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) |
Peginterferon
alfa-2a (40KD) (PEG-IFNa-2a) plus ribavirin in cirrhotic
patients with chronic hepatitis C: Results of a multicentre open-label expanded
access program in Canada
Sherman M,
Yoshida E, Deschesnes M, Krajden
M, Bain V, Peltekian K, Anderson F, Kaita K, Simonyi S, Lee SS.
Introduction
Management of relapsers and nonresponders
to previous interferon-based therapy is an important, but unresolved issue. We
evaluated the efficacy and tolerability of peginterferon alfa-2a (40KD)
(PEG-IFNa-2a) plus ribavirin in this important
subgroup 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) who failed to respond or relapsed after
previous conventional interferon mono- or combination therapy were eligible.
Patients were assigned to PEG-IFNa-2a 180
µg/week plus ribavirin 800 mg/day for 24 (A) or 48 weeks (B) at the discretion
of the investigator. The program was initiated before the optimal treatment duration and
ribavirin dosage for genotype-1 and 2/3 were determined. SVR was defined as undetectable HCV
RNA (<50 IU/mL) 24-weeks after treatment completion. This
analysis was conducted by intention-to-treat.
Results
(table)
120 relapsers (35 to monotherapy, 80 to
combination therapy; details unknown for 5) and 241 nonresponders (53 to
monotherapy, 180 to combination therapy, details unknown for 8) were enrolled.
Baseline characteristics were similar in both groups although more
nonresponders had genotype-1 infection (84% vs. 65%). Most patients were
assigned to group B (323/355, 91%). Among relapsers to monotherapy 10/24
genotype-1 patients and 7/10 genotype 2/3 patients had SVRs.
Among relapsers to combination therapy 17/54 genotype-1 patients and 12/23
genotype 2/3 patients had SVRs. Among nonresponders
to monotherapy 9/42 genotype-1 patients and 4/10 genotype 2/3 patients had SVRs. Among nonresponders to combination therapy 30/153
genotype-1 patients and 7/21 genotype 2/3 patients had SVRs.
The incidence of serious adverse events was similar in nonresponders (5%) and
relapsers (8%).
Conclusions
The overall SVR rate was 40% (48/120) in
relapsers and 23% (55/241) in nonresponders after treatment with PEG-IFNa-2a plus RBV 800 mg/day. These ‘real world’ results in a large
patient cohort demonstrate that it is possible to cure previous nonresponders
and relapsers to interferon-based therapy. Use of optimal treatment regimens
may yield even higher SVR rates in these difficult-to-treat patients.
|
Patient
group, N |
Mean
baseline characteristics |
SVR by genotype, n (%) |
|||||||
|
Male (%) |
Age (yr) |
BMI |
Advanced
fibrosis (%) |
HCV
genotype (%) |
All |
1 |
2/3 |
||
|
1 |
2/3 |
|
|
|
|||||
|
Rel,
120 |
83 (69) |
47.3 |
27.2±5.0 |
56 (47) |
78 (65) |
38 (32) |
48 (40) |
27 (35) |
19 (50) |
|
NR, 241 |
173 (72) |
47.5 |
27.6±4.4 |
120 (50) |
202 (84) |
32 (13) |
55 (23) |
39 (19) |
11 (34) |
|
NR = patients who did not have a
virological response at any time during a previous course of IFN or IFN/RBV; Rel = patients who relapsed after an on-treatment
virological response during a previous course of IFN or IFN/RBV. Advanced
fibrosis = bridging fibrosis or cirrhosis |
|||||||||
Pegylated
interfon for treatment of acute hepatitis C in Egypt
Shouman SI, Mohamed MK, Esmat G, Attalla M, Mansour H, Rekacewicz C, Rafaat R, Sharaf N, El Hosseiny M, El-Daly
M, El-Kafrawy S, Abdel-Hamid
M, Pol S, Fontanet A.
Background
and aims
Early treatment of acute hepatitic C with standard interferon has shown sustainable
viral response in patients predominantly infected by genotypes 1, 2 and 3.
However, response to treatment of patients infected with genotype 4 and
efficacy of pegylated interferon in the treatment of acute hepatitis C, have
not been studied yet. The aim of the study was to evaluate the efficacy and
tolerance of three-month pegylated interferon (PEG-IFNα-2a) alone in
Egyptian patients with acute hepatitis C.
Method
Symptomatic acute hepatitis C patients were
enrolled sequentially in an open arm clinical trial. Patients were identified
through an ongoing surveillance study in two Fever Hospitals in Greater Cairo.
Only patients who maintained a positive HCV viremia 3
month after the onset of symptoms were treated. The study regimen was
PEG-IFNα-2a (180mg/week)
for 12 weeks. If patients were still positive for HCV viremia
at 12 weeks of treatment they continued for another 12 weeks of therapy. The
efficacy criteria was sustainable virological response with negative HCV viremia 6 months after the end of treatment.
Results
Between May 2003 and April 2004, 14 patients were
enrolled: 9 were males; the median age was 30.5 years
(range 21 to 53); and the modes of infection were IVDU (5), medical procedures
(6), needle stick injury (1) and occupational exposure (2). All patients had a
negative HCV RNA PCR after 12 weeks of treatment. Of the 12 patients who
completed their 6-month follow-up after the end of treatment, 10 (83% - 95% CI [52%-98%]) were still HCV RNA PCR negative. Data from the 2
remaining patients are still awaited. No major side
effects were observed during the course of treatment.
Conclusion
These preliminary results show a good
response rate among Egyptian patients presumably infected with HCV genotype 4.
Pegylated interferon monotherapy, administered only once per week for 12 weeks
is highly effective in treating non resolved acute HCV.
Evidence
that serum ribavirin steady-state concentrations do not correlate with early
virological response during peginterferon alfa-2a + ribavirin combination
therapy for chronic hepatitis C
Souvignet C, Stanke-Labesque
F, Bronowicki J-P, Larrat
S, Quesada J-L, Zarski J-P.
Background/aims
Ribavirin in
combination with pegylated interferon is the standard treatment for chronic hepatitis
C. Despite recommendations for ribavirin dosage based on body weight of the
patient, serum ribavirin concentrations display high inter-individual
variability that could explain severe side effects or lack of efficacy in some
patients. The present study aimed to define the relation between serum
ribavirin concentration and viral load drop on combination treatment.
Methods
Thirty-six patients
chronically infected with the hepatitis C virus (genotypes 1 or 4) were treated
with standard treatment (180 µg Peginterferon alfa-2a once weekly and 1000-1200
mg ribavirin twice daily). During the first three months of treatment, the
serum ribavirin concentration was sequentially monitored using a HPLC specific
assay, in parallel with measures of viral load (Roche Amplicor™
HCV test, v2.0) and haemoglobin level at the same
time points (Days 0, 7 and 14, and Weeks 4 and 12).
Results
The steady-state
concentration of ribavirin was reached at Week 4: 1.99 ± 0.73 mg/ml (Variation
coefficient = 41 %). Mean drop of viral load was -2.26 ± 0.97 log UI/ml at Week
4 and -2.93 ± 0.77 log UI/ml at Week 12. Undetectable HCV-RNA was noted in 36
percent of the patients at Week 4 and 83 percent at Week 12. No significant
correlation was found between serum ribavirin concentration (Week 4) and viral
load drop (Week 12): r = 0.071 (p = 0.679). The ribavirin concentration that
gave an early virological response in 50 percent of the patients (ED50)
was 2.17 mg/ml. The ribavirin concentration that gave 2 g/dL
drop of haemoglobin in 50 percent of the patients (TD50)
was 2.44 mg/ml at the same timepoint (Week 12).
Conclusions
During the first three months of combination treatment for chronic hepatitis C (Peginterferon alfa-2a + ribavirine), the drop of viral load does not correlate with serum ribavirin concentration. These data suggest that interindividual variations of serum ribavirin levels do not significantly impact early virological response rate. Actually, the interest of therapeutic drug monitoring of ribavirin will depend on further analysis of sustained virologic response data after long-term follow-up of this patient cohort.
Clustering
of poor prognostic factors in patients with chronic hepatitis C
Swain M,
Foster GR, Fried MW, Hadziyannis SJ, Heathcote EJ, Jensen D, Lee SM, Pockros
PJ, Sulkowski M, Trepo C.
Introduction
Body weight is a
modifiable factor that influences the outcome of interferon-based therapy for
chronic hepatitis C. Sustained virological response (SVR) rates tend to
decrease as body weight increases. The mechanism whereby body weight affects
the response to treatment is not completely understood, but is likely to be multifactorial. We assessed the complex relationship
between body weight and a range of baseline host- and hepatitis C virus
(HCV)-related factors that influence the outcome of interferon-based therapy.
Methods
Baseline data from two multinational, randomized, controlled phase III
studies assessing the efficacy and safety of peg-IFNα-2a (40KD)/ribavirin
for the treatment of hepatitis C were combined (NEJM. 2002;347:975; Ann Intern
Med 2004;140:346). Patients were classified into 3 groups: <65 kg,
65–<85 kg, and ³85 kg. Baseline patient- and
HCV-related characteristics were analyzed according to body weight.
Results(table)
Data from a total of 2404 patients were included in the analysis. Body
weight was positively correlated with body mass index (BMI), the proportion of
male patients, the proportion of black patients, those reported to have
acquired HCV through intravenous drug use (IVDU), and with a histological
diagnosis of cirrhosis. A greater proportion of patients infected with HCV
genotype 1 were in the highest weight group (³85 kg)
than in the other lower weight groups, although this was not statistically
significant. There was no apparent correlation between body weight and ALT
levels.
Conclusions
Body weight has a complex relationship with a range of patient- and
disease-related characteristics. In general, patients in the highest weight
group were much more likely to be male, black, to have cirrhosis and to have
been infected through IVDU. This clustering of poor prognostic characteristics
may explain the lower SVR rates observed in heavier patients.
|
Patient- and HCV-related factors at baseline according to body weight |
||||
|
Characteristic* |
Body
weight in kg (N) |
|||
|
|
<65
(512) |
65
to <85 (1145) |
³85 (747) |
p |
|
Male – n (%) |
144
(28.1) |
855
(74.7) |
638
(85.4) |
<
0.0001 |
|
Black race – n (%) |
8
(1.6) |
27
(2.4) |
56
(7.5) |
<0.0001 |
|
Age – yearsa |
41.1
± 11.0 |
42.9
± 10.0 |
42.6
± 8.1 |
0.005 |
|
BMI – kg/m2a |
21.8
± 2.3 |
25.4
± 2.7 |
31.2
± 4.8 |
<
0.0001 |
|
Infected by IVDU – n (%) |
136
(26.6) |
395
(34.5) |
318
(42.6) |
<
0.0001 |
|
Serum ALT ± SD
– IU/La |
83.5
± 59.5 |
90.0
± 61.4 |
88.2
± 61.9 |
0.4721 |
|
Cirrhosis – n (%) |
68
(13.3) |
217
(19.0) |
179
(24.0) |
<
0.0001 |
|
Country – USA |
107
(20.9) |
351
(30.7) |
443
(59.3) |
<
0.0001 |
|
Serum HCV RNA (106 copies/mL)a |
5.8
± 8.5 |
6.3
± 7.1 |
5.9
± 6.3 |
0.0009 |
|
HCV genotype
1 – n (%) |
305
(59.6) |
685
(59.8) |
478
(64.0) |
0.0853 |
|
HCV genotype 2 or 3 – n (%) |
184
(35.9) |
417
(36.4) |
244
(32.7) |
0.0853 |
|
aMean ± SD; *Cochran-Armintage
Trend test for binary data and Jonckheere-Terpstra
Trend test for ordinal/continuous data |
||||
Prediction
of sustained virological response at week 4 of peginterferon alfa-2a (40KD)
plus ribavirin treatment in chronic
hepatitis C patients with persistently ‘normal ’ ALT levels
Tran A, Gitlin N, Rodriguez-Torres M, O'Brien C, Zeuzem S, Lardelli P, Blotner S, Tong M.
Introduction
In general, the absence of an early
virological response (EVR) at week 12 of combination therapy with peginterferon
alfa-2a (40KD) plus
ribavirin has high negative predictive value (NPV) for
the probability of achieving an SVR. We aimed to determine whether this criterion
could be applied at week 4 of treatment.
Methods
422 patients with persistently normal ALT levels
(£30 IU/L, on
≥3 occasions over 18-months) were randomized to 24 or 48wks
of treatment with peginterferon alfa-2a (40KD) 180µg/wk/RBV 800mg/d. The study
was conceived before pivotal studies revealed that RBV 1000/1200mg/day is optimal for genotype 1.
SVR was defined as undetectable HCV RNA (<50 IU/mL)
after 24wks of follow-up. Rapid virological response (RVR) was defined as
undetectable HCV RNA or a ≥2-log10 decline in HCV RNA at week
4.
Results
(table)
The negative predictive value of an RVR in
genotype 1 patients treated for 48 weeks (79%) is lower than that of an EVR at
week 12 in the same group (96%, J Hepatol
2004;40(Suppl):48). However, when only patients with
genotype 1 and a high viral load are considered, the NPV is 100% at week 4. The
NPV of an RVR was 50% in the overall genotype 2/3 patient population.
Conclusions
The results
show that general treatment decisions should not be based on an RVR at week 4
in patients treated with peginterferon alfa-2a (40KD) plus ribavirin. The high
NPV of an RVR at week 4 in genotype 1, HVL patients is intriguing. Extending
treatment duration to 72 weeks in patients without an RVR (predominantly
genotype 1, ≈40% HVL) significantly improved SVR rates in a recent trial
(TeraViC-4, J Hepatol 2004;40(suppl 1):150).
Thus, further study is required to determine the optimal duration of treatment
for genotype 1 patients without an RVR at week 4.
|
Patients (N) |
With a rapid virological response at wk 4 (%): |
With an SVR at wk
72 (%): |
PPV |
NPV |
|
All genotype 1 pts treated x 48 wk (141) |
61/141 (43) |
57/141
(40) |
66% |
79% |
|
Genotype 1 HVL treated x 48 wk (51) |
25/51 (49) |
14/51
(27) |
56% |
100% |
|
All genotype 2,3 pts treated x 24 or 48
wks (117) |
109/117 (93) |
88/117
(75) |
77% |
50% |
|
Genotype 2,3 HVL treated x 24 or 48 wks (56) |
51/56 (91) |
39/56
(70) |
71% |
40% |
|
HVL
= high viral load = HCV RNA >800,000 IU/mL ; PPV =
positive predictive value (probability of an SVR after an RVR); NPV = negative
predictive value (probability of no SVR without an RVR) |
||||
Peginterferon
alfa-2a (40KD) plus ribavirin in treatment-naive patients with chronic
hepatitis C and genotype 2 or 3 infection: individual estimated probability of
sustained virological response (SVR)
Weiland O, Fried MW, Hadziyannis SJ, Messinger D, Freivogel K, Chaneac M, Foster GR.
Introduction
We constructed an "SVR Calculator'' for the
purpose of estimating the probability that an individual patient will achieve
an SVR after treatment with peginterferon alfa-2a (40KD) (peg-IFNα-2a)
plus ribavirin. The probability can be calculated at baseline, or after 12
weeks’ treatment, and can include assumptions about adherence.
Methods
A logistic regression model was developed with
data from genotype 2/3 patients treated with peg-IFNα-2a 180mcg/wk and
ribavirin 800 or 1000/1200mg/day for 24 or 48wks in two pivotal trials (Fried
NEJM 2002; Hadziyannis Ann Intern Med 2004). The
influence of pre-treatment (gender, age, race, BMI, bodyweight, viral load, ALT
quotient, histology (non-cirrhotic vs cirrhotic) and
treatment-related factors (duration, ribavirin dose, adherence) on SVR rates
was examined. Data outside the 5th-95th percentiles were excluded to minimize
the influence of extreme values. A ‘model’ patient was created with the median
values of variables that significantly influenced SVR rates. The probability of
an SVR in a hypothetical patient is estimated by varying input parameters.
Results
Data from 532 genotype 2/3 patients were used to
populate the model. Baseline viral load and adherence significantly modified
the probability of an SVR for genotype 2 patients. Significant factors that
affected the probability of achieving an SVR for genotype 3 patients are
tabulated. The probability of an SVR in the model genotype 3 patient (BMI=25;
HCV-RNA=3.3x106copies/mL, noncirrhotic)
was 80% (95% CI: 74%-85%). Treatment duration (24/48wk) and ribavirin dose (800
or 1000/1200mg/d) were not significant factors for either genotype 2 or 3.
Conclusion
By varying the
input parameters the individual probability of achieving an SVR with peg-IFNα-2a plus ribavirin in a patient
infected with genotype 2 or 3 can be calculated. This tool can be used to guide
treatment decisions and to help motivate patients to stay on therapy.
|
Probability of an
SVR (%, 95% CI) in a genotype 3 patient after treatment
with peginterferon alfa-2a (40KD) plus ribavirin* |
||||||
|
Population |
Viral load
(copies/mL) |
BMI (kg/m2) |
Cirrhosis |
|||
|
(no. of pts used in the model) |
1 x 106 |
24 x 106 |
18 |
30 |
Yes |
No |
|
All pts (n = 318) |
84 (73–91) |
78 (69–85) |
88 (80–94) |
72 (61–81) |
72 (60–82) |
80 (74–85) |
|
Adherent pts (n=247)y |
93 (84–97) |
88 (81–93) |
95 (90–98) |
83 (73–90) |
83 (72–91) |
90 (85–93) |
|
Pts with an EVR (n = 304) |
88 (77–95) |
81 (72–88) |
91 (83–96) |
76 (65–85) |
75 (63–85) |
84 (77–89) |
|
Adherent pts with an EVR
(n =245)y |
94 (85–97) |
88 (81–93) |
96 (90–98) |
84 (74–91) |
83 (72–91) |
90 (86–94) |
|
*Estimated by modifying the baseline
characteristics of the model patient as indicated. Treatment duration 24 or
48 weeks with ribavirin 800-1200 mg/day. EVR: undetectable HCV RNA or 2-log10 decrease in
HCV RNA at wk 12; SVR: Undetectable HCV RNA <50 IU/mL at end of follow-up.
yAdherence = treatment with both drugs for >80% of the
planned duration |
||||||
Are
there differences in baseline characteristics or treatment outcomes with
peginterferon alfa-2a (40KD) (PEG-IFNα-2a) and ribavirin in patients
infected with HCV genotype 1a versus 1b?
Zarski J-P, Smith C, Hadziyannis
SJ, Rakela J, Hassanein T,
Lee SD.
Introduction
We compared baseline characteristics and
outcomes in HCV genotype 1a/1b patients enrolled in pivotal trials of
PEG-IFNα-2a (40KD) (PEGASYS®) plus RBV (COPEGUS®)
(Fried NEJM 2002; Hadziyannis Ann Intern Med 2004).
Methods
Baseline characteristics of all genotype 1
patients treated with combination therapy were included. SVR rates in patients
treated with PEG-IFNα-2a (40KD) 180 mg/week plus RBV 1000/1200 mg/d were compared. SVR
was defined as undetectable serum HCV RNA (<50 IU/mL) at end 24 weeks’
follow-up. Data were analyzed by univariate and
multivariate logistic regression analysis.
Results
(ITT)
1323 genotype 1 patients were enrolled in
the trials. Genotype 1b patients tended to be older (mean age 45 vs. 41 yrs),
were more likely to be Asian (11% vs. 2%), and to have cirrhosis/bridging
fibrosis (23% vs. 17%), and were less likely to have acquired HCV
through intravenous drug use (IVDU; 21% vs. 44%) and to be from the
The ITT population included 567 genotype
1a/1b patients. A total of 119/265 (45%;
95%CI: 39-51%) genotype 1a patients and 160/302 (53%; 95%CI: 47-59%)
genotype 1b patients achieved an SVR. The SVR rate was significantly higher in
genotype 1b than 1a patients in the univariate
analysis (P=0.0039) and when adjusted for prognostic factors in the
multivariate analysis (P=0.0016).
Conclusion
There are subtle but significant
differences in the characteristics of patients infected with genotype 1a and
1b. In this retrospective analysis SVR rates were significantly higher in
genotype 1b-infected patients treated for 48 weeks with PEG-IFNα-2a (40KD)
plus RBV.
Effect
of genotype and other baseline factors on response to peginterferon alfa-2a
(40KD) (PEGASYS®) in HBeAg-positive chronic hepatitis B: results
from a large, randomised study
Cooksley G, Manns
M, Lau GKK, Liaw Y-F, Marcellin
P, Chow WC, Thongsawat S, Gane
E, Fried MW, Zahm F.
Background
Recent data show that peginterferon alfa-2a
(40KD) (PEGASYS®) provides significantly higher rates of
sustained HBeAg seroconversion than lamivudine in HBeAg-positive chronic
hepatitis B (CHB) [Lau et al, AASLD 2004]. Baseline factors, such as HBV
genotype, ALT or HBV-DNA have been shown to influence treatment response in
CHB.
Objectives
To study the impact of baseline factors on
sustained HBeAg seroconversion in a large, multinational study in
HBeAg-positive CHB
Methods
HBeAg-positive patients (n=814) received
(1:1:1) either peginterferon alfa-2a (180μg once-weekly) + placebo,
peginterferon alfa-2a + lamivudine (100mg once-daily) or lamivudine. Patients
were treated for 48 weeks and assessed after 24-weeks of follow-up (week 72).
Results
Overall, HBeAg seroconversion rates at week
72 were significantly higher with peginterferon alfa-2a (32%; P<0.001) and
combination therapy (27%; P=0.023) than with lamivudine (19%). In multivariate
analyses, high ALT, low HBV-DNA, and low HBeAg levels at baseline were
significant predictors of HBeAg seroconversion (P≤0.001). Rates of HBeAg
seroconversion stratified by genotype and other relevant baseline factors are
presented in the Table.
Conclusions
HBV genotype C patients receiving
peginterferon alfa-2a (40KD) (PEGASYS®) monotherapy responded
equally well to treatment as genotype B patients. This contrasts with data on
conventional IFNa, which identified genotype C as being
more ‘difficult-to-treat’. High ALT, low HBV-DNA and low HBeAg levels at
baseline were predictive of response in patients with HBeAg-positive CHB.
However, patients with normal/low ALT, who are currently not recommended for
treatment due to poor response, may benefit from peginterferon alfa-2a
monotherapy.
|
Table 1: HBeAg seroconversion rates at week
72 by baseline variables |
|||
|
|
PEGASYS + placebo (n=271) |
PEGASYS + lamivudine (n=271) |
Lamivudine (n=272) |
|
Genotype A B C D |
12/23
(52%) 23/76
(30%) 50/162
(31%) 2/9
(22%) |
4/18
(22%) 24/82
(29%) 43/156
(28%) 2/11
(18%) |
3/15
(20%) 17/73
(23%) 26/162
(18%) 3/17
(18%) |
|
ALT
(x ULN) <=2* >2–5 >5 |
27/92
(29%)# 36/121
(30%) 24/58
(41%) |
19/93
(20%)§ 30/111
(27%) 25/67
(37%) |
19/96
(20%)‡ 20/129 (16%) 13/47
(28%) |
|
HBV-DNA (log10
cp/ml) <=9.07 >9.07–10.26 >10.26 |
37/70
(53%) 39/138
(28%) 11/63
(17%) |
20/56
(36%) 40/147
(27%) 14/68
(21%) |
24/78 (31%) 21/123 (17%) 7/71 (10%) |
|
HBeAg (IU/ml) <=186.3 (median) >186.3 (median) |
57/138 (41%) 29/129 (22%) |
44/127 (35%) 30/143 (21%) |
38/138 (28%) 12/131 (9%) |
|
*ALT values
were abnormal (ie, >1 x ULN) at screening but normal
at baseline in: # 20 patients; § 14
patients and ‡ 26 patients |
|||
on-treatment
predictors of sustained biochemical and virological response in patients with
HBeag-negative chronic hepatitis B (CHB) treated with peginterferon alfa-2a
(40KD) (pegasys®)
Farci P, Marcellin
P, Lu Z-M, Diago M, Lai M-Y, Gurel
S, Kittis G, Yurdaydin C, Zahm F, Bonino F.
Background
Patients with HBeAg-negative CHB had
significantly higher rates of response, sustained for 24 weeks after the end of
treatment, with peginterferon alfa-2a (40KD) (PEGASYS®) or
peginterferon alfa-2a plus lamivudine than with lamivudine monotherapy [Marcellin et al., NEJM 2004]. In patients with chronic
hepatitis C, week 12 HCV-RNA levels are used to identify patients unlikely to
achieve a therapeutic response, thereby avoiding unnecessary treatment and
reducing costs. Similar on-treatment predictors of response in patients with
CHB have yet to be defined.
Objectives
To evaluate on-treatment predictors of
response among patients receiving peginterferon alfa-2a (PEGASYS®)
monotherapy in a large multinational study in patients with HBeAg-negative CHB.
Methods
HBeAg-negative patients in one study arm
(n=177) received peginterferon alfa-2a 180μg once-weekly for 48 weeks and
were assessed 24 weeks after the end of treatment (week 72). HBV DNA on
treatment was analysed for the potential in
predicting sustained [1] ALT normalisation and [2]
HBV DNA <20,000 copies/ml, both measured at week 72.
Results
At week 72, rates of ALT normalisation and HBV-DNA <20,000 copies/ml were
significantly higher in patients with HBV-DNA <400 copies/ml at week 12 (70%
and 61%, respectively) than in patients with HBV-DNA ≥400 copies/ml (53%
and 31%; P=0.023 and P<0.001). Therefore, patients reaching HBV-DNA <400
copies/ml at week 12, had the best chance of a sustained response. Patients who
did not have a 1.0 log reduction in HBV-DNA from baseline or who had HBV-DNA
levels >7.0 log at week 12 had an approximately 80% probability of not
achieving a sustained response. However, <10% of patients receiving
peginterferon alfa-2a monotherapy met these criteria, and 20% of them achieved
a sustained response at week 72 despite the modest initial HBV-DNA response.
Conclusions
Reduction of HBV-DNA
below 400 copies/ml at week 12 was associated with sustained response to
peginterferon alfa-2a (40KD) (PEGASYS®) monotherapy 24 weeks after
the end of treatment. However, this association was not sufficiently strong to
discriminate with precision, based on HBV-DNA levels at week 12, which patients
were likely/ unlikely to have a response to peginterferon alfa-2a monotherapy
at week 72.
greater
viral suppression with lamivudine +/- peginterferon alfa-2a (Pegasys®)
does not translate into improved rates of sustained HBeAg seroconversion:
results from a large, multinational study
Fried MW, Lau GKK, Piratvisuth
T, Luo K-X, Chow WC, Paik SW, Chang WY, Flisiak R, Pluck N,
Berg T.
Background
It remains unclear
whether HBV-DNA must be suppressed by a certain amount or below a specific
level in order to achieve HBeAg seroconversion. Furthermore, the optimal
duration of HBV-DNA suppression, before and after HBeAg seroconversion, that
will sustain seroconversion remains unknown.
Objectives
To evaluate the association between
on-treatment viral suppression and [1] HBeAg seroconversion and [2] YMDD
mutation development in patients with HBeAg-positive chronic HBV enrolled in a
large, randomised, multinational study of
peginterferon alfa-2a (40KD) (PEGASYS®) alone,
peginterferon alfa-2a plus lamivudine, and lamivudine alone.
Methods
HBeAg-positive patients (n=814) received
(1:1:1) either peginterferon alfa-2a (180μg once-weekly) + placebo,
peginterferon alfa-2a + lamivudine (100mg once-daily) or lamivudine alone.
Patients were treated for 48 weeks and assessed after 24 weeks of follow-up
(week 72). HBV-DNA was measured with COBAS-AMPLICOR
HBV MONITOR®; YMDD mutants with the
Results
The relationship between end-of-treatment
HBV-DNA response, occurrence of YMDD mutants and sustained HBeAg seroconversion
are presented in the Table.
Conclusions
Mean HBV-DNA
suppression was greater with peginterferon alfa-2a plus lamivudine and
lamivudine monotherapy compared to peginterferon monotherapy (see Table).
However, HBeAg seroconversion rates 24 weeks after the end of treatment were
highest with peginterferon alfa-2a monotherapy, suggesting that that more
potent HBV-DNA suppression does not necessarily translate into improved HBeAg
seroconversion rates. Increased HBV-DNA suppression with combination therapy
resulted in a lower incidence of YMDD mutation than seen with lamivudine alone.
|
HBV-DNA suppression at end of treatment,
incidence of YMDD mutants and HBeAg seroconversion at week 72 [95%
CI] |
|||
|
|
PEGASYS + placebo (n=271) |
PEGASYS + lamivudine (n=271) |
Lamivudine (n=272) |
|
Week 48 (end of treatment) |
|||
|
Mean HBV-DNA reduction (log10 cp/ml) vs baseline |
-4.5 [-4.1 to -4.9] |
-7.2 [-6.9 to -7.5] |
-5.8 [-5.4 to -6.1] |
|
HBV-DNA <400
cp/ml |
25%
[20 to 31] |
69% [63 to 74] |
40%
[34 to 46] |
|
Presence of YMDD mutant |
NA |
11%
[8 to 16] |
35%
[29 to 41] |
|
Week 72 (24 weeks after the end of
treatment) |
|||
|
HBeAg seroconversion |
32%
(p<0.001*) |
27%
(p=0.023*) |
19% |
|
HBeAg seroconversion in pts with HBV-DNA
<400 cp/ml at week 48 |
49/68
(72%) [60 to 82] |
63/186
(34%) [27 to 41] |
36/108
(33%) [25 to 43] |
|
* vs. lamivudine |
|||
Sustained
HbsAg seroconversion in patients with chronic hepatitis B treated with
peginterferon alfa-2a (40KD) (pegasys®)
Hadziyannis S, Lau GKK, Marcellin P, Piratvisuth T, Cooksley G, Bonino F, Chuttaputti A, Diago M, Jin R,
Pluck N.
Background
HBsAg seroconversion (loss of HBsAg and
appearance of anti-HBs) is considered to be the
ultimate goal of anti-HBV treatment. It is, however, a rare event occurring in
a negligible number of patients treated with nucleos(t)ide analogues, mostly in patients with HBV genotype A and
after >1 year of continuous therapy.
Objectives
To describe HBsAg
responses in 1351 patients with HBeAg-positive or -negative CHB who were
enrolled in two randomised, partially double-blind,
multinational studies comparing peginterferon alfa-2a (40KD) (PEGASYS®),
peginterferon alfa-2a plus lamivudine, and lamivudine alone.
Methods
HBeAg-positive (n=814) and -negative
(n=537) patients received (1:1:1) either peginterferon alfa-2a (180μg
once-weekly) + placebo, peginterferon alfa-2a + lamivudine (100mg once-daily)
or lamivudine. Patients were treated for 48 weeks and assessed 24 weeks after
the end of treatment (week 72). Patients were considered to have sustained HBsAg seroconversion only if they were HBsAg-negative/anti-HBs-positive
at week 72.
Results
Over 75% of patients in the studies were of
Asian origin; predominant HBV genotypes in the study populations were B (27%)
and C (50%). Overall HBsAg seroconversion rates at
week 72, and rates stratified by ethnicity and genotype are shown in the Table.
HBsAg seroconversion only occurred in patients
achieving HBeAg seroconversion - among responders with HBeAg seroconversion,
the rate of HBsAg seroconversion was 10% with
peginterferon alfa-2a-containing therapy and 0% with lamivudine.
Conclusions
In our study, patients
treated with a peginterferon alfa-2a-containing regimen for a defined duration
achieved sustained HBsAg seroconversion, while
patients treated with lamivudine did not.
The magnitude of HBV-DNA suppression on treatment does not seem to be
the major factor leading to HBsAg response, but rather the additional immunomodulatory effect associated with peginterferon
alfa-2a (40KD) (PEGASYS®) treatment.
|
HBsAg seroconversion at week 72 (24 weeks after the end of
treatment) |
||||||
|
|
HBeAg-positive CHB |
HBeAg-negative CHB |
||||
|
PEGASYS + placebo (n=271) |
PEGASYS+ lamivudine (n=271) |
Lamivudine (n=272) |
PEGASYS + placebo (n=177) |
PEGASYS+ lamivudine (n=179) |
Lamivudine (n=181) |
|
|
Mean drop in HBV-DNA (log10 cp/ml) at week 48 |
-4.5 |
-7.2 |
-5.8 |
-4.1 |
-5.0 |
-4.2 |
|
HBsAg seroconversion |
8
(3%) p=0.004* |
8
(3%) p=0.004* |
0 |
5
(3%) p=0.03* |
3
(2%) |
0 |
|
Asian/Oriental Caucasian HBV genotype A B C D |
3/238
(1%) 5/24
(21%) 5/23
(22%) 0/76
(0%) 3/162
(2%) 0/9
(0%) |
5/238
(2%) 3/23
(13%) 2/18
(11%) 1/82
(1%) 4/156
(3%) 0/11
(0%) |
– – – – – – |
3/108
(3%) 2/66
(3%) 2/11
(18%) 1/43
(2%) 2/63
(3%) 0/55
(0%) |
2/112
(2%) 1/65
(2%) 1/10
(10%) 2/41
(5%) 0/69
(0%) 0/54
(0%) |
– – – – – – |
|
* vs. lamivudine |
||||||
peginterferon
alfa-2a (40KD) (PEGASYS®) versus peginterferon alfa-2a plus
lamivudine versus lamivudine in HBeag-positive chronic HBV: effect of previous
treatment and drug exposure on sustained response
Lau GKK, Piratvisuth T, Luo K-X, Marcellin P, Thongsawat S, Gane E, Fried MW, Cooksley G, Button P, Liaw Y-F.
Background
In chronic hepatitis C, previous treatment
and extent of drug exposure seem to have an impact on response rates. In
patients with chronic hepatitis B (CHB) the effects of previous anti-HBV
treatment and exposure to study drug on responses to pegylated interferon are
less well investigated.
Objectives
To
investigate the effect of previous treatment and drug exposure on efficacy and
safety in a randomised, partially double-blind,
multinational study.
Methods
HBeAg-positive patients (n=814) received
(1:1:1) either peginterferon alfa-2a (180μg once-weekly) + placebo,
peginterferon alfa-2a + lamivudine (100mg once-daily) or lamivudine. Patients
were treated for 48 weeks and assessed 24 weeks after the end of treatment
(week 72). Treatment with any anti-HBV drug 6 months before study entry was not
permitted. Analysis of drug exposure was performed only in the peginterferon
alfa-2a monotherapy arm.
Results
The effects of previous treatment with
either interferon and/or lamivudine on HBeAg seroconversion rates are shown in
the table. Regardless of whether patients were pre-treated or not, HBeAg
seroconversion rates at week 72 were higher with peginterferon alfa-2a and
combination therapy than with lamivudine.
The rate of adherence to peginterferon
alfa-2a was high, with 78% of patients receiving >90% of the total drug
dosage (>7776μg). HBeAg seroconversion rates were 28% in those
receiving <90% of the total drug dosage and 33% in those receiving >90%
of the total drug dosage.
Conclusions
Peginterferon alfa-2a
(40KD) (PEGASYS®) provided higher rates of HBeAg seroconversion than
lamivudine, irrespective of whether the patients had or had not received previous
anti-HBV therapy. Previous treatment with interferon or lamivudine did not
substantially affect HBeAg seroconversion rates with peginterferon alfa-2a in
this study. Adherence to peginterferon alfa-2a in this study was excellent.
|
HBeAg seroconversion rates at week 72 by
previous treatment |
|||
|
|
PEGASYS + placebo (n=271) |
PEGASYS + lamivudine (n=271) |
Lamivudine (n=272) |
|
All patients (ITT) |
32% p<0.001* |
27% p=0.023* |
19% |
|
Pts without previous anti-HBV therapy‡ |
66/214
(31%) p=0.018* |
59/221
(27%) p=
0.115* |
42/208
(20%) |
|
Pts with previous exposure to
conventional IFN |
13/30
(43%) P=0.047* |
11/32
(34%) P=0.038* |
4/32
(13%) |
|
Pts with previous exposure to
lamivudine |
10/31
(32%) P=0.065* |
6/24
(25%) P=0.253* |
7/42
(17%) |
|
* vs lamivudine ‡
includes lamivudine and conventional or pegylated interferon |
|||
Sustained
response to peginterferon alfa-2a (40KD) (PEGASYS®) in
HBeAg-negative chronic hepatitis B.
1-year follow-up data from a large, randomised multinational study
Marcellin P, Lau GKK, Bonino F, Farci P, Hadziyannis S, Piratvisuth T, Germanidis G, Yurdaydin C, Lai
M-Y, Pluck N.
Background
Patients with HBeAg-negative chronic
hepatitis B (CHB) had significantly higher rates of sustained response with
peginterferon alfa-2a (+/- lamivudine) than with lamivudine monotherapy [Marcellin et al, NEJM 2004].
Objectives
To assess the durability of response one
year after the end of treatment.
Methods
HBeAg-negative patients received either
peginterferon alfa-2a (180μg once-weekly) + placebo, peginterferon alfa-2a
+ lamivudine (100mg once-daily) or lamivudine. Patients were treated for 48
weeks and assessed 24 weeks after the end of treatment (initial study). All
study centres were offered participation in a
roll-over 5-year long-term observational study (LT-study). Preliminary results
generated 48 weeks after the end of treatment (week 96) are presented.
Results
Thirteen of 54 (24%) study centres opted not to take part in the LT-study. Overall,
304 of 537 patients (57%) analysed in the initial
study participated in the LT-study; more patients in the peginterferon
alfa-2a-containing arms (63% and 62%) than in the lamivudine arm (45%)
participated. The proportion of initial study non-responders not participating
in the LT-study was higher in the lamivudine arm (65%) than in the
peginterferon alfa-2a monotherapy arm (53%).
In the initial study, normal ALT, HBV-DNA
<20,000 and <400 copies/ml, all assessed 24 weeks after the end of
treatment, were significantly higher with peginterferon alfa-2a (+/-
lamivudine) than with lamivudine (P<0.01). Rates of response in the initial
and LT-studies are presented in the table.
Conclusions
In patients with HBeAg-negative CHB
receiving peginterferon alfa-2a, rates of biochemical and virologic
response seen one year after the end of treatment were similar to those
reported 24 weeks after the end of treatment in the initial study. A 48-week
course of peginterferon alfa-2a (40KD) (PEGASYS®) is able to induce
high rates of sustained biochemical and virological responses one year after treatment
discontinuation.
|
Responses 24 weeks after the end of treatment (initial study, all patients) |
|||
|
|
PEGASYS |
PEGASYS+LAM |
LAM |
|
ALT normal # |
105/177
(59%) |
107/179
(60%) |
80/181
(44%) |
|
HBV DNA<20,000 copies/ml # |
76/177
(43%) |
79/179
(44%) |
53/181
(29%) |
|
HBV<400 copies/ml |
34/177
(19%) |
35/179
(20%) |
12/181
(7%) |
|
Responses 48 weeks
after the end of treatment (LT-study, all
patients with available data ) |
|||
|
ALT normal # |
58/99
(59%) |
51/98
(52%) |
28/65
(43%) |
|
HBV DNA<20,000 copies/ml # |
41/97
(42%) |
40/97
(41%) |
20/65
(31%) |
|
HBV<400 copies/ml * |
17/102
(17%) |
15/104
(14%) |
6/75
(8%) |
|
# co-primary endpoints in the initial
study *if week 96 value was missing, week 84
value was used |
|||
Effect
of ALT flares on efficacy and safety of peginterferon alfa-2a (40KD) (PEGASYS®),
peginterferon alfa-2a plus lamivudine and lamivudine in HBeAg-positive chronic
hepatitis B (CHB)
Piratvisuth T, Luo
K-X, Marcellin P, Chang WY, Berg T, Flisiak R, Chao Y-C, Paik SW, Thongsawat S, McCloud P
Background
In HBeAg-positive CHB, marked ALT flares
during IFN-based treatment have been associated with HBeAg seroconversion and
viral suppression. In contrast, marked flares after discontinuation of nucleos(t)ide analogues may lead
to potentially life-threatening disease exacerbations.
Objectives
To investigate the effect of ALT elevations
on efficacy and safety in a randomised, partially
double-blind, multinational study.
Methods
HBeAg-positive patients (n=814) received (1:1:1) either
peginterferon alfa-2a (180μg once-weekly) + placebo, peginterferon alfa-2a
+ lamivudine (100mg once-daily) or lamivudine. Patients were treated for 48
weeks and assessed after 24 weeks follow-up (week 72). For this analysis,
marked ALT elevations (maximums) were defined as either >10xULN or >5x
baseline ALT levels (bALT), and moderate flares as
>5-≤10xULN.
Results
On-treatment ALT >10xULN was seen in
18%, 13% and 11% of patients receiving peginterferon alfa-2a, combination
therapy and lamivudine, respectively; and ALT >5x bALT
in 5%, 6% and 4%, respectively. The association between on-treatment ALT
maximums and HBeAg seroconversion at week 72 is shown in the Table. During
follow-up, ALT >10xULN was seen in 12%, 13% and 15% of patients with
peginterferon alfa-2a, combination therapy and lamivudine, respectively; and
ALT >5x bALT in 7%, 11% and 11%, respectively.
Eight patients had a flare in ALT during
follow-up that was considered a serious adverse event (4 following
peginterferon alfa-2a ± lamivudine; 4 following lamivudine monotherapy). In 2
patients (of 272) receiving lamivudine monotherapy this led to hepatic
decompensation – resulting in one liver transplant and one death.
Conclusions
Marked on-treatment ALT
elevations were generally more frequent with peginterferon alfa-2a (40KD)
(PEGASYS®) monotherapy and were more common in patients with HBeAg
seroconversion 24 weeks after the end of treatment. In contrast, marked
follow-up flares were generally more frequent with lamivudine and in two
patients led to irreversible liver failure.
|
On-treatment ALT maximums and HBeAg
seroconversion at week 72 |
||||
|
|
PEGASYS + placebo (n=271) |
PEGASYS + lamivudine (n=271) |
Lamivudine (n=272) |
|
|
HBeAg seroconversion rates in: |
|
|||
|
All patients (ITT) |
87/271
(32%) |
74/271
(27%) |
52/272 (19%) |
|
|
|
||||
|
Patients with ALT >5x bALT |
6/14
(43%) |
6/16
(38%) |
3/12
(25%) |
|
|
|
||||
|
Patients with ALT >10x ULN |
20/48
(42%) |
12/35
(34%) |
3/31
(10%) |
|
|
Pts with ALT >5-<10 x ULN |
28/74
(38%) |
27/86
(31%) |
16/64
(25%) |
|
|
Patients with ALT <=5 x ULN |
39/149
(26%) |
35/150
(23%) |
33/177
(19%) |
|