Hepatitis C Research
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Abstract 281. Durability of Sustained Virologic
response in patients with Chronic Hepatitis c after treatment With
Interferon 2b Alone or in Combination with Ribavirin
This study looked at 400 patients in 3 studies who achieved a sustained response. The key findings were:
The purpose of this study was to assess the durability of
response in patients who were sustained responders 24 weeks after therapy.
John McHutchison reported in an oral session on a analysis of 2089 patients
from 3 large scale international studies comparing interferon alfa-2b alone
to interferon alfa-2bplus ribavirin (Davis et al, NEJM 1998;339:1493,
McHutchison et al NEJM 1998; 339:1485; Poynard et al, Lancet 1998;352:1426).
Many of these patients have been followed for up to 4 years. This analysis
looked at the 558 patients who achieved a sustained response to evaluate
their rate of failure. Of the 558 SVRs 455 patients received IFN+RBV and 103
patients received IFN. 395 of the 558 agreed to participate in this
long-term follow-up. All patients were treatment-naive or relapsers and
received 24 or 48 weeks treatment. Of the 395 patients, 151 naive received
IFN/RBV for 48 weeks, 112 naive patients received IFN/RBV for 24 weeks, 59
relapsers received IFN/RBV for 24 weeks, 61 received IFN alone for 48 weeks,
and 12 received IFN alone for 24 weeks (4 naive 24 weeks, 61 naive 48 weeks,
8 relapse 24 weeks).
· All 10 late relapsers reappearance of HCV-RNA within 2.5 years after
stopping therapy or 2 years after the 24 week follow-up period.
Based on 2 biopsies 20 months apart, this
study reported:
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).
Improved Stabilized Worsened Sustained Responders 86% 12% 2% Relapsers 43% 36% 21% Non-responders 36% 43% 21%
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.
*RBV optimized weight based dosing Improved Stabilized Worsened Sustained Responders 25% 68% 7% Relapsers 16% 67% 17% Non-responders 17% 62% 21%
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. Rate Before Therapy After Non-responders 0.053 0 Sustained Responders 0.063 0 p<0.001
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. Rate Before Therapy After Non-responders 0.135 0 Sustained Responders 0.139 -0.591 p<0.001 Poynard said the sustained responders
experienced a dramatic decrease or regression in fibrosis rate.
*With Optimized weight based dosing
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.
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 We would like to thank Jules Levin
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| Abstract 676. ACUTE HEPATITIS C: NATURAL COURSE AND RESPONSE TO ANTIVIRAL TREATMENT | ||
| Tilman J Gerlach, Reinhart
Zachoval, Norbert Gruener, Maria-Christina Jung, Klinikum Grosshadern
Med Dept II, Muenchen Germany; Axel Ulsenheimer, Winfried Schraut, Inst
fuer Immunologie, Muenchen Germany; Albrecht Schirren, Klinikum
Grosshadern Med Dept II, Muenchen Germany; Martin Waechtler, Markus
Backmund, Gen Hosp MŸnchen Schwabing, Muenchen Germany; Helmut Diepolder,
Gerd Pape, Klinikum Grosshadern Med Dept II, Muenchen Germany Below is the program book abstract, which I think portrays the essence of the oral presentation at the AASLD meeting. Another report on this presentation is being prepared. As you may know, German researchers first reported on treating acute HCV at DDW in the Spring 2001. A published article followed by much attention occurred in the Fall 2001. Identifying persons with acute HCV is very difficult just as it is in identifying acutely infected persons with HIV. But, if such a person can be identified treatment consideration may be crucial. Identification & treatment of acutely infected persons can be an important public policy position. This may have particular application to health care workers. Background: Although screening of blood products for hepatitis C virus (HCV) has virtually eliminated post-transfusion hepatitis C, HCV still causes about 20% of cases of acute hepatitis today. These patients frequently present with acute symptomatic hepatitis C, which differs in many aspects from patients with post-transfusion hepatitis C. Little is known, however, about the natural course and the optimal treatment strategy for acute hepatitis C as it presents today. Methods: The diagnosis of a HCV in fifty-six consecutive patients was based on seroconversion to anti-HCV antibodies or clinical and biochemical criteria (acute onset of hepatitis with elevation of ALT at least 10x the upper limit of normal, exclusion of other liver diseases) and on the presence of HCV-RNA by RT-PCR in the first serum sample. Results: Fifty-six consecutive patients with acute hepatitis C were diagnosed in two large referral centers for infectious diseases and hepatology. 47/56 patients presented with symptomatic disease (fatigue (24%), abdominal pain (14%), jaundice (24%), nausea (19%)) while 9/56 were clinically asymptomatic. The major risk factors for acute HCV infection were IV-drug abuse (n=14), recent medical procedures (n=17), HCV-positive sexual partner (n=5), and needle-stick injury in medical employees (n=5), in 15 patients (27%) no risk factor or possible source of infection could be identified. Six patients received immediate antiviral therapy (IFN-a alone or in combination with ribavirin), 10 patients refused to therapy or were not eligable for IFN-a therapy. In 50 patients, not being treated immediately, the natural course of acute HCV was further studied: 34/50 (68%) patients initially cleared the virus spontaneously within a median of 11,9 weeks (range 2 to 24 weeks), but only twenty-three (47%) persistently remained HCV-RNA negative until the end of follow-up (median 23months, range 6 to 55 months) and were classified as self-limited hepatitis C. In eleven patients (22%) HCV RNA relapsed after a median of 23 weeks (range 8-86 weeks) and 16/50 (32%) patients did not clear HCV infection spontaneously and developed chronic hepatitis C. Patients with self-limited hepatitis C (n=22) and those developing chronic hepatitis C (n=28) did not differ with regard to age, risk factors for HCV infection, HCV-genotype, or initial viral load. However, symptomatic disease, female sex, and a high peak bilirubin level were strong predictors of spontaneous HCV clearance. While 49% of patients with symptomatic acute HCV cleared infection spontaneously, none of the patients with asymptomatic acute HCV (n=9) cleared HCV infection without treatment. Since the majority (86%) of patients with spontaneous viral clearance lost HCV RNA within twelve weeks after onset of symptoms, antiviral therapy was recommended to patients who did not loose HCV RNA by week 12 after onset of symptoms. Of 34 patients with chronic hepatitis C, 24 patients started either interferon-alpha alone or in combination with ribavirin. So far, twenty-one patients responded with loss of HCV-RNA and normalization of aminotransferases; 15 of 16 IFN-responders who have completed follow-up (>6 months after end of treatment) are sustained responders and one patient relapsed. Five responders are still under follow-up (end-of-follow-up sustained response rate 82%) and three patients did not respond to antiviral therapy. Although not mentioned in the results but discussed in the oral presentation was the 6 patients who were treated immediately upon identification. And I recall 4 or 5 of them had a virologic response. Conclusions: In the management of acute HCV infection a high spontaneous viral clearance rate within the first twelve weeks after onset of symptoms has to be considered. The strategy to treat symptomatic patients who remained HCV-RNA positive beyond three months after onset of disease led to an overall sustained viral clearance in 90% of patients, while unnecessary treatment was avoided in those with spontaneous viral clearance. In contrast patients with asymptomatic acute HCV infection are unlikely to clear the virus spontaneously and antiviral therapy should be commenced as early as possible. |
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HALT-C Trial: 4-year study of
Maintenance Therapy in 1350 patients |
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| Written for NATAP by Mark Sulkowski, MD,
Johns Hopkins University School of Medicine Abstract 279. Retreatment of Interferon And Interferon-Ribavirin Non-Responders with Peginterferon-alpha-2a (Pegasys) And Ribavirin: Initial Results from the Lead-In Phase of the Halt-C Trial The HALT-C trial was designed to determine if long term maintenance interferon therapy, administered over 4 years, could prevent histologic progression, reduce the development of hepatocellular carcinoma and the need for hepatic transplantation in patients with chronic HCV and advanced fibrosis or cirrhosis who remain HCV-RNA (+) despite therapy. Since peginterferon plus ribavirin is more effective than standard interferon/ribavirin for treatment of chronic HCV all patients enrolled in the HALT-C trial were first treated with peginterferon plus ribavirin during the lead-in phase of this trial. This study is enrolling 1350 patients with advanced liver disease (bridging fibrosis/cirrhosis, Ishak Fibrosis stage > 3) and no evidence of hepatic decompensation. All patients had previously failed to respond to interferon-based therapy administered for at least 12 weeks. After screening, all patients received pegylated interferon alfa-2a (180 mcg weekly) plus ribavirin (1 - 1.2 grams/day). Patients who are HCV-RNA (-) at week 20 continue therapy for 48 weeks total. Patients who are HCV-RNA (+) either stop treatment or receive a maintenance dose of Pegasys 90ug/week for 3.5 years. Dr. Adrian Di Bisceglie presented on-treatment virologic response data on the first 268 patients who completed at least 20 weeks of therapy within this ongoing study. For the purpose of this presentation, viral response was defined as an undetectable HCV-RNA level at treatment week 20. 15 (5.6%) patients discontinued therapy prior to week 20. At week 20, 107 of 268 patients (42%) (based on an intention-to-treat analysis) had an undetectable HCV RNA level. These patients will continue therapy for an additional 28 weeks and, per protocol, will not enter the "maintenance" phase of the study. There were several important "sub-group" analysis presented. Persons who had only failed prior interferon monotherapy were much more likely to achieve a response than those who failed prior interferon/ribavirin combination therapy (53% > 31%) and African-Americans were significantly less likely to respond than others (10% < 43%). In addition, a large number of patients had dose reductions of the PEG-interferon (53%), ribavirin (44%) or both (47%). Thus, while the discontinuation rate was quite low (~5%), it remains uncertain if such dose reductions will impair the overall effectiveness of the therapy. Nonetheless, these results are encouraging and suggest that persons with advanced liver disease who failed to respond virologically to prior therapy may benefit from a course of pegylated interferon/ribavirin. Editorial note: Baseline data for 268 patients-- 41% of patients in study had cirrhosis at baseline. 84% were genotype 1. Mean ALT was 124. 88% were Caucasian. 63% had received IFN+RBV. Mean HCV-RNA was 3.5 million IU/mL. Mean age 50. The degree of fibrosis was associated with response (44% Ishak 3-4 [bridgng fibrosis] vs 31% Ishak 5-6 [cirrhosis], p=0.03). Gender was not associated with response (40 vs male vs 36% female, NS). Genotype was a factor in response Genotype 2b: 88%; genotype 3a: 93%, genotype 1a: 30%; genotype 1b: 39%; genotype 2a: 35%. Baseline HCV-RNA did not appear to influence response. Mean reduction in HCV-RNA was 3.7 log; 45% had a 3+ log reduction, while 15% had a 2-log reduction, 21% had a 1-log reduction, and 18% had <1-log reduction. It will be interesting to see if the patients with little viral load reduction demonstrate improved, stopped, or slowed fibrosis. The long-term goals or outcomes from HALT-C will take several years to achieve. These interim results are similar to those seen in several other smaller studies reported at the conference. |