NEJM Publishes Results of Trial Comparing Pegasys Plus Ribavirin to
Rebetron for Chronic Hepatitis C

http://www.hivandhepatitis.com/hep_c/news/092702a.html

By Ronald Baker, PhD

The double combination of Pegasys (pegylated interferon alfa-2a)
plus ribavirin provides a considerable clinical advantage over
Rebetron (standard interferon alfa-2b plus ribavirin*) for the
treatment of chronic hepatitis C, according to results of a study
published today (9/26/02) in the New England Journal of Medicine
(NEJM).

The NEJM article outlines study results first presented at Digestive
Disease Week 2001 in Atlanta, GA (April 2001). This randomized,
controlled clinical trial was conducted in 81 centers worldwide from
February 1999 to April 2001 and involved 1,121 patients with chronic
hepatitis C.

The study results show that once-weekly Pegasys plus ribavirin is
well tolerated and produces significant improvements in sustained
virological response (SVR) compared with Rebetron (interferon
alfa-2b plus ribavirin) or Pegasys monotherapy in patients with
chronic hepatitis C.
Although the preliminary results of this study have been known since
April 2001, publication of the study in the NEJM gives more weight
to the outcomes and conclusions drawn by the investigators and
ensures careful scrutiny by peer reviewers.

Highlights of Study Outcome
The authors note that Pegasys plus ribavirin significantly enhanced
the sustained virological responses (SVR), defined as the absence of
detectable HCV RNA 24 weeks after cessation of therapy, regardless
of viral genotype or viral load, when compared to Rebetron. Below
are the outcomes for specific patient populations (Table 1):
"Significantly higher" overall SVR of 56% for Pegasys/ribavirin
compared to 44% with interferon alfa-2b/ ribavirin (Rebetron) and
29% for Pegasys alone;

SVR of 46% for genotype 1 patients (most difficult-to-treat patient
population) using Pegasys/ribavirin compared to 36% for Rebetron
group 21% for Pegasys plus placebo;

For genotype 1 patients and high HCV levels (>2 million copies per
milliliter), there was a substantial increase in SVR of 41% among
patients treated with Pegasys/ribavirin versus 33% in the Rebetron
group and 13% for Pegasys plus placebo;

Patients with genotypes 2/3 using Pegasys/ribavirin obtained an SVR
of 76% versus 61% with the Rebetron-treated group and 45% for
Pegasys plus placebo;

For patients with genotype 4, the SVR were 77%, 36% and 44%,
respectively.

Patients with cirrhosis using Pegasys/ribavirin had an SVR of 43%
compared to 33% with Rebetron-treated patients;

Three factors independently and significantly increased the odds of
achieving a sustained virological response: HCV non-1 genotype, 40
years of age or less and body weight less than 75 kg; and

The overall safety profiles of the treatment regimens were similar.

Table 1. Sustained virological response as a function of HCV
genotype and HCV genotype plus base-line HCV RNA.


VariablePeginterferon alfa-2a + Ribavirin
(n=453)Interferon alfa-2b
+ Ribavirin
(n=444)Peginterferon alfa-2a + Placebo (n=224)
no. (%)
HCV Genotype
All patients255/453 (56)*197/444 (44)66/224 (29)
Genotype 1138/298 (46)†103/285 (36)30/145 (21)
Genotypes 2, 3106/140 (76)‡ 88/145 (61)31/69 (45)
Genotype 410/13 (77)§4/11 (36)4/9 (44)
Base-line HCV RNA
£ 2 ´ 106 copies/mL [109 copies/L]99/159 (62)║78/150
(52)32/69 (46)
>2 ´ 106 copies/mL [109 copies/L]156/293 (53)¶119/292
(41)34/155 (22)
HCV Genotype and Base-line HCV RNA
Genotype 1
£ 2 ´ 106 copies/mL [109 copies/L]64/115 (56) 40/94
(43)17/44 (39)
>2 ´ 106 copies/mL [109 copies/L]74/182 (41)63/189
(33)13/101 (13)
Missing12-
Genotype 2 and 3
£ 2 ´ 106 copies/mL [109 copies/L]30/37 (81) 34/52
(65)11/19 (58)
>2 ´ 106 copies/mL [109 copies/L]76/103 (74) 54/93
(58)20/50 (40)
Histological Diagnosis
Cirrhosis24/56 (43)18/54 (33)7/34 (21)

Fried and others. NEJM 2002; 347(13).
Background
Chronic hepatitis C historically is a difficult to treat condition.
However, the development of the pegylated interferons has
significantly improved treatment response rates, especially when
used in combination therapy with ribavirin.

Treatment with Pegasys (peginterferon alfa-2a) alone produces
significantly higher sustained virologic responses (SVR) than
treatment with Roferon (standard interferon alfa-2a) alone in
patients with chronic hepatitis C virus (HCV) infection.

The current study compared the efficacy and safety of Pegasys plus
ribavirin, Rebetron (standard interferon alfa-2b plus ribavirin),
and Pegasys alone in the initial treatment of chronic hepatitis C.

Study Objectives
The primary objectives of the this study were to compare the
efficacy and safety of peginterferon alfa-2a (Pegasys) plus
ribavirin, interferon alfa-2b plus ribavirin (Rebetron), and
peginterferon alfa-2a alone in the initial treatment of chronic
hepatitis C;

Inclusion Criteria
Treatment-naïve (no previous interferon or ribavirin therapy)
Male or female patients greater than or equal to 18 years of age
Serologically-proven chronic hepatitis C
HCV RNA level greater than or equal to 2000 copies
Persistently abnormal serum alanine aminotransferase (ALT) levels
Liver biopsy consistent with chronic hepatitis C

Exclusion Criteria
neutropenia
thrombocytopenia
Anemia
HIV infection
Decompensated liver disease
Abnormal serum creatinine
Existing severe depression or other psychiatric disease
Significant comorbid medical condition
Alcohol or drug dependance within one year of study entry

Study Design
In this randomized, controlled clinical trial, 1121 patients were
randomly assigned in a 2:1:2 ratio to receive subcutaneous,
once-weekly injections of 180 micrograms peginterferon alfa-2a
(Pegasys) plus ribavirin or placebo, or subcutaneous, thrice-weekly
injections of 3 MIU interferon alfa-2b plus ribavirin (Rebetron) for
48 weeks.
Randomization was stratified by country and HCV genotype (1 and
non-1). Participants were followed for 24 weeks after cessation of
therapy. The sponsor, investigators and patients who received
peginterferon alfa-2a were blinded to who received ribavirin or
placebo. Ribavirin was given orally at a dose of 1000 or 1200 mg per
day depending upon body weight (£ or >75 kg, respectively).
Efficacy Assessment
The primary efficacy end point was sustained virological response
(SVR), defined as undetectable HCV RNA measured by PCR (Cobas
Amplicor HCV [version 2.0], lower limit of detection of 100 copies
[50 international units] per milliliter) at the end of follow-up.
For patients with at least 20 weeks of follow-up, the last observed
HCV RNA level was used in efficacy assessments. All others with
shorter duration of follow-up were considered nonresponders to
treatment.
Predictive Value of Early Virological Response
By week twelve, 86 percent of patients treated with the
peginterferon alfa-2a plus ribavirin had achieved a virological
response, defined as a 2-log10 decrease from base-line HCV RNA
levels (97/390), or undetectable serum HCV RNA (293/390) (Table 2).

The absence of early virological response was not associated with
early treatment discontinuations or dose modifications. Of those
with early virological response, 65 percent subsequently achieved
sustained virological response. Those with undetectable HCV RNA by
week 12 were more likely to achieve sustained virological response
compared to those who had only a two-log decrease in HCV RNA. In
contrast, among the 63 patients who did not have an early
virological response, only two achieved sustained virological
response, resulting in a negative predictive value of 97 percent.
Safety
Most adverse events in all treatment groups were those commonly
associated with interferon-based treatment (Table 2). A lower
incidence of 'influenza-like' symptoms, such as pyrexia, myalgia and
rigors, was observed in patients treated with peginterferon alfa-2a
plus ribavirin or placebo than in those treated with interferon
alfa?2b plus ribavirin.
While few patients had a history of depression or active depression
at baseline, a lower incidence of depression was seen in patients
treated with peginterferon alfa-2a plus ribavirin or placebo than in
those treated with interferon alfa-2b plus ribavirin (20 and 22
percent vs. 30 percent).
Three patients died after end of treatment, one in the interferon
alfa?2b plus ribavirin group (hypertensive heart disease) and two in
the peginterferon alfa-2a plus placebo group (drowning and malignant
hepatic neoplasm). None of the deaths was considered related to
treatment.

Table 2. Incidence of discontinuation, dose modification, or adverse
events.

Variable no. (%)Peginterferon alfa-2a
+ RibavirinInterferon alfa-2b
+ RibavirinPeginterferon alfa-2a
+ Placebo
Discontinuation*
Patients who withdrew during week 1 to week 48100 (22)140
(32)72 (32)
Insufficient response (n)345949
Adverse event324313
Laboratory abnormality†1242
Refused treatment15225
Violation of entry criteria020
Failure to return573
Other violation230
Patients who withdrew during week 49 to week 7219 (4)14 (3)6
(3)
Dose modification‡§Peginterferon alfa-2a Ribavirin Interferon
alfa-2b Ribavirin Peginterferon alfa-2a Placebo
Adverse event48 (11) 95 (21)47 (11) 97 (22)14 (6)39 (17)
Laboratory abnormality111 (25) 108 (24)36 (8) 84 (19)54 (24) 9
(4)
Anemia4 (1) 99 (22)13 (3) 83 (19)0 (<1)8 (4)
Neutropenia91 (20) 6 (1)24 (5) 1 (<1)38 (17)0 (<1)
Thrombocytopenia18 (4) 2 (<1)1 (<1)0 (<1)14 (6) 1 (<1)
Adverse events‡║
Fatigue¶ 242(54)244 (55)95 (44)
Headache ¶ 211 (47)230 (52)115 (52)
Pyrexia¶195 (43)247 (56)85 (38)
Myalgia¶189 (42)220 (50)94 (42)
Insomnia168 (37)174 (39)52 (23)
Nausea130 (29)145 (33)58 (26)
Alopecia128 (28)151 (34)48 (22)
Arthralgia121 (27)112 (25)64 (29)
Irritability109 (24)123 (28)56 (25)
Rigors¶106 (24)157 (35)52 (23)
Pruritus101 (22)88 (20)41 (18)
Depression 100 (22)134 (30)45 (20)
Appetite decreased 96 (21)98 (22)24 (11)
Dermatitis 95 (21)80 (18)29 (13)

Fried and others. NEJM 2002; 347(13).

Study Implications
Pegasys (peginterferon alfa-2a) plus ribavirin was significantly
more effective than Rebetron (standard interferon alfa-2b plus
ribavirin) or Pegasys alone for the treatment of chronic hepatitis
C. Overall, the sustained virological response was similar to that
reported for PEG_Intron (peginterferon alfa-2b plus ribavirin)
(Manns. Lancet 2001).

In the current study, improved efficacy was seen with subgroups of
patients generally considered to have treatment-resistant
characteristics. In particular, patients across all HCV genotypes
and those with high base-line HCV RNA levels (>2 million copies per
milliliter) had higher sustained virological responses when treated
with Pegasys plus ribavirin than those treated with interferon
therapy.
For patients considered to have the most treatment-resistant
disease, HCV genotype 1 and high base-line viral levels, there was a
substantial increase in sustained virological response when treated
with peginterferon alfa-2a plus ribavirin, compared with those
treated with interferon plus ribavirin.
Early prediction of virological response to interferon-based therapy
can help identify patients who are unlikely to achieve a sustained
virological response, and allow clinicians the option to discontinue
treatment, saving patients the side effects and cost of additional
therapy; or patients with the best chance of achieving sustained
virological response, which may encourage patient adherence to
therapy.
Therefore, the observed predictive values of early virological
response may serve as useful prognostic and therapeutic tools for
clinicians. In the current study, absence of an early virological
response to peginterferon alfa-2a plus ribavirin by week 12 was
highly predictive of not achieving sustained virological response
(97 percent).
The incremental benefit of continuing therapy beyond 12 weeks for
those patients who have not had an early virological response must
be considered for each patient, individually. The positive
predictive value for sustained virological response (65 percent in
this study) by week 12 may be clinically useful by providing the
opportunity for physicians and patients to judge the likelihood of
ultimately achieving sustained virological response.
Several adverse events typically associated with use of interferon
(including influenza-like symptoms and depression) occurred less
frequently with Pegasys, alone or in combination with ribavirin,
than with rebetron. This is a particularly important observation
demonstrating that superior efficacy can be achieved with PEgasys
plus ribavirin without commensurate increases in those adverse
events most commonly associated with interferon-based therapies.
Pegasys monotherapy was generally better tolerated than the
ribavirin-containing regimens. As is usual with interferon-based
therapy, reductions in neutrophil and platelet counts occurred with
all treatments. Although these decreases were higher in patients
treated with PEgasys plus ribavirin than in those treated with
interferon alfa-2b plus ribavirin, they did not appear to be
associated with serious consequences and were effectively managed by
dose modifications.
Interestingly, for those patients treated with Pegasys plus
ribavirin who had an early virological response, completion of
therapy with dose reductions was not associated with a significant
decrease in efficacy.
Pegasys offers significantly enhanced sustained virological
responses in all patients (regardless of HCV genotype or viral load)
and a once-weekly dosing schedule, without compromising safety. The
ability to use HCV RNA levels at week 12 to predict the absence of
sustained virological response will be a useful clinical tool.
"These data are important because we know that for certain patients,
we can use a lower dose of therapy and cut the treatment duration by
half without sacrificing efficacy," said Donald Jensen, MD, a US
investigator in the trial and director of Hepatology at
Rush-Presbyterian-St. Luke's Medical Center in Chicago.

"Early prediction of virological response is a valuable tool for
physicians," said Dr. Fried. "It can help identify who is likely to
succeed with this treatment. Importantly, it can also help
clinicians to determine whether to discontinue therapy for those not
responding, saving patients the side effects and cost of additional
therapy," he said. Dr. Fried cautioned that this must be considered
on an individual patient basis.
The results of this study show that combination therapy with Pegasys
plus ribavirin provides a considerable clinical advance over
Rebetron.

Editor's Note: Since the completion of this study, preliminary
results of a Phase III trial of Pegasys plus ribavirin were
presented at the 37th EASL (April 2002, Madrid). The results suggest
an even higher SVR in patients treated with Pegasys/ribavirin
compared to Rebetron than shown in the current study.
Pegasys has been approved in 47 countries, including the European
Union. Pegasys has also been submitted for review by regulatory
authorities in the US and Roche expects approval for Pegasys
monotherapy and for Pegasys/ribavirin combination therapy before the
end of 2002. RB
9/27/02

References
MW Fried and others. Peginterferon Alfa-2a plus Ribavirin for
Chronic Hepatitis C Virus Infection. The New England Journal of
Medicine 2002; 347(13): 975-982. September 26, 2002.

Adherence in HCV Therapy



Adherence to combination therapy enhances
sustained response in genotype-1-infected
patients with chronic hepatitis C

In the current issue if Gastroenterology John
McHutchison and colleagues reported an analysis
of a group of studies, and the primary aim of
this analysis was to evaluate the effect of
adherence on sustained response rates to
combination therapy (interferon -2b or
peginterferon -2b plus ribavirin) in patients
with chronic hepatitis C. In short, the results
showed that >80% adherence resulted in 25%
better response rates for genotype 1, the
hardest to treat patient group. For genotype 2
patients they did not see a significant
improvement associated with better adherence.
The message is that adherence in HCV therapy
improves response rates just as in HIV. Below in
this article there is a discussion of methods to
improve adherence that may be useful in treating
HCV. But unlike in HIV there are few programs in
place to address these needs.

The main reasons for not achieving the adherence
goals (80/80/80) were adverse events to therapy
in >75% of the patients. In the remaining
patients, failure to attend scheduled
appointments, withdrawal of consent, and
nonadherence in the absence of apparent side
effects were the other reasons for not achieving
adherence targets in this study.

A preliminary data analysis presented at
hepatitis science conferences from Pegasys plus
ribavirin studies also show appreciable
improvements in response with >80% adherence. In
genotype 1 patients who achieved a viral
response by week 12, 65% who were >80% adherent
achieved a sustained response vs a 46% sustained
response for patients who were <80% adherent.
The preliminary findings suggest patients in
this study who had a viral response by week 12
and dose reduced still had a good sustained
response rate. Further study is needed to
confirm the effects of dose reduction, and if
dose reduction during the first 12 weeks is more
harmful than after 12 weeks. Here is link to
full report of this study:
http://www.natap.org/2001/aasld2/day6h.htm

In all, 1010 patients treated with interferon
a-2b (Schering-Plough) and ribavirin and 511
patients treated with peginterferon a-2b
(PEG-Intron; Schering) plus ribavirin were
considered in this analysis. These subgroups of
patients evaluated in the aforementioned studies
had been randomized to receive either interferon
a-2b 3 times a week (for 24 or 48 weeks) in
combination with daily ribavirin or,
alternatively, peginterferon a-2b at a dose of
1.5 µg/kg per week subcutaneously as a single
injection with ribavirin 800 mg daily for 48
weeks. These patient subgroups were selected
because they were those that received the most
effective regimens in these respective trials.
Data from a separate monotherapy trial of 304
patients treated with peginterferon a-2b, 1.5
µg/kg per week, and 303 patients who received
interferon a-2b 3 times a week for 48 weeks were
also analyzed to evaluate the effect of
adherence on response in this trial.

For this analysis, the amount of each drug
administered to a patient was obtained from drug
dispensing/return records and patient dosing
diaries. Patients receiving combination therapy
were divided into 2 groups for analysis: (1) the
80/80/80 subgroup, comprising patients who were
80% adherent (i.e., received 80% of their total
interferon dose and 80% of the ribavirin dose)
and were treated for 80% of the expected
duration of therapy; and (2) the <80/<80/80
subgroup, comprising patients who underwent dose
reduction (<80% of 1 or both drugs for 80%
expected duration). Patients who withdrew from
the study prematurely were excluded from the
analysis. The goal of 80% of the planned drug
dosage for 80% of the assigned duration
represents an adherence criterion that had been
adopted previously in the assessment of the
efficacy of other pharmaceutical agents,
including HIV drug therapy, antihypertensive
drug therapy, and orally administered cancer
drug therapies.

In this analysis the observation of improved
response was apparent only for genotype 1
infected patients, those most difficult to
treat. The results tabulated in table format
below show an increase in response by 25% for
genotype 1, but there was no statistically
significant improvement in response for genotype
2.

Most patients in these clinical trials were able
to be adherent because of these patients'
motivation and their management in controlled
trials at tertiary referral centers, however,
these findings may not be representative or
applicable to the larger universe of patients
managed in clinical practice. Thus patients
treated in community practices or in centers
with limited expertise in the management of
chronic hepatitis C may have lower response
rates than those observed in this study.
Nevertheless, it seems reasonable that the
concept of adherence to therapy should also
apply to patients treated outside the realm of
clinical trials. Further prospective studies are
needed to address this issue.

Of the 1010 patients evaluated who received
interferon -2b plus ribavirin, 218 were excluded
from further analysis because the duration of
therapy was <80% of the assigned treatment
regimen. Most of the remaining patients who were
treated for longer than 80% of the planned
duration, 631 of 792 (80%), also received >80%
of both their interferon -2b and ribavirin
doses. Similarly, for the 511 patients receiving
peginterferon -2b 1.5 µg/kg per week plus
ribavirin, 88 were excluded from the analysis,
and of the remaining 423, 305 (72%) were
adherent and received >80% of both medications
as defined previously. Of the 304 patients who
received peginterferon -2b 1.5 µg/kg per week
alone, 45 (15%) were excluded because they
failed to achieve at least 80% of the assigned
duration of therapy. Likewise, 56 (18%)
individuals were excluded from the 303 patients
who received interferon -2b alone. Most of the
remaining patients in these monotherapy trials
were adherent to therapy, with 236 of 259 (91%)
and 242 of 247 (98%) receiving >80% of
peginterferon -2b 1.5 µg/kg per week and
interferon -2b alone, respectively.

ADHERENCE TECHNIQUES

In HIV infection and other diseases, adherence
to therapy is related to the number of
medications taken per day, dietary restrictions
required for these medications, side effects and
complications of the medications, dosing
frequency, pill size, and the drug combinations
used. In addition, low literacy level, beliefs
regarding therapy (whether erroneous or
otherwise), lack of support, inconvenient
appointments, and lack of transportation have
all been associated with a lack of adherence to
therapy in HIV-infected patients. In HIV
infection, the most common reasons for lack of
adherence or skipping doses are simply
forgetting, being "too busy," side effects, and
feeling ill, all of which would seem to apply to
patients with chronic hepatitis C undergoing
therapy. Demographic variables, such as gender,
age, race, socioeconomic status, and history of
prior substance abuse, generally do not predict
poor adherence to HIV therapy.

Such variables associated with nonadherence
notwithstanding, physicians are able to
accurately predict adherence in only about 50%
of patients. Thus methods to monitor and improve
adherence may help improve the likelihood of
successful outcome during and after treatment of
any disease process. Although no gold standard
exists for monitoring adherence in clinical
trials or in practice, theoretically, directly
observed therapy (as previously used for
tuberculosis) may be impracticable in hepatitis
C treatment regimens, but it could be made
available to a limited number of patients
considered to be at high risk for nonadherence.
Although currently impractical in hepatitis C
treatment regimens, directly observed therapy
could be facilitated by once-weekly
peginterferon dosing regimens. Patient
self-reporting, as in our studies, is less
accurate than other potential methods but is a
common and convenient way of aiding adherence. A
medication diary is also an important behavioral
tool that may help reinforce adherence.
Electronic monitoring devices, such as
medication event monitoring systems, may also
increase adherence, and future studies of
hepatitis C therapy involving these
microprocessor recorders could provide a better
assessment of the effect of adherence. In HIV
therapy, encouraging telephone calls and
feedback about viral loads have proven to
improve adherence, but evidence to support their
approach in hepatitis C therapy is lacking.
Still, these approaches merit consideration. A
number of other factors may impair treatment
adherence in hepatitis C, including language
barriers, negative staff attitudes toward
injecting drug users, and social circumstances,
such as lack of family support. Strategies to
improve adherence include encouraging
"reasonable" adherence instead of demanding full
adherence, involving family members or
significant others in the treatment process, and
anticipating presumptively and responding to
adverse social situations that could reduce
adherence. Although patients themselves are the
primary determinants of adherence, the
importance of the role of health care providers
should not be overlooked.

It may be possible to use a similar
adherence-efficacy model in future clinical
trials to gauge the impact of patient adherence
on therapeutic outcome, and potentially to
determine ideal drug dosages for those most
compliant to therapy.

The findings of this study indicate that
adherence with prescribed medication regimens
does improve sustained response rates in
patients with chronic hepatitis C infection.
Further research must now be conducted in
prospective trials to determine factors
associated with adherence or lack thereof and
strategies for improving adherence, in an
attempt to enhance sustained response rates.
Theoretically, patient education about side
effects, necessary lifestyle changes during
therapy, treatment of depression, support
groups, telephone and frequent clinic follow-up
visits, printed materials, pill boxes,
reminders, and self-monitoring devices, as well
as simplification of treatment regimens, all
have the potential to improve adherence.
Certainly, the introduction of peginterferon, by
reducing the number and frequency of injections,
has also simplified the treatment regimen, which
may facilitate adherence to therapy.

Although more work in improving adherence is
necessary, our results suggest that adherence
will enhance the likelihood of achieving a
virologic response during the first 3-6 months
of therapy, and that maintaining adherence in
patients who have responded to treatment by week
12-24 will lead to an increase in sustained
virologic response rates.

RESULTS

These patients (80/80/80) were patients who took
80% interferon -2b plus 80% ribavirin for more
than 80% of the expected duration of therapy.
Patients who did not complete 80% of the
duration of the study and who took less than 80%
of interferon and ribavirin did not respond
nearly as well.



The overall SVR for study patients was 54%, and
42% for patients with genotype 1. As you can see
adherence increased response from 54% to 63% and
42% to 51%.

Adherence did not appear to enhance virologic
response in patients with HCV-2 or -3 infection
treated for either 24 or 48 weeks. 82% to 90%
was not statistically significant but
improvement in genotype 1 was significant.

Whereas most patients who reduced their dose
within the first 12 weeks of therapy maintained
a reduced dose during the remainder of therapy,
few if any patients who were not adherent during
the first 12 weeks became adherent thereafter. A
trend was observed between early dose reductions
and impaired sustained response rates; this
trend was less apparent for those who required
dose reductions late in the course of therapy.
But the results of this analysis were not
statistically significant. We attempted to
analyze the effect of dose reduction of each
drug on the sustained response rate; however,
>80% of the patients who received >80% of either
interferon -2b or peginterferon -2b also
received >80% of the doses of ribavirin. Thus we
were unable to distinguish which drug was more
important in terms of the impact of adherence on
sustained response.
http://www.natap.org/

Pegasys + Ribavirin: study results published



In the current issue of New England Journal of
Medicine, the study of Pegasys + ribavirin
conducted by Michael Fried and co-investigators
was published. This study was presented publicly
at the DDW Conference in the Spring of 2001.

A total of 1121 patients were randomly assigned
to treatment and received at least one dose of
study medication, consisting of:

--180 µg of peginterferon alfa-2a once weekly
plus daily ribavirin (1000 or 1200 mg, depending
on body weight), or

--weekly peginterferon alfa-2a plus daily
placebo, or

--3 million units of interferon alfa-2b thrice
weekly plus daily ribavirin for 48 weeks.

STUDY WITHDRAWAL

More patients withdrew for insufficient response
in IFN/RBV group than Pegasys-ribavirin patients
(43 vs 32). Less patients withdrew from
Pegasys-ribavirin group than IFN/RBV group (34
vs 59). There were less adverse events for
patients receiving Pegasys alone (13 vs 32
Peg/RBV & 43 IFN/RBV).

DOSE MODIFICATION

There were more dose modifications in
Pegasys/RBV patients than IFN/RBV patients due
to neuropenia. The dose changes were in the
interferon: 20% modified Pegasys dose vs 5%
modified IFN dose. As well, thrombocytopenia
(reduced platelets) led to more dose changes in
patients receiving Pegasys than in patients
receiving IFN (4% Peg/RBV, 6% in Peg monotherapy
arm vs <1% in IFN/RBV group).

ADVERSE EVENTS

Although side effects and adverse events are
common with HCV therapy, the patients receiving
Pegasys/RBV had significantly less incidence of
certain side effects than patients receiving
IFN/RBV: depression (22% vs 30%), myalgia (body
aches: 42% vs 50%), pyrexia (43% vs 56%), rigors
(shakes: 24% vs 35%).

Author's Discussion

Among patients considered to have the most
treatment-resistant disease Ñ that is, those
with both HCV genotype 1 and high base-line
viral levels Ñ a substantially higher proportion
of those treated with peginterferon alfa-2a plus
ribavirin had a sustained virologic response
than of those treated with interferon alfa-2b
plus ribavirin.

Early prediction of virologic response to
interferon-based therapy can help identify
patients who are unlikely to have a sustained
response and allow clinicians the option to
discontinue treatment, saving patients the side
effects and cost of additional therapy. In the
current study, 97 percent of patients who did
not have an early virologic response to
peginterferon alfa-2a plus ribavirin by week 12
never had a sustained virologic response. The
incremental benefit of continuing therapy beyond
12 weeks for patients who have not had an early
virologic response must be considered for each
patient individually.

This study was designed to treat patients for 48
weeks, regardless of HCV genotype. Therefore, we
cannot comment on shorter treatment periods.
(edit note: but the Greek study of
Pegasys+ribavirin reported at the European liver
meeting in April 2002 found that genotype 2/3
were successfully treated with only 24 weeks
therapy, with slide shows:
http://www.natap.org/2002/easl/day1.htm

Don't forget these studies are in HCV
momoinfected patients, not HIV/HCV coinfected
patients where response rates appear to be less.

Several adverse events typically associated with
the use of interferon (including influenza-like
symptoms and depression) occurred less
frequently with peginterferon alfa-2a, alone or
in combination with ribavirin, than with
interferon alfa-2b plus ribavirin. Monotherapy
with peginterferon alfa-2a was generally better
tolerated than the ribavirin-containing
regimens. As is usual with interferon-based
therapy, there were reductions in neutrophil and
platelet counts with all treatments. Although
these decreases were greater in patients treated
with peginterferon alfa-2a plus ribavirin than
in those treated with interferon alfa-2b plus
ribavirin, they did not appear to be associated
with serious sequelae and were effectively
managed by dose modifications. Interestingly,
for patients treated with peginterferon alfa-2a
plus ribavirin who had an early virologic
response, completion of therapy with dose
reduction was not associated with a substantial
decrease in efficacy.

Virologic Response

Significantly more patients treated with
peginterferon alfa-2a plus ribavirin had
end-of-treatment virologic responses than
patients treated with interferon alfa-2b plus
ribavirin (69 percent vs. 52 percent, P<0.001)
or peginterferon alfa-2a plus placebo (69
percent vs. 59 percent, P=0.01) (Figure 1).
Significantly more patients treated with
peginterferon alfa-2a plus ribavirin had a
sustained virologic response (i.e., no
detectable HCV RNA 24 weeks after cessation of
therapy) than those treated with interferon
alfa-2b plus ribavirin (56 percent vs. 44
percent, P<0.001) or peginterferon alfa-2a plus
placebo (56 percent vs. 29 percent, P<0.001).

Forty-six percent of patients with HCV genotype
1 who received peginterferon alfa-2a plus
ribavirin had a sustained virologic response, as
compared with 36 percent of those who received
interferon alfa-2b plus ribavirin (P=0.01) and
21 percent of those who received peginterferon
alfa-2a plus placebo (P<0.001). Among the
patients with HCV genotype 2 or 3, significantly
more of those treated with peginterferon alfa-2a
plus ribavirin had a sustained virologic
response than of those treated with interferon
alfa-2b plus ribavirin (76 percent vs. 61
percent, P=0.005). Among patients with HCV
genotype 1 and high base-line viral RNA levels
(more than 2 million copies per milliliter), 41
percent of those receiving peginterferon alfa-2a
plus ribavirin had a sustained virologic
response, as compared with 33 percent of those
receiving interferon alfa-2b plus ribavirin.
Among patients with low viral load (<2 million
copies) and genotype 1 Pegasys+ribavirin had
better Sustained response than
interferon+ribavirin (56% vs 43%). Among
patients with cirrhosis, 43 percent of those
treated with peginterferon alfa-2a plus
ribavirin and 33 percent of those treated with
interferon alfa-2b plus ribavirin had a
sustained virologic response. See table 2 of
viral responses at end of this report.

Independent Factors Associated with a Sustained
Virologic Response

In multivariable analyses to identify predictors
of sustained virologic response among patients
who received peginterferon alfa-2a plus
ribavirin, our final multiple
logistic-regression model, including the
following factors, was entered in the final
stepwise regression analysis: sex, race (white
vs. nonwhite), age (40 years vs. >40 years),
body weight (75 kg vs. >75 kg), pretreatment
viral load (2 million copies per milliliter vs.
>2 million copies per milliliter), pretreatment
alanine aminotransferase quotient (>3 vs. 3),
pretreatment histologic diagnosis (cirrhosis vs.
noncirrhosis), and HCV genotype (1 vs. non-1).

Three factors independently and significantly
increased the odds of achieving a sustained
virologic response: an HCV genotype other than 1
(odds ratio, 3.25; p<.001), an age of 40 years
or less (odds ratio, 2.60;p<.001), and a body
weight of 75 kg or less (odds ratio, 1.91;
P=0.002).

Predictive Value of Early Virologic Response

By week 12, 86 percent of patients (390 of 453)
treated with peginterferon alfa-2a plus
ribavirin had had a virologic response, defined
as a 2-log decrease from baseline HCV RNA levels
(97 patients) or no detectable serum HCV RNA
(293 patients). The absence of an early
virologic response was not associated with early
treatment discontinuation (before week 12) or
dose modification (data not shown). Of those
with early virologic responses, 65 percent
subsequently had a sustained virologic response.
Those with no detectable HCV RNA by week 12 were
more likely to have a sustained virologic
response than those who had only a 2-log
decrease in HCV RNA (221 of 293 vs. 32 of 97).
In contrast, among the 63 patients who did not
have an early virologic response, 61 (97
percent) did not have a sustained virologic
response.

Safety

The proportions of patients withdrawn from
treatment because of laboratory abnormalities or
other adverse events were similar in the groups
receiving peginterferon alfa-2a plus ribavirin
(3 percent for laboratory abnormalities and 7
percent for other adverse events), peginterferon
alfa-2a plus placebo (1 percent and 6 percent,
respectively), and interferon alfa-2b plus
ribavirin (1 percent and 10 percent)

The median hemoglobin values decreased between
weeks 1 and 8 in all treatment groups, then
stabilized, and then returned to near base-line
values after treatment was completed. The
maximal decrease was greater in patients treated
with peginterferon alfa-2a plus ribavirin (3.7 g
per deciliter) or interferon alfa-2b plus
ribavirin (3.6 g per deciliter) than in patients
treated with peginterferon alfa-2a plus placebo
(2.2 g per deciliter). There was no association
between the incidence of serious cardiovascular
events and the incidence of anemia.

The median neutrophil counts decreased from base
line in all treatment groups, particularly
during the first two weeks of treatment, and
then stabilized for the remainder of the
treatment period, increasing rapidly to
base-line values after the completion of
treatment. Four patients (three receiving
peginterferon alfa-2a plus ribavirin and one
receiving interferon alfa-2b plus ribavirin)
discontinued treatment because the neutrophil
count was below 500 per cubic millimeter. The
median platelet counts remained close to
base-line values throughout treatment with
interferon alfa-2b plus ribavirin but decreased
progressively during the first eight weeks of
treatment with peginterferon alfa-2a plus
ribavirin or placebo, before stabilizing. After
treatment was completed, the median platelet
counts returned to normal within four weeks. Two
patients with thrombocytopenia (one receiving
peginterferon alfa-2a plus placebo and the other
receiving interferon alfa-2b plus ribavirin) had
serious bleeding. Five patients (four receiving
peginterferon alfa-2a plus ribavirin and one
receiving peginterferon alfa-2a plus placebo)
discontinued treatment because of
thrombocytopenia.

Most adverse events in all study groups were
those commonly associated with interferon-based
treatment. Patients treated with peginterferon
alfa-2a plus ribavirin or placebo had a lower
incidence of influenza-like symptoms, such as
pyrexia, myalgia, and rigors, than those treated
with interferon alfa-2b plus ribavirin. Although
few patients had a history of depression or
active depression at base line (1 to 2 percent
and 3 to 5 percent, respectively), a substantial
minority reported depression during the study.
Patients treated with peginterferon alfa-2a plus
ribavirin or placebo had a lower incidence of
depression than those treated with interferon
alfa-2b plus ribavirin (22 percent and 20
percent vs. 30 percent). Three patients died
after the end of treatment. One patient who had
received interferon alfa-2b plus ribavirin died
of hypertensive heart disease, and two who had
received peginterferon alfa-2a plus placebo
died, one from drowning and the other from liver
cancer. None of the deaths were considered
related to treatment.


More patients withdrew for insufficient
response in IFN/RBV group than Pegasys-ribavirin
patients (43 vs 32). Less patients withdrew from
Pegasys-ribavirin group than IFN/RBV group (34
vs 59). There were less adverse events for
patients receiving Pegasys alone (13 vs 32
Peg/RBV & 43 IFN/RBV).

DOSE MODIFICATION

There were more dose modifications in
Pegasys/RBV patients than IFN/RBV patients due
to neuropenia. The dose changes were in the
interferon: 20% modified Pegasys dose vs 5%
modified IFN dose. As well, thrombocytopenia
(reduced platelets) led to more dose changes in
patients receiving Pegasys than in patients
receiving IFN (4% Peg/RBV, 6% in Peg monotherapy
arm vs <1% in IFN/RBV group).

ADVERSE EVENTS

Although side effects and adverse events are
common with HCV therapy, the patients receiving
Pegasys/RBV had significantly less incidence of
certain side effects than patients receiving
IFN/RBV: depression (22% vs 30%), myalgia (body
aches: 42% vs 50%), pyrexia (43% vs 56%), rigors
(shakes: 24% vs 35%)
www.natap.org

HCV-Infected Patients with Normal ALT May Benefit from Liver Biopsy
By Brian Boyle, MD
Infection with hepatitis C virus (HCV) infection can lead to
progressive liver disease, and this is associated with high rates of
morbidity and mortality. To this point, the assessment of a
patient's risk for progressive liver disease, and the need for HCV
treatment, has usually involved a liver biopsy since this is
considered the most reliable test for assessing the severity of
liver disease. There have been efforts to arrive at non-invasive,
biochemical markers of the level of liver disease present in
HCV-infected patients; however, the unreliability of these assays
has led to biopsy remaining the "gold standard" for assessment of
liver disease in these patients.
In a retrospective study published in Hepatology investigators
assessed the value of the alanine aminotransferase (ALT) level for
predicting histologic findings in patients infected with HCV.

In their discussion, the authors noted that this study was
undertaken due to conflicting studies regarding the correlation of
ALT with histologic findings on liver biopsy, with some showing
significant fibrosis in patients with normal ALT levels while others
do not, and to explore whether the common treatment algorithm, which
excludes patients with normal ALT levels from liver biopsy and
treatment, is correct.
In the study, data were collected on 864 HCV RNA-positive patients.
ALT values were obtained from patients at the time a liver biopsy
was performed, and normal ALT values were defined as normal values
obtained at serial evaluations during a 6-month period. Using the
METAVIR system, 99% of those with elevated ALT levels had a score of
at least F1 (mild fibrosis) and 88% had a score greater than A1F1
(mild inflammation and fibrosis). Among patients with persistently
normal ALT values, 65% had a score of at least F1 and 26% had a
score greater than A1F1.
The authors conclude, "A liver biopsy could be considered useful in
patients with normal ALT levels, not only to reassure those with
minimal liver disease but also to single out the small proportion of
patients with more significant histologic findings who may benefit
most from antiviral therapy. Altogether, these results suggest the
need to reassess the algorithm for liver biopsy practice aiming at
the best individual risk/benefit ratio."
10/21/02
Reference
P Pradat and others. Predictive Value of ALT Levels for Histologic
Findings in Chronic Hepatitis C: A European Collaborative Study.
Hepatology 2002; 36:973-977.

Copyright 2002 by http://HIVandHepatitis.com All Rights Reserved.
Reproduction of articles for personal or educational use is
encouraged and does not require permission from the publisher.

Abstract 281. Durability of Sustained Virologic response in patients
with Chronic Hepatitis c after treatment With Interferon 2b Alone or
in Combination with Ribavirin
This study looked at 400 patients in 3 studies who achieved a
sustained response. The key
findings were:


late relapse (after achieving the sustained response) occurred
only in 2.5% of patients
the late relapsers occurred within the first 2 years. There were
no relapsers after 2 years
2 relapsers had detectable HCV-RNA in the liver; 3 had detectable
HCV-RNA in the liver and did not relapse
the risk of relapse after achieving sustained response was 5%
The purpose of this study was to assess the durability of response
in patients who were sustained responders 24 weeks after therapy.
John McHutchison reported in an oral session on a analysis of 2089
patients from 3 large scale international studies comparing
interferon alfa-2b alone to interferon alfa-2bplus ribavirin (Davis
et al, NEJM 1998;339:1493, McHutchison et al NEJM 1998; 339:1485;
Poynard et al, Lancet 1998;352:1426). Many of these patients have
been followed for up to 4 years. This analysis looked at the 558
patients who achieved a sustained response to evaluate their rate of
failure. Of the 558 SVRs 455 patients received IFN+RBV and 103
patients received IFN. 395 of the 558 agreed to participate in this
long-term follow-up. All patients were treatment-naive or relapsers
and received 24 or 48 weeks treatment. Of the 395 patients, 151
naive received IFN/RBV for 48 weeks, 112 naive patients received
IFN/RBV for 24 weeks, 59 relapsers received IFN/RBV for 24 weeks, 61
received IFN alone for 48 weeks, and 12 received IFN alone for 24
weeks (4 naive 24 weeks, 61 naive 48 weeks, 8 relapse 24 weeks).

Serum HCV-RNA was measured by NGI LLQ 100 copies/ml. These patients
are also assess yearly for disease progressionby physical exam and
hemotological and biochemical (ALT/AST) testing. This analysis was
completed as of February 2001 and the endpoint was viral relapse
after achieving sustained response. About 2/3 of patients were male,
42-47 years of age, and about 74-79 kg. 37% were genotype 1, 26%
genotype 2, 34% genotype 3, and 3% genotype 4/5. Although there is a
low percentage of genotype 1 in this analysis McHutchison said that
they found no difference in study outcomebetween genotyp 1 vs
non-genotype 1. Baseline fibrosis Metavir Stage: 60-80% of patients
had F0-F1. 12-29% had F3/F4. And 4-20% had missing information.
Baseline viral load was 3.0-4.1 million copies/ml. ALT was 3.2 to
3.6 times the upper limit of normal.

RESULTS

· 59% of the 395 patients in the study have been followed for 4
years after the end of treatment, 3% for 5 years, 26% for 3 years,
8% for 2 years, and 3% for 1 year.

· Only 10 out of 395 patients (2.5%) who had a sustained response
(24 weeks after ending treatment)--
7 had received IFN/RBV
5 of 7 were naive and relapsed in 3-24 weeks after stopping
therapy
2 were relapsers
3 patients received IFN alone
· All 10 late relapsers reappearance of HCV-RNA within 2.5 years
after stopping therapy or 2 years after the 24 week follow-up
period.

· There have been no relapses after 2 years of follow-up.

· Researchers looked at naive vs relapser, 24 vs 48 weeks treatment,
genotype 1 vs non-genotype 1, low vs high viral load, low vs higher
fibrosis, and found no factor predicted relapse

· The overall risk for late relapse looking out to 4 years was <5%,
when using Kaplan-Meier curve, except for the 12 patients who
received IFN alone for 24 weeks who had a high risk for late relapse
--The corresponding actuarial likelihood (Kaplan-Meier) of
maintaining response after 4 years in patients who initially
achieved SR is: IFN/RBV 24 weeks therapy naive 97%, IFN/RBV 48 weeks
therapy naive 99%, and IFN/RBV 24 weeks therapy relapsers 96%

· There were 5 patients who had HCV-RNA detected in their liver (not
blood) in the 24 week post-treatment liver biopsy. These 5 patients
were sustained responders so they had PCR negative in the blood. Two
of the 5 subsequently relapsed

· 95% had normal ALT during the long-term follow-up of this study

· One patient developed liver cancer (hepatocellular carcinoma). He
had pre-existing cirrhosis, was a sustained responder (I think he
was a previous relapser IFN alone) who has not relapsed. HCC
developed 39 months after treatment. Other than this 1 patient there
was no evidence of hepatic decompensation as documented by physical
exam

Impact of Pegylated Interferon alfa-2b (Peg-Intron) and
Ribavirin on Progression
of Liver Fibrosis in patients with Chronic Hepatitis C

Reported by Jules Levin

Based on 2 biopsies 20 months apart, this study reported:


Sustained responders improved activity grade, were less likely to
have worsened activity, and less likely to see worsened fibrosis

On average non-responders with fibrosis (F2, F3, and F4) could
stop fibrosis progression

On average sustained responders with fibrosis (f2, F3, and F4)
show regression of fibrosis

49% with cirrhosis showed some degree of reversal of cirrhosis
from F4 stage to either F3, F2 or F1; achieving a sustained
response was a significant factor

Thierry Poynard first commented on aims of therapy: (1) to achieve a
sustained virologic response which permits fibrosis regression,
disappearance of extrahepatic manifestations, disappearance of
contamination risks; (2) to block fibrosis progression in patients
without a sustained virologic response (perhaps also using a
suppressive maintenance therapy).

Editorial note from Jules Levin: Blocking fibrosis progression in
nonresponders remains controversial. A number of studies have found
fibrosis can be slowed or stopped in transient responders and
nonresponders. Some studies have found nonresponders are not able to
block fibrosis progression. And it also depends how you define a
nonresponder. Mitch Shiffman reported in his study in
Gastroenterology (1999; 117: 1164-1172) that patients with some
early viral load reduction (1.4 log) and some early fibrosis
improvement during therapy are able to sustain viral load reduction
and improved histology (liver condition) with ongoing maintenance
interferon therapy for the two years of this study. What about
patients who are unable to reduce viral load at all and who don't
show early fibrosis improvement? I think this remains a question.
Two large multiple-year studies HALT-C by the NIH & Roche and
CO-PILOT from Schering are exploring this question now. The findings
Poynard presented here and earlier at EASL in the Spring of 2001
have been controversial. The question of whether nonresponders can
reverse, slow or stop fibrosis progression is perhaps the most
controvesial question currently. Poynard first presented this data
at EASL but the presentation here at AASLD had several additional
new pieces of information. Several observers and researchers I spoke
with at AASLD do not buy his findings (the controversy). One doctor
told me he does not see these kinds of benefits in his practice. I
think other researchers do feel these data have merit.

Poynard pooled data on 3,010 HCV treatment naive, HIV negative
patients with paired biopsies from 4,493 patients in 4 trials
receiving 10 different regimens (Poynard et al, McHutchison et al,
Lindsay et al, and Mannes et al.)

The ten regimens included IFN 24 weeks, IFN 48 weeks, PegIntron 0.5
ug/kg, PegIntron 1.0 ug/kg, PegIntron 1.5 ug/kg, IFN/RBV 24 weeks,
IFN/RBV 48 weeks, PegIntron 0.5 ug/kg+RBV, PegIntron 1.5 ug/kg/RBV.

Some characteristics of the 3,010 patients: 66% male, 43 years age,
80 kg weight, 53% IVDUs, genotype 1 70%, genotype 2 28%, genotype
4,5,6 3%, viral load 4 million.

Duration of HCV infection for patients was 18 years. Duration
between the 2 biopsies was 20 months. The size of the biopsy in mm
was 16.

25% had fibrosis (F2 13%, F3 7%, F4 5%-cirrhosis), and 73% had F1
(minimal fibrosis) and 2% had F0 (no fibrosis). About about 1/3 of
patients had each of severe, moderate or mild activity (A1, A2, or
A3).

The histological impact of each regimen was estimated by the
percentage of patients with at least one grade improvement in the
necrosis and inflammation (METAVIR score), the percentage of
patients with at least one stage worsening in fibrosis METAVIR score
and by the fibrosis progression rate per year.

Activity Grade Improvement (at least one grade improvement Metavir
score)
Improved
Stabilized Worsened
Sustained Responders 86% 12%
2%
Relapsers 43%
36% 21%
Non-responders 36%
43% 21%

This was new information presented for the first time at AASLD and
not earlier at EASL. Being able to achieve a sustained virologic
response is an important factor in being able to achieve a
significant improvement in activity. Obviously, choosing the most
effective regimen (its potency and tolerability) is important in
being able to achieve a sustained response significantly and in turn
improved activity and fibrosis. So, you want to use the most potent
(antiviral activity) and tolerable regimen. Tolerabiliy is important
because with more side effects and adverse events adherence may be
more challenging.

Poynard reported an analysis of the change in activity grade by each
of the ten regimens including PegIntron 1.5 ug/kg+RBV using the
optimized weight based dose of RBV.


IFN alone 24 weeks: 39% of patients improved, 39% stabilized, 24%
worsened

IFN alone 48 weeks: 41% improved, 40% stabilized,19% worsened

Peg-Intron 0.5 ug/kg: 48% improved, 35% stabilized, 20% worsened

Peg-Intron 1.0 ug/kg: 49% improved, 33% stabilized, 18% worsened

Peg-Intron 1.5 ug/kg: 49% improved, 33% stabilized, 18% worsened

IFN+RBV 24 weeks: 51% improved, 34% stabilized, 15% worsened

IFN+RBV 48 weeks: 64% improved, 24% stabilized, 12% worsened

Peg 0.5+RBV: 70% improved, 24% stabilized, 6% worsened

Peg 1.5+RBV: 65% improved, 23% stabilized, 12% worsened

Peg 1.5+RBV*: 73% improved, 21% stabilized, 6% worsened

*RBV optimized weight based dosing

I think its important to note that no data was presented by Poynard
on the statistical significance of the differences between the
regimens, either on the slides or verbally in his talk. So, you
don't know if for example there is a real difference between the 41%
of patients receiving IFN for 48 weeks who showed improvement and
the 49% who showed improvement using PegInron 1.5 ug/kg. Or for that
matter, you don't know for sure if there is a significant difference
between standard IFN+RBV taken for 48 weeks (64% improved),
PegIntron 0.5 ug/kg+RBV (70%), PegIntron 1.5 ug/kg+RBV (65%
improved), and PegIntron 1.5 ug/kg+ optimzed dose of RBV based on
weight (73%). In fact, Poynard's data shows little difference if any
between the 70% of patients who saw improvement using the low dose
of Pegintron 0.5+RBV compared to the patients receiving PegIntron
1.5 ug/kg+ optimized weight based dose of RBV who Poynard reported
73% of these patients experienced improved activity grade. There may
not be any significant difference between 70% and 73%.

Fibrosis Stage Variation

(the percentage of patients with at least one stage change in
fibrosis METAVIR score). The biopsies were performed 20 months apart
so Poynard suggested that given more time fibrosis ought to continue
to improve further for some patients. In particular, you might
expect if any will continue to improve it would be sustained
responders and perhaps some patients continuing on maintenance
therapy.
Improved
Stabilized Worsened
Sustained Responders 25% 68%
7%
Relapsers 16%
67% 17%
Non-responders 17%
62% 21%

Again, Poynard did not present data on the statistical significance
between any of the differences between the groups. But, he did
comment orally in his presentation that the differences in the
worsening category (7% vs 17% vs 21%) were statistically
significant. I think its fair to conclude that a sustained responder
has a better chance for improved fibrosis than a relapser and moreso
than a non-responder. The difference in the worsening category
between sustained responders and non-responders and relapsers (21%
vs 7% and 17%) strikes my attention.

Fibrosis Progression Rate Per Year

Poynard reported the fibrosis progression rate per year in 1900
patients with F0-F1 (no or minimal fibrosis) with paired biopsies
and known duration of infection.
Rate Before Therapy
After
Non-responders 0.053
0
Sustained Responders 0.063 0
p<0.001

Poynard is reporting here that in patients with HCV alone and little
or no fibrosis their fibrosis progression rate per year stopped
whether they were a non-responder or sustained responder. Since the
biopsies were performed 20 months apart, you don't know what might
occur regarding the fibrosis progression rate in 2-3 years or longer
for non-responders. Non-responders may start progressing after being
off therapy for a while. How long off therapy does it take for
progression to get going or to get back to baseline? I don't know of
any data on this. But some doctors tell me they think the benefit
can last for a little while. Follow-up biopsies should be helpful in
evaluating this.

Poynard reported on an analysis of fibrosis progression rate per
year in 679 patients with extensive fibrosis (F2, F3, F4) with
paired biopsies and known duration of therapy. Poynard commented
that the progression rates in this group were very high before
therapy.
Rate Before Therapy
After
Non-responders 0.135
0
Sustained Responders 0.139
-0.591
p<0.001
Poynard said the sustained responders experienced a dramatic
decrease or regression in fibrosis rate.

Fibrosis Stage Variation By Regimen

The percentage of patients with at least one stage change in
fibrosis METAVIR score. Again, the biopsies were 20 months apart.


IFN 24 weeks: 12% of patients receiving this regimen experienced
improved fibrosis, 65% stabilized, and 23% worsened
IFN 48 weeks: 16% of patients improved fibrosis, 66% stabilized,
and 18% worsened


Peg 0.5 ug/kg: 22% improved, 62% stabilized, 17% worsened

Peg 1.0 ug/kg: 21% improved, 62% stabilized, 16% worsened

Peg 1.5 ug/kg: 17% improved, 65% stabilized, 18% worsened

IFN/R 24 wks: 20% improved, 66% stabilized, 14% worsened

IFN/R 48 wks: 20% improved, 66% stabilized, 14% worsened

Peg 0.5/RBV: 23% improved, 67% stabilized, 10% worsened

Peg 1.5/RBV: 23% improved, 57% stabilized, 20% worsened

Peg 1.5/R*: 24% improved, 68% stabilized, 8% worsened

*With Optimized weight based dosing

So far there does not appear to be any difference between the
percent of patients showing improved or stabilized fibrosis stage
between most of the regimens. In particular, there is no difference
between Peg 1.5 with optimized weight based RBV dosing, Peg 1.5 with
RBV but without weight based RBV dosing, and standard IFN + RBV for
48 weeks.

Again, Poynard did not present any data on the statistical
significance of differences between groups in his slides. But he
pointed out orally that there was a significant difference between
the 8% worsening in the Peg 1.5+ optimized RBV arm compared to the
14% experienced by IFN/RBV 48 weeks arm. But, he did not comment on
the point that the Peg 0.5/RBV arm was 10% compared to 8% with
optimized RBV dose & higher PegIntron dose. Although, the biopsies
were only 20 months apart and so some patients, as Poynard points
out, may continue to improve further.

Factors Associated With Absence of Extensive Fibrosis at 24 Months

n=2861, (20 months between biopsies), multivariate analysis


The baseline fibrosis stage (F0, F1) had the most impact. Patients
with little or minimal fibrosis (stage F0, F1) had an 88% reduced
risk for having extensive fibrosis in the second biopsy 20 months
after the first biopsy and after therapy (Odds Ratio 0.12,
p<0.001)

Achieving a sustained virologic response had the second most
impact reducing risk for extensive fibrosis on the 2nd biopsy by
64% (OR 0.36, p<0.001)

Age lower than 49 had the third most impact reducing risk by 49%
(OR 0.51, p<0.001)

Interestingly, Body Mass Index (<27) had the fourth most impact by
reducing risk by 35% (OR 0.65, p<0.001)

Baseline activity (A0, A1: patients with little or no activity)
had the fifth most impact by reducing risk by 30% (OR 0.70,
p<0.02)

Viral Load <3.5 million reduced risk by 21% (OR 0.79, p=0.03)

I think the most interesting from the above data is that body mass
index had an effect on outcome, Having more body mass increased
risk. Expectedly, low viral load and achieving a sustained response
were significant factors in reducing risk for having significant
fibrosis in the 2nd biopsy.

Predictability of SVR After 12 week PCR Response

Poynard reported data similar to found with Pegasys+RBV on the
predictability of sustained response based on the viral load
response at 12 weeks. The analysis included 174 patients from the
database who received PegIntron 1.5+RBV. 90% (n=120) who were PCR
negative at week 12 achieved a sustained response. 26% who had a 2
log or greater reduction in PCR (n=23) achieved a sustained
response. And 0 patients with <2 log reduction in viral load (n=31)
at week 12 achieved a sustained response. The Pegasys analysis on
using 12-week PCR response to predict outcome was more extensive and
can be read in the NATAP AASLS report on this topic.

Can Cirrhosis Be Reversed?

153 patients with cirrhosis were included in this analysis. Poynard
called these results surprising-- 49% (n=75) reversed cirrhosis. In
the first biopsy 153 patients had F4 stage fibrosis (cirrhosis). In
the second biopsy 23 patients had regressed to stage 3 (f3), 26
patients regressed to stage 2 (F2), 23 patients regressed to stage 1
(F1). And 78 patients still had stage 4. Poynard did comment on the
sample size of liver taken in biopsy alluding to the limitations
this presents.

Using a univariate analysis Poynard found the following significant
factors in reversing cirrhosis:


using a reinforced regimen which I think he defined as IFN for
greater then 24 weeks which I assume means or includes 48 weeks
IFN/RBV and PegIntron/RBV regimens translates into a greater
likelihood of reversing cirrhosis

achieving a sustained response (33% vs 15%) increases chance of
reversing cirrhosis

reduction of activity grade in the second biopsy after therapy was a
factor. 45% of patients with activity grade of A0/A1 in second
biopsy reversed cirrhosis compared to 23% who did not have activity
grade of A0/A1


Another study using Pegasys monotherapy presented by Jenny Heathcote
showed patients with cirrhosis could improve their histology (a
histologic response in this study was defined as a decrease of at
least 2 points on the 22-point Histological Activity Index). 30%
using Pegasys montherapy achieved a sustained response vs 8% using
standard interferon.

www.natap.org/2001/sep/can_cirrhotics090401.htm
Please visit the above website for more information.
We would like to thank Jules Levin

Abstract 676. ACUTE HEPATITIS C: NATURAL COURSE AND
RESPONSE TO ANTIVIRAL TREATMENT
Tilman J Gerlach, Reinhart Zachoval, Norbert Gruener,
Maria-Christina Jung, Klinikum Grosshadern Med Dept II,
Muenchen Germany; Axel Ulsenheimer, Winfried Schraut, Inst
fuer Immunologie, Muenchen Germany; Albrecht Schirren,
Klinikum Grosshadern Med Dept II, Muenchen Germany; Martin
Waechtler, Markus Backmund, Gen Hosp MŸnchen Schwabing,
Muenchen Germany; Helmut Diepolder, Gerd Pape, Klinikum
Grosshadern Med Dept II, Muenchen Germany

Below is the program book abstract, which I think portrays the
essence of the oral presentation at the AASLD meeting. Another
report on this presentation is being prepared. As you may
know, German researchers first reported on treating acute HCV
at DDW in the Spring 2001. A published article followed by
much attention occurred in the Fall 2001. Identifying persons
with acute HCV is very difficult just as it is in identifying
acutely infected persons with HIV. But, if such a person can
be identified treatment consideration may be crucial.
Identification & treatment of acutely infected persons can be
an important public policy position. This may have particular
application to health care workers.

Background: Although screening of blood products for hepatitis
C virus (HCV) has virtually eliminated post-transfusion
hepatitis C, HCV still causes about 20% of cases of acute
hepatitis today. These patients frequently present with acute
symptomatic hepatitis C, which differs in many aspects from
patients with post-transfusion hepatitis C. Little is known,
however, about the natural course and the optimal treatment
strategy for acute hepatitis C as it presents today.

Methods: The diagnosis of a HCV in fifty-six consecutive
patients was based on seroconversion to anti-HCV antibodies or
clinical and biochemical criteria (acute onset of hepatitis
with elevation of ALT at least 10x the upper limit of normal,
exclusion of other liver diseases) and on the presence of
HCV-RNA by RT-PCR in the first serum sample.

Results: Fifty-six consecutive patients with acute hepatitis C
were diagnosed in two large referral centers for infectious
diseases and hepatology. 47/56 patients presented with
symptomatic disease (fatigue (24%), abdominal pain (14%),
jaundice (24%), nausea (19%)) while 9/56 were clinically
asymptomatic. The major risk factors for acute HCV infection
were IV-drug abuse (n=14), recent medical procedures (n=17),
HCV-positive sexual partner (n=5), and needle-stick injury in
medical employees (n=5), in 15 patients (27%) no risk factor
or possible source of infection could be identified. Six
patients received immediate antiviral therapy (IFN-a alone or
in combination with ribavirin), 10 patients refused to therapy
or were not eligable for IFN-a therapy. In 50 patients, not
being treated immediately, the natural course of acute HCV was
further studied: 34/50 (68%) patients initially cleared the
virus spontaneously within a median of 11,9 weeks (range 2 to
24 weeks), but only twenty-three (47%) persistently remained
HCV-RNA negative until the end of follow-up (median 23months,
range 6 to 55 months) and were classified as self-limited
hepatitis C. In eleven patients (22%) HCV RNA relapsed after a
median of 23 weeks (range 8-86 weeks) and 16/50 (32%) patients
did not clear HCV infection spontaneously and developed
chronic hepatitis C. Patients with self-limited hepatitis C
(n=22) and those developing chronic hepatitis C (n=28) did not
differ with regard to age, risk factors for HCV infection,
HCV-genotype, or initial viral load. However, symptomatic
disease, female sex, and a high peak bilirubin level were
strong predictors of spontaneous HCV clearance. While 49% of
patients with symptomatic acute HCV cleared infection
spontaneously, none of the patients with asymptomatic acute
HCV (n=9) cleared HCV infection without treatment.

Since the majority (86%) of patients with spontaneous viral
clearance lost HCV RNA within twelve weeks after onset of
symptoms, antiviral therapy was recommended to patients who
did not loose HCV RNA by week 12 after onset of symptoms. Of
34 patients with chronic hepatitis C, 24 patients started
either interferon-alpha alone or in combination with
ribavirin. So far, twenty-one patients responded with loss of
HCV-RNA and normalization of aminotransferases; 15 of 16
IFN-responders who have completed follow-up (>6 months after
end of treatment) are sustained responders and one patient
relapsed. Five responders are still under follow-up
(end-of-follow-up sustained response rate 82%) and three
patients did not respond to antiviral therapy. Although not
mentioned in the results but discussed in the oral
presentation was the 6 patients who were treated immediately
upon identification. And I recall 4 or 5 of them had a
virologic response.

Conclusions: In the management of acute HCV infection a high
spontaneous viral clearance rate within the first twelve weeks
after onset of symptoms has to be considered. The strategy to
treat symptomatic patients who remained HCV-RNA positive
beyond three months after onset of disease led to an overall
sustained viral clearance in 90% of patients, while
unnecessary treatment was avoided in those with spontaneous
viral clearance. In contrast patients with asymptomatic acute
HCV infection are unlikely to clear the virus spontaneously
and antiviral therapy should be commenced as early as
possible.

HALT-C Trial: 4-year study of Maintenance Therapy in 1350
patients


Written for NATAP by Mark Sulkowski, MD, Johns Hopkins University
School of Medicine

Abstract 279. Retreatment of Interferon And Interferon-Ribavirin
Non-Responders with Peginterferon-alpha-2a (Pegasys) And Ribavirin:
Initial Results from the Lead-In Phase of the Halt-C Trial

The HALT-C trial was designed to determine if long term maintenance
interferon therapy, administered over 4 years, could prevent
histologic progression, reduce the development of hepatocellular
carcinoma and the need for hepatic transplantation in patients with
chronic HCV and advanced fibrosis or cirrhosis who remain HCV-RNA
(+) despite therapy. Since peginterferon plus ribavirin is more
effective than standard interferon/ribavirin for treatment of
chronic HCV all patients enrolled in the HALT-C trial were first
treated with peginterferon plus ribavirin during the lead-in phase
of this trial.

This study is enrolling 1350 patients with advanced liver disease
(bridging fibrosis/cirrhosis, Ishak Fibrosis stage > 3) and no
evidence of hepatic decompensation. All patients had previously
failed to respond to interferon-based therapy administered for at
least 12 weeks. After screening, all patients received pegylated
interferon alfa-2a (180 mcg weekly) plus ribavirin (1 - 1.2
grams/day). Patients who are HCV-RNA (-) at week 20 continue therapy
for 48 weeks total. Patients who are HCV-RNA (+) either stop
treatment or receive a maintenance dose of Pegasys 90ug/week for 3.5
years.

Dr. Adrian Di Bisceglie presented on-treatment virologic response
data on the first 268 patients who completed at least 20 weeks of
therapy within this ongoing study. For the purpose of this
presentation, viral response was defined as an undetectable HCV-RNA
level at treatment week 20. 15 (5.6%) patients discontinued therapy
prior to week 20. At week 20, 107 of 268 patients (42%) (based on an
intention-to-treat analysis) had an undetectable HCV RNA level.
These patients will continue therapy for an additional 28 weeks and,
per protocol, will not enter the "maintenance" phase of the study.
There were several important "sub-group" analysis presented. Persons
who had only failed prior interferon monotherapy were much more
likely to achieve a response than those who failed prior
interferon/ribavirin combination therapy (53% > 31%) and
African-Americans were significantly less likely to respond than
others (10% < 43%).

In addition, a large number of patients had dose reductions of the
PEG-interferon (53%), ribavirin (44%) or both (47%). Thus, while the
discontinuation rate was quite low (~5%), it remains uncertain if
such dose reductions will impair the overall effectiveness of the
therapy. Nonetheless, these results are encouraging and suggest that
persons with advanced liver disease who failed to respond
virologically to prior therapy may benefit from a course of
pegylated interferon/ribavirin.

Editorial note: Baseline data for 268 patients-- 41% of patients in
study had cirrhosis at baseline. 84% were genotype 1. Mean ALT was
124. 88% were Caucasian. 63% had received IFN+RBV. Mean HCV-RNA was
3.5 million IU/mL. Mean age 50. The degree of fibrosis was
associated with response (44% Ishak 3-4 [bridgng fibrosis] vs 31%
Ishak 5-6 [cirrhosis], p=0.03). Gender was not associated with
response (40 vs male vs 36% female, NS). Genotype was a factor in
response Genotype 2b: 88%; genotype 3a: 93%, genotype 1a: 30%;
genotype 1b: 39%; genotype 2a: 35%. Baseline HCV-RNA did not appear
to influence response. Mean reduction in HCV-RNA was 3.7 log; 45%
had a 3+ log reduction, while 15% had a 2-log reduction, 21% had a
1-log reduction, and 18% had <1-log reduction. It will be
interesting to see if the patients with little viral load reduction
demonstrate improved, stopped, or slowed fibrosis.

The long-term goals or outcomes from HALT-C will take several years
to achieve. These interim results are similar to those seen in
several other smaller studies reported at the conference.

Pegylated interferon alfa/ribavirin in persons who failed to prior
interferon based therapy



Written for NATAP by Mark Sulkowski, MD, Johns Hopkins University
School of Medicine

The majority of patients, particularly those with HCV genotype 1,
treated with standard interferon alfa-2b plus ribavirin fail to
achieve a sustained virologic response. Thus, there is considerable
interest in the efficacy of pegylated interferons plus ribavirin in
the treatment of HCV infection in persons who failed prior
combination therapy. Several studies at the 52nd AASLD meeting in
beautiful Dallas, TX addressed this important question.

Abstract 277. Analyses of 40 KDA Peginterferon Alfa-2a (Pegasys) in
Combination With Ribavirin, Mycophenolate Mofetil, Amantadine, or
Amantadine Plus Ribavirin In Patients That Relapsed or Did Not
Respond To Rebetron_ Therapy: A Report Of Two Randomized,
Multicenter, Efficacy And Safety Studies

Dr. Nid Afdhal presented on-treatment and end-of-treatment data from
two randomized, controlled studies which retreated patients who had
previously failed to suppress HCV RNA ("non-responders" or had
experienced a re-emergence of HCV RNA following discontinuation of
therapy ("relapsers") with PEG-IFN alfa-2a (180 mcg SC weekly) plus
the following adjuvant therapies: 1) ribavirin 1 - 1.2 grams/day
(RBV); 2) mycophenlate mofetil (CellCept) 1 gram twice daily (MMF);
3) amantadine 200 mg twice daily (AMA); 4) ribavirin 1 - 1.2
grams/day and amantadine 200 mg twice daily (RBV +AMA).
Non-responders
48 weeks - ETR
RBV (n=30) 25%
MMF (n=29) 28%
AMA (n=28) 11%
RBV + AMA 40%
(n=31)

Relapsers:
48 weeks-ETR
RBV (n=32) 61 %
MMF (n=29) 72%
AMA (n=31) 42%
RBV + AMA 71%
(n=31)

This ongoing study indicates that some patients who failed to
respond to standard interferon/ribavirin may benefit from an
additional course of therapy with pegylated interferon plus other
agents. However, these results must be viewed with several caveats.
First, it is anticipated the approximately 20% of EOT responders
will experience a virologic relapse after a course of interferon
plus ribavirin. Thus, the sustained response rates will be
considerably lower for all treatment groups. In addition, ribavirin
prevents relapse and there is little reason to believe that MMF or
AMA will prevent relapse in a similar manner. Consequently, one may
expect the sustained response rates to be considerably lower in the
MMF and AMA groups than in the groups that received ribavirin.
Furthermore, the medical rationale for the use of either MMF or AMA
is dubious at best and, while new and better therapies are urgently
needed, it remains doubtful that these agents will have any role in
the future management of chronic HCV infections.

Abstract 279. Retreatment of Interferon And Interferon-Ribavirin
Non-Responders with Peginterferon-alpha-2a (Pegasys) And Ribavirin:
Initial Results from the Lead-In Phase of the Halt-C Trial

The HALT-C trial was designed to determine if long term maintenance
interferon therapy, administered over 4 years, could prevent
histologic progression, reduce the development of hepatocellular
carcinoma and the need for hepatic transplantation in patients with
chronic HCV and advanced fibrosis or cirrhosis who remain HCV-RNA
(+) despite therapy. Since peginterferon plus ribavirin is more
effective than standard interferon/ribavirin for treatment of
chronic HCV all patients enrolled in the HALT-C trial were first
treated with peginterferon plus ribavirin during the lead-in phase
of this trial.

This study enrolled patients with advanced liver disease (Ishak
Fibrosis stage ³ 3) and no evidence of hepatic decompensation. All
patients had previously failed to respond to interferon-based
therapy administered for at least 12 weeks. After screening, all
patients received pegylated interferon alfa-2a (180 mcg weekly) plus
ribavirin (1 - 1.2 grams/day).

Dr. Adrian Di Bisceglie presented on-treatment virologic response
data on the first 268 patients who completed at least 20 weeks of
therapy within this ongoing study. For the purpose of this
presentation, viral response was defined as an undetectable HCV-RNA
level at treatment week 20. 15 (5.6%) patients discontinued therapy
prior to week 20. At week 20, 107 of 268 patients (40%) (based on an
intention-to-treat analysis) had an undetectable HCV RNA level.
These patients will continue therapy for an additional 28 weeks and,
per protocol, will not enter the "maintenance" phase of the study.
There were several important "sub-group" analysis presented. Persons
who had only failed prior interferon monotherapy were much more
likely to achieve a response than those who failed prior
interferon/ribavirin combination therapy (53% > 21%) and
African-Americans were significantly less likely to respond than
Caucasians (10% < 41%).

In addition, a large number of patients had dose reductions of the
PEG-interferon (53%), ribavirin (44%) or both (47%). Thus, while the
discontinuation rate was quite low (~5%), it remains uncertain if
such dose reductions will impair the overall effectiveness of the
therapy. Nonetheless, these results are encouraging and suggest that
persons with advanced liver disease who failed to respond
virologically to prior therapy may benefit from a course of
pegylated interferon/ribavirin.

Abstract 987. Peg-Interferon alpha-2b Plus Ribavirin for Treatment
of Patients with Chronic Hepatitis C Who Have Previously Failed to
Achieve A Sustained Virologic Response Following Interferon alpha-2b
or Interferon alph-2b Plus Ribavirin Therapy

In a poster session, Dr. Mark Sulkowski and colleagues presented
preliminary data from an ongoing multicenter study of pegylated
interferon alfa-2b (weight-based 1.5 mcg/kg weekly or fixed dose 100
mcg < 80 kg and 150 mcg > 80 kg weekly) plus ribavirin 800mg/day in
patients who failed to achieve a sustained response following
interferon-based therapy ("non-responders" and "relapsers").

Of 511 enrolled subjects, viral response data after 12-weeks of
therapy was available on 481 patients. Overall, 35% of patients had
an undetectable HCV RNA level after 12 weeks of therapy and no
significant difference was observed in viral response or adverse
events between patients who received fixed versus weight-based
PEG-interferon dosing. The week 12 viral response rate was 26.5%
among "non-responders" and 55.2% among "relapsers." As has been
observed in other studies, persons with HCV genotype 1 and
African-Americans were less likely to respond virologically. In this
study patients will remain on therapy for an ad