Posters –
Tuesday May 23, 2006 8:00AM Hepatitis C
HCV
Treatment Issues and Early Drug Development
S. Seiwert; S. W. Andrews; H. Yang; H. Tan; B.
Marafino; R. Rieger; R. B. Franklin; J. Pheneger; P. A. Lee; Y. Jiang; A. L.
Kennedy; S. M. Wenglowsky; M. R. Madduru; G. A. Doherty; K. R. Condroski; C.
Lemieux; L. Pieti Opie; F. Sullivan; N. Neitzel; G. P. Hingorani; J. Otten; B.
Brandhuber; G. Vigers; J. A. Josey; L. M. Blatt
Current
treatment options for chronic HCV infections provide sustained virologic
response rates of ~50%, indicating novel therapeutic approaches are needed. We
therefore embarked on a rational drug design campaign to produce inhibitors of
the HCV NS3/4A protease. ITMN 191 emerged from this discovery effort and was
nominated as a preclinical candidate. Here we describe the preclinical
characterization of ITMN 191.
In
biochemical assays using HCV NS3/4A protease domains derived from genotypes 1b,
1a, 2, or 3, the EC50 value of ITMN 191 is <300 pM, 400 pM, 400
pM, and 12.4 nM, respectively. Its EC50 value against full-length
genotype-1b protease is 900 pM. ITMN 191 retains subnanomolar to low-nanomolar
potency against the NS3/4A variants at positions A156 and D168 that confer
resistance to other experimental NS3/4A inhibitors. In a genotype-1b replicon
system EC50 = 2.1 nM and EC90 = 5.6 nM. ITMN 191 is 97.9%
bound by human serum protein, and its replicon potency is shifted modestly by
human serum. ITMN 191 does not inhibit a panel of selected serine proteases, a
broader ligand panel, or hERG ion channel. Its CC50 value is >50
μM. ITMN 191 does not inhibit CYP isoforms 1A2, 2C19, 2C9, or 2D6 at 10
μM; it inhibits roughly 33% of the activity of the 3A4 isoform at this
concentration. Use of CYP inhibitors show ITMN 191 to be metabolized by
multiple CYP isoforms. After 120 min incubation with rat, dog, human, or monkey
hepatocytes, 81%, 73%, 35%, or 19% of input compound remained intact, respectively.
After a regimen in which a human equivalent dose of 290 mg BID PO was
administered for 7 days, compound trough liver levels in rats and
cynomolgus monkeys were 390-fold and 52-fold the EC90 value,
respectively, after the last dose in the study. Plasma exposure was linear with
dose in both species to at least 300 mg/kg.
In
conclusion, ITMN 191 is a highly potent, orally absorbed inhibitor of the
NS3/4A protease found in the liver of rats and cynomolgus monkeys at levels
predictive of human efficacy. Based on these data, ITMN 191 has been nominated
for preclinical development and is currently undergoing IND-enabling
toxicologic assessment.
K. R. Condroski; H. Zhang; S.
Seiwert; J. A. Ballard; B. A. Bernat; B. Brandhuber; H. Colwell; D. Smith; G.
Vigers; S. W. Andrews; A. L. Kennedy; Y. Jiang; S. M. Wenglowsky; J. A. Josey;
L. M. Blatt
A
need exists for novel treatments of chronic hepatitis C since the current
standard of care, PEG IFN-α-2 + ribavirin, results in a sustained
virologic response in ∼50% of patients. Recent advances in the field have
identified the HCV serine protease NS3/4A as a promising target for drug
discovery. Developing potent inhibitors of NS3/4A has been challenging from a
medicinal chemistry standpoint due to its relatively flat and largely
featureless binding site. Additionally, rapid error-prone replication leading
to multiple active genotypes and quasi-species has slowed the drug discovery
process for HCV NS3/4A inhibitors. In our effort to design potent inhibitors of
HCV NS3/4A protease we used an iterative structure-based design approach
powered by protein crystallography that guided the rational design of analogs
leading to the effective optimization of the P2 moiety, the linker, the P1’
moiety and contacts to the NS3/4A catalytic triad. By gaining potency from
optimized contacts in each region of the target, it was possible to achieve
exceptionally potent NS3/4A inhibitors that maintain potency across genotypes
and mutant strains. These efforts resulted in identification of ITMN 191, a
potent, selective HCV NS3/4A protease inhibitor. Analysis of a crystal
structure of an ITMN 191–NS3/4A protease complex led to an understanding of the
structural factors responsible for the subnanomolar potency of ITMN 191 in
NS3/4A of genotype 1 and its significant potency against NS3/4A derived from
HCV genotypes 2 and 3. In addition, these studies inform the differences in
activity observed for prototypical peptide-based protease inhibitors such as
VX-950 and SCH 503034. In conclusion, these studies rationalize the potency
characteristics of the preclinical candidate ITMN 191.
R. Rieger; P. A. Lee; S. Seiwert;
S. W. Andrews; G. P. Hingorani; T. K. Pope; J. Pheneger; N. Neitzel; R. B.
Franklin; J. A. Josey; L. M. Blatt
Inhibition of the HCV serine
protease, NS3/4A, represents a promising new strategy for control of chronic
HCV infection. Given that viral replication of HCV is reported to occur
primarily in hepatocytes, achieving high drug concentrations in liver is
believed to be critical to the clinical success of protease inhibitors. In
addition, clinical trials with peptide-based NS3/4A protease inhibitors have
demonstrated a positive correlation between the magnitude of antiviral effect
and the trough concentration of drug in plasma, which is thought to be a
surrogate for trough concentrations of drug in liver. With the goal of
identifying potent NS3/4A protease inhibitors providing high liver
concentrations, particularly at trough, we analyzed a series of macrocyclic
peptidomimetic inhibitors for plasma pharmacokinetic (PK) parameters and tissue
concentrations (liver and heart) following a single oral dose of 30 mg/kg in
Sprague-Dawley rats. These data demonstrated that modest structural changes
resulted in radically different compound ratios between liver, plasma, and
heart. ITMN 191 provided an average liver Cmax of 3,098-fold the replicon EC90
value and much lower exposures in plasma (10-fold less) and heart (50-fold
less). ITMN 191 concentrations in plasma and liver were further examined in
multidose PK studies in rats, dogs, and monkeys. Following a 7-day PO BID
dosing regimen of 30 mg/kg in rats, average concentrations of compound in liver
at apparent Cmax and trough were 1,646-fold and 152-fold the EC90 value,
respectively, after the last dose on Day 7. A liver-to-plasma ratio of 2.4:1
was observed at apparent Cmax. Following a 7-day PO BID dosing regimen of 15
mg/kg dose in beagle dogs, average concentrations of compound in liver at
apparent Cmax and trough were 3,048-fold and 58-fold the EC90 value,
respectively, after the last dose on Day 7. A liver-to-plasma ratio of 51:1 was
observed at apparent Cmax. Lastly, following a 7-day PO BID dosing regimen of
15 mg/kg dose in cynomolgus monkeys, average concentrations of compound in
liver at apparent Cmax and trough were 238-fold and 52-fold the EC90 value,
respectively, after the last dose on Day 7. A liver-to-plasma ratio of 70:1 was
observed at apparent Cmax. In conclusion, the high Cmax and trough liver
concentrations of ITMN 191 across three preclinical species contributed to the
decision to nominate it for further development.
S. Brand; J. Dambacher; F.
Beigel; M. Storr; T. Olszak; K. Zitzmann; B. Goeke; C. J. Auernhammer; A. Kaul;
R. Bartenschlager; H. Diepolder
Background:
IL-28A and IL-29 belong to a novel
group of interferons named IFN-lambdas. Recently, we demonstrated antiviral
properties for these cytokines in intestinal epithelial cells (Am J Physiol
Gastrointest Liver Physiol 2005; 289:G960-8).
Aims:
The aim of this study was to analyze
receptor expression, signal transduction and antiviral functions, particularly
against hepatitis C virus (HCV) infection, mediated by IL-28A and IL-29 in hepatic
cells.
Methods:
The mRNA expression of IL-10R2 and
IL-28R1, the receptor subunits required for IL-28A and IL-29 signaling, was
determined by RT-PCR in hepatic cell lines. Lambda-interferon induced signal
transduction was analyzed by Western blotting using phospho-specific antibodies
against STAT proteins. The activation of the antiviral proteins was analyzed by
luciferase assays and Northern Blot analysis. The effect of IL-28A and IL-29 on
replication of HCV was analyzed in Huh-7 cells stably expressing HCV replicons
and firefly genes using luciferase assays. The IL-28A mRNA expression in HCV
infected human liver biopsy samples (n=10) and control liver biopsy samples
(n=19) was measured by quantitative PCR. To analyze regulation of IL-28 mRNA
expression in viral infection in vivo, C57/BL6 mice were infected i.v. with one
million pfu murine cytomegaly virus (MCMV) of the Smith strain for 45 hours.
Murine IL-28 mRNA expression in liver tissue was measured by RT-PCR.
Results:
Both receptor subunits necessary for
IFN-lambda signaling (IL-10R2 and IL-28R1) are expressed in the hepatic cell
lines HepG2, Hep3B and Huh-7. The IL-28R receptor complex is functional
resulting in increased phosphorylation of STAT-1 and STAT-3 proteins following
IL-28A and IL-29 stimulation. Moreover, both cytokines activate the
transcription of the antiviral proteins MxA and 2’,5’-OAS. 100 ng/ml of IL-28A
and IL-29 decreased HCV replication in Huh-7 cells to 1.76 ± 0.08% and 1.38 ±
0.20%, respectively (control 100%, IFN-alpha 10 U: 0.31 ± 0.14%). IL-28A mRNA
expression was significantly higher in liver biopsy samples of HCV patients
than in samples of patients with non-viral hepatitis (36.7-fold increase;
p<0.05). Similarly, murine IL-28 mRNA expression was increased 3-fold in
liver tissue from MCMV infected mice compared to uninfected control mice
(p=0.003).
Conclusion:
Hepatic IL-28 mRNA expression is
elevated in human HCV and murine CMV infection and IFN-lambda mediated
signaling inhibits HCV replication in vitro. These results suggest that
IFN-lambda could play a role in the antiviral immune defense against HCV and
may have a therapeutic potential.
D. Dugourd; R. W. Siu; J. R. Fenn
Celgosivir
is an alpha glucosidase inhibitor that is being developed for the treatment of
Hepatitis C virus (HCV) infections in humans. The purpose of this study was to
evaluate the in vitro antiviral activity of celgosivir and its major
metabolite, castanospermine, when combined with current approved therapies
(ribavirin, interferon α2b, or both) in a surrogate model of HCV (Bovine
Viral Diarrhea Virus (BVDV)). Compounds alone or in combination were tested
against BVDV in infected Madin-Darby Bovine Kidney (MDBK) cells. Synergies were
analyzed using isobolograms and volume of synergy measurements (MacSynergy II™
software). The celgosivir-interferon α2b combination was significantly
more synergistic than the celgosivir-ribavirin combination (~3-fold), or the
ribavirin-interferon α2b combination (~2-fold). Similarly, the
castanospermine-interferon α2b double combination was more synergistic
than the castanospermine-ribavirin combination (~5-fold), or the
ribavirin-interferon α2b combination (~3.3-fold). The combinations of
celgosivir-interferon α2b or castanospermine-interferon α2b led to
significant decreases in the EC50s of celgosivir (up to >20-fold) and
castanospermine (up to >50 fold). The effective EC50s of celgosivir or
castanospermine were further reduced by the addition of ribavirin. The
cytotoxicity of the double and triple combinations was additive or less than
additive, indicating that combinations of celgosivir or castanospermine with
ribavirin and/or interferon α2b were generally less toxic than expected.
These results indicate that the combination of celgosivir with interferon
α2b or with interferon α2b and ribavirin may be effective in the
treatment of HCV.
S. Abe; R. Narita; T. Oto; A.
Tabaru; M. Otsuki
Background and Aims:
It
is well-known that the patients with HCV genotype 2a/2b have higher sustained
virological response than those with genotype 1b after interferon (IFN)
treatment in chronic hepatitis C (CHC). However, it is not clarified whether
there is a difference in activation of T lymphocytes among HCV genotypes after
IFN treatment. We evaluated the relationship between HCV genotypes and the host
immune response by examining the levels of serum soluble interleukin-2 receptor
(sIL-2R) that reflects activation of T lymphocytes.
Methods:
One
hundred and eleven CHC patients were included. Forty patients received IFN
monotherapy (group A): 6-10 million units (MU) of IFN-α2b daily for 14
days followed by 3 times per week (tiw) for a total of 24 weeks, whereas 71
patients received the combination therapy with IFN and ribavirin (RBV) (group
B): 6-10 MU of IFN-α2b daily for 14 days followed by tiw for a total of 24
weeks and 600 or 800 mg RBV per day. We measured serum sIL-2R levels in those
patients before (T0) and 2 weeks (T2) after the treatment.
Results:
The
sustained response rates in genotype 2a/2b patients were significantly higher
than those in genotype 1b patients both in group A (77.8% vs 38.5%, P = 0.0146)
and B (88.9% vs 25.0%, P < 0.0001). In IFN-sustained responders, sIL-2R
levels at T2 were significantly higher than those at T0 both in group A and B
(P = 0.0049 and P = 0.0002, respectively). In IFN-nonresponders, sIL-2R levels
at T2 were not different from those at T0 (P = 0.0555) in group A, but were
significantly higher than those at T0 (P = 0.0143) in group B. In genotype 1b
patients, sIL-2R levels at T2 were not different from those at T0 (P = 0.1520)
in group A, but were significantly higher than those at T0 (P = 0.0274) in
group B. In genotype 2a/2b patients, sIL-2R levels at T2 were significantly
higher than those at T0 both in group A and B (P = 0.0025 and P < 0.0001,
respectively).
Conclusion:
These
findings suggest that the activation of T lymphocytes after IFN treatment
contributes to high sustained response rates, especially in patients with HCV
genotype 2a/2b.
E. Rubinchik; D. J. Erfle; J. J.
Clement; C. J. Pasetka
Celgosivir is a novel antiviral agent
currently in clinical development for the treatment of chronic hepatitis C
virus (HCV) infection. Non-clinical and clinical studies indicate that,
following oral administration, celgosivir (6-O-butanoyl castanospermine) is
readily converted to its primary metabolite castanospermine. Both celgosivir
and castanospermine inhibit alpha-glucosidase-I, an enzyme that is involved in
the processing of viral glycoproteins. In peripheral blood, celgosivir is
detected only sporadically for a short period after dosing while
castanospermine is present at significantly higher levels for a much longer
period. However, the extent of liver exposure to celgosivir has not been
conclusively established as the low peripheral blood levels may be the result
of first-pass metabolism. The objective of this study was to determine
celgosivir and castanospermine levels in the portal and caudal venous blood
during the first hour following oral celgosivir dosing.
Five male Sprague-Dawley rats with
portal vein catheters were administered celgosivir orally at 400 mg/kg. Blood
samples were collected from the portal and caudal veins at pre-determined
time-points. The heparinised blood was immediately extracted with an acetone/methanol
mixture. Celgosivir and castanospermine concentrations were determined using
high performance liquid chromatography coupled with mass spectrometric
detection.
Following oral dosing, celgosivir was
detected in both portal and caudal venous blood. Celgosivir concentrations in
the portal vein were on average 4.4-13.2 times higher than those in peripheral
circulation. The average maximum concentration (Cmax) of celgosivir in the
portal vein was 1,887 ng/mL with an area under the curve (AUC0-60 min)
of 1,003 ng.hr/mL. Comparatively, the portal vein Cmax of castanospermine was
105,630 ng/mL with an AUC0-60 min equivalent to 63,876 ng.hr/mL. The
average celgosivir concentration in portal blood was up to 3.4% of the total
amount of both analytes.
Based on the results described, it
was concluded that following oral celgosivir dosing the liver was exposed to
both celgosivir and castanospermine, with the majority of drug being converted
to castanospermine prior to liver exposure. This conversion most likely
occurred in the gastrointestinal tract.
D. Jensen; A. Di Bisceglie; N.
Gitlin; B. Freilich; K. Reddy; V. Feinman; S. Arora; P. Marcellin
The REPEAT study is currently
investigating the efficacy/safety of Peg-IFNα-2a (40KD) plus RBV in
previous non-responders to Peg-IFNα-2b (12KD)/ribavirin. Here, we report
results of a protocol-planned interim efficacy/safety analysis after 12 weeks
of re-treatment.
Methods:
Non-responders to ≥12 weeks of
approved doses of Peg-IFNα-2b (12KD)/ribavirin who remained HCV RNA
positive throughout treatment were eligible. 950 patients were randomized to 1
of 4 groups: Peg-IFNα-2a (40KD) 360 μg/week for 12 weeks then 180
μg/week for a further 60 or 36 weeks (Arms A and B, respectively);
Peg-IFNα-2a (40KD) 180 μg/week for 72 or 48 weeks (Arms C and D,
respectively). All 942 treated patients received RBV 1000/1200 mg/d. HCV RNA
was measured by quantitative (≥600 IU/mL) or qualitative (≥50
IU/mL) PCR assay. Data from Arms A+B (Peg-IFNα-2a [40KD] fixed-dose
induction), and Arms C+D (Peg-IFNα-2a [40KD] standard dose) were combined.
Results
(Table):
Baseline characteristics were similar
in the 2 groups. At week 12, a significantly greater proportion of patients
treated with fixed-dose induction Peg-IFNα-2a (40KD) had an early
virological response (EVR; HCV undetectable, HCV non-quantifiable, or ≥2-log10
drop in HCV RNA), compared with standard-dose Peg-IFNα-2a (40KD). No
substantial increase was seen in the incidences of adverse events (AEs) and
serious AEs in patients treated with fixed-dose induction vs standard-dose
Peg-IFNα-2a (40KD).
Conclusion:
Over the first 12 weeks of
retreatment, standard doses (180 μg/week) of Peg-IFNα-2a (40KD) plus
RBV are associated with an EVR rate of 45% in previous non-responders to
Peg-IFNα-2b (12KD)/ribavirin. A fixed induction dose (360 μg/week) of
Peg-IFNα-2a (40KD) plus RBV was found to be even more effective than
standard doses at inducing an EVR (62%); moreover, the safety profile of
Peg-IFNα-2a (40KD) plus RBV did not appear to be compromised in patients
receiving fixed induction doses.
|
N (%)†
|
Peg-IFNα-2a
(40KD) dose during weeks 1−12 (+RBV
1000/1200mg/d) |
|
|
180
µg/week (n=469) |
360
µg/week (n=473) |
|
Male |
319 (68) |
297 (63) |
|
Mean age ± SD, yrs |
48.8 ± 8.8 |
48.3 ± 9.1 |
|
Caucasian/Black |
413 (88)/42 (9) |
418 (88)/39 (8) |
|
Genotype 1 / 2 or 3 |
425 (91) / 16 (3) |
429 (91) / 17 (4) |
|
Mean HCV RNA ± SD, x106 IU/mL |
4.9 ± 5.7 |
5.4 ± 6.6 |
|
Cirrhosis/advanced fibrosis |
133 (28) |
119 (25) |
|
Median duration of previous treatment,
weeks |
28 |
28 |
|
EVR‡ at week 12 |
210 (45) |
291 (62)* |
|
Peg-IFNα-2a (40KD) dose modified or
discontinued |
63 (13) |
88 (19) |
|
≥1 AE/serious AE |
430 (92)/19 (4) |
441 (93)/10 (2) |
Abstract
T1801 – Impact of Therapy of Chronic Hepatitis C (CHC) on Quality of Marital
Relationships.
M.
O'Brien; L. S. Rosenthal; E. Lebovics
BACKGROUND:
Impairment
of quality of life by therapy of CHC has been documented in studies utilizing validated
social science questionnaires. Specific impact on close valued relationships
such as marital or significant others has not been examined.
METHODS:
Questionnaires
were sent to 445 consecutive patients treated with either interferon-alpha 2b
or pegylated interferon plus ribavirin. Questions addressed communication
within the relationship, sexual intimacy, ability to share household
responsibilities, quality of shared leisure time, arguing, and overall quality
of the marriage prior to treatment initiation, during treatment, and after
treatment completion. Responses were scored on a scale of 1 to 5, with 5 being
the highest functioning. Also, patients were asked whether they separated or
divorced during or shortly after their treatment and if this was attributable
to therapy.
RESULTS:
Of
114 respondents, 15 patients (13.1%) were either separated (n=10; 8.8%), or
divorced (n=5; 4.4%) during or shortly after treatment. Six of the 10 who
separated and 2 of the 5 who divorced stated this was in part secondary to CHC
therapy. Mean scores for all parameters assessing aspects of the marital
relationship significantly decreased from baseline to during therapy
(p<0.001 for each) and returned to baseline after therapy. 35% of patients
had no impairment in communication, 49% had a drop of 1-2 points, and 12% a
drop of 3-4 points. 30% reported no change in sexual intimacy, 50% had a drop
of 1-2 points, and 19% a drop of 3-4 points. 27% reported no change in sharing
household responsibilities, 48% had a drop of 1-2 points, and 23% a drop of 3-4
points. 29% reported no change in quality leisure time spent with spouse, 32%
had a drop of 1-2 points, and 16% a drop of 3-4 points. 49% reported no change
in frequency of tense arguments with significant other, 37% had a drop of 1-2
points, and 7% a drop of 3-4 points. 53% reported no impairment in overall
quality of marriage, 37% had a drop of 1-2 points, and 7% a drop of 3-4 points.
CONCLUSIONS:
· CHC therapy impairs marital relations and may
contribute to separation and divorce.
· Patients should be counseled prior to initiation of
therapy of these potentially life altering effects, and appropriate care taken
to prevent such outcomes.
· Future studies should address whether these results
differ from a population matched for psychosocial conditions.
P.
Kwo; I. Jacobson; R. Brown; B. Freilich; B. Afdhal; J. Santoro; S. Becker; A.
Wakil; D. Pound; E. Godofsky; R. Strauss; D. Bernstein; S. Flamm; N. Bala; V.
Arraya; M. Davis; H. Monsour; J. Vierling; F. Regenstein; V. Balan; M.
Dragutsky; M. Epstein; R. Herring; L. H. Griffel; C. Brass
Background:
Registration trials using PEG IFN and ribavirin,
conducted by investigators experienced in the treatment of CHC have
demonstrated SVR rates of 54-56%. Whether these SVR rates can be replicated in
clinical practice in the community remains unclear. Aim: To determine
investigator factors that affect SVR rates in patients receiving PEG IFN
alfa-2b 1.5 ug/kg/week with ribavirin for HCV treatment.
Methods:
Patients in academic or community settings with CHC
were randomized to PEG IFN alfa-2b 1.5 ug/kg once weekly plus RBV 800 mg/day or
RBV based on weight. Treatment was 48 weeks for patients with HCV G1, patients
with G2 or 3 were randomized to 24 or 48 weeks. Follow-up for all patients was
24 weeks. HCV RNA was determined by PCR. 25 academic and community investigators,
all having participated in CHC registration trials or having extensive
experience in HCV therapy served as regional PIs . High enrollment sites (≥
25 patients enrolled) had selected data verified by study monitor. Analyses
performed by logistic regression analysis. Results: 225 sites enrolled 4913
patients with overall SVR of 43.6%., 923/4913 (18.8%) were treated at regional
PI sites, 3990/4913 were at non-regional PI sites(81.2%). 3114/4913 patients
were treated at monitored sites (63.4%). 1800/4913 patients (36.6%) dropped out
(DO).
Conclusions:
1. Patients within regional PI sites are more like to
achieve SVR and less likely to drop out than patients within non-regional PI
sites
2. Within non-monitored sites (<25 patients
enrolled), patients within regional PI sites are more like to achieve SVR and
less likely to drop out than patients within non-regional PI sites
3. No differences were seen in SVR or DO for monitored
and non-monitored sites.
Research Support: Schering Plough
|
SVR all
patients |
SVR
regional PI patients |
SVR
non-regional PI patients |
OR |
p-value
|
|
2140/4913(43.56%) |
445/923 (48.21%) |
1695/3990 (42.48%) |
1.261 |
0.0016 |
|
SVR all patients |
SVR monitored sites |
SVR non-monitored sites |
|
|
|
2140/4913 (43.56%) |
1372/3114 (44.06%) |
768/1799 (42.69%) |
1.057 |
0.3518 |
|
SVR all monitored patients |
monitored regional SVR |
monitored non-regional SVR |
|
|
|
1372/3144 (43.64%)) |
351/763 (45.88%) |
1021/2351 (43.43%) |
1.11 |
0.2121 |
|
SVR all non-monitored patients |
SVR regional non-monitored patients |
SVR non-regional non-monitored patients |
|
|
|
768/1799 (42.69%) |
94/160 (58.75%) |
674/1639 (41.12%) |
2.039 |
<0.0001 |
|
DO all patients |
DO regional PI patients |
DO non-regional PI patients |
|
|
|
1800/4884(36.86%) |
312/921 (33.88%) |
1488/3963(37.55%) |
0.852 |
0.0376 |
|
DO all patients |
DO monitored sites |
DO non-monitored sites |
|
|
|
1800/4884 (36.86%) |
1124/3104 (36.21%) |
676/1780 (37.98%) |
0.927 |
0.2182 |
|
DO all monitored patients |
monitoredregional DO |
monitored non-regional DO |
|
|
|
1124/3104 (36.21%) |
268/762 (35.17%) |
856/2342 (36.55%) |
0.942 |
0.4932 |
|
DO all non-monitored patients |
DO regional non-monitored patients |
DO non-regional non-monitored patients |
|
|
|
676/1780 (37.98%) |
44/159 (27.67%) |
632/1621 (38.99%)) |
0.599 |
0.0054 |
Abstract T1803 – Employment Status and Work Performance during Therapy
of Chronic Hepatitis C (CHC)
M.
L. O'Brien; L. S. Rosenthal; E. Lebovics
BACKGROUND
Impairment of quality of life by therapy of CHC has
been documented in studies utilizing validated social science questionnaires.
Impact on work performance is ill-defined.
METHODS
Questionnaires were sent to 445 consecutive patients
who underwent treatment with either interferon alpha 2b or pegylated interferon
plus ribavirin. Six questions addressed ability to concentrate at work and cope
with job stress, work stamina, perception of evaluation by superiors,
absenteeism, and overall quality of work performed. Responses were scored 1 to
5 (very poor/poor/fair/good/excellent) for before, during, and after treatment.
Also, patients were asked whether they discontinued work (fired/quit/disability
leave) and whether CHC therapy contributed to any change in employment status.
RESULTS
116 patients responded. Among this group, 30 (26%)
were either fired (n=6, 5%), quit (n=2, 2%) or took disability leave (n=22,
19%) from their jobs during CHC treatment. All patients who were fired or quit
and 86% of those who took leave attributed their change in employment status to
adverse effects of CHC therapy. Mean baseline scores (prior to CHC therapy) for
each of the 6 work performance questions was between 4 and 5. During therapy,
mean scores for each question dropped to between 2 and 3 (p<.001). Scores
returned to baseline levels after therapy. Of note, 59% of patients reported
that CHC therapy caused a decline in their overall work performance.
CONCLUSIONS
·
In this series CHC therapy was associated with a 26% rate of
discontinuation of employment due to either termination or temporary disability
leave.
·
59% of patients reported a significant impairment of overall
work performance.
·
On the whole, there
was no perception of work performance impairment at baseline and after therapy
was completed. Patients should be counseled accordingly prior to initiation of
therapy.
Abstract T1804 – The
Treatment of Chronic Hepatitis C in HIV Infected Patients: A Meta-Analysis
A. I. Kim; R. Bouajram; A. Dorn;
S. Saab
Background:
Hepatitis C (HCV) disease appears
accelerated in patients coinfected with human immunodeficiency virus (HIV). The
objective of our study was to further understand incremental improvement and
safety concerns with combinations of peginterferon, interferon and ribavirin
based on data obtained from prospective randomized contolled trials (RCTs).
Methods:
A search of MEDLINE and the Cochrane
database, and a hand search of abstracts from national meetings was performed.
We extracted data on baseline characteristics, types of treatment, efficacy,
and adverse events.
Results:
In 6 RCTs, 1756 patients were
randomized. Sustained virologic response (SVR) was greater for patients treated
with peginterferon plus ribavirin compared to patients treated with interferon
plus ribavirin (odds ratio [OR], 3.00; 95% confidence interval [CI], 2.27-3.96;
P=<0.0001)(Figure 1). This increased SVR with peginterferon and ribavirin
was also true for patients with HCV genotypes 1 or 4 (OR, 4.40; CI 2.75-7.03;
P=<0.0001) and genotypes 2 or 3 (OR, 2.56; CI 1.71-3.85; P=<0.0001). SVR
rates were also higher with peginterferon and ribavirin as compared to
peginterferon monotherapy (OR, 2.60; CI, 1.84-3.67; P=<0.0001). Severe
adverse effects (OR, 1.09,CI, 0.74 – 1.4, P=<0.59) and withdrawal rates (OR,
0.97,CI, 0.75 – 1.25, P=<0.79) were similar between patients treated with
peginterferon and ribavirin compared to patients treated with interferon and
ribavirin.
Conclusion:
·
Patients with chronic HCV with HIV coinfection have a
greater likelihood of achieving SVR with treatment of peginterferon plus
ribavirin.
·
The likelihood of serious adverse effects and study
withdrawal were similar.
H. B. El-Serag; K. K. Patel; N. Wintfeld; J. Green; S.
D. Sullivan
Introduction
Patients
with mild CHC treated with peginterferon alfa-2a (40KD) plus ribavirin attain
higher sustained virological response (SVR) rates than patients with incomplete
septa or cirrhosis [1]. This report utilizes these findings to assess the
cost-effectiveness of treating patients with mild CHC with peginterferon
alfa-2a (40KD) plus ribavirin.
Methods:
Data
for HCV genotype 1 patients with mild CHC [1] were obtained from two phase III
multinational, randomized, controlled trials [2,3]. Mild CHC was defined as a
fibrosis score of F0, F1, or F2 using the METAVIR scale. Treatment of patients
with mild CHC with peginterferon alfa-2a (40KD) (180 µg/week) plus ribavirin
(1000/1200 mg/day) resulted in an SVR of 56% (95% CI 50-63%) [1]. The life-time
disease progression to cirrhosis, hepatocellular carcinoma, and liver
transplant in patients who failed to achieve an SVR was based on published data
[4]. The impact of EVR at week 12 (85%; 95% CI 80-89%) on the cost of treatment
was included in the model. Quality of life weights and resource costs were
based on published literature. Costs related to the treatment of adverse events
were not included in the analysis.
· Costs (in US$ 2004) and benefits were discounted at
3%.
· Sensitivity analyses were performed to evaluate
uncertainty in model parameters.
· The model was run until 100% of the cohort had
died.
· The incremental cost-effectiveness ratio (ICER) was
computed as the incremental total medical cost divided by the incremental gain
in quality-adjusted life-years (QALYs)
Results:
Cost-effectiveness
Compared
with no treatment, peginterferon alfa-2a (40KD) plus ribavirin was associated
with an increase in 1.46 QALYs in HCV genotype 1 patients with mild chronic
hepatitis C, yielding an incremental cost per QALY gained of $3396.
Sensitivity analyses
· Despite wide variations in model parameters,
including an SVR rate as low as 50%, an EVR rate as low as 80%, and a time
horizon as short as 20 years, the ICER did not exceed $27,000 per QALY
gained.
· The ICER did not fall below the commonly cited
threshold in the USA of $50,000 per QALY gained until the SVR rate was
decreased to as low as 13%. This provides
further evidence of the robustness of the model results.
· The most influential parameters in this analysis
were the time horizon and the discount rate.
Conclusion:
· Compared with no treatment, for adults with mild
CHC, peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) is a
cost-effective treatment strategy in the US setting.
· The cost-effectiveness of peginterferon alfa-2a
(40KD) plus ribavirin compared with no treatment in these patients is most
likely a result of a reduction of the incidence of future complications,
including cirrhosis, hepatocellular carcinoma and liver transplantation, and an
increase in life expectancy and QOL.
· The practice of determining the need for antiviral
therapy based on histology may need reassessment in view of these findings.
1Shiffman et al. Gastroenterology 2005;128(Suppl)
Abstr S1568
2Zeuzem et al. Gastroenterology 2004;127:1724
3Fried et al. NEJM 2002;347:975
4Hui et al. J Hepatol 2003;38:511
I. M. Jacobson; R. S. Brown;
B. Freilich; N. Afdhal; P. Kwo; J. Santoro; S. Becker; A. Wakil; D. Pound; F.
Ahmed; L. H. Griffel; C. A. Brass; G. WIN-R Study
Background:
Pretreatment Hepatitis C (HCV) viral
levels have been associated with the likelihood of achieving a sustained
virologic response (SVR) during the course of antiviral therapy with pegylated
interferon and ribavirin (RBV).
Aim:
To assess the relationship of pretreatment
HCV viral load with SVR rates in patients with genotype 1 using data from the
WIN-R Trial, the largest HCV therapeutic trial to date.
Methods:
Patients in a community setting with
chronic hepatitis C were randomized to Peg IFN alfa-2b 1.5 µg/kg once weekly
plus RBV 800 mg/day or RBV based on weight: <65 kg- 800 mg/day, 65 to <85
kg- 1000 mg/day, 85 to < 105 kg- 1200 mg/day, and 105-125 kg- 1400 mg/day.
Treatment was 48 weeks for patients with HCV genotype 1. Follow-up for all
patients was 24 weeks. HCV RNA was determined by PCR (Taqman/SPRI) at weeks 24,
48 and 72. SVR rates were analyzed according to baseline HCV viral loads in
patients with genotype 1. Low viral load was defined as < 2 million cop/ml;
high viral load was defined as ≥ 2 million cop/ml.
Results:
225 sites enrolled 4913 patients
(2444 FD and 2469 WBD) who received at least one dose of drug.
Intention-to-treat analysis showed a significant improvement (p=0.02) in SVR
with WBD (44%) compared to FD (41%). 3018 patients had genotype 1 with an
overall SVR rate of 33% (984/3018). In patients with genotype 1, SVR rates were
significantly higher (p = 0.006) in patients with a low HCV viral load (35%,
452/1279) than in those with a high viral load (31%, 532/1739). SVR rates in
patients with viral load < 2 million cop/ml were compared with patients with
viral loads ≥ 2 million cop/ml as shown in the Table. Reductions in SVR
were noted in more patient groups with baseline HCV RNA levels of 2-15 million
cop/ml than in patients with > 15 million cop/ml.
Conclusion:
Within the genotype 1 patient
population with high viral load as defined traditionally (≥2 million
cop/ml), those with very high viral loads do not have impaired rates of SVR.
|
HCV
viral load (cop/ml) |
SVR
(n) |
p
value* |
|
< 2 million |
35% (452/1279) |
- |
|
2-5 million |
30% (167/550) |
0.039 |
|
5-10 million |
30% (153/504) |
0.456 |
|
10-15 million |
25% (70/279) |
0.001 |
|
15-20 million |
39% (53/136) |
0.401 |
|
20-30 million |
35% (61/174) |
0.942 |
|
30+ million |
29% (28/96) |
0.222 |
K. Tang; E. Herrmann; E. Paulon;
I. Pachiadakis; N. Tatman; R. Williams; S. Zeuzem; N. Naoumov
Background
and aims:
48 weeks of peginterferon combination
therapy is the current consensus recommendation for the treatment of chronic
hepatitis C genotype 1 (CHC-G1) patients. The likelihood of a SVR is increased
considerably among patients showing an early on-treatment viral response (EVR).
We aimed to establish whether shorter durations of this treatment could be
given without a compromise in therapeutic efficacy.
Methods:
Forty-five treatment-naïve,
non-cirrhotic CHC-G1 patients were treated with peginterferon-α2a plus
ribavirin (P2aR). Patients with undetectable HCV RNA within 12 weeks of
treatment were randomised to continue a further 12, 24, or 36 weeks of
treatment from the time of viral clearance. The remaining patients all received
48 weeks of the same treatment unless EVR was not attained. Plasma HCV RNA was
quantitated in all patients by real-time RT-PCR (TaqMan™) at days: 0, 1, 2, 3
and weeks 1, 2, 4, 8, 12, and monthly thereafter. Early viral kinetic patterns,
during treatment, were determined by mathematical modelling. Hepatocyte HCV RNA
was measured to examine relationships with treatment duration and outcome.
Results:
·
32/45 (71%) patients had undetectable HCV RNA by 12
weeks of treatment (TW12).
·
11 patients were randomised to receive a further 12
weeks of treatment (G12), 10 received 24 weeks (G24), and 11 had a further 36
weeks of therapy (G36).
·
Of the remaining 13 patients (G48), 10 had an EVR, and
had a full 48 weeks of treatment.
·
ITT analyses showed EVR in 42/45 patients (93%), ETR
89%, and SVR 56%. Among patients with undetectable HCV RNA by TW12, 21/32 (66%)
had a SVR.
·
G12 patients underwent a mean treatment duration of
18.9±3.6 weeks, with SVR in 5/11 patients (46%),
·
G24 patients were treated for 31.6±3 weeks, SVR 8/10
patients (80%), and G36 patients were treated for 43±10.4 weeks, SVR in 8/11
patients (73%).
·
Duration of treatment and viral load at TW12 were
found to be significant predictors of SVR by multivariate analyses.
·
Viral kinetic parameters from mathematical modelling
did not differ significantly between G12, G24, and G36.
·
The mean antiviral efficacy (ε) was lower in G48
(49.5% vs 86.3%, p=0.025), as was the treatment-induced infected cell loss
(Mδ) (0.17 vs 0.58/day, p=0.019), compared to the randomised groups
combined.
Conclusions:
·
In HCV-G1 patients, a minimum of 24 weeks of
viremia-free time on P2aR is required for achieving a high rate of SVR.
·
32 weeks of total treatment duration appears
sufficient to obtain SVR in a substantial subset of patients showing rapid viral clearance.
·
Prolonged therapy above 48 weeks may be necessary for
slow responders to achieve a good outcome.
N. Gitlin; A. Di Bisceglie; P. Marcellin;
H. Bonkovsky; R. Rai; M. Rizzetto; G. Teuber; D. Jensen
REPEAT will assess the
efficacy/safety of Peg-IFNα-2a (40KD) + RBV in prior non-responders to
Peg-IFNα-2b (12KD)/ribavirin. We report outcomes in patients (pts) with
cirrhosis/advanced fibrosis according to geographic region from a
protocol-planned interim efficacy/safety analysis after 12wks of retreatment in
REPEAT.
Methods:
Prior non-responders to ≥12wks
of Peg-IFNα-2b (12KD)/ribavirin who were HCV RNA positive throughout
treatment were eligible. 950 pts were randomized to 1 of 4 groups:
Peg-IFNα-2a (40KD) 360μg/wk for 12wks then 180μg/wk for 60 or 36
wks (Arms A or B); Peg-IFNα-2a (40KD) 180μg/wk for 72 or 48 wks (C or
D). All 942 pts treated received RBV 1000/1200mg/d. HCV RNA was measured by
quantitative (≥600 IU/mL) or qualitative (≥50 IU/mL) PCR at
baseline and after 12 wks' retreatment. Data from Arms A+B (Peg-IFNα-2a
[40KD] induction dose), and C+D (Peg-IFNα-2a [40KD] standard dose) were
combined. Outcomes were assessed in pts with a local baseline histological
diagnosis of cirrhosis/advanced fibrosis.
Results
(Table):
Cirrhosis/advanced fibrosis was
present in 133/469 pts (28.4%) receiving Peg-IFNα-2a (40KD) 180μg/wk
and 119/473 pts (25.2%) receiving Peg-IFNα-2a (40KD) 360μg/wk.
Baseline characteristics were generally similar in the 2 groups. At wk 12, more
pts with cirrhosis/advanced fibrosis receiving induction-dose Peg-IFNα-2a
(40KD) achieved an early virological response (EVR; HCV RNA undetectable,
unquantifiable or ≥2-log10 drop), vs standard-dose Peg-IFNα-2a
(40KD). Virological response rates in pts with cirrhosis/advanced fibrosis were
similar in US/Canadian and European/Brazilian pts across both treatment groups.
Conclusion:
Induction-dose (360μg/wk)
Peg-IFNα-2a (40KD) (PEGASYS®) + RBV (COPEGUS®) is more effective than
standard-dose (180μg/wk) Peg-IFNα-2a (40KD) + RBV over the first 12
wks of retreatment in pts with cirrhosis/advanced fibrosis who have previously
failed to respond to Peg-IFNα-2b (12KD)/ribavirin. Outcomes in these pts
do not appear to differ according to geographic region.
|
|
Peg-IFNα-2a (40KD) dose during wks 1−12
(+RBV 1000/1200mg/d) |
|
|
180µg/wk
(C+D; n=133) |
360µg/wk
(A+B; n=119) |
|
Baseline
characteristics |
No. of
patients (%) |
|
Male |
102
(77) |
80
(67) |
|
Mean age±SD, yrs |
51.1±8.0 |
51.7±9.1 |
|
Caucasian |
119 (89) |
110 (92) |
|
Genotype 1 |
121 (91) |
108 (91) |
|
Mean HCV RNA±SD, x106 IU/mL |
5.2±5.6 |
4.5±5.5 |
|
EVR‡ at wk 12 |
|
All patients |
50 (38) |
60 (50) |
|
USA/Canada |
21/55 (38) |
21/45 (47) |
|
Europe/Brazil |
29/78 (47) |
39/74 (53) |
J. Wade; E. Snoeck; M. Lamb;
F. Duff; K. Wang; J. Grippo; K. Jorga
Addition of ribavirin to interferon-based therapy
reduces relapse rates during follow-up in a dose-dependent manner in patients
with CHC. However, higher sustained virological response rates, with higher
doses of ribavirin, must be balanced against potential increases in
dose-dependent anemia. As such, a thorough understanding of the pharmacokinetics
of ribavirin will help achieve optimal treatment outcomes. We analyzed the
population pharmacokinetics of ribavirin (COPEGUS®) in CHC patients, including
those receiving concurrent peginterferon alfa-2a (40KD) (PEGASYS®).
Methods:
7025 plasma concentration measurements from 380
subjects recruited to 5 clinical studies were analyzed; 3 studies were phase I
crossover studies where subjects received ribavirin as a single 600mg dose, and
2 were randomized, multinational, phase III studies in which the dose of
ribavirin was 800, 1000 or 1200 mg/day, where samples were collected at steady
state (weeks 8–48). The population pharmacokinetic model developed to describe
ribavirin pharmacokinetics was a 3-compartment model with a sequential zero order
followed by a first-order absorption process. Inter-occasion variability and
food effects were included.
Results
(Table):
The only covariate with a clinically significant
influence on ribavirin pharmacokinetics was lean bodyweight (LBW, range
41–91kg), influencing both clearance (15.3-23.9L/h over the LBW range) and the
volume of the larger peripheral compartment (V2; the volume of distribution of
the first peripheral compartment) (3506-6206L over the LBW range). Ribavirin
clearance varied by <20% across the renal function range and between ethnic
groups. Residual variability was very low for the final model (17%).
Conclusion:
The model provided a good description of ribavirin
pharmacokinetics in CHC patients, as confirmed by the accurate estimates of the
parameter values and the low residual variability. LBW was the only covariate
that influenced clearance or volume of distribution, supporting the current
recommendation that ribavirin dose should be adjusted according to bodyweight
to ensure adequate exposure in patients with difficult-to-treat genotype 1
infection.
|
Parameter
|
Estimation
|
Std
error (%) |
Interindividual
variability (%) |
Std
error (%) |
|
Clearance |
19.8 L/h* |
1.8 |
16 |
29 |
|
LBW on CL |
0.00869 |
20 |
- |
- |
|
Bioavailability (F1) (high fat meal) |
1.46 |
4.8 |
22 |
14 |
|
Central Volume (V1) |
472 L |
8.2 |
42 |
25 |
|
1st Peripheral Volume (V2) |
4910 L* |
5.6 |
37 |
31 |
|
LBW on V2 |
0.011 |
32 |
- |
- |
|
2nd Peripheral Volume (V3) |
871 L |
4.9 |
18 |
43 |
|
Residual error |
17.0 % |
5.5 |
- |
- |
J. S. Kadam; K. Jones; R.
Peterson; L. Dove; D. Pearce; T. Hassanein; L. Doonquah; M. Glesby; L. Heller;
D. Aboulafia; J. Rodriguez; H. Bonilla; J. Galpin; J. Aberg; B. Johnston; R.
Liu; I. M. Jacobson; A. H. Talal
Background:
HIV/HCV co-infection is a major cause
of liver-related morbidity and mortality. Pegylated interferon (PEG-IFN) and
ribavirin (RBV) are frequently associated with neutropenia and anemia. We
conducted a prospective, randomized trial in HIV/HCV co-infected patients to
compare two management strategies, dose-reduction vs. growth factor
supplementation, for treatment of anemia and neutropenia secondary to RBV and
PEG-IFN, respectively.
Methods:
103 HIV/HCV co-infected,
therapy-naïve subjects with baseline hemoglobin (hgb) levels of ≥11 gm/dl
and absolute neutrophil counts (ANC)≥1,200/mm3 received PEG-IFN α-2b
1.5ug/kg/wk and RBV 13 ± 2 mg/kg/day for up to 48 weeks. Hgb and ANC were
measured at baseline and weeks 1,2,4 and monthly thereafter. Subjects were
randomized pretreatment; those who had ≥3 gm/dL decline in hgb or hgb ≤10
gm/dL received either recombinant human erythropoietin (epoetin alfa) 40,000
U/wk (group A, n= 44) or RBV dose reduction to 10 mg/kg/d (group B, n= 46).
Subjects whose ANC was ≤750 cells/mm3 received either granulocyte-colony
stimulating factor 5 mg/kg twice weekly (group A, n=44) or PEG-IFN dose
reduction to 1.0 ug/kg/wk (group B, n=46). We calculated the maximum hgb and
ANC decline by subtracting the nadir hgb or ANC from the baseline measurement.
Similarly we calculated the maximum hgb or ANC increase by subtracting the
highest hgb or ANC from the nadir value.
Results:
Seventy-two percent of the patients
were male, 43% African American, 84% genotype 1, 60% stage 1-2, and 58%
acquired HCV via injection drug use. The baseline mean hgb was 14.53 ± 2.7
gm/dL and mean ANC was 2396 ± 1046 cells/mm3. At week 4,44 patients(24-group A,
20-group B) were anemic. Maximal mean hgb decline (week 4) did not differ
between the two groups(group A: 3.17 ± 1.5, group B: 3.51 ± 1.43 gm/dL,p=NS).
Maximal mean hgb increase also did not differ between the groups(group A: 2.53
± 1.83, group B: 1.7 ± 1.05 gm/dL, p=NS). Thirty patients had an ANC ≤
750 cells/mm3(13-group A,17-group B). At week 2, maximal mean ANC decline did
not differ between the groups (group A: 937.75 ± 642.1, group B: 1146.5 ± 377
cells/mm3, p=NS). Maximal mean ANC increase also did not differ between the
groups (group A: 738.38 ± 1180.65, group B: 219 ± 1031.29 cells/mm3, p=NS).
Fatigue (73%) was the most common adverse event. Seven patients discontinued
secondary to severe adverse events, 5 of which were likely related to
PEG-IFN/RBV therapy.
Conclusion:
Growth factor supplementation and
dose reduction appear to be equally effective for the management of neutropenia
and anemia in HIV/HCV co-infected individuals treated with PEG-IFN and RBV.
T. Sakai; S. Iino; T. Okuno; M.
Omata; K. Kiyosawa; H. Kumada; G. Yamada; N. Hayashi
Peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin
(COPEGUS®) produced sustained virological response (SVR) rates of up to 52%
[Ann Intern Med 2004;140:346] in genotype 1 patients in large, randomized,
multinational, phase III trials. As these trials did not include Japanese
patients, we compared the efficacy and safety of peginterferon alfa-2a (40KD)
alone or in combination with ribavirin in Japanese patients with HCV genotype
1b infection.
Methods:
Treatment-naïve adults with genotype 1b infection,
quantifiable HCV-RNA, elevated ALT activity and a liver biopsy consistent with a
diagnosis of chronic hepatitis C were randomized equally in a double-blind
manner to peginterferon alfa-2a (40KD) 180 µg/week plus either ribavirin
600-1000 mg/day or placebo for 48 weeks. The primary efficacy endpoint was SVR
(HCV RNA <50 IU/mL after 24 weeks’ untreated follow-up). Patients were
stratified according to HCV-RNA level (<800,000 vs ≥800,000 IU/mL).
ITT analysis was used.
Results
(Table):
200 patients were randomized to treatment. The SVR
rate in the combination therapy group was significantly higher than that in the
monotherapy group, regardless of baseline HCV-RNA level (odds ratio [OR] 4.55;
95% CI 2.48–8.37; p<0.001). Multiple logistic regression analysis showed
that no included variables significantly and independently influenced the odds
of achieving an SVR. In patients receiving monotherapy, a lower baseline
HCV-RNA level (OR 0.997; 95% CI 0.995–0.999; p=0.002) and younger age (OR
0.939; 95% CI 0.900–0.979; p=0.001) significantly increased the likelihood of
achieving an SVR. Adverse events were generally mild and typical of those
associated with interferon-based therapy.
Conclusion:
Peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin
(COPEGUS®) is effective and well tolerated in treatment-naïve Japanese patients
infected with HCV genotype 1b. The 61% SVR rate in genotype 1b patients exceeds
those reported previously in international trials.
|
Treatment
|
Baseline
characteristics |
SVR
rate, n (%) |
||||
|
Age (years) |
Male, n (%) |
Weight (kg) |
Overall |
Baseline HCV-RNA (IU/mL) |
||
|
<800,000 |
≥800,000 |
|||||
|
Peginterferon alfa-2a (40KD) + ribavirin |
52 |
62 (63) |
63 |
60/99 (61)* |
32/49 (65)* |
28/50 (56) |
|
Peginterferon alfa-2a (40KD) + placebo |
51 |
62 (61) |
62 |
26/101 (26) |
19/53 (36) |
7/48 (15) |
A. Knott; E. Dieperink; M.
Wingert; P. Thuras; P. Hauser; J. Davison; S. Currie; S. B. Ho
Background:
Depression
is often considered a contraindication for interferon (IFN) alfa-based
antiviral treatment. Currently there are few data indicating whether patients with
depression can safely receive antiviral treatments.
Aim:
Determine
safety and efficacy of IFN-based therapies for chronic hepatitis C patients
with active depressive illness.
Methods:
Retrospective
chart review of 91 HCV patients at 4 urban VA Medical Centers who screened
positive for depressive symptoms and underwent Peg-IFN alfa-based therapy
combined with weight-based ribavirin. Primary outcome: antiviral treatment
outcome.
Results:
The
sample was predominantly male (95.6%), Caucasian (86.8%), genotype 1 (63.7%).
Almost half had fibrosis stage 3 or 4. Average entry Beck Depression Inventory
(BDI) was 18.0 (SD ±8.3), with 33% of patients having a BDI ≥20. Almost
75% (68/91) of patients had a current diagnosis of depression, 47% (43/91) had
anxiety disorders and 16% (15/91) had other psychiatric diagnoses. Alcohol and
other substance use disorders (SUD-marijuana, cocaine, methamphetamine) were
diagnosed in 22% (20/91) and 16% (15/91) respectively, and 26% (24/91) used
recreational drugs in the last year. 65 (71.4%) patients were on
antidepressants prior to antiviral treatment, 9 (9.9%) patients started
antidepressants during treatment. Significant differences in patient
characteristics existed between the 4 sites (number of current/lifetime MH
diagnoses, current MH diagnoses). Approximately one-quarter (24/91) of patients
terminated treatment early (1% [1/91] psychiatric and 3% [3/91] SUD related
non-compliance, 12% [11/91] unable to tolerate side effects, 2% [2/91] adverse
event, 1% [1/91] medical reasons, 4% [4/91] multiple reasons). Entry BDI ≥20
(OR=4.09, 95% CI 1.34-12.49) and having used drugs in the 12 months prior to
treatment start (OR=3.99, 95% CI 1.14-13.99) were associated with early
termination of antiviral treatment, while liver biopsy stage ≥2 (OR=.25,
95% CI .07-.88) reduced the likelihood of early termination. Of the 72
evaluable patients, 27 (37%) achieved SVR and 17/72 (25%) were non-responders
at 24 weeks.
Conclusions:
·
The data
indicate that HCV patients with depressive symptoms who start antiviral
treatment evaluation with BDI scores ≥20 and recent recreational drug use
are at higher risk for early termination of antiviral treatment. These patients
warrant closer medical and psychiatric follow up prior to and during antiviral
treatment.
·
Conversely,
these results also suggest that patients with stable depressive disorders and
baseline BDI <20 may be effectively treated with interferon-based therapy.
·
Alothough most
of the same were psychiatrically ill, few patients terminated interferon
therapy due to psychiatric or SID related non-compliance.
E. Zehnter; S. Mauss; C. John;
R. Heyne; B. Moeller; T. Lutz; B. Bokemeyer; R. Kihn; G. Moog; H. Vornkahl; U.
Alshuth; D. Hueppe
Aim:
Predictive factors that have been
identified up to date in treatment of cHC patients shall be analyzed through a
German wide observational study, developed by the “Association of German
Independent Gastroenterologists” (bng, Berufsverband Niedergelassener
Gastroenterologen Deutschlands e.V.) and Hoffmann-La Roche AG.
Patients
and methods:
From March 2003 – March 2005, 9414
patients in various phases of cHC treatment were assessed in an observational
quality assurance trial. 4001 of these patients received treatment with
peginterferon alpha-2a, mostly in combination with Ribavirin. For 1175 patients
treated according to consensus guidelines, treatment has been completed. For
these patients descriptive, univariate and multivariate analyses (logistic
regression model (LR), with 95% confidence intervals for the odds ratio (OR))
were performed to determine factors associated with SVR (sustained virologic
response: defined as result of HCV-PCR qualitatively negative or quantitatively
below detection limit, meaning ≤650 IU/ml 24 weeks after end of
treatment).
Results:
Over all SVR was attained in 838 of
1175 patients (71%). In univariate analyses, SVR was significantly associated
with GT-2/3 (p=0.000), age < 40 y (p=0.000), body weight < 85 kg
(p=.001), BMI < 25 kg/m2 (p=0.012), GGT male ≥ 66, female ≥ 39
U/l (p=0.000), platelets ≥ 150000 /µl (p=0.000), serum ferritin < 200
µg/l (p=0.000) and EVR (defined as ≥ 2-log10 drop in HCV RNA or HCV RNA
undetectable (p=0.000). No predictions could be established for gender, GPT and
viral load.
In a multivariate analysis, EVR was
the strongest independent significant predictive factor OR=0.40 (0.16-0.102)
controlled for the effect of platelets (OR=7.690 (2.146-27.553) and serum
ferritin (OR=2.326 (1.296-4.177).
Conclusion:
The best predictors of curative
chances for antiviral therapy of HCV-patients under non-clinical conditions are
EVR, normal serum ferritin and normal platelets. Other established biological
markers as GT, age, body weight, BMI and GGT were confirmed to predict curative
chances under non-clinical conditions.
S. S. Hamid; W. Jafri; Z.
abbas; F. Ismail; Z. Abbas; K. Mumtaz; S. Abid
Hepatitis C virus (HCV) genotype 3
responds well to combination interferon and ribavirin therapy and may require a
shorter treatment than the recommended 24 weeks. Some reports are available of
short course therapy using pegylated interferons, but none using standard
(non-pegylated) interferon α.
AIMS:
This on-going randomized study was
designed to compare the efficacy of interferon α and ribavarin therapy
given for 16 weeks vs 24 weeks, in achieving sustained virological response in
patients with favorable predictive factors who are infected with HCV genotype
3.
METHODS:
Adult patients (between 16-45 yrs of
age) with fully compensated liver disease and no clinical, radiological or
biopsy evidence of cirrhosis, were started on interferon alpha 2b 3 miu three
times per week along with weight based ribavirin 800-1200 mg/day. Patients who
became HCV PCR negative, with normal ALT, after 4 weeks of therapy, were
randomized to receive either a further 12 (trial arm) or 20 weeks of therapy
(standard arm). Sustained virological response (SVR) was assessed at 24 weeks
after the end of therapy in both the groups by checking ALT and HCV RNA by PCR.
RESULTS:
A total of 75 patients have been
enrolled in the short course trial arm and 64 in the standard therapy arm so
far. Pre-treatment characteristics including age, serum ALT levels and other
lab values were similar in both groups. End of treatment response has occurred
in 63/75 (84%) in the short course arm and 58/64 (90%) in the standard arm,
while SVR has occurred in 85% patients (51/60) who have completed the study in
the short course and in 83% patients (40/48) in the standard treatment arm
(p=0.1). Men were more likely to relapse in both treatment arms (8/9 in the
short course and 5/8 in the standard arm). Side effects, including cytopenias,
were similar in the two treatment arms (mean hemoglobin drop of 2.3 gms/dl,
mean WBC drop of 1.9 mm3 and platelet drop of 17,000/hpf).
CONCLUSIONS:
·
This study demonstrates that, in carefully selected
patients with HCV genotype 3 infection, 16 weeks of therapy with standard
interferon α in combination with ribavirin is as effective as 24 weeks
therapy in achieving a high rate of SVR.
·
This promises to be the most cost effective therapy
reported as yet for the treatment of HCV type 3 infection. Further studies
using even shorter courses of combination therapy seem warranted in HCV
genotype 3 infection.
E. Zehnter; S. Mauss; C. John;
R. Heyne; B. Moeller; T. Lutz; B. Bokemeyer; R. Kihn; G. Moog; H. Vornkahl; U.
Alshuth; D. Hueppe
Injection drug use is the most common
mode of acquisition of new HCV infections in the western world. However the
feasibility of treating patients on opioid maintenance therapy is still under
discussion.
Methods:
The Association of German independent
Gastroenterologists (bng) in cooperation with Hoffmann-La Roche, Germany, is
conducting a nationwide observational study. Between March 2003 and September
2005 data from >10000 patients have been documented at > 500 centers.
Cross sectional analyses for patients with drug use (DU) or without (NDU), who
have started a treatment with peginterferon alfa-2a (40KD) and ribavirin were
done. Data of treatment, compliance and side effects were recorded.
Results:
In 2217/9414 pts concomitant disease
is drug and/or alcohol abuse. Treatment rate for alcohol abusers is 19.8%
(142/717) and for drug users 29.3% (551/1883). Demographic data are available
for 635 treated DU vs 3366 NDU: mean age DU 36.1 y, NDU 42.8 y, 75.8%/59.2%
male, naive/relapser/unknown DU 89.6/6.5/3.9%, NDU 84.1/11.3/4.6%, BMI
24.5/25.0 kg/m2, mean duration of infection: 8.4y/12.0 y, distribution of GT-1
in DU/NDU 49.6%/ 61.5%, GT-2/3 47.1%/35.1% and GT-4,5,6 3.3%/3.4%.
As of September 2005 338/394 DU
(85.8%) and 704/874 NDU (83.3%) reached an Early Virological Response at week
12 (≥2-log10 drop in HCV RNA or HCV RNA undetectable).
To date, 95.1% DU (N=212/223) and
93.1% NDU (N=1042/1119) have achieved EoT-Responses. Complete treatment data
are available for 208 DU and 967 NDU patients, who were treated according to
consensus recommendations. Sustained Virological Response (SVR) was achieved by
153/208 DU (73.6%) and 645/967 NDU-patients (66.7%).
A total of 87/446 DU and 407/2315 NDU
(18.7%/17.6%) patients have discontinued therapy: 28.7%/40.8% due to
virological nonresponse, 19.5%/26.5% for poor tolerability, 19.5%/12.3% were
lost to follow-up, 13.8%/8.1% for personal reasons and 23.0%/9.6% for lack of compliance.
Conclusion:
Pegylated interferon alfa-2a and
Ribavirin seems reasonably safe and sufficiently effective in patients with
drug abuse, mainly patients on methadone substitution. In spite of comparable
efficacy results, treatment outcome varies due to inhomogeneity of patient
groups i.e. age, sex, duration of infection and genotype.
A. Schaefer; M. Scheurlen; B.
Weissbrich; K. Schoettker; M. R. Kraus
Background
and aims:
The goal of our study was to
determine a putative contribution of cytokine-induced depression to a
predictive model of sustained virological response (SVR) in chronic hepatitis
C. The analysis comprised a control for known predictors of SVR (e.g. virus
genotype and gender).
Methods:
In a longitudinal study, we included
a sample of 101 therapy-naïve HCV outpatients who were enrolled frm July 2000
to March 2004. They received a combination treatment with pegylated interferon
alfa-2b and ribavirin. Neuropsychiatric side-effects were monitored
prospectively (Hospital Anxiety and Depression Scale, DSM-IV criteria for major
depression).
The primary end point with respect to
SVR was failure to detect HCV by PCR 24 weeks after the antiviral therapy.
Results:
Overall SVR rate was 72.3 %.
Classification data (DSM-IV criteria; HADS cutoff) and the extent of
interferon-induced depressive symptoms were not significantly linked to virus
eradication. Consideration of other potentially confounding variables did not
increase the predictive value of depression for therapy outcome.
Virus genotype (P = 0.045) and gender
(P = 0.016) contributed significantly to a predictive logistic regression
model. However, mean (P = 0.811) and maximum (P = 0.744) increases in HADS
depression were no significant predictors of SVR.
Conclusion:
·
There is no evidence for a significant direct
association between depression and the efficacy of antiviral treatment in
chronic hepatitis C.
·
Patients experiencing no or minor neuropsychiatric
side effects do not have to worry about a “lower chance” of successful therapy.
·
Therefore, interferon-induced depressive symptoms are
still important to be monitored and treated if necessary – however, they cannot
be used to predict the individual’s therapy success.
Abstract T1817 –
Registry of Liver Diseases: Phase I
S. E. Steinberg
Introduction:
The
establishment of registries of patients with various diseases has been
identified as a critical element in the developing infrastructure of clinical
and translational research. Among the capabilities of clinical registries are
the ability to monitor the natural history of disease; to identify areas of
investigation; to evaluate the feasibility of testing a hypothesis; to identify
subjects for basic science evaluations; and to expedite the implementation of
clinical studies. LRI has initiated a registry of diseases of the liver with
the aim of beginning to address these goals.
Methods:
Five
academic centers were identified. A scientific advisory board was convened to
determine the liver diseases to be included. These are: Alcoholic, alpha 1
anti-trypsin deficiency, autoimmune, congenital hepatic fibrosis,
hemochromatosis, hepatitis C, hepatitis B, hepatocellular carcinoma, NASH,
non-A non-B non-C hepatitis, primary biliary cirrhosis, primary sclerosing
cholangitis, and Wilson’s. A technology task force was convened to design an
application that would facilitate the enrollment of patients in a centralized
registry, while functioning as a “local” research database for the general use
of each center. The registry application was developed utilizing SQL server
which provided each site with a full copy of its own data and the ability to
modify locally to support specific projects (e.g. tracking of stored serum and
tissue samples). De-identified data from each site is uploaded to the master
database nightly. Data was acquired electronically when available and
supplemented by hand entry. HIPAA guidelines are observed and IRB approval was
obtained for each participating institution.
Results:
· The challenge of building a registry includes the
huge burden of data collection. The technology solution has worked well and
facilitated data collection.
· Application designed and implemented
· Firewall/security interfaces implemented
· Automated lab data importation implemented
· Automated de-indentified data uploads
· Web enabled
Analysis
of the initial phase of data accumulation has yielded 44,655 records including
18,545 HCV; 4,486 HBV; 2,652 NASH; 1,8972 Other liver diseases. It is
recognized that the disease distribution, while generally reflecting the
incidence in the general population, is also affected by the academic interests
of the individual sites. The local functionality afforded the individual sites
provides them with powerful tools to maintain and analyze their own data, while
contributing to the central repository.
Conclusions:
· The “feasibility” phase of the implementation of a
registry of liver disease has been successfully completed.
· Preliminary analyses of subsets of data has begun
to yield useful information.
· A large data based (>44,000) records of patients
with liver disease is now available for chart review and prospective studies
· The ongoing challenge will be to continue to expand
the number of records and the data set and to add additional sites.
Abstract T1818 –
Treatment of Hepatitis C Related Cryoglobulinemia with Rituxan.
A.Goldenberg, M.D.,
L.Teperman, M.D., P. Kelley, R.N., L.Hong, RPA-C, H.Tobias, M.D., Ph.D A.
Goldenberg; L. Teperman; L. Hong; P. Kelley; H. Tobias
Introduction:
Cryoglobulinemia associated with
chronic hepatitis C virus (HCV) infection produced neuropathy, rash, and
vasculitis in two patients despite interferon and ribavirin treatment of HCV
viremia.
Methods:
Two non-cirrhotic patients with
active HCV increasing cryoglobulinemia and clinical deterioration were treated
with Rituxan. Patient 1 (Pt-1)was 55 year old female, with HCV PCR RNA
5.47LogIU and patient 2 (Pt-2) a 51 year old male with HCV PCR RNA 4.9LogIU.
Both presented with fatique lower extremity parathesisas and skin rash with
biopsy proven vasculitis while receiving Pegasys (pt1) and Peg Intron (pt2),
respectively. Each demonstrated a faint serum IgM kappa monoclonal paraprotein
and elevated cryoglobulins (pt1 = 5% and pt2 =13%). Pt1’s bone marrow
demonstrated less than 1% kappa restricted CD38/CD138 plasma cells and pt2’s
bone marrow showed polyclonal B cells. Rituxan was administered at 375 mg per
meter squared every week for 8 weeks.
Results:
Pt-1's lower extremity skin lesions
resolved, and the parathesias were markedly reduced. Cryoglobulin was <1%.
IgM kappa paraprotein remained detectable. IgG level normalized to 749.
Rheumatoid factor level of 1907 IU/ml decreased to 626 IU/ml. Pt-2's Raynaud's
complaints resolved. The IgM kappa paraprotein remained detectable and the IgG
level normalized to 707. The cryoglobulins decreased to 4%.
Conclusions:
1. Rituxan can decrease serum
cryoglobulin levels in patient's with HCV infection receiving interferon.
2. Rituxan's effect on suppressing
HCV related cryoglobulinemia may be modulated by interferon treatment.
F. Hasan; K. Alsarraf; W. Qabandi
Background:
Hepatitis C is endemic in the Middle East where
genotype 4 accounts for most cases. Data regarding the safety and efficacy of
peginterferon plus ribavirin for the treatment of chronic hepatitis C in
children and adolescents, particularly those infected with genotype 4 are
limited.
Aim:
The aim of this study is to evaluate the efficacy and
tolerability of peginterferon alfa-2b in combination with ribavirin in
adolescents chronically infected with HCV genotype 4.
Patients and
Methods:
In an open-labeled, uncontrolled pilot study, 12
adolescents (range 14-17 years) were treated with subcutaneous peginterferon
alfa-2b at a dose of 1.5 mcg/kg body weight once per week plus oral ribavirin
(15 mg/kg / day) for 48 weeks. Patients were followed up for 24 weeks. All
patients had biopsy proven hepatitis without cirrhosis.
Results:
One patient withdrew from the study due to developing
insulin dependent diabetes mellitus 4 months into treatment. The remaining
patients took at least 80% of the prescribed dose of pegylated interferon and
ribavirin. Sustained viral response was observed in 9 patients (75 %). The most
frequent side effect was flu like illness which was reported in all patients.
Sixty seven percent had leucopenia, but only one individual required therapy
with a growth factor. Four patients had anemia requiring ribavirin dose
reduction. One patient developed hypothyroidism.
Conclusion
·
Adolescents chronically infected with HCV genotype 4 appear
to have a favorable response to therapy with peginterferon alfa-2b plus
ribavirin
·
Relatively mild histologic abnormalities (ie, the absence of
severe fibrosis and cirrhosis) may explain the high SVR rate observed in this
study
·
Therapy was well tolerated
·
Larger trials are needed to determine the optimal dose and
duration of therapy in this patient population
E. Snoeck; J. Wade; M. Lamb; F. Duff; J. Grippo; K.
Jorga
Introduction
Generalized
additive models (GAM) were used to describe the likelihood of an SVR and risk
of anemia in patients with chronic hepatitis C (CHC) receiving peginterferon
alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®).
Methods:
Data
from 1732 CHC patients with elevated ALT levels treated with peginterferon alfa
2a (40KD) plus ribavirin in two randomized, multinational studies were pooled.
Probabilities of SVR (HCV <50 IU/mL at end of follow-up; n=1036 genotype 1
patients) and anemia (hemoglobin <10 g/dL at any time during treatment;
n=1732 patients of all genotypes) were modelled using GAM analyses, with
numerous clinical variables considered for entry into the models. Baseline
hemoglobin was only considered in the analysis for anemia.
Results:
In
HCV genotype 1 patients, the probability of an SVR increased with increasing
ribavirin dose/kg (Fig a), and with baseline ALT. Older age, a higher ribavirin
apparent oral clearance and cirrhosis had a negative impact on achieving an
SVR. The probability of anemia increased as a function of the ribavirin dose/kg
(Fig b). Female gender and increasing ribavirin dose/kg were the most important
prognostic factors for anemia, followed by low baseline hemoglobin, older age,
low baseline ALT quotient and cirrhosis.
Conclusion:
The
current GAM analysis shows that there is a substantial dose-dependent effect on
SVR in HCV genotype 1-infected patients with ribavirin (Copegus) doses >10
mg/kg/day in combination with peginterferon-alfa-2a (40 KD) (PEGASYS).
The
analysis also shows that ribavirin doses at or below 15 mg/kg/day are
associated with little difference in the incidence of anemia.
These
results trigger hypotheses worth of prospective evaluation:
o
The first is
that, for heavier patients, ribavirin doses >1200 mg/day are likely to be
associated with an additional efficacy benefit and a manageable anemia risk,
provided that the dose does not greatly exceed 15 mg/kg/day (1200 mg dose for a
100 kg patient = 12 mg/kg/day).
o
The second is
that HCV genotype 1-infected patients are likely to benefit from maintaining a
cumulative ribavirin dose closer to 15 mg/kg/day during the treatment
course. This can be safely achieved
through more gradual dose modification than the currently approved single-step
reduction to 600 mg/day.
o
Both hypotheses
are currently being evaluated in on-going clinical trials.
J. F. Rossignol; B. E. Korba; S.
M. Kabil
Introduction.
Nitazoxanide is an anti-infective drug from a new
class called the thiazolides. It is marketed in the United States for treating
gastroenteritis caused by Cryptosporidium parvum and Giardia lamblia
and is in late stages of development for treating Clostridium difficile-associated
disease. Based on earlier screening suggesting antiviral properties of the
thiazolides, we tested nitazoxanide and its active circulating metabolite,
tizoxanide, against hepatitis C virus in cell cultures. We also report the
results of a patient with chronic hepatitis C treated with nitazoxanide after
previously failing a 48-week course of peginterferon plus ribavirin.
Methods.
Nitazoxanide, tizoxanide, ∝-interferon, and ribavirin were evaluated for activity
against hepatitis C virus in AVA5 cell cultures. A 53 year-old Egyptian male
with chronic hepatitis C, genotype 4, who had failed to achieve a sustained
response to a 48-week course of peginterferon plus ribavirin was treated with
nitazoxanide. Before treatment, the patient had normal ALT with a viral load of
3,650,400 IU. Nitazoxanide was administered by oral route, 500 mg twice daily
with food for 32 weeks, and the patient was evaluated every 4 weeks during
treatment. Evaluations included physical examination, laboratory safety tests
and RT PCR for quantitation of HCV RNA.
Results.
The activity of nitazoxanide, tizoxanide, ∝-interferon and ribavirin against
hepatitis C virus replication in AVA5 cell cultures is presented below:
|
Compound |
CC50
(µM) |
EC50
(µM) |
EC90
(µM) |
Selectivity
Index |
|
∝ - Interferon |
>10,000* |
2.2 ± 0.2* |
8.5 ± 0.6* |
>4,545 |
|
Ribavirin |
61 ± 2.9 |
94 ± 10 |
>100 |
0.6 |
|
Nitazoxanide |
38 ± 1.9 |
0.045 ± 0.003 |
0.539 ± 0.044 |
844 |
|
Tizoxanide |
5.2 ± 0.4 |
0.034 ± 0.004 |
0.419 ± 0.051 |
152 |
The patient treated with nitazoxanide showed a 1 log10
reduction of serum HCV RNA at week 4 (3,650,000 declined to 331,000 IU) . The
reduction was maintained through week 20. At week 24, the viral load declined
to 5,000 IU, and at weeks 28 and 32, virus was undetectable. ALT remained
normal throughout treatment. No significant adverse events were reported. The
patient is continuing treatment to week 48 at which time treatment will be
discontinued and sustained response will be evaluated.
Conclusions.
Our results suggest that nitazoxanide is effective in
treating chronic hepatitis C. Double-blind placebo-controlled studies are being
conducted in the United States and internationally.
D. Hueppe; E. Zehnter; M. P.
Manns; S. Mauss; M. Zankel
BACKGROUND:
Pegylated
interferon (PEG-IFN alfa) and Ribavirin (RBV) are the standard of care for
hepatitis C virus (HCV) treatment. The efficacy and safety of PEG-IFN alfa-2b
and RBV was observed in Germany in a post marketing surveillance study under
daily life conditions. The patients were treated in hospitals, in medical practices
and in medical practices that are members of the German association of
gastroenterologists in private practice (bng).
METHODS:
· Between September 2003 and November 2005, 219
active sites have treated 2318 naive or relapsed HCV patients with PEG-IFN
alfa-2b and RBV and documented their cases.
· Number of evaluable patients that reached end of
therapy – 1259
· Number of evaluable patients that reached end of
follow-up - 545
· Genotype distribution:
o
Genotype 1 -
53.5%
o
Genotype 2 - 8.0%
o
Genotype 3
- 33.7%
o
Genotypes 4
thru 6 - 2.8%
o
Missing
genotype information 1.8%
· Patient characteristics
o
Age - 40.4
(median 39.0)
o
Weight -78.4
(median 74)
o
Height -173.1
(median -173)
o
Male – 61.4%
o
Female – 37.1%
o
Cirrhosis – 5%
o
On substitution
Tx.
o
Caucasian –
82.9%
· Patient treatment characteristics prior to
treatment:
o
Treatment naïve
– 90.1%
o
Relapsers –
9.9%
If
HCV-RNA was negative at 12 weeks of treatment or if there had been more than 2
log drop in HCV-RNA after 12 weeks of treatment, therapy was continued. 1259
evaluable patients reached the end of the therapy yet.
RESULTS:
· HCV RNA negativity at end of therapy – 74.1%
(naïve); 47.5% (relapsers)
· SVR by BMI – 65.7% (all patients): 63.6% (<18.5
BMI); 70.5% (18.5-25.0 BMI); 58.3% (25.0-30.0 BMI); 56.9% ( ≥30.0 BMI);
No
data from the poster on adverse events was available.
CONCLUSION:
· The response rates show that in Germany, the
quality and safety of the treatment of chronic hepatitis C under real life
conditions is on a high level.
· A normal BMI (>=18.5–<25.0) favours the
efficacy of the therapy.
· Patients with abnormal transaminase values had a
higher chance to be HCV-RNA negative at the end of the therapy.
E. Zehnter; S. Mauss; C. John;
R. Heyne; B. Moeller; T. Lutz; B. Bokemeyer; R. Kihn; G. Moog; H. Vornkahl; U.
Alshuth; D. Hueppe
Introduction:
In
an effort to measure the quality of treatment of patients with chronic
hepatitis C the Association of German independent Gastroenterologists (bng) in
cooperation with Hoffmann-La Roche, is conducting a nationwide observational
study that consists of documenting screening and treatment data.
Methods:
Between
March 2003 and September 2005 data from >10000 patients has been documented
at > 500 centres. Cross sectional analyses for all GT-2 and GT-3 patients
were done, who have started a treatment with peginterferon alfa-2a (40KD) and
ribavirin. Data of treatment, compliance and side effects were recorded.
Results:
· Demographic data are available for 1481 treated
GT-2 (N=290) and GT-, 3 (N=1191) GT-3):
o
mean age GT-2
44,2y, GT-3 36.6 y,
o
57.9%/66.7%
male,
o
Naïve /
relapser/ unknown GT-2 91.0/4.8/4.2%, GT-3 88.6/7.0/4.4%,
o
BMI 25.1/24.3
kg/m2, mean duration of infection: 11.2y/9.6 y,
o
Source of
infection (>1 answer possible):
§ IV drug abuse 39.7%, in GT-2 and 64.2% in GT-3,
§ Transfusion 19.7%/9.2%,
§ Medical measures 10.7%/5.4%,
§ Unknown 25.9%/14.6%;
§ 95.8%/97.3% of patients were treated with a
combination therapy.
· As of September 2005, 168/182 patients with GT-2
(92.3%) and 661/702 with GT-3 (94.2%) reached an Early Virological Response at
week 12 (≥2-log10 drop in HCV RNA or HCV RNA undetectable).
· To date, 97.5% GT-2 (N=158/162) and 95.4% GT-3
(N=636/667) have achieved EoT-Responses.
· Complete treatment data are available for 522
patients, who were treated according to consensus recommendations.
o
Sustained
Virological Response (SVR) was achieved by 85/106 GT-2 (80.2%) and 346/416
GT2/3-patients (83.2%).
o
A total of
21/85 (7.2%/7.1%) patients have discontinued therapy:
§ 9.5%/9.4% due to virological nonresponse,
§ 42.9%/25.9% for poor tolerability,
§ 9.5%/24.7% were lost to follow-up,
§ 9.5%/11.8% for personal reasons and
§ 19.1%/25.3% for lack of compliance.
Conclusion:
· The results of this observational trial show that
peginterferon alfa-2a (40KD) and ribavirin therapy is effective and well
tolerated in GT-2/3 patients with chronic hepatitis C in clinical practice.
· The individual analysis of GT 2 and-3 shows clearly
that baseline data like age and source of infection differ considerably.
Therefore larger cohorts should be analysed separately to genotype 2 and 3 with
respect to efficacy and tolerability, too.
N. Izumi; S. Iino; T. Okuno;
M. Omata; K. Kiyosawa; H. Kumada; N. Hayashi; G. Yamada; T. Sakai
Introduction:
Despite major improvements in the
treatment of chronic hepatitis C, some patients do not respond to, or relapse
following, interferon-based treatment. We evaluated the efficacy and safety of
peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in Japanese
patients who had not responded to conventional interferon monotherapy. This is
the first trial investigating peginterferon alfa-2a (40KD) plus ribavirin in
previously-treated Japanese patients.
Methods:
Previously-treated adults with
detectable HCV-RNA, elevated ALT and a liver biopsy consistent with a diagnosis
of chronic hepatitis C were treated with peginterferon alfa-2a (40KD) 180
µg/week plus ribavirin 600–1000 mg/day for 48 weeks. Patients were classified
either as non-responders (no HCV-RNA suppression below detection limits) or
relapsers (reversion to HCV-RNA positive status after suppression) to previous
interferon monotherapy. The primary efficacy endpoint was sustained virological
response (SVR; undetectable [<50 IU/mL] HCV-RNA after 24 weeks’ untreated
follow-up). ITT analysis was used.
Results
(Table):
100 patients received treatment, and
54% achieved an SVR. SVR rates were similar in previous non-responders and
relapsers, and in patients with high and low baseline HCV-RNA levels. Logistic
regression analysis indicated that younger age significantly and independently
increased the likelihood of achieving an SVR (odds ratio 0.92; 95% CI
0.88–0.97; p=0.001). Baseline HCV-RNA, fibrosis grade, age or bodyweight had no
influence on SVR. Adverse events were generally mild in severity and were
typical of those associated with interferon-based therapies. Overall, 16% of
patients withdrew because of adverse events or laboratory abnormalities.
Conclusion:
Peginterferon alfa-2a (40KD)
(PEGASYS®) plus ribavirin (COPEGUS®) is associated with a relatively high
response rate in Japanese chronic hepatitis C patients who failed to respond to
or relapsed after conventional interferon monotherapy.
|
Baseline
characteristics |
|||
|
Mean age, years |
52 |
||
|
Males, n (%) |
74 (74) |
||
|
Mean bodyweight, kg |
67 |
||
|
SVR rate, n (%) |
|||
|
|
All patients |
Non-responders |
Relapsers |
|
All |
54/100 (54) |
19/40 (48) |
35/60 (58) |
|
Genotype 1b |
43/84 (51) |
18/36 (50) |
25/48 (52) |
|
Genotype non-1b |
11/16 (69) |
1/4 (25) |
10/12 (83) |
W.
HCV Meta-Analysis; P. L. Almasio; L. Cavalleto; L. Chemello; D. Hueppe; S.
Mauss; F. Poordad; N. N. Zein; S. Herrine; C. Trepo; D. Frame; K. Fahrbach; S.
D. Ross
Objective:
To
explore predictors of sustained viral response (SVR) in treatment-naïve chronic
HCV patients treated with weight-based PEG-IFN alfa-2b (alfa-2b) or fixed dose
PEG-IFN alfa-2a (alfa-2a) + ribavirin (RBV) in observational settings outside
of clinical trials.
Methods:
Clinical
investigators identified primarily through independent congress abstracts were
recruited to contribute de-identified data for analysis. Eligible patients were
treatment-naïve adults with chronic HCV (G1, G2, or G3), receiving PEG-IFN+RBV.
Patients in clinical trials, those treated prior to 2001, with HIV or HBV
co-infection, or with decompensated liver disease were excluded. Within each
genotype the primary efficacy measure of SVR was analyzed using a hierarchical
generalized linear model (HGLM) to control for patient- and site-level
variation, and an adjusted odds ratio (OR) was calculated for the difference
between PEG-IFNs. Patient selection criteria and analytic methods were
determined prospectively by an expert panel. Prognostic impact of treatment
regimen, weight, site, baseline ALT quotient, age, gender, and race were
assessed.
Results:
Six
sites (2 US, 2 German, 2 Italian) contributed data, totaling 824 patients (506
G1, 147 G2, 171 G3). Mean baseline weight for G1 patients was 78.4 kg for
alfa-2a and 75.5 kg for alfa-2b (BMI 26.7 vs. 26.6, respectively). SVR in G1
patients was significantly higher for alfa-2b vs. alfa-2a (49% vs. 36%; HGLM
analysis OR = 1.62, 95% CI 1.10-2.39, p=0.017). For G1 patients, higher
baseline weight was a significant negative predictor of SVR (p=0.012). There
was also a marginally significant (p=0.073) treatment x weight interaction,
indicating a larger difference in SVR rates between the two PEG-IFNs (higher
SVR observed with alfa-2b) as patient weight increases. Baseline ALT, race,
age, and gender were not statistically significant predictors of SVR.
Insufficient data were available to include fibrosis score, viral load, baseline
platelet count, alcohol use, or concomitant medications in the model.
Differences in SVR between PEG-IFNs for G2 and G3 patients were not
significant, nor did any of the covariates used in the model reach statistical
significance.
Conclusions:
Treatment
with PEG-IFN alfa-2b has an advantage relative to PEG-IFN alfa-2a in achieving
SVR in treatment-naïve, HCV+, G1 adults. Higher baseline weight was a
significant negative prognostic factor for SVR. In G2 and G3, for which fewer
patients were available for analysis, no statistically significant effects of
treatment or patient covariates were observed. Cumulative analyses are planned
to incorporate data from additional sites.
M. Akamatsu; H. Yoshida; S.
Shiina; T. Teratani; H. Yoshida; J. Imamura; Y. Kondo; T. Ooki; R. Tateishi; N.
Yamashiki; T. Kawabe; M. Omata
Background
Interferon
(IFN) therapy improves life-expectancy among chronic hepatitis C patients
(Yoshida, Gastroenterology 2002;123:483) and HCC patients after tumor ablation
(Shiratori, Ann Intern Med 2003;138:299). We conducted this retrospective study
to evaluate the prognosis of HCC in patients who had achieved sustained
virologic response (SVR) to previous IFN therapy.
Methods
We
compared overall and recurrence-free survival rates between 18 HCC patients who
received IFN therapy and achieved SVR before HCC development (SVR group) and
468 HCC patients with Child-Pugh class A liver function who had not received
interferon (controls).
Results
The
overall survival rates were 77.2%, 45.9%, and 23.3% in the controls and 94.1%,
85.6%, and 85.6% in the SVR group at 3, 6, and 9 years, respectively. Cox
proportional hazard regression revealed that the risk of death was
significantly reduced in the SVR group (Risk Ratio: 0.225, 95% CI: 0.056 -
0.910, P = 0.0363). Recurrence-free survival, analyzed exclusively among those
who received curative ablation or surgery, did not differ significantly.
Conclusion
Patients
with HCC who had achieved SVR by previous IFN therapy showed excellent
survival. Cumulative recurrence rates did not differ and the improved survival
seemed to be attributable mainly to sustained liver function.
E. Zehnter; S. Mauss; C. John;
R. Heyne; B. Moeller; T. Lutz; B. Bokemeyer; R. Kihn; G. Moog; H. Vornkahl; U.
Alshuth; D. Hueppe
Introduction
The
Association of German independent Gastroenterologists (bng) in cooperation with
Hoffmann-La Roche, Germany, is conducting a nationwide observational study to
determine the quality of treatment for chronic hepatitis C in routine clinical
practice. This ongoing study includes screening and treatment phases and has as
a goal, the establishment of optimal care for these patients.
Methods:
Between
March 2003 and September 2005 data from >10000 patients have been documented
at > 500 centres. A cross sectional analyse for all GT-1 patients was done,
who have started a treatment with peginterferon alfa-2a (40KD) and ribavirin.
Results of efficacy, tolerability and compliance were recorded.
Results:
Demographic
data are available for 2384 treated GT-1 patients:
· mean age 44,0 y,
· 59.2% male,
· naive/relapser/unknown 82.5/12.9/4.6%,
· BMI 25.2 kg/m2,
· mean duration of infection: 12.4y,
· source of infection (>1 answer possible):
o
iv drug abuse 34.8%,
o
transfusion
23.7%,
o
medical action
11.0%,
o
unknown 25.3%.
o
97% of patients
were treated with a combination therapy.
o
As of September
2005 1220/1560 (78%) patients reached an Early Virological Response at week 12
(≥2-log10 drop in HCV RNA or HCV RNA undetectable).
To
date, 77.6% GT-1 (N=782/1008) have achieved EoT-Responses. Complete treatment
data are available for 618 patients, who were treated according to consensus
recommendations. Sustained Virological Response (SVR) was achieved by 363/618
GT-1 (58.7%).
A
total of 361 (15.1%) GT-1 patients have discontinued therapy:
· 46.3%, due to virological nonresponse,
· 24.7% for poor tolerability,
· 11.9% were lost to follow-up,
· 8.0% for personal reasons and
· 8.0% for lack of compliance.
While
less than 10% of the patients got less than 80% of the cumulative dose
regarding peginterferon alfa 2 for 48 weeks, it was more than a quarter of the
patients regarding ribavirin for 48 weeks.
Conclusion:
· The results of this observational trial show that
peginterferon alfa-2a (40KD) and ribavirin therapy is effective and well
tolerated in GT-1 patients with chronic hepatitis C in daily clinical practice.
· When treated according to current guidelines,
patients achieved results similar to those achieved in controlled clinical
trials.
· This observational study contributes importantly to
health care research of patients with chronic hepatitis C.
J. Koskinas; G. Zacharakis; J.
Sidiropoulos; J. Elefsiniotis; S. Savvas; D. Kountouras; M. Schina; P.
Kostopoulos; A. Archimandritis
Background:
Peg-IFN treatment in patients with
chronic HCV infection induces neutropenia with subsequent dose reductions that
may reduce the SVR. Granulocyte colony-stimulating factor (G-CSF) has been used
by some physicians instead of the standard dose reduction practice. However,
additional studies are required before these agents can be recommended for
routine use.
Aim:
To evaluate the safety and benefits
of G-CSF compared to standard practice of dose reduction in patients with
peg-IFN induced neutropenia.
Methods:
Open-label study of 39 treated-naïve
patients of 249 (16%) with chronic hepatitis C genotype-1 infection who were on
treatment with PEG-INFa-2b 1.5mcg/kg/week and RBV 800-1400mg/day weight based
and developed significant neutropenia (ANC<1000/L). They received either a
flexible scheme of 150-300ug G-CSF SC twice a week (one day after and two days
before Peg-IFN injection), (Group A, 20 pts) or had escalating dose reduction
of Peg-IFN for 2wks or discontinuation for 1-2 wks in unresolved cases (Group
B, 19 pts). HCV-RNA was measured by Cobas Amplicor (Roche). Results: Both
groups had no significant differences before treatment regarding age (53±9
years vs 47±7), sex (55% males vs 50%), HCV-RNA levels (2.76±1.9 million IU/ml
vs 2.23±2.1), Hb levels (13.5±2.3 mg/dl vs 14±1.7) and WBC (6000/mm3 vs 5800),
respectively. The mean decline of the neutrophils was 1760±1030/mm3 at 11±8.6
wks and 1630±890 at 12.3±6.1 in group A and B respectively. Patients who
received G-CSF maintained neutrophil count between 1420-2720/mm3 and remained
on G-CSF support for 29 wks (2-40). In this group, 12/20(60%) had EVR and 6/20
(30%) SVR. In group B, Peg-IFN was
temporarily withdrawn in 3/19 and reduced to 0.5mcg/kg/wk in 4/19 patients. The
neutrophil count ranged between 1320-3400/mm3. In this group, 9/19 (47%) had
EVR and 4/19 (21%) SVR (significant lower compared to group A, p<0.001). All
patients completed 48wks of treatment with no major side effects or infection.
No related to G-CSF side effects were encountered.
Conclusions:
The use of G-CSF 1) is safe and
allows adherence to treatment schedule in patients with chronic HCV-1 infection
who develop neutropenia during treatment, and, 2) relates to higher EVR and SVR
and therefore it should be considered in clinical practice
W. Vogel; H. Brunner; M.
Rosenbeiger; I. W. Graziadei; A. Maieron; K. Jilek; R. Stauber
About 30% of chronic hepatitis C
(CHC) patients have persistently normal ALT (PNALT). This group of patients has
been excluded from pivotal treatment trials. There is evidence that these pts
respond similarly to those with elevated ALT to treatment with interferon and
ribavirin, however, further studies are warranted. In this prospective,
multicenter, open-labeled trial 240 de novo pts with biopsy-proven CHC with
normal or elevated ALT levels received PegIntron 1,5 µg/kg/wk & Rebetol
0,8-1,2g/d for 48 weeks (genotype 1/4) or 24 weeks (genotype 2/3).
Study
design:
Pts were stratified according to
elevated or normal (>3 measurements over 3 months) ALT, high or low viral
titer (cut-off 800.000 IU/ml, bDNA HCV RNA 3.0 assay; Bayer Diagnostics) and
genotypes (GT) 1/4 or 2/3. Baseline data are available from 225 pts: 107 pts
with PNALT (83 pts with GT 1/4, median ALT was 29 U/l, 24 pts with GT 2/3,
median ALT was 25 U/l) and 118 pts with elevated ALT (88 patients with GT 1/4,
median ALT was 79 U/l, 30 pts with GT 2/3, median ALT was 135).
Results:
There was no statistical significant
difference in pretreatment characteristics between the two groups. 65,1% of pts
with PNALT had a viral load lower or equal 800.000 IU/ml vs 66,4% of pts with
elevated ALT. From 114/225 pts viral load was determined after week 4: 51,8%
had undetectable RNA (49,2% PNALT and 54,9% high ALT; 37% of GT 1/4 pts and 93%
of GT 2/3 pts). After week 12 167/225 pts were evaluated: 71,3 % had
undetectable RNA (76,3% PNALT and 67% high ALT; 66% of GT 1/4 and 90% of GT
2/3).
195 pts have so far completed the
study. 14,4% of these pts withdraw because of AEs; 4,1% had a breakthrough on
therapy, and 14,9% did not show a 2log drop at week 12. Of these 195 pts 71,3%
had undetectable RNA at end of treatment (74,1% normal ALT and 69,1% high ALT;
64% GT 1/4 and 89% GT 2/3). The differences in responses between the normal and
high ALT group are not significant.
In an univariate analysis there is a
significant difference in median virus load between pts with ETR response vs
nonresponders (324000 IU/ml vs 754000 IU/ml; p < 0,001). Adjusted for GT and
ALT level this difference remains statistically significant (p < 0,001).
There is trend to a higher ETR
response in patients with a baseline viral load lower or equal 800000 IU/ml,
and this trend is even significant in pts with GT 1/4 and elevated ALT (72,5%
vs 43,5%).
Conclusions:
These findings suggest that pts with
PNALT stratified for GT and viral load show the same ETR receiving as do
patients with elevated ALT.
J. Nelligan; J. M. Loftis; M.
Fireman; S. Ruimy; B. Zucker; A. Linke; D. Indest; P. Hauser
Introduction
The prevalence of chronic hepatitis C
viral (HCV) infection among veterans who access Veterans Affairs (VA) medical
facilities is approximately three times higher than that of the general U.S.
population, 5.4% vs. 1.8%. Veterans with HCV also commonly have comorbid
psychiatric diagnoses. This is particularly concerning because
interferon-α (IFN) therapy is associated with psychiatric side effects
(e.g., depression, irritability) and patients with psychiatric diagnoses are often
excluded from IFN therapy.
Aim
The purpose of this study was to
assess the effects of prior psychiatric diagnoses on IFN therapy completion and
response rates.
Results
Eighty two veterans [male (96%), mean age
51±5.3 years] who underwent IFN therapy between 2002 and 2005 at the Portland
VA Medical Center consented to have their medical records reviewed. Data
revealed that 54 (66%) veterans were diagnosed with a psychiatric or substance
use disorder more than 1 year prior to starting IFN therapy, 8 (10%) were
diagnosed in the year preceding the start of IFN therapy, and 20 (24%) had no
psychiatric or substance use disorder. The most common psychiatric disorder was
major depression (35 patients -56%), followed by posttraumatic stress (25
patients-40%) and anxiety disorders (8 patients-13%). The most common substance
use disorder was alcohol abuse 24 patients-39%) followed by dependence on
alcohol (23 patients - 37%), cocaine (6 patients - 10%), opiates (4
patients-6%), and other drugs (12 patients-19%). Of the 20 patients with no
psychiatric history, 6 were started on a psychotropic medication during IFN
therapy. Similarly, of 22 veterans with a psychiatric history and no record of
psychiatric medication use prior to initiating IFN therapy, 6 started a
psychotropic medication during IFN therapy. Treatment outcomes showed that of
the patients who had completed IFN therapy, sustained viral response rates
(SVR) were similar among all groups (see Table below).
Conclusion
·
Although 39% of patients terminated treatment early,
only 1 patient terminated for psychiatric reasons despite the high prevalence
of psychiatric comorbidity (n=62, 76%).
·
Taken together, these findings suggest that with
routine mental health screening and coordinated care involving mental health,
chemical dependency and medical professionals, patients with comorbid
psychiatric diagnoses can successfully complete IFN therapy and achieve
response rates comparable to those patients without psychiatric disorders.
|
Treatment
Variables |
Previous
psychiatric diagnosis (n=54) |
Diagnosed
w/psychiatric illness 1 year prior to IFN (n=8) |
No
previous or current psychiatric diagnosis (n=20) |
|
IFN therapy completion (%) |
34(62) |
4(50) |
12(60) |
|
SVR (%) |
24(44) |
3(38) |
9(45) |
N. Mehta; U. K. Murthy; V.
Kaul; P. Mehta; L. Bank; B. Buniak; A. Goel; B. Kane; R. Levine; D. Reedy; A.
Strapko
Background
We found a low SVR in HCV patients treated between Jul
2001 to Jul 2004 in the Central New York region.
Aims
1. To compare patient cohorts between different
practice sites. 2. To identify variables affecting overall SVR in the region
and at individual practice sites.
Methods
A retrospective review of 373 treatment naïve patients
treated with peg-interferon alfa 2a/2b and ribavirin at University Hospital
(Univ), Veterans’ Affairs medical center (VA), a University affiliated practice
(UA) and 5 community practices (CP) was performed. Demographic, clinical,
histologic, laboratory and HCV treatment-related data were collected. Patients
who failed to complete intended duration of therapy (early d/c) and patients
lost to follow-up were considered treatment-failures. Chi-square analysis was
used to compare variables between sites.
Results
Overall SVR in 373 patients was 33.2%.
Patient characteristics at individual sites were
significantly different (Table 1).
Ribavirin dose, dose reduction and use of growth
factors was significantly different among various sites (Table 2).
Conclusions
1) Although there was a striking difference in HCV
patient characteristics there was no difference in SVR among sites.
2) Even though community practices had a higher
percentage of females, Caucasians, non-genotype 1, and less advanced fibrosis,
SVR was low.
3) Further studies are required to investigate this
lower than expected SVR.
|
Site
(n) |
Univ
(75) |
VA
(70) |
UA
(114) |
CP
(114) |
p
value |
|||||
|
SVR % |
26.7 |
32.9 |
37.7 |
33.3 |
0.48 |
|||||
|
Age (mean in yrs) |
45.9 |
49.7* |
46.2 |
46.9 |
<0.01 |
|||||
|
Male % |
62.7 |
92.9* |
67.5 |
63.2 |
<0.001 |
|||||
|
Caucasian % |
63.2* |
82.1 |
84.5 |
76.9 |
<0.01 |
|||||
|
African American % |
30.9* |
16.4 |
8.2 |
13.8 |
<0.01 |
|||||
|
Genotype 1 % |
79.4* |
82.6* |
61.5 |
69.4 |
<0.01 |
|||||
|
High Viral load % |
43.2* |
63.8 |
50.5 |
61.1 |
<0.03 |
|||||
|
Advanced Fibrosis/ Cirrhosis % |
46.5* |
33.3 |
31.9 |
23.5* |
<0.02 |
|||||
|
Psychiatric diagnosis % |
37.3 |
64.3* |
57 |
30.7 |
<0.001 |
|||||
|
Diabetes mellitus % |
17.3* |
11.4 |
8.8 |
5.3 |
0.05 |
|||||
|
Site (n) |
Univ (75) |
VA (70) |
UA (114) |
CP (114) |
p value |
|||||
|
SVR % |
26.7 |
32.9 |
37.7 |
33.3 |
0.48 |
|||||
|
Early dc % |
37 |
21 |
21 |
29 |
0.06 |
|||||
|
Mean ribavirin mg/kg (sd) |
11.3 (3.8)* |
13.1 (2.8) |
12.9 (2.7) |
12.4 (2.4) |
<0.01 |
|||||
|
Ribavirin dose>10.6mg/kg % |
62.2* |
88.2 |
84 |
79.4 |
<0.01 |
|||||
|
Dose reduction % |
26.7 |
31.4 |
10.5* |
24.6 |
<0.01 |
|||||
|
Epo/ G-CSF use % |
7/0 |
46/23* |
18/10 |
10/6 |
<0.001 |
|||||
E. Dieperink; J. Leskela; M. Dieperink;
B. Evans; J. Durfee; K. McCarthy; P. Thuras; S. B. Ho
Background:
Nearly one third of veterans with
chronic hepatitis C(HCV)infection are diagnosed with Posttraumatic Stress
Disorder(PTSD).HCV patients with PTSD are frequently excluded from antiviral
therapy but no studies exist regarding the effect of antiviral treatment on
PTSD.
Purpose:
To better characterize PTSD symptoms
in patients with HCV treated with pegylated interferon-alfa and ribavirin.
Methods:
Patients with PTSD diagnoses seen in
a Hepatitis Clinic were prospectively followed at baseline, 4,8,12, and 24
weeks with two measures of PTSD symptoms(the Mississippi Scale for combat
Related PTSD(Mississippi) and the PTSD Checklist-Military Version(PCL-M)), a
measure of hostility/irritability (the Buss-Durkee questionnaire), and the Beck
Depression Inventory(BDI).A comparison group of patients with PTSD and HCV who
were not treated with antiviral therapy were followed using the same
time-points and questionnaires. Five subjects with HCV and PTSD treated with
antiviral therapy and 11 comparison subjects have completed the study. All
subjects were treated as needed by their current mental health providers.