Maintenance Therapy Does It Work ???

HALT-C in the final analysis: A molehill out of a mountain
Piero L. Almasio
published online 20 March 2009.
Uncorrected Proof
from Jules: is it possible that if you looked at patients who were able to stay on peginterferon in the treatment group, they would have shown benefit: "in the treatment group, a sizable number of patients (157 out of 517, 30.4%) discontinued the therapy mainly because of adverse effects (hematological abnormalities, depression) or simply refused to continue, with the result that at the end of the trial less than 60% of the cases still in the study, but without clinical outcomes, took the intended dose of peginterferon." Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, Wright EC, Lee WM, Lok AS, Bonkovsky HL, Morgan TR, Ghany MG, Morishima C, Snow KK, Dienstag JL, HALT-C Trial Investigators.
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 90μg 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, 0.81–1.27; 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. (ClinicalTrials.gov number, NCT00006164.) 2008 Massachusetts Medical Society.
[Abstract reproduced by permission of N Engl J Med 2008;359:2429–2441].
Article Outline
It seems reasonable to evaluate the efficacy of any interventional approach, whether prophylactic or therapeutic, and to ascertain to what extent the natural history of a disease has been modified in terms of morbidity and mortality. Therefore, an accurate knowledge of the clinical course of a particular medical condition, in the absence of active involvement on the part of the physician, is of paramount relevance when we want to appraise the long-term effect of a drug. In the field of chronic liver disease there is vast evidence that the removal of the etiological agent may reduce the risk complications, the occurrence of hepatocellular carcinoma (HCC), and liver-related mortality. In fact, it has been demonstrated that the persistent eradication of HBV or HCV after antiviral therapy, or removal of iron overload in patients with hereditary hemochromatosis, is associated with a better prognosis [1], [2], [3]. However, the rate of complete success in HCV-related liver disease is far from satisfactory, particularly in the treatment of an advanced form of hepatic damage, or if some co-factors, such as HBV or HIV co-infection, alcohol abuse or obesity are present. The scientific assumptions that led to the conception and organisation of the mega trial called “Hepatitis Antiviral Long-Term Treatment Against Cirrhosis (HALT-C)”, the results of which were recently published [4], are based on evidence that emerged in the late 1990s. The first finding was that interferon (IFN) therapy could reduce viral load, ameliorate histological activity and block progression of fibrosis even in non-responders [5]. The second was that prolonging IFN therapy up to 2 years was significantly associated with a decrease of necro-inflammatory activity and hepatic fibrosis compared to subjects treated for six months [6]. The randomised clinical trial was initiated under the sponsorship of the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) to find a treatment for non-responders with bridging fibrosis or cirrhosis on liver biopsy [7]. The main outcomes were the deterioration of liver disease in terms of an increase in the Ishak fibrosis score (evaluated histologically by liver biopsy), and decompensation, HCC development and death (observed in the clinical setting). Even with 10 liver units across the USA participating in the study, the duration of patient enrollment was quite long, lasting for 4 years, and ended in August 2004. From a screened population of 1739 patients, 1050 subjects were subsequently randomised and, among them, 899 cases completed the study. It is worth noting that in the same period, two other trials aimed at evaluating the efficacy of maintenance therapy in non-responders were also initiated (one under the sponsorship of the pharmaceutical industry) (Table 1), though neither has been published as a full paper, only in abstract form [8], [9].. The interpretation of the study from the perspective of the glass being half full showed that the treated arm of the trial had a greater reduction in HCV RNA, ALT and hepatic necroinflammation compared with the untreated group. Interestingly, 18 patients (3.5%) had a sustained virologic response after 3.5 years of peginterferon alone, in contrast to only one control subject. According to the “glass is half empty” view, on the other hand, was that at the end of the study the rate of fibrosis progression was similar among treated and untreated patients (20.7% vs. 22.4%), and the number of cases with primary outcomes was comparable (64/517 vs. 70/533), with an apparent excess of deaths (13 vs. 8) in patients receiving the active drug. Furthermore, when the authors separately analyzed the occurrence of primary outcomes in non-cirrhotic patients in whom peginterferon could have had a greater chance of efficacy, the treatment group had a higher incidence of events. Finally, in the treatment group, a sizable number of patients (157 out of 517, 30.4%) discontinued the therapy mainly because of adverse effects (hematological abnormalities, depression) or simply refused to continue, with the result that at the end of the trial less than 60% of the cases still in the study, but without clinical outcomes, took the intended dose of peginterferon. These negative results are perfectly in line with those observed in the COPILOT study [8]. By an intention-to-treat analysis, the rate of the patients with liver-related outcome was higher in those treated with peginterferon compared with the colchicine arm (21.2% vs. 18.5%), with a slight excess of HCC occurrence in the first group (22 out of 286 vs. 13 out of 269). Unfortunately, adjunctive data on efficacy of low-dose peginterferon long-term maintenance on relevant clinical endpoints are not yet available from the EPIC3 trial.
It is not an easy task to explain these negative results when a number of previous studies, even if derived from non-randomised controlled studies, have demonstrated a “protective” effect of IFN treatment on HCC development independently of viral clearance [10]. In the HALT-C study the vast majority of patients were previous non-responders, without any significant decline in serum HCV RNA during the previous full dose course of peginterferon plus ribavirin. In addition, more than 90% of patients had a decline of viremia less than one log during maintenance therapy, and no attempt was made to manipulate the dose of cytokine in order to maintain viral suppression in patients partially sensitive to the therapy. An additional analysis presented at the last EASL meeting, in Milan [11], could detect no benefit, even in the subgroup of patients with HCV RNA inhibition, in either the initial twelve week run-in phase, when patients received peginterferon at full dose in association with ribavirin, or the long-term maintenance phase during which viral suppression was achieved. The degree of lead-in HCV RNA suppression was associated with a decrease of clinical events at the end of the trial, but not in terms of fibrosis progression. The hypothesis that the non-use of ribavirin during the 3.5 years of maintenance therapy was a relevant factor in the clinical failure has yet to be assessed.
In conclusion, the publication of the final report of HALT-C is the “swan song” of maintenance therapy as an effective approach in non-responders with chronic HCV infection, and therefore its conclusions will find no place in clinical practice. However, the trial has left the scientific community a treasure trove of knowledge related to HCV-related liver disease with one freely available Internet site (www.haltctrial.org) and more than twenty papers published in top-flight medical journals.
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>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.