV. SVR was 42% in the 55 relapsers. Overall, for all 321 patients, there was no impact of advanced fibrosis or cirrhosis on SVR, but this was not separately analyzed in relapsers.
Outcome of antiviral therapy in nonresponders
Two meta-analyses of trials of IFN plus RBV in the retreatment of nonresponders to IFN monotherapy indicated SVRs of only 13% to 14% (confidence interval 11% to 17%), with SVRs of 8% for genotype 1 and 15% for other genotypes [32,33]. None of these studies was able to de-fine the impact of cirrhosis on SVR due to inadequate sample sizes.
PEG-IFN plus RBV has been used in the retreatment of nonresponders to both IFN monotherapy and IFN plus RBV. In the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial  overall SVR was 18%: 28% in those whose prior treatment was IFN monotherapy but only 12% in those whose prior treatment was IFN plus RBV. SVR in patients with biopsy-proven cirrhosis (n=233) was 11%, compared to SVR of 23% in noncirrhotics (n=371) (P=.0005). On-treatment rates of clearance of HCV RNA for cirrhotics versus noncirrhotics were 26% vs 40% at week 20 and 23% vs 37% at week 48. The low rate of virological response in cirrhotics in HALT-C was due to the study's focus on retreatment of prior nonresponders, high proportion of patients infected with genotype 1, and protocol-driven dose reductions in both PEG-IFN and RBV based on cytopenias.
The large number of cirrhotics enrolled in the HALT-C trial permitted examination of factors contributing to reduced SVR in this population of patients .The entire group of patients enrolled in the lead-in phase of HALT-C  was evaluated (n=1045), of whom 391 had biopsy-proven cirrhosis (Ishak 5 or 6). Four subgroups based upon noncirrhotic vs cirrhotic histology and platelet count cutoff of 125,000/µL were compared. Those with least severe disease were defined by noncirrhotic biopsy and platelet count >125,000/µL. Those with greatest severity of disease were defined by cirrhotic biopsy and platelet count of ≤125,000/µL. Usual predictors of response, such as age, gender, percent genotype 1, percent African American, high viral load, type of prior therapy, and dose reductions did not account for the reduction in SVR from least severe (SVR 23%) to most severe (SVR 9%) disease.
These results suggest that extensive fibrosis, especially cirrhosis, independently impairs response to IFN-based antiviral therapy.
Decompensated cirrhosis refers to patients with histologically proven cirrhosis who have experienced significant biochemical deterioration (thrombocytopenia, hypoalbuminemia, hyperbilirubinemia, coagulopathy) or clinical complications (ascites, spontaneous bacterial peritonitis, jaundice, encephalopathy, variceal hemorrhage, renal dysfunction).
Patients with decompensated cirrhosis are at-risk for death from complications and typically are in need of liver transplantation for survival.
Cirrhotics with hepatitis C who experience decompensation have a 5-year survival of only 50% without transplantation .
Disease severity and selection of potential candidates
Cirrhosis due to HCV is the leading indication for liver transplantation in the United States. Generally, patients with hepatitis C who have been listed for liver transplantation have experienced one or more episodes of clinical decompensation. However, decompensation, per se, is not necessarily synonymous with either severity of underlying liver disease or immediate risk of death. If the patient's hepatic and renal function, as measured by bilirubin, prothrombin time (INR), and creatinine, remain stable despite the episode of decompensation, model for end-stage liver disease (MELD) score is unchanged and predicted 90-day survival is unaffected. In fact, in the development of MELD, clinical complications of portal hypertension (variceal bleed, ascites, edema, encephalopathy, SBP) did not add predictive value for survival above that contributed by bilirubin, INR, and creatinine [36,37].
Although an episode of clinical decompensation heralds a change in the course of chronic liver disease, recovery is common and patients may stabilize. Examination of MELD scores in patients on the US waiting list for liver transplantation indicates that approximately 90% of HCV patients listed at active status have MELD scores ≤18 (www.OPTN.org). The range of results in biochemical tests for MELD scores between 6 and 18 spans the normal to moderately abnormal spectrum. For example, bilirubin 1.8 mg/dL, INR 1.8, and creatinine 1.3 mg/dL yields a MELD score of 18. This suggests that many patients with clinical decompensation, including those on the transplant waiting lists, have reasonable hepatic function and reserve.
The Consensus Development Conference on Liver Transplantation and Hepatitis C suggested that patients with MELD scores of 18 or less could be considered for treatment . In addition, the AASLD practice guidelines state that patients referred for liver transplantation with mild degrees of hepatic compromise could be considered for antiviral therapy, initiated at low dose, "as long as treatment is administered by experienced clinicians, with vigilant monitoring for adverse events" . Thus, in contradistinction to popular belief, it is very possible that a sizeable proportion of patients with chronic hepatitis C and decompensation might be candidates for antiviral therapy.
We have used a low-accelerating dose regimen (LADR) in treatment of more advanced disease for three reasons . First, patients with advanced disease may be intolerant of standard doses of IFN and RBV. Second, clearance of hepatitis C may not only halt disease progression but result in clinical remission and avoid the need for transplantation. Third, clearance or suppression of hepatitis C prior to transplant might avoid recurrence of hepatitis C in the liver allograft, ultimately improving graft and patient survival.
The severity of disease in patients that we treated with LADR was representative of that in patients with moderately advanced liver disease and similar to that in the majority of patients on the US waiting list. Two-thirds had a history of clinical decompensation, 90 (73%) were listed before, during, or after LADR, and 47 underwent transplantation.
Despite use primarily of nonpegylated IFN, and conservative application of growth factors, LADR achieved EOTR of 46% and SVR of 24% in patients with advanced disease. Virological response was compromised by genotype 1 infection, severity of liver disease (CTP class C), failure to achieve target doses, and duration of therapy. EOTR was 30% and SVR 13% in patients with genotype 1 infection, but 82% and 50% in patients with non-1 genotypes. Side effects, complications of advanced liver disease, and cytopenias were commonly encountered, limited dose escalations, and contributed to dose reductions. Growth factors were used sparingly but allowed some patients to achieve full dose therapy and SVR. Use of PEG-IFN, which has greater antiviral effect, and maintenance of higher doses of antiviral drugs by more liberal use of growth factors might be expected to improve results with LADR.
Fifteen patients experienced 22 serious adverse events, 16 of which occurred during the course of treatment, and 2 that may have contributed to mortality. Most adverse events were complications common to patients with advanced liver disease (encephalopathy, gastrointestinal bleeding, worsening ascites). In contrast, certain complications, such as infection, diabetes, thrombocytopenia, and venous thromboembolism, may have been more directly related to IFN. This experience highlights the need to exercise caution in treatment and maintain very close supervision of these patients during the course of therapy.
Perhaps the most important finding of our study was prevention of post-transplant recurrence of HCV by pretransplant antiviral therapy. Twelve of 15 (80%) of patients who were HCV RNA-negative pretransplant lacked posttransplant recurrence. In contrast, all 32 who were HCV RNA-positive pretransplant recurred post-transplant. Overall, 15 of 47 were rendered HCV RNA-negative at the time of liver transplantation (32%), and 12 of 47 (26%) were spared HCV recurrence. Six of the patients in our cohort were recipients of LDLT and none relapsed. The ability to schedule the date of transplantation in LDLT may be of particular advantage in the setting of pretransplant antiviral therapy.
Two other groups have studied IFN therapy prior to transplantation [41,42]. Forns and colleagues  treated 30 cirrhotic patients, with an anticipated time to transplantation of less than 4 months, with IFN α-2b (5 mU/d) plus RBV 800 mg/d. Eighty-three percent had genotype 1b HCV and median duration of treatment was 9 weeks. Nearly all experienced significant side effects, and 63% required dose reductions in IFN or RBV. Nine patients (30%) were negative for HCV RNA at the time of transplantation, and, of these, 6 remained negative post-transplant (20%). Thomas and colleagues used daily injections of 5 mU IFN α-2b in 20 patients and reported that 12 were HCV RNA-negative at time of transplant (60%), but only 4 (20%) remained free of recurrence post-transplantation . The 20% prevention of recurrence was similar to that observed in the Forns study (6/30, 20%) and in our experience with LADR (12/47, 26%).
Crippin and colleagues treated 15 patients with more advanced disease (CTP score 11.9 ± 1.2) . No patient experienced sustained response, two who were transplanted had recurrence of HCV, and the study was halted due to serious side effects. In contrast to Crippin, we reported an SVR of 26% in 23 patients with CTP class C treated with LADR, despite CTP score 11.1 ± 1.1 and MELD score 16.8 ± 3.0. However, our patients with SVR were mainly infected with non-1 genotypes; only 1 of 14 patients with genotype 1 and CTP class C had SVR.
Clinical status at the time of initiation of antiviral therapy appears to be the main limiting factor in decompensated HCV cirrhosis because of poor tolerability of the drug regimen . Dose reductions and discontinuations will compromise clinical efficacy in patients with decompensated cirrhosis as they do in patients with milder disease. Although still undetermined, baseline laboratory abnormalities (e.g., elevated bilirubin levels, high INR, low platelet counts), preceding clinical events (e.g., ascites, spontaneous bacterial peritonitis), and patient's status (e.g., CTP score, MELD score) might be helpful in predicting tolerability and clinical outcomes. It is currently recommended that patients with decompensated cirrhosis should only be treated with antiviral therapy by experienced clinicians or in the setting of a clinical trial.
Management issues in treatment of decompensated cirrhosis
Many of these patients may have neutropenia, thrombocytopenia, and anemia prior to institution of treatment. Use of IFN, PEG-IFN, and RBV in this population will tend to worsen or precipitate cytopenias.
Dose and duration of treatment
The Consensus Development Conference on Liver Transplantation and Hepatitis C suggested that an LADR may be preferred in the treatment of this population . However, there are no controlled trials comparing treatment regimens and the optimum regimen remains to be defined.
Although unproven, development or exacerbation of cytopenia in patients with cirrhosis may increase the risk for infection, bleeding, and anemia-related fatigue, poor stamina, or exercise intolerance. Two strategies for management of cytopenias have been separately advocated: dose reduction or use of growth factors (granulocyte-colony stimulating factor, G-CSF, and erythropoietin analogues, EPO). The value of either G-CSF or EPO in preventing complications or enhancing virological response is unknown. However, the alternative strategy, dose reduction, may compromise the primary objective of achieving the highest rate of virological response.
The primary goal of antiviral therapy, sustained viral clearance, can be achieved in only a minority of patients with cirrhosis, and this is especially the case in those with more severe disease or decompensation. Secondary goals, including inhibition of inflammation, stabilization of fibrosis, prevention of clinical deterioration, and reduction of risk of hepatoma, become major objectives.
The National Institutes of Health-sponsored HALT-C (Hepatitis C Antiviral Long-Term treatment against Cirrhosis) trial is an ongoing multicenter US trial of maintenance PEG-IFN therapy to prevent fibrosis progression and clinical decompensation . Results from the randomized phase of HALT-C have not yet been presented or published. COPILOT (Colchicine versus PEG-Intron Long-term trial ) is another large, US multicenter study of maintenance PEG-IFN therapy. In this study, prior nonresponders with fibrosis or cirrhosis (80% of cases had cirrhosis) are randomized to receive either PEG-IFN α-2b (0.5 µg/kg/wk) or colchicine for 4 years. Preliminary data after 1 year indicate a trend toward lower viral load and a lower frequency of clinical events in patients treated with PEG-IFN . A follow-up report of 2-year data indicated an annual event rate [which included death, transplantation, hepatoma, 2-point or more progression in CTP (Child-Turcotte-Pugh) score, and variceal hemorrhage] of 7% in the colchicinetreated arm versus 3.5% in the PEG-IFN maintenance arm (P=.003) . A third maintenance trial, EPIC (Efficacy of Peg Interferon in Hepatitis C), will compare PEG-IFN α-2b to no treatment. Recommendations regarding utility and efficacy of maintenance therapy will depend upon the results from these trials.
An algorithm describing treatment options and outcomes for patients with cirrhosis is given (Figure 1) . Current data from existing clinical trials suggest that 41% of clinically compensated patients with advanced fibrosis or cirrhosis and genotype 1 HCV and 73% with genotypes 2 or 3 HCV can achieve SVR.
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A. Patients with compensated cirrhosis should be treated with a standard antiviral regimen, such as the current treatment standard of PEG-IFN plus RBV. SVR is 40% to 50%. Patients with SVR may still need long-term monitoring for clinical complications of cirrhosis and development of hepatoma. Patients who experience relapse or fail to respond may be considered for maintenance therapy.
B. Patients with decompensated cirrhosis (MELD <18) who are not listed may be candidates for LADR. Treatment is most effective for genotypes 2 and 3 with SVR of approximately 50%. SVR is less likely (10% to 20%) in patients with genotype 1.
Patients who relapse may be considered for another course of potentially curative treatment at higher dose or under support of growth factors, particularly if they are tolerant of the side effects of antiviral medication. Otherwise, those who relapse or fail to respond might be candidates for maintenance treatment.
C. Patients with decompensated cirrhosis (MELD <18) who are listed for transplantation may be candidates for LADR. Those experiencing SVR should maintain listed status and be monitored for complications, including hepatoma. Patients who relapse should be considered for antiviral therapy up to the time of transplantation. Treatment should be withdrawn and not reinstituted in nonresponders.
(From Journal of Hepatology, V42, Everson G. Management of cirrhosis due to chronic hepatitis C, S65-S74 © 2005 with permission from The European Association for the Study of Liver)
These results have prompted many to advocate aggressive therapy in well-compensated cirrhotics (CTP class A) who lack evidence of clinical decompensation. However, response of cirrhotics to antiviral therapy declines with increasing severity of liver disease and nonresponse to prior IFN-based treatments.
Reasons for low SVR in decompensated cirrhotics include high prevalence of genotype 1 HCV, inability to achieve full doses of IFN and RBV due to side effects and dose-limiting cytopenias, and risk of complications related to deteriorating liver function.
Although rates of SVR are low in decompensated cirrhotics, on-treatment clearance of HCV from blood occurs more frequently, and three reports have suggested that pretransplant clearance of HCV RNA from blood may reduce risk of post-transplant recurrence of hepatitis C. Carefully controlled trials of antiviral therapy in decompensated cirrhosis to define safety and efficacy are needed.
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