Patients
infected with hcv-5 present the same response rate than patients infected with
HCV-1: results from the Belgian randomised trial for naive and relapsers
(BERNAR)
D’heygere F, George C, Nevens
F, Van Vlierberghe H, Van Der
Meeren O.
Introduction
HCV genotype 5 (HCV-5) shows a world-wide
distribution mainly restricted to
Method
We reviewed the HCV-5 patients from the
database of the Belgian Randomised Trial for Naïve and Relapsers (BERNAR-1),
which has enrolled 443 patients that were naïve to therapy or relapsed after a
conventional interferon (IFN) based therapy. Patients received either
peginterferon alfa-2a (40KD) (PEGASYS) 180µg qw for
48 weeks (n=11), either IFN 6 MIU tiw for 12 weeks
then 3MIU tiw for 36 weeks (n=10), both in
combination with ribavirin 1000-1200mg/day for 48 weeks. A subset of HCV-1
infected patients was then selected from the study database to match the HCV-5
population according to age category (< vs
>40), gender (male vs female), baseline viral load
category (< vs >=800,000IU/mL), cirrhosis
status (yes vs no), pretreatment
status (naïve versus relapse) and treatment group (PEGASYS vs
IFN).
Results
21 patients with HCV-5 infection, and 21
patients with HCV-1 infection fully matching the characteristics of the HCV-5
patients, were identified in our database. In both groups, patients were mostly
female (52%), naïve to therapy (81%), aged >40 (95%), had baseline viral
load<800,000IU/mL (62%) and no cirrhosis (80%). A sustained virological
response (SVR) was observed in 10/21 patients in the HCV-5 group (48%) and in
8/21 patients in the HCV-1 group (38%; p=0.530); in the PEGASYS group, the SVR
rate was 55% in both HCV-5 and HCV-1 patients.
Conclusions
Patients infected with HCV-5 present the same
response rate than patients infected with HCV-1. When treated with
peginterferon alfa-2a (40KD) plus ribavirin for 48 weeks, 55% of patients
achieved an SVR.
Combined
pegylated interferon alfa-2a and ribavirin in treatment of chronic hepatitis C
in Egypt
Elmakhzangy H, Rekacewicz C, Shouman SI, Mohamed HN, Esmat G, Ismail A, Rafaat R, El Hosseiny M, El-Daly
M, El-Kafrawy S, Abdel-Hamid
M, Fontanet A, Pol S, Mohamed MK.
Background and aims
While Hepatitis C Virus (HCV) genotype 4 is
widely prevalent in
Method
Chronically HCV infected patients were
enrolled in an open label trial after signing an informed consent. Patients
with advanced and decompensated cirrhosis were not included. The study regimen
was PEG-INF (180mg/week) and RBV (11.5mg/kg/day) for 48 weeks. If patients were still positive for HCV viremia after 24 weeks of therapy, the treatment was
interrupted. The efficacy was assess at the end of treatment (End of treatment
response ETR) and 6 months after the end of treatment (sustainable virological
response SVR) by an undetectable HCV viremia.
Results
Among the 100 patients enrolled, 85% were
males, the mean (± S.D.) age was 42 years (±8.8), the mean Body Mass Index
(BMI) was 29 Kg/m2 (±5.1) and the pretreatment liver histology
showed for 49 patients a A1-F1 METAVIR index while 35 patients had a A3 or F3
index. Treatment was interrupted after the 24 first weeks of treatment for 22
patients because of a positive HCV viremia. Among the
95 patients with data available at week 48, the ETR was 69.5 % (95% CI [59.2% –
78.5%]). The ETR varied according to the METAVIR index from 54% to 78%,
respectively, for A3 or F3 patients and A1-F1 (P<0.05). The SR
evaluated on the 80 patients who have already reached the 72 week visit was 61%
(95% CI [49.7% – 71.4%]).
Conclusion
SVR with combined therapy among these
patients presumably infected with genotype 4 falls within the range observed
with other genotypes. Treatment was well tolerated.
Age and
sustained virological response in patients with persistently ‘normal’ alt and
chronic hepatitis C treated with peginterferon alfa-2a (40KD) plus ribavirin
Gane E, Pockros
PJ, Farci P, Diago M, Lardelli P, Blotner S, Martinelli A.
Introduction
Data suggest that there may be a negative
relationship between increasing age and sustained virological response (SVR) in
patients with chronic hepatitis C (CHC). This analysis aimed to explore the
relationship between age, baseline characteristics and SVR in CHC patients with
persistently ‘normal’ ALT treated with peginterferon alfa-2a (40KD) and
ribavirin.
Methods
422 patients with ALT levels within the
normal laboratory range (≤ 30IU/L) on ≥3 occasions over 18 months
were randomised to receive 24 or 48 weeks treatment
with peginterferon alfa-2a (40KD) 180mg/week
plus ribavirin 800mg/day, or no treatment. All patients were monitored for 72
weeks (Zeuzem, Gastroenterology 2004). The study was
initiated before prospective studies indicated that ribavirin 1000/1200mg/day
is optimal for genotype 1. The primary endpoint was SVR, defined as
undetectable HCV RNA by qualitative PCR after 24 weeks untreated follow-up. Results
were retrospectively analysed according to age
(≤40 or >40 years) and HCV genotype (1 vs
2/3).
Results
(table)
Patients aged >40 years had lower SVR
rates (overall and across each genotype) than patients aged ≤40. Baseline
demographics also differed between the two groups, with the older subgroup
having a higher proportion of males and African Americans, and a greater BMI
and pre-treatment HCV RNA titre than the younger
subgroup.
Conclusions
In patients with CHC and persistently
‘normal’ ALT levels, age appears to be an important factor in determining
response to peginterferon alfa-2a (40KD) plus ribavirin. This may support the
consideration of antiviral therapy once a positive diagnosis has been made.
However, the role of other confounding factors (male gender, African American
race and high baseline HCV titre) cannot be excluded.
Further studies are warranted.
|
Genotype & treatment duration (N) |
Baseline characteristics by age group
(≤40 vs >40yr) –N (%) |
SVR rate % |
||||||||
|
Male
gender |
AA
race |
BMI |
HCV
RNA |
|||||||
|
≤40 |
>40 |
≤40 |
>40 |
≤40 |
>40 |
≤40 |
>40 |
≤40 |
>40 |
|
|
G1
24wk (144) |
24 (47) |
39 (42) |
3 (6) |
10 (11) |
24.5 |
26.4 |
0.8 |
1.1 |
12 |
14 |
|
G1 48wk (141) |
15 (33) |
39 (41) |
1 (2) |
12 (13) |
25.2 |
27.3 |
0.6 |
1.1 |
54 |
34 |
|
G2,3 24wk (58) |
7 (37) |
16 (41) |
1 (5) |
3 (8) |
25.2 |
27.1 |
1.4 |
1.8 |
79 |
69 |
|
G2,3 48wk (59) |
7 (29) |
18 (51) |
2 (8) |
3 (9) |
23.6 |
26.0 |
0.9 |
1.9 |
88 |
71 |
|
AA = African American race; BMI = mean
body mass index in kg/m2; Mean HCV RNA level in IU/mL x 106 |
||||||||||
Cost-effectiveness
of peginterferon alfa-2a (40KD) plus ribavirin in treatment of chronic hepatitis
C (CHC) in HIV-HCV co-infection
Hornberger J, Carosi
G, Puoti M, Bruno R, Green J, Katel
KK, Giuliani G.
The recent AIDS Pegasys Ribavirin International
Coinfection Trial (APRICOT) demonstrated the efficacy of peginterferon alfa-2a
plus ribavirin (RBV) and interferon alfa plus ribavirin (IFN/RBV) in patients
co-infected with HIV-HCV. The
cost-effectiveness of treating CHC with peginterferon alfa-2a/RBV has not been
assessed in this patient population.
Methods
We
developed a Markov Model of CHC disease progression in HIV-HCV co-infection to
assess the cost-effectiveness of peginterferon alfa-2a/RBV compared with
IFN/RBV. Estimates of
progression rates came from published studies.
Treatment effect on sustained virological response (SVR) was based on
findings from APRICOT. The analysis was
a cohort of patients with mean age 40 years and HIV-HCV co-infection. Mortality
from HIV was based on published results of HIV Swiss Cohort Study. Quality of
life and costs for each health state were based on literature estimates and on
the Italian health care setting. Costs in 2003 euros and benefits were
discounted at 3%. The Italian National Health Service (NHS) perspective was
used.
Results
In genotype 1 patients, quality-adjusted life years
(QALYs) and costs increase with peginterferon
alfa-2/RBV relative to IFN/RBV by 0.76 and € 7,324, respectively. In genotype 2/3 patients, QALYs
and costs increase by 1.44 years and € 6,222, respectively. In genotype 1 and 2/3 patients, peginterferon
alda-2a/RBV is cost-effective compared with IFN/RBV (Genotype 1, € 9,684 per
QALY gained; Genotype 2/3 € 4,320 per QALY gained).
Conclusions
Based on our model, peginterferon alfa-2a/RBV is
predicted to increase overall survival, and has cost-effectiveness ratios
against IFN/RBV that are within acceptable ranges adopted by the NHS.
Peginterferon
alfa-2a (40KD) plus ribavirin in cirrhotic patients with chronic hepatitis C:
results of a multicentre open-label programme in Canada
Lee SS, Bain V, Peltekian K,
Krajden M, Yoshida E, Deschesnes
M, Heathcote EJ, Bailey R, Simonyi S, Sherman M.
Introduction
In the only prospective randomized study
conducted exclusively in patients with bridging fibrosis/cirrhosis, the overall
SVR rate after 48 weeks of treatment with peginterferon alfa-2a (40KD) (PEG-IFNa-2a) 180µg/week was 30% (Heathcote NEJM
2000;343:1673-80). Patients in clinical trials are highly selected and
motivated, and whether the same response rates can be achieved in routine
clinical practice remains unknown. We evaluated the efficacy and tolerability
of PEG-IFNa-2a/ribavirin in treatment-naïve
patients enrolled in a multicentre, open-label
expanded access program in a routine clinical setting.
Methods
Anti-HCV antibody-positive adults with
detectable HCV RNA (>600 IU/mL) were eligible. Patients with a histological
diagnosis of fibrosis/cirrhosis (F3/F4) were eligible provided they had
compensated liver disease (Child-Pugh A). At the investigator’s discretion
patients were assigned to PEG-IFNa-2a
180µg/week plus ribavirin 800mg/day for 24 (A) or 48 weeks (B). The program
was initiated before the optimal treatment duration and ribavirin dosage for
genotype-1 and 2/3 were known. This analysis was conducted by
intention-to-treat.
Results
(Table)
174 of 508 (34%) patients had
fibrosis/cirrhosis. These patients were older, had a higher BMI and were more
likely to have genotype-1 infection than noncirrhotic
patients. Most patients (380/508, 75%) were assigned to group B. The SVR rate
in fibrotic/cirrhotic patients was 44% (34% in genotype-1, and 58% in genotypes
2/3). Noncirrhotic patients had higher SVRs: 41% in genotype-1; 77% in genotypes 2/3. The
incidence of serious adverse events was similar in fibrotic/cirrhotic (5%) and noncirrhotic patients (5%).
Conclusion
The efficacy of PEG-IFNa-2a/ribavirin in this study was similar to that in cirrhotic
patients treated with the same regimen in a randomized pivotal study in which
different treatment durations and ribavirin dosages were compared (Hadziyannis. Ann Intern Med 2004;140:346). Our results
demonstrate that this combination is effective and safe in patients with
fibrosis/cirrhosis and results obtained in clinical trials can be achieved in
routine clinical practice. Further improvement in SVR may be obtained with an
optimal ribavirin dose in genotype-1 patients.
|
Patient group, Total N |
Mean baseline
characteristics |
SVR by group and genotype, n (%) |
||||||
|
Age (yr) |
BMI |
HCV genotype (%) |
Aa |
B |
||||
|
1 |
2/3 |
other |
2/3 |
1 |
2/3 |
|||
|
Cirrhotic,
174 |
48 |
28 |
118 (68) |
53 (30) |
3 (2) |
23/35 (66) |
40/118
(34) |
8/18(44) |
|
Noncirrhotic, 334 |
42 |
27 |
196 (59) |
127 (38) |
11 (3) |
72/91
(79) |
81/196
(41) |
26/36(72) |
|
A = PEG-IFNa-2a/ribavirin x 24wk; C = PEG-IFNa-2a/ribavirin x 48wk; SVR = undetectable HCV RNA (<50 IU/mL) 24-weeks after end of treatment. aNo genotype 1 patients were enrolled in group A. |
||||||||
Are
changes in lymphocytes during peginterferon alfa-2a (40KD) and ribavirin
treatment in patients with co-infection related to HCV response? Findings from
APRICOT
Pérez-Guzmán E, Pastore G, Cadeo
G, Antunes F, Staszewski S,
Ortega E, Katlama C, Messinger
D, Depamphilis J, Torriani F.
Introduction
In APRICOT, peginterferon alfa-2a (40KD)
plus ribavirin produced a sustained virological response (SVR) rate of 40% in
HIV-HCV co-infected patients, and did not adversely affect HIV disease status (Torriani, NEJM 2004). In this subsequent analysis of
APRICOT data, we aimed to determine the effects of peginterferon alfa-2a (40KD)
plus ribavirin treatment on CD4+ cells according to outcome (SVR vs. no SVR).
Methods
289 co-infected patients were treated with
peginterferon alfa-2a (40KD) 180mg/week
plus ribavirin 800mg/day. Patients had compensated liver disease, CD4+ count
≥100 cells/mL, and stable HIV disease. SVR was defined as undetectable
HCV RNA (<50IU/mL) after 24 weeks of untreated follow-up. Blood samples were
collected to monitor changes in lymphocytes. Only patients who received 48
weeks’ treatment were included in the analysis (n=217).
Results
(FIGURE)
Total lymphocyte counts decreased from
baseline during treatment (mean: -0.8 x109/L
at week 48 in both subgroups) but returned to baseline levels during follow-up.
CD4+ cell counts also decreased from baseline during treatment. The decrease
was greater in patients achieving an SVR than in patients without an SVR, and
was proportional to the baseline CD4+ count. As with lymphocytes, CD4+ cell
counts returned to pre-treatment levels during follow-up. The mean percentage
of CD4+ lymphocytes (%CD4+) increased slightly during treatment in both
subgroups (maximum increase of 4% in each group after 24 weeks’ treatment). At
week 72, there appeared to be a slight rebound in %CD4+ in patients who
achieved an SVR, whereas %CD4+ returned to pre-treatment levels in those who
did not achieve an SVR.
Conclusions
Changes in CD4+ cells associated with
peginterferon alfa-2a (40KD) plus ribavirin treatment appear to be independent
of HCV virological response. Although changes occur in CD4+ cells during
treatment, levels return to baseline following treatment cessation.
z
Preliminary
health outcomes results of treatment with peginterferon alfa-2a (40KD) plus
ribavirin for chronic hepatitis C genotype 1 in daily routine clinical
practice: the HERACLES project
Planas R, Solá R,
Diago M, Olveira A, Romero-Gómez M, Barniol R, Benítez A, Casanovas T,
Muñoz-Sánchez M, on behalf of the Heracles Study Group.
Introduction
Since
publication of 12-week predictability data (Fried et al. NEJM 2002) much
interest in
Objective
To document DCP in treatment-naïve patients
infected with HCV genotype 1 treated with peginterferon alfa-2a (40KD) plus
ribavirin in centers with regulatory approval (Spanish R.D.561/1993) before
both products were marketed in Spain.
Methods
This was an electronic observational,
electronic data capture study. Eligible patients had detectable HCV RNA,
elevated serum ALT levels and compensated liver disease.
Results (table)
A total of 494 patients have been enrolled.
Age, weight, BMI, gender, liver damage on biopsy, baseline viral load,
treatment adherence, serum ALT, AST, ALP, leucocytes, platelets and albumin and
their possible relationship with early virological response at week 12 (EVR12)
and week 24 (EVR24) have been analyzed. Of the factors analyzed, only treatment
adherence had a significant relationship with EVR12 (p=0.0297) and only
baseline HCV RNA levels were correlated with EVR24 (p=0.0463). Safety data was
consistent with the known profile of this combination.
Conclusions
The evaluation of EVR12 is feasible
under DCP in
|
N (%) |
Week 12 |
Week 24 |
|
Scheduled visit |
391 |
291 |
|
HCV RNA determined |
313 |
209 |
|
EVR (≥2-log10 decrease
in HCV RNA) |
236 (75) |
176 (84) |
Peginterferon alfa-2a (40KD) plus ribavirin is as
effective in patients relapsing after conventional interferon based therapy
than in naïve patients: results from the BERNAR-1 trial
Nevens F, Van Vlierberghe H, D'heygere
F, Delwaide J, Adler M, Henrion
J, Henry JP, Hendlisz A, Michielsen
P, Bastens B, Brenard R,
Van Der Meeren O.
Background
Treatment with
peginterferon alfa plus ribavirin (RBV) is standard of care in the initial
treatment of chronic hepatitis C (CHC). The Belgian Randomised trial for Naïve
and Relapsers (BERNAR-1) investigated the safety and efficacy of this regimen
versus a conventional interferon-based combination therapy, and compared naïve
patients versus patients who relapsed after initial treatment with conventional
interferon with or without ribavirin.
Methods
Study medication consisted
of peginterferon alfa-2a (40KD) (PEGASYS) 180µg qw
for 48 weeks, or interferon alfa-2a 6MIU tiw for 12
weeks then 3MIU tiw for 36 weeks (IFN), both combined
with RBV (1,000 or 1,200mg/day) for 48 weeks. Randomisation was stratified
according to pretreatment status (treatment-naïve
versus relapse) and presence of cirrhosis.
Results
443 patients were
randomised and received at least one dose of study medication (ITT, missing=failure). The baseline parameters were well
balanced across treatment arms. The patients were predominantly male (54%),
Caucasian (91%), older than 40 (68%), with a BMI >25kg/m² (50%); 16% had
cirrhosis; 22% were relapsers. At baseline, 63% of patients had genotype 1
infection and 34% had HCV-RNA >800,000IU/mL. A significantly higher
proportion of patients in the PEGASYS group
than in the IFN group had a sustained virological response (SVR): 52% vs. 27%,
p<0.001. The proportion of patients with SVR in the naïve population was 54%
(PEGASYS) versus 27% (IFN); in the relapse group, 43% (PEGASYS) vs. 26% (IFN).
The difference between treatment groups was highly statistically significant in
both naïve and relapse populations (p<0.001), while the difference in
response rate between naïve and relapsers was not statistically significant
(p=0.237).
Conclusions
The CHC population in
The influence of cumulative peginterferon alfa-2a (40
KD) and ribavirin (RBV) exposure on sustained virological response (SVR) rates
in patients with genotype 1 chronic hepatitis C
Reddy KR, Hadziyannis SJ, Diago M, Marcellin
P, Lopez-Talavera JC, Wright T.
Introduction
Patients who receive full doses and durations of PEG-IFN /RBV combination therapy have higher SVR rates. In this analysis, we investigated the relationship between cumulative drug exposure to RBV, and SVR rates.
Methods
Pooled data from 569 patients randomized to 48 weeks of PEG-IFN alfa-2a (40KD) 180 μg/wk + RBV 1000/1200 mg/d in two phase III trials were analyzed. Cumulative exposure defined as total drug administered (based on recorded at clinic visits and validated against diaries) was evaluated.
Results
Of 427 patients (75%) who completed treatment with PEG-IFN, 182 (43%) had their RBV dose reduced to <97% compared with 114 (27%) who had their PEG-IFN dose reduced to <97%; 62 patients (15%) had reductions of both drugs to <97%. SVR rates for patients who completed treatment with decreasing cumulative RBV dose were: 66% (>97% dose), 59% (80-97%), 57% (60-80%) and 33% (<60%). Only 12 patients (3%) discontinued RBV prior to week 42 while remaining on treatment with PEG-IFN (table). Discontinuations for both drugs were due to insufficient therapeutic response (n=53), laboratory abnormalities/adverse events (n=65), or other reasons (n=24).
Conclusion
In conclusion, patients were more likely to
maintain assigned doses of PEG-IFN alfa-2a (40KD) compared to assigned doses of
RBV throughout treatment. Discontinuation of RBV before 42 weeks in PEG-IFN
treatment completers was uncommon, but the results suggested that SVR was
diminished from ~61% in those completing both therapies (even if at reduced
doses) to ~42%. All of these factors are likely to compromise response.
Avoiding RBV dose reductions and dose discontinuations will likely improve
overall SVR, although the magnitude of this benefit remains to be determined.
|
SVR by duration of RBV exposure and % cumulative exposure
to PEG-IFN alfa-2a (40KD) |
|||
|
|
Proportion
of optimal cumulative PEG-IFN alfa-2a (40KD) dose over 48 weeks |
||
|
Duration |
>97% |
≤97% |
Discontinued
PEG-IFN alfa-2a (40KD) |
|
RBV discontinuation before 12 weeks of
therapy |
0%
(0/3) |
0%
(0/1) |
0%
(0/26)* |
|
RBV discontinuation between 12 weeks and
36 weeks |
66.6%
(2/3) |
66.7%
(2/3) |
8.2%
(8/98) |
|
RBV discontinuation after >36 weeks
and before 42 weeks |
0%
(0/0) |
50%
(1/2) |
8.3%
(1/12) |
|
RBV continued for longer than 42 weeks |
62.8%
(193/307) |
57.4%
(62/108) |
16.7%
(1/6) |