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Nonresponders in Apricot Achieve Histologic Response, Improve Liver
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Reported by Jules Levin
This study examined the histologic response (improvement of condition of the liver) in HCV/HIV coinfected patients who received Pegasys plus ribavirin in the large international Apricot Study. 69% of patients receiving Pegasys/ribavirin who achieved a sustained viral response (SVR) had a histologic improvement, but perhaps most important nonresponders to Pegasys/RBV also achieved a histologic improvement (43% of patients who received Pegasys/RBV). These are important findings since they show that patients who do not achieve a sustained viral response are still able to show improvement in the condition of the liver. A greater percent of nonresponders to Pegasys+RBV achieved improved histology than patients receivinf IFN/RBV (32%) or Pegasys alone (30%) in this study. Also important is that evaluation of histologic response was done by paired biopsies, one before the study but the second one was shortly after treatment in the study was completed. Histologic improvements can take a long time so certainly in patients who achieved SVR in this studsy you can expect histology to continue to improve over several years. Will nonresponders continue to see an increase in improved histology? It is important to continue followup of these patients to evaluate if this improvement is sustained and for how long. Finding an answer to this question can be helpful in designing length & timing for Maintenance Therapy regimens.
In a separate abstract at AASLD histologic change was evaluated in patients with advanced fibrosis or cirrhosis who received IFN, Pegasys 90 ug/week or Pegasys 180 ug/week in an older study conducted several years ago. I will report details of this study in a second report. Briefly, SVR was 37% for Pegasys 180 ug/wk, 16% for Pegasys 90 ug/wk, & 9% for IFN alone. Patients were monoinfected (HCV alone) & did not receive ribavirin. 70-80% of patients had cirrhosis (stage 4) & 17-29% had stage 3 bridging cirrhosis. Fibrosis stage improved in 35% & 25% of patients receiving Pegasys 180 ug/wk & 90 ug/wk, respectively, vs 27% in the IFN group (not significant differences). More patients treated with Pegasys 180 ug/wk & 90 ug/wk had improvements in activity grade (28% & 31%, respectively vs 11% in IFN group) (significant differences). Of note, most patients with SVR had improvements in disease activity and fibrosis. A lesser percent of virologic relapsers had improvements but a significant proportion of them had improvements. Virologic nonresponders showed improvements but it was a small percentage of them (16% showed improved fibrosis, 7% activity, 5% both activity & fibrosis). Full details to follow in forthcoming report.
Mark Nelson (Chelsea & Westminster Hospital, London) reported in an oral talk at AASLD on the interesting & important histological responses to Pegasys plus ribavirin (Copegus) in HCV/HIV coinfected patients in the Apricot Study, a trial of Pegasys+RBV in coinfected patients. Histologic improvements are when the condition of your liver improves, if the stage of your liver disease reverses. Prior studies have shown that achieving a sustained viral response can reverse liver disease for a significant portion of patients.
Apricot results were reported earlier in 2004 at the CROI conference. Patients were randomized to standard IFN alfa-2a 3 times weekly subcutaneous injections plus ribavirin (n=285), Pegasys 180 ug/wk once a week injection plus placebo (n=286), or Pegasys 180 ug/wk once weejkly injections plus ribavirin 800mg day (n=289). Patients were treated for 48 weeks and there was a 24-week followup period to evaluate SVR- sustained viral response.
SVRs were overall, 40% for Pegasys/RBV, 20% for Pegasys/placebo, and 12% for IFN/RBV.
The objective of this analysis was to investigate a possible correlation between virologic responses and histologic improvements, that is --does liver disease improve in coinfected patients in this study if they achieve a sustained viral response or if they achieve less of a viral response. Patients in the study had paired biopsies taken <15 months before this study and 56 days or more after treatment was completed. Paired biopsies were read by the local pathologist at each study site (n=401). A histologic response was defined as a 2-point ot greater reduction in Ishak-modified Histologic Activity Index (HAI) score in patients with paired biopsies.
Patient baseline characteristics were relatively comparable across the 3 treatment arms: CD4 count of 500+, HAI score 7.9-8.3, 15% had cirrhosis, HCV RNA (5.2 IU/mL IFN/RBV, 6.6 IU/mL Peg/placebo, 5.6 IU/mL Peg/RBV), BMI 24-25 kg/m2, 80% Caucasian, 82% male, 41 yrs old.
HAI SCORES AT BASELINE- ALL PATIENTS TREATED
TOTAL SCORE -130 patients in each group
IFN/RBV: 8.0
PEG/placebo: 7.9
PEG/RBV: 8.0
NECROINFLAMMATION (grade)- 130-150 patients in each group
IFN/RBV: 5,6
Peg/placebo: 5.5
Peg/RBV: 5,6
FIBROSIS (stage)- 130 patients in each group
IFN/RBV: 2.4
Peg/placebo: 2.4
Peg/RBV: 2.4
HAI SCORES AT BASELINE IN PATIENTS WITH PAIRED BIOPSIES
Were similar to all patients
TOTAL SCORE -130 patients in each group
IFN/RBV: 8.3
PEG/placebo: 8.0
PEG/RBV: 8.1
NECROINFLAMMATION (grade)- 130-150 patients in each group
IFN/RBV: 5,5
Peg/placebo: 5.8
Peg/RBV: 5,5
FIBROSIS (stage)- 130 patients in each group
IFN/RBV: 2.5
Peg/placebo: 2.5
Peg/RBV: 2.5
RESULTS
HISTOLOGIC RESPONSE (HR)
IFN/RBV: 41%
Peg/placebo: 39%
Peg/RBV: 57%
(Peg/RBV treatment was statistically significantly better than both arms: p=0.04 vs IFN/RBV, p<0.017 vs Peg/placebo).
CHANGE IN TOTAL HAI SCORE
IFN/RBV: -1.2 (n=1320
Peg/placebo: -0.6 (n=134)
Peg/RBV: -1.9 (n=135)
Again, Peg/RBV was statistically significantly better than both other arms (p=0.015 & p=0.001=, respectively).
Its important to bear in mind that these improvements were found shortly after completed treatment. Over time liver should continue to improve more.
CHANGE IN NECROINFLAMMATORY SCORE
IFN/RBV: -1.2
Peg/placebo: -0.9
Peg/RBV: -1.8 (significantly better than both comparisons)
CHANGE IN FIBROSIS SCORE
IFN/RBV: 0.0
Peg/placebo: 0.3
Peg/RBV: -0.2
Significantly better response than Peg/placebo p=0.006
HR IN PATIENTS WITH SVR
IMPROVED:
74% in IFN/RBV (n=20)
62% Peg/placebo (n=23)
69% Peg/RBV (n=51)
NO CHANGE:
22% IFN/RBV (n=6)
30% Peg/placebo (n=11)
26% Peg/RBV (n=19)
WORSENED:
4% IFN/RBV (n=1)
8% Peg/placebo (n=3)
5% Peg/RBV (n=4)
worsening=2 or more point increase in HAI score; no change=change of +1, -1, or 0 in HAI score.
HR IN PATIENTS WITHOUT SVR
IMPROVED:
32% for IFN/RBV
30% for Peg/placebo
43% for Peg/RBV
NO CHANGE:
43% for IFN/RBV
36% for Peg/placebo
34% for Peg/RBV
WORSENED:
26% for IFN/RBV
34% for Peg/placebo
23% for Peg/RBV
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