Cirrhosis

Impact of Pegylated Interferon alfa-2b (Peg-Intron) and Ribavirin on Progression of Liver Fibrosis in patients with Chronic Hepatitis C Reported by Jules Levin

	Based on 2 biopsies 20 months apart, this study reported: Sustained responders improved activity grade, were less likely to have worsened activity, and less likely to see worsened fibrosis On average non-responders with fibrosis (F2, F3, and F4) could stop fibrosis progression On average sustained responders with fibrosis (f2, F3, and F4) show regression of fibrosis 49% with cirrhosis showed some degree of reversal of cirrhosis from F4 stage to either F3, F2 or F1; achieving a sustained response was a significant factor Thierry Poynard first commented on aims of therapy: (1) to achieve a sustained virologic response which permits fibrosis regression, disappearance of extrahepatic manifestations, disappearance of contamination risks; (2) to block fibrosis progression in patients without a sustained virologic response (perhaps also using a suppressive maintenance therapy). Editorial note from Jules Levin: Blocking fibrosis progression in nonresponders remains controversial. A number of studies have found fibrosis can be slowed or stopped in transient responders and nonresponders. Some studies have found nonresponders are not able to block fibrosis progression. And it also depends how you define a nonresponder. Mitch Shiffman reported in his study in Gastroenterology (1999; 117: 1164-1172) that patients with some early viral load reduction (1.4 log) and some early fibrosis improvement during therapy are able to sustain viral load reduction and improved histology (liver condition) with ongoing maintenance interferon therapy for the two years of this study. What about patients who are unable to reduce viral load at all and who don't show early fibrosis improvement? I think this remains a question. Two large multiple-year studies HALT-C by the NIH & Roche and CO-PILOT from Schering are exploring this question now. The findings Poynard presented here and earlier at EASL in the Spring of 2001 have been controversial. The question of whether nonresponders can reverse, slow or stop fibrosis progression is perhaps the most controvesial question currently. Poynard first presented this data at EASL but the presentation here at AASLD had several additional new pieces of information. Several observers and researchers I spoke with at AASLD do not buy his findings (the controversy). One doctor told me he does not see these kinds of benefits in his practice. I think other researchers do feel these data have merit. Poynard pooled data on 3,010 HCV treatment naive, HIV negative patients with paired biopsies from 4,493 patients in 4 trials receiving 10 different regimens (Poynard et al, McHutchison et al, Lindsay et al, and Mannes et al.) The ten regimens included IFN 24 weeks, IFN 48 weeks, PegIntron 0.5 ug/kg, PegIntron 1.0 ug/kg, PegIntron 1.5 ug/kg, IFN/RBV 24 weeks, IFN/RBV 48 weeks, PegIntron 0.5 ug/kg+RBV, PegIntron 1.5 ug/kg/RBV. Some characteristics of the 3,010 patients: 66% male, 43 years age, 80 kg weight, 53% IVDUs, genotype 1 70%, genotype 2 28%, genotype 4,5,6 3%, viral load 4 million. Duration of HCV infection for patients was 18 years. Duration between the 2 biopsies was 20 months. The size of the biopsy in mm was 16. 25% had fibrosis (F2 13%, F3 7%, F4 5%-cirrhosis), and 73% had F1 (minimal fibrosis) and 2% had F0 (no fibrosis). About about 1/3 of patients had each of severe, moderate or mild activity (A1, A2, or A3). The histological impact of each regimen was estimated by the percentage of patients with at least one grade improvement in the necrosis and inflammation (METAVIR score), the percentage of patients with at least one stage worsening in fibrosis METAVIR score and by the fibrosis progression rate per year. Activity Grade Improvement (at least one grade improvement Metavir score)

	This was new information presented for the first time at AASLD and not earlier at EASL. Being able to achieve a sustained virologic response is an important factor in being able to achieve a significant improvement in activity. Obviously, choosing the most effective regimen (its potency and tolerability) is important in being able to achieve a sustained response significantly and in turn improved activity and fibrosis. So, you want to use the most potent (antiviral activity) and tolerable regimen. Tolerabiliy is important because with more side effects and adverse events adherence may be more challenging. Poynard reported an analysis of the change in activity grade by each of the ten regimens including PegIntron 1.5 ug/kg+RBV using the optimized weight based dose of RBV. IFN alone 24 weeks: 39% of patients improved, 39% stabilized, 24% worsened IFN alone 48 weeks: 41% improved, 40% stabilized,19% worsened Peg-Intron 0.5 ug/kg: 48% improved, 35% stabilized, 20% worsened Peg-Intron 1.0 ug/kg: 49% improved, 33% stabilized, 18% worsened Peg-Intron 1.5 ug/kg: 49% improved, 33% stabilized, 18% worsened IFN+RBV 24 weeks: 51% improved, 34% stabilized, 15% worsened IFN+RBV 48 weeks: 64% improved, 24% stabilized, 12% worsened Peg 0.5+RBV: 70% improved, 24% stabilized, 6% worsened Peg 1.5+RBV: 65% improved, 23% stabilized, 12% worsened Peg 1.5+RBV: 73% improved, 21% stabilized, 6% worsened RBV optimized weight based dosing I think its important to note that no data was presented by Poynard on the statistical significance of the differences between the regimens, either on the slides or verbally in his talk. So, you don't know if for example there is a real difference between the 41% of patients receiving IFN for 48 weeks who showed improvement and the 49% who showed improvement using PegInron 1.5 ug/kg. Or for that matter, you don't know for sure if there is a significant difference between standard IFN+RBV taken for 48 weeks (64% improved), PegIntron 0.5 ug/kg+RBV (70%), PegIntron 1.5 ug/kg+RBV (65% improved), and PegIntron 1.5 ug/kg+ optimzed dose of RBV based on weight (73%). In fact, Poynard's data shows little difference if any between the 70% of patients who saw improvement using the low dose of Pegintron 0.5+RBV compared to the patients receiving PegIntron 1.5 ug/kg+ optimized weight based dose of RBV who Poynard reported 73% of these patients experienced improved activity grade. There may not be any significant difference between 70% and 73%. Fibrosis Stage Variation (the percentage of patients with at least one stage change in fibrosis METAVIR score). The biopsies were performed 20 months apart so Poynard suggested that given more time fibrosis ought to continue to improve further for some patients. In particular, you might expect if any will continue to improve it would be sustained responders and perhaps some patients continuing on maintenance therapy.

	Again, Poynard did not present data on the statistical significance between any of the differences between the groups. But, he did comment orally in his presentation that the differences in the worsening category (7% vs 17% vs 21%) were statistically significant. I think its fair to conclude that a sustained responder has a better chance for improved fibrosis than a relapser and moreso than a non-responder. The difference in the worsening category between sustained responders and non-responders and relapsers (21% vs 7% and 17%) strikes my attention. Fibrosis Progression Rate Per Year Poynard reported the fibrosis progression rate per year in 1900 patients with F0-F1 (no or minimal fibrosis) with paired biopsies and known duration of infection.

	Poynard is reporting here that in patients with HCV alone and little or no fibrosis their fibrosis progression rate per year stopped whether they were a non-responder or sustained responder. Since the biopsies were performed 20 months apart, you don't know what might occur regarding the fibrosis progression rate in 2-3 years or longer for non-responders. Non-responders may start progressing after being off therapy for a while. How long off therapy does it take for progression to get going or to get back to baseline? I don't know of any data on this. But some doctors tell me they think the benefit can last for a little while. Follow-up biopsies should be helpful in evaluating this. Poynard reported on an analysis of fibrosis progression rate per year in 679 patients with extensive fibrosis (F2, F3, F4) with paired biopsies and known duration of therapy. Poynard commented that the progression rates in this group were very high before therapy.

	Poynard said the sustained responders experienced a dramatic decrease or regression in fibrosis rate. Fibrosis Stage Variation By Regimen The percentage of patients with at least one stage change in fibrosis METAVIR score. Again, the biopsies were 20 months apart. IFN 24 weeks: 12% of patients receiving this regimen experienced improved fibrosis, 65% stabilized, and 23% worsened IFN 48 weeks: 16% of patients improved fibrosis, 66% stabilized, and 18% worsened Peg 0.5 ug/kg: 22% improved, 62% stabilized, 17% worsened Peg 1.0 ug/kg: 21% improved, 62% stabilized, 16% worsened Peg 1.5 ug/kg: 17% improved, 65% stabilized, 18% worsened IFN/R 24 wks: 20% improved, 66% stabilized, 14% worsened IFN/R 48 wks: 20% improved, 66% stabilized, 14% worsened Peg 0.5/RBV: 23% improved, 67% stabilized, 10% worsened Peg 1.5/RBV: 23% improved, 57% stabilized, 20% worsened Peg 1.5/R: 24% improved, 68% stabilized, 8% worsened With Optimized weight based dosing So far there does not appear to be any difference between the percent of patients showing improved or stabilized fibrosis stage between most of the regimens. In particular, there is no difference between Peg 1.5 with optimized weight based RBV dosing, Peg 1.5 with RBV but without weight based RBV dosing, and standard IFN + RBV for 48 weeks. Again, Poynard did not present any data on the statistical significance of differences between groups in his slides. But he pointed out orally that there was a significant difference between the 8% worsening in the Peg 1.5+ optimized RBV arm compared to the 14% experienced by IFN/RBV 48 weeks arm. But, he did not comment on the point that the Peg 0.5/RBV arm was 10% compared to 8% with optimized RBV dose & higher PegIntron dose. Although, the biopsies were only 20 months apart and so some patients, as Poynard points out, may continue to improve further. Factors Associated With Absence of Extensive Fibrosis at 24 Months n=2861, (20 months between biopsies), multivariate analysis The baseline fibrosis stage (F0, F1) had the most impact. Patients with little or minimal fibrosis (stage F0, F1) had an 88% reduced risk for having extensive fibrosis in the second biopsy 20 months after the first biopsy and after therapy (Odds Ratio 0.12, p<0.001) Achieving a sustained virologic response had the second most impact reducing risk for extensive fibrosis on the 2nd biopsy by 64% (OR 0.36, p<0.001) Age lower than 49 had the third most impact reducing risk by 49% (OR 0.51, p<0.001) Interestingly, Body Mass Index (<27) had the fourth most impact by reducing risk by 35% (OR 0.65, p<0.001) Baseline activity (A0, A1: patients with little or no activity) had the fifth most impact by reducing risk by 30% (OR 0.70, p<0.02) Viral Load <3.5 million reduced risk by 21% (OR 0.79, p=0.03) I think the most interesting from the above data is that body mass index had an effect on outcome, Having more body mass increased risk. Expectedly, low viral load and achieving a sustained response were significant factors in reducing risk for having significant fibrosis in the 2nd biopsy. Predictability of SVR After 12 week PCR Response Poynard reported data similar to found with Pegasys+RBV on the predictability of sustained response based on the viral load response at 12 weeks. The analysis included 174 patients from the database who received PegIntron 1.5+RBV. 90% (n=120) who were PCR negative at week 12 achieved a sustained response. 26% who had a 2 log or greater reduction in PCR (n=23) achieved a sustained response. And 0 patients with <2 log reduction in viral load (n=31) at week 12 achieved a sustained response. The Pegasys analysis on using 12-week PCR response to predict outcome was more extensive and can be read in the NATAP AASLS report on this topic. Can Cirrhosis Be Reversed? 153 patients with cirrhosis were included in this analysis. Poynard called these results surprising-- 49% (n=75) reversed cirrhosis. In the first biopsy 153 patients had F4 stage fibrosis (cirrhosis). In the second biopsy 23 patients had regressed to stage 3 (f3), 26 patients regressed to stage 2 (F2), 23 patients regressed to stage 1 (F1). And 78 patients still had stage 4. Poynard did comment on the sample size of liver taken in biopsy alluding to the limitations this presents. Using a univariate analysis Poynard found the following significant factors in reversing cirrhosis: using a reinforced regimen which I think he defined as IFN for greater then 24 weeks which I assume means or includes 48 weeks IFN/RBV and PegIntron/RBV regimens translates into a greater likelihood of reversing cirrhosis achieving a sustained response (33% vs 15%) increases chance of reversing cirrhosis reduction of activity grade in the second biopsy after therapy was a factor. 45% of patients with activity grade of A0/A1 in second biopsy reversed cirrhosis compared to 23% who did not have activity grade of A0/A1 Another study using Pegasys monotherapy presented by Jenny Heathcote showed patients with cirrhosis could improve their histology (a histologic response in this study was defined as a decrease of at least 2 points on the 22-point Histological Activity Index). 30% using Pegasys montherapy achieved a sustained response vs 8% using standard interferon. www.natap.org/2001/sep/can_cirrhotics090401.htm

Can Cirrhotics Achieve a Histologic Response?

Study Design: 271 patients with cirrhosis or bridging fibrosis were randomly assigned to receive subcutaneous treatment with 3 million units of interferon alfa-2a three times weekly (88 patients), 90 µg of peginterferon alfa-2a once weekly (96), or 180 µg of peginterferon alfa-2a once weekly (87). Treatment lasted 48 weeks and was followed by a 24-week follow-up period. Study assessed efficacy by measuring HCV RNA and alanine aminotransferase and by evaluating liver-biopsy specimens. A histologic response was defined as a decrease of at least 2 points on the 22-point Histological Activity Index.
(NEJM, Jenny Heathcote, 343, 1673-80) full article in PDF format ...>

Histologic Response
Most of the 271 patients enrolled had cirrhosis at base line. As is common with other trials in patients with liver disease,2,3 nearly one third of the patients did not return for second biopsies. Among the 184 patients with paired liver biopsies, the proportion who had a histologic response was lower among the patients assigned to receive unmodified interferon (31 percent) than among those assigned to 90 µg of peginterferon alfa-2a (44 percent [P=0.22]) and those assigned to 180 µg (54 percent [P=0.02]) (Table 3). A histologic response correlated with a sustained virologic response; among the patients with a virologic response at week 72, 80 percent of those assigned to receive interferon alfa-2a also had a histologic response, as did 100 percent of those assigned to 90 µg of peginterferon alfa-2a and 88 percent of those assigned to the 180-µg dose. The virologic response was similar among patients with bridging fibrosis or cirrhosis. A histologic response was seen in 26 percent, 33 percent, and 35 percent, respectively, of patients who did not have a sustained virologic response. The histologic response also correlated with the biochemical response at week 72: 40 percent, 79 percent, and 82 percent of the patients who had a biochemical response to interferon alfa-2a or peginterferon alfa-2a at 90 µg or 180 µg, respectively, also had a histologic response.

Virologic Response
The rates of sustained virologic response (the response at week 72) were 8 percent, 15 percent, and 30 percent in patients assigned to unmodified interferon alfa-2a, 90 µg of peginterferon alfa-2a, and 180 µg of peginterferon alfa-2a, respectively (P=0.001 for the comparison between 180 µg of peginterferon alfa-2a and interferon alfa-2a [Table 3]). A response to therapy at week 12 predicted a sustained response; at week 12, all of the 26 patients who had a sustained response to 180 µg of peginterferon alfa-2a had had a decrease in viral load by a factor of at least 100 as compared with base line, and 23 of them had had undetectable HCV RNA.

Normalization of ALT in HCV Patients with Cirrhosis Significantly Reduces the Risk of Hepatocellular Carcinoma

There have been several retrospective cohort studies on the inhibition of hepatocellular carcinoma (HCC) development in chronic hepatitis C (CH-C) patients. However, a definitive analysis from a prospective study is not yet available.

Japanese researchers undertook a prospective study of interferon therapy for chronic hepatitis C patients with cirrhosis to elucidate the role of antiviral therapy for inhibition of HCC with long-term observation of 5 years as a second end-point of prior prospective antiviral studies (Shiratori Y et al. Hepatology 1999, Liver 2000).

300 patients (238 for the treatment group and 62 for control) were registered in this prospective study. Patients received regular medical check-up using blood tests and abdominal ultrasonography to detect HCC every 3-6 months. The effect of antiviral therapy on inhibition of HCC development was analyzed with Cox proportional hazard model and a time dependent covariate analysis.

HCC was detected in 74 patients during 5-year follow-up; 56 (23%) from the 238 interferon-treated patients and 18 (29%) from the 62 untreated patients. Of the 53 and 185 patients with sustained virological response (SVR) and non-sustained response (Non-SVR), HCC developed in 7 (13%) and 49 (27%), respectively.

The cumulative incidence of HCC in interferon-treated patients was slightly lower than that in untreated patients. However, when the patients were stratified according to SVR, cumulative HCC incidence among the SVR patients was lower as compared with the Non-SVR and untreated patients.

Of the clinical parameters, SVR to interferon was the strongest factor for inhibition of HCC development. Time dependent covariate analysis revealed that the risk ratio of interferon therapy for HCC development was only 0.889, but negativity of HCV RNA and normalization of serum ALT related to an inhibition of HCC with marginal significance. More importantly, sustained normalization of ALT in patients with Non-SVR was related to an inhibition of HCC development (RR=0.23, 95%CI: 0.05-0.99, p=0.049).

Conclusion: Sustained normalization of serum ALT in cirrhotic patients even without sustained virological response from antiviral therapy significantly reduced the risk of HCC development.

02/03/03

Reference
Y Shiratori and others. LONG-TERM PROSPECTIVE STUDY OF ANTIVIRAL THERAPY ON REDUCED DEVELOPMENT OF HEPATOCELLULAR CARCINOMA IN CHRONIC HEPATITIS C PATIENTS WITH CIRRHOSIS. Abstract 774. 53rd AASLD. November 1-5, 2002. Boston, MA. Hepatology 2002: Vol 36 No 4, Pt 2 of 2.

News from Hepatitis Week of July 6, 2003 / Vol. 3 No. 27

Study: Half of Cirrhosis Patients Respond to Pegasys and Ribavirin

The largest-ever analysis of data on hepatitis C patients with cirrhosis, or advanced liver disease, concluded that half of them respond to treatment with Pegasys in combination with Copegus (ribavirin), according to results presented at the 38th Annual Meeting of the European Association for the Study of the Liver.

Dr. Patrick Marcellin, a hepatologist at the Hospital Beaujon in France, said a meta-analysis of two Phase-III Pegasys combination studies involving hepatitis C patients with cirrhosis found that:

Among those treated with a standard dose of Pegasys plus 1000/1200 mg of ribavirin for 48 weeks, 49 percent achieved a sustained viral response, as compared to 33 percent who received conventional combination therapy;
Among those who also had the genotype 1 virus -- “ the most difficult to treat but most common form of hepatitis C -- 38 percent achieved a sustained viral response using Pegasys combination therapy versus 25 percent with conventional combination therapy.
Among those with genotype 2/3 virus, the rate of cure rose to 72 percent with Pegasys combination therapy versus 45 percent with conventional combination therapy

The Management of Ascites in Cirrhosis: Report on the Consensus Conference of the International Ascites Club

Ascites refers to fluid accumulation around the liver and other abdominal organs. Ascites occurs in more than 50% of cirrhotic patients within 10 years of the diagnosis of cirrhosis.

Cirrhotic ascites accounts for over 75% of patients who present with ascites, with the remaining 25% being due to malignancy (10%), cardiac failure (3%), pancreatitis (1%), tuberculosis (2%), or other rarer causes.

There have been several changes in the clinical management of ascites over recent years. An International Ascites Club Consensus Meeting on the management of ascites agreed on the recommendations reviewed here. The consensus meeting was supported by an unconditional educational grant from Searle, Spain.

These recommendations have been updated in line with subsequent recent publications of controlled clinical studies. The full consensus document is published in the July 2003 issue of Hepatology. Following is a brief summary of the consensus observations and recommendations:

“Ascites is a common complication of cirrhosis, and heralds a new phase of hepatic decompensation in the progression of the cirrhotic process. The development of ascites carries a significant worsening of the prognosis.”

“It is important to diagnose non cirrhotic causes of ascites such as malignancy, tuberculosis, and pancreatic ascites since these occur with increased frequency in patients with liver disease.”

“The International Ascites Club, representing the spectrum of clinical practice from North America to Europe, have developed guidelines by consensus in the management of cirrhotic ascites from the early ascitic stage to the stage of refractory ascites.”

“Mild to moderate ascites should be managed by modest salt restriction and diuretic therapy with spironolactone or an equivalent in the first instance. Diuretics should be added in a stepwise fashion while maintaining sodium restriction.”

“Gross ascites should be treated with therapeutic paracentesis followed by colloid volume expansion, and diuretic therapy.”

“Refractory ascites is managed by repeated large volume paracentesis or insertion of a transjugular intrahepatic portosystemic stent shunt (TIPS). Successful placement of TIPS results in improved renal function, sodium excretion, and general well-being of the patient but without proven survival benefits.”

“Clinicians caring for these patients should be aware of the potential complications of each treatment modality and be prepared to discontinue diuretics or not proceed with TIPS placement should complications or contraindications develop.”

“Liver transplantation should be considered for all ascitic patients, and this should preferably be performed prior to the development of renal dysfunction to prevent further compromise of their prognosis.”

07/02/03

Source

KP Moore and others. The management of ascites in cirrhosis: Report on the Consensus Conference of the International Ascites Club. Hepatology 38(1): 258-266.)

Selected References

M Kugelmas and others. Preliminary observation: oral zinc sulfate replacement is effective in treating muscle cramps in cirrhotic patients. Journal of the American College of Nutrition 2000;19:13-15.

A Porcel and others. Dilutional hyponatremia in patients with cirrhosis and ascites. Archives of Internal Medicine 2002;162: 323-328.

A Sanyal and others for the North American Study for Treatment of Refractory Ascites. A randomized controlled study of TIPS versus large volume paracentesis in the treatment of refractory ascites. Gastroenterology 2003;124: 634-643.

• Additional Stories on: Liver Issues (Cirrhosis)

Combining Induction and Prolonged Maintenance Therapy Produces High Sustained Virological Response in Chronic HCV Patients

Results of prior studies show that chronic hepatitis C patients with genotype 1 infection, liver cirrhosis, high viral load, or those who have not responded to anti-viral treatment in the past have limited chances of clearing the virus, even with pegylated interferon plus ribavirin therapy.

In this study in the Netherlands, researchers treated such patients with a treatment schedule that combines high dose induction Interferon (IFN), prolonged daily IFN and ribavirin treatment.

Twenty-four consecutive patients were included in this study with either genotype 1 infection, cirrhosis, previous non-response to IFN or a combination of these poor-response characteristics.

Patients were treated with 10 million units (MU) of IFN daily for 4 weeks followed by 5 MU/day until week 24, 3 MU/day until week 52 and 3 MU thrice weekly until week 76 in combination with 1-1.2 g ribavirin daily. HCV RNA levels were assessed weekly until week 4 and at least once every 3 months thereafter, by a validated assay with a detection limit below 500 copies/mL.

Both intention to treat (ITT) and per protocol (PP) analysis showed a high sustained virological response (ITT 67%, PP 80%). A virological response occurred rapidly (before 8 weeks of treatment) in all patients with a sustained response. Relapse after stopping therapy was observed in only 5%.

Side effects were observed frequently, and six patients had to be hospitalized.

With this new treatment regimen that combines induction- and prolonged daily interferon treatment with ribavirin, it seems possible to eliminate hepatitis C virus in the majority of patients that have an a priori limited chance of sustained response.

Further clinical evaluation of intensive interferon and ribavirin combination therapy (now also including PEG-interferon) is recommended in centers that can provide close patient monitoring and experienced hepatological support.

Hepatology & Gastroenterology and Epidemiology & Biostatistics, Erasmus MC / University Medical Centre Rotterdam, the Netherlands.

06/06/03

Reference
JM Vrolijk and others. High sustained virological response in chronic hepatitis C by combining induction and prolonged maintenance therapy. Journal of Viral Hepatitis 10(3): 205-209. May 2003.



	http://www.hcvadvocate.org/ HCV cirrhosis is a life threatening disease Bennet Cecil, MD About one in five American patients with HCV have cirrhosis. The average age of these cirrhotic patients is 50 years, but 6-10% of this subgroup dies each year. In other words, cirrhotic patients die at the speed of 80 year-old Americans. As the average age of patients with HCV increases each year, the percentage developing cirrhosis will increase. After twenty years of infection about 20% of patients develop cirrhosis and after fifty years of infection, about half develop cirrhosis. The Centers for Disease Control and Prevention has predicted that deaths from HCV will triple as Americans age. Fortunately, most patients with hepatitis C have mild or moderate liver damage, and do not have an increased risk of death. Hepatitis C is almost always a slowly progressive disease, giving patients a long window of opportunity to cure their infection. If HCV is successfully eradicated, the liver improves each year instead of worsening. Only the liver and the bone marrow have this ability to regenerate. Over a period of years, the scar tissue in the liver will diminish after HCV is eradicated by successful antiviral therapy. Even biopsy proven cirrhosis has been shown to reverse in some patients. The risk of liver cancer or failure also falls, and with it the risk of premature death. With few exceptions, hepatologists have not risen to the challenge of treating patients with advanced HCV cirrhosis with antiviral therapy. They have used the excuse that there is not enough data to recommend treatment. They have purposefully avoided starting clinical trials that enroll patients with advanced cirrhosis. Instead, more and more patients with HCV cirrhosis are added to the liver transplant list. About 18,000 patients are on the list with only 4-5,000 livers available. About 30% of them have genotype 2 or 3 strains of the virus, which have an excellent chance of responding to even low doses of interferon. Thousands of other patients are not on the liver transplant list because they are too old, too poor or are too sick with non-hepatic diseases. Successful treatment of cirrhotic patients requires more than one year of treatment to prevent viral relapse once therapy is completed. Every single viral particle must be eliminated to prevent relapse, and the virus hides in scar tissue in cirrhotic patients. The worse the liver fibrosis, the longer treatment must last. In the HALT C study, which enrolled mostly patients with early cirrhosis, about a third of patients became undetectable for HCV-RNA on treatment. Unfortunately, half of them relapsed when therapy was stopped. In non-cirrhotic patients, only about 20% of treatment responders relapse. Cirrhotic patients do not tolerate full doses of interferon and ribavirin very well. They tend to drop their white blood cell counts, become anemic and drop their platelet counts quickly. I start with a quarter dose of pegylated interferon or less in cirrhotic patients and raise the dose every week or two. If the pegylated interferon is working, the viral level falls by 90% or more each month. It the patient responds, I add ribavirin at 400-600 mg per day. The dose is increased by 200 mg each month up to 800-1,200 mg per day. Many cirrhotic patients need Procrit and/or Neupogen to keep the red blood cell and absolute neutrophil counts in an acceptable range. A few need Neumega to keep the platelet count above 30,000. Treating advanced HCV cirrhosis with pegylated interferon plus ribavirin is an off label use and has not been approved by the FDA. Pharmaceutical companies cannot promote or advertise it. Patients and physicians can use drugs off label if they decide that the benefits exceed the risks. Liver transplant evaluation can be done concurrently and is necessary for interferon nonresponders. I hope that more physicians will offer this option to their patients with HCV cirrhosis, because I believe it will reduce the number of deaths from HCV cirrhosis.