|
24 vs 48 weeks Pegasys/RBV in HCV Genotype 2/3
Coinfection:
does this study answer the question
|
| |
| |
Reported by Jules Levin
An Italian research group (Puoti, Zanini et al, Master
coinfection study group, IAS/Rio, poster MoPpLB0103) studied
whether 24 or 48 weeks therapy (Pegays+ribavirin) showed better
viral outcomes for HCV/HIV patients with genotype 2/3. As it
turned out 92-100% of study patients had genotype 3. The
incidence of relapses in patients who were HCV RNA negative at
end of treatment was the main outcome compared between the two
groups.
The authors concluded that these study results "suggest that the
optimal duration of therapy in coinfected patients with
genotypes 2/3 is at least 48 weeks", because the study observed
a higher relapse rate among patients who were HCV negative after
24 weeks therapy compared to those who were HCV negative after
48 weeks therapy.
Does this study answer the question?
I don't think this study was conducted in a manner to provide a
conclusive answer to the question. To better address the
question therapy and patients should be stratified by baseline
viral load, the presence of cirrhosis, and perhaps other
characteristics. That is, if you select patients with all the
characteristics that would lend themselves to achieving an SVR
with only 24 weeks therapy, that would be a better patient
population in which to study this question. Such characteristics
would include: patients with >500 CD4s and <50 copies/ml, with
reconstituted immune systems; no fatty liver; no cirrhosis,
early stage HCV disease; low HCV viral load; full adherence; use
of EPO; undetectable HCV RNA by week 4 or 8. Perhaps these
patients could achieve better outcomes with shorter than 48
weeks therapy. Even with these considerations it is reasonable
to think that in HIV at least 48 weeks therapy is necessary to
optimize response rates.
BACKGROUND: In HCV monoinfection, study results show the
24 weeks therapy with peginterferon plus ribavirin may be
adequate duration of therapy for patients with genotype 2/3. The
Hadziyannis study of Pegasys plus 800mg daily ribavirin found
73-78% SVR rates for genotype 2/3 for 24 or 48 weeks therapy
regardless of viral load levels at baseline of weight. This
study set a standard for 24 weeks therapy with peginterferon
plus RBV in genotypes 2/3 who are HCV monoinfected. However,
this study did not examine the effects of adherence on outcomes
of 24 vs 48 weeks therapy. It is possible that high adherence
levels (80-100%) would have resulted in a better SVR rate with
48 weeks therapy. Dose reductions of peginterferon or ribavirin
were likely to have occurred more often for patients receiving
48 weeks therapy. So, you could make a case that a patients with
100% adherence and no dose reductions would achieve better SVR
rates with 48 weeks therapy. But, perhaps 24 weeks might be
adequate for most patients.
A study published in the NEJM (June 2005) found that for HCV
monoinfected genotype 2/3 patients with undetectable HCV RNA
after 4 weeks of peginterferon alfa-2b plus ribavirin, 12 weeks
of therapy was as effective as 24 weeks of therapy in terms of
SVR rates. But there was a slight suggestion that the risk for
relapse could be a bit higher in the 12-week group. Here is link
to study article:
Peginterferon Alfa-2b and Ribavirin for 12 vs. 24 Weeks in HCV
...
www.natap.org/2005/HCV/062305_01.htm
Another consideration is long-term outcomes over the course of
many years. Although SVR rates appear the same with 24 or 48
weeks duration of therapy for patients in certain categories,
will this hold up 10-20 years in the future?
BACK TO ITALIAN COINFECTION STUDY
36 patients received 48 weeks of Pegasys + ribavirin therapy
(800-1200 mg/daily dosed by weight). Only 2 (11%) of the 19
patients concluding the 48-week treatment period relapsed.
Per-protocol analysis showed a significantly lower relapse rate
in the patient group receiving 48 weeks therapy compared to
those receiving only 24 weeks therapy (11% vs 40%, p=0.04),
"that was not observed in the ITT analysis 53% vs 40%" (stated
in the program book).
STUDY AIM: to optimize duration of treatment for chronic
hepatitis C in persons infected by HIV and HCV genotype 2 or 3.
STUDY DESIGN: Randomized prospective, open, controlled trial,
METHODS: The study enrolled patients on stable ART >6 weeks, CD4
count >200 & HIV RNA <10,000 c/ml, or ART naďve with CD4 count
>300. All patients received Pegasys at 180 mcg once a week by
subcutaneous injection in combination with ribavirin 10.6-13
mg/kg/day for 28 weeks. Ribavirin dose was based on weight: <65
kg, 800 mg daily; 66-85 kg, 1000 mg daily; >85 kg, 1200 mg
daily.
All patients showing negative HCV RNA at 24 weeks were
randomized at the 28th week to: stop treatment or continue
treatment for an additional 20 weeks for a total of 48 weeks
therapy. Of the128 coinfected patients who were enrolled in the
study 74 were HCV PCR negative after 24 weeks of therapy.
The incidence of relapses in patients who were HCV RNA negative
at end of treatment was the main outcome compared between the
two groups. 128 patients were enrolled. 46 patients (36%)
stopped treatment before 24 weeks: 20 (16%) because of adverse
events and 26 (20%) for intolerance. 30 of these 46 (65%) showed
HCV RNA negativity during treatment, but 14 out of 30 (47%)
relapsed after stopping treatment. 8 out of 82 patients (10%)
did not show negative HCV RNA at the end of the first 24 weeks
of treatment. THEN, 74 patients were randomized: 38 to stop
treatment and 36 to continue treatment for a total of 48 weeks.
15 (40%) of the patients who stopped at 24 weeks relapsed after
treatment withdrawal.
17 patients from the group that continued treatment prematurely
stopped therapy: 4 for serious adverse event (2 relapsed) and 13
for intolerance (11 relapsed). Only 2 (11%) of the 19 patients
concluding the 48-week treatment period relapsed.
ADVERSE EVENTS
Serious adverse events were reported in 40 (31%) of the 128
patients in weeks 0-24, and 8 (22%) of patients in weeks 28-48
of treatment. The overall SAE-related treatment withdrawal rate
was 18%: 12% (n=16) of the 128 patients during weeks 0-24, and
8% (n=3) in the 36 patients during weeks 28-48. This shows
patients probably got used to the side effects or were better
able to tolerate them after a while. Or the patients continuing
therapy had more incentive to continue.
During weeks 0-24 (n=128) there were 8 grade 3 neuropsyciatric
events (7/8) cases resolved with peginterferon and/or RBV dose
reduction, and 5 grade 4 cases. During weeks 28-48 there was 1
grade 3 and 1 grade 4 neuropsychiatric event. The grade 3 event
resolved with peginterferon and/or RBV dose reduction.
ANEMIA: There were 6 cases of grade 3 anemia (all
resolved with peginterferon and/orRBV dose reduction) and 1 case
of grade 4 anemia during weeks 0-24. During weeks 28-48 there
were 2 cases of grade 2 anemia (resolves with peginterferon
and/or RBV dose reduction) and 1 case of grade 4 anemia.
NEUTROPENIA: there were 10 cases of grade 3 neutropenia
(all resoleved with peginterferon and/or RBV dose reduction) and
1 case of grade 4 during weeks 0-24. During weeks 28-48 there
were 2 cases of grade 3 neuropenia (all resolved with peg and/or
RBV dose reduction) and no grade 4 cases.
THROMBOCYTOPENIA: there was 1 case of grade 3 (resolved
with peg and/or RBV dose reduction) and 2 cases of grade 4.
There were no cases during weeks 28-48.
There was 1 case of neuropathy reported, grade 4 during weeks
28-48.
The study apparently did not use adjunctive therapy such as EPO
for anemia or neutropenia.
|
| * |
| Treatment of
Genotype 4 HCV
Studies continue to yield conflicting data
on the treatment of genotype 4 HCV, which is the most prevalent
type in the Middle East and parts of Africa. While some have
shown that genotype 4 is resistant to treatment (like genotype
1), others suggest it may be easier to treat (like genotypes 2
and 3). In the July Journal of Viral Hepatitis, M.
Derbala and colleagues reported on a study of 61 patients with
chronic genotype 4 HCV in Egypt. Subjects received either
conventional interferon plus ribavirin or Peg-Intron plus
ribavirin. End-of-treatment response rates were 35% in the
conventional interferon group and 43% in the Peg-Intron group.
SVR rates were 26% and 33%, respectively – closer to those seen
for genotype 1 than for genotypes 2/3 in other studies. In
contrast to past research, however, end-of-treatment and
sustained response rates did not differ significantly between
conventional and pegylated interferon. The authors concluded
that, “the poor response of genotype 4 in Egypt (genotype 4a) to
different forms of interferons may be related to an intrinsic
resistance to the direct antiviral effect of interferon.”
In related news, S. Kamal and colleagues
reported on a study of treatment duration and viral kinetics in
patients with genotype 4 HCV in the June issue of Gut.
In this trial, 287 subjects were randomly assigned to received
Peg-Intron plus ribavirin for 24, 36, or 48 weeks. Using an
intent-to-treat analysis (all randomized patients were included
in the analysis), SVR rates were 29%, 66%, and 69%,
respectively. Subjects who went on to achieve SVR showed greater
antiviral efficacy and rapid viral load decline from baseline to
week 4. There was no significant difference in efficacy when
comparing 36 and 48 weeks of therapy, but the incidence of
adverse side effects was higher in the group treated longer. It
is unclear why SVR rates in Kamal’s study were about twice as
high as those obtained by Derbala, especially since both trials
were conducted in Egypt, and thus patients could be expected to
have similar demographic factors with respect to HCV variants.
http://www.hcvadvocate.org/news/newsRev/2005/HJR-2.12.html#3 |
European Union's
CHMP Adopts Positive Opinion for Shorter Course of
PEGINTRON(R) and REBETOL(R) Combination Therapy for Certain
Hepatitis C Patients with Genotype 1 and Low Viral Load
|
| |
| |
This press release was issued by
Schering-Plough.
KENILWORTH, N.J., July 29 /PRNewswire-FirstCall/ --
Schering-Plough Corporation (NYSE: SGP - News) today
reported that the Committee for Medicinal Products for Human
Use (CHMP) of the European Medicines Agency (EMEA) has
issued a positive opinion recommending approval of revised
dosing instructions which allow a shorter, 24-week course of
weight-based PEGINTRON (1.5 mcg/kg once weekly) and REBETOL
(800 - 1,200 mg) daily combination therapy among a subgroup
of patients with hepatitis C virus (HCV) genotype 1
infection and low viral load (< 600,000 IU/ml). A shorter
24-week course of therapy can be considered for these
patients who have achieved rapid virologic response, defined
as undetectable virus (HCV-RNA negative) at week 4 of
treatment that is maintained through week 24. A 92
percent sustained virologic response was achieved with 24
weeks of treatment among the 41 percent of patients who met
the criteria for early response.
PEGINTRON and REBETOL combination therapy was previously
approved in the EU for a 48-week course of therapy for all
patients with genotype 1 who exhibit virological response at
week 12. Approval of this shorter PEGINTRON and REBETOL
combination treatment regimen cuts by half the duration of
therapy for a subset of hepatitis C patients with genotype 1
and low viral load. This is the only treatment regimen
approved in the European Union (EU) for a 24-week course of
therapy in certain genotype 1 patients.
The CHMP recommendation serves as the basis for a European
Commission approval of this labeling change. A Commission
Decision will result in Marketing Authorization with unified
labeling that will be valid in the current EU 25 member
states as well as in Iceland and Norway.
"The important results of this clinical study with PEGINTRON
and REBETOL reflect the ongoing efforts of Schering-Plough
to define optimal dose and treatment schedules for specific
HCV patient groups," said Robert J. Spiegel, M.D., chief
medical officer and senior vice president of medical
affairs, Schering-Plough Research Institute.
Study Results
The recommended labeling change for PEGINTRON and REBETOL is
based on results of a clinical study involving 235 patients
with HCV genotype 1 and low viral load who received 24 weeks
of combination therapy with weight-based PEGINTRON (1.5
mcg/kg once weekly) and REBETOL (800 - 1,400 mg daily); only
two patients weighing >105 kg received the 1,400 mg dose).
In the study, 41 percent of patients (97/235) had
undetectable plasma HCV-RNA levels at week 4 and week 24 of
therapy. Patients in this subgroup achieved a 92 percent
(89/97) rate of sustained virological response (SVR). The
high sustained response rate in this group of patients was
identified in an interim analysis and prospectively
confirmed.
Genotype 1 virus is the most common worldwide, the most
difficult to treat successfully and accounts for about 70
percent of HCV infections among European patients overall,
varying by geography. For patients with HCV genotypes 2 or
3, the EU labeling for PEGINTRON recommends that all
patients be treated for 24 weeks. Patients infected with HCV
genotype 4 are considered harder to treat and generally 48
weeks of therapy is recommended.
About PEGINTRON and REBETOL Combination Therapy
PEGINTRON and REBETOL combination therapy for chronic
hepatitis C was approved in the European Union (EU) in March
2001. The recommended dose in the EU for combination therapy
is PEGINTRON 1.5 mcg/kg/once weekly plus REBETOL 800-1,200
mg daily, adjusted to body weight. PEGINTRON had previously
received centralized marketing authorization in the EU and
is marketed as a monotherapy in cases of intolerance or
contraindication to ribavirin for the treatment of adult
patients with chronic hepatitis C.
PEGINTRON, recombinant interferon alfa-2b linked to a 12,000
dalton polyethylene glycol (PEG) molecule, is a once-weekly
therapy dosed according to patient body weight that is
designed to achieve an effective balance between antiviral
activity and elimination half-life. REBETOL is an oral
formulation of ribavirin, a synthetic nucleoside analog with
broad-spectrum antiviral activity.
Chronic hepatitis C is estimated to affect more than 10
million people in major world markets, including 5 million
in Europe. It is a leading cause of chronic liver disease
and one of the most common reasons for liver transplant in
Europe.
Important Information Regarding U.S. Labeling for PEG-INTRON
and REBETOL
WARNING
Alpha interferons, including PEG-INTRON, cause or aggravate
fatal or life- threatening neuropsychiatric, autoimmune,
ischemic, and infectious disorders. Patients should be
monitored closely with periodic clinical and laboratory
evaluations. Patients with persistently severe or worsening
signs or symptoms of these conditions should be withdrawn
from therapy. In many but not all cases these disorders
resolve after stopping PEG-INTRON therapy.
Ribavirin causes hemolytic anemia. Anemia associated with
REBETOL therapy may exacerbate cardiac disease that has led
to fatal and nonfatal myocardial infarctions. Patients with
a history of significant or unstable cardiac disease should
not be treated with REBETOL. It is advised that complete
blood counts (CBC) be obtained at baseline and at weeks 2
and 4 of therapy or more frequently if clinically indicated.
REBETOL and combination REBETOL/PEG-INTRON therapy must not
be used by women, or male partners of women, who are or may
become pregnant during therapy and during the 6 months after
stopping therapy. REBETOL and combination REBETOL/PEG-INTRON
therapy should not be initiated until a report of a negative
pregnancy test has been obtained immediately prior to
initiation of therapy. Women of childbearing potential and
men must use effective contraception (at least two reliable
forms) during treatment and during the 6- month
post-treatment follow-up period. Significant teratogenic
and/or embryocidal effects have been demonstrated for
ribavirin in all animal species in which adequate studies
have been conducted. These effects occurred at doses as low
as one twentieth of the recommended human dose of REBETOL.
If pregnancy occurs in a patient or partner of a patient
during treatment or during the 6 months after treatment
stops, physicians are encouraged to report such cases by
calling (800) 727-7064.
PEG-INTRON
There are no new adverse events specific to PEG-INTRON as
compared to INTRONÂ A (interferon alfa-2b, recombinant) for
Injection, however, the incidence of some (e.g., injection
site reactions, fever, rigors, nausea) were higher. The most
common adverse events associated with PEG-INTRON were
"flu-like" symptoms, occurring in approximately 50% of
patients, which may decrease in severity as treatment
continues. Application site disorders were common (47%), but
all were mild (44%) or moderate (4%) and no patient
discontinued, and included injection site inflammation and
reaction (i.e., bruise, itchiness, irritation). Injection
site pain was reported in 2% of patients receiving PEG-INTRON.
Alopecia (thinning of the hair) is also often associated
with alpha interferons including PEG-INTRON.
Psychiatric adverse events, which include insomnia, were
common (57%) with PEG-INTRON, but similar to INTRON A (58%).
Depression was most common at 29%. Suicidal behavior
including ideation, suicidal attempts, and completed
suicides occurred in 1% of patients during or shortly after
completing treatment with PEG-INTRON.
PEG-INTRON/REBETOL is contraindicated in patients with
autoimmune hepatitis, decompensated liver disease, and in
patients with hemoglobinopathies (e.g., thalassemia major,
sickle-cell anemia).
The following serious or clinically significant adverse
events have been reported at a frequency less than 1% with
PEG-INTRON or interferon alpha: severe decreases in
neutrophil or platelet counts, hypothyroidism,
hyperglycemia, hypotension, arrhythmia, ulcerative and
hemorrhagic colitis, development or exacerbation of
autoimmune disorders including thyroiditis, RA, systemic
lupus erythematosus, psoriasis, pulmonary disorders (dyspnea,
pulmonary infiltrates, pneumonitis and pneumonia, some
resulting in patient deaths), urticaria, angioedema,
bronchoconstriction, anaphylaxis, retinal hemorrhages, and
cotton wool spots.
In the PEG-INTRON/REBETOL combination trial the incidence of
serious adverse events was 17% in the PEG-INTRON/REBETOL
groups compared to 14% in the INTRON A/REBETOL group. The
incidence of severe adverse events in the PEG-INTRON/REBETOL
combination therapy trial was 23% in the INTRON A/REBETOL
group and 31-34% in the PEG-INTRON/REBETOL groups. Dose
reductions due to adverse reactions occurred in 42% of
patients receiving PEG-INTRON (1.5 mcg/kg)/ REBETOL and in
34% of those receiving INTRON A/REBETOL.
REBETOL should not be used in patients with creatinine
clearance less than 50 mL/min.
Schering-Plough Corporation is a global science-based health
care company with leading prescription, consumer and animal
health products. Through internal research and
collaborations with partners, Schering-Plough discovers,
develops, manufactures and markets advanced drug therapies
to meet important medical needs. Schering-Plough's vision is
to earn the trust of the physicians, patients and customers
served by its more than 30,000 people around the world. The
company's Web site is www.schering-plough.com.
|
|
| |
| |
|
|
|
| |
|
|
| |
NATAP http://natap.org/
_______________________________________________
Peginterferon-α-2a
(40KD) and Ribavirin for 16 or 24 Weeks in Patients With Genotype 2 or 3
Chronic Hepatitis C
“…patients chronically
infected with HCV-2 (independent from pretreatment viremia) and those
infected with HCV-3 and a pretreatment HCV RNA level equal or below 800,000
IU/mL, who can achieve a rapid virologic response defined as HCV RNA below
600 IU/mL at week 4, can be treated for only 16 weeks with peginterferon-α-2a
and ribavirin without compromising the chances for a sustained virologic
response. The data of the present study are less conclusive for
HCV-3-infected patients with a pretreatment viremia above 800,000 IU/mL, who
achieve a rapid virologic response as well as for those patients who cannot
achieve a rapid virologic response…”
Gastroenterology
Volume 129, Issue 2, Pages 522-527 (August 2005)
Data of the present study were presented in part at the 55th Annual Meeting
of the American Association for the Study of Liver Diseases, October
29-November 2, 2004, Boston, Massachusetts.
Michael von Wagner⁎,
Miriam Huber‡, Thomas Berg§, Holger Hinrichsen‖,
Jens Rasenack¶, Tobias Heintges#, Alexandra Bergk§, Christine Bernsmeier‖,
Dieter Häussinger#, Eva Herrmann⁎,
Stefan Zeuzem*
ABSTRACT
Background & Aims: Standard therapy of patients with chronic hepatitis C
virus (HCV) infected with HCV genotype-2 or -3 is the combination of
pegylated interferon-α
and ribavirin for 24 weeks. Whether shorter treatment durations are possible
for these patients without compromising sustained virologic response rates
is unknown.
Methods: Patients chronically infected with HCV-2 (n = 39), HCV-2/3 (n = 1),
or HCV-3 (n = 113) were treated with peginterferon-α-2a
(180 μg/wk)
plus ribavirin 800-1200 mg/day. HCV RNA was quantitatively assessed after 4
weeks. Patients with a rapid virologic response (HCV RNA below 600 IU/mL)
were randomized for a total treatment duration of 16 (group A) or 24 weeks
(group B). All patients with HCV RNA ≥600 IU/mL at week 4 (group C) were
treated for 24 weeks. End-of-treatment and sustained virologic response were
assessed by qualitative RT-PCR (sensitivity 50 IU/mL).
Results:
Only 11 of 153 patients (7%) were allocated to group C. End-of-treatment
and sustained virologic response rates were 94% and 82%, (group A), 85% and
80% (group B), and 73% and 36% (group C), respectively.
In patients infected with genotype HCV-3 and high viral load (>800,000
IU/mL), a significant lower sustained virologic response rate was found than
in patients infected with HCV-3 and a viral load lower or equal to 800,000
IU/mL (59% vs 85%, respectively; P = .003).
Conclusions: In HCV-2 and -3 (low viral load)-infected patients who
have a rapid virologic response, treatment for 16 weeks with peginterferon-α-2a
and ribavirin is sufficient. In patients infected by HCV-3 (high viral
load), longer treatment may be necessary.
MORE RESULTS
Virologic Response According to HCV Genotype and Pretreatment Viremia
Sustained virologic response rates in genotype HCV-2-infected patients
were higher than in genotype HCV-3-infected patients (92% vs 73%,
respectively) and were not affected by pretreatment viremia. Genotype
HCV-3-infected patients with a baseline viremia above 800,000 IU/mL,
however, achieved a lower sustained virologic response rate compared with
patients with a baseline viremia equal or below 800,000 IU/mL (59% vs 85%,
respectively, P = .003).
No differences in sustained virologic response rates were observed between
treatment groups A and B for patients infected with genotype HCV-2. The
sustained virologic response rate of HCV-3-infected patients with a
pretreatment viremia equal or below 800,000 IU/mL was not compromised by a
16-week treatment duration (group A) compared with 24 weeks (group B)
(Figure 2). The sustained virologic response rate in HCV-3-infected patients
with a baseline viremia above 800,000 IU/mL was higher with 24 weeks of
combination therapy in group B than with 16 weeks treatment in group A (67%
vs 55%, respectively, P > .2) but did not reach statistical significance.
Characteristics of the Patients
This study was performed between January 2002 and March 2004 in 6 German
tertiary referral centers. According to the inclusion and exclusion
criteria, 153 patients were enrolled: 39 (26%) and 113 patients (74%) were
infected with genotypes HCV-2 and -3, respectively, whereas in 1 patient
(<1%), genotypes HCV-2 and -3 could not be differentiated.
Virologic and Biochemical Response
After 4 weeks treatment with peginterferon-α-2a
plus ribavirin, HCV RNA was below 600 IU/mL in 142 of 152 patients (93%).
This rapid virologic response was achieved by 37 of 38 patients (97%)
infected with genotype HCV-2 and by 103 of 112 patients (92%) infected with
genotype HCV-3 (P > 0.2). These patients and 1 patient who was negative at
week 2 with a missing HCV RNA result at week 4 were randomized to groups A
(n = 71) and B (n = 71). Patients with HCV RNA ≥600 IU/mL at week 4,
including 1 patient with missing HCV RNA results at weeks 2 and 4, were
allocated to group C (n = 11).
An overall intent-to-treat virologic response at the end of therapy was
achieved in 135 of 153 patients (88%) and a sustained virologic response in
119 of 153 patients (78%). Virologic response rates were similar in patients
randomized to either 16 weeks (group A) or 24 weeks of combination therapy
(group B). In groups A and B, 67 of 71 patients (94%) and 60 of 71 patients
(85%) achieved an end of treatment response and 58 of 71 patients (82%) and
57 of 71 patients (80%) sustained a virologic response, respectively. This
corresponds to a difference in sustained virologic response between groups A
and B of at most 11.5% (97.5% 1-sided confidence interval). The sustained
virologic response rate in patients without a rapid virologic response who
were treated for 24 weeks (group C), however, was lower than in group B (36%
vs 81%, respectively, P = .005), whereas the end-of-treatment response rate
was only slightly lower in group C (72% vs 84%, respectively, P = ns).
Sustained biochemical response rates in groups A, B, and C were 89%, 87%,
and 67%, respectively. Sustained biochemical response was observed in 110 of
115 sustained virologic responders (96%), whereas 5 sustained virologic
responders did not show a biochemical response with ALT levels ranging up to
2.95 times the upper limit of normal. Each of the 5 subjects was infected
with HCV-2.
Other Predictors of Response
From multivariate logistic regression analysis of all patients, genotype
HCV-2, low viral load, and low
γ-glutamyltransferase
(GGT) value were independent factors of sustained virologic response. When
the analysis was based on patients infected with genotype HCV-3 only,
baseline viral load (P = .01) and GGT value (P = .02) remained as
independent negative predictors for sustained virologic response. Fibrosis
score and GGT were slightly higher in patients without rapid virologic
response (group C) compared with patients with rapid virologic response
(groups A and B); however, differences did not reach statistical
significance.
Adverse Events and Dose Modifications
Seven serious adverse events were reported by the 153 patients enrolled into
this study (bacterial infection, carcinoma, diverticulitis, paranoid
reaction, pneumonia, pregnancy of partner, tuberculosis). Only 1 patient
(group B) discontinued therapy because of an adverse event (intravenous drug
abuse). In addition, 8 patients (1 in group A, 5 in group B, and 2 in group
C) prematurely withdrew from therapy for nonsafety reasons. Adverse events
were typical of those previously reported with combination therapy with (pegylated)
interferon and ribavirin. In general, the frequency of adverse events was
lower in the 16-week treatment group (group A) compared with the 24-week
treatment groups (groups B and C).
Twenty-two of 153 patients (14%) and 17 of 153 patients (11%) required dose
reduction or treatment interruption because of adverse events of
peginterferon-α
and ribavirin, respectively. Neutropenia (3%) and anemia (6%) were the most
common adverse events leading to dose modification.
AUTHOR DISCUSSION
Discussion
return to Article Outline
Previous studies have convincingly shown that combination therapy with
pegylated interferon-α
plus ribavirin for 24 weeks achieves similar sustained virologic response
rates in patients infected with genotype HCV-2 or -3 as combination therapy
for 48 weeks.9,10 Subsequent approaches are currently investigating whether
either the dose for peginterferons and/or the duration of therapy can be
reduced without compromising sustained virologic response rates. In the
present study, patients infected with genotype HCV-2 or -3 who achieved a
rapid virologic response were randomized to either the standard treatment
duration of 24 weeks or a shorter duration of 16 weeks. Patients received a
standard dose of peginterferon-α-2a
(180 μg
once per week) and weight-based ribavirin doses (800-1200 mg/day).
The mechanism of action of ribavirin in the treatment of patients with
chronic hepatitis C remains unknown. Ribavirin in addition to (pegylated)
interferon enhances the virologic response and more importantly reduces
relapse rates in patients who achieve an end-of-treatment virologic
response. Therefore, it was decided to use a high dose of ribavirin
(800-1200 mg/day according to body weight) in the present study to avoid
virologic relapse, particularly in patients randomized to 16 weeks of
combination therapy. During the course of the present study, Hadziyannis et
al reported that 24 weeks of combination therapy with a flat ribavirin dose
of 800 mg/day is sufficient in patients infected with genotype HCV-2 or -3.9
Whether 800 mg of ribavirin per day is sufficient for treatment durations
shorter than 24 weeks will be answered by an international multicenter trial
(ACCELERATE).
The present study demonstrates that 16 weeks of therapy with peginterferon-α-2a
plus weight-based ribavirin is sufficient for patients chronically infected
with genotype HCV-2 or -3 who achieve a rapid virologic response at week 4.
Patients treated for 16 weeks also tended to report adverse events less
frequently than patients treated for 24 weeks. The rapid virologic response
was independent from baseline HCV RNA levels. Seven percent of mainly
HCV-3-infected patients could not achieve a rapid virologic response at week
4 and were treated according to current guidelines for 24 weeks. The
sustained virologic response rate, however, was significantly impaired in
these patients.
Several studies have shown that an early virologic response predicts
sustained virologic response.12-14 A less than 2 log10 decline of HCV RNA
within the initial 12 weeks of therapy has been generally accepted as an
early stopping algorithm with a negative predictive value of 98%-100%.12,15
However, this algorithm is only useful in genotype HCV-1-infected patients,
and less than 2% of patients infected with genotype HCV-2 or -3 are unable
to meet this criterion.
In the present study, the sustained virologic response rate was higher in
patients infected with HCV-2 than in those infected with HCV-3, supporting
the concept that virologic response rates should be presented according to
single genotypes rather than to a combination of genotypes. The rapid and
the sustained virologic response rates in HCV-2-infected patients were above
90%, suggesting that neither quantification of HCV RNA before starting nor
during therapy is required to define the duration of treatment in these
patients.
In HCV-3-infected patients, however, a different algorithm may be required.
Within the group of chronically HCV-3-infected patients treated for 16
weeks, a higher virologic relapse rate was observed in patients with a
baseline HCV RNA concentration of more than 800,000 IU/mL, and, in this
subgroup, the sustained virologic response rate was lower for the 16-week
compared with the 24-week treatment group. Quantification of HCV RNA at
baseline and at early time points during therapy (eg, at 4 weeks as in the
present study) may allow to individualize treatment duration in these
patients. However, further detailed analyses of baseline parameters, initial
viral decline, and sustained virologic outcome are required to define the
optimal duration of therapy in these patients. It is also conceivable that a
small subgroup of HCV-3-infected patients can be identified according to
baseline parameters and/or slower early decline of HCV RNA, who may benefit
from longer than 24 weeks of therapy.
The concept of shorter combination therapy with pegylated interferon and
ribavirin in patients chronically infected with genotype HCV-2 or -3 is
supported by 2 other trials. In an uncontrolled study, Dalgard et al
determined the efficacy of 14 weeks combination treatment with peginterferon-α-2b
(1.5 μg/kg
once per week) plus ribavirin (800-1400 mg according to body weight) in
HCV-2- or HCV-3-infected patients who achieved an early virologic response,
defined as undetectable HCV RNA at weeks 4 and 8. Ninety-five of 122
patients (78%) fulfilled these early virologic response criteria, and 85 of
the 95 patients achieved a sustained virologic response.16 Mangia et al
observed a sustained virologic response rate of 89% in mainly HCV-2-infected
patients who received peginterferon-α-2b
(1.0 μg/kg
once per week) plus ribavirin (1000-1200 mg according to body weight) for a
total duration of 12 weeks if they were HCV RNA negative at week 4.17
In conclusion, patients chronically infected with HCV-2 (independent from
pretreatment viremia) and those infected with HCV-3 and a pretreatment HCV
RNA level equal or below 800,000 IU/mL, who can achieve a rapid virologic
response defined as HCV RNA below 600 IU/mL at week 4, can be treated for
only 16 weeks with peginterferon-α-2a
and ribavirin without compromising the chances for a sustained virologic
response. The data of the present study are less conclusive for
HCV-3-infected patients with a pretreatment viremia above 800,000 IU/mL, who
achieve a rapid virologic response as well as for those patients who cannot
achieve a rapid virologic response. Additional trials are required to
optimize treatment duration in these patients.
Etanercept Treatment to Slow Fibrosis Progression Shows No
Histological or Biochemical Improvement in Chronic HCV Genotype 1
Nonresponders to Peginterferon/Ribavirin
There is no
established treatment that prevents the progression of fibrosis in patients
who fail interferon-based combination antiviral treatment. Tumor necrosis
factor (TNF) alpha is an important mediator in the development of fibrosis,
thereby implicating a possible role for the inhibition of TNF alpha (etanercept)
in the treatment of
chronic Hepatitis C (CHC).
The aim of the current
study was to asses the efficacy of etanercept treatment on the
necroinflammatory and fibrotic change in patients with CHC infection,
genotype 1,
nonresponders to interferon-based combination antiviral treatment.
Ten patients with CHC
genotype 1, nonresponders to antiviral treatment with pegylated interferon
and ribavirin, were enrolled. Active HCV infection was documented by a
positive HCV RNA by PCR (Cobas Amplicor).
Etanercept was
administered for 24 weeks duration at a dose of 25 mg subcutaneously twice
weekly.
A
liver biopsy prior and post etanercept treatment was obtained and
reviewed by an independent pathologist using the METAVIR score.
Patients were followed
monthly for evaluation of side effects and liver related blood tests for a
period of 32 weeks.
Results
·
Of the ten
patients enrolled, 50% (5/10) were
women
of mean age 50 years, and 50% (5/10) were men of mean age 40 years.
·
One patient
was withdrawn due to abnormal elevation in
serum
alanine aminotransferase (ALT); one patient was lost to follow up.
·
Eight post
treatment liver biopsies were evaluated;
·
12% (1/8)
had an improvement in the stage of
fibrosis, 88% (7/8) had no change in fibrosis.
·
The mean
baseline platelet count (PLT) and ALT level were (177,000 MCL/120
U/L) respectively.
·
None of the
differences between platelet count and ALT levels at baseline and at follow
up achieved statistical significance (p >0.05).
·
Even though
one patient had an improvement in the stage of biopsy after treatment, these
results did not reach statistical significance.
Conclusion
This is the first analysis of etanercept treatment for inhibition of hepatic
fibrosis in patients with chronic HCV, genotype 1, nonresponders to
combination antiviral therapy. There was no significant histological or
biochemical improvement.
06/01-05
Reference
R J Marrero and
others. A Pilot Study Of Etanercept Treatment for Inhibition of Fibrotic
Progression in Chronic Hepatitis C Infection. Abstract S1557. DDW 2005. May
14-18, 2005. Chicago, IL.
Predictors of Treatment Failure in Patients with Hepatitis
C Genotypes 2 or 3
Sustained
virologic response (SVR)
following antiviral therapy in
genotype 2 and 3 HCV patients is accomplished in most cases,
although a small number of patients fail to respond (NR) or relapse (Rel)
after discontinuation of therapy.
Understanding predictors
of treatment failure in this “highly treatment-sensitive” population may
allow the development of novel therapeutic approaches. The aim of the
present study, presented at DDW 2005, was to assess predictors of treatment
failure (NR and Rel) in patients with HCV genotypes 2 and 3.
All treatment-naive
Caucasian patients with chronic HCV genotype 2 and 3 infection at The
Cleveland Clinic Foundation between 2001 and 2004 were identified (59
patients).
Those who received at
least one dose of
peginterferon (fixed dose PEG 2a [Pegasys] or
weight-based
PEG 2b) [PegIntron] and ribavirin were included whereas
liver transplant recipients, co-infected hepatitis B and/or HIV
patients were excluded.
Identification of
variables associated with treatment failure was done by comparing variables
of interest between SVR and non-SVR groups using Wilcoxon test for
continuous variables and Chi-Square for categorical variables.
Individual logistic
regression was done to obtain Odds Ratios (OR).
Multivariate modeling was
done to identify independent predictors of treatment failure.
Results
·
Overall,
14/59 (24%) patients failed to achieve SVR (7 NR and 7 Rel).
·
Male gender,
history of alcohol abuse, non-weight-based therapy, and presence of
histologically advanced disease were identified as predictors of failure to
achieve SVR by univariate analysis.
·
Multivariable logistic regression analysis model (whole model p=0.0006)
identified history of alcohol abuse and non-weight-based treatment as
significant independent predictors of failure to achieve SVR in these
patients.
·
More
patients with genotype 3 failed to achieve SVR, although not statistically
significant.
Conclusions
The authors conclude, “A
subgroup of Caucasian HCV patients with genotype 2 and 3 infections less
likely to achieve SVR may potentially benefit from weight-based
peginterferon therapy.”
“Excessive alcohol intake
appears to contribute to treatment failure in patients infected with HCV
genotype 2 or 3 infections”
“Novel therapeutic
approaches such as longer duration of treatment may lead to better outcomes
in this population.”
06-01-05
Reference
A M Qadri and
others. Predictors Of Treatment Failure in Patients With Hepatitis C
Genotypes 2 or 3 Infections. Abstract S1565. DDW 2005. May 14-18, 2005.
Chicago, IL.
Enrollment Completed for Phase IIb Trial of Valopicitabine
plus Pegasys Combination Therapy for HCV Genotype 1 Patients Non-responsive
to Peginterferon/Ribavirin
Idenix Pharmaceuticals
announced that it has completed enrollment of its phase IIb clinical trial
of
valopicitabine (NM-283) with more than 170 treatment refractory
hepatitis C genotype 1 patients. The company believes that this
is the first time an antiviral experimental drug that acts directly against
the hepatitis C virus has reached this stage of clinical testing.
"Today, there are very
limited treatment options for treatment refractory hepatitis C patients, or
patients that have failed prior treatment with existing hepatitis C
therapies. Among this patient population, approximately 10 percent respond
to
re-treatment with the current standard of care,
pegylated
interferon plus ribavirin," said Jean-Pierre Sommadossi, Ph.D.,
Idenix's chairman and chief executive officer. "Since standard treatment is
only effective in about half of genotype 1 patients, it is estimated that
30,000 - 40,000 patients in the US will fail treatment each year. Our
development program for valopicitabine is seeking first to address this
major, growing, unmet need."
Phase IIb Trial Design
Valopicitabine is being
evaluated in a phase IIb clinical trial in patients who have previously
failed treatment with pegylated interferon plus ribavirin. This six-month
head-to-head trial, comparing the
combination of valopicitabine plus Pegasys to
ribavirin plus Pegasys, is evaluating more than 170 hepatitis C
genotype 1 patients who have previously failed at least 3 months of
treatment with pegylated interferon plus ribavirin. Idenix expects to report
initial clinical data from this phase IIb trial in the fall of 2005.
Currently, the company anticipates initiating a phase III clinical trial in
this patient population in the first half of 2006.
About Valopicitabine
(NM283)
Valopicitabine (NM283) is
an oral, novel nucleoside analog that was co- discovered by Idenix and the
University of Cagliari through a cooperative laboratory agreement under the
direction of Dr. Paolo LaColla, Director of the Department of Biomedical
Sciences and Technologies of the University. Valopicitabine (NM283) is
currently being developed in combination with pegylated interferon for use
in both HCV treatment refractory and HCV treatment-naive patient
populations.
About Hepatitis C
There are approximately
170 million people worldwide with chronic hepatitis C virus (HCV) infection,
of which approximately 2.7 million are in the United States. Chronic HCV
infection accounts for 40 percent of end-stage
cirrhosis, 60 percent of
liver cancer and 30 to 40 percent of
liver transplants in the United States and other industrialized
countries.
Responses to current
treatment options are frequently inadequate due to the inability of some
patients to tolerate these treatments and by their limited effectiveness,
particularly in patients infected with HCV genotype 1. The genotype 1 strain
of HCV is the most treatment-resistant HCV genotype and is estimated to
cause more than 70 percent of the reported cases of hepatitis C in the US
and Japan, and more than 65% of the reported cases of hepatitis C in Western
Europe.
About Idenix
Idenix
Pharmaceuticals is a biopharmaceutical company engaged in the discovery,
development and commercialization of drugs for the treatment of human viral
and other infectious diseases. Idenix's current focus is on the treatment of
infections caused by hepatitis B virus, hepatitis C virus and human
immunodeficiency virus (HIV). Idenix's headquarters are located in
Cambridge, Massachusetts. The company also has drug discovery and
development operations in Montpellier, France and drug discovery operations
in Cagliari, Italy. For further information about Idenix, please visit
http://www.idenix.com.
More Articles on Valopicitabine (NM-283) on HIV and Hepatitis.com
Articles
on Other Anti-HCV Experimental Therapies
06/03/05
Source
Idenix
Pharmaceuticals. Idenix Pharmaceuticals Completes
Enrollment of Valopicitabine (NM283) Phase IIb Trial in Treatment-refractory
Hepatitis C Genotype 1 Patients. Press Release. May 31, 2005.
|
