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Management of cirrhosis due to chronic hepatitis C
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Journal of Hepatology
April 2005 Supplement
Gregory T. Everson
University of Colorado School of Medicine, University of Colorado Health Sciences Center, 4200 East 9th Avenue, B-154, Denver, CO 80262, USA
Summary
Antiviral therapy for patients with chronic hepatitis C and compensated cirrhosis, decompensated cirrhosis, or patients on the waiting list for liver transplantation is evolving. An algorithm suggesting one approach is provided. Current data from existing clinical trials suggest that 41% of patients with genotype 1 HCV and 73% with genotypes 2 and 3 HCV with advanced fibrosis or early compensated cirrhosis can achieve SVR. 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 severity of liver disease and nonresponse to prior interferon-based treatments. In a single center experience of treatment of decompensated cirrhotics with genotype 1 HCV, SVR was only 11%. In contrast, SVR in genotypes 2 and 3 was 50%. Reasons for low SVR in decompensated cirrhotics include high prevalence of genotype 1 HCV, inability to achieve full doses of interferon and ribavirin due to side effects and dose-limiting cytopenias, and risk of complications related to deteriorating liver function. Although SVR rates are low in decompensated cirrhotics, on-treatment clearance of HCV from blood occurs in approximately 30% of genotype 1 patients and 80% of genotype 2 and 3 patients treated with nonpegylated interferon plus ribavirin. In addition, three reports suggest 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. In the absence of virologic cure, maintenance therapy with peginterferon may slow disease progression and reduce rate of clinical decompensation. The results of three large trials of maintenance therapy are anxiously awaited. Until the results from these maintenance trials become available, it may be reasonable to consider maintenance treatment for patients with advanced fibrosis or cirrhosis who experienced virologic relapse after cessation of combination therapy, or those who had significant viral suppression or biochemical response on combination therapy.
Selected Highlights from Article
--peginterferon, may have beneficial effects on hepatic fibrosis, independent of its effect on viral clearance...histology improved in 31, 44, and 54% of patients treated with (monotherapy) interferon alfa-2a, peginterferon alfa-2a, 90E g/wk, and peginterferon alfa-2a, 180E g/wk
--study results suggest that extensive fibrosis, especially cirrhosis, independently impairs response to interferon-based antiviral therapy.
--Decompensated cirrhosis refers to patients with histologically-proven cirrhosis who have experienced significant biochemical deteriorationor clinical complicationsÉ..Patients with decompensated cirrhosis are at-risk for death from complications and typically are in need of liver transplantation for survival
--It is generally assumed that patients with hepatitis C and decompensation may be too sick to be treated with the combination of interferon plus ribavirin...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 therapyÉ.If biochemical parameters were the sole determinant, most patients with clinical decompensation, including those on transplant waiting lists, could meet criteria for initiation of therapy
--The primary goal of antiviral therapy, sustained viral clearance, can be achieved in only a minority of patients with cirrhosis, especially 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.
--Interferon can improve liver disease -- histologic improvement on liver biopsyNecrosis and inflammation improved in 39% of patients receiving standard interferon for 24 weeks and in 73% of patients receiving pegylated interferon alfa-2b plus ribavirin
--Sustained viral clearance halted progression of fibrosis and reversed cirrhosis in 49% of 153 cirrhotic patients
In one study, peginterferon alfa-2a reduced hepatic fibrosis to a greater extent than interferon-
--Sustained virologic responders demonstrated greatest improvement (-0.59 stage, P<0.0001)
--Relapsers experienced lesser (-0.34 stage, P=0.0007)
-- and nonresponders little (-0.13 stage, P=NS) improvement
In a 2nd study, Alric treated biochemical responders who were virologic nonresponders with maintenance interferon and also demonstrated histologic improvement (SEE MAINTENANCE THERAPY SECTION BELOW)
ABSTRACT
"Maintenance therapy with gradual reduction of the interferon dose over one year improves histological response in patients with chronic hepatitis C with biochemical response: results of a randomized trial"
Background/Aims: Our aim was to assess whether histological response was improved by continuing interferon-alpha (IFN) treatment in patients with chronic hepatitis C (HCV) with a biochemical response and no viral clearance after a usual IFN treatment.
Methods: Fifty-seven patients with normal alanine aminotransferase (ALAT) levels and positive HCV RNA at the end of a 1 year IFN treatment were randomly assigned to either group 1 (n =28) where IFN was stopped, or group 2 (n =29) where IFN was continued for 1 more year with gradual reduction of the dose to keep serum ALAT activity below the upper limit of normal. Liver biopsies were obtained before, and then 6 months after the end of treatment.
Results: Knodell"s index improved between paired biopsies in group 2 (8.2± 2.4 vs. 5.5± 2.1), but not in group 1 (8± 2.3 vs. 6.5± 2). In post-treatment biopsies, the METAVIR activity score was significantly lower in group 2 than in group 1 (0.7± 0.2 vs. 1.1± 0.3, P < 0.05). In group 2, an improvement of the METAVIR fibrosis score was observed (1.3± 0.4 vs. 1.1± 0.2), whereas fibrosis progressed in group 1 (1.3± 0.4 vs. 1.6± 0.4).
Conclusions: Maintenance therapy by the minimal dose of IFN able to maintain biochemical response prevents histological progression in the sub-group of patients without virological response.
ARTICLE OUTLINE
1. Compensated cirrhosis
1.1. Natural history
1.2. Antiviral treatment
1.2.1. Naive to prior therapy
1.2.2. Retreatment of relapsers and nonresponders
2. Decompensated cirrhosis
2.1. Natural history
2.2. Assessment of severity of illness
2.3. Antiviral treatment
2.4. Management issues in treatment of decompensated cirrhosis
2.4.1. Cytopenias
2.4.2. Dose and duration of treatment
2.4.3. Growth factors
2.4.4. Post-treatment followup of responders
3. Maintenance therapy
ARTICLE TEXT
In 1999, the World Health Organization reported that there were 169.7 million cases of hepatitis C (HCV) worldwide with 31.9 million in Africa, 13.1 million in the Americas, 21.3 million in Eastern Mediterranean, 8.9 million in Europe, 32.3 million in South-East Asia (included India and Indonesia), and 62.2 million in the Western Pacific (includes China and Japan) 1. An analysis of 21,241 serum samples from US citizens greater than 6 years of age who participated in NHANES III 2 indicated a prevalence of 1.8% or 3.9 million. Seventy four percent of those with positive HCV antibody also test positive for HCV RNA, yielding an estimated 2.7 million Americans with active infection. Another analysis has suggested that 1.7 million Americans have had hepatitis C (HCV) for over 20 years, and by the year 2015 this number will swell to 3 million 3. Given a rate of 12.5% progression to cirrhosis 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. (note from Jules Levin: because HIV can accelerate HCV disease progression, coinfected patients are at much greater risk for compensated & decompensated cirrhosis; and for cirrhosis to develop much more quickly as studies show HIV can accelerate HCV 2-5 times more quickly. When you consider coinfected patients in general have considerably less access to care and treatment, the consequences are more serious). If one applies the US rates for proportion of HCV RNA positivity, duration of infection, and time required for development of cirrhosis to the world's population of individuals with HCV, then 7.8 million currently have cirrhosis. By 2015, there will be 13.8 million cases of cirrhosis due to HCV. Obviously, management of cirrhosis due to hepatitis C will continue to be a major issue for the foreseeable future for hepatologists, gastroenterologists, and primary care providers throughout the world.
Compensated cirrhosis
1.1. Natural history
Epidemiologic 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 is defined not only histologically but also by clinical, laboratory, and radiologic criteria and progresses from a stage of compensation to a stage of decompensation. The term compensation defines patients with biopsy-proven cirrhosis, but 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 3.6-6.0%/yr, 1.4-3.3%/yr, and 2.6-4.0%/yr, respectively [12-15] (Table 1). Cirrhotics with hepatitis C who experience decompensation have a five year survival of only 50% 12.
Table 1. Annual risk (% per yr) of decompensation of liver disease, development of hepatoma (HCC), or death in patients with compensated cirrhosis
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1.2. Antiviral treatment
The main goal of therapy in compensated cirrhosis is sustained virologic 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 16. Recommendations regarding maintenance therapy await results from these trials.
1.2.1. Naive to prior therapy
The published large, randomized, controlled trials of interferon-based therapy included a small percentage of patients with either advanced bridging fibrosis or compensated cirrhosis [17-24]. Cirrhosis on liver biopsy was not an exclusion to therapy but criteria for initiation of treatment were normal or near-normal bilirubin, prothrombin time, and albumin and absence of history of clinical decompensation. Virtually all patients with cirrhosis in these trials were in the presymptomatic, compensated stage and classified as Child-Turcotte-Pugh class A. Patients with more advanced disease were not included. For example, although entry criteria allowed for platelet counts as low as 90,000/EÊl [22,24] or 100,000/EÊl [17-21,23], mean platelet counts in these trials were within the normal range. Although sustained virologic response (SVR) was lower in patients with advanced fibrosis or cirrhosis, SVR similarly improved in both fibrotic/cirrhotics and nonfibrotics with changes in antiviral regimens. In fibrotic/cirrhotics, as in nonfibrotics, SVR increased with increased duration of therapy, addition of ribavirin, and use of pegylated interferons (Table 2). SVRs were 5-15% for interferon monotherapy, 20-30% for peginterferon monotherapy, 30-40% for interferon plus ribavirin, and 40-50% for peginterferon plus ribavirin. Response was lowest in patients with genotype 1 infection, particularly those with high viral load. The most favorable report on treatment of advanced fibrotics or compensated cirrhotics was that of Hadziyannis 23, where 48 weeks of peginterferon alfa-2a (Pegasys) plus ribavirin achieved an SVR of 50% (41% in genotype 1 and 73% in genotypes 2 and 3). However, only 35 of the 115 patients (30%) that were included in this analysis had biopsy-proven cirrhosis.
Table 2. Sustained virologic response (SVR) in patients naive to prior therapy
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Abbreviations: Cirrh, number of patients with cirrhosis; SVR, sustained virologic response; I-2b, interferon alfa-2b; I-2a, interferon alfa-2a; R, ribavirin; wk, weeks; HVL, high viral load (either >2 million copies/ml or >850,000IU/ml); PI-2a, peginterferon alfa-2a; PI-2b, peginterferon alfa-2b; PI-2a90, arm treated with 90E g/wk; PI-2a180, arm treated with 180E g/wk; PI-2bLD, low-dose arm of trial; PI-2bHD: high-dose arm of trial; R800, arm receiving 800mg/d ribavirin; R1-1.2, arm receiving 1-1.2g/d ribavirin. Compared to noncirrhotics (data not shown), the SVR of cirrhotic patients in these trials was generally 5-10% lower. Rates of SVR improved with change in therapy from interferon monotherapy to the current treatment standard of peginterferon plus ribavirin. Patients with genotype 1 are less likely to achieve SVR and best chance for SVR is with full-dose peginterferon plus ribavirin given for 48 weeks. Patients with genotypes 2 and 3 achieve SVR with lower doses of ribavirin given for only 24 weeks.
The study of Heathcote, et al., specifically focussed on the treatment of patients with cirrhosis 25. Two hundred 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 interferon alfa-2a, 3 MU tiw, peginterferon alfa-2a, 90E g/wk, or peginterferon alfa-2a, 180E g/wk. Entry criteria included absolute neutrophil count >1500/EÊl and platelet count >75,000/EÊl. 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/EÊl, 3400/EÊl, and 3100/EÊl The mean platelet counts for the three arms of the trial were 153,000/EÊl, 162,000/EÊl, and 166,000/EÊl. SVRs were 8, 15, and 30% for interferon alfa-2a, peginterferon 90EÊg, and peginterferon 180EÊg. The difficulty in treating patients with genotype 1 infection and high viral load was highlighted. None of the latter patients treated with peginterferon, 90E g/wk, (0/32) and only 10% treated with peginterferon, 180E g/wk, (3/29) achieved SVR (Table 2 under Ôpeginterferon monotherapy').
Despite the relatively low rates of SVR in the Heathcote trial 25, there were two additional important findings. First, the end of treatment virologic response rates with peginterferon were relatively robust, 42% for peginterferon, 90E g/wk, and 44% for peginterferon, 180E g/wk, and significantly better than that achieved with nonpegylated interferon (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 peginterferon monotherapy. Second, histology improved in 31, 44, and 54% of patients treated with interferon alfa-2a, peginterferon alfa-2a, 90E g/wk, and peginterferon alfa-2a, 180E g/wk, respectively. Histologic improvement was most common in virologic responders but also occurred in patients without virologic response. The implication is that interferon, especially peginterferon, may have beneficial effects on hepatic fibrosis, independent of its effect on viral clearance.
1.2.2. Retreatment of relapsers and nonresponders
Relapsers are more likely to respond to retreatment than nonresponders [26-28]. There have been two main randomized controlled trials of the retreatment of relapsers after interferon monotherapy with interferon plus ribavirin, but few patients with either bridging fibrosis or cirrhosis were included [21,29]. In the Davis trial 21, SVRs were similar between fibrotic (46%) and nonfibrotic (49%) patients. In the Saracco trial 29, low fibrosis score (≤Ishak 2) was associated with greater likelihood for SVR. The impact of cirrhosis on SVR could not be adequately assessed in either trial since only 3% in the Davis trial and 6% in the Saracco trial had cirrhosis. In both trials, genotype was a major determinant of SVR. SVR was 22-33% for genotype 1 patients treated for 24 weeks and 45-50% in those treated for 48 weeks. In contrast, SVR for genotypes 2 and 3 ranged from 68 to 73% whether treated for 24 or 48 weeks. Although the results by genotype were not further analyzed for impact of fibrosis or cirrhosis, it is likely that rates of SVR would be less for patients with cirrhosis.
Two meta-analyses of trials of interferon plus ribavirin in the retreatment of nonresponders to interferon monotherapy indicated SVRs of only 13-14% (CI 11-17%), with SVR of 8% for genotype 1 and 15% for other genotypes [30,31]. None of these studies was able to define impact of cirrhosis on SVR due to inadequate sample sizes.
Peginterferon plus ribavirin may be useful in the retreatment of relapse 27, but projected (calculated) and actual rates of SVR in retreatment of nonresponders have ranged from 5 to 18% [26,27,32]. In the HALT-C trial (hepatitis C antiviral long-term treatment against cirrhosis trial) overall SVR was 18%; 28% in those whose prior treatment was interferon monotherapy, but only 12% in those whose prior treatment was interferon plus ribavirin. SVR in patients with biopsy-proven cirrhosis (N=233) was 11%, compared to SVR of 23% in noncirrhotics (N=371) (P=0.0005). On-treatment rates of clearance of HCV RNA for cirrhotics vs noncirrhotics were 26 vs 40% at week 20, and 23 vs 37% at week 48. The low rate of virologic response in cirrhotics in HALT C was due to the study's focus of retreatment of prior nonresponders, high proportion of patients infected with genotype 1, and protocol driven dose reductions in both peginterferon and ribavirin based on cytopenias.
Decompensated cirrhosis
2.1. Natural history
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 five year survival of only 50% without transplantation 12.
2.2. Assessment of severity of illness
Although, long-term survival is adversely affected by decompensation, patients typically are treated for clinical complications, recover from acute events, and stabilize, at least temporarily. They are frequently evaluated and listed for liver transplantation and comprise approximately 40% of the patients on transplant waiting lists. On December 22, 2004, 37% of the 17,393 patients listed for liver transplantation in the US had either a primary or secondary diagnosis of hepatitis C (Organ Procurement and Transplantation Network data, ).
For purpose of discussion, I would emphasize that decompensation 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, MELD score is unchanged and predicted 90 d 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 [34,35]. Thus, although an episode of clinical decompensation heralds a change in course of chronic liver disease and predicts worse long-term survival, recovery and stabilization is common and short-term survival may be unaffected.
How sick are patients who have experienced decompensation? Because decompensated patients are frequently listed for liver transplantation, waiting list patients are a subpopulation that may be representative of general group of decompensated patients. Examination of MELD (model for end-stage liver disease) scores in patients on the US waiting list for liver transplantation indicates that 90% of HCV patients listed at active status have MELD scores ≤18 (). The range of biochemical tests between MELD 6-18 span the normal to moderately abnormal spectrum. For example, bilirubin 1.8mg/dL, INR 1.8, and creatinine 1.3mg/dL yields MELD score 18. I conclude, that many patients with clinical decompensation, including those on the transplant waiting lists, have reasonable hepatic function and reserve.
It is generally assumed that patients with hepatitis C and decompensation may be too sick to be treated with the combination of interferon plus ribavirin. The decision to exclude patients with decompensation from clinical trials of antiviral therapy was based upon the concern that therapy may lead to further deterioration. This was based on clinical judgment, not data. However, we now know that clinical complications may not predict short-term survival and that many patients with decompensation actually have relatively stable laboratory tests that fall within the FDA-approved guidelines for institution of antiviral therapy. If biochemical parameters were the sole determinant, most patients with clinical decompensation, including those on transplant waiting lists, could meet criteria for initiation of therapy.
The consensus development conference on liver transplantation and hepatitis C suggested that patients with MELD scores 18 or less could be considered for treatment 36. In addition, the AASLD practice guidelines state that patients referred for liver transplantation with mild degree of hepatic compromise could be considered for antiviral therapy, initiated at low dose, Ôas long as treatment is administered by experienced clinicians, with vigilant monitoring for adverse events' 37. 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.
2.3. Antiviral treatment
Experience with treatment of decompensated cirrhosis is limited. We have previously reported our experience in treating sicker patients many of whom had a history of clinical decompensation [38,39]. In this study, 102 patients were treated with the combination of interferon alfa-2b plus ribavirin using an initially low, but accelerating dose regimen (LADR). Eighty seven percent had biopsy-proven cirrhosis, and 13% had bridging fibrosis. Five percent had a pretreatment platelet count of less than 50,000/mL, and 36% dropped below 50,000/mL during treatment. Sixty-six percent of patients had 1 or more complications before treatment, including variceal hemorrhage, ascites, spontaneous bacterial peritonitis, or encephalopathy. The mean pretreatment CTP score was 7.1±2.0. An end-of-treatment virologic response was achieved in 39% of patients (35 of 91), and SVR was achieved in 22% of patients (20 of 91). Patients who had SVR prior to transplant did not recur post-transplantation. Sixteen of the 56 nonresponders (27%) discontinued treatment because of side effects, most commonly fatigue and flu-like symptoms. Four patients experienced hepatic encephalopathy, and 3 developed infections. There were also 3 episodes of gastrointestinal hemorrhage that occurred several weeks after treatment had been discontinued. The 2 factors that predicted response to treatment were the ability to achieve full-dose therapy and non-1 HCV genotype.
Data were particularly encouraging for patients with genotype 2 and 3 where end-of-treatment response was 80% and SVR 50%, and the recommendation of the consensus development conference on liver transplantation and hepatitis C was to consider these patients for pre-transplant antiviral therapy 36. In contrast, the risk/benefit ratio of treating patients with genotype-1 infection remains to be defined by randomized controlled trials. Cirrhotic patients require close monitoring during treatment and therapy is best administered in liver clinics affiliated with liver transplant programs. Centers treating this group of patients should have extensive experience in management of advanced liver disease, hepatitis C, and liver transplant recipients 37.
Forns and colleagues treated 30 patients with hepatitis C and cirrhosis awaiting liver transplantation with an estimated time to transplantation of 5 months or less 40. Eighty three percent of patients were infected with genotype 1 HCV and 50% were CTP A, 43% were CTP B, and 7% were CTP C. Treatment was initiated with 3 MU tiw interferon alfa-2b plus 800mg/d ribavirin but side effects were frequent and 63% required dose reductions. Nine patients (30%) achieved on-treatment clearance of HCV RNA from blood and 6 patients (20%) remained free of HCV post-transplantation. An additional 43% of nonresponders experienced a decline in viral load of ≥2log10 prior to transplantation. This experience prompted the authors to conclude that pretransplant antiviral therapy should be considered as one of several possible strategies to prevent or reduce post-transplant HCV recurrence.
Thomas and colleagues used daily interferon alfa-2b in 20 patients (67% genotype 1) for 14±2.5 months and cleared HCV from the blood in 60% prior to transplantation 41. Four patients (20%) remained free of hepatitis C in the post-transplant period and were free of histologic hepatitis in post-transplant biopsies.
Crippin and colleagues conducted a small study with interferon alfa-2b and ribavirin in patients with severely decompensated cirrhosis awaiting liver transplantation 42. The conditions of the patients in this trial were more critical than in the studies by Everson and Forns, with a higher mean pretreatment CTP score (11.9±1.2). Patients in this multicenter, open-label trial were randomized to receive interferon alfa-2b 1 mIU three times a week (n=3), interferon alfa-2b 3 mIU three times a week (n=6), or interferon alfa-2b 1 mIU once daily plus ribavirin 400mg/day (n=6). Even with low-dose interferon, 33% (5 of 15) of patients in this study experienced on-treatment HCV-RNA clearance using the less sensitive branched-chain DNA assay. However, adverse events occurred in 13 of 15 patients (87%), and 20 of the 23 events were considered severe, including thrombocytopenia (7), neutropenia (4), hepatic encephalopathy (3), hypothyroidism (1), hyperbilirubinemia (1), pancreatitis (1), Staphylococcus aureus arthritis (1), ventral hernia (1), and culture-negative empyema with death (1). Because of the high rate of complications, the study was prematurely terminated, and the authors cautioned physicians regarding the hazards of antiviral therapy in patients with decompensated HCV cirrhosis.
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 to the drug regimen 43. Dose reductions and discontinuations will compromise clinical efficacy in the patients with decompensated cirrhosis as it does in patients with milder disease. Although still undetermined, baseline laboratory abnormalities (e.g. elevated bilirubin levels, high international normalized ratio, 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 [36,37,44].
2.4. Management issues in treatment of decompensated cirrhosis
2.4.1. Cytopenias
Many of these patients may have neutropenia, thrombocytopenia, and anemia prior to institution of treatment. Use of interferon and ribavirin in this population will tend to worsen or precipitate cytopenias. Treatment-related neutropenia and thrombocytopenia is more common and severe with peginterferon compared to nonpegylated interferon. The benefit of higher virologic response rates with peginterferon may be counter-balanced by complications related to cytopenias.
2.4.2. Dose and duration of treatment
The consensus development conference on liver transplantation and hepatitis C suggested that a low-accelerating dose regimen of therapy (LADR) may be preferred in the treatment of this population 36. However, there are no controlled trials comparing treatment regimens and the optimum regimen remains to be defined. In Forns experience, use of higher initial doses of both interferon and ribavirin resulted in dose reductions in about two-thirds of patients 40. For these reasons, suggested starting doses are interferon alfa-2b, 1.5 MU tiw, peginterferon alfa-2b, 0.5ug/kg/wk, or peginterferon alfa-2a, 90ug/wk, plus ribavirin, 600mg/d. Patients with creatinine clearance <50ml/min should be started at a lower dose of ribavirin, 400mg/d. Dose adjustments are made every two weeks. Interferon is first increased as tolerated to achieve full dose treatment within 2-4 weeks. Next the dose of ribavirin is subsequently increased, in increments of 200mg, every two weeks as tolerated, to attempt to achieve an estimated optimally effective dose between 11 and 13mg/kg/d. It must be emphasized that full dose therapy is rarely achieved in patients with more severe cirrhosis due to side effects and dose-limiting cytopenias.
Patients on this therapy require frequent measurement of CBC and biochemistry, approximately every 2 weeks, until stabilization of dose, and then monthly thereafter. HCV-RNA should be measured every 3 months. Patients who fail to respond at 12 weeks of treatment with at least a 2log drop in HCV-RNA should be dropped from treatment. Expected duration of initial treatment, once the patient achieves optimal doses of both interferon and ribavirin, would be 6 months for genotypes 2 and 3, and 12 months for genotype 1.
The desired outcome from this therapy is sustained viral response. However, relapse rates may be higher than noncirrhotic HCV patients, particularly with genotype 1, due to inability to achieve optimal doses of both interferon or ribavirin [32,33,38-42]. If treatment is stopped and relapse occurs, one may consider re-institution of antiviral therapy. An alternative approach could be continuation of antiviral therapy for responding genotype 1 patients to the time of transplantation.
2.4.3. Growth factors
Interferon is associated with neutropenia, thrombocytopenia, and mild anemia primarily due to suppression of bone marrow. Ribavirin is associated with anemia due both to hemolysis and bone marrow suppression. Development or exacerbation of cytopenia is in patients with cirrhosis may increase the risk for infection, bleeding, and anemia-related fatigue, poor stamina, or exercise intolerance.
Two strategies are used to control these side effects: 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 virologic response is unknown. However, the alternative strategy, dose reduction, may compromise the primary objective of achieving the highest rate of virologic response. Dietrich has demonstrated that use of EPO during treatment of chronic hepatitis C with interferon plus ribavirin can increase hemoglobin concentrations and maintain higher doses of ribavirin 45. For these reasons, use of growth factors is favored over dose reduction in the management of cytopenias.
2.4.4. Post-treatment followup of responders
Patients should be monitored for relapse at 1, 3, and 6 months post-treatment 36, and consideration given for re-institution of treatment for those who relapse. Sustained responders may stabilize and slow or cease progression of their underlying liver disease. However, cirrhotic patients should continue to be screened for hepatocellular carcinoma, according to accepted guidelines, even after clearance of HCV. Fifty percent of patients with chronic hepatitis C and cirrhosis have current or past histories of significant alcohol use or abuse. Maintenance of abstinence from alcohol must be emphasized.
Maintenance therapy
The primary goal of antiviral therapy, sustained viral clearance, can be achieved in only a minority of patients with cirrhosis, especially 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.
In Heathcote's study of compensated cirrhosis, 50% of the patients receiving 180ug/wk of pegylated interferon alfa-2a demonstrated histologic improvement on liver biopsy 25. Shiffman and colleagues demonstrated that patients who either suppressed or eradicated HCV-RNA were more likely to experience improvement in liver necroinflammation compared to virologic nonresponders 46. An analysis of 3010 patients treated in 4 randomized trials examined the impact of therapy on inflammation and fibrosis 47. Necrosis and inflammation improved in 39% of patients receiving standard interferon for 24 weeks and in 73% of patients receiving pegylated interferon alfa-2b plus ribavirin (P<0.001). Sustained viral clearance halted progression of fibrosis and reversed cirrhosis in 49% of 153 cirrhotic patients. Camma conducted a meta-analysis encompassing 1013 patients and found that peginterferon alfa-2a reduced hepatic fibrosis to a greater extent than interferon (difference of -0.14 Knodell HAI fibrosis stage, P=0.04) 48. Sustained virologic responders demonstrated greatest improvement (-0.59 stage, P<0.0001). Relapsers experienced lesser (-0.34 stage, P=0.0007) and nonresponders little (-0.13 stage, P=NS) improvement. Additional studies are needed to verify these intriguing observations. A 2800-patient study from Japan suggested that interferon therapy was associated with a reduced risk for hepatoma (risk ratio, 0.516 [95% confidence interval, 0.358-0.742]; P<0.001), especially in patients who experienced an SVR or sustained biochemical response 49. These results must be interpreted with caution since there is potential for selection bias in nonrandomized, retrospective analyses and responses of Western and Japanese patients to antiviral therapy may differ.
Shiffman examined the effect of interferon alfa-2b (3 MU tiw for 24 months) versus no treatment on histologic progression in 53 patients with prior nonresponse to interferon 50. Knodell fibrosis score decreased in treated patients from 2.5 to 1.7, and 80% had histologic improvement. In comparison, untreated patients experienced an increase in mean fibrosis scores from 2.2 to 2.4 and histologic worsening in 30%. Alric treated biochemical responders who were virologic nonresponders with maintenance interferon and also demonstrated histologic improvement 51.
The National Institutes of Health-sponsored HALT-C (hepatitis C antiviral long-term treatment to prevent Cirrhosis) trial is an ongoing multicenter US trial of maintenance pegylated interferon to prevent fibrosis progression and clinical decompensation 16. Patients are first treated with 24 weeks of pegylated interferon alfa-2a 180ug/wk plus ribavirin 1.0-1.2g/d. The results of this Lead-In phase of treatment in HALT C patients with cirrhosis are described above. Virologic nonresponders at week 20 are randomized to either no further therapy or 90ug/wk of pegylated interferon alfa-2a for an additional 3.5 years. Study end points include histologic progression, and development of clinical decompensation, liver cancer, need for liver transplantation, or death. 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 peginterferon therapy. In this study, prior nonresponders with fibrosis or cirrhosis (80% of cases) are randomized to receive either peginterferon alfa-2b (0.5ug/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 peginterferon 52. A followup report of 2-year data, indicated an annual event rate (included death, transplant, hepatoma, 2 point or more progression in CTP (Child-Turcotte-Pugh) score, and variceal hemorrhage) of 7% in the colchicine-treated arm versus 3.5% in the peginterferon maintenance arm (P=0.003) 53. A third maintenance trial, EPIC (Efficacy of Peg Interferon in Hepatitis C), will compare peginterferon alfa-2b to no treatment. Recommendations regarding utility and efficacy of maintenance therapy will depend upon the results from these trials.
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