the response to interferon - based therapy for patients with compensated cirrhosis due to hepatitis c has been evaluated in several trials , both as the focus of prospective study , as well as in subgroup ( post hoc ) analyses of large registration trials . despite the improved efficacy of peginterferons , the sustained virological response
( svr ) rate is suboptimal in cirrhotic patients , relative to non - cirrhotic patients .
however , the treatment of patients with compensated cirrhosis has recently been encouraged by the international liver transplant society expert panel in 2003 which concluded that patients with relatively compensated cirrhosis , defined by a meld score of 18 or less , are acceptable treatment candidates .
1 the likelihood of achieving an svr with interferon - based therapy in cirrhotic patients can be deduced from prior studies which focused upon , or incorporated patients with , advanced fibrosis .
arguably , the most important trial on this issue was conducted by heathcote and colleagues in patients with advanced stage fibrosis or cirrhosis .
2 patients were randomized to peginterferon -2a , at one of two doses ( 90 mcg or 180 mcg weekly ) , or standard interferon .
the svr rate was greatest for those treated with peginterferon alpha-2a 180 mcg weekly for 48 weeks ( 30% ) ; this is in comparison to a svr rate of only 8% in those treated with standard , thrice weekly , interferon . in subgroup analysis comparing those with bridging fibrosis to those with cirrhosis
, there did not appear to be a statistically significant difference between the groups in terms of achieving an svr .
the patients infected with genotype 1 who received the 180 mcg dose of pegylated interferon had a 12% svr rate , in comparison to 51% non - type 1 genotypes treated with this dose .
further analysis of data from the heathcote trial revealed that treatment was associated with histological improvement , especially in the group that experienced an svr . comparing the pegylated interferon group ( 180 mcg ) group to standard interferon , histological improvement occurred in 54% and 31% respectively .
pertinent to the issue of histological effects of therapy , poynard pooled data retrospectively from 4 large randomized controlled trials that included paired biopsies .
3 this analysis included data on 3,010 patients treated for either 24 or 48 weeks .
overall , improvement in both the inflammatory grade and histologic stage of disease were associated with therapy .
of the 153 cirrhotic patients with svr included in this analysis , 75 ( 49% ) had significant improvement in fibrosis after treatment .
interferon - based therapy may provide additional benefit by reducing the risk of hepatocellular carcinoma in cirrhotic patients as suggested in preliminary studies . in a study among 103 patients with hcv - related cirrhosis ,
those receiving interferon had a lower incidence of hepatocellular carcinoma and improved survival after 4 years .
4 a reduction in the risk for hepatocellular carcinoma in cirrhotic patients was also detected in a japanese trial of patients on interferon monotherapy for a median of 3 years .
5 therefore , in addition to establishing a target for therapeutic efficacy in patients with advanced fibrosis , early studies suggest potential histological and survival benefits of interferon - based treatment .
insight into the efficacy of combination therapy with pegylated interferon and ribavirin in cirrhotic patients can be obtained from the large registration trials for pegylated interferon . in the peginterferon alfa-2b registration trial , the 6% of participants that had cirrhosis demonstrated a lower svr rate compared to those study subjects without cirrhosis .
6 cirrhotic patients treated with pegylated interferon alfa-2b , 1.5 mcg / kg weekly in plus ribavirin 800 mg a day for 48 weeks had a 44% svr ; in comparison , patients treated with standard interferon alfa-2b , 3 million units three times a week plus ribavirin for 48 weeks had a slightly lower response rate of 41% . in the second published pivotal trial of combined therapy with pegylated interferon and ribavirin , cirrhotic patients treated with peginterferon alfa-2a plus ribavirin for 48 weeks had svr rate of 43% , compared to 33% in patients treated with standard interferon combined with ribavirin .
non - cirrhotic patients enrolled into this study had svr rates of 58% and 46% respectively .
7 results of two ongoing prospective studies are awaited to answer an important question that remains ; is there any benefit of prolonged treatment of patients with advanced fibrosis or cirrhosis , even in the absence of svr ? the national institutes of health sponsored halt - c trial ( hepatitis c antiviral long term treatment against cirrhosis ) , is a multicenter study of the potential benefit of prolonged peginterferon therapy in mitigating the progression of fibrotic liver disease . 8 in this study , 391 of the 1045 patients enrolled into the initial 
preliminary results show that cirrhosis alone impaired response to therapy , with lower svr rates compared to non - cirrhotic patients .
9 in the copilot study ( colchicine versus peg - intron long term ) , enrollees are predominantly cirrhotic patients who failed prior treatment .
10 an interim analysis suggested a benefit to pegylated interferon therapy , over colchicine , in reducing complications associated with cirrhosis .
long term outcome data from this trial and other suppressive protocols will determine the efficacy of such an approach .
11 in summary , patients with advanced fibrosis or cirrhosis have a lower svr compared to non - cirrhotic patients , even with the latest combination therapy .
cirrhotic patients may tolerate therapy less well , given the propensity for thrombocytopenia and leucopenia , as was seen in the three large trials that included cirrhotic patients . 2 , 4 , 11 in practice ,
the use of these agents is costly and has not been studied rigorously in a randomized controlled format to assess their value and impact on efficacy of therapy although they are now widely used in patients receiving interferon therapy .
chronic hcv infection is the leading indication for liver transplantation ( lt ) in the united states and europe . given the accelerated progression of hcv following lt
, the observation than higher pre - transplant viral load is associated with poorer transplant outcome , and the difficulties in treatment of the infection following lt 12 , it is reasonable to emphasize the importance of pre - transplant treatment of hcv .
the international liver transplantation society expert panel provided guidelines when considering interferon - based treatment in patients with hcv - cirrhosis . as seen in table 1 ,
clearly , there are major obstacles toward treatment of this group of patients . since the advent of meld - based allocation , with the associated lessened importance of waiting time , those awaiting liver transplant are more ill . the resulting poor synthetic function , presence of hepatic encephalopathy and hypersplenism limit the candidacy of patients for interferon - based therapies .
pre - transplant hcv treatment enthusiasm has also been curbed by the lower rates of sustained virologic response in those with fibrotic disease compared to those with less severe histology .
several advances in hcv therapy have allowed incremental progress in overcoming these hurdles . as described above ,
peginterferons have shown better efficacy that unmodified interferons in the treatment of cirrhotic stage hcv . 2
additionally , the use of growth factors , specifically g - csf and erythropoietin , has allowed more aggressive dosing of interferon and ribavirin .
13 , 14 finally , growing experience with antiviral therapy in this high - risk group has led to novel approaches and increasing success .
table 2 provides details on the published results of antiviral therapy in this difficult - to - treat population .
early published results with interferon / ribavirin - based regimens were unfavorable , leading to concern for the safety of such an approach .
crippin and colleagues randomized end - stage liver disease patients on the transplant waiting list to three dose regimens : interferon alfa-2b , 1 million units ( mu ) daily , interferon alfa-2b 3mu t.i.w . , and interferon alfa-2b
1mu daily with ribavirin 400 mg po bid . 15 these very sick patients ( cpt mean 11.9 ) were subject to strict eligibility requirements : platelet count > 45,000/ml , hemoglobin > 11 g / dl , and absolute neutrophil count ( anc)>1250/ml . dose reductions or study discontinuation were mandated for anc < 750/ml or platelets < 45,000/ml and anc < 500/ml or platelets < 20,000/ml , respectively .
ribavirin dose was decreased for hemoglobin < 10 g / dl and discontinued for hemoglobin < 8.0 g / dl . of those patients
screened , 47% met entry criteria ( most excluded for thrombocytopenia ) of whom 33% ( 5/15 ) cleared virus on treatment . of two patients that went to lt , one was a responder , but relapsed .
of concern was the safety profile : 20 severe adverse drug reactions were reported , including two serious infections , one of which led to multi - organ system failure and death .
enrollment was discontinued well short of intentions because of these complications . despite this setback , enthusiasm for pre - transplant therapy
thomas and colleagues reported their experience with high - dose unmodified interferon monotherapy in 2003 .
16 this report was similar to a similar protocol used in 1995 by the same principal investigator .
this regimen , which employed g - csf to maintain anc > 1500 cells / ml was well tolerated , with temporary dose discontinuation in 3/20 ( 15% ) .
forns and colleagues used relatively high - dose interferon / ribavirin therapy in their cohort of 30 patients awaiting transplantation in spain in an effort to reduce viral load at the time of lt .
17 when the investigators estimated 4 months remained until transplantation , interferon alfa-2b 3mu / day and ribavirin 800 mg / day were initiated , with a resulting mean treatment period of 12 weeks in 30 patients .
the virologic response rate on therapy was 30% , with two - thirds of responders remaining non - viremic after lt .
as in other such trials many wait - listed patients did not meet eligibility requirements ( 38% ) , and side effects were common . despite the use of g - csf and erythropoietin , dose reduction of interferon was required in 60% , while ribavirin dose was decreased in 23% of study patients .
everson and colleagues offer the largest series to date with a unique low accelerating dosage regimen ( ladr ) .
18 one hundred twenty four patients were treated with unmodified interferon or peginterferon at low initial dose , with increases every two weeks toward standard target doses .
duration of therapy was intended to be 24 weeks in genotypes 2 and 3 and 48 weeks in genotype 1 infection .
hematologic inclusion criteria included anc > 800 cells / ml , hemoglobin > 10 g / dl and platelets > 35,000/ml .
one fourth to one sixth of the patients referred to our clinic with advanced liver disease were treated with lad during his period .
 end of treatment response was seen in 46% while the svr rate was 22% .
svr was associated with non-1 genotype , cpt class a , and a complete course of therapy . as expected in this very ill set of patients , adverse drug reaction rates were relatively common , with two such events potentially contributing to patient mortality .
of the 15 patients that were virologically negative at the time of transplantation , 12 remained hcv(- ) for at least six months following lt .
although the data are mixed on the effectiveness and safety of interferon - based therapies in patients with decompensated cirrhosis , the demonstrated possibility of viral eradication in this group with possible improvement in hepatic synthetic function and improved post - transplant outcome provide an important rationale for further studies in this area .
future work will focus on pegylated accelerating dose regimens , the increased use of growth factors and non - interferon based antiviral therapies .
currently , it is advisable to treat such patients only in experienced centers with close monitoring for adverse events . 1 , 19
the morbidity of recurrent hcv following liver transplantation has made pre - transplant antiviral therapy a high priority for research .
the low accelerating dosage regimen of everson and colleagues has demonstrated good efficacy but must be replicated in other cohorts and centers .
the development of new , non - immunomodulatory antiviral agents promises to be a significant advance in the treatment of this population .
ultimately , individualization of the anti - viral regimen chosen in each case may lead to better efficacy rates with less adverse drug reactions and side - effects .
international liver transplantation society expert panel consensus conference proposed guidelines for interferon - based treatment of patients with cirrhosis 1 summary of results from interferon - based treatment regimens in patients with advanced liver disease
 despite the improved efficacy of peginterferons , the rate of sustained virologic response is suboptimal in cirrhotic patients , relative to non - cirrhotic patients . 
 however , the treatment of patients with compensated cirrhosis has recently been encouraged by expert panels . 
 interferon - based therapy may provide additional benefit by reducing the risk of hepatocellular carcinoma in cirrhotic patients as suggested in preliminary studies . 
 results of two ongoing prospective studies are awaited to answer the important question of the effectiveness of suppressive interferon therapy , even in the absence of sustained virologic response . given the importance of recurrent hcv following liver transplantation , attention has been directed toward the antiviral treatment of patients with advanced liver disease . this approach needs to be pursued with caution given the potential morbidity of the therapy . 
 recently , a low accelerating dosage regimen has provided excellent results and is the subject of additional inquiry . 
1. Treatment in compensated cirrhosis
2. Treatment of advanced liver disease
3. Research Direction
Figures and Tables