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HALT-C Patient Subgroups That Appear To Benefit From Maintenance Therapy
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here is link to the slides presented by the HALT-C research team at EASL 2008 in Milan where you can see a small group of patients, n=23, who achieved >4 log HCV RNS reduction during maintenance therapy, and it appears in the slides they had better clinical outcomes but statistically no significant fibrosis improvement, and authors concluded: "it remains to be determined if clinical outcomes and fibrosis progression can be reduced in those patients with persistent and profound viral suppression (especially those who remain persistently HCV RNA undetectable) during peginterferon maintenance therapy" -
HALT-C Study Design Flawed - (04/28/08)
"In summary, the HALT-C trial demonstrated that prolonged low-dose PEG IFN therapy can not reduce the occurrence of clinical outcomes in a large population of patients with noncirrhotic fibrosis or cirrhosis who had an initial nonresponse to antiviral standard therapy.
Does this mean that maintenance PEG IFN treatment cannot be recommended at all? Subpopulations from the HALT-C trial who had a substantial HCV RNA log10 decline during the initial treatment with full-dose PEG IFN and ribavirin, however, may have a decelerating disease progression by year 3.5.[6] Furthermore, detailed subanalysis of the patient group with Ishak 3-4 fibrosis at baseline and who had improved inflammation associated with ALT decrease at year 1.5 showed that these patients had less fibrosis progression,[7] indicating that a subgroup of patients may benefit from long-term treatment.."
Advanced chronic hepatitis C: How to handle if you cannot halt?
Hepatology April 2009
Wolf Peter Hofmann, Stefan Zeuzem
Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universitat,
Frankfurt, Germany
Potential conflict of interest: Dr. Zeuzem is a consultant for, advises, is on the speakers' bureau of, and received grants from Roche and Schering-Plough.
Editor(s) for this article:
Kris Kowdley 1, Geoffrey McCaughan 2, Christian Trautwein 3
1Seattle, WA
2Newtown, Australia
3Aachen, Germany
Article Text
Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, Wright EC, et al.; HALT-C Trial Investigators. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon, N Engl J Med 2008 359:2429-2441. (Reprinted with permission.)
Abstract
BACKGROUND: In patients with chronic hepatitis C who do not have a response to antiviral treatment, the disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain. METHODS: We conducted a randomized, controlled trial of peginterferon alfa-2a at a dosage of 90 microg per week for 3.5 years, as compared with no treatment, in 1050 patients with chronic hepatitis C and advanced fibrosis who had not had a response to previous therapy with peginterferon and ribavirin. The patients, who were stratified according to stage of fibrosis (622 with noncirrhotic fibrosis and 428 with cirrhosis), were seen at 3-month intervals and underwent liver biopsy at 1.5 and 3.5 years after randomization. The primary end point was progression of liver disease, as indicated by death, hepatocellular carcinoma, hepatic decompensation, or, for those with bridging fibrosis at baseline, an increase in the Ishak fibrosis score of 2 or more points. RESULTS: We randomly assigned the patients to receive peginterferon (517 patients) or no therapy (533 patients) for 3.5 years. The level of serum aminotransferases, the level of serum hepatitis C virus RNA, and histologic necroinflammatory scores all decreased significantly (P<0.001) with treatment, but there was no significant difference between the groups in the rate of any primary outcome (34.1% in the treatment group and 33.8% in the control group; hazard ratio, 1.01; 95% confidence interval, 0.81 to 1.27; P=0.90). The percentage of patients with at least one serious adverse event was 38.6% in the treatment group and 31.8% in the control group (P=0..07). CONCLUSIONS: Long-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who had not had a response to initial treatment with peginterferon and ribavirin.
Comment
A course of antiviral treatment with pegylated interferon (PEG IFN) alfa and ribavirin leads to sustained virologic response (SVR) in about half of the individuals with chronic hepatitis C. Fortunately, SVR has been shown to be associated not only with durable elimination of circulating hepatitis C virus (HCV) RNA from the patients' serum but also with a favorable overall clinical outcome and improved health-related quality of life..
Fibrosis progression can be blocked or even reverted, as has been shown in large studies with paired liver biopsies performed at baseline and after antiviral therapy. Poynard et al. reported biopsy results from 3,010 patients who underwent IFN-based antiviral therapy.[1] Regardless of the treatment response, more than 80% of all patients showed unchanged or better fibrosis scores after therapy compared with baseline.
Several studies have indicated that IFN alfa treatment is also associated with decreased rates of hepatocellular carcinoma (HCC). According to two independently published meta-analyses in which data from mostly nonrandomized trials comparing standard IFN with no treatment were analyzed, IFN alfa had a preventive effect on HCC development.[2][3]
Another retrospective study performed in 479 patients who had advanced fibrosis by the time of initiation of antiviral therapy reported that SVR is associated with a substantial reduction of other hard clinical endpoints such as liver-related death and hepatic failure.[4] The 5-year occurrence of liver-related death was 4.4% among SVR patients versus 12.9% among those who did not respond. Hepatic failure did not occur among responders, and the 5-year occurrence was 13.3% among nonresponders.
Treatment options are few for individuals who do not have an SVR. With respect to some encouraging data on the effect of IFN alfa also in the absence of SVR, maintenance therapy with low-dose IFN alfa in patients with advanced fibrosis and who were nonresponders became a popular practice of many hepatologists.
The Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial is the first published randomized controlled trial of prolonged therapy with low-dose PEG IFN in previous nonsustained responders to standard therapy with PEG IFN in combination with ribavirin.[5] In this study, 1,050 patients with chronic hepatitis C and advanced fibrosis (Ishak fibrosis score of 3 or more) were randomly assigned to the treatment group (PEG IFN alfa-2a in a dosage of 90 g per week for 3.5 years [n = 517]) or to the control group (n = 533). Liver biopsies were performed at baseline and at 1.5 and 3.5 years after randomization. During the randomized phase of the trial, patients were seen every 3 months for history taking, physical examination, and laboratory testing. Abdominal ultrasound was performed every 12 months.
The primary outcome variable was progression of liver disease within 1,400 days after randomization, as indicated by death, hepatic decompensation, HCC, a Child-Turcotte-Pugh score of 7 or more on two consecutive visits, or for noncirrhotic patients at baseline an increase in Ishak hepatic fibrosis scores of at least 2 points.
Not surprisingly, HCV RNA and alanine aminotransferase (ALT) levels were lower in the treatment group after 1.5 years and 3.5 years. However, HCV RNA differed in only 0.59 log10 between groups after 3.5 years. ALT levels were within normal range after 3.5 years of treatment in 35.1% of treated patients and 22.6% of controls.
Concerning the primary outcomes (death, hepatic decompensation, hepatocellular carcinoma, or fibrosis progression), there were no differences within the treatment group and the control group. Indeed, the proportions of patients with a primary outcome were 30.4% and 29.5% in the two groups, respectively.
When data were analyzed according to the strata noncirrhotic fibrosis and cirrhosis, the proportion of patients with clinical outcome (death, hepatic decompensation, hepatocellular carcinoma) were higher in the cirrhosis stratum. According to the group assignment, the proportion of cirrhotic patients with clinical outcomes was similar in the treatment or control group. However, among noncirrhotic fibrosis patients, clinical outcomes were more frequent in treated patients than in controls (11.9% versus 8.3%). Among patients with bridging fibrosis at baseline, cirrhosis developed by year 3.5 in similar percentages of treated and control patients (28.2% and 31.9%, respectively). The occurrence of HCC could not be prevented by PEG IFN treatment. There were 12/517 patients in the treatment group and 15/533 patients in the control group who developed HCC. After 3.8 years the death rate was 6.6% among treated patients and 4.6% among controls. Mortality was not different in cirrhotic patients who were treated or not. It is worth noting that deaths occurred more often in treated patients versus nontreated noncirrhotic fibrosis patients (5.0% versus 1.9%, respectively [P = 0.04]).
Dose modifications and adverse events (AEs) in the HALT-C trial also raise some concerns about long-term PEG IFN use. By year 3.5, only 58.9% of patients were receiving the full 90 g/week dosage of PEG IFN. AEs occurred more frequently in the treatment group compared with controls (38.6% versus 31.8%), and 330 patients had at least one serious AE. AEs resulting in treatment cessation were mainly myelotoxicity and depression.
In summary, the HALT-C trial demonstrated that prolonged low-dose PEG IFN therapy can not reduce the occurrence of clinical outcomes in a large population of patients with noncirrhotic fibrosis or cirrhosis who had an initial nonresponse to antiviral standard therapy.
Does this mean that maintenance PEG IFN treatment cannot be recommended at all? Subpopulations from the HALT-C trial who had a substantial HCV RNA log10 decline during the initial treatment with full-dose PEG IFN and ribavirin, however, may have a decelerating disease progression by year 3.5.[6] Furthermore, detailed subanalysis of the patient group with Ishak 3-4 fibrosis at baseline and who had improved inflammation associated with ALT decrease at year 1.5 showed that these patients had less fibrosis progression,[7] indicating that a subgroup of patients may benefit from long-term treatment.
Preliminary results from other randomized controlled trials on maintenance PEG IFN treatment were presented in the last months including a multicenter randomized prospective trial of PEG IFN in a cohort of 88 patients with cirrhosis.[8] In this trial, patients are randomly assigned to treatment with PEG IFN alfa-2b (0.35-1 g/kg/week) or to an observation arm. By the time of the interim analysis, HCC occurred in six patients in the observation arm but in none of the treatment arm patients. Furthermore, hepatic decompensation was less frequent in the treatment arm.
In the COPILOT study, a large number of nonresponder patients with Ishak fibrosis score >3 are currently randomized to receive PEG IFN alfa 2b (0.5 g/kg/week) or colchicine 0.6 mg twice daily for a 4-year period.[9] Colchicine has been used with different outcomes as an anti-inflammatory and antifibrotic medication. By the time of a recent interim analysis, 55 patients in the colchicine arm and 51 patients in the PEG IFN arm had completed the 4-year treatment period. Independently of the administered treatment, 49% of these patients did not achieve a 4-year event-free survival. The presence of portal hypertension significantly influenced clinical outcome in either treatment arm.
Another randomized prospective trial on maintenance PEG IFN therapy, the Epic-3 trial for nonresponder patients with Metavir fibrosis scores 2 who receive PEG IFN alfa-2b (0.5 g/kg/week), is still ongoing. In this trial, 2,293 patients were initially included for full-dose retherapy.[10] Those who did not respond are currently receiving maintenance therapy for up to 5 years.
Is there a way to reduce the risk for HCC? In recent years, several host and external factors that are associated with the development of HCC in patients with chronic hepatitis C were identified. Host factors include age at diagnosis and at infection, male sex, and several comorbidities such as liver steatosis and diabetes mellitus.[11] The 5-year occurrence of HCC among cirrhotic HCV patients with and without diabetes mellitus was reported to be 11.4% and 5.0%, respectively.[12] External factors are mainly alcohol consumption and cigarette smoking. Contrarily, coffee consumption was identified to inversely correlate with the risk for HCC. In a recent meta-analysis of 10 studies (2,260 HCC cases), a 41% reduction in the risk of HCC among coffee drinkers compared with never-drinkers was reported.[13]
Many patients with chronic hepatitis C use complementary and alternative medications, and some clinical trials have shown that herbal products may have therapeutic potential. In a systemic review from 2003, 13 randomized trials with a total of 818 patients and 14 different herbs including silymarin and glycyrrhizin were analyzed.[14] In some trials, HCV RNA decline and ALT normalization was observed; however, there was no firm evidence supporting herbal products for chronic hepatitis C. In a substudy from the HALT-C trial, the use and potential effects of silymarin was examined.[15] About 17% of the HALT-C trial population concomitantly took silymarin at baseline of the trial. No benefit on HCV RNA or ALT levels were found; however, silymarin users had fewer symptoms and better quality-of-life indices as nonusers.
The most promising improvements for patients with chronic hepatitis C include the development of direct antivirals such as HCV protease and polymerase inhibitors.[16][17] Two protease inhibitors (telaprevir and boceprevir) are currently undergoing phase III clinical trials. In the future, safety and efficacy studies of these new compounds in the setting of advanced chronic hepatitis C will be necessary.
ABSTRACT from EASL Milan:
144 SUPPRESSION OF SERUM HCVRNA LEVELS DURING MAINTENANCE PEGINTERFERON (PEGIFN) ALFA-2A THERAPY AND CLINICAL OUTCOMES IN THE HALT-C TRIAL
M.L. Shiffman1, C. Morishima2, K.L. Lindsay3, J.C. Hoefs4, J.L. Dienstag5, G. Szabo6, W.M. Lee7, E.C. Wright8, for the HALT-C Trial Group9. 1Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA, 2Department of Laboratory Medicine, University of Washington, Seattle, WA, 3Division of Gastroenterology and Liver Disease, University of Southern California, Los Angeles, CA, 4Division of Gastroenterology, University of California - Irvine, Irvine, CA, 5Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 6Liver Center, University of Massachusetts Medical School, Worcester, MA, 7Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 8Department of Health and Human Services, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA E-mail: mshiffma@vcu.edu
The primary analysis of the HALT-C Trial demonstrated that PEGIFN maintenance therapy did not reduce complications of cirrhosis, HCC, liver transplantation (LT) or mortality in patients with chronic HCV and advanced fibrosis or cirrhosis (AASLD 2007). This analysis assessed the relationship between viral suppression and clinical outcomes.
Methods: 764 patients who failed to achieve SVR with PEGIFN 180 mg/week and ribavirin during the HALT-C lead-in phase were evaluated. 378 were randomized to maintenance PEGIFN (90 mg/week) and 386 received no additional treatment for 3.5 years (controls).. No patient had a history of CTP>6, ascites, hepatic encephalopathy (HE), variceal hemorrhage (VH) or HCC. HCVRNA was measured by Roche COBAS_ Monitor and/or Amplicor v.2.0 tests.
Results: During lead-in treatment 425 (56%) patients had <2 log decline in HCVRNA from their pre-treatment baseline; 178 (23%) had >4 log decline and/or became HCVRNA undetectable with subsequent breakthrough or relapse. After randomization, serum HCVRNA remained within 1 log of pre-treatment values in 381 (99%) control and 273 (72%) maintenance patients. Only 30/88 patients with >4 log suppression in HCVRNA during lead-in treatment maintained this degree of viral suppression with maintenance PEGIFN. Clinical outcomes (2-point CTP increase, ascites, HE, VH, HCC, LT, death) occurred in significantly fewer patients with profound decline in HCVRNA during the lead-in. When HCVRNA declined by <2 logs, 2-4 and >4 logs from the pre-treatment baseline during leadin treatment outcomes occurred in 20%, 23% and 7% of patients on maintenance PEGINF and 20%, 13% and 10% in controls (both p<0.05). Outcomes occurred in 18%, 22% and 12% of patients on maintenance PEGIFN when HCVRNA was continuously suppressed by these same amounts (p = NS). 13/29 patients with repeatedly undetectable HCVRNA over 3.5 years on maintenance PEGIFN achieved SVR.
Conclusions: A significant decline in clinical outcomes was observed in patients with chronic HCV and advanced fibrosis or cirrhosis who achieved a profound decline in HCVRNA (>4 log and/or undetectable with subsequent breakthrough or relapse) with full-dose PEGIFN and ribavirin whether or not they remained on maintenance therapy. Whether additional clinical benefit can be derived when profound HCVRNA suppression is maintained with PEGIFN remains unproven.
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