Sunday Forums: Clinical
Etiology
172. Low serum adiponectin levels in a transgenic mouse model of
hepatitis C infection
A. Delgado; Y. Kamegaya; S.
H. Jordan; S. Agrawal; Y. Hiasa;
R. T. Chung
Background
and Aims:
Recent studies have demonstrated an association
between HCV infection and insulin resistance. However, the underlying
mechanisms for this association remain unclear. We sought to evaluate whether
HCV decreases in vivo levels of adiponectin, an
anti-inflammatory adipokine known to induce insulin
sensitivity.
Methods:
Transgenic (Tg) mouse models
expressing HCV core and HCV core-E1-E2 proteins under the control of the HBV
enhancer and albumin promoter, respectively, were created on a hybrid
C57BL/6/FVB background as previously described (Kamegaya
Y., Hepatology 41: 660-7, 2005). On this background, mice do not develop
significant liver pathology. Twenty-eight Tg (18
core, 10 core-E1-E2) and 12 littermate controls were evaluated. All mice were
16 to 18 months old. Serum samples were collected following an overnight fast,
and immediately frozen at –80C. Adiponectin levels
were measured using Luminex ELISA technology.
Results:
Mean adiponectin levels were
16.45 μg/ml for non-Tg
vs. 13.79 μg/ml for Tg
mice (p = 0.2). There were no differences in adiponectin
levels observed between the core and core-E1-E2 Tg
animals. The greatest difference in frequencies was observed for the group of adiponectin levels <10 μg/ml
(36% Tg vs. 9% non-Tg).
Thus, adiponectin was dichotomized at the critical
value of 10 μg/ml, and low adiponectin
was defined as any value below 10 μg/ml.
Logistic regression was used to compare the probability of having a low adiponectin level between the Tg
and non-Tg groups. The odds of having a low adiponectin level were 30.4 (1.6 – 583.8) times greater
(p=0.02) for the Tg than the non-Tg
group.
Conclusions:
HCV Tg mice were
significantly more likely to have low adiponectin
levels as compared with non-Tg mice. These data
demonstrate an in vivo association between HCV and low adiponectin
levels, and suggest that HCV structural protein expression alone may suffice to
decrease adiponectin levels. These results provide a
plausible mechanism for HCV-associated insulin resistance.
173. The prevalence of metabolic syndrome
in veterans with chronic hepatitis C virus.
P. K. Pandya; S. C. Mathur; P. Callahan; P. Shah; D. Reker
Background:
In addition to traditional predictors of poor response
to antiviral therapy for chronic hepatitis C such as viral load, genotype,
race, and advanced fibrosis, recent evidence has implicated obesity related
factors such as insulin resistance and hepatic steatosis. The prevalence of
insulin resistance and related MS in veteran population with chronic hepatitis
C has not been systematically studied.
Methods:
We performed a cross-sectional analysis of the
prevalence of the metabolic syndrome in chronic hepatitis C infection. We
evaluated 38 consecutive veterans referred for evaluation of chronic hepatitis
C, who were drinking less than 20 g alcohol per day (by standard
questionnaire). We hypothesized that the metabolic syndrome (MS) would be
associated with worse hepatic histology than HCV infection alone. We collected
detailed demographic, anthropometric, serologic, histologic
and metabolic parameters in order to compare metabolic, virologic and histologic status between subjects with and without the MS.
Insulin resistance was defined as a HOMA-R (fasting insulin (mU/L) x fasting glucose (mmol/L)/22.5)
greater than 2.5. MS was defined by the presence of 3 or more ATP III criteria.
Additional data included determination of hs-CRP,
TNF-α, IL-6, adiponectin and leptin.
Groups were compared using t-test and/or Fisher’s exact analysis.
Results:
The average age, BMI, viral load, ALT and HOMA were
53.3±7.0, 28.0±6.3, 2.57x106, 59.4±38.3 and 4.7±7.4 respectively. All but one
of the patients were male. Caucasians and African Americans comprised 71% and
18.4% of the cohort. The predominant genotype in the cohort was Type 1 (81%).
Twenty of the 38 veterans studied met the ATP III criteria for the MS. Veterans
with the MS had higher BMI (p=0.001), HOMA-R (p=0.012), and leptin
(p=0.008), while no differences were seen (p=ns) in age, race, ALT, TNF-α,
Il-6, adiponectin, hs-CRP,
viral load, or genotype. Patients with MS had significantly higher prevalence
of steatosis (p=0.001) and fibrosis on biopsy (p=0.001).
Conclusion:
Metabolic syndrome was present in 53% of veterans
referred with chronic hepatitis C. Leptin but not adiponectin was significantly associated with the metabolic
syndrome. Veterans with metabolic syndrome have more steatosis and advanced
fibrosis. The high prevalence of metabolic syndrome may adversely impact
outcomes with antiviral therapy in veterans.
174. Immunohistochemical expression of junctional
proteins and intestinal permeability are altered in Hepatitis C virus (HCV)
related chronic hepatitis (HCV-CH).
L. Martorelli; S. Anna; P.
Esposito; L. deMagistris; M. Russo; M. Generoso; M. Carteni'; G. Riegler; F. Ferraraccio; A. Fasano
Background/rationale:
Altered intestinal permeability values (IP) and
intestinal ultra-structural abnormalities have been shown in cirrhotic patients
as well as other liver diseases.
Aims:
To study the IP, serum levels of the intestinal tight
junction (tj) modulator zonulin
(Z), and the immunohystochemical expression of junctional proteins occludin, claudin, desmoglein and
intracellular actin in duodenal mucosa of HCV-CH
patients.
Methods:
The IP was evaluated by the Lactulose/Mannitol (LA/MA) test. Serum Z levels were determined by
sandwich-ELISA. Distal duodenum biopsies were obtained by EGD and processed for
immunohystochemistry. Staining was obtained with
antibodies specific for occludin, claudin-4,
desmoglein-3, and actin. Twenty-five consecutive
naïve HCV-CH patients were enrolled (12 males, 13 females, mean age 59,9 ±10,5,
range 35-72); none of them was on interferon treatment. All enrolled patients
underwent IP and Z investigation; 9 of them gave informed consent to perform an
EGD with duodenal biopsies.
Results:
The LA/MA mean ± SD value in the 25 patients studies
was 0.025±0.020, with 8 patients (32%) having LA/MA values higher than the
normal cut off (< 0.028). The mean ± SD value of Z in the 25 patients
resulted 1.27±1.64 ng/mg protein, with 10 of them
(40%) having Z values higher than the normal cut off (< 0.6 ng/mg protein). There was a correlation between elevated
LA/MA and serum zonulin levels. Occludin
immunoreactivity at the cell membrane surface
resulted diminished in all cases but one (decrement ranging between 50-90% as
compared to normal controls). These changes were paralleled by an increased cytoplasmatic occludin immunoreactivity (2-50%), suggesting a displacement of the tj protein from the membrane boundary to the cytoplasm.
Claudin-4 expression resulted diminished by 30-60% in all cases and was
associated to a decrease in actin immunoreactivity
(45-85%). Desmoglein immunoreactivity
also decreased by 45-70%.
Conclusions:
Alteration in IP was detected in a one third of the
HCV-CH patients studied and was associated to elevated serum Z values. These
changes were associated to modification of tj
proteins expression and localization. Our data suggest that a subgroup of
HCV-CH patients has increased serum Z and changes in tj
proteins distribution compatible with altered IP. These changes may lead to
increased non-self antigens access that may influence the course of the liver
disease.
A. Iwai; H. Marusawa; Y.
Takada; H. Egawa; M. Nabeshima;
T. Chiba
Background:
Interferon (IFN)-α2b plus ribavirin (RBV)
combination therapy is widely used for recurrent hepatitis C following liver
transplantation; however, the rate of sustained virological response (SVR) in
transplant patients has been limited. Recurrent hepatitis C in transplant
patients differs from that in immunocompetent
individuals in several ways such as immunosuppressive condition and extremely
high viral loads. However, it remains unclear whether viral and host factors
determine the effectiveness of combination therapy in those patients.
Aim:
The aim of this study was to identify the host and
viral factors associated with a SVR to antiviral therapy in patients with
recurrent hepatitis C after living-donor liver transplantation (LDLT).
Methods:
Twenty-three patients receiving the IFN-α2b plus
RBV combination therapy for recurrent hepatitis C after LDLT were enrolled. The
hepatitis C virus (HCV) genome clones circulating in sera of those recipients
were cloned by reverse transcription–polymerase chain reaction.
Results:
Twenty of the 23 patients (87%) were infected with HCV
genotype 1b. Before treatment, all patients had serum HCV RNA levels over 100
KIU/mL by the Amplicor HCV 2.0 assay. Moreover, HCV
RNA levels were greater than 850 KIU/mL (ranging from 850 to 21,200 KIU/mL) in
17 cases (74%), which is equivalent to 8.5 × 105 to 2.12 × 107 copies/mL HCV
RNA, indicating that a majority of the patients in this study had high baseline
viral loads before treatment. SVR was achieved in seven of 23 patients (30%).
Predictive factors for SVR included; (1) 2log10 decline in HCV RNA at two weeks
after the start of therapy, (2) disappearance of HCV RNA at four or 24 weeks
after the start of therapy, (3) frequency of positivity
for HLA-B51, and (4) frequency of negativity for HLA-A26. Since the
pretreatment high viral load showed no association with SVR, we asked whether
other viral factors played roles in determining response to the combination
therapy in transplant recipients. We found several novel defective HCV clones
in four (33%) of twelve recipients’ sera with genotype 1b and extremely high
HCV RNA loads (over 850 KIU/ml). All defective HCV clones had deletions in the
envelope region of HCV genome. Interestingly, no patients with defective clones
showed a 2log10 decline in HCV RNA at two weeks after the start of therapy.
Conclusions:
Early decline in serum HCV RNA after treatment was
closely associated with SVR. The circulating defective HCV clones are present
and might be responsible for resistance to the combination therapy in patients
with recurrent hepatitis after liver transplantation.
A. Bergk; C. Sarrazin; M. von Wagner; G. Teuber;
P. Buggisch; V. Weich; B. Wiedenmann; T. Berg
Introduction:
Current treatment guidelines for the therapeutic
management of chronic hepatitis C virus (HCV) genotype 1 infected patients
include a week 12 stopping rule for nonresponders defined by a drop of viral
load less than 2 log10 in patients treated with pegylated interferon and
ribavirin. Nevertheless there has been no convincing prognostic tool to easily
and reliably predict viral relapse after the end of 48 weeks of treatment.
Aims:
Aim of the present study was to evaluate the
predictive value of a minimal residual HCV viremia for a relapse in genotype 1
infected patients with early virologic response to therapy.
Patients and
methods:
We retrospectively analyzed viral kinetics at week 12
and response of 773 treatment naive HCV genotype 1-infected patients using
PegIFNα-2a/b and ribavirin treated at our outpatient clinics. For the
detection of residual viremia at week 12 a quantitative real-time PCR with a
lower limit of detection of 10IU/mL (TaqMan) was
used.
Results:
Using standard quantitative HCV-RNA assays at week 12
75% (430/773) of the patients treated with PegIFNα-2a/b and ribavirin
showed an early virologic response defined by week 12 viral load drop ≥2
log10. By re-analyzing 222 available serum samples of early virologic
responders by TaqMan a residual viremia could be
detected in 84 out of 222 patients (38%). The presence of viremia highly
correlated with a viral relapse after the end of 48 weeks of treatment
(p<0,001). Residual viremia was detectable by real-time PCR at week 12 in
only 19 out of 126 sustained responders (15%) as compared to 69 out of the 96
relapse patients (72%) (p<0,001).
A relapse occurred in 78% of the patients who had
detectable HCV viremia at week 12 (68/88) as compared to only 19% (25 out of
134 patients) if HCV RNA was undetectable at week 12. The relative risk to
suffer from a relapse was 3.5 and 0.26 in patients with and without residual
hepatitis C viremia at week 12, respectively (p<0,001).
Discussion:
Using a highly sensitive real-time PCR the detection
of minimal residual hepatitis C viremia at treatment week 12 was in 78%
associated with a viral relapse after the end of therapy and is therefore a
valuable prognostic tool for the prediction of individual treatment outcome.
Treatment of patients with detectable viremia at week 12 should be individually
intensified by either prolonging treatment duration or preventing dose
reductions by the application of erythropoetin or
GM-CSF.
HCV Treatment Forum:
195. Generation and Characterization of HCV
Replicons with Reduced Sensitivity to ITMN 191, a Macrocyclic Inhibitor of NS3/4A
S. Seiwert; S. W. Andrews;
H. Tan; K. R. Condroski; J. A. Ballard; B. A. Bernat; J. A. Josey; L. M. Blatt
The standard of care for chronic HCV infection affords
a sustained virologic response in ~50% of chronic HCV patients—thus the need
for novel therapeutic approaches. We therefore embarked on a rational drug
design campaign to produce inhibitors of the HCV NS3/4A protease. ITMN 191 (an
active site inhibitor with a macrocyclic structure)
emerged from this discovery effort and was nominated as a preclinical
candidate. In a genotype-1b replicon system, ITMN 191 displays an EC50 of 2.1 nM and an EC90 of 5.6 nM. It has
liver levels in multiple species predictive of efficacious exposure in humans
at moderate doses, and displays an acceptable tolerability profile.
Methods:
To understand the resistance profile of ITMN 191, we
incubated it with a genotype-1b HCV replicon in increasing concentrations
ranging from 20 nM to 320 nM
(10-fold to 160-fold the original EC50 value). As measured by its EC50 value,
the potency of ITMN 191 was reduced by 149-fold against replicons
that persist in the presence of 320 nM ITMN 191.
Sequence analysis demonstrated that all such replicons
carried the previously identified mutation D168A; this mutation disrupts a salt
bridge to R155. Structural modeling suggests that loss of this salt bridge
would partially occlude binding of ITMN 191’s fluoro-isoindolene
P2 group. In a biochemical activity assay, D168A shifted the EC50 of ITMN 191
from <300 pM to 4.5 nM.
The majority of replicons that persist in the
presence of 320 nM ITMN 191 additionally carried both
V116M and E30A mutations. Biochemical characterization of the potential
contribution of these mutations is underway.
Conclusion:
In conclusion, HCV replicons
with reduced sensitivity to ITMN 191 harbor a D168A mutation. The additional
presence of V116M and E30A mutations in ITMN 191–resistant replicons,
residues that are far from the binding site of ITMN 191, suggests that if these
sequence changes contribute to replicon fitness or ITMN 191 resistance, it is
through an indirect mechanism. Interestingly, the D168V mutation that confers
resistance to the macrocyclic inhibitor BILN-2061 was
not observed in this study. Biochemical analysis has previously demonstrated
that ITMN 191 retains subnanomolar potency against
D168V. Additionally, it is noteworthy that mutations that confer reduced
sensitivity to both BILN-2061 and linear tetrapeptide
inhibitors such as VX-950 (A156T/V) were not identified in this study. Again,
previous biochemical analysis has confirmed that ITMN 191 retains subnanomolar potency against A156T. Thus, ITMN 191 has a
favorable cross-resistance profile with VX-950 and related linear tetrapeptides, and potentially with other macrocyclic inhibitors as well.
D. Nelson; V. Rustgi; V. Balan; M. Sulkowski; L. Lambiase; R. Dickson; R. Weisner;
G. Davis; A. Muir; L. Novello; R. Yu; W. Freimuth; A. Neumann; J. McHutchison;
M. Subramanian
Background
and Aims:
Albuferon (alb-IFN) is a novel recombinant protein
consisting of IFNa genetically fused to human
albumin. This ongoing Phase 2, dose-ranging study evaluates the safety and
efficacy of alb-IFN in chronic HCV patients who were non-responders (failed to
achieve EVR12 or clear HCV RNA on therapy) to previous IFNa
based regimens.
Methods:
Subjects were randomized into 3 alb-IFN SC treatment
cohorts (900 mcg Q2w, 1200 mcg Q2w or 1200 mcg Q4w) in combination with
ribavirin (RBV) 1000-1200 mg/d. After evaluating safety data, 2 higher dose
cohorts of alb-IFN 1500 mcg Q2w and 1800 mcg Q2w were enrolled. The treatment
duration is 48w with 24w follow-up. The primary efficacy end-point is SVR. The
initial 3 cohorts have completed 48w treatment and 12w data for the highest
dose cohort is currently available.
Results:
Subject demographics and antiviral response for the
115 subjects enrolled are summarized in the table. At w12, the overall
antiviral response in the 1800 mcg Q2w cohort was the highest despite having a
greater proportion of prior PEG-IFN+RBV non-responders. The slope of HCV RNA
decline at w4-12 was significantly more rapid (P<0.01) for the 1800 mcg
cohort compared to the 900-1500 mcg cohorts in genotype 1, prior PEG-IFN+RBV
non-responders. The w24 antiviral response was comparable across the 900-1500
mcg cohorts. Most patients who were RNA negative at w24 remained negative at
w48. Antiviral response at w12 and w24 was predictive of w48 end-of-treatment
response for the 900-1200 mcg cohorts. Overall, alb-IFN in combination with RBV
was well tolerated and the safety profile in the 1500 mcg and 1800 mcg cohorts
was comparable to the 900-1200 mcg cohorts in type, incidence and severity of AEs.
Conclusions:
Alb-IFN at doses up to 1800 mcg Q2w in combination
with RBV is safe and demonstrates significant antiviral activity in prior IFNa non-responder patients. Further studies are warranted
and are ongoing.
M. R. Kraus; O. Al-Taie; A.
Schaefer; M. Pfersdorff; M. Scheurlen
Background
and aims:
Interferon-induced depression is still a major problem
in antiviral therapy of chronic hepatitis C. By the use of SSRIs,
this therapy-induced side effect can be successfully managed in most cases.
However, so far little is known about underlying mechanisms and reliable
predictive factors associated with cytokine-induced depressive symptoms.
The aim of the present study was to investigate the
putative role of the 5-HT1A C(-1019)G serotonin receptor polymorphism in a
prediction model for IFN-induced depression.
Methods:
In a longitudinal single-center study, we included a
volunteer sample of 139 HCV outpatients. These were enrolled between 1997 and
2004 and received (combination) treatment with (pegylated) interferon alfa-2b
(and ribavirin).
Before and during interferon therapy, depression was
monitored using the Hospital Anxiety and Depression Scale (HADS) and interview
data (DSM-IV criteria for major depression / major depressive disorder).
EDTA blood samples were drawn from all patients, and
subsequent genotyping of the serotonin receptor polymorphism (HTR1A-1019) was
realized by DNA isolation extraction and polymerase chain reaction in an ABI
PRISMTM 310 Genetic Analyzer (according to standard protocols).
Results:
According to our data, there was a significant effect
of the HTR1A receptor polymorphism on the occurrence of interferon-induced
depression during antiviral therapy. Both higher incidence and extent of
depressive symptoms were significantly associated with carriers of the G
allele. ANOVA analyses showed that maximum (P=0.011) and mean (P=0.024)
increases in HADS depression scores on antiviral therapy were significantly
affected by the HTR1A-1019 polymorphism. Also, the occurrence of clinically
relevant HADS depression scores (cutoff criterion ≥ 9) was significantly
associated with the allelic variation (Chi-square test, P=0.017).
Conclusions:
Our findings suggest allelic variation in 5HT1A
expression to play a significant role in the development of interferon-induced
depression in the antiviral treatment of chronic hepatitis C. Prediction models
of interferon-induced depressive symptoms that are based on the HTR1A-1019
polymorphism should be further investigated.
198. Treatment of Chronic Hepatitis C in Thalassemic and Sickle Cell Disease Patients with
Interferon Alfa2b (IFN) and Ribavirin(RBV).
d. b. ancel; D. Chaslin-Ferbus; x. J. Amiot; I. Hagege; J. Schaeffer Plumet; S. Pol; R. Girot; j. b. grange
Prognosis of patients with congenital haemolytic anaemia has greatly
improved in recent years, particularly among those suffering from thalassemic syndrome. In this population, hepatic
complications due to post-transfusion viral hepatitis and iron overload become
one of the main causes of death. The 1999 Consensus statement of the EASL
listed anaemia as an absolute contra-indication to
RBV in hepatitis C. Aim: to assess the efficacy and safety of IFN and RBV
treatment among patients with congenital haemolytic anaemia
Methods:
Ten patients (mean age: 27.4 ± 6.3 yr) were included:
5 sickle cell disease (4 treatment-naïve, 1 non responder) and 5 thalassemic major patients (1 naïve, 4 non responders).
Eight patients (5 sickle cell, 3 thalassemic
patients) were treated with PEGIFN and RBV. Two thalassemic
patients were treated with IFN monotherapy. PEGIFN was given at full dose. RBV
was started with an undervalued dose (400mg/d), then progressively increased
according to weight based recommended dose. Duration of treatment was 24 or 48
wk.
Results:
HCV genotypes were 1 and 4 in 8 cases. All sickle cell
disease patients had a fibrosis METAVIR score ≦2, whereas 4/5 thalassemic patients were F4. A
virological response at the end of treatment was achieved in 9/10 patients, and
a sustained virological response (SVR) in 6/10 patients (3 thalassemic
patients including 2 with cirrhosis). Five of the six SVR were obtained with
combination therapy. The 6 sustained responders did not present any hepatic
complication during the follow-up. A non responding thalassemic
patient died of hepatocellular carcinoma recurrence after liver
transplantation. The mean increase in transfusion requirements during treatment
compared with the same period prior to treatment was 22% in thalassemic
patient group (growth factors were not administered). No sickle cell patient
needed transfusion during or after treatment periods. Surprisingly, the haemoglobin level during and at the end of treatment was
higher than the pretreatment value among 4/5 sickle cell patients (none of them
being treated beforehand by hydroxyurea).
Conclusion :
In this pilot study, overall SVR was 60 %, despite the
unfavourable genotypes of most patients. Combination
therapy with IFN and RBV achieved a high SVR rate (62.5%, 5/8 patients). The
increased transfusion requirements during treatment in thalassemic
patients are acceptable. Among sickle cell patients, no previous case of
excellent haematological tolerance under RBV and
without hydroxyurea pre-treatment has been reported in
literature: our data suggest the use of a full dose RBV and PEGINF from the
start of treatment in these patients.
C. Howell; T. Dowling; M. Haritos; N. Terrault; W. Thelma; M. Taylor
African Americans (AA) infected with hepatitis C virus
(HCV) genotype 1 have significantly lower rates of HCV clearance than Caucasian
Americans (CA) following treatment with peginterferon
alfa (PEGIFN) and ribavirin. In the Virahep-C study,
this racial difference in virologic response was observed during the first 4
weeks of therapy.
Aim:
To compare PEGIFN pharmacokinetics and pharmacodynamics (i.e. serum 2,5 OAS kinetics) in
relationship to virologic responses during the first 28 days of PEGIFN-2a and
ribavirin treatment in AA and CA HCV genotype 1 patients.
Methods:
401 treatment-naïve, HCV genotype 1 patients (196 AA
and 205 CA) were treated with PEGIFN-2a (180 mcg/wk) and ribavirin (1000-1200
mg/day) for up to 48 weeks. Ninety-six patients who received PEGIFN without
dose alteration during the first 4 weeks of treatment and who had PEGIFN and
2,5-OAS serum levels measured before treatment and on treatment-days 1, 2, 3,
7, 14 and 28 were selected for this study. PEGIFN and serum 2,5-OAS (pharmacodynamic marker) levels were measured by ELISA and
by RIA (Roche Molecular Diagnostics, Alameda, CA). The maximum PEGIFN
concentration (Cmax) and area under the serum
concentration-time curve (AUC) values from day 0 to 7 were determined using
non-compartment PK analysis. Serum HCV RNA levels were measured using the Amplicor HCV Monitor Test, version 2.0 assay.
Results:
At baseline, AA and CA patients were similar in
regards to age, gender distribution, body weight, BMI, alcohol or tobacco use,
liver histology, creatinine clearance, baseline HCV RNA levels, and HCV 1
subtype distribution, but AA had a lower mean serum ALT level (p = 0.003).
There were no differences between AA and CA in either Cmax
or AUC from day 0-7 after first PEGIFN dose, but AA were more likely to have a Tmax by day 3 (p = 0.03) and had a greater PEGIFN level on
day 28 (18.0 ± 8 vs. 15.5 ± 7 ng/mL, p = 0.03) and
higher 2,5-OAS levels on day 2, 3, 14, and 28 (p < 0.05). In contrast, AA
had a significantly smaller decline in serum HCV RNA from pretreatment to day
28 (p =0.02 day 14 and 28). There was a negative correlation between serum
PEGIFN-2a (p < 0.05) and HCV RNA levels on days 7 (r = -0.23, p = 0.09), 14
(r = -0.30, p = 0.03), and 28 (r = -0.32, p = 0.02) in CA but not in AA.
Likewise, there was a negative correlation between serum 2,5-OAS levels on day
2-14, and HCV RNA levels from day 2-28 in CA (p < 0.05) but not in AA.
Conclusion:
The weaker virologic response in AA HCV genotype 1
patients compared to CA patients during the first 4 weeks of PEGIFN-2a and
ribavirin treatment is not explained by racial differences in serum PEGIFN and
serum 2,5-OAS kinetics.
200. Evaluation of a HCV Patient Support
Program’s Impact on Patient Adherence
M. Hussein; J. S. Benner; D. Lee; A. Sesti; D. S. Battleman
Background:
For patients with hepatitis C virus (HCV), poor
adherence to antiviral therapy is a common barrier to treatment success.
Challenges associated with administration and tolerability make this issue
especially true of pegylated interferons + ribavirin. The Be In Charge® program
(BIC) is a comprehensive patient support program for HCV patients; it encourages
adherence by providing 24-hour inbound and proactive outbound on-call nursing
support and mailings of HCV educational materials throughout therapy.
Objectives:
The purpose was to determine the effect of BIC on
patient adherence to peginterferon alfa-2b
combination therapy (peg-2b).
Methods:
A retrospective cohort analysis comparing BIC
enrollees to a matched control group was conducted. Subjects were included if
they were ≥18 years of age; started peg-2b on or after 1/1/2004; and
could be followed for at least 12 weeks after treatment initiation. To reduce
potential selection bias from self-enrollment in the program, BIC enrollees
were propensity score-matched to peg-2b starters not enrolled in BIC
(controls), based on clinical and demographic characteristics. Filled
prescription records were used to measure adherence based on the number of
injections dispensed and proportion of patients who received an average of
≥1 injection per week during follow-up. Adherence was compared using
paired chi-square and t-test.
Results:
The BIC group consisted of 780 eligible subjects who
were observable for ≥12 weeks, including 638 and 333 subjects observable
for 24 and 48 weeks, respectively. Of control subjects, 8572, 7014, and 4071
subjects were observable for 12, 24, and 48 weeks, respectively. Compared to
non-BIC subjects, BIC enrollees were more likely to be female (53% vs. 41%,
P<0.0001) and to use injection delivery devices vs. vials (74.0% vs. 56.7%,
P<0.0001). In the matched analysis, BIC subjects refilled 1.2 more
injections (95% confidence interval [CI] 0.52, 1.83; P<0.0001) than the
control cohort within 12 weeks, 2.7 more (95% CI 1.5, 3.8; P<0.0001) within
24 weeks, and 6.7 more (95% CI 4.3, 9.1; P<0.0001) within 48 weeks. Compared
to matched controls, BIC enrollees were more likely to refill ≥12
injections within 12 weeks of initiation (72% vs. 64%, P=0.0005), ≥24
injections within 24 weeks (52% vs. 41%, P<0.0001), and ≥48 injections
within 48 weeks (22% vs. 13%, P=0.0020).
Conclusion:
These findings suggest the BIC program significantly
improves adherence to peg-2b. Additional research is needed to ascertain which
aspects of the program are most effective and which patients are most likely to
benefit from this intervention.