Hepatitis C
Newsletter
Best of the American Association for
the Study of Liver Disease (AASLD) 2012Meeting
Late Breakers 1
- 1
Clinical Trials, Cohort Studies, Pilot Studies 2
– 20
Basic and Applied Science, Pre-Clinical Studies 20
- 25
HIV/HCV Coinfection 25
- 31
Complementary and alternative medicine 31 - 34
Epidemiology, Diagnostics & Miscellaneous Works 34 - 49
Liver Cancer 40
- 57
Post Transplant – New! 57
- 62
Late
Breakers!
1. A 12-Week Interferon-free Treatment Regimen
with ABT-450/r, ABT-267, ABT-333 and Ribavirin Achieves SVR12 Rates (Observed
Data) of 99% in Treatment-Naïve Patients and 93% in Prior Null Responders with
HCV Genotype1 Infection
A regimen of 3 direct acting antiviral medicines plus ribavirin was well
tolerated and achieved high 12-week post-treatment viral elimination rates in
both new patients and prior null responders with hepatitis C virus genotype 1
infection.
2. High Rate of Sustained Virologic Response
with the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir
(Nucleotide NS5B Inhibitor), With or Without Ribavirin, in Treatment-Naïve
Patients Chronically Infected With HCV Genotype 1, 2, or 3
A 24-week regimen of an all oral combination of once-daily daclatasvir (DCV)
plus sofosbuvir (SOF) achieved high 12-week viral elimination rates in
previously untreated patients infected with hepatitis C virus genotype 1, 2, or
3.
3. An Interferon-free, Ribavirin-free 12-Week
Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 Yielded SVR4 of
94% in Treatment-Naïve Patients with Genotype (GT) 1 Chronic Hepatitis C Virus
(HCV) Infection
A 12-week interferon and ribavirin free regimen of three direct-acting
antivirals, daclatasvir, asunaprevir, and BMS-791325 was well tolerated and
achieved high 4-week post-treatment viral elimination rates in treatment-naïve
patients infected with hepatitis C virus genotype 1.
4. High Efficacy Of GS-7977 In Combination
With Low or Full dose Ribavirin for 24 weeks In Difficult To Treat HCV Infected
Genotype 1 Patients : Interim Analysis From The SPARE Trial
A 24-week regimen of nucleotide NS5B inhibitor GS-7977 combined with low
dose ribavirin was highly effective in suppressing hepatitis C virus
replication in difficult to treat patients.
Clinical
Trials, Cohort Studies, Pilot Studies
Dietary Cholesterol Intake is
Associated with Liver Disease Progression in Hepatitis C Infection: Analysis of
the HALT-C trial. L. Yu, G.
Ioannou. ABSTRACT FINAL ID: 940
It is unknown
whether dietary cholesterol influences disease progression in hepatitis C virus
(HCV) infection. METHODS: Using data
from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C)
Trial, we analyzed whether dietary cholesterol was associated with histological
and clinical progression in patients with advanced fibrosis (Ishak fibrosis
score 3 or 4) and compensated cirrhosis (Ishak fibrosis score 5 or 6).
Cholesterol intake was estimated at baseline, then 1.8 years later, using the
Block Food Frequency Questionnaire (FFQ). Histological progression was defined
by an increase in Ishak fibrosis score of 2 or more points on repeat liver
biopsy in patients with advanced fibrosis. Clinical progression was defined by:
death, variceal bleeding, encephalopathy, ascites, peritonitis, hepatocellular
carcinoma, CTP score ≥7 or transplantation. RESULTS: Higher cholesterol intake was associated with higher
intake of other macronutrients and alcohol, younger age, male sex, higher ALT
and Ishak inflammation score. Using the average cholesterol intake from
patients who completed both FFQ’s (N=617), higher
cholesterol
intake was strongly associated with disease progression. After adjustments for
age, sex, race, cirrhosis status, body mass index, interferon treatment group,
lifetime alcohol, smoking, coffee intake and other macronutrients intake, each
higher quartile of cholesterol intake was associated with a 50% increase in the
risk of histological or clinical progression (adjusted hazard ratio [AHR] 1.49,
95% CI 1.18-1.88, P-value for trend = 0.001). Compared to
patients in
the lowest quartile of cholesterol intake (31.6–151.8 mg/day), patients in the
2nd (151.9-219.9 mg/day, AHR 1.85, 95% CI 1.04-3.20), 3rd (219.9-309.6 mg /day,
AHR 2.70, 95% CI 1.52-4.80) and 4th quartile (311.8-1118 mg/day, AHR 3.26, 95%
CI 1.52-6.99) had progressively increased risk of histological or clinical
progression. Using cholesterol intake estimated from the 2nd FFQ (N=750), the
strength of the association between higher dietary
cholesterol
and histological or clinical progression was weaker, but remained statistically
significant (AHR 1.27, 95% CI 1.01-1.59, P-value for trend = 0.04). Using
cholesterol intake estimated from the baseline FFQ (N=765), there remained an
association between higher cholesterol intake and histological progression (AHR
1.31, 95% CI 1.02-1.68, P-value for trend = 0.03), but not clinical progression
(AHR 1.19, 95% CI 0.92-1.52, P-value for trend = 0.2).
CONCLUSION: High dietary cholesterol intake was
associated with greater risk of disease progression in HCV patients with
advanced fibrosis and compensated cirrhosis.
Importance of Hepatitis C Virus in
Peripheral Blood Mononuclear Cells versus Serum of Children Suffering From
Chronic Hepatitis C: Pre- and Past-Treatment. M.A. El Guindi, M. Hassan, I.
El-Henawy, O. ABSTRACT FINAL ID: 1132
INTRODUCTION: Hepatitis C virus (HCV) is a major
cause of liver disease and one of the most important health issues worldwide
specially Egypt. The prevalence of HCV in Egyptian children ranges between 2%
and 10%. Relapse of HCV after anti viral therapy is a major problem,
postulating presence of extrahepatic sites suitable for HCV replication, one of
which is peripheral blood mononuclear cells (PBMCs). The aim of this study is
to assess HCV-RNA in PBMCs versus serum of children with chronic HCV. Subjects
and METHODS: The study involved 16
children, aged 4-16 years, diagnosed with chronic HCV, and attended the
Pediatric Hepatology Department, National Liver Institute, Menoufiya
University. All patients were subjected to thorough clinical, radiological and
laboratory tests after obtaining written informed consents from parents. All
patients were HCV-antibodies positive, and serum HCV-RNA positive. Patients
were treated with antiviral therapy consisting of pegIFN-α2a (180ug/1.73m2
/week subcutaneously) plus ribavirin (15 mg/kg/day orally) for 48 weeks.
Reverse transcription-nested PCR was done. Retrotranscription was performed
using SR1 primer (for plus strand) and SF1 primer (for minus strand) HCV-RNA
was monitored in serum and PBMC preparations before, mid-treatment and at the end
of treatment. RESULTS: According to
the response to antiviral therapy, patients were classified into responders (5
patients who achieved SVR) and non-responders (11 patients stopped treatment at
24 weeks). At the time of diagnosis
(retrospectively),
HCV RNA plus strands were detected in PBMCs of all responders and in PBMCs of
10 of the non responders (90.9%). HCV RNA minus strands were detected in PBMCs
of only one of the responders (20%) while they were detected in PBMCs of 9 of
the non responders (81.8%) (p- value < 0.05). After 24 weeks of antiviral therapy,
5 patients were negative for HCV-RNA in serum while only 3 of them patients
were negative for HCV-RNA in
PBMCs. After
48 weeks of antiviral therapy, all 5 patients were negative for HCV-RNA in
serum while 2 of them (40%) still had HCV-RNA plus strand in their PBMCs. Those
2 patients received additional 24 weeks antiviral therapy till PBMCs became
free of HCV-RNA.
CONCLUSION: Patients with minus strand HCV RNA in
PBMCs showed a significantly lower response to IFN, suggesting that
minus-strand HCV RNA in PBMCs is one of the factors predicting response to IFN
therapy. PBMCs infected with HCV can serve as a virus reservoir. HCV RNA serum
negative patients who had HCV RNA in their PBMCs after completion of antiviral
therapy (40%) would be at great risk of HCV recurrence and treatment should be
continued till PBMCs are free.
Hepatitis C virus (HCV) genotype 1 (G1)
infection with low viral load (LVL) and rapid virologic response (RVR) to
peginterferon and ribavirin (PEG/RBV) can be treated without a protease
inhibitor (PI), irrespective of IL-28B status or patient ethnicity.
B. Pearlman,
C. Ehleben. ABSTRACT FINAL ID: 151
BACKGROUND: G1 patients with LVL represent about
20% of all G1 infections. Abbreviated 24-week PEG/RBV regimens have been
recommended for G-1 LVL patients that achieve RVR (nearly half). The current standard-of-care
for G1 patients is PEG/RBV/PI; yet, no prospective trial has shown that a PI
may be obviated in selected patients without adversely impacting SVR rates. It
is also unclear if African American (AA) patients can benefit from the same
treatment truncation strategy. METHODS:
Therapy-naïve LVL (<600,000 IU/ml) GI patients from 2 Atlanta clinics
(n=249) were treated with 4 weeks of PEG-alfa2b (1.5 mcg/kg/wk) plus RBV (1-1.2
gm/day), and if RVR was achieved, were randomized 1:1 into 24 weeks additional
PEG/RBV/boceprevir (800 mg tid) [28 weeks total therapy, GROUP A] or 20 weeks
additional
PEG/RBV [24
weeks total therapy, GROUP B]. Patients were stratified by IL-28B genotype
(rs12979860). Primary endpoint was SVR-12. RESULTS:
Of 179 patients, 49% (n=88) achieved RVR and were randomized to group A (n=41)
or to group B (n=38). Baseline characteristics were not significantly different
between groups including mean age, mean BMI, percentage male subjects,
percentage with impaired fasting glucose, genotype subtype (1a 39 vs. 37%; 1b
61% vs. 63%), IL-28B status (CC 66 vs. 66%; non-CC 34 vs. 34%), F3/F4 fibrosis
(20 vs. 18%), AA subjects (32 vs. 34%), in groups A and B, respectively.
Overall SVR rates were not statistically different between Groups A and B (90
vs. 89%, respectively p=0.8). Relapse rates were 3% in Group A and 6% in Group
B (p=0.52). Regardless of IL-28B genotype, SVR rates were similar between
groups (C/C 96% in both groups, p=0.51; non-CC 79 vs. 77%, in groups A and B
respectively, p=0.72 ) AA SVR rates were 78% in group A and 83% in group B
(p=0.67). G1b patients achieved higher SVR rates relative to those of G1a in
both arms (Group A G1a 81%, G1b 96%; Group B G1a 85%, G1b, 92%), yet the differences
across groups were not statistically significant. Dose reductions (A 32% B29%,
p=ns) and discontinuations (A 7% B 5%, p=ns) were similar between arms. CONCLUSION: This prospective,
randomized trial demonstrates for G1 LVL patients who achieve a RVR with PEG/RBV,
the addition of a protease inhibitor produces similar SVR rates compared to
those of PEG/RBV therapy
alone,
irrespective of IL28B genotype, virus subtype or African American ethnicity. Since
this group comprises approximately 10% of all G1 infections, this treatment
strategy may engender substantial cost savings. The study is ongoing, and
results should be duplicated in larger, multicenter trials before this strategy
is adopted.
Hepatitis B and C are associated with
Non-Hodgkin Lymphoma: cross-sectional study of the National Inpatient Sample
database. M. Moehlen, A. Abbas, L.A. Balart. ABSTRACT FINAL ID: 907
BACKGROUND: Independent associations of hepatitis B
(HBV) and C (HCV) to non-Hodgkin lymphoma (NHL) have been previously reported,
although proven links have not yet been established. AIM: Assess the associations of HBV and HCV with NHL in a large
nationwide cohort within the United States. METHODS: We performed a cross-sectional study using the National
Inpatient Sample database for the years 2005-2009. All discharges of adults
that contained ICD-9 codes for HBV and HCV were included as the hepatitis group
(exposed).
An equal
number of non-hepatitis diagnosed patients randomly sampled from the database
served as the comparison group (non-exposed). NHL was identified in each group
using ICD-9 codes and the rates were compared using standard statistical
methods. A multivariate logistic regression analysis was used to assess the independent
effect of hepatitis on the outcome of NHL. RESULTS:A
total of 1,055,912 patients’ discharges were included in the analysis.
Discharges that contained HCV ICD-9 codes were 479,661 (45%) while those with
HBV were 48,295 (5%), the rest 50% represents the comparison group. Median age
at admission was 53 years, male percentage was 51%, and Caucasians were 51% of
the total included population.
The
univariate analysis found HBV to have the highest rate of NHL, 2.1% (1,019
cases) compared to 0.82% (3,966 cases) and 0.65% (3,470 cases) for HCV and the
comparison group, respectively (p<0.001). In multivariate analysis, hepatitis
status was an independent risk factor for NHL with HBV having the largest
effect size (OR=3.32, p<0.001) (Table). CONCLUSIONS:
This is the largest cross-sectional study within the United States
confirming the associations of HBV and HCV with NHL. Our results are in
agreement with previous reports linking HBV and HCV with NHL. There is a
limited understanding of the pathophysiology of HBV and HCV infection and the
activation and transformation of B-cell lymphocytes into lymphomas. Our study
highlights the need to further study these associations and implement
measures to
prevent and treat HBV and HCV infection.
Factors influencing the quality of life
on patients with chronic hepatitis C, evaluated with generic questionnaire
SF-36. R. Teixeira, L.D. Silva, C.C. da Cunha,
N.S. Monteiro, et al. ABSTRACT FINAL ID: 986
Quality of
life is a complex issue that involves physical, mental, psychological and
emotional wellbeing, as well as social relationships, like family and friends.
Several studies have demonstrated a decrease in the quality of life on chronic
hepatitis C patients with no significant liver disease. AIM: To evaluate factors associated with the decrease in quality of
life on patients with chronic hepatitis C (HCV). METHODS: 125 consecutive patients with HCV were enrolled in the
study. All patients completed several surveys including MINI-Plus 5.0, Hamilton
Depression Rating Scale, Hospital Anxiety and Depression Scale, CAGE. The
quality of life was evaluated by generic questionnaire Medical Outcomes Study
36-Item Short-Form Health Survey (SF-36), with 8 domains: functional capacity,
physical aspects, emotional aspects, social aspects, mental health, pain,
vitality and general health condition. RESULTS:
Demographic and clinical characteristics were: mean age 54.0 ± 8.9 yrs; 57.6%
female; 16.8% compensated cirrhosis; 28.8% current depression and 7% and 21%,
current and past alcohol dependence, respectively; 33.7% hypertensive and 19%
diabetics. MDD was associated with low SF-36 scores in all domains (p<0.01).
There was no association between reduction of the SF-36 score and alcoholism.
The score of functional capacity domain was reduced in HCV-patients with
hypertension (p=0.003) or diabetes mellitus (p <0.001) when compared to
HCV-patients without these comorbidities. CONCLUSION:
Several factors, in addition to the disease limited
to the liver,
affect the quality of life on HCV patients. The clinical evaluation becomes
relevant in the follow-up of those individuals, mainly as to the emotional,
social and mental health aspects, that must be carefully investigated.
Impact of SVR on all-cause and
liver-related mortality in a cohort of Veterans with chronic hepatitis C. E. Dieperink, P. Thuras, S. Colton, A.
et al. ABSTRACT FINAL ID: 1010
PURPOSE: Determine whether SVR and other
factors reduce all-cause and liver-related mortality in Veterans with hepatitis
C. METHODS: Retrospective chart
review of all patients who initiated antiviral treatment for chronic hepatitis
C between 1/1/1997 and 12/31/2009 at a single VAMC. We obtained antiviral
treatment type, SVR, death, reason for death, liver biopsy, problem-list
co-morbidities, and whether patient was seen by the mental health practitioner
in the HCV clinic using an integtrated care case management approach.
Chi-Square and logistic regression were used to determine factors associated
with mortality. RESULTS: Of the 541
patients, 99% (533/541) were male. Mean age at initiation of first antiviral
treatment was 51.5. Liver biopsies were performed on 80% (435/541) of patients
pre-treatment. An additional 34 patients had a clinical diagnosis of cirrhosis
before treatment. Median follow-up was 7.5 years. As of May 15, 2012 40.5%
(219/541) obtained an SVR and 19.4% (105/541) had died. Race, genotype, having
cirrhosis before the first antiviral treatment, and the number of antiviral
treatments had no impact on all-cause mortality. Having one of the following on
the problem list had no impact on all cause mortality: stroke, heart disease,
any substance use disorder, alcohol use disorder, depression, PTSD, psychosis
or bipolar disorder or diabetes. Liver-related deaths were more likely for genotype
1 than genotype 2 or 3, and in cirrhotics (23.1%) vs non-cirrhotics (10.1%).
Patients with SVR had significantly reduced liver-related mortality compare
with non-SVR patients [2.7% vs. 18.9%, X2 (1, N=541) =31.5, p<.0001] but
there was no difference in non-liver related death (5.9% vs. 7.5%). Patients
seen by integrated care mental health staff were less likely to die from any
cause (15% vs 23% (p=.01)) and less likely to die from liver disease
(9.4% vs 15.1
(p=.03)). In a step-wise logistic regression SVR conferred an almost 8-fold
reduction in liver-related mortality (OR=.13, .056-.314), and this effect was
present both in noncirrhotics (OR= .10, .03-.27) and to a lesser extent in
cirrhotics (OR=.34, .07-1.6).
CONCLUSIONS: SVR significantly reduces
liver-related mortality in both patients with and without cirrhosis at
baseline. In addition, seeing an integrated mental health practitioner reduced
all-cause and liver-related mortality. The combination of effective therapies
to increase SVR rates and a strategy of integrated care protocols for patient
management are important factors for reducing mortality from HCV.
Sustained Responders have Lower Rates
of Liver-Related Events and a Better Quality of Life and Productivity Compared
with Non-Responders/Relapsers after Antiviral Treatment of Chronic Hepatitis C.
S. Mauss, J.Petersen, T. Witthoeft, et
al. ABSTRACT FINAL ID: 800
BACKGROUND: Limited data exist regarding
liver-related morbidity and health-related quality of life after treatment of chronic
HCV infection with interferon (IFN)-based therapies in the real-life setting.
We therefore conducted a non-interventional follow-up survey in German
gastroenterological practices to compare long-term clinical outcome in patients
who achieved sustained virologic response (SVR) or non-SVR after IFN-based HCV
treatment. METHODS: Patients with
chronic hepatitis C who achieved SVR / Non-SVR after IFN-based treatment
≥3 years ago and who are still under routine medical observation were
enrolled by 45 gastro-enterological centers in Germany. Significant clinical
events related to progression of liver disease (ascites, variceal bleeding,
hepatic malignancy and liver transplantation) were recorded. Health-related
quality of life (HRQOL) was assessed by the SF-36 questionnaire. RESULTS: From May 2009 until October
2010 N=1355 patients (male 58.0%, mean age 49.2 ±11.48 yrs) infected with G1
(62.4%), G2 (8.1%), G3 (26.3%) and G4/other (3.2%) have been enrolled. Median
follow up was 4 yrs (range 3 to 8 yrs). 42 and 1313 pts were treated with
non-pegylated / pegylated IFN in combination with ribavirin. In total 759/1355
(56%) achieved SVR after first therapy. Only 3 SVR patients (0.4%) developed a
liver-related clinical event in contrast to 31 (6.2%) non-SVR patients. Of the
34 pts patients who had significant liver-related clinical events, 24 (including
the 3 pts with SVR) had baseline cirrhosis. Non-SVR patients had significantly
lower scores on the eight SF-36 domains (each P<0.0001) indicating lower
HRQOL. In addition, non-SVR patients were more likely to have a lower productivity
as assessed by a lower frequency of employment (41% vs 56%, P<0.0001), a
lower number of working hours/week (27 vs 32, P=0.0031) and a higher number of
outpatient (9.4 vs 5.3, P<0.0001) as well as inpatient visits (0.9 vs 0.1,
P=0.0013) after HCV treatment. Regarding HRQOL and productivity, similar and
significant differences were obtained following stratification by gender, age
(≤50 years/>50 years), type of non-SVR (non-response/relapse) and
number of antiviral treatments (1/>1).
CONCLUSIONS: SVR has a profound impact on
liver-related morbidity suggesting a clinical and not only virological cure of
chronic hepatitis C. In addition, SVR is associated with a better quality of
life and productivity. Altogether our results demonstrate the beneficial effect
of successful HCV treatment in a large real-world population.
Decreased health-related quality of
life (HRQoL) in chronic hepatitis C (CHC): association with major depressive
disorder (MDD), anxiety disorders, clinical comorbidity and sociodemographic
factors. R. Teixeira, L.D. Silva, L.R. da Cunha,
R.F. Araújo, C.C. et al. ABSTRACT FINAL ID: 980
BACKGROUND: In addition to the known morbidity and
mortality, many CHC patients report reduced HRQoL as compared with healthy
controls, regardless of the severity of liver disease. Mood, illness severity
and health behaviour affect HRQoL in several medical disorders. In the case of
HCV infection, the interrelationships among these biopsychosocial factors are
not fully understood. Aims: (1)To characterize the variability of HRQoL in CHC
patients and, (2)To evaluate factors that may influence HRQoL. METHODS: 125 HCV RNA-positive
outpatients
were enrolled
during their visit to the Viral Hepatitis Ambulatory. All patients completed
several surveys including Mini-International Neuropsychiatry Interview
(MINI-Plus 5.0), Hamilton Depression Rating Scale (HDRS), Hospital Anxietyand
Depression Scale (HADS), Cut down, Annoyed, Guilt, and Eye-opener questionnaire
(CAGE). HRQoL was evaluated by Liver Disease Quality of Life Questionnaire
(LDQOL1.0), consisting of the SF-36 generic measure of HRQoL and 12
disease-specific dimensions for patients with liver disease. The protocol was
approved by Ethical Board of UFMG. Data were analyzed by SPSS 17.0. A
hierarchical multiple linear regression analyses were used in order to quantify
the simultaneous and mutually independent contribution of clinical, psychiatric
and sociodemographic variables. RESULTS:
Baseline characteristics of CHC patients: mean age 54.0 ± 8.9 yrs; 57.6%
female; 16.8% compensated cirrhosis, 28.8% current depression and 23.2% anxiety
disorders. MDD was associated with lower LDQOL scores in 10 domains, excluding
sexual function(p=0.15) and sexual problems
(p=0.43), independently of liver stage disease. Anxiety disorders were
associated with reduction in 3 LDQOL domains: health distress(p=0.003), stigma
of liver disease(p=0.007) and sexual problems (p=0.04). Worse quality of life
was found in patients with current or previous alcohol abuse or dependency for
the domain loneliness(p=0.009). Cirrhosis, diabetes and blood
hypertension
were associated with lower LDQOL scores in 3 domains: sexual function(p=0.02),
sexual problems(p=0.01) and memory(p=0.006), respectively. Higher levels of
education were associated with lower LDQOL scores in 3 dimensions: health
distress(p=0.02), hopelessness (p=0.02) and stigma of liver disease(p=0.04). CONCLUSIONS: These results emphasize
the importance of assessing psychiatric comorbidities, especially depression and
anxiety disorders and, lifestyle behaviours in HCV clinical care. There is a
clear need to adopt a biopsychosocial
model of care
when looking at strategies to improve HRQoL among patients living with
hepatitis C.
The Impact of Lifetime Drug Use on
Hepatitis C Treatment Outcomes in Privately Insured Members of an Integrated
Health Care Plan. M. Pauly, R.
Cunanan, G.L. Witt, et al. ABSTRACT FINAL ID: 955
PURPOSE: Despite the high prevalence of drug abuse
among patients with hepatitis C virus infection (HCV), data on the relation of
drug abuse to HCV treatment outcomes in insured household populations is
lacking. METHODS: We previously
reported the impact of alcohol in 421 treatment naïve HCV patients in an
integrated healthcare plan, treated with pegylated interferon α and
ribavirin between Jan 2002 and Jun 2008 (Russell et al Hepatology in press). We
examined the relation of lifetime drug use to treatment outcome. For drugs used
at least 5
times, a
detailed lifetime frequency history was obtained in 259 (61.5%) eligible
patients. Drugs assessed were marijuana; the non-medical use of stimulants,
sedatives, and opioids; hallucinogens; and inhalants. Use was examined for
HCV-relevant periods: prior to diagnosis; from diagnosis to treatment
initiation, during the 6 mos before treatment, during treatment, and from the
end of treatment to determination of sustained viral response (SVR). A drug summary
measure, lifetime drug years, was calculated. Data on host and viral risk
factors known to influence HCV treatment outcome were extracted from medical
records or patient interviews.
FINDINGS: The prevalence of drug use was high. 3
or more drugs were used by 57.9% of patients and 61.2% had injected drugs. Most
had stopped using by the time HCV was diagnosed, and patients reduced their
drug intakes still further in the months prior to and during treatment (Table
1). SVR was not lower in patients using any of these drugs, using 3 or more
drugs, or not abstaining 6 mos prior to HCV treatment. Nor was higher lifetime
frequency of drug use
associated
with lower SVR rates. A presumed clinically irrelevant, but statistically
significant positive relation was observed between stimulant use and SVR, after
controlling for known host and viral factors. Drug years was positively related
to SVR. CONCLUSION: Drug use prior
to HCV treatment did not have a negative impact on treatment outcomes in our
population. A history of drug use should not be considered a deterrent to HCV
treatment in members of an integrated health care plan who are motivated to
seek treatment and closely monitored.
% patients
using drugs in critical time periods (N=259). Prior to HCV Diag <6 mos
before
Treatment
During HCV treatment Marijuana 83.8 16.8 8.5 Stimulant 71.9 3.1 0.4 Opiate 38.5
1.9 1.2 Sedative 40.4 2.7 0.4 Hallucinogen 51.5 0.4 0.8 Inhalant 16.5 0.4 0.8
Factors Influencing Likelihood of
Compliance in Chronic Hepatitis C with Patients Receiving Pegylated Interferon
Plus Ribavirin. L. Rover, C.
Escheik, L. Gerber, M. et al. ABSTRACT
FINAL ID: 75
BACKGROUND: Maximizing subjects’ ability to adhere
to treatment requires an understanding of relevant biological and behavioral
factors. Outcomes may be aided by early identification and proper treatment. AIM: To learn if psychobehavorial
measures correlate with compliance in subjects with chronic hepatitis C (HCV)
treated with Pegylated Interferon and Ribavirin (PIR). METHODS: 63 subjects with HCV participated in a prospective
clinical trial of PIR. History and physical examination provided
sociodemographic information. Compliance scores were based on attendance and
adherence to doctor’s orders. Patients with a score greater than 83% were
considered compliant. Standardized patient reported outcomes were done at
baseline: State Trait Anger Expression Inventory-2 scales (STAXI-2) included,
Feeling Like Expressing Anger Verbally (S-Ang/V), Feeling Like Expressing Anger
Physically (SAng/P), Angry Reaction (T-Ang/R), Trait Anger (T-Ang), Anger
Expression-Out (AX-O), and other anger measures;
Short
Form-36; Chronic Liver Disease Questionnaire–HCV (CLDQ-HCV) that measures
Activity/Energy (AEM), Emotion (EMM), Worry (WOM), Systemic (SYM), and CLDQ-HCV total
score. Data were analyzed using Fisher exact and Wilcoxon Mann-Whitney U tests
and Spearman rank order sum. Statistical analyses were performed using SAS (v
9.3). RESULTS: Eighty-four percent
completed all patient reports. Data were analyzed by comparing two groups:
45 (71%)
individuals who complied to treatment (Comp) and 18 (29%) who did not (NonComp). The Comp
group had a mean age of 47.4±7.4 years (62% female) with 33 (73%) married and
34(76%) employed; Non Comp, 46.6±9.4 years (67% female) with 14 (78%) married
and 14 (78%) employed. Of the entire cohort, 50 individuals had genotype 1 (81%
Comp; 68% NonComp). Group differences were not statistically significant. The
likelihood of compliance was lower in subjects who had more self-reported
symptoms of S-Ang/V (p=<.01). Subjects on anti-depressants at the start of
the study reported more T-Ang/R (p=.01), T-Ang (p=.03) AX-O (p=.02), EMM
(p=.04), WOM (p=.05), and SYM (p=.06); and total CLDQ-HCV symptoms (p=.03). CONCLUSIONS: HCV patients treated with
PIR were less likely to be compliant if they reported more anger and worry at
baseline. Subjects receiving anti-depressant medication at baseline reported
significantly more symptoms on the STAXI-2 and quality of life impairment
reported by CLDQ-HCV. It is beneficial to assess level of anger and worry
before PIR treatment and to use psychobehavioral measures as a tool for
monitoring patients during treatment and addressing their needs for
interventions.
Randomized Controlled trial of Motivational
Enhancement Therapy to Reduce Alcohol in Patients with Chronic Hepatitis C. E. Dieperink, P. Thuras, K. McMaken, C.
et al. ABSTRACT FINAL ID: 794
PURPOSE: Randomized single blind study to
determine whether Motivational Enhancement Therapy (MET) reduces alcohol use in
HCV patients who are currently drinking alcohol compared to an educational
control condition (EDU). METHODS:
Eligible patients were recruited from the Minneapolis and Portland VA’s and
were randomized to either MET or EDU. MET is a 4 session manualized treatment
for patients with alcohol use problems using motivational interviewing, a
directive approach designed to resolve ambivalence. The education control
condition consisted of 4 sessions including: sleep hygiene, nutrition and diet,
stress management and fitness and exercise. Alcohol use was measured with the
time-line follow back (TLFB) at baseline, 3 months, and 6 months. Inclusion
criteria were: HCV+ viral load, drinking 7 or more drinks for each of the
preceding 2 weeks or having a heavy drinking day (4 or more
drinks in one
day) per week for 2 weeks and having a DSM-IV alcohol use disorder. Exclusion
criteria were: cocaine, methamphetamine or opioid dependence within the past 6
months, CNS trauma, significant cognitive impairment, dementia, encephalopathy,
or acute psychiatric instability. A mixed-effects model was used to determine
whether MET reduced alcohol use compared to the control condition. All patients
signed written informed consent. RESULTS:
A total of 135 subjects were randomized. Most of the subjects were male 95.6%
(129/135), and white 68.1% (92/135). Mean drinking days in the past month at
baseline for the MET group was 20.0 and for EDU was 20.3. At three months the
MET group reported significantly fewer drinking days (9.3) compared with the
education group (12.9) this difference was maintained at 6 months (8.4 vs.
12.9; F(2,242.5)=3.2, p=.042). The effect size for the difference in drinking
days at 3 months Cohen’s d=.35 and at 6 months d=.40. CONCLUSIONS: MET should be considered a first-line treatment for
HCV patients with alcohol use disorders who continue to drink. As MET is a
brief alcohol treatment it may be ideally suited for integrated care clinics
where mental health practitioners are collocated and where resources are
limited.
The impact of virologic resistance and
adherence on treatment failure in a cohort of hepatitis C virus (HCV) infected
patients treated with telaprevir (TVR) and boceprevir (BOC). C. Velazquez, W.M. Rosenberg, C.
Velazquez, S. et al. ABSTRACT FINAL ID: 1089
INTRODUCTION: Phase 3 studies show that up to 73% of
patients failing treatment with TVR or BOC develop drug-resistance mutations (DRM).
In this study we report the incidence and nature of treatment failure in a
prospective cohort of 53 patients with chronic HCV infection treated with
either TVR or BOC combined with pegylated interferon-alfa and ribavirin
(PEG/R).
METHODS: All patients had baseline HCV RNA
levels >10,000 IU/ml and evidence of at least bridging fibrosis. All
patients treated with BOC had previously failed PEG/R treatment. Patients
treated with TVR were either treatment naïve or experienced. HCV viral load was
determined using a validated in-house assay. Virologic failure (VF) was defined
as HCV RNA >1000 IU/ml at week 4 or 12 for patients treated with TVR or HCV
RNA >100IU/ml at week 12 for those
treated with
BOC respectively, or an increase of >1log10 viral load from nadir. Genotypic
resistance was performed using standard population Sanger sequencing. Nested
RT-PCR was used to amplify viral RNA and the first 181 amino acids of the NS3
protease were sequenced.
RESULTS: Forty two of 53 patients (79%) were
treated with TVR and 11 (21%) with BOC. A total of 13 patients (25%) had VF (12
TVR, 1 BOC) of which DRMs were detected in 10 (77%). All patients who developed
VF with DRMs had HCV genotype 1a and were treated with TVR. Mutations evolved
at NS3 positions 155 and 36; Arg to Lys at 155 and/or Val to Met or Leu or
Val/Met at 36, none of which were detected at baseline. Nine patients were
treatment experienced (4null responders, 3 relapsers, 2
breakthrough) and 1 was naïve. DRMs were first detected during or after TVR
triple therapy (4 at week 4, 2 at week 8, 2 at week 12 and 2 at week 24). Three
patients with VF did not have identifiable DRMs by population sequencing (2
TVR, 1 BOC). In the TVR treated patients without detectable mutations VF occurred during PEG/R therapy and was detected
at week 24. Both had subtype 1b and severe fibrosis (1 a previous
null
responder and 1 treatment naïve).The BOC treated patient had subtype 1a HCV
with moderate fibrosis and was a previous relapser. When questioned, all 3
patients reported failure to ingest a fatty meal with their medication or poor adherence
to TVR or BOC. CONCLUSION:
In this
cohort DRMs were identified by population sequencing in 77% of treatment
failures, comparable to that seen in Phase 3 trials; all infected with HCV
genotype 1a and most were treatment experienced. No novel DRMs were identified.
All the patients failing treatment without DRMs reported either inability to
tolerate a fatty meal or poor adherence to medication. This observation
requires further investigation.
Consequences of Current Hepatitis C
Direct Anti-Viral Agents (Telaprevir and Boceprevir) on the Health-Related
Quality of Life. O. Mousa, L.
Pham, C.I. Egwim, et al. ABSTRACT FINAL ID: 982
PURPOSE: Our aim is to evaluate the effect of
the new HCV Direct Acting Agents (DAA): Telaprevir (TVR) and Boceprevir (BVR),
on health-related quality of life of hepatitis C patients in a community
practice. METHODS: :We administered
the short form 36 (SF-36) Health-related Quality of Life Questionnaire to HCV
patients undergoing treatment with TVR or BVR, as part of the pegylated
interferon and ribavirin based triple therapy, at the Liver Associates of Texas
Hepatology Clinics. 87 patients completed at least the baseline survey during
scheduled clinic visits between 7/1/2011 and 5/31/2012 and were eligible for
this interim statistical analysis. Patients attended an HCV education class and
signed an informed consent before enrollment. The endpoint is to study the
effect of HCV DAAs on the physical and mental health of HCV patients. SPSS v19
and Minitab v16 were used for statistical analysis. RESULTS: Data analysis was performed on 87 patients (68 in TVR
group vs 19 in BVR group). 31 patients completed surveys at both baseline and
week 12 (25 on TVR: 6 on BVR). Mean Age is 54 years (SD=8.4), mean BMI is 30.5 kg/m2
(SD=6.7), Males 49.4%. Analysis showed a drop in the mean scores of the eight
SF-36 domains in both treatment groups at Week 12 compared to Baseline, with a
relative improvement in all the SF-36 domains in the TVR group at week 24
except the Body Pain (BP). The Wilcoxon Signed Rank test was used for paired
data analysis of
patients
completing both baseline and week 12 surveys. Analysis of the TVR group (n=25)
showed a statistically significant worsening in the health related quality of:
Physical Functioning, Role Physical, Role Emotional, Social Functioning and Vitality,
while analysis of the BVR group (n=6) showed a statistically significant
worsening of one health domain, the Social Function (94.1% CI: 50-100 baseline,
12.5-43.8 week 12). The Mann Whitney U test was
used to
compare both treatment groups at baseline and showed no significant differences
in the health domains. At week 12, a statistically significant deterioration in
the Social Functioning (p = 0.0273) was more evident in the BVR treatment
group. CONCLUSION: The new DAAs
affect health related quality of life in various ways. TVR affects both the Physical
and Mental Components, whereas BVR predominately affects the Mental component
and the Social
Function.
These findings may be clinically relevant in the treatment of HCV patients in
the era of DAAs.
VX-222, Telaprevir and Ribavirin in
Treatment-Naïve Patients with Genotype 1 Chronic Hepatitis C: Results of the
ZENITH Study Interferon-Free Regimen. I.M.
Jacobson, M.S. Sulkowski, E.J. Gane, et al. ABSTRACT FINAL ID: 231
BACKGROUND AND AIMS: ZENITH assessed the safety,
tolerability and antiviral activity of VX-222 (nonnucleoside polymerase
inhibitor) with telaprevir (TVR)(protease inhibitor) alone (DUAL), with
ribavirin (RBV)(TRIPLE) or with peginterferon alfa-2a (Peg-IFN)/RBV (QUAD), in
chronic HCV genotype 1 treatment-naïve patients. Here we present TRIPLE interim
results.
METHODS: Genotype 1b (n=23, Arm E) and 1a
patients (n=23, Arm F) received VX-222 400mg BID, TVR 1125mg BID, and RBV
1000-1200mg/day for 12 weeks (wks). Patients with undetectable HCV RNA at Wk 2
and 8 were eligible to stop all treatments at Wk 12; those with detectable HCV
RNA at Wk 2 and/or 8 received 24 additional wks Peg-IFN/RBV. On-treatment
results presented for all through Wk 12 and SVR12 for those eligible to stop treatment
at 12
wks. SVR for
all will be presented. RESULTS: HCV
RNA was <LLOQ in 91% of Arm E/F patients at Wk 4 with 91% Arm E and 57% Arm
F <LOD. 83% of E/F patients had HCV RNA <LOD at Wk 12. 3 TRIPLE patients
experienced viral breakthrough (vBT); all IL28B non-
CC. 5 and 6
patients in Arms E and F, respectively, were eligible to stop treatment at Wk
12; of these, 5/5 and 4/6 achieved SVR12. Patients had NS3 and NS5B resistant
variants at vBT or relapse. 2 patients (4%) withdrew due to adverse events (AE).
During the TVR/VX-222 phase, most AEs were mild/moderate with diarrhea (50%),
rash (37%, all mild), nausea (30%), pruritis (30%) and fatigue (24%) most
common. The incidence/severity of rash and anemia were both lower than QUAD
(400mg)(rash 60% with 10% moderate, 7% severe; anemia 37%).
CONCLUSIONS: In a pilot study that included an all
oral, interferon-free regimen of TVR/ /VX-222/RBV, the majority of patients had
undetectable HCV RNA at Wks 4 and 12, with a higher rate of HCV RNA <LOD at
Wk 4 in genotype 1b. Among patients eligible to stop at Wk 12, high SVR12 rates
were observed in this small pilot study, and the regimen was well-tolerated.
Twelve- or 16-Week Treatment With
Daclatasvir Combined With Peginterferon Alfa and Ribavirin for Hepatitis C
Virus Genotype 2 or 3 Infection: Command GT2/3 Study.
G.J. Dore, E.
Lawitz, H.A. Tatum, et al. ABSTRACT FINAL ID: 762
BACKGROUND: The current recommended treatment for
chronic HCV genotype (GT) 2 or 3 infection is 24 weeks (wk) of peginterferon
alfa + ribavirin (peg-alfa/RBV). Combining direct-acting antivirals with
peg-alfa/RBV can enhance virologic responses, potentially allowing shorter
treatment durations. Daclatasvir (DCV; BMS-790052) is a first-in-class NS5A
replication complex inhibitor with broad coverage in vitro against HCV GT 1-4.
Study AI444-031 evaluates short-term treatment (12 or 16 wk) with DCV 60mg QD
combined with peg-alfa 2a (180mcg weekly)/RBV (400mg BID) in patients with
chronic HCV GT2 or 3. METHODS: Adult
treatment-naïve patients with chronic HCV GT2 or 3 were randomly assigned to
receive DCV + pegalfa/RBV for 12 wk, DCV + peg-alfa/RBV for 16 wk, or placebo
(PBO) + peg-alfa/RBV for 24 wk. The primary efficacy endpoint is sustained
virologic response 24 wk posttreatment (SVR24); we present on-treatment results
through wk 16. HCV RNA assay LLOD was <10 IU/mL. RESULTS: 71 patients with GT2 and 80 with GT3 were treated. DCV 12
wk (N=50), DCV 16 wk (N=50) and PBO (N=51) arms were generally well balanced at
baseline for viral and host factors that have been correlated with treatment
response. More patients with GT3 vs 2 were cirrhotic (range 14.8%-26.9% vs
0%-4.2% across treatment arms); 38.5%-44.4% of patients with GT3 and
25.0%-41.7% of patients with GT2 had IL28B (rs12979860) CC genotype. Virologic
response rates at wks 4 (RVR) and 12 (cEVR) were higher in both DCV arms vs PBO
for GT2 and 3 cohorts (Table). Responses in DCV arms were similar for GT2 vs 3
despite a higher proportion of GT3 patients having underlying cirrhosis. All
GT2 patients with IL28B genotype CC (n=23) achieved cEVR; however in GT2
patients with non-CC, cEVR rates were higher in the DCV 12 wk (12/13; 92.3%)
and 16 wk (12/15; 80.0%) groups vs PBO (12/18; 66.7%). IL28B genotype had no
consistent effect on cEVR rates in patients with GT3. There were 2 viral breakthroughs
(DCV 16 wk, PBO). The most frequently reported treatment-related adverse events
(AEs) were those typically associated with peg-alfa/RBV use, including fatigue,
cytopenias, and depression. CONCLUSION:
Treatment with peg-alfa/RBV/DCV enhances early viral suppression compared with
peg-alfa/RBV, supporting a potential role for DCV in the treatment of chronic
HCV GT2 or GT3 infection.
Peginterferon Lambda-1a (Lambda) is
Associated With Less Autoimmune Thyroid Disease and Serious Autoimmune Disease
Than Peginterferon Alfa-2a (Alfa) When Used in Combination With Ribavirin (RBV)
for the Treatment of Chronic Hepatitis C Virus Infection. P. Fredlund, J.L.Hillson, T.E. Gray, et
al. ABSTRACT FINAL ID: 781
BACKGROUND: Treatment with peginterferon alfa is
associated with increased risk of autoimmune disease. Lambda exerts antiviral
effects through a unique receptor with limited distribution outside the liver.
In a phase 2b study of treatment-naïve patients, Lambda in combination with
ribavirin (RBV) demonstrated robust virologic responses with reduced
cytopenias, arthralgias, myalgias, and flu-like symptoms compared to Alfa/RBV.
Here we
report the
relative rates of thyroid dysfunction and serious autoimmune disease. METHODS: 525 treatment-naïve
noncirrhotic patients received daily oral RBV and weekly Lambda (120, 180 or
240μg) or Alfa (180μg) for up to 24 (HCV genotype [GT] 2, 3) or 48
(HCV GT1, 4) weeks. Exploratory retrospective analysis was performed of adverse
events (AE) included in the MedDRA version 14.0 SMQ Thyroid Dysfunction,
serious AE consistent with autoimmune disease, and frequency of clinically
significant abnormalities of thyroid stimulating hormone (TSH). Patients with TSH ≥10
mIU/L, ≤0.01 mIU/L, or both were reviewed in a blinded manner by an
expert endocrinologist and classified as follows: (a) inadequate or excessive
thyroid replacement in patients with pre-existing thyroid disease, (b)
exacerbation of pre-existing autoimmune thyroid disease, (c) new primary
hypothyroidism, (d) painless thyroiditis, (e) Graves’ disease, or (f) not
determined. RESULTS: The odds of a
reported AE of thyroid dysfunction was 5.2 times greater on Alfa vs Lambda.
Similarly, the odds of a reported significant elevation or reduction in TSH was
5.1 times greater on Alfa. Median time to abnormal TSH was 20.14 (4.0-44.1)
weeks. Blinded review found most TSH
elevations reflected new-onset hypothyroidism requiring treatment, while most
low TSH reflected probable painless thyroiditis and resolved without sequelae.
Review of serious AEs consistent with autoimmunity revealed 4 events (1
panniculitis, 2 sarcoidosis, 1 pseudotumor cerebri) among 133 (3.0%) Alfa
recipients, and 1 event (uveitis) among 392 (0.2%) Lambda recipients.
Peginterferon Lambda-1a (Lambda) is
less likely to induce clinically significant neuro-psychiatric symptoms during
the treatment of chronic hepatitis C virus (HCV) infection, compared to
peginterferon alfa-2a (Alfa) A.J.
Muir|S. Srinivasan, D. Dimitrova, J.et al. ABSTRACT FINAL ID: 793
BACKGROUND: Alfa interferons are associated with
significant neurologic and psychiatric adverse events (AEs), often limiting
treatment options for patients with chronic HCV infection. Lambda is a novel
type III interferon that exerts its antiviral effects through a unique receptor
with limited distribution outside the liver. Here we describe neuropsychiatric
effects of Lambda and Alfa, using Becks Depression Inventory (BDI II) scores
and reported AEs from the phase 2 EMERGE study. METHODS: Treatment–naïve, noncirrhotic patients (N=525) received
daily ribavirin and weekly Lambda (120, 180 or 240μg) or Alfa (180μg)
for up to 24 weeks (GT2/3) or 48 weeks (GT1/4). AEs included in the MedDRA
version 14.0 SMQ Nervous System Disorder or Psychiatric Disorder, and BDI II
scores (0-19, minimal/mild depression; 20-28, moderate; 29-63, severe) were
examined for differences in frequency/changes from baseline for Lambda (pooled data)
and Alfa. RESULTS: All comparisons
are reported for Alfa vs Lambda recipients, respectively. AEs characterized as
nervous system disorders were reported for 51.9% (69/133) and 39.3% (154/392).
Headache (39.8% vs 26.3%) and dizziness (10.5% vs 7.9%) were reported most
frequently. AEs characterized as psychiatric disorders were observed in 46.6% (62/133)
vs 40.6% (159/392). Depression was reported in 11.3% vs 12%; irritability in
12.8% vs 16.6%; and affect lability in 5.3% vs 0.8%. One instance of suicidal
ideation was reported in the Lambda 120 μg group. 3 patients discontinued
due to psychiatric AEs: 2/133 (1.5%) in the Alfa group and 1/392 (0.25%) in the
Lambda group. A greater mean increase (worsening) in BDI II score from baseline
was observed at Week 48 among GT1/4 Alfa recipients (+4.3; 95%CI=2.3, 6.3) vs
GT1/4 Lambda recipients (+0.4; 95%CI=-1.25, 2.0). Results were similar in GT2/3
patients.
BDII scores
≥20, which indicate moderate to severe depressive symptoms, were less
frequent in the Lambda group (Table). CONCLUSIONS:
Chronic HCV–infected GT1/4 patients treated with Lambda experienced fewer AEs
related to the nervous system and fewer depressive symptoms vs patients treated
with Alfa. Depression and psychiatric AEs will be
evaluated
further in Lambda Phase 3 studies.
Association of Chronic Liver Disease
with Depression: A Population-Based Study. M.
Otgonsuren, M. Afendy, Z.M. , M. Otgonsuren, et al. ABSTRACT FINAL ID: 953
BACKGROUND: Chronic liver diseases (CLD) are
associated with depression and other
neuropsychiatric
disorders. AIM: The aim of this
study was to assess the potential association of different types of CLD with
depression in a population-based cohort. METHODS:
We examined data from National Health and Nutrition Examination Survey (NHANES)
for 2005-2010. We included adult patients (age over 18 years) with chronic
hepatitis C or CH-C (HCV Antibody and HCV RNA-positive), chronic hepatitis B or
CH-B (HBs-Antigen-positive), alcohol related liver disease or ALD (defined as
>20 gram of alcohol consumption per day and elevated aminotransferases) and
non-alcoholic fatty liver disease or NAFLD (defined as elevated
aminotransferases in the absences of other liver diseases and excessive alcohol
use). PHQ-9 survey was used as a depression screener. Univariate and
multivariate analyses were performed to determine independent variables
associated with each type of CLD and depression. Both SUDAAN® v.10.1 (Research
Triangle Institute (RTI) International, Research Triangle Park, NC, USA) and
SAS® v.9.3 (SAS Institute Incorporation, Cary, NC) were used for the analyses. RESULTS: The cohort included 15,263
participants. After multivariate analysis, CH-B was
independently
associated with being Black (OR= 5.09, 95% CI: 2.41-10.76) or other races
including being Hispanic (OR= 4.74, 95% CI: 2.32-9.70). On the other hand, ALD
was independently associated with younger age (OR=0.97 95% CI:0.96-0.97), male
gender (OR=0.82, 95% CI:0.74-0.91), but adversely associated being
American-Mexican (OR=1.55, 95% CI: 1.30-1.84), and moderate to heavy smoking
(OR=3.64, 95% CI: 3.09-4.30). furthermore,
insulin resistance (OR=2.65, 95% CI: 1.98-3.55) and diabetes mellitus (OR=1.54,
95% CI: 1.11-2.13) were independently associated with NAFLD. CH-C was
independently associated with age (OR=1.05, 95% CI: 1.03-1.07), male gender (OR=1.88,
95% CI: 1.19-2.97), black race (OR=2.50, 95% CI:1.50-4.18), smoking (OR=6.20,
95% CI: 1.62-23.68), injection drug use (OR=52.86, 95% CI:32.87-85.03) and
depression (OR=2.87, 95% CI: 1.78-4.62). In fact, CH-C was the only type of CLD
that was independently associated with depression. CONCLUSIONS: Although depression has been suspected to be
associated with a number of liver diseases, this independent association is
only with CH-C at the population level. This association remains strong even
after adjustment for known risk factors for CH-C such as
intravenous
drug use.
Determinants of Treatment Completion
and Efficacy in Drug Users Assessed by Meta-analysis. R.B. Dimova, M. Zeremski, I.M.
Jacobson, A. et al. ABSTRACT FINAL ID: 959
BACKGROUND: Hepatitis C virus (HCV)-infected drug
users (DUs) have largely been excluded from HCV care. Whether exposure to
services targeting DUs in HCV care affects the likelihood of completing therapy
and achieving a sustained virological response (SVR) remains unclear.
Therefore, we conducted a systematic review and meta-analysis of the available
literature on treatment completion and SVR rates in DUs treated with
pegylatedinterferon
(PEG-IFN)/ribavirin
(RBV). We assessed effects of specific treatment approaches and services to
promote HCV care among DUs as well as demographic and viral characteristics.
METHODS: Studies that included at least 10 DUs
treated with PEG-IFN/RBV and that reported treatment outcomes were analyzed.
Each study was coded independently by two investigators. Homogeneity (I2) was
assessed using Cochran’s test, and pooled rates estimated using random effects
modeling. Meta-regression was used to analyze for sources of heterogeneity. RESULTS: Thirty-six studies including
2866 patients were retrieved, and 32 of them specified the rate of treatment completion.
We estimated a pooled treatment completion rate among DUs of 83.4% (95%
confidence interval [CI]: 77.1%; 88.9%), I2=90.2%, p<0.0001. When restricted
to studies that included both addiction-treated and untreated patients during
HCV therapy, we found that the higher the proportion of patients treated for
addiction during HCV therapy, the higher the treatment completion rate
(p<0.0001). We also identified a trend of increasing treatment
completion
when the proportion of patients on substitution therapy at baseline increases
(p=0.058). Further, we estimated a pooled SVR rate of 55.5% (95% CI: 50.6%;
60.3%). Infection with genotype 1/4 (p=0.0012) and the proportion of HIV
co-infected DUs (p=0.0173) significantly influenced the SVR rate. Among
genotype 1/4 patients, the SVR rate was estimated to be 44.9% (95% CI: 41.0%;
48.9%). Among studies with HCV mono-infected DUs, the SVR
rate was
58.1% (95% CI: 54.6%; 61.5%) and among studies including HIV/HCV co-infected
DUs, the rate was 43.3% (95% CI: 35.9; 51.1).CONCLUSIONS: Treatment of addiction during HCV therapy results in
higher treatment completion. Our pooled SVR rate for PEG-IFN/RBV-treated DUs is
very similar to that obtained in registration trials conducted in the general
population. Treatment of addiction during HCV therapy will likely continue to
be important for HCV-infected DUs undergoing treatment with more complex
regimens such as those containing direct acting antivirals.
Once Daily Sofosbuvir (GS-7977) Plus
Ribavirin in Patients with HCV Genotypes 1, 2, and 3: The ELECTRON Trial. E.J. Gane, C.A. Stedman, R.H. Hyland, et
al. ABSTRACT FINAL ID: 229
BACKGROUND: The first 5 arms of the ELECTRON trial
showed that 12 wks of treatment with sofosbuvir (SOF, formerly GS-7977), a
uridine nucleotide analog, plus ribavirin (RBV) is highly effective in
treatment-naïve patients infected with genotype (GT) 2/3 hepatitis C virus
(HCV). We report arms 7-11, designed to evaluate SOF + RBV in treatment-naïve
and null responder GT 1 patients and treatment-experienced GT 2/3 patients
(prior null response, breakthrough, or relapse), and to determine the
feasibility of regimens with a shorter duration or reduced dose of RBV in
treatment-naïve GT 2/3 patients. METHODS:
5 arms of non-cirrhotic HCV patients were enrolled. 3 arms received SOF + RBV
(1000/1200 mg) × 12 wks: 10 GT 1 prior null responders (Arm 7), 25
treatment-naïve GT 1 patients (Arm 8); and 25 treatment-experienced GT 2/3
patients (Arm 9). In addition, 25 treatment-naïve GT 2/3 patients received SOF
+ RBV (1000/1200 mg) × 8 wks (Arm 10) and 10 treatment-naïve GT 2/3 patients
received SOF + RBV (800 mg) × 12 wks (Arm 11). RESULTS: 95 patients were enrolled in the 5 arms. All 85 patients
in Arms 7-10 achieved RVR. There were no ontreatment breakthroughs or
discontinuations. Of the 25 treatment-naïve GT 1 patients, 22 (88%) achieved
SVR4. Of
the 10 GT 1
prior null responders, 1 achieved SVR12; the other 9 relapsed prior to
post-treatment wk 4. Of the 24 treatment-experienced GT 2/3 patients for whom
data are available, 18 (75%) achieved SVR4. Two of these patients subsequently
relapsed 8 wks after completing therapy for a total of 8 relapses on or before
SVR8. To date, no S282Tcontaining mutations have been detected by either
population or deep sequencing in any of the relapsers treated with
SOF + RBV.
SOF + RBV was well tolerated in all arms and no patient discontinued early.
Adverse events were generally mild and consistent with RBV treatment; no SAEs
were attributed to SOF treatment. Grade 3/4 laboratory abnormalities were
infrequent and generally consistent with RBV toxicity. SVR12 results for all
arms will be presented. CONCLUSIONS:
SOF + RBV elicited a rapid decline in HCV RNA in all treatment groups. All
patients with Wk 4 data had RVR and no on-treatment viral breakthrough was
observed. SOF + RBV for 12 wks provided high rates of SVR in treatment-naïve
patients and in treatment-experienced GT 2/3 patients. Although all patients
attained HCV RNA <LOD during treatment, GT 1 prior null responders had
suboptimal rates of SVR. For those who failed the 12-week SOF + RBV regimen,
either longer treatment duration or the addition of another DAA may be needed
for these difficult-to treat populations, who have no currently approved
treatment options.
Impact of baseline (BL) HCV RNA to
predict treatment outcome in HCV genotype 2 and 3 patients receiving peginterferon
(PegIFN) alfa-2a (40KD)/ribavirin (RBV): analysis of data from the
multinational PROPHESYS cohorts. M.L.
Shiffman, G. Parruti, P. Ferenci, et al. ABSTRACT FINAL ID: 787
BACKGROUND: PegIFN/RBV remains the standard of
care for patients (pts) infected with HCV genotype (G)2 and 3. Pts treated with
PegIFNα2a(40KD)/RBV who achieve a rapid virologic response (RVR) and have
low BL HCV RNA can shorten treatment to 16 wks. Low viral load is not clearly
defined but is often cited between 400,000 and 800,000IU/mL. This analysis
explored whether an optimized virologic threshold could be identified to
predict
treatment
outcomes in HCV G2 and 3 pts prescribed PegIFNα2a (40KD)/RBV. METHODS: PROPHESYS comprised 3
separate, non-interventional cohort studies of pts receiving therapy for
chronic hepatitis C according to country-specific requirements. This analysis
included all treatment-naive, HCV mono-infected G2 (N=485) or 3 (N=591) pts
with available BL HCV RNA results prescribed standard dosing of PegIFNα2a
(40KD) and RBV. Receiver operating characteristics (ROC) curves and generalized
additive models (GAM) were used to explore the relationship between BL HCV RNA
level and treatment outcome (RVR and SVR, respectively).
RESULTS: Based on GAM plots, higher BL HCV RNA
values were associated with a lower probability of RVR and SVR, though the
association with SVR was stronger. Using ROC curves no optimized virologic
threshold was identified that discriminated the likelihood of achieving an RVR.
For SVR, thresholds of 600,000 and 1,200,000IU/mL were identified for HCV G2
and 3 pts respectively; however, these were only modestly better than selecting
thresholds of 400,000 or 800,000IU/mL. Thus RVR and SVR rates for various
thresholds of BL HCV RNA were estimated (Table). Overall, RVR was a strong
predictor of SVR; in pts with an RVR, SVR rates were highest among pts with BL
HCV RNA ≤400,000IU/mL and tended to decline with increasing BL HCV RNA. CONCLUSION: Although we identified
thresholds predicting treatment outcome with PegIFNα2a (40KD)/RBV for HCV
G2 or 3, they do not greatly improve the discrimination between high/low BL HCV
RNA vs. traditional thresholds. Pts with
an RVR had a
high probability of SVR, with SVR rates highest in those with BL HCV RNA
≤400,000IU/mL.
Clinical Depression and psychiatric
events during HCV therapy withTelaprevir or Boceprevir. L. Pham, O. Mousa, C.I. Egwim, et al. ABSTRACT
FINAL ID: 978
PURPOSE: Our aim is to evaluate the effect of
the new Direct Acting Agents (DAA): Telaprevir (TVR) and Boceprevir (BVR), on
the psychiatric health of hepatitis C patients. METHODS: We utilized the Beck Depression Inventory-II (BDI-II) to
assess depression in our prospective cohort study of 110 HCV patients
undergoing treatment with TVR or BVR, as part of the triple therapy of HCV at
the Liver Associates of Texas Hepatology Clinics. The
patients
attended an HCV education class and signed an informed consent before
enrollment. Those who completed the survey during baseline scheduled visits and
at a 4 week interval between 7/1/2011 and 5/31/2012 were eligible for interim
statistical analysis. The endpoint is to study the effect of current DAAs on
depression severity in Chronic HCV patients. SPSS v19 was used for statistical
analysis and included descriptive statistics and regression analysis.
RESULTS: 110 patients receiving triple therapy
were enrolled: 81 patients received TVR and 29 received BVR. Mean age 54.5
years (SD 7.89), mean body mass index 30.1 Kg/m2 (SD 6.47) and 48.2% are males.
During scheduled clinic visits, the patients reported the feeling of depression
in 32.9% of TVR patients, 24.1% of BVR patients and 35.1% of patients who
discontinued therapy from any cause. The BDI-II conducted at week 12 showed
Moderate to Extreme depression in 11.5% (3/26) of patients in the TVR group.
Moderate depression was noticed in 50% (2/4) of the BVR group. 2 patients of
the TVR group experienced extreme depression at week 4 (1/40) and at week 12
(1/26), while one patient in the BVR group experienced severe depression at
week 8 (1/10). Percentage of patients with severe depression and suicidal
ideation that led to treatment discontinuation was 1.2% (1/82) of TVR group vs
3.4% (1/29) of BVR group. There is no statistically significant difference in
the depression severity at 12 weeks of therapy compared to baseline in patients
treated with either TVR or BVR. No other psychiatric events that required
hospitalization or medical therapy were reported. Other symptoms reported
during therapy include Asthenia 32.4%, Insomnia 18%, Irritability 9% and
Anxiety 5.4%. CONCLUSION: Mild
Depression is commonly seen in patients being treated with triple therapy and
does not lead to treatment discontinuation. Rates of severe and extreme
depression weren’t significantly different among the two current DAAs.
First Report of Peginterferon
Lambda/Ribavirin in Combination With Either Daclatasvir or Asunaprevir in HCV
Genotype 1 Japanese Subjects: Early Sustained Virologic Response (SVR4) Results
From the D-LITE Japanese Sub-Study. N.
Izumi, M. LaTaillade, R. Scricca, D.S. et al. ABSTRACT FINAL ID: 234
BACKGROUND: Peginterferon lambda-1a (Lambda; type
III interferon with limited extrahepatic receptor distribution) and direct
acting antivirals (DAAs) are being developed for treatment of chronic hepatitis
C. Lambda+RBV (L/R) combined with daclatasvir (DCV; first-in-class selective
NS5A replication complex inhibitor) or asunaprevir (ASV; potent NS3 protease
inhibitor) are evaluated in the phase 2b D-LITE study (AI452008) in HCV GT1. We
report
sustained
virologic response at posttreatment Week 4 (SVR4) in a prespecified D-LITE
substudy in Japanese patients. METHODS:
Treatment-naive patients were randomly assigned to L/R/DCV, L/R/ASV or
peginterferon alfa-2a/R/placebo (A/R). L/R/DAA recipients with protocol-defined
response (PDR+; Week (Wk) 4 HCV RNA <25 IU/mL, Wk12
undetectable
[<10 IU/mL]) were treated for 24 wks. Those without PDR received a further
24 wks of L/R. All A/R recipients were treated for 48 wks. Lambda and alfa were
dosed at 180μg QW; DCV 60mg QD; ASV 200mg BID; RBV weight-based BID. RESULTS: 21 patients were treated, all
HCV GT1b. At this analysis, only DAA recipients with PDR (5/6 [83%] on
L/R/ASV [1
discontinuation Wk2 for LFT elevation], 8/8 [100%] on L/R/DCV) had posttreatment data through Wk4(Table). Two
PDR+ patients in each arm had non-CC IL28B genotypes (2/5 [40%] L/R/ASV; 2/8
[25%] A/R/DCV); all achieved SVR4. L/R/DCV was better tolerated than L/R/ASV,
with no SAEs, no AE-related discontinuations, and no Grade 3-4 transaminase or
bilirubin elevations in the L/R/DCV arm. CONCLUSIONS:
Lambda/R-based regimens with ASV or DCV were highly effective in Japanese
patients. 83% and 100%, respectively, achieved PDR, all of whom subsequently
achieved SVR4. L/R/DCV was better tolerated than L/R/ASV. Among Japanese
patients with HCV GT1b, L/R/DCV demonstrated rapid and early sustained
virologic response and was very well-tolerated.
Hemoglobin Decline >2 g/dL During
Peginterferon Alfa-2b (Peg-2b)/ Ribavirin (RBV) Treatment Predicts Favorable
SVR in Patients with HCV Genotype 1 and HCV Genotype 2/3 Infection Without
Erythropoietin Use. G.
Teuber, S. Mauss,D. Hueppe, et al. ABSTRACT FINAL ID: 789
BACKGROUND: It has been shown that anemia and the
hemoglobin (Hb) decline during Peg2b/RBV treatment of genotype 1 (G1) infection
predict favorable SVR rates (Sulkowski M, Gastroenterology 2010). However, approximately
50% of the patients (pts) with anemia received erythropoietin, which may have
confounded the association between Hb decline and SVR. We here investigated
whether the association between Hb decline and SVR can be confirmed for pts
treated for HCV G1 and for HCV G2/3 infection in real-life without
erythropoietin treatment for anemia. METHODS:
Data of pts treated for chronic hepatitis C within the German Peg2b/RBV
observational study were retrospectively analyzed. Pts were treated with Peg2b
1.5 μg/kg/wk + weight-based RBV (800-1200 mg/day) for up to 48 wks. RESULTS: 1851 pts with G1 infection had
baseline and at least one Hb measurement during therapy. Overall SVR rate was
42.6% (789/1851). A significant (p=0.0004) difference in SVR rates was obtained
by comparing pts with Hb declines >2 g/dL (44.6%, 673/1510) with those who
experienced Hb declines ≤2 g/dL (34.0%, 116/341). Hb declines >2 g/dl
were significantly associated with higher SVR rates in difficult-to-treat G1
pts, such as pts elder than 50 years or with high baseline viral load (Table).
Similar results were obtained for 1308 pts treated for HCV G2/3 infection.
Again, pts with Hb declines > 2g/dl achieved significantly higher SVR rates
(71.3%) than pts with Hb declines ≤2 g/dL (62.1%). In this study only one
patient with G1 infection received erythropoietin treatment for anemia. CONCLUSIONS: Patients treated for HCV
G1 and G2/3 infection in real-life achieve up to 15% higher SVR rates when they
develop a Hb decline >2 g/dL during Peg2b/RBV treatment. This beneficial
effect is unrelated to erythropoietin use.
Rapid and early virologic response to
Cepeginterferon-alfa-2b in combination with ribavirine in treatment-naïve
patients with chronic HCV. O.
Znoyko, E. Klimova, S. Maximov, et al. ABSTRACT FINAL ID: 807
BACKGROUND: Cepeginterferon-alfa-2b is a new pegylated
interferon-alfa (IFN-α) molecule consisting of linear polyethylene glycol
(PEG) (molecular weight 20 kDa) linked to IFN-alfa strictly at one site through
N-terminal cysteine amino group. 1.5 and 2.0 μg/kg weekly doses of
cepeginterferon-alfa-2b were selected for further studies in HCV-infected
patients based on esults of Phase I study. METHODS:
Multicenter open-label randomized
prospective phase II study of efficacy and safety of cepeginterferon-alfa-2b in
comparison with peginterferon-alfa-2b within combination therapy of hepatitis
C. 150 treatment-naïve patients with genotype 1, 2, and 3 HCV were randomized
into 3 groups: cepeginterferon-alfa-2b 1.5 μg/kg weekly,
cepeginterferon-alfa-2b
2.0 μg/kg weekly, and a reference group of peginterferon-alfa-α2b 1.5
μg/kg weekly in combination with ribavirine 800-1400 mg/day. RESULTS: In patients with HCV genotype 2 and 3, rapid
and early virologic response (RNA HCV level below the
detection
limit of 15 IE/mL or ≥ 2log10 decrease of viral load after 4 or 12 weeks
of treatment) were achieved in 100% of patients in all treatment groups (per
protocol analysis). In patients with HCV genotype 1, rapid virologic response
was observed in 66.7% and 77.8% of patients receiving cepeginterferon-alfa-2b
1.5 and 2.0 μg/kg weekly vs. 75% in the group of
peginterferon-alfa-α2b 1.5 μg/kg weekly (p>0.05 for all treatment
groups). After 12 weeks of treatment, early virologic response was recorded in
92.3% and 96% vs. 84% of patients, correspondingly (p>0.05 for all treatment
groups). Safety profiles of investigational products were similar.
Administration of cepeginterferon alfa-2b 2.0 μg/kg weekly was associated
with a higher incidence of adverse effects requiring dose adjustment in
comparison to cepeginterferon-alfa- 2b or peginterferon-alfa-α2b 1.5
μg/kg weekly. CONCLUSIONS:
Cepeginterferon-alfa-2b is at least non-inferior to peginterferon-alfa-α2b
in regard to frequency of rapid and early virologic response. Overall, adverse
events occurring during the treatment with cepeginterferon-alfa-2b are dose-dependent;
however, their frequency is no more than in patients receiving standard doses
of peginterferon-alfa- α2b.
Age- and Gender-Related Differences in
SVR and Relapse Following Treatment of HCV Genotype 3 (G3) Infection with
Peginterferon Alfa-2b (Peg2b)/Ribavirin (RBV) in Real-Life. S. Mauss|D. Hueppe, E. Zehnter, et al. ABSTRACT
FINAL ID: 812
BACKGROUND: Because of the current lack of direct
antiviral drugs, improvement of HCV G3 treatment can be achieved only by optimization
of dual therapy. Preliminary data suggest lower SVR rates for G3 infected elder
patients. We therefore aimed to identify the contributing factors. METHODS: Within a multicenter
observational study in Germany 1328 of 4061 patients with chronic hepatitis C
were infected with G3. Of these, 1090 patients had documented treatment with
Peg-IFNα-2b 1.5 μg/kg/wk plus RBV (800-1200 mg/day) for a median of
24 weeks and were included in this retrospective analysis. Patients were
stratified according to baseline viral load, age, gender and platelet count. RESULTS: A SVR rate of 66.3% (723/1090)
was observed in the overall G3 population. SVR rates of 66.7% (371/556) and
66.6% (321/482) were not different in patients with low (<600.000 IU/ml) and
high (≥600.000 IU/ml) baseline viral load. Patients ≥ 40 years
achieved significantly (p=0.0002) lower SVR rates (59.5%, 245/412) than
patients < 40 years (70.5%, 478/678). This was related to a marked increase
of relapse rates from 7.9 to 23.4% in elder patients while non-response rates
remained comparable (6.8 vs 10.7%). The decline in SVR was most prominent in
male patients ≥40 years and accompanied by significantly higher relapse
rates compared to female patients [Table]. In addition, there was a 2-fold
higher proportion of low baseline platelet count <150 n/L in the male
population suggesting that advanced fibrosis could in part contribute to the
differences between female and male patients. CONCLUSIONS: In G3 patients older age affects SVR pre-dominantly in
male patients by higher relapse rates and not by primary non-response. In
contrast to previous reports premenopausal women due not have higher SVR rates compared
to men. The effect of age on relapse may be overcome by prolonged therapy and
should stimulatein individualized treatment strategies in older patients with
G3 infection.
High Early Response Rates with Protease
Inhibitor Triple Therapy in a Multicenter Cohort of HCV-Infected Patients
Awaiting Liver Transplantation. E.C.
Verna, T. Lukose, S.K. Olsen, et al. ABSTRACT FINAL ID: 52
BACKGROUND: Hepatitis C Virus (HCV) is a leading
indication for liver transplant (LT), and recurrent HCV diminishes post-LT
survival. HCV treatment with peginterferon (PEG) and ribavirin (RBV) pre-LT is
limited by poor tolerability and efficacy, but can prevent recurrent HCV if
virologic response (VR) is achieved. The addition of a protease inhibitor (PI)
to PEG/RBV increases VR rates in genotype 1 (G1) HCV, however safety and
efficacy data in
patients
awaiting LT are lacking. METHODS:
Consecutive PI-treated patients with G1 HCV awaiting LT (listed or in evaluation)
from 2 centers were assessed. HCV RNA undetectability (<LOD) at weeks 4 and
12 and safety were the primary endpoints. The majority (90%) was treated with
telaprevir as PI. 25% had a PEG/RBV lead-in (LI) for a median of 31 days, 30%
had SBP prophylaxis, and 40% growth factors. RESULTS: 20 patients (median age 59, 75%
male, 10%
Hispanic, 10% Black) have been treated for a median (range) of 14 (9-21) weeks,
including LI. 65% were previously treated (69% null/partial, 31% relapsers). At
initiation, median (range) laboratory and UNOS MELD were 8 (6-16) and 9 (7-31),
respectively; 9 (45%) had hepatocellular carcinoma with UNOS exception. 20%
each had a history of ascites or encephalopathy. Median (IQR) HCV RNA
pre-treatment was 6.08 log IU/ml (5.72-6.45). 90% and 70% of patients completed
4 and 12 weeks of PI therapy, respectively. At week 4 of PI, 8/18 (44%) were
<LOD, 3/18 (17%) were detected but unquantifiable (<LOQ), and 7 (39%)
were >LOQ. At week 12 of PI, 10/14 (71%) were <LOD, 2/14 (14%) were
<LOQ and 2/14 (14%) were >LOQ. The median (IQR) decline in viral load at
4 and 12 weeks of PI were 6.11 log IU/ml (5.74-6.60) and 6.20 log IU/ml
(5.74-6.66), respectively. Median (range) days from PI initiation to <LOD
was 28 (14-109), among the 13 achieving it. No viral breakthrough occurred.
Early discontinuation occurred in 5 (25%) patients (1 non-response, 1 rash, 1
optic neuritis, 2 liver decompensation). Neither patient with decompensation
received LI or SBP prophylaxis, and one underwent LT at week 3 and remains
<LOD 3 weeks post-LT. Overall, 2 (10%) had SAEs with hospitalization, but
none died, required transfusion, or had significant renal failure. CONCLU-SIONS: A high rate of early
on-treatment VR is possible with triple therapy in patients awaiting LT,
despite advanced fibrosis, high viral loads and a high rate of prior
non-response. However, caution is needed as early discontinuation was common
and 10% of patients decompensated. Longer follow-up is needed, but VR
maintained for even short periods prior to LT might prevent recurrent HCV and
further study of this approach is warranted.
Basic
and Applied Science, Pre-Clinical Studies
Cannabinoid Receptor 2 (CB2) Q63
Variant in Chronic Hepatitis C: An Association with a More Severe Hepatocellular
Necrosis. N. Coppola, M. Macera, M. Pisaturo, et
al. ABSTRACT FINAL ID: 186
AIMS:
to evaluate in patients with chronic hepatitis C the clinical impact of the
rs357661398 single nucleotide polymorphism (SNP) of the CNR2 gene leading to
the substitution of the Arg (R) of codon 63 of the Cannabinoid Receptor 2 (CB2)
with a Gln (Q). PATIENTS AND METHODS:
169 consecutive anti-HCV/HCV-RNA positive patients (HCV group) were enrolled
from April 2007 to December 2011 at the time of their first liver biopsy: males
59.1%; median age 53 years (range 18-80), median serum HCV-RNA 9x10E5 IU/ml
(range 200-6.5x10E7), 70.4% with genotype 1. A control group of 51 consecutive
patients with chronic hepatitis B (HBV group) who underwent their first liver
biopsy in the same period was established: males 68.6%; median age 47 years
(range 27-69); median serum HBV-DNA 1.5x10E5 IU/ml (range 150-1.1x10E7); all
HBV genotype D and anti-HBe positive. All patients in the study were naive to
antiviral therapy and were screened for the CNR2 rs357661398 SNP by direct
sequencing. RESULTS: The prevalence
of patients with CB2-63 QQ variant was similar in the two groups (10.7% and
9.8%). CB2-63 RR variant was more frequently identified in patients in HBV
group than in those in HCV group (47.1% vs 27.2%, p<0.05), while CB2-63 RQ
in HCV group than in those in HBV group (62.1% vs. 43.1%, p<0.05). Regarding
HCV group, patients with CB2-63 QQ variant showed higher aminotransferase serum
levels and higher score of Histological Activity Index (HAI) (Table 1); the
logistic regression analysis identified CB2-63 QQ variant and fibrosis score as
the only independent predictors of a more severe HAI (>8) (p <0.0001). DISCUSSION: The homozygosis for CB2 Q63
variant is more frequent in HBV than in HCV patients. In chronic hepatitis C
this variant predict a more severe hepatocellular necrosis.
IL28B
rs12979860 CC Genotype, Metabolic Profile and SVR in Patients with Genotype 1
Chronic Hepatitis C.
S. Petta, S. Grimaudo, C. Cammà, et al ABSTRACT FINAL ID: 1016
BACKGROUND
AND AIMS:
Patients with genotype 1 chronic hepatitis C (G1-CHC) frequently display
steatosis and insulin resistance (IR), due to both metabolic and viral factors.
Clinically, this translates to accelerated liver disease progression and a
reduced response to therapy. Sustained virological response (SVR) in G1-CHC is
also strongly associated with olymorphisms near the IL28B gene, but the
interaction between IL28B genotype and insulin resistance and their combine
effects of SVR has not been defined. We tested the association between the
IL28B rs12979860 genotype and metabolic features, including IR, and evaluated
their relative impact on SVR. METHODS:
Four hundreds and thirty-four G1-CHC consecutively biopsied patients in three
tertiary centers were genotyped for the IL28B rs12979860 SNP. Their metabolic
profile included assessment of lipid levels and insulin resistance (IR) by the
homeostasis model assessment (HOMA-IR). RESULTS:
IL28B CC patients had higher levels of total and LDL cholesterol, lower
triglycerides, and a lower prevalence of both IR and moderate-severe steatosis
(p<0.05). By multiple logistic regression analysis, BMI (OR 1.223,
p<0.001), triglycerides (OR 1.007, p=0.006), IL28B CC (OR 0.378, p=0.001)
and HCVRNA >850000UI (OR 1.803, p=0.01) were independently associated with
IR. IL28B CC (OR 8.350, p<0.001) and IR (OR 0.432, p=0.005), but not
steatosis (OR 0.582, p=0.25), were independently associated with SVR. See later
re strengthening this if we can show an interaction. CONCLUSIONS: In G1-CHC patients the IL28B rs12979860 CC genotype
is associated with reduced insulin resistance independent of the classical risk
factors. Both IL28B rs12979860 genotype and HOMA-IR additively and
interactively strongly influence the outcome of antiviral therapy.
Interferon-λ3
determines response to pegylated interfern/ribvirin therpy in chronic hepatitis
C patients.
K. Murata, M. Sugiyama, Y. Aoki, et al
ABSTRACT FINAL ID: 1021
BACKGROUND
& AIMS: We
identified single nucleotide polymorphisms (SNP) associated with
interleukin-28B gene (IL28B), encoding IFN-λ3, as predicting factors for
non-responders to pegylated interferon-α/ribavirin (Peg-IFN/RBV) therapy
by genome-wide association study (GWAS) in Japanese patients with chronic
hepatitis C (CHC)(Tanaka Y, Mizokami M, et al. Nat genet 2009). However, the
genetic variation of IL28B failed to predict the treatment response at about
20%. Therefore, we investigated IFN-λs production in peripheral blood
mononuclear cells (PBMCs) and analyzed its association with genetic variations
in IL28B and responses to treatment. METHODS:
Message and protein levels of IFN-λs induced by ex vivo stimulation of
PBMC with IFN-α, following stimulation with toll-like receptor (TLR)
agonists (TLR3; Poly I:C, TLR7; R-837), as measured by quantitative real-time
polymerase chain reaction (PCR) and our newly developed enzyme-linked
immnosorbent assay (Sugiyama M, Murata K, et al. Hepatol Res 2012), were
compared with clinical data. All subjects were evaluated for SNP near IL28B
(rs8099917, rs12979860). Non-invasive evaluation of liver fibrosis was done by
acoustic radiation force impulse (ARFI) elastography. RESULTS: In most cases, both SNPs were in linkage disequilibrium,
and rs8099917 was better associated with the therapeutic response. Therefore,
we used rs8099917 for following analysis (TT is considered as predictive factor
for a favorable response to Peg-IFN/RBV whereas TG/GG is for an unfavorable
response). R-837 along with IFN-α induced IFN-λs, whereas poly I:C
failed the prominent induction in both healthy volunteers (n=12) and CHC
patients (n=94). In CHC patients with TT genotype, IFN-λ3 was more
robustly upregulated by R-837 than those with TG/GG, whereas no significances
were observed in IFN-λ1, IFN-λ2. Importantly, IFN-λ3 production
determined the response (transient responder vs non-responder) in CHC patients
with genotype 1b who had previously failed Peg-IFN/RBV treatment (n=41),
regardless of IL28B genotypes (p=4.0×10-9). Our method more accurately
predicted treatment efficacies at 97.6% than did IL28B genotyping (63.4%).
Based on multivariate logistic analysis, treatment failure in patients with TT
genotype was associated with high sheared wave velocity by ARFI, implicating
the mechanism of non-responsiveness to Peg-IFN/RBV therapy in advanced liver
fibrosis. CONCLUSIONS: Genetic or
post-transcriptional regulations of IFN-λ3 have key roles for the response
to Peg-IFN/RBV therapy, which supported our GWAS data. Our method could provide
more accurate prediction for the efficacy of Peg-IFN/RBV therapy than genetic
analysis.
HCV
infection of human stem cell-derived hepatocytes and potential strategy for
treatment of viral liver diseases.
A. Carpentier, Q. Li, F. Zhang, et al ABSTRACT FINAL ID: 1290
Treatment for hepatitis C has
improved but many patients do not respond to current therapy.
Accumulating evidence indicate
that patient specific factors significantly affect the response to antiviral
treatments. However, in vitro models recapitulating hepatitis C virus (HCV)
infection in the context of the patient specific genetic background are
missing. Generation of patient specific induced pluripotent stem cells (iPSC)
and the technology to developmentally program these cells to hepatic lineage
offer great promise. In this context, we hypothesize that this approach could
be useful in developing a relevant personalized model for HCV infection in
vitro. Moreover, the iPSCs approach could allow the generation of autologous
patient-specific hepatocytes with promising opportunity for cell therapy of
viral liver diseases. We generated iPSCs from primary fibroblasts using
lentiviral vectors, and characterized them in comparison to embryonic stem
cells. Human pluripotent stem cells were efficiently differentiated into
hepatocyte like cells (HLC), as demonstrated by induction of hepatic genes and
secretion of hepatic proteins (AFP and albumin) in the supernatant. Moreover
these cells recapitulate hepatocyte-specific metabolic functions like lipid and
glycogen accumulation, and indocyanin green metabolism. These HLC were
subsequently infected with HCV. During the first week post-infection,
increasing level of intracellular HCV RNA could be detected in these cells,
confirming entry of the virus and replication of the viral genome. Infection of
HLC were further confirmed by hepatitis C dependent fluorescence relocalization
assay. Moreover, we assessed HCV RNA, core protein and infectivity in the
supernatant, confirming the production of infectious virus by HCV-infected HLC.
These infected cells also respond to antiviral therapy, such as
interferon-α and 2'-methylcytidine, a nucleoside analog inhibitor of HCV
polymerase. Interestingly, HCV infection also induces intrinsic innate immune response
including interferon response, as previously described in infected primary
human hepatocytes. In conclusion, we demonstrated that HLC derived from patient
pluripotent stem cells support infection by HCV. This approach constitutes a
unique tool to analyze the induction of innate immunity in response to HCV
infection and antiviral treatment in the context of the patient's genetic
background. Moreover, by targeting proviral cellular factors or introducing
antiviral factors in these cells, we hope to generate HCV resistant-patient
specific-hepatocytes. This approach holds promises for cell therapy of
hepatitis C, particularly for patients with end-stage liver diseases.
Il28b
polymorphism, rs12979860, determines the activity of liver lymphocytes. A. Marlu, V. Leroy, J.H. Zarski, et al
ABSTRACT FINAL ID: 181
Polymorphism of IL28B is
correlated with a sustained virological response (SVR) in Hepatitis C Virus
(HCV) infected patients treated with Pegylated Interferon-α combined with
Ribavirin. The single nucleotide polymorphism (rs12979860), located near the
IL28B gene, defines two alleles C/T, C allele being associated to SVR.However,
the effect of this polymorphism on immune functions of the liver, the site of
HCV production, and the mechanism of SVR remain still unknown. Chronically
HCV-infected genotype 1 patients were genotyped for IL28B rs12979860. Liver
samples were collected from the needle biopsy prior treatment. Single cell
suspensions were prepared by mechanical disruption. Liver lymphocytes (T, Treg,
NK and NKT) were identified by flow cytometry for the expression of CD45, CD3,
CD4, CD8,CD56 and FoxP3 as markers and CD107a for degranulation activity.
Immunohistochemistry were performed on in paraffin sections for the detection
of CD8 and FoxP3. Statistical analysis was done with Mann-Whitney "U"
test and Wilcoxon matched-t test. Lymphocytes from 52 fresh liver biopsies
displayed similar distributions of T
(CD3), NKT (CD3, CD56) and NK (CD56)among CD45 cells, whatever the IL28B
genotype of the patients. Strikingly, higher degranulation activity, revealed
by CD107a surface expression, was observed in T (p=0.000), NKT (p=0.002) and NK
cells (p=0.015) of patients with CC genotype (n=17) compared to patients with
CT or TT genotypes (n=35); patients with CC genotype displayed two fold higher
degranulation activity than patients with CT genotype in T (p=0.001), NKT
(p=0.002) and NK cells (p=0.011); no significant difference was observed
between patients with CT and TT genotypes. Sections of liver from 19 patients
showed the frequency of CD4-FoxP3 lymphocytes two fold higher (p=0.004) in
patients with CC genotype (n=11) as compared to patients with CT genotype (n=8)
supporting the presence of Treg.Ratio between the number of CD8 cells and FoxP3
cells in parenchymatous necro-inflammatory areas was maintained in the early
stage of the chronic hepatitis only in patients with CC genotype, whereas this
ratio was reduced in patients with CT genotype due to lower number of FoxP3
cells.These data provide new insights into the role of IL28B polymorphism
related to SVR in treatment of HCV genotype 1 infected patients. CC genotype,
which is linked to a good response to therapy, is associated to higher
efficiency of effector lymphocytes (T, NK and NKT) of the liver. The liver
immune response appears tightly regulated as suggested by the links between CD8
cells and CD4-FoxP3 cells.
Identification
of Interferon Effector Genes as New Targets for HCV Antiviral Develop-ment. D.N. Fusco, C. Brisac, E.A.
Schaefer, et al. ABSTRACT FINAL ID: 1031
PURPOSE: The mechanisms underlying
antiviral effects of interferon-alpha (IFN-a) have not been completely
elucidated due to a lack of tools to systematically evaluate the hundreds of
IFN stimulated genes (ISGs) and technical challenges related to study of
hepatitis C virus (HCV). To identify IFN-regulated modulators of HCV infection,
we developed an HCV replicon-based high-throughput screening assay for use with
RNA interference libraries (Tai AW,et al. Cell Host Microbe. 2009;5:298-307), followed
by an image based screening platform using fully infectious JFH1 HCV that
enables study of the entire HCV lifecycle (Li Q, et al. PNAS,.
2009;106:16410-5). We have optimized a platform for high throughput image-based
RNAi screening for host factors involved in the IFN response to fully
infectious HCV (JFH1). Using this platform, we performed a whole genome siRNA
screen for anti-HCV interferon effector genes (IEGs). METHODS: Huh 7.5.1 hepatocytes are transfected with siRNA. Two days
later, cells are treated with IFNa. One day later, cells are inoculated with
JFH1 HCV. Two days post-infection, cells are stained with HCV core antibody and
Hoechst nuclear stain, then imaged using an automated microscope to determine
the percent infected cells. Rescue from IFN treatment is scored as a 2-fold
increase in percent infection above plate mean. Our positive control for IFN
rescue, IFNa receptor 1 (IFNAR), rescues ~50% of HCV replication from IFNa
suppression, and our negative control,non-targeting (NT3), does not rescue HCV
from IFN compared to plate mean. RESULTS:
We identified several known HCV ISGs (eg TYK2, ISGF3G) as well as previously
unknown IEGs, including P285, ALG10, and MYST1. The siRNAs used to silence
these genes were validated for mRNA knockdown. IFN stimulation analysis
revealed that P285 is upregulated at the mRNA level by IFN alpha and lambda,
but ALG10 and MYST1 are not, In addition, these genes appear to rescue HCV from
IFN at one or more steps of the HCV lifecycle.
CONCLUSION: This powerful approach makes it
possible to identify in an unbiased manner host genes that regulate HCV
containment by IFN and, by extension, fail in patient populations with high
rates of persistence. It appears that multiple effectors of the IFN response
(IEGs) are not upregulated at the mRNA level by IFN, and thus compose a
distinct class of non-ISG IEGs. These IEGs may inform design of novel antiviral
drugs.
miRNAs
involved in insulin resistance are regulated in vitro by HCV infection. M. García-Valdecasas, A. Rojas,
L.A. Rojas, et al. ABSTRACT FINAL ID: 1086
BACKGROUND
AND AIMS: The
hepatitis C virus induces insulin resistance and steatosis, but the molecular
mechanisms involved in these processes are not yet completely understood. PTEN
is an inhibitor of PI3K protein which plays an essential role in the insulin
signaling pathway. PTEN is down-regulated in infected cells. The aim of this
work is to analyze the mechanism in which JFH1 interacts with PTEN and PI3K,
and with others downstream proteins of the insulin signaling pathway,studying
the expression of miRNAs targeting PTEN (miRNA29a and b), and the role of a
PI3K inhibitor (LY294002) in viral replication. METHODS: Huh7.5 cells were grown and infected with the JFH1
replicon (1 particle/cell). LY294002 (10μM) or insulin (10nM)were added to
the cells. Total RNA extraction was performed 48 hours after the media was
changed. The expression of the different genes was quantified using the qRT-PCR
Quantace (Bioline) kit and analysis of specific proteins analyzed by Western-Blot.
miRNA expression was quantified using the miScripReverseTranscription and
miScript SYBR®Green commercial Kits (Quiagen). RESULTS: Huh7.5 cells
infected with JFH1 showed decreased PTEN and PI3K protein levels. In cells
infected and with hyper-insulinemia, PTEN was further decreased whereas PI3K
showed no difference compared to control experiments. When Huh7.5 cells were
treated with the PI3K inhibitor LY294002, gene expression of PI3K was increased
in control 1.6 (±0.3) and in virus 2.6 (±0.9) fold induction respectively,
likely due to a feed-back cellular
response. AKT and mTOR, downstream proteins of the PI3K pathway, are increased
in control and infected cells treated with LY294002 (AKT: 1.7±0.7 vs. 1.6±0.01
fold induction; mTOR: 1.5±0.1 vs. 2.6±0.8 fold induction). Other proteins of
the insulin signaling pathway PTEN4, PTP1B and PTP2 showed increased gene
expression. LY294002 inhibitor did not affect significantly viral replication
rates (decreasing by 20% compared to α-interferon). miRNA29a and 29b (targeting
PTEN), were increased 1.5 (±0.01) and 2.1 (±0.1) fold induction in cells
infected with JFH1. CONCLUSION: PI3K
inhibitor LY294002 modulates gene expression and slightly decreases viral
replication, probably due to inhibition of IRS1 phosphorylation. miRNA29a and
29b induction could explain the reduction of PTEN levels and seems to be a link
between HCV infection and metabolic disorders.
Effect of Chronic Hepatitis C Virus
Infection on Bone Mineral Density. J.
Lin, T. Hsieh, P. Chen, et al. ABSTRACT FINAL ID: 987
PURPOSE: Whether chronic hepatitis C virus
(HCV) infection is a risk factor for the develop-ment of bone disease has long
been controversial. For this reason, we conducted a thorough investigation of
bone turnover markers and bone mineral density (BMD) in a homogenous cohort of
patients with non-cirrhotic chronic HCV infection. METHODS: Chronic HCV-infected participants (n = 69) were recruited
into a prospective cohort study and underwent dual- energy X-ray absorptiometry
for determination of BMD. Fibrosis staging was evaluated according to the
noninvasive index FIB-4. T-scores at the femoral neck and lumbar spine were
used as the primary outcome variables to assess the association between degree
of liver fibrosis and BMD. Osteoporosis was defined as a T-score ≦ -2.5, and osteopenia as a T-score
between -1.0 and -2.5. RESULTS: The
population was 41% male with a mean age of 53.6 years. The mean BMD, Z-score,
and T-score values of lumbar spine in chronic hepatitis C (CHC) patients were
significantly lower than those in healthy controls (p <0.001). The rate of
osteoporosis for CHC patients between 45 and 54 years was significantly higher
than that of the control group (p = 0.011). Bone alkaline phosphatase and
C-terminal cross-linking telopeptide of type I collagen levels were also
significantly higher in the reduced BMD population. Patients with more advanced
liver fibrosis had significantly lower BMD (Table). CONCLUSION: Reduced BMD is common in this population of chronic
HCV-infected patients, by increased bone turnover in the osteodystrophy
pathogenesis, probably associated with liver disease severity.
HIV/HCV
Coinfection
Treatment of Chronic Hepatitis C
Improves Clinical Outcomes Despite Lack of Achievement of Sustained Virological
Response in HIV-HCV Coinfected Patients with Advanced Liver Fibrosis. P. Labarga, J. Fernández-Montero, F.
Rick, E. et al. ABSTRACT FINAL ID: 988
BACKGROUND: HCV clearance following hepatitis C
therapy is associated with significant reductions in liver-related
complications and death. A potential benefit of hepatitis C therapy in the
absence of achievement of SVR has been pointed out occasionally. This
information could be particularly relevant in HIV/HCV-coinfected patients, in whom
treatment response is lower and liver disease occurs faster. METHODS: Retrospective study of
clinical end-points in a large cohort of HIV/HCV-coinfected patients who had longitudinal
assessment of liver fibrosis by elastometry (FibroScan). Follow-up ended at the
time of last visit, first liver decompensation event or death. Patients were
split out into two groups, failures to peginterferon/ribavirin and never treated
patients. Liver fibrosis progression was defined as a shift from Metavir
estimates ≤F2 to F3-F4, or by >30% increase in liver stiffness values
in patients with baseline Metavir estimates of F3-F4. RESULTS: A total of 389 patients were analyzed, 201 (52%) treatment
failures and 188 (48%) never treated. The main characteristics of these two
groups were comparable (mean age 41 years-old, 72% males, 86% former IDUs, 92%
on HAART, mean CD4 count >450 cells/uL, mean HCV-RNA 5.5 log IU/mL).
Differences between treated and untreated patients were noticed for the
proportion of HCV genotypes 1/4 (90% vs 81%, p=0.008), baseline Metavir F3-F4
(44% vs 26%, p<0.001), HBsAg+ (2.4% vs 7.6%, p=0.02) and alcohol abuse (9.2%
vs 15.3%, p=0.08).After a median follow-up of 68 months, treated versus
untreated patients experienced similar liver fibrosis progression (26% vs 20%,
p=0.1), liver decompensation events (12% vs 13%, p=0.6), and deaths (2% vs 0%,
p=0.1). However, in
the subset of
patients with baseline Metavir F3-F4, liver decompensation events or deaths
occurred less frequently in treated than untreated patients (19% vs 42%,
p=0.005). This finding was confirmed after adjusting for baseline haemoglobin,
platelets or CD4 counts. A Cox regression analysis in the whole population
confirmed that baseline Metavir F3-F4 was the only predictor of liver
decompensation events or death in this population. CONCLUSIONS: Treatment of chronic hepatitis C is associated with a
reduced incidence of liver complications and death in HIV-infected patients
with advanced liver fibrosis. This benefit might result from an
anti-inflammatory effect of therapy and/or a better socio-clinical profile of
treated than untreated patients.
Differences in CD4+ and CD8+ Memory
T-cell Expression in HIV, Hepatitis C (HCV), and HIV/HCV Coinfection are
Influenced by HIV and HCV Infection Status. A.
Hodowanec, S. Kincaid, M. Bahk, G. et al. ABSTRACT FINAL ID: 1055
BACKGROUND: Increased immune activation with
dysregulated T-cell mediated immune responses may be associated with
accelerated liver fibrosis in HIV/HCV-coinfected patients. Differences in CD4
and CD8 T-cell subset expression in patients with HIV-monoinfection,
HCV-monoinfection, and HIV/HCV-coinfection have not been fully explored. METHODS: Fifty-nine age (median, 53
years) and sex (male=43/female=16)-matched patients were stratified: A) HIVmonoinfection
(N=15), B) HCV-monoinfection with chronic hepatitis C (CHC) (N=15), C)
HIV/HCV-coinfection with CHC (N=14), and D) HIV/HCV-seropositive with cleared
HCV (N=15). All HIV+ patients had undetectable HIV RNA, and current CD4 counts
in strata A and C were matched to CD4 at estimated time point of HCV clearance
in strata D (median, CD4=420 cells/ml). The estimated median duration of HCV
infection among strata B, C, and D was 26 years (range, 3-40 years).
Sociodemographic data and liver- and HIV-related laboratory results were
recorded and cells collected for CD4 and CD8 naïve T-cell (CD45RA+CCR7+),
central memory T-cell (CD45RA-CCR7+), terminal effectors expressing RA (TEMRA)
T-cell (CD45RA+CCR7-), and effector memory T-cell (CD45RA-CCR7-) measurement
via flow cytometry. All subjects underwent transient elastography to stage
liver fibrosis. Immune
markers were
analyzed in multivariate models across strata using pair-wise t-tests. RESULTS: Mean CD4 central memory T-cell
expression was greater among HCV-monoinfected patients (24%) than HIV-monoinfected
patients (18%)(p=0.018), HIV/HCV-coinfected patients with CHC (20%)(p=0.014),
and HIV/HCVcoinfected patients with cleared HCV (18%)(p=0.003). CD8 central
memory T-cell expression was also greater in HCV-monoinfection (12%) than
HIV-monoinfection (6%)(p=0.033) and HIV/HCV-coinfection with cleared HCV (5%)(p=0.001).
Conversely, CD4 TEMRA T-cell expression was lower in HCV-monoinfection (7%)
versus HIVmonoinfection (17%)(p=0.006) and HIV/HCV-coinfection with cleared HCV
infection (16%)(p=0.007). There was no significant difference in CD4 or CD8
naïve T-cell or effector memory T-cell expression across strata. Overall, advanced
fibrosis was associated with lower CD8 central memory (p=0.027) and higher CD8
TEMRA (p=0.003) T-cell expression. CONCLUSIONS:
HCV-monoinfection appears to be associated with a greater reserve of central
memory cells that may limit terminal effector activity in patients with
longstanding chronic HCV infection. These findings may reflect a relative quiescent
immune environment in HCV-monoinfection compared to concurrent HIV infection,
in which increased
immune
activation may contribute to accelerated rates of liver fibrosis.
Individuals coinfected with human
immunodeficiency virus and hepatitis C virus are at increased risk of reduced
bone mineral density and bone fracture: a systematic review.
L. Rivera, H.
Thein, ABSTRACT FINAL ID: 972
The
prevalence of chronic viral hepatitis infection is a concern for HIV-infected
individuals in the era of highly active antiretroviral therapy. We aimed to
examine whether coinfection with HIV and hepatitis C virus (HCV) in adults is
associated with low bone mineral density (BMD) or an increased risk of bone
fracture compared to either monoinfected or uninfected individuals. We
performed a systematic literature review in May 2012 of studies published since
1980. Studies reporting BMD or bone fracture as a powered outcome and a measure
of association between
HIV/HCV
coinfection and either outcome were included. Baseline risk factor data were
extracted. Ten studies met the inclusion criteria, with 4 cross-sectional
studies examining low BMD and 5 studies (1 case-control, 5 longitudinal) examining
bone fracture. The majority of coinfected patients were antiretroviral-treated.
Four studies compared low BMD between HIV/HCV coinfected individuals (n=729)
and HIV monoinfected (n=966) or uninfected controls (n=224) and showed that the
odds of reduced BMD was 45% greater in the coinfected individuals than the
controls (pooled OR=1.45, 95% CI=1.13-1.88). Studies examining bone fracture in
coinfected individuals compared to controls were heterogeneous in the measures
of association chosen to report this comparison; results were pooled where
possible. Pooling three studies that reported the odds of experiencing bone
fracture indicated that the odds of coinfected
individuals
(n=1,686) experiencing fracture is 145% greater than monoinfected (n=9,507) or
uninfected (n=26,652) controls (pooled OR=2.45, 95% CI=1.97-3.03). Two studies
reported incidence rate ratios. Pooling these, fracture incidence rate in the
coinfected individuals (n=851) was 2.92 times (95% CI=2.52-3.39) the incidence
rate experienced by monoinfected (n=5,736) or uninfected controls (n=26,530).
Finally, pooling hazard ratios for fracture generated by 3 studies indicated
that the hazard of fracture experienced by coinfected patients (n=38,207) is
1.77 times (95% CI 1.55-2.01) the hazard for monoinfected (n=379,025) or
uninfected controls (n=3,111,567). Our analyses indicate that HIV/HCV
coinfected individuals are significantly more likely to experience low BMD or
bone fracture compared to monoinfected or uninfected controls. The higher
fracture rates observed among HIV/HCV coinfected patients might be due to the
additive effects of HIV infection and antiretroviral therapy on BMD. Due to the
heterogeneity
of the published reports, these conclusions, however, necessitate further study
of the association to validate our findings.
The impact of IL28B rs12979860 SNP and
advanced liver fibrosis on response-guided therapy in HIV/HCV coinfected
patients of particular clinical interest. M.
Mandorfer, T. Reiberger, B.A. Payer, et al. ABSTRACT FINAL ID: 943
OBJECTIVE: According to current European AIDS
Clinical Society (EACS) guidelines for the treatment of chonic hepatitis C,
HCV-Genotype (GT) and rapid virologic response (RVR) exclusively determine
chronic hepatitis C therapy duration in HIV/HCV coinfected patients. The aim of
our study was to investigate the impact of interleukin 28B rs12979860 SNP
(IL28B) and advanced liver fibrosis on the association between treatment
duration and sustained virologic response (SVR) in groups of HIV/HCV coinfected
patients in which either shortening or extension of treatment duration is recommended.
METHODS: 327 HIV/HCV coinfected
patients who received antiviral therapy with pegylated interferon plus
ribavirin (PEGIFN+RBV) were included in this multinational, retrospective
study. Patients with either GT2/3 and RVR (GT2/3-RVR) or GT1/4 without RVR
(HCV1/4-noRVR) were divided into groups according to their treatment duration
(12-36 vs. 36-60 and 36-60 vs. 60-84 weeks, respectively). Liver biopsies and
liver stiffness measurements were available in 289 patients. Advanced liver
fibrosis was defined as either METAVIR F3/F4 or liver stiffness >9.5 kPa. RESULTS: Patient characteristics: 81%
male, mean age: 40.9±7.6 years, concomitant antiretroviral therapy: 82%, mean baseline
CD4+ T-lymphocyte count: 534±251 cells/μl, mean treatment duration:
41.6±16.2 weeks, GT1/4: 68%, advanced liver fibrosis: 42%, IL28B non-C/C: 57%.
RVR and SVR were observed in 34% and 53% of patients, respectively. In
HCVGT1/4-noRVR patients, a trend toward higher SVR rates (59%) in patients with
extended treatment duration (60-84) compared to patients treated for 36-60
weeks (40%) was observed (p=0.055), regardless of IL28B (IL28B C/C: 75% vs.
48%, p=0.117; IL28B non-C/C: 52% vs. 33%, p=0.132). While SVR rates were
comparable
between HCV1/4-noRVR patients without advanced liver fibrosis treated for 36-60
and 60-84 weeks (51% vs. 62%, p=0.432), significantly lower SVR rates were
observed in patients with advanced liver fibrosis (12% vs. 46%, p=0.022).
HCV2/3-RVR patients with shortened treatment duration (12-36 weeks) displayed
high rates of SVR ranging from 80% to 100%, regardless of IL28B and advanced
liver fibrosis. CONCLUSIONS: Our
study supports the extension of therapy duration to 72 weeks for HIV/HCV
coinfected patients with GT1/4-noRVR as recommended by current EACS guidelines,
regardless of IL28B. Especially GT1/4-noRVR patients with advanced liver
fibrosis benefit from 72 weeks of treatment. In patients with GT2/3-RVR, the
shortening of treatment duration to 24 weeks is associated with excellent SVR
rates, regardless of IL28B and advanced liver fibrosis.
Sustained virological response and
occurrence of end stage liver disease event (ESLD) in HIV/HCV-related
cirrhosis, ANRS C013 HEPAVIH cohort (France). D. Salmon, P. Sogni, K. Lacombe, et al.
ABSTRACT FINAL ID: 952
BACKGROUND: ESLD has become the main cause of
severe morbidity and mortality in HIV/HCV coinfected patients. The aim of this
study was to assess the impact of anti-HCV treatment on ESLD, (hepatocellular carcinoma
(HCC) or liver decompensation ), in HIV/HCV coinfected cirrhotic patients. METHODS: Cirrhotic patients enrolled in
the ANRS CO13 HEPAVIH multicenter prospective cohort between 2006 and 2008 with
no previous liver decompensation or HCC at cohort inception were included (1).
Liver fibrosis stage at
enrolment was
evaluated using an algorithm combining liver biopsy and non-invasive liver
fibrosis tests previously validated (1). Sustained virological response (SVR)
was defined as undetectable serum HCV RNA at 24 weeks after treatment. RESULTS: 241 patients were included and
followed-up for a median duration of 3.2 years (IQR: 2.3-4.1). Median age
was 49 years
(IQR:46-53), 139 (59%) had a genotype 1, median CD4 was 433/mm3 and 85% had
undetectable HIV RNA; 32 patients presented a first liver decompensation or HCC
during the follow-up. The cumulative incidence rate of first liver
decompensation or HCC, was 4% at one year, 8% at two years, 11.5% at three
years, 14% at four years, and 19% at five years.
Overall, 76%
(183/241) of patients were treated for HCV (prior to cohort inception or during
follow-up) and 24% (58/241) remained treatment naïve. Among HCV-treated
patients for whom SVR could be assessed, SVR was present in 33% (51/152) of
patients. The proportion of patients with a first ESLD episode was higher among
HCV-untreated compared to that in HCV-treated patients (respectively 31% 18/58
vs. 8% 14/183, p<0.001). Among HCV-treated patients, the proportion of
patients with a first ESLD episode was higher in patients with no SVR compared
to that in patients with SVR (respectively 13% 8/101 vs 2% 1/51, p=0.0035).
Indeed, ESLD events in non SVR patients were: 8 liver decompensations (2
hepatic encephalopathies, 4 ascites and 2 ascites with jaundice) and 5 HCC;
whereas in patients with SVR, after a median follow-up of 4 years (IQR:2-7)
after viral clearance, only one patient was diagnosed with HCC. CONCLUSIONS: SVR in HIV/HCV co-infected
patients with cirrhosis is associated with a significantly lower incidence of HCC
or liver decompensation. Even if no SVR is achieved, HCV treatment could have a
positive impact in this population.
Treatment of acute HCV infection in HIV
co-infection: Influence of HCV genotype and ribavirin upon treatment outcome. C. Boesecke, M. Vogel, J.K. Rockstroh, et
al ABSTRACT FINAL ID: 49
INTRODUCTION: The ongoing epidemic of acute
hepatitis C (AHC) infection among MSM highlights the need to identify factors
allowing for optimal HCV treatment outcome in HIV co-infected individuals. Here
we evaluate the impact of baseline HCV genotype (GT) and added ribavirin (RBV)
on sustained virological response (SVR) rates. Material & METHODS: 303 HIV-infected patients from
4 European countries with diagnosed AHC infection were treated
early with
pegylated interferon (pegIFN) and ribavirin (RBV) (n=273) or pegylated
interferon alone (n=30), followed prospectively and evaluated for virological
response rates. Fisher's exact test, chi-square test and binary logistic regression
model were used for statistical analysis.
RESULTS: All patients were male, median age was
39 years. Main routes of transmission were MSM (95%) and IVDU (3%). In 75% of
patients clinical signs of acute hepatic infection were missing. 69% of
patients were infected with HCV GT 1, 4.3% with GT 2, 10.6% with GT 3 and 16.1%
with GT 4. Median baseline HCV RNA was 991.500IU/ml, median CD4 T cell count
472 cells/ul. 64,8% of all patients received HAART. By univariate analysis,
there were no statistical
differences
at baseline for HCV or HIV characteristics between patients with GT 1/4 (group
1) and patients with GT 2/3 (group 2) infection apart from pegIFN + RBV
combination therapy: Patients with GT 2/3 were less likely to be treated with
combination therapy (p=0,006).
Overall SVR
rate was 69.3% (210/303). RVR (p≤0,001), 48w treatment duration
(p≤0,001) and GT 2/3 (p=0,024) were significantly associated with SVR.
Interestingly, SVR rates were significantly higher in group 2 receiving pegIFN
and RBV (33/35) when compared with pegIFN mono-therapy (6/10) (94% vs. 60% respectively;
p=0.016). In multivariate analysis, pegIFN/RBV combination therapy (p=0.017)
and rapid virological response (RVR) (p=0,022) were significantly associated
with SVR in group 2. In group 1, RVR (p≤0,001) and 48w treatment duration
(p≤0,001) were significantly associated with SVR. CONCLUSIONS: Treatment of acute HCV GT 2 and 3 infections is
associated with higher SVR rates suggesting different cure rates depending on
HCV genotype similar to the genotype effects seen in chronic HCV therapy. In
addition, ribavirin is important in the management of AHC in HIV-positive
patients; for GT 2/3 infections almost all patients clear virus with
combination therapy. Early antiviral treatment of acute HCV infection in HIV
co-infected individuals results in virological response rates which are
significantly higher than those obtained in treatment of chronic HCV
co-infection.
Assessment of Boceprevir (VICTRELIS™)
Pharmacokinetic/Pharmacodynamic Relation-ships
for Sustained Viral Response (SVR) and Occurrence of Anemia : Results in HCV/ HIV
Co-infected Patients and in Combined Mono and Co-Infected Patients. L.A. Wenning, R. Liu, K. Tsai, H. et
al. ABSTRACT FINAL ID: 770
BACKGROUND: Boceprevir (BOC) is a hepatitis C
(HCV) protease inhibitor (PI) approved for treatment of HCV genotype 1 (G1)
infection with peg-interferon/ribavirin (PR). In healthy volunteers, BOC
concentrations were reduced by ritonavir-boosted HIV PIs. BOC pharmaco-kinetics
(PK) in a Phase 2 study in HCV/HIV co-infected patients were characterized, and
PK/PD relationships explored with SVR and anemia. METHODS: Co-infection data were from a 48-week trial of 64 subjects
on BOC/PR and 34 subjects on PR. A population PK model was used to estimate BOC
PK parameters from 281 concentration measurements in 51 patients (94% had an
HIV PI in their ARV), taken from weeks 6 to 48 of BOC/PR treatment. PD
endpoints were SVR at 12 weeks posttherapy, anemia (hemoglobin <10 g/dL),
and severe anemia (Hgb <8.5 g/dL). For some analyses, data were pooled with
209 mono-infected treatment-naïve (SPRINT-2) and experienced (RESPOND-2)
patients from Phase 3 studies who had pop PK, SVR24 and anemia data. Logistic
regression models assessed the relationship between the event
(SVR or
anemia) and BOC PK (AUC, Cmax, or C8hr). The resulting odds ratio (OR)
represents the fold-change in odds (probability of event/no event) going from
the 25th to 75th percentile of PK values. RESULTS:
In the coinfection study, BOC AUC and C8hr were on average 20% and 27% lower
compared to Phase 3, but with large overlap in values between co-infected and
mono-infected patients. Over the range of BOC PK observed in these studies, no
significant relation-ships were observed between any BOC PK parameter and SVR
or severe anemia (see table for BOC C8hr; results for AUC and Cmax were
similar). Statistically significant relationships were identified between BOC
PK and anemia (<10) in the pooled analysis. There was no evident correlation
between BOC PK and total RBV dose. CONCLUSIONS:
BOC exposure was reduced in the co-infection population compared to
mono-infected subjects in Phase 3, most likely reflecting DDI between boosted
HIV PIs and BOC. No relationship was observed between BOC PK and SVR,
indicating that the reduced BOC exposure is not likely to substantially impact
efficacy against HCV. Lower BOC exposure was associated with a reduced
incidence of anemia. RBV PK was not collected in the co-infection study, so it
cannot be ruled out that this result is confounded by exposure to RBV (which is
known to influence rate of anemia).
Clinical factors that predict
noncirrhotic portal hypertension (NCPH) in HIV-infected patients: a proposed
diagnostic algorithm. N.
Parikh, T. Kushner, V. Martel-Laferriere, D. et al. ABSTRACT FINAL ID: 1186
PURPOSE: NCPH is a clinical entity that has been
described in HIV-infected patients and is associated with the use of certain antiretrovirals
(ARV), especially didanosine (ddI). The purpose of our study was to determine
clinical factors that could be used to diagnose NCPH in HIV-infected patients. METHODS: A retrospective case-control
study was performed in 42 HIV-infected patients with NCPH and 55 without NCPH. Cirrhosis
was excluded with the use of liver biopsy and/or transient elastography.
Hepatitis B and C were also excluded. RESULTS:
Cases and
controls were similar in age, race, and HIV duration. NCPH patients had a
longer mean exposure to ARVs (15.2 vs. 8.2 years, p < 0.001), a lower nadir
CD4 count (164 vs. 388 mm3, p < 0.001) and a lower current CD4 count (344
vs. 647 mm3, p < 0.001). More cases than controls were exposed to ddI (92.9%
vs 16.4%, p < 0.001). Among the cases, 37 (88.1%) had esophageal varices
(EV), 36 (85.7%) had splenomegaly, and 20 (47.6%) had ascites while
only 1
patient (1.8%) had splenomegaly in the control group. The majority (52.4%
(n=22)) of cases presented with EV bleeding. Cases also had lower albumin (3.8
vs. 4.5 g/dl, p < 0.001), hemoglobin (12.4 vs. 14.2 g/dl, p < 0.001), platelets
(117 vs. 198 x 103/uL p < 0.001) as well as greater alkaline phosphatase
(150 vs. 87.2 U/l, p < 0.001), AST (57 vs. 37 U/l, p = 0.002), INR (1.2 vs.
1.0, p = 0.008) and total bilirubin (0.95 vs. 0.58 mg/dl, p = 0.037) compared
to
the controls.
Mean transient elastography score was higher in the cases (10.6 vs. 5.6 kPa, p
< 0.001). Based on this analysis, we hypothesized a set of six criteria to
diagnose NCPH in HIV patients (Table 1). Ninety-three percent (n=39) of the
cases met at least 3 out of 6 criteria while 96.3% (n=53) of the controls met a
maximum of 1 criterion. If meeting 3 of 6 criteria was considered a positive
diagnostic test, then the test carried 92.8% sensitivity and 100%
specificity
for NCPH. CONCLUSION:This is the
largest series of NCPH reported to date. In this cohort, meeting at least 3 out
of 6 proposed criteria resulted in a diagnostic sensitivity of 92.8% and
specificity of 100% for NCPH in HIV patients. This data suggests a future
larger trial
is warranted to further validate these criteria.
Assessment of Boceprevir (VICTRELIS™)
Pharmacokinetic/Pharmacodynamic Relationships for Sustained Viral Response
(SVR) and Occurrence of Anemia : Results in HCV/HIV Co-infected Patients and in
Combined Mono and Co-Infected Patients
L.A. Wenning,
R. Liu, K. Tsai, et al. ABSTRACT FINAL ID: 770
BACKGROUND: Boceprevir (BOC) is a hepatitis C
(HCV) protease inhibitor (PI) approved for treatment of HCV genotype 1 (G1)
infection with peg-interferon/ribavirin (PR). In healthy volunteers, BOC
concentrations were reduced by ritonavir-boosted HIV PIs. BOC pharmaco-kinetics (PK) in a Phase 2 study in
HCV/HIV co-infected patients were characterized, and PK/PD relationships
explored with SVR and anemia. METHODS:
Co-infection data were from a 48-week trial of 64 subjects on BOC/PR and 34
subjects on PR. A population PK model was used to estimate BOC PK parameters
from 281 concentration measurements in 51 patients (94% had an HIV PI in their
ARV), taken from weeks 6 to 48 of BOC/PR treatment. PD endpoints were SVR at 12
weeks posttherapy, anemia (hemoglobin <10 g/dL), and severe anemia (Hgb
<8.5 g/dL). For some analyses, data were pooled with 209 mono-infected
treatment-naïve (SPRINT-2) and experienced (RESPOND-2) patients from Phase 3
studies who had pop PK, SVR24 and anemia data. Logistic regression models
assessed the relationship between the event
(SVR or
anemia) and BOC PK (AUC, Cmax, or C8hr). The resulting odds ratio (OR)
represents the fold-change in odds (probability of event/no event) going from
the 25th to 75th percentile of PK values. RESULTS:
In the coinfection study, BOC AUC and C8hr were on average 20% and 27% lower
compared to Phase 3, but with large overlap in values between co-infected and
mono-infected patients. Over the range of BOC PK observed in these studies, no
significant relationships were observed between any BOC PK parameter and SVR or
severe anemia
(see table
for BOC C8hr; results for AUC and Cmax were similar). Statistically significant
relationships were identified between BOC PK and anemia (<10) in the pooled
analysis. There was no evident correlation between BOC PK and total RBV dose. CONCLUSIONS: BOC exposure was reduced
in the co-infection population compared to mono-infected subjects in Phase 3,
most likely reflecting DDI between boosted HIV PIs and BOC. No relationship was
observed between BOC PK and SVR, indicating that the reduced BOC exposure is
not likely to substantially impact efficacy against HCV. Lower BOC exposure was
associated with a reduced incidence of anemia. RBV PK was not collected in the
co-infection study, so it cannot be ruled out that this result is confounded by
exposure to RBV (which is known to influence rate of anemia).
Complementary
and Alternative Medicine
Prospective Randomized Study Comparing
Enhancement of the Antiviral Efficacy between Vitamin D3 (cholecalciferol) and
1α(OH)D3 (alfacalcidol) Administered in Combination with
Pegylated-Interferon plus Ribavirin in the Treatment of Chronic Hepatitis C.
N. Nakayama,
S. Mochida, J. Funyu, ABSTRACT FINAL ID:
798
BACKGROUND AND AIM: Abu-Mouch et al. reported that SVR
ratio increased in patients with chronic hepatitis C when pegylated-interferon
(Peg-IFN) plus ribavirin therapy was done in combination with vitamin D
intake.In their trial, cholecalciferol, non-activated vitamin D3 supplement,
was adopted for the combination therapy, while alfacalcidol, activated
1α-hydroxy (OH) vitamin D3, is generally used for the treatment of
osteoporosis. Thus, wedesigned an intention-to-treat prospective randomized
study to compare the potentiation of antiviral efficacy between cholecalciferol
and alfacalcidol. METHODS: A total
of 45 naïve patients with chronic hepatitis C, genotype 1b and serum HCV-RNA
levels greater than 5Log IU/mL, were enrolled from 10 hospitals. They were
given either of cholecalciferol at a dose of 2,000 IU/day or
alfacalcidol
of 0.5 μg/day for 4 weeks, and then they received Peg-IFNα-2a (180
μg/week) plus ribavirin (600 or 800mg/day) in combination with vitamin D
similarly as was in lead-in therapy for 48 or 72 weeks according to the response-guided
manner. RESULTS: There were 22 and
23 patients, respectively, in the cholecalcidol and alfacalcidol groups.
Demographic and
clinical
features of patients were similar between both groups. Serum levels of 25(OH)D
were increased only in patients in cholecalcidol group during lead-in therapy;
the levels at 4 weeks after the therapy were significantly higher than those in
alfacalcidol group (p<0.001). In contrast, serum 1α, 25(OH)2D levels
were not different between both groups. At present, serum HCV-RNA levels at 12
weeks after the initiation of combined Peg-IFN plus ribavirin therapy
were assessed
in 12 patients in each group, and RVR and cEVR were obtained in 4 (33%) and 8
(67%) patients, respectively, in cholecalcidol group and in 1 (8%) and 6
patients (50%) in alfacalcidol group. Among these, 17 patients(71%) showed
major allele of IL28B SNPs (rs909917), and the decrease of serum HCV-RNA levels
during 4 weeks of the combination therapy was greater in cholecalcidol group
(n=9; 5.08 Log IU/mL) than in alfacalcidol group (n=8; 3.99 Log IU/mL)
(p<0.05).Conclusion: Non-activated vitamin D3, cholecalcidol,
provided superior potentiation of the antiviral activity of Peg-IFN plus
ribavirin than activated 1α(OH)D3, alfacalcidol, especially in patients
with the major allele of IL28B SNPs. Our clinical obser-vations were in line
with the experimental findings obtained using HuH-7 cells (Matsumura T, et al. Hepatology,
in press). Impact of cholecalcidol, as compared with that of alfacalcidol, on
the antiviral therapy forchronic hepatitis C should be further evaluated
through assessment of the SVR ratio.
Extremely low vitamin D levels are
associated with increased mortality in patients with liver cirrhosis. F. Grünhage, M. Krawczyk, C. Stokes, M.
et al. ABSTRACT FINAL ID: 1561
BACKGROUND: Vitamin D serves an important role in
regulating immune response mechanisms, and vitamin D deficiency has been associated
with unfavourable outcomes in patients infected with chronic hepatitis C.
Patients with advanced liver disease frequently suffer from vitamin D
deficiency. However, it remains unknown whether vitamin D deficiency has an
influence on
mortality in these patients. Thus, we prospectively studied a cohort of
patients with advanced liver disease to assess the influence of vitamin D
deficiency on survival. PATIENTS AND METHODS:
Ninety-two patients with liver cirrhosis (mean age, 55 years; range, 19-76
years; 66% males; CTP stage C, 41%) were included in our prospective
single-center survival study. Serum for determination of vitamin D status was
available from 61 patients. AUC analysis, Chi-square statistics and
multivariate binary regression analysis were used to
determine the
optimal cut-off. Vitamin D levels were determined using a chemiluminescence
immunoassay. RESULTS: Median vitamin D levels were 8.2 ng/ml (range <4 ng/ml
– 95.8 ng/ml) Overall, 51% of patients (31/61) died during a minimal follow-up
of 24 months. AUC analysis determined a vitamin D level of 6 ng/ml as optimal
cut-off for discriminating survivors from non-survivors. Kaplan-Meier analysis
of survival confirmed low vitamin D levels as a
significant
predictor of death (p=0.004). Of note, multivariate analysis identified low
vitamin D levels (OR = 6.3; CI: 1.2 – 31.2; p=0.024) and MELD scores (OR = 1.4;
CI: 1.2 – 1.7; p<0.001) as independent predictors of survival. Patients with
low vitamin D levels died more often
from septic
complications (43%) than patients with vitamin D levels > 6 ng/ml (20%).
CONCLUSION: Extremely low serum levels of vitamin D
levels are associated with increased mortality in patients with advanced liver disease.
Infectious complications are more frequent in these patients. We speculate that
a impaired immune function due to vitamin D deficiency may explain this
observation. Further studies in larger cohorts are warranted to replicate this
finding.
PNI and CONUT as Potential Tools for
Nutritional Assessment in Patients with Chronic Liver Disease. E. Taniguchi, T. Kawaguchi, M. Itou,
T. et al. ABSTRACT FINAL ID: 1554
BACKGROUNDS & AIMS: A lot of patients with chronic liver
disease are at risk of malnutrition. Therefore, simple and useful methods of
nutritional assessment are required for ordinary medical care. Prognostic
nutritional index (PNI) and controlling nutritional status (CONUT) are simple
assessments constructed of only two or three biochemical examinations of blood
(albumin, total lymphocyte count, and total cholesterol). We investigated the potential
of PNI and CONUT as a nutritional assessment tool in patients with chronic
liver disease. PATIENTS & METHODS:
We enrolled 165 patients, aged 18–85 years, with chronic liver disease. These
patients were nutritionally assessed by PNI or CONUT, demonstrating the
association with the severity of chronic liver disease or anthropometric values
such as body mass index (BMI), mid-arm muscle circumference (AMC), or triceps
skinfold thickness (TSF). Nutritional status was classified into four degrees
of severity as follows: PNI≥50 or CONUT 0 or 1, no malnutrition;
40≤PNI<50 or CONUT 2–4, mild malnutrition; 30≤PNI<40 or CONUT
5–8, moderate malnutrition; PNI<30 or CONUT 9–12, severe malnutrition. The
severity of chronic liver disease was classified into four degrees as follows: chronic
hepatitis (CH) or liver cirrhosis (LC, Child-Pugh class A, B, and C).
Nonparametric multiple comparisons among the groups were analyzed by the
Kruskal–Wallis test. RESULTS: The
value of PNI was significantly decreased according to the severity of chronic
liver disease (CH 43.4, LCA 41.9, LC-B 33.6, and LC-C 30.0, P<0.001).
Similarly, the value of CONUT was significantly increased (CH 3.3, LC-A 3.7,
LC-B 7.6, and LC-C 8.8, P<0.001). On the other hand, BMI, AMC, or TSF showed
no significant association with the severity of chronic liver disease.
According to the nutritional status assessed by CONUT, the anthropometric values
of BMI (none 25.7, mild 23.0, moderate 22.9, and severe 22.3, P<0.05), AMC
(none 104.4%, mild 99.5%, moderate 96.0%, and severe 92.7%, P<0.001), and
TSF (none 139.7%, mild 110.3% moderate 98.6%, and severe
88.2%,
P<0.001) were significantly decreased. Similarly, the values of AMC (none
108.3%, mild 98.6%, moderate 95.7%, and severe 94.1%, P<0.05) and TSF (none
126.1%, mild 115.2%, moderate 99.9%, and severe 88.2%, P<0.05) were
significantly decreased according to the nutritional status assessed by PNI. CONCLUSIONS: Because PNI and CONUT were
well associated with both the severity of chronic liver disease and anthropometric
values, these are potential tools for nutritional assessment in patients with
chronic liver disease. In addition, these methods would be useful for ordinary
medical care because of their simplicity.
Safety and anti-HCV Effect of Prolonged
Intravenous Silibinin in HCV-Genotype 1 Subjects in the Immediate Liver
Transplant Period. R.
Bárcena, M.A. Rodriguez-Gandía, A. Albillos, et al. ABSTRACT FINAL ID: 210
BACKGROUND: HCV reinfection after liver
transplantation (LT) is the rule in patients with HCV-cirrhosis, and HCV-RNA
reaches pre-LT levels within the first month after LT. Intravenous Silibinin
(iv-SIL) monotherapy has shown a potent in vivo anti-HCV effect, regardless HCV
genotype or IL28B genotype. OBJECTIVE
AND METHODS: To assess the safety and anti HCV effect of prolonged iv-SIL
administration (20mg kg/d) started immediately before LT and maintained
thereafter for at least 21 days in 9 consecutive HCV-LT subjects with
HCV genotype
1 since September 2011, in comparison to a control, non-treated group of 7
consecutive prior transplanted subjects receiving the same immunosuppressive
regimen: Basiliximab (day 0 and 4), Prednisone 20mg/day with progressive
tappering, Tacrolimus started at day 3, micophenolate mofetil (1g bid). RESULTS: Both groups showed similar
baseline features (age, gender, HCC as the indication for LT, HCV-RNA, bilirubin,
AST, ALT, creatinin). All subjects in iv-SIL group showed significant,
maintained and progressive decreases in HCV-RNA levels, with no viral
breakthrough during therapy (Table 1). Mean HCV-RNA drop at week 3 was -4.1±1.3
log10 IU/ml(-2,41; -6.36). Four patients (44%) reached negative HCV-RNA,
maintained during iv-SIL treatment, vs none in the control group, but HCV-RNA
relapsed in all after a median of 20,5 days (16-28) following iv-SIL withdrawal.
There was a trend to lower baseline HCV-RNA levels in patients with HCV RNA
negativization (5.1±0.8 vs
5.7±0.5 log10
IU/ml p=0.1). iv-SIL cases not reaching negative HCV-RNA (iv-SIL-P) showed
marked decreases in HCV-RNA when compared to controls (Table 1). Treatment was
extended to 6 weeks in two iv-SIL cases reaching HCV-RNA negativization after
week 2. There were not clinical adverse effects, and, as reported previously,
iv-SIL produced asymptomatic transient hyperbilirubinemia (week 2, 4.2±2.2 vs
2.5±3.6mg/dl; p=0.02). Acute rejection episodes and analytical post-LT values
were similar in both groups. CONCLUSIONS:
1. prolonged iv-SIL monotherapy led to significant and progressive
decreases in HCV-RNA after LT, with
negativization
in 44%, and no HCV-RNA breakthrough during treatment. 2. this potent antiviral
effect, however, was not able to avoid HCV recurrence after LT. 3. prolonged
iv-SIL was safe, with transient asymptomatic hyperbilirubinemia as the only
analytical effect.
Epidemiology,
Diagnostics, and Miscellaneous Works
Remote rural therapy of Hepatitis C
patients by telemedicine can be facilitated by the use of paired wireless
Bluetooth electronic stethoscopes. A.
Moore, R.A. ABSTRACT FINAL ID: 77
Hepatitis C
therapy is particularly challenging in rural communities, where the resources
and expertise for safe and effective treatment are generally non-existent. Even
when teleconferencing technology is available, the ability to assess and
examine patients on treatment is often not adequate to ensure the safety of the
treatment. Of particular concern is the risk of cardiac and pulmonary
complications, which although uncommon, are potentially severe and life
threatening. The provider can normally evaluate patients for these potential
complications with a careful exam of the heart and lungs. In this study,
Bluetooth® enabled wireless stethoscopes used with a PC-based communication
software were deployed at both the site of the provider and the patients, allowing
the auscultation of the heart and lungs by the remotely linked provider with
exceptional clarity. The study was conducted between the “hub” office of North
Country HealthCare, a federally qualified healthcare clinic in Flagstaff,
Arizona and rural satellites in the northern Arizona communities of
Springerville, Eager, Winslow, Show Low, Holbrook and Kingman. 78 patients were
evaluated as potential candidates for Hepatitis C antiviral therapy and
over the
subsequent 18 months, 25 patients completed the 6 or 12 month course of therapy
with pegylated interferon and ribavirin with telemedicine visits conducted on a
monthly basis. The physical examinations were conducted with the aid of the
(3M™ Littmann®Electronic Model 3200 Stethoscope, a commercially available
digital, cardiology-grade stethoscope with the capacity to record and send
real-time sounds to a computer in the exam room via Bluetooth.
The 3M™
Littmann® Scope-to-Scope Tele-Auscultation System software enabled the
stethoscope signal to be sent in real time from one stethoscope to another via
two computers on the secure network. Support staff in the satellite sites were
trained in the presentation of the patients to the hub provider using the video
network. Initial physician examination auscultation findings were verified by
providers at the satellite sites and were recorded independently.
During
therapy, abnormal auscultatory findings were detected and confirmed in 2
patients, resulting in the ordering of chest radiograms to evaluate for
pulmonary complications.
CONCLUSION: The utilization of electronic
Bluetooth® enabled stethoscopes used with software affords the opportunity to
safely evaluate and treat patients with Hepatitis C antiviral therapy in remote
locations. Patients who otherwise would not have access to specialty care at
this level can benefit by the application of this promising new technology.
The Chronic Liver Disease Questionnaire-
Hepatitis C (CLDQ-HCV): A Sensitive and Valid Health Related Quality of Life
Instrument. A.
Loria, C. Escheik, L. Gerber, et al. ABSTRACT FINAL ID: 937
BACKGROUND: The
biopsychosocial model of health has been shown to have utility as a treatment outcome
measure for patients with chronic liver disease (CLD). The use of patient
reported outcomes (PROs) such as health-related quality of life are important
in natural history and efficacy trials. CLDQ-HCV is a disease-specific health related
quality of life (HRQL) instrument developed for patients with chronic hepatitis
C (CH-C). AIM: To demonstrate
that
CLDQ-HCV identifies significant differences in HRQL between patients with CH-C
and healthy blood donors (BD), and can detect meaningful change in HRQL over
time. METHODS: 162 subjects were
included [62 CH-C and 100 BD]. CH-C patients received PEG-Interferon and
Ribavirin (PEG-IFN+RBV) with duration based on genotype and virologic response.
During treatment, CH-C patients completed CLDQ-HCV questionnaire. Scores are
based on a
Likert
scale from 0 (worst) to 7 (best), and measure Activity/Energy (AEM), Emotion
(EMM), Worry (WOM), Systemic (SYM) and CLDQ-HCV Total score. Clinical data were
also collected. Patients completed CLDQ-HCV questionnaires at baseline, 4, 24
weeks of treatment and 24 weeks follow-up. Baseline and follow-up HRQL scores
were compared to to baseline scores and to scores from BD. A clinically
important difference for CLDQ-HCV scores is defined as
score
change of 0.5. Mann-Whitney U test was performed on demographic and
questionnaire data. RESULTS: The baseline
CLDQ-HCV total score for CH-C patients was 5.7±0.7 vs. 6.2±0.5 for BD
(p<.0001). Domain scores for CLDQ-HCV were also significantly lower for CH-C
patients [Emotional Domain of CLDQ-HCV (EMM): 5.9±0.4 (BD) vs. 5.6±0.6 (CH-C)
(p<.003), Worry Domain (WOM) 6.9±0.2 (BD) vs. 5.7±0.9 (CH-C) (p<.0001)].
During treatment with PEG_INF+RBV, CLDQ-HCV total scores fell rapidly by 4
weeks of treatment (CH-C: 5.4±0.9) and remained low until the end of treatment
(5.68±0.8). All scores improved after discontinuation of treatment and CLDQ-HCV
total score reached 6.3±0.6 at 24 weeks of follow-up. For patients who achieved
sustained virologic response, CLDQ-HCV total
score
was 6.6 which is significantly higher than baseline scores for CH-C and higher
than healthy blood donors. CONCLUSIONS:
The CLDQ-HCV questionnaire is able to distinguish differences between CH-C
patients and healthy BD controls. In addition, CLDQ-HCV is sensitive to change
over time, and demonstrated meaningful clinical change in HRQL in CH-C patients
treated with PIR. This provides additional data for validity of CLDQ-HCV.
Check Hep C: A Demonstration Project
for Providing Comprehensive Community-Based Screening, Linkage and Medical
Services to New Yorkers with or at Risk for Chronic Hepatitis C Infection. A. Jordan, E.J. Rude, N. Johnson, J. et
al. ABSTRACT FINAL ID: 135
BACKGROUND: Hepatitis C virus infection (HCV)
disproportionately affects marginalized and stigmatized populations such as
drug users, the homeless, and immigrants from high prevalence areas, many of
whom lack health insurance and social support and, thus, experience
difficulties accessing and maintaining HCV-related care. To help reduce illness
and death from HCV, the New York City Department of Health and Mental Hygiene
developed the Check Hep C program which includes 1) community awareness, 2)
expanded HCV screening and diagnosis, 3) support to link HCV RNA positive
patients to services, and 4) mentoring and training of community physicians. METHODS: Using Knowledge Translation as
our theoretical framework, Check Hep C was developed to address individual and
structural-level barriers to the implementation of these evidence-based HCV
screening and care practices. RESULTS:
Beginning 5/2012, a diverse set of community partners located in neighborhoods
with excess numbers of reported cases of HCV began collaborating on Check Hep
C. Screening of high risk individuals is conducted in syringe exchange
programs, a drug users' union and federally-qualified health centers (FQHCs).
Each participant with a positive HCV RNA test is assigned to a patient
navigator, who provides HCV education and counseling, assists with enrollment
in benefits programs, accompanies patients to medical appointments, refers
patients to supportive services such as housing and substance use treatment,
and facilitates effective patient-provider communication. Clinical providers at
FQHCs receive in-person and telemedicine mentoring from academic HCV
clinicians. A community-wide electronic medical record has been implemented to
ensure continuity of care starting from initial contact with Check Hep C
program providers; this system will record patient outcomes related to
diagnosis, retention in care and response to treatment. DISCUSSION: Although treatment of HCV can be curative and reduce
morbidity and mortality, many chronically infected individuals remain
undiagnosed and do not receive appropriate care or treatment. Check Hep C seeks
to address these gaps at the community level by increasing the capacity to
screen, diagnose and care for patients with chronic HCV and to coordinate
services within a large urban area where many people are at risk of HCV and
many barriers to care exist.
Hepatitis C population in Germany,
changing over time. D.M.
Klass, H. Hinrichsen, |G. Teuber, et al. ABSTRACT FINAL ID: 958
BACKGROUND AND AIMS: The disease burden of chronic
hepatitis C (CHC) is well known. Treatment advances over the last years with
individualized regimes and very recently with the introduction of protease
inhibitors changed the landscape of hepatitis C treatment. How the hepatitis C
patients characteristics shifted over the course of these treatment advances is
largely unknown. In order to evaluate the change of the CHC population, we retrospectively
analyzed data from three German PegIFN/RBV observational studies. METHODS: Three German-wide,
internet-based, non-interventional studies were assessed in cooperation with
the Association of German Gastroenterologists in private practice (bng) and
Roche (ML17071 and ML19464 from 2002-2007 and ML25724 ongoing from fall 2011).
These real-life cohort studies assessed the safety and efficacy of PegIFN 180
μg/w plus weight-based RBV (800–1200 mg/d) for up to 48 weeks and in
addition assessed screening parameters for patients that were not treated. Until
March 2012, for ML17071/19464 19,115 patients (8563 treated, 10552 not treated)
and for ML25724 1,768 patients (1350 treated, 418 not treated) with CHC were
included. RESULTS: In general,
compared to the two earlier studies (ML17071/ML19464) in the most recent and
ongoing study ML25724 the CHC patients are older, have a longer disease
duration, show more often signs of an advanced disease and have had prior
hepatitis C treatment with a non-response or relapse (Table). Predominant
reasons for decision not to start treatment directly in genotype 1 patients are
patients refusal because of fear of treatment (ML25724 51%, ML17071/ML19464
26%) and decision to treat at some later time point (ML25724 44%,
ML17071/ML19464 14%).
CONCLUSIONS: During the course of at least 5 years,
the German populations with chronic hepatitis C progressed in age, disease
severity and overall parameters that are associated with poor treatment
response. This might be largely accountable to the negative selection of prior
hepatitis C treatment attempts.
Hepatitis E virus infection among
chronic hepatitis C-infected patients: risk factors and clinical outcome. D. Hotho, B.E. Hansen, H.L. Janssen,
R.J. de Knegt. ABSTRACT FINAL ID: 969
BACKGROUND AND AIMS: Acute hepatitis E virus (HEV)
infection is emerging in industrialized countries and can cause severe
hepatitis in immunocompromised patients. Data on prevalence are scarce and the
exact routes of transmission in both immunocompetent and immunocompromised patients
need to be determined. Furthermore, it is unclear if HEV-co-infection, like
hepatitis A virus infection, could lead to worsening of liver disease in
chronic
hepatitis C
virus (HCV) infected patients. We studied prevalence of and risk factors for HEV
infection among chronic HCV-infected patients. METHODS: For our analysis of risk factors, we used a well defined
cohort of chronic HCV-infected patients who were treated with
peginterferon/ribavirin between 2000 and 2009. Patients of whom a pretreatment
serum sample was available were included. Anti-IgM-HEV and anti-IgG-HEV serum
antibody detection was performed using an enzymelinked immunosorbent assay
(Wantai, Singapore). RESULTS: 321 chronic HCV-infected patients were treated
in the study period and 261 patients could be included. Mean age was 45 years
(14-70) and patients were predominantly male (67%), of European origin (72%)
and 59 patients (23%) had cirrhosis. Anti-IgG-HEV was positive in 54 patients
(21%) and anti-IgM-HEV was positive in 1 patient (2%). Following multivariate
regression analysis, older age (OR 1.0, p=0.02), Egyptian origin (OR: 6.3,
p=0.02) and the
absence of
injecting drug use (IDU) (OR 3.0, p=0.02) were associated with positive IgG-HEV
serology. Within European patients, multivariate regression analysis identified
age (OR 1.1, p=0.01) but not non-IDU (p=0.06) as risk factor of positive HEV
serology. Sixteen (27%) patients with and 38 patients without cirrhosis showed
positive IgGHEV serology (p=0.1). Even with correction for age, positive
IgG-HEV serology was not associated with the presence
of cirrhosis
(p=0.6). CONCLUSIONS: Among HCV-infected patients, HEV prevalence is
high (21%) and associated with older age, Egyptian origin and the absence of a
history of IDU. Patients affected do not show chronic HEV co-infection or more
severe liver disease. These risk factors for positive HEV IgG-serology suggest
dietary practices as route for transmission for HEV and contradict the
previously reported risk of IDU for HEV infection.
Hepatitis C infection in Italian Psoriatic
patients: prevalence and correlation with psoriasis severity score. G. Barbarini, A. Perretti, L.
Sangiovanni. ABSTRACT FINAL ID: 973
OBJECTIVES: The incidence of Hepatitis C and
psoriasis in the Western World is respectively 2.6% and 0.8 to 3%. A link
between these two conditions has been recently focused. We evaluated the
prevalence of Hepatitis C in patients with psoriasis and its correlation with
psoriasis severity. METHODS: 184
psoriatic patients were included in our study ; we considered their liver
function data , virological parameters (HCVAb , HCVRNA and genotypes) and PASI
(Psoriasis Area and Severity Index). 2154 healthy subjects from the general
population represented our control group. RESULTS:
We found a higher prevalence of Hepatitis C markers in psoriatic patients than
in healthy subjects (7.7% vs 3.3% p=0,005) ; this prevalence increased with age
in both groups. Psoriatic patients HCVAb positive ,either RNA+, either RNA-,
showed a mean PASI score significantly increased compared to HCVAb negative
ones (11,5±10.2 p<
0,001). In
HCVRNA positive patients we observed onset or worsening of psoriasis during
Interferon pus Ribavirin treatment even if their main PASI score was not
different from that of HCVAb+ RNA+ or RNA- psoriatic patients not receiving IFN
therapy (27.6±16.4 vs20.6±11.6 respectively). CONCLUSIONS: This study shows an association between Hepatitis C
and Psoriasis and emphasizes the role of HCV screening in all psoriatic
patients in order to decide the optimal treatment strategy for both infections.
An important role of HCV infection in the pathogenesis of this skin disease
could be supposed ; in HCV+ patients PASI is more severe than in HCV- ones.
Interferon treatment for HCV infection can trigger the onset of psoriasis or
worsen its symptoms.
Characteristics and Clinical Management
of a Large Cohort of Hepatitis C Patients from a Northern California Integrated
Health Plan. M. Manos, V.
Shvachko, M. Pauly, et al. ABSTRACT FINAL ID: 965
BACKGROUND: The population health perspective on hepatitis
C is evolving rapidly as direct-acting antiviral therapies are introduced and
birth cohort based HCV screening recommendations are implemented. We evaluated
the characteristics and management of a hepatitis C cohort just prior to these
changes. METHODS: We studied adult
chronic hepatitis C patients in the Northern California Kaiser Permanente
Medical Care Program with
health plan
membership for ≥15 months July 2009 - December 2010. Patients with HIV
(2%), chronic HBV (2%) and history of end stage liver disease, hepatoma, or
liver transplant (6%) were excluded. Data were obtained from electronic
records. Care measures were assessed for July 2009-December 2010 (study
window), or as “ever” based on records for 1995-2010. RESULTS: Findings for the 10,809 eligible patients are below. Most
(79%) were baby
boomers born
1945-64, 27% had history of drug abuse. Over 70% were in the health plan for >10
years. Of the 74% with HCV genotype (GT) results, 69% were GT1. Before the
study period, 12% had evidence of sustained virologic response to therapy.
During the period, 73% had a visit for hepatitis care and 5% received
treatment. Patients with specialist (20%) versus primary care (53%) visit(s)
for hepatitis were more likely to receive a comprehensive panel of
liver tests
(61% vs. 25%, p<.0001). CONCLUSIONS:
In this community-based hepatitis C cohort, almost a third had received HCV
treatment, and almost half had a liver biopsy. Many were using psychotropic
and/or opioid prescription drugs. Screening for HAV and HBV was common;
comprehensive liver testing was less frequent. Patients evaluated by a
specialist were most likely to receive liver-specific management. The findings
reveal common comorbidities, as well as opportunities for improved care. Future
studies will determine how new antivirals impact patterns of care, and whether
broader screening will substantially alter the demographic and clinical composition
of hepatitis C patient populations.
Prioritization of Hepatitis C Patients
For Treatment with Direct Acting Antiviral Agents
J. Chhatwal,
M.S. Roberts, |M.A. Dunn, M.S. Roberts, K.B. Chopra. ABSTRACT FINAL ID: 152
PURPOSE: The launch of direct-acting antiviral
agents (DAAs) saw a surge of patients requesting treatment for chronic
hepatitis C who had deferred treatment with peginterferon-ribavirin, which
resulted in waiting lists of patients because of a limit on the number of
patients who could initiate treatment every week. Such waiting lists are also
expected where DAAs will become available in the future or when next-generation
DAAs become available. Our purpose was to formulate need-based prioritization
of patients for treatment with DAAs that would maximize their value to society.
METHODS: We developed a
decision-analytic Markov model that simulated the treatment regimens of the
FDAapproved DAAs and the natural history of hepatitis C disease. Our model’s
states included METAVIR fibrosis score (F0–F4), decompensated cirrhosis (DC),
hepatocellular carcinoma (HCC), liver-transplant (LT), and liver-related deaths
(LRD). We used efficacy data from the registration trials of telaprevir and
boceprevir—ADVANCE, REALIZE, SPRINT-2 and RESPOND-2, and estimated progression
rates of hepatitis C disease from previously published studies. We compared two
scenarios: (1) get immediate treatment; (2) get treatment after 1-year because
of resource scarcity; and projected quality-adjusted life-years (QALYs),
incidence of DC, HCC, LT and LRD per 1000 patients. We evaluated the impact of
wait for treatment by fibrosis stage, previous treatment response (relapse,
partial-response and null-response), IL28B polymorphism, age, and sex. RESULTS: The projected gain in QALYs by
immediate treatment versus receiving treatment after 1-year in a 50-year old cirrhotic
patient who is treatment naïve, prior relapser, partial responder and null
responder were 0.54, 0.71, 0.51 and 0.27, respectively. The corresponding
reductions in the incidence of DC, HCC, LT and LRD per 1000 patients were between
10–24, 12–31, 2–5 and 17–44, respectively. The gains in QALYs by immediate
treatment in cirrhotic patients by IL28B genotype were between 0.52–0.76
(highest in C/C genotype). The gain in QALYs in F0–F3 patients by immediate
treatment was between 0.04–0.07. In addition, the gain in QALYs in younger
patients was higher than that in older patients. CONCLUSIONS: Our recommended prioritization order (from highest to
lowest) by patient characteristics is: (1) Cirrhosis ([a] younger age, [b]
prior relapser, [c] treatment naïve, [d] IL28B genotype C/C, [e] partial
responder [f] others), (2) METAVIR score F3 ([a] younger age, [b] others), and
(3) METAVIR score F0–F2. We provide a need-based prioritization of patients
that is clinically intuitive and will maximize the value of DAAs to society.
Indications for Screening among
Reported Cases of Hepatitis C Virus Infection from Enhanced Hepatitis Surveillance
Sites—United States, 2004–2010. R.
Mahajan, S.J. Liu, M. Klevens, et al. ABSTRACT FINAL ID: 944
OBJECTIVES: Risk-based screening for hepatitis C
virus (HCV) infection has been considered
unsuccessful
in identifying many HCV-infected US residents. Thus, the Centers for Disease
Control and Prevention (CDC) is developing recommendations to screen persons
born from 1945 through 1965, the ‘Baby Boom’ cohort, many of whom are unaware
of their infection. Using 2004-2010 data from four enhanced surveillance sites,
we examined indications for screening by birth cohort (before 1945, 1945-1965,
and after 1965) among reported HCV cases. METHODS:
Cases were determined by positive HCV laboratory markers reported to health
departments. Upon receiving a new report, the health department conducted a medical
chart review of the case to abstract information about demographics and
indications for testing. Information was abstracted using standardized case
report forms designed by CDC. These forms were collected by health departments
to create a surveillance database. RESULTS:
Of 110,223 cases of chronic HCV infections reported during 2004-2010, 74,578
(68%) were in persons born during 1945-1965. Indications for screening were
abstracted for 45,034 (41%) cases; of these, 29,544 (66%) reported at least one
CDC-recommended risk factor as reason for HCV screening. Injection drug use was
the main risk factor reported for persons born in birth cohorts after 1945 (60%
and 80%). For other non-CDC-specified reasons for testing—i.e., factors known
to be associated with increased risk of infection but not specifically
recommended by CDC as reasons for screening-- 40% (17,887/45,034) had a history
of incarceration. Overall, about 78% of all chronic HCV cases reported to CDC
were in the birth cohort from 1945 through 1965 or had either a history of
injection drug use or of incarceration. CONCLUSIONS:
These data support proposed new CDC recommended age-based guidelines for
screening of HCV in the 1945-1965 birth cohort, especially if supplemented by
continued risk-based screening.
Knowledge about Infection is the Only
Predictor of Treatment in Patients with Chronic Hepatitis C (CH-C). Z.M. Younossi, M. Stepanova, M. Afendy,
et al. ABSTRACT FINAL ID: 961
BACKGROUND: HCV is the leading cause of cirrhosis
and liver cancer in the U.S. To potentially reduce the future burden of HCV in
the U.S., the Centers for Disease Control (CDC) has recently recommended “Birth
Cohort Screening” of the U.S. adult population. Furthermore, HCV treatment
regimens with the new Direct Acting Antivirals (DDAs) have better efficacy with
shorter duration of treatment. Our aim was to assess independent predictors of receiving
treatment in a cohort of HCV infected patients. METHODS: The Hepatitis C follow-up questionnaires of the National
Health and Nutrition Examination Surveys (NHANES) conducted between 2001-2010
were used. The NHANES participants who tested positive for HCV RNA were
followed by CDC 6 months after initial testing with questions related to their
awareness of their infection and history or intention to receive treatment. RESULTS: A total of
500 NHANES
participants were tested positive for HCV RNA and attempted to follow-up. Of
these, only 203 had completed the follow-up questionnaire (response rate of
40.6%). Of those, only 101 (50%) knew about their prior knowledge. Furthermore,
only 34 HCV-RNA+ patients (17%) had received treatment while 169 (83%) were not
treated. Possible reasons for not receiving treatment were not seeing a health
professional (26.0%%) or lack of recommendation for follow-up (31.4%), fear of
unpleasant side effects (5.9%), unwillingness to do self injections
(3.0%), high
cost of treatment (7.7%) and hope for a better treatment (2.4%). In
multivariate analysis, prior knowledge about their HCV infection in
HCV-positive individuals was independently associated with receiving routine
care from a doctor or HMO [OR (95% CI)=2.481 (1.087-5.662)] as was higher
income (relative to poverty threshold for that year)
[OR=1.447
(1.077-1.944)]. Furthermore, being male [OR=0.302 (0.126-0.725), being in good
to excellent health [OR=0.368 (0.149-0.912)], and consuming excessive amounts
of alcohol [OR= 0.207 (0.068-0.636)] were all independently associated with the
lack of awareness about being infected with HCV. On the other hand, although a number
of variables (such as health insurance, education, co-morbidities) demonstrated
trends for association with having received treatment, “prior knowledge” about
their HCV infection was the only independent predictor of receiving anti-HCV
treatment [OR: 4.364 (1.618-11.77)]. CONCLUSIONS:
Knowledge about having HCV infection is the only independent predictor of
receiving treatment. Therefore, Birth Cohort Screening of the U.S. general
population could lead to wider identification of HCV and potentially better
management of the future burden of HCV and its complications.
Acoustic Radiation Force Impulse
Imaging for evaluation of antiviral treatment response in chronic hepatitis C. M. Friedrich-Rust, N. Forestier, A.
Gaus, C. Sarrazin, L. Gerber, M. Schneider, G. Dultz, S. Zeuzem, ABSTRACT FINAL
ID: 1375
PURPOSE: Antiviral therapy can stop progression
of liver fibrosis and partially reverse it. Non-invasive methods have not only
shown good diagnostic accuracies for the assessment of liver fibrosis, but have
also shown similar results to liver biopsy for the prediction of long-term
survival. First studies have shown that transient elastography (TE) can be used
to monitor fibrosis after antiviral therapy. Acoustic Radiation Force Impulse
(ARFI)- Imaging is a novel ultrasound-based elastography method which is
integrated in a conventional ultrasound machine
enabling the
combination of elastography and conventional screening ultrasound. The aim of
the present study was to demonstrate a significant difference of ARFI –values
in patients with sustained virological response (SVR) and in patients without
SVR (Non-response/Relapse).
Materials and
METHODS: 98 patients infected with
chronic hepatitis C (mainly with HCVgenotype 1) who received a pegylated
interferon and ribavirin-based regimen and had completed antiviral treatment at
least 6 months ago (47 patients with SVR, 51patients with non-response/relapse)
were prospectively included in the study. All patients received ARFI-imaging,
transient elastography and laboratory evaluation on the same day. RESULTS: Significantly lower ARFI and
TE values were observed for 47 patients with SVR as compared to 51 patients
without SVR
with median ARFI-values of 1.37m/s vs. 2.00 (p=0.0021), and median TE-values
4.9 kPa vs. 11.1 kPa (p<0.001), respectively. CONCLUSION: ARFI-imaging und TE might be useful non-invasive tools
to assess liver fibrosis changes in patients with hepatitis C after antiviral
therapy. Bar diagram of median ARFI values in the overall patient groups and in
the subgroup of patients with SVR and patients with Non-Response/Relapse. The
difference between the two subgroups was statistically significant (p=0.0021).
Medication Use in Patients with Chronic
Hepatitis C (HCV) from a U.S. Commercial Claims Database: Inadequacy of
Prescribing Information for Assessment of Potential Drug Interactions. C.L. Mayer, J.C. Lauffenburger, J.F.
Farley, et al. ABSTRACT FINAL ID: 136
PURPOSE: It is important that practitioners are
adequately prepared to assess CYP3A and P-gp drugdrug interaction (DDI)
potential when initiating triple therapy in patients with HCV. To determine how
frequently practitioners are required to assess DDI potential, the 20 most
frequently filled prescriptions and the most widely used drugs with suspected
DDI potential were identified. Prescribing information was evaluated. METHODS: Chronic HCV patients (ICD-9
070.54, 070.44) ≥ age 18 were identified in a large claims database.
Continuously enrolled patients with ≥1 inpatient or ≥2 outpatient
diagnoses were grouped into yearly cross-sectional cohorts from 2006-2010. Medications
were ordered by number of claims. Drugs with the potential to interact with
boceprevir (BOC) or telaprevir (TVR) were identified from www.hep-druginteractions.org.
One claim per cross-section was required to identify patients with pharmacy
benefit using drugs with DDI potential; drugs with ≥5% use were assessed.
Patients
could
contribute to multiple cross-sections if meeting criteria for multiple years. RESULTS: Of 121,163 patients ≥18
with chronic HCV, 71,584 met the study criteria and 53,461 (79,185
cross-sections) had a pharmacy benefit. Mean age was 51.2 ± 7.5 years; 62.2%
were male. Of the 20 most frequently filled prescriptions, 6 have DDI potential;
4 have clear recommendations for management. Twenty drugs with DDI potential
and ≥5% use were identified. Of these,
approximately
5% are contraindicated with either BOC or TVR; 5% and 15% have recom-mendations
to avoid use for BOC and TVR; 25% and 35% have recommendations to reduce the
dose and/or monitor for BOC and TVR; and 65% and 45% lack a recommendation in
the prescribing information for BOC and TVR, respectively. CONCLUSION: Drugs with the potential to interact with BOC and TVR
are frequently utilized by patients with HCV. Current prescribing information
does not adequately prepare practitioners to assess DDI potential for
approximately half of the drugs they are likely to encounter. These data can
inform more targeted DDI recommendations.
Percent of
population using drugs with DDI potential
zolpidem
17.4* diazepam 7.9
codeine 16.0
bupropion 7.2*
prednisone
15.4 trazodone 7.1
tramadol
14.3* fluconazole 6.8
citalopram
13.5 sertraline 6.4
fluticasone
13.1 clarithromycin 6.1
methylprednisolone
13.0 sildenafil (Viagra) 5.4
alprazolam
11.8* clonazepam 5.3
amlodipine
10.2* simvastatin 5.2
escitalopram
8.1* venlafaxine 5.0
*one of the
20 most frequently filled
Screening for hepatitis C viral
Infection in a tertiary care cancer center. A.
Saxena, P. Mahale, D.P. Kontoyiannis, H.A. ABSTRACT FINAL ID: 970
BACKGROUND: Screening for hepatitis C virus (HCV)
in persons with risk factors can lead to early identification of infected
patients. As a result, risk-based screening is currently recommended by the AASLD/IDSA/ACG
guidelines. There is paucity of information regarding HCV screening in cancer
patients, a group with significant morbidity and mortality. Therefore we sought
to determine the effectiveness of risk factor-guided and birth cohort
screenings for early recognition of HCV infection in a tertiary care cancer
center. METHODS: Patients with
hematological malignancies (leukemia, lymphoma, stem cell transplantation) are
routinely
screened for
anti-HCV antibody (HCVab) at the initial visit to our center. The study group
included all patients with hematological malignancies who tested positive for
HCVab between January 2008 and December 2011. Patients with a known history of
HCV infection prior to screening were excluded. Risk factors were defined per
AASLD/IDSA/ACG guidelines and their identification accuracy was determined
among primary oncologists based on data collected from
medical
records. Following the new CDC recommendation, the number of patients with
positive HCVab born from 1945 through 1965 (“baby boomers”) were identified. RESULTS: Two hundred and fifty-nine
patients with hematological malignancies tested positive for HCVab on routine screening
during the study period. The exclusion of those with a history of HCV left a
subgroup of forty-nine patients who were further analyzed. Only 10 (20%) of 49
patients were identified with at least one risk factor by the primary oncologists.
Most patients [33/49 (67%)] with new HCVab were born from 1945 through 1965.
The majority [37/49 (76%)] of patients analyzed either fell inside the birth
cohort or had an identifiable risk factors for HCV. CONCLUSION: A targeted risk-based screening program for recognition
of HCV might be suboptimal in cancer centers. Relying on a patient’s history
alone may not be adequate enough to identify patients with serological evidence
of HCV. However, future implementation of a policy that integrates assessment
of HCV risk factors and birth cohorts screening likely will improve the
detection rate of HCV.
Molecular and Epidemiological Profiles
of Hepatitis C Virus in Mainland China. W.
Ju, S. Yang, Q. Wang, H. et al. ABSTRACT FINAL ID: 941
Determination
of HCV genotype is significant for the prediction of response to anti-viral
therapy and duration of treatment. This is an epidemiological study of patients
infected chronically with HCV in mainland China. A total of 853 HCV RNA
positive serum samples were collected from chronic HCV infected patients from
23 administrative units in mainland China during 2009.10 - 2011.6. The serum
samples were subjected to RT-PCR followed by direct DNA sequencing and
phylogenetic analysis of NS5B and/or CORE-E1 regions. HCV genotypes were
available in 811 samples [95.1% (811/853)]. The results indicated new trends of
HCV infection in mainland
China.
Phylogenetic analysis revealed that genotype 1, 2, 3 and 6 were detected. No
genotype 4 and 5 strains were found. The distribution of HCV subtypes was 1b,
2a, 3a, 6a, 3b, 6n, and 1a at frequencies of 73.1%, 18.5%, 3.2%, 2.5%, 1.8%,
0.5%, and 0.4%, respectively. HCV subtype 1b was the most frequent in mainland
China followed by 2a. The HCV genotype distribution differed according to the
patients’ region of origin and genotypes 3 and 6 represented an increasingly
wide range of geographic distribution. Patients infected with HCV subtype 1b
and 2a were found statistically older than those infected with 3a, 3b, 6a and
6n, respectively. Blood transfusion was the main route of transmission. IDUs and
tattooing / piercing were more common among patients with genotype 3 compared
with those with genotype 1. This study is the largest report of molecular
epidemiology of HCV in mainland China and demonstrates a genetic heterogeneity
of HCV infection, with at least four HCV genotypes and seven subtypes. Clinical
trials of
direct anti-HCV agents (DAA) should consider this genetic heterogeneity.
Screening for HCV based on traditional
risk factors in foreign-born communities in NYC misses many infected persons. P. Perumalswami, S.H. Factor, L.
Kapelusznik, et al. ABSTRACT FINAL ID: 938
An Institute
of Medicine Report in 2010 focused on the unmet need to identify persons with
chronic viral hepatitis. At least 10% of persons with chronic HCV do not fall
within the current high-risk groups with traditional risk factors (TRF) for
screening. The NHANES III data suggests that HCV prevalence is highest in US
residents born from 1945 to 1964 and is likely to be added to current TRF
screening guidelines by the Centers for Disease Control (CDC). METHODS: In May 2009 we started
Hepatitis Outreach NEtwork (HONE), a viral hepatitis screening and linkage to
care program targeting foreign-born communities at risk for HBV & HCV. HONE
coordinated efforts with community organizations and the NYC Dept of Health to
offer hepatitis teaching sessions and screening. All participants provided consent
and testing included HCV Ab. All HCV+ participants were invited for a free
follow-up visit. Patient navigators linked participants to care. RESULTS: HONE conducted 25 didactic and
screening events from May 2009 to July 2011. Of 1,647 persons screened, 1,603
(97%) consented. The median age was 51, 54% were women, and participants were
born in 68 countries. Compared to US population estimates, the study sample had
a lower percentage of high school graduates (54% vs. 87%), lower median
household income (<$15K vs. $49K) and lower percentage of health
insurance
(44% vs. 83%). In univariate analysis of TRF for HCV, injection drug use, HIV,
and prior blood transfusion were significantly associated (p < .05). If we
had screened for HCV in persons with TRF rather than all patients, only 25
(33%) of the 75 HCV+ persons would have learned of their infection. If we had
screened for HCV in persons with TRF and/or persons who were born from 1945 to
1964, only 49 (64%) of the 75 HCV+ persons would have been
diagnosed. If
we had screened for HCV in persons with TRF and/or persons who were born from
1945 to 1964 and/or persons born in countries with prevalence of HCV >3%, 61
(82%) of the 75 HCV+ persons would have been diagnosed. Thirty-two (42%) HCV+
attended a follow up visit. Given the anticipated approval of direct acting
antivirals, 3 were recommended to start treatment and 2 have started. CONCLUSION: This study supports the
addition of CDC’s proposed birth cohort screening to TRF screening for HCV.
Screening for HCV in foreign-born communities is
currently not
practiced. HONE data supports the IOM’s recommendation to consider screening
persons born in Egypt and supports targeted screening in persons born in
countries with high HCV prevalence. The study also underscores the persistent
challenges in ensuring follow up in patients who need further evaluation and
treatment.
Mortality in Status 7 Patients: The
Dark Side of the Liver Waiting List? Y.
Lee, A.M. Allen, W. Kim, et al. ABSTRACT FINAL ID: 41
BACKGROUND/AIMS: Waitlist mortality is one of the most
widely publicized parameters for effectiveness of organ allocation and
distribution policies. Under the current liver transplant (LTx) policy, when
patients are considered temporarily unsuitable for LTx, they are designated as
inactive (‘status 7’). While a large number of individuals belong in status 7
at any give time, the impact of their status on waitlist mortality is not well
known. METHODS: All adult primary
LTx candidates with end stage liver disease registered on waiting list from
January 2005 to
December 2008
were identified in the Organ Procurement and Transplantation Network (OPTN)
data. Patients with a diagnosis of hepatic malignancies were excluded. Patients
were followed forward in time tracking status changes as well as waitlist
deaths. RESULTS: Out of a total of
14,178 waitlist registrants that met the eligibility criteria, 4,095 (29%) were
made status 7 at
least once
while waiting. We divided the status 7 registrants into two groups: those made
inactive with MELD ≦25
and those with MELD >25. The latter is thought to be enriched with patients
too sick to transplant, whereas the former is unlikely to include a large
number of those patients. In the table, the majority of status 7 patients had
low MELD. There was no striking difference in the distribution of diagnosis. As
expected, the prevalence of ascites and hepatic encephalopathy was higher in the
high MELD group. While survival at 1 year was significantly higher in the low
MELD group, more deaths occurred in the low MELD group than the high MELD
group. Out of the total 4,313 waitlist deaths, 40% (n=1,729) occurred in the
status 7 group, of which majority was in the low MELD group (n=1,218). CONCLUSION: Many LTx recipients become
status 7 after waitlist registration. A large proportion of waitlist deaths
occur in status 7, a majority with a low MELD. While all death on waitlist
represents a tragedy, mortality statistics may need
to be
adjusted to exclude patients who are made inactive without real intention for
reactivation.
Pain, Narcotic Use, and Healthcare
Utilization in Chronic Liver Disease. S.
Rogal, ABSTRACT FINAL ID: 138
PURPOSE: Recent attention has been focused on
risk factors for high healthcare utilization among patients with cirrhosis, but
pain, narcotic use, and psychiatric symptoms have not been evaluated in these
models. METHODS: A consecutive
sample of 1286 patients with chronic liver disease being seen in an outpatient
hepatology clinic was assessed by retrospective chart review. Number of clinic
visits, phone calls, and hospitalizations over a 6-month period were collected.
Pain was assessed by numeric pain scale. The association of pain and narcotic
use with
number of
patient phone calls to clinicians or clinic visits was assessed first with
t-tests and then with linear regression using stepwise backwards elimination.
Chi-square testing and logistic regression models using stepwise backwards elimination
were used to determine associations of pain and narcotic use with hospital
admission. Models evaluated demographics, history of substance abuse,
psychiatric symptoms, and stage, symptoms, and etiology of liver disease
as potential
confounders. RESULTS: Over a 6-month
period, hospitalization was more common among patients with pain (13% vs. 7%,
p<0.0001) and narcotic use (18% vs. 6% p<0.0001). Pain and narcotic use
were independently and significantly associated with median number of clinic
visits and phone calls (p<0.0001). In multivariate modeling, hospitalization
was significantly
associated
with narcotic use (OR=2.80, p<0.0001), older age (OR=1.02, p=0.02), Child’s
C cirrhosis (OR=4.14, p<0.0001), emotional dysfunction (OR=1.00,
p<0.002), and ascites (OR=2.98, p=0.004). In multivariate modeling, subjective
complaints of body pain and narcotic use were significantly associated with
number of phone calls and clinic visits, as were hepatitis C, nicotine history,
advanced cirrhosis, and functional impairment related to emotional
distress.
Other factors associated with number of clinic visits included unmarried
marital status and non-white race, while number of phone calls was
significantly associated with ascites and female gender. CONCLUSIONS: Psychiatric symptoms and the presence of pain were
significantly linked to healthcare utilization among patients with cirrhosis
and suggest that psychiatric care and pain management should be part of
comprehensive medical treatment. Given the association of narcotic use with
subsequent hospitalization and healthcare utilization
while
controlling for these other factors, a narcotic-sparing pain management regimen
may be optimal in chronic liver disease.
Optimal noninvasive markers for fibrosis
stage in chronic hepatitis C. M.
Lu, L. Lamerato, S.C. Gordon et al. ABSTRACT FINAL ID: 1015
PURPOSE: Several non-invasive, serum-based
biomarkers of fibrosis have been developed and
validated for
chronic hepatitis C (CHC) under controlled conditions within relatively small,
treatment naïve CHC cohorts. Our analysis sought to validate three of those
markers, APRI, FIB-4, and AST/ALT ratio, in a cohort of both treated and
untreated CHC patients from four HMO Research Network health systems enrolled in
the Chronic Hepatitis B & C Cohort Study (CHeCS), utilizing biopsy and
laboratory data collected during routine care. METHODS: Liver biopsy results and lab values for aspartate
aminotransferase (AST), alanine aminotransferase (ALT), and platelet count were
abstracted from electronic medical records. Fibrosis scores from different
scoring systems (IASL, Batts Ludwig, Metavir, Ishak, Knodell, Scheuer) were
mapped to an F0-4 equivalent scale. Among biopsied patients, APRI
(AST-to-platelet ratio-index), FIB-4 (based on age, ALT, AST, and platelet
count), and AST/ALT ratio were imputed based on lab results collected within 7
days of each other and within 6 months of the biopsy. Logarithmic
transformation was applied to normalize the APRI, FIB-4, and AST/ALT ratio
distributions. For each of the three markers, analysis of variance (ANOVA) was
conducted to detect significance of overall effect, followed by pairwise comparisons
between fibrosis levels if an overall effect was detected at p<0.05. The
predictive ability of each marker to differentiate advanced fibrosis (F3-F4)
from absent-to-moderate fibrosis (F0-F2) was measured by the area under the
receiver operating characteristics curve (AUC). Nonparametric Mann-Whitney U
test was used test for
significant
differences between AUCs. RESULTS:
We identified 2202 patients with available biopsy and lab values for imputing
APRI, FIB-4, and AST/ALT ratio. Median age at biopsy was 50 years and the
fibrosis stage distributions were: 11%(F0), 22%(F1), 28%(F2), 18%(F3) and 21%(F4).
For each biomarker, the mean was significantly higher for each successive
fibrosis level from F0 to F4 (p<0.05), with the exception of the difference
between the F3 and F4 levels for AST/ALT ratio (p=0.11). The AUCs and their
95%CIs in distinguishing severe fibrosis (F3-F4) from absent-to-moderate
fibrosis (F0-F2) were: 0.78 (0.76,0.80) for APRI, 0.82 (0.80,0.84) for FIB-4,
and 0.64 (0.62,0.67) for AST/ALT ratio. There was a significant difference
between the AUCs of FIB-4 and APRI, and between APRI and AST/ALT ratio. CONCLUSION: In a large observational
cohort study of both treated and untreated CHC patients, FIB-4 was superior to APRI
or AST/ALT ratio at distinguishing severe fibrosis from absent-to-moderate
fibrosis.
Diagnostic Performance of a Rapid
Magnetic Resonance Imaging Method of Measuring Hepatic Steatosis. M.J. House, T.G. St. Pierre, E.K. Gan, et
al. ABSTRACT FINAL ID: 1482
BACKGROUND AND AIMS: Hepatic steatosis is associated with an
increased risk of developing serious liver disease and other clinical sequelae of
the metabolic syndrome. However, visual estimates of steatosis on histological
sections are subjective and reliant on an invasive procedure with associated
risks. The aim of this study was to test the ability of a rapid magnetic
resonance
imaging (MRI) method to diagnose clinically relevant grades of hepatic
steatosis in a cohort of patients with a variety of liver diseases. METHODS: Sixty-two patients with a
range of liver diseases underwent liver biopsy and MRI. There were 19 cases
with NASH, 17 with hepatitis B or C, 9 with NAFLD, 4 with autoimmune hepatitis,
4 with primary schlerosing cholangitis, and 3 with alcoholic liver disease.
Hepatic steatosis was quantified firstly using an opposed-phase, in-phase
gradient echo, single breath-hold MRI methodology and secondly, using liver
biopsy with visual estimation by a histopathologist and by computer-assisted
morphometric image analysis. The area under the receiver operating
characteristic (ROC) curve
was used to
assess the diagnostic performance of the MRI method against the biopsy
observations. RESULTS: Our MRI
approach had high sensitivity and specificity at all hepatic steatosis
thresholds (Table 1). Areas under ROC curves were 0.963, 0.993, and 0.975 at
the NASH CRN thresholds of 5%, 33%, and 66% liver fat, respectively. MRI measurements
were strongly associated with visual (r2 = 0.84) and computer-assisted
morphometric (r2 = 0.84)
estimates of
hepatic steatosis from histological specimens. CONCLUSION: The proposed MRI approach, using a conventional, rapid,
gradient echo method, has high sensitivity and specificity
for
diagnosing liver fat at all grades of steatosis, irrespective of the underlying
liver disease.
Implementation of the First Department
of Veterans Affairs Specialty Care Access Network - Extension of Community
Healthcare Outcomes (SCAN-ECHO) Program for Chronic Liver Disease G.L. Su, H. McCurdy, A.W. Tai, K.R. et
al. ABSTRACT FINAL ID: 134
BACKGROUND: Chronic liver disease continues to be
a major problem, with the number of veterans carrying the diagnosis of HCV
cirrhosis doubling over the last decade. Primary care providers have limited
access to specialists in liver disease, yet are faced with the burden of care
for these complicated patients. With the goal of improving access to specialty
care, particularly from rural and underserved areas, the VA Ann Arbor
Healthcare System, as part of the national Specialty Care Transformation
Initiatives, implemented the first SCAN-ECHO program
in chronic
liver disease. We modified the method used by Project ECHO, merging case-based
distance learning with co-management of care for delivery within the VA health
system.
METHODS: Using the electronic consult system, we
re-routed cases submitted to the general Liver clinic to Liver SCAN-ECHO
clinics after obtaining permission from primary care providers. The Liver
SCAN-ECHO clinic occurred via dedicated video-teleconferencing with multiple
site participation and consisted of both case-based learning, in which primary
care providers interacted with the specialists and received immediate
consultation for the patients, as
well as a
short didactic session on a liver specific topic. The entire clinic was
eligible for continuing medical education credit. Data from these clinics were
prospectively collected.
RESULTS: From the period of June 2011 to May
2012, 36 clinics were held. 153 patients were “seen” in this manner with 136
"new" patients and 17 "return" patients. 43 primary care
providers participated from 16 sites. These included 4 VA medical centers and
their community based outpatient clinics (CBOC). The most common diagnoses were
chronic hepatitis C infection, nonalcoholic fatty liver disease, and cirrhosis.
The average patient would have traveled
187 miles
round-trip (range 14 - 484 miles) to Liver clinic. As a result of the SCAN-ECHO
clinic, 28,597 miles of patient travel were saved. Post session evaluations by
primary care providers rated the conference. On a scale of 1 to 4 where 1 was
“not at all” and 4 was “very much”, primary care providers rated the question
of whether the conference addressed “how to implement ideas” at a mean of 3.93
and whether the conference was “relevant to my practice” at a mean of 3.93 (n=
83 evaluations).CONCLUSION: In
summary, we demonstrated the feasibility of implementing this innovative model
of care for patients with chronic liver disease within the VA health system. In
our preliminary assessment, this appears to be a highly
effective method
to decrease veteran travel and increase provider competency.
What Factors Explain Excess Risk of
Death among Black Liver Transplant Recipients?
N. Lauder, L.
Boulware. ABSTRACT FINAL ID: 179
BACKGROUND: Factors explaining well-documented
disparities in graft failure among Black liver transplant recipients compared
to recipients of other ethnicities have been poorly explored.
METHODS: We examined differences in graft
failure among black and white and other ethnic deceased donor liver transplant
recipients in UNOS during the post-Model of End Stage Liver Disease (MELD) era
(Jan2003-Jan2009). We explored the factors contributing to blacks’ excess
hazard of graft failure in time-to-event models, sequentially adjusting for
demographic (age, gender), insurance status, and transplant-related factors
recipient diagnosis, MELD score, HLA mismatch number. We also explored the role
of donor age, gender and ethnicity as potential risk factors. RESULTS: Among 12,727 total recipients,
blacks (n=1092) were younger than whites (n=9530) and others (n=2105) (mean
age: 50.3, 53.0 and 53.1, respectively, both p<.001), had fewer HLA matches
(% of 6 matches: 8.9, 16.8, and 14.3, respectively, p<.001) and were more
likely to be diagnosed with Hepatitis C (% diagnosed = 33.0, 29.0, and 28.0,
respectively, p<.01). Before adjustment, blacks had nearly 60 percent
greater hazard of graft failure compared to whites (HR [95% CI]: 1.58
[1.32-1.89], p<.001) while graft failure for others did not differ from
whites (1.04 [0.88-1.22], p>.05). In a nested model, recipient age accounted
for 5.7% of the excess risk among blacks. Adjusting for donor characteristics,
greater donor age and ethnicity was associated with increased risk of graft
failure. There was an increase risk of failure for recipients with donors
greater than age 30 (HR [95% CI]: 1.48 [1.28-1.72], p<.001) and greater than
age 60 (HR [95% CI]: 2.43 [2.03-2.91], p<.001) compared to those with donors
<30 years of age. Recipients with Latino donors had an increased risk of
failure compared to those with white donors. Having a black donor was not
associated with increased risk nor was ethnicity mismatch between recipient and
donor. Further, level of HLA mismatch was not associated with increased risk.
Donor characteristics and/or mismatch did not account for the observed excess
risk among blacks. CONCLUSION: We
identified an excess risk of graft failure among blacks in a large nationally
representative sample. Older age and having an older, Latino donor were
additional risk factors. However, no factors measured in this study could
account for excess risk among blacks. Studies exploring social, behavioral and
biological mechanisms underlying disparities in transplant outcomes are
warranted.
Clinical Presentation of Chronic Liver
Disease in Germany: Role of Etiology, Age and Gender. A. Tromm, |J. Petersen, P. Buggisch, et al ABSTRACT
FINAL ID: 776
BACKGROUND: Many patients (pts) with chronic liver
disease are asymptomatic or may have nonspecific symptoms such as fatigue in
the absence of hepatic synthetic dysfunction. Information regarding the
presentation of chronic liver disease in Germany is still scarce. We
investigated the frequency of asymptomatic and symptomatic presentations of
chronic liver disease according to HCV status, gender and age. METHODS: Based on ALT/AST
screening
between 12/2008 and 12/2010, 3161 pts with elevated liver enzymes were identified
by 19 German hospitals and gastroenterological practices. Clinical
presentations by symptoms (e.g. fatigue, pruritus) were retrospectively
analyzed by gender, age and HCV status. Only pts with information on HCV status
were included. Patients with liver cirrhosis were excluded from the analysis. RESULTS: Of 2400 pts with chronic liver
disease N=1018 had chronic HCV infection while N=1382 suffered from
HCV-negative chronic liver disease (NASH: N=699; alcohol: N=157; hepatitis B:
N=143; autoimmune: N=80; PBC/PSC: N=62; genetic/metabolic: N=105; other:
N=136). Liver disease was asymptomatic in 42.7% and 43.4% of pts with/without
HCV and declined from 45.3% and 47.7% to 37.1% (p=0.013) and 31.9%
(p<0.0001) in pts <50 years / >50 years. Fatigue was the most common
symptom in both groups with a higher frequency of 49% compared to 34.7% in pts
with/without HCV (p<0.001) and increased only
slightly with
increasing age from 46.7% and 35.8% (<50 years) to 54.4% (p=0.02) and 40.6%
(>50 years; p=0.10). In contrast, pts without HCV showed a 2-fold higher
frequency of abdominal pain/discomfort (26.4%) compared to HCV patients (13.2%,
p<0.0001) with a maximum of 34.2% in pts >50 years. In both groups the
frequency of above symptoms together with pruritus and weak concentration did
not differ between females and males while arthralgia
was more
frequentin females than males with HCV infection (6.5% vs 2.9%, p<0.01).
CONCLUSIONS: The present study demonstrates a high
frequency (>40%) of asymptomatic chronic liver disease in the German
population. The frequency of symptoms seems to be determined by etiology of
liver disease and age rather than by gender. Our results confirm a particularly
high prevalence of fatigue in pts with chronic HCV infection.
Limiting Donors to Those of Younger Age
in Hepatitis C infected Liver Transplant Recipients Does Not Increase Wait-list
Time, Drop-out or Death. J.A.
Flemming, C. Freise, F.Y. Yao, et al. ABSTRACT
FINAL ID: 8
BACKGROUND: Donor age (DA) is the single most
important donor factor influencing disease
severity and
graft loss in liver transplant (LT) recipients with hepatitis C (HCV). With the
goal of improving HCV outcomes, our institution actively restricted DA in HCV
candidates to 50 years of age or less starting October 1, 2009. AIMS: To determine whether this
practice of restricting DA among HCV candidates increased time on the waitlist
(WL) or increased WL death/drop-out. METHODS:
Patients listed for LT at our center between March 1, 2002 and
December 31,
2011 were identified using the United Network for Organ Sharing database. Three
different time periods were compared to reflect events prior to and after DA
restriction: Era 1: March 1 2002 – December 31, 2005 (DA risk unrecognized),
Era 2: January 1 2006 – September 30, 2009 (no specific policy), and Era 3:
October 1, 2009 – December 31, 2011 (DA restriction policy). Risk of WL
death/drop-out according to the date of listing was examined using competing
risks (CR) regression. Post-transplant survival was assessed with Kaplan Meier analysis.
RESULTS: 1,145 patients (median age
56 yrs, 72% male, 8% African-American, 20% HCC exception) with HCV were listed
for LT during this time; Era 1=518, Era 2=371, Era 3=256. 480 patients with HCV
underwent LT during the observationperiod. Median donor age decreased
significantly by Era, but median WL days did not change significantly in those
transplanted
(table). Moreover, the sub-hazard for WL death/drop-out was lower in Eras 2 and
3 vs. Era 1, after adjusted for age, sex, HCC exception and MELD at
listing,(table). Two-year post-LT survival was high, without significant
differences between Eras (table). CONCLUSION:
Our practice of DA restriction is not associated with significantly longer WL
time, nor does it increase WL death/drop-out. Although we have not seen a
change in post-LT
mortality
with this policy, longer post-LT follow-up is needed before the true effect of
DA restriction can accurately be estimated.
Liver
Cancer
Incidence of hepatocellular carcinoma
in precirrhotic and cirrhotic chronic B and C hepatitis: Systematic review with
data from 39 trials and 10.231 patients. M.
Thiele, L.L. Gluud, E.K. Dahl, et al. ABSTRACT FINAL ID: 524
INTRODUCTION: Chronic hepatitis B and C increases
the risk of developing hepatocellular carcinoma (HCC). METHODS: We performed a systematic review on the incidence of HCC
in treated and untreated patients with chronic hepatitis B and C in randomised
controlled trials, prospective cohorts and case control series. Electronic and
manual searches were combined (last update May 2012). HCC person-time incidence
rates/100.000 person years were calculated with 95% confidence intervals using
person years as the exposure variable and assuming a Poisson distribution for registered
events (cases of HCC). Subgroup analyses in which patients were stratified by
antiviral therapy and cirrhosis were performed. Calculations were performed in
STATA version 11 (StataCorp, TX, USA). RESULTS:
In total 10.231 patients from 39 trials and studies were included (randomised
controlled trials, n=14 and prospective
cohort and
case control studies, n=24). Among patients with hepatitis B, 3909 received
antiviral therapy (interferon and/or nucleos(t)ides) and 3125 were controls
(untreated). Among patients with hepatitis C,1804 received treatment (interferon
alone or with ribavirin) and 1393 were controls (untreated). The HCC incidence
in chronic hepatitis B was 757/100.000 person year in treated patients (95% CI
635-895; five year incidence 3.7%) and 1460/100.000 person year in untreated
patients (95% CI 1289-1649; five-year incidence 7.1%). In subgroup analyses of
patients with cirrhosis, the incidence rates were 2120/100.000 (95% CI
1573-2795; five year incidence 10.2%) for treated and 2763/100.000 person year
(95% CI 2376-3194; five year incidence 13.1%) for untreated patients. Patients
with chronic hepatitis C had a high risk of developing HCC. The HCC incidence
was 1988/100.000 person year for treated (95% CI 1709-2299; five year incidence
9.6%) and 3101/100.000 person year for untreated (95% CI
2694-3553,
five year incidence 14.6%). In subgroup analyses of patients with cirrhosis and
chronic hepatitis C, the HCC incidence was 2687/100.000 person year in treated
(95% CI 2261-3172, five year incidence 12.7%) and 4655/100.000 person year in
untreated patients (95% CI 3941-5463; five year incidence 21.2%). CONCLUSION: Chronic hepatitis B
patients without cirrhosis carry a low risk of HCC and the value of
surveillance can be questioned. The risk is almost 100 fold in patients with
cirrhosis and chronic hepatitis B. Both treated and untreated patients with HBV
and HCV cirrhosis has a substantial risk of HCC.
Efficacy and safety of hepatic arterial
infusion chemotherapy in patients with advanced hepatocellular carcinoma. T. Yamashita, T. Terashima, K. Arai, H.
et al. ABSTRACT FINAL ID: 577
BACKGROUND: In Japan, hepatic arterial infusion
chemotherapy (HAIC) has been used to patients with advanced hepatocellular carcinoma
(aHCC). In our department, interferon (IFN)-combined 5-fluorouracil (5-FU)
continuous HAIC has been positively introduced to in aHCC. We analyzed efficacy
and safety of IFN-combined 5-FU continuous HAIC retrospectively.
METHODS: Consecutive patients with measurable
histologically or radiologically confirmed aHCC (major vascular invasion and/or
bilobular multiple ≥5 nodules) were treated with following protocol:
continuous 5-FU HAIC (300mg/m2 day1-5, day8-12) and IFN (IFN alpha-2b 3M IU,
intramuscularly, 3 times per week for 4 weeks or pegylated IFN-alpha-2b
1.0μg/kg,
subcutaneously,
every week for 4 weeks) was administrated with or without cisplatin (CDDP
20mg/m2 or DDP-H 18.8mg/m2, day 1, day 8). The treatment cycles repeated for 6
weeks with 2 weeks rest. Response rate (RR), tumor control rate (TCR), median
survival time (MST), progression free survival (PFS) adverse events and
factorial analysiswere performed. RESULTS:Two
hundred thirty three patients (80% male, median age 65 yrs., 55% Child-Pugh
class A, 35% Child-Pugh class B, 54% Hepatitis C, 66% recurrence, median tumor
diameter 39 mm, 47% macroscopic vascular invasion, 18% extrahepatic spread)
were enrolled. In all patients, RR was 27% (CR 5%, PR 22%) and TCR was 55%.
Combination of CDDP increased RR but statistically insignificant (30.6% vs.
22%, p=0.16). Child-Pugh class was not affected to RR
(class A 33%
vs. class B 26%, p=0.29). MST and PFS in all patients were 10.7 months and 3.2
months, respectively. MST of Child-Pugh class A patients was not differ to that
of Child-Pugh class B (13.0 months vs. 9.1 months, p=0.15). PFS was also not
different (4.3 months vs. 3.7 months, p=0.23). Factorial analysis
(multivariate) revealed tumor diameter<5cm and albumin≥3.5g/dL as
factors to predict RR. Moreover, ECOG-PS 0, macroscopic vascular invasion absent,
distant metastasis absent, albumin≥3.5g/dL and AFP<400ng/mL were
revealed as prognostic factors. Most frequently treatment induced Grade 3/4
adverse events (AEs) were hematological toxicity (thrombopenia 32%, neutropenia
31%, anemia 6%) and non-hematological toxicity (liver dysfunction 13%, nausea
11%, malaise 3%), but these AEs were controllable. CONCLUSION: HAIC using IFN and continuous infusion of 5-FU was
effective to aHCC even in impaired hepatic reserve, Child-Pugh class B
patients. This HAIC should be selected to intrahepatic aHCC patients who failed
to sorafenib therapy because of adverse events or insufficient efficacy or
patients who is inadequate to sorafenib therapy.
Disease Presentation and Treatment in
Patients with Hepatocellular Carcinoma (HCC) Associated with Hepatitis B Virus
(HBV/HCC) and Patients with Hepatitis C Virus Associated HCC (HCV/HCC) J.M. Wantuck, P. Lee, N.B. Ha, et al. ABSTRACT FINAL ID: 524
PURPOSE: Both HBV and HCV infection are common
causes of HCC and each has distinct
epidemiology
and clinical characteristics. HBV/HCC and HCV/HCC patients may also differ but
data on this is limited. METHODS: A
retrospective study was conducted to examine clinical characteristics of 1,110
consecutive patients seen between 01/1991 and 10/2011 at a U.S. university
hospital with HBV/HCC (n=415) or HCV/HCC (n=695). RESULTS: Patients in both groups were similar in age (60±11years)
and gender distribution (79% male). The majority
(87%) of
HBV/HCC patients were Asian though 32% of HCV/HCC patients were also Asian
(p<0.0001). HCV/HCC patients were more likely to have cirrhosis as compared
to HBV/HCC (94% vs. 58%,p<0.0001). With regard to cancer staging, more
HCV/HCC patients presented with stage A (46% vs. 41%,p<0.0001), while a
larger proportion of HBV/HCC patients presented with Stage C/D disease (27% vs.
14%,p<0.0001) (Figure 1). Likewise, HBV/HCC
patients were
less likely to meet Milan criteria (36% vs. 47%,p<0.0001). Compared to
HCV/HCC patients, HBV/HCC patients were more likely to get partial hepatic
resection (26% vs. 9%,p<0.0001) and less likely to undergo liver transplantation
(LT) (6% vs. 15%,p<0.0001). On multiple logistic regression also inclusive
of gender and MELD scores, negative predictors for LT were older age (OR=0.93,
p<0.0001) and higher BCLC scores (OR=0.78,p=0.001)
while
positive predictors were cirrhosis (OR=21.4, p=0.004) and non-Asian ethnicity OR=2.5,p=0.002).
HCV is not an independent predictor for LT (OR=1.11,p=0.76). One-quarter of
patients in both groups received only supportive care (25%). CONCLUSIONS: HBV/HCC patients presented
with more advanced HCC though only half had cirrhosis. HBV/HCC patients were
more likely to undergo hepatic resection but much less likely to undergo LT.
Non-Asian ethnicity was a significant independent predictor for liver
transplantation on multivariate analysis. Additional studies are needed to study
factors contributing to the lower rate of LT in Asian HCC patients and high
rate of supportive-care only patients in all groups.
Predictive factors for the development
of hepatocellular carcinoma in chronic hepatitis C following sustained
virological response to interferon therapy. M.
Kurosaki, N. Izumi ABSTRACT FINAL ID: 998
BACKGROUND AND AIMS: Sustained virological response (SVR)
to interferon (IFN) therapy could decrease the incidence of hepatocellular
carcinoma (HCC) in chronic hepatitis C. However, HCC still develop in some patients
after achieving SVR. The aim of the present study was to define risk factors
for development of HCC following SVR. METHODS:
This was a nationwide multicenter study conducted by Japanese Red Cross Liver
Study Group, involving 18 hospitals and medical centers. A total of 778
genotype 1b chronic hepatitis C patients who had SVR to IFN therapy from 1992
to 2009 were enrolled. Patients with past history of HCC were excluded. Median
period of follow up was 5.7 years. RESULTS:
The cumulative incidence of HCC was 0.9 % in 1-yr, 3.7 % in 3-yr, 6.5 % in
5-yr, and 10.9% in 7-yr, respectively. Cox regression analysis showed that age
(hazard ratio (HR): 2.22, P=0.001), platelet counts (HR: 1.90, p<0.0001),
AST levels (HR: 1.59, p=0.048), and alpha-fetoprotein (AFP) levels at 24 weeks
after IFN therapy (HR:4.54, p<0.0001) were independent predictive factors
for the cumulative development of HCC. For the prediction of HCC development
within 5 years after IFN therapy, independent risk factors were older age (area
under the ROC curve (AUROC) 0.740, p<0.0001, optimal cut-off: 60 years old),
lower platelet counts (AUROC 0.698, p<0.0001, optimal cut-off: 150 (109/L))
and higher AST at 24 weeks after IFN therapy (AUROC 0.732, p<0.0001, optimal
cut-off: (30 U/L). The hazard ratio of HCC development within 5 years was 61.5
in older patients with high AST and low platelet counts compared to younger
patients having low AST and high platelet counts (95% confidence interval (CI):
8.58-543.2, p<0.0001). For the prediction of HCC development beyond 5 years,
AFP levels at 24 weeks after IFN therapy was the sole significant factor (AUROC
0.720, p<0.0001). Using the optimal cut-off value of 5.0 ng/ml, the sensitivity
and specificity to predict HCC development beyond 5 years was 60% and 73%,
respectively. Compared to patients with AFP <5.0 ng/ml, the hazard ratio of
HCC development beyond 5 years was 4.6 for those with AFP 5 to 10 ng/ml (95%
CI: 2.13-9.76, p<0.0001), and 22.3 for those with AFP >10 ng/ml (95% CI:
9.01-55.02, p<0.0001). CONCLUSIONS:
Predictive factors for development of HCC following SVR were older age, lower
platelet counts, higher AST, and higher AFP levels at 24 weeks after IFN
therapy. The optimal cut-off value of AFP for the prediction of HCC development
beyond 5 years was as low as 5.0 ng/ml. Patients with these predictive factors
may be the candidate for a careful HCC surveillance even after the complete
eradication of hepatitis C virus.
Postoperative antiviral therapy with
pegylated interferon plus ribavirin associated with reduced recurrence of
hepatitis C virus-related hepatocellular carcinoma. Y. Hsu, Y. Hsu, J. Lin, et al. ABSTRACT
FINAL ID: 165
BACKGROUND: Hepatocellular carcinoma (HCC)
commonly recurs after surgical resection without effective adjuvant therapy.
Pegylated interferon plus ribavirin has been shown efficacious in preventing
the development of hepatitis C virus (HCV)-related HCC, but its efficacy in
reducing HCC recurrence remains unknown. Objective: We aimed to investigate
whether postoperative antiviral therapy reduced recurrence of HCV-related HCC after
resection. METHODS: This
population-based retrospective cohort study analyzed the Taiwan National Health
Insurance Research Database. After screening 17,574 patients undergoing liver
surgery for a first-time diagnosis of HCC between October 2003 and December
2008, we identified 893 patients with antiviral-naïve HCV infection who had
curative resection without recurrence within one year. Ninety five eligible
patients received postoperative pegylated interferon plus ribavirin (treated
cohort), and were matched 1:4 in age, gender, and cirrhosis status with 380
patients using no antiviral agent (untreated cohort). Patients were followed up
for HCC recurrence and mortality since one year after surgery. RESULTS: The HCC recurrence rate was
significantly lower in the treated than the untreated cohort (32.39% versus 47.69%
after 3 years of follow-up, p=0.004). With adjustment for multiple confounders
including death occurring prior to HCC recurrence, the recurrence risk was
reduced nearly by half (hazard ratio 0.52; 95% CI, 0.34-0.80) among treated
patients. Multivariate stratified analyses confirmed antiviral therapy was
consistently associated with attenuated risk of HCC recurrence across
subgroups. Moreover, mortality was lower in the treated cohort significantly (1.92%
vs. 17.68% after 3 years of follow-up, p=0.004). CONCLUSIONS: Postoperative pegylated interferon plus ribavirin is
associated with reduced recurrence of surgically resected HCV-related HCC. A.
Recurrence of surgically resected hepatocellular carcinoma in patients without
and without postoperative antiviral therapy; B. Mortality rates between the
treated and untreated cohorts.
Outcomes in patients with small
hepatocellular carcinoma and chronic hepatitis C infection treated with RFA and
antiviral therapy. N.M.
Kemmer, A. Alsina, G.W. Neff, et al. ABSTRACT FINAL ID: 592
INTRODUCTION: Hepatocellular carcinoma (HCC) is the
third most common cause of death worldwide. The risk of developing HCC in
patients suffering from cirrhosis is increased in the setting of chronic HCV.
Objective: To determine the tumor recurrence, safety, and survival outcomes of
HCC patients with chronic hepatitis C (genotype 1) infection after receiving radiofrequency
ablation (RFA) and antiviral therapy using peg-alfa interferon and weight
based
ribavirin. METHODS: Using our
institution’s database, we identified all patients with chronic Hepatitis C
(HCV) genotype 1 and small HCC (less than 3.0 cm) between December 2007 –
December 2010. The following data was extracted; sustained virological rate
(SVR), tumor necrosis rate and tumor recurrent rate, and 1-year survival rate.
HCC recurrence and monitoring was done using serum a-fetoprotein (AFP) test and
radiological findings. RESULTS:
During the study period, there were 75 patients (42 males, 33 females, age 43
years (32-54) with HCC (≤3cm) and HCV (genotype 1). We divided the
patients into two groups: control group (n=33) received RFA only and treatment
group (n=42) received RFA and peg-alfa interferon with weight based ribavirin.
The tumor complete necrosis rate at three months in the control group was
24.24% versus Rx group was 50% (P<0.05). The one-year viral suppression in
the control group was 30.3% versus Rx group 64.28% (P<0.05). The HCC
recurrence rate in the control group was 38.39% versus Rx group 7.1%
(P<0.05). The one-year survival rate was 30.3% in control group versus Rx
group 61.9% (P<0.05). CONCLUSION:
The above results demonstrate potential benefits of adding antiviral therapy
and suppressing HCV virus in patients with compensated cirrhosis and small HCC
undergoing RFA. Further trials involving larger number of patients are needed
to delineate the overall impact of HCV eradication in the patient with
compensated cirrhosis and HCC. As the antiviral therapies continue to evolve
future trials may offer an opportunity at viral eradication prior to LTx thus improving
long term outcomes.
Liver stiffness as a predictor of
hepatocellular carcinoma development in chronic hepatitis C patients receiving interferon-based
anti-viral therapy. Y.
Narita, T. Genda, H. Tsuzura, et al. ABSTRACT FINAL ID: 533
BACKGROUND AND AIMS: Many patients with chronic hepatitis C
(CHC) receive interferon (IFN)-based antiviral therapy. Because it not only
prevents progression to cirrhosis but also reduces the risk of hepatocellular carcinoma
(HCC) development. However, HCC development is not rare after IFN therapy even
in patients who achieve a sustained viral response (SVR). Assessment of the
risk of HCC development is clinically important in the management of patients,
but the risk factors for HCC development have not been established for patients
receiving IFN therapy. Recent studies suggested that liver stiffness measurement
(LSM), a procedure developed for the noninvasive assessment of liver fibrosis,
has a predictive value for HCC development in cases of several kinds of chronic
liver disease. We attempted to elucidate the usefulness of LSM for assessing
the risk of HCC development in CHC patients who receive IFN therapy. METHODS: The study included 151
consecutive CHC patients who received IFN
therapy. All
patients underwent percutaneous liver biopsy and LSM was performed using
FibroScan® before IFN therapy was initiated. Univariate and multivariate Cox
proportional hazard analyses were used to estimate the hazard ratios (HRs) of
the clinical, viral and biochemical characteristics for HCC development. The
cumulative incidences of
HCC
development were evaluated using Kaplan-Meier plot analysis and the log-rank
test. RESULT: During the median follow-up
time of 600 days, 9 of the 151 patients developed HCC after IFN therapy.
Univariate Cox proportional hazard analysis showed that age (HR 1.09, P =
0.038), LSM (HR 1.11, P = 0.001), platelet count (HR 0.81, P =0.006), and
non-SVR (HR 9.32, P = 0.036) were associated with HCC development. Multivariate
analysis identified 3
independent
risk factors for HCC development: LSM (≥14.0 kPa, HR 5.58, P = 0.020),
platelet count (≤14.0 × 104/μL, HR 5.59, P = 0.034), and non-SVR (HR
8.28, P = 0.049). Kaplan–Meier plot analysis showed that the cumulative incidence
of HCC development at 3 years was 60%, 8%, and 0% in patients with all 3 risk
factors, 2 or 1 of the 3 risk factors, and none of the 3 risk factors,
respectively. The differences between the 3 groups were statistically
significant
(P <
0.001). CONCLUSION: LSM-based risk
assessment was successfully used to stratify the risk of HCC development in patients
receiving IFN-based antiviral therapy. These results indicate the usefulness of
LSM before IFN therapy for the management of CHC patients.
Hepatocellular Proliferation and
Metabolic Syndrome Risk Factors are Increased in Non-Cirrhotic Hepatocellular
Carcinoma: A Case-Control Study. B.
Schlansky, Z. Jiang, K.D. Ingram, et al. ABSTRACT FINAL ID: 557
PURPOSE: Hepatocellular carcinoma (HCC) arising
in the absence of underlying cirrhosis or hepatitis B (HBV) infection is
increasingly recognized, particularly in hepatitis C (HCV) infected persons. We
performed a casecontrol study to evaluate clinical and histologic
characteristics associated with non-cirrhotic HCC. METHODS: Consecutive HBV-negative patients with pathologic
diagnoses of HCC without background cirrhosis on resection were
retrospectively
identified from 2005-2012. 4 control groups of 10 patients were selected – 1)
cirrhosis with HCC; 2) cirrhosis without HCC; 3) less than stage 3 fibrosis, no
HCC, HCV-positive; and 4) less than stage 3 fibrosis, no HCC, HCV-negative. Clinicodemographic
characteristics were abstracted from the medical record. Hematoxylin and eosin (H&E)
stains of non-HCC background liver were assessed by 2 pathologists for
inflammation, fibrosis, and steatosis. Ki-67 immunohistochemistry was performed
to assess proliferation, with stained hepatocyte nuclei counted by 2 blinded
examiners from 20 high-power microscopic fields, and then averaged. RESULTS: We identified 26 patients with
non-cirrhotic HCC; mean age was 65 years, with 62% male, 96% White race, 23%
heavy alcohol users, 42% diabetic, 69% hypertensive, 31% obese, and 31%
HCV-positive. H&E median inflammation grade was 1 (interquartile range (IQR)
0-1), fibrosis stage 1 (IQR 0-2), and steatosis score 1 (IQR 0-2). Compared to
cirrhotics with HCC, the study group had less frequent alcohol use and obesity
(p<.01), and less background inflammation (p<.01) and steatosis (p=.06).
Compared to non-cirrhotic HCV-positive patients without HCC, the study group
had more frequent hyper tension and hyperlipidemia (p<.01), but routine
histology did not differ (p=.28-.31). Compared to non-cirrhotic HCV-negative
patients without HCC, the study group had more frequent diabetes (p<.01),
hypertension (p=.06), obesity (p=.04), and steatosis (p=.04). The non-cirrhotic
HCV-negative group had low Ki-67 staining; otherwise Ki-67 staining did not
differ between study and control groups (p=.45-.98). Among HCV-positive
patients, Ki-67 staining was markedly increased in background liver of
non-cirrhotic HCC patients compared to non-cirrhotic patients without HCC
(p=.04). CONCLUSIONS: 1.
Non-cirrhotic HCC patients display frequent metabolic syndrome risk factors
despite having minimal steatosis. 2. Hepatocellular proliferation is increased
in background liver of non-cirrhotic HCV-infected persons with HCC compared to
those without HCC. Targeted HCC surveillance of non-cirrhotic HCV-infected
persons with the metabolic syndrome or pronounced hepatocellular proliferation
warrants investigation.
Impact of metformin on HCC prognosis in
presence and absence of HCV infection
H.M. Hassabo,
M. Iwasaki, K. Soliman, Y. et al. ABSTRACT FINAL ID: 547
BACKGROUND: Hepatitis C virus (HCV) is a known
risk factor for hepatocellular carcinoma (HCC). Several studies showed that
diabetes mellitus (DM) increases the risk of HCC; however the antidiabetic
treatment with metformin can reduce the risk of HCC among diabetics. We aimed
to assess the influence of metformin treatment on the overall survival of
diabetic patients with HCC. METHODS:
Between 2000 and 2012 total of 644 patients with pathologically confirmed HCC
were prospectively enrolled in our clinical epidemiology study and each patient
was personally interviewed for demographic and HCC risk factors. Participants
reported their detailed history of DM including duration and type of treatment
of the DM. Baseline clinical
information
and prognostic factors were retrieved from the medical records. Median survival
was estimated by using the Kaplan-Meier product-limit method, and significant
differences between the survival times were determined by using the log-rank
test. To identify independent prognostic factors for overall survival, hazard
ratios (HR) and 95% CIs were calculated by using Cox proportional hazard models
with a backward stepwise selection procedure. RESULTS: Total of 224 HCC patients had prior evidence of chronic
HCV infection (34.8%) and 221 had prior history of diabetes mellitus (34.3%).
DM was significantly common in patients without HCV infection (39.3%) than in
patients with HCV-related HCC (25%), P =.001. Although we observed no
statistical impact of DM on overall survival of HCC patients in presence and
absence of HCV infection, HCC DM patients who were treated with metformin had
longer
survival
duration in presence of HCV infection (Median survival 30.3 months) as compared
to non-metformin users (Median survival 16.5 months), p=.05 (Table 1). After
adjustment for baseline clinical predictors of patients’ survival including
staging, prior treatment, AFP, cirrhosis, age, sex, and race, the Cox
regression analysis indicated 80% mortality reduction in the metformin users
(HR=0.1-0.5) in HCV-induced, P=0.001. CONCLUSIONS:
Metformin users among DM patients with HCC had a favorable survival compared
with patients without metformin treatment. This observation was supported by
recent study in patients with Radio-frequency
ablation suggesting the significant anti-cancer and anti-inflammatory activity
of metformin.Prognostic effect of metformin on HCC
Predicting the treatment efficacy of sorafenib
in patients for hepatocellular carcinoma: a multi-center retrospective study in
Japan. T. Yamashita, S. Kaneko, M. Kudo, K.
Ikeda. ABSTRACT FINAL ID: 571
BACKGROUND: We performed a multi-institutional
joint research in patients with advanced hepatocellular carcinoma to reveal the
factors predicting the treatment effect to sorafenib in routine Japanese
clinical settings. METHODS: An
integrated database was created using individual patient data from 21 Japanese
hospitals. Response rate, survival, adverse events and factors related to
treatment effect were analyzed retrospectively. Antitumor effect was
evaluated by
RECIST v1.1 criteria, and toxicity was graded according to the NCI CTC-AE v3.0.
Factorial analyses were performed by Kaplan-Meier method, log-rank test, the
Cox proposal hazard regression model, Fisher direct method and logistic
regression analysis. RESULTS:
Three hundred
eighty eight patients (79% male, median age 71 yrs, 76% Child-Pugh A, 23%
Child-Pugh B, 62% Hepatitis C, 22% macroscopic vascular invasion, 51%
extrahepatic spread) were enrolled. In the patients, 32% received reduced
dosage less than 800mg daily. In all patients, median survival time (MST) and
time to treatment failure (TTF) were 10.7 months and 2.1 months, respectively.
Disease control rate (DCR) was 49% (CR 0.3%, PR 7% and SD 41%). Child-Pugh
class B patients showed the tendency to inferior DCR (48% vs. 43%; p=0.058),
MST and TTF were shorter than class A patients (MST: 6.4 months vs. 11.7
months; p<0.01, TTF: 1.4 months vs. 2.1 months; p=0.043). Initial dosage of
treatment did not have any effect on DCR, MST and TTF. Factorial analysis
(univariate) revealed ECOG-PS 0, maximum tumor diameter <3cm,
albumin≥3.5g/dL, alphafetoprotein (AFP)<100ng/mL and des-gamma-carboxy
prothrombin (DCP)<400mAU/mL as factors to predict DCR. Multivariate analysis
revealed albumin and AFP as predictive factors. Moreover, ECOG-PS 0, Child-Pugh
class A,
maximum tumor
diameter <3cm, albumin>3.5g/dL and AFP<100ng/mL were revealed by
univariate analysis, and finally tumor diameter was extracted as factors
related TTF. Most frequently drug induced Grade 3/4 adverse events were
hand-foot skin reaction (HFSR) (10%), hypertension (10%), diarrhea (4%), and
anorexia (4%). CONCLUSIONS: Sorafenib
is effective in Child-Pugh class A patients of advanced hepatocellular
carcinoma in Japan. Several clinical
factors
associated to treatment efficacy of sorafenib may help to select the beneficial
patients to sorafenib.
Hepatocellular carcinoma: Ethnic
disparities in viral etiology. The Harlem Experience
Y. Siba, J.
Kretchy, A. Gupta, J. Culpepper-Morgan. ABSTRACT FINAL ID: 608
BACKGROUND: Hepatocellular carcinoma (HCC) is the
most rapidly increasing cancer in the U.S. The prevalence of hepatitis B and C
in HCC in the U.S is approximately 18% and 29% respectively. Harlem Hospital,
NY serves a demographically unique community of color with 45% African
Americans (AA), 35% Hispanic Americans (HA), 10% African immigrants (AI) and
10% others. METHOD: A retrospective
cohort review was done to describe the epidemiology and clinical
characteristics of patients with primary HCC seen at Harlem Hospital between
Jan 2000 and Dec 2010 (n=46). RESULTS:
Seropositivity for HCV was 70% (32/46) and 26% (12/46) for HBV in patients with
HCC. 6.5% (3/46) were coinfected with HBV. In 4.3% (2/46) the etiology of HCC
was undetermined, p<0.0005 vs. U.S average. The average
age was 61
years, range 38-85. 75% (35/46) were male. The racial background for
HBV-related HCC was 75% (9/12) AA, 8.3% (1/12) HA, and 16.7% (2/12) AI. Whereas
for HCV-related HCC, it was 75% (24/32) AA, 12.5% (4/32) HA and 12.5% (4/32)
AI. HBV-related-HCC occurred at a younger age (52 years, ±9.5 SD) than
HCV-related-HCC (61years, ± 9.4 SD), p = 0.007. 26% (8/32) HCV patients had
positive HBcAb. The prevalence of cirrhosis in the HBV
group was
58.3% (7/12) and 81.3% (26/32) in the HCV group. Thrombocytosis, which has been
associated with large tumor volumes and adverse outcome was less common in
women with HCC 30% (3/10) than men 70 % (7/10) p=0.0069 and HBV more than HCV
33% (4/12) vs. 15.6% (5/32), p=0.0263. HCC without cirrhosis occurred in 33% (4/12)
of HBV compared to 18% (6/32) of HCV, p= 0.045. Only 26% (12/46) were followed
up in the GI – Hepatology
Clinic for
HCC surveillance prior to diagnosis. The mortality rates for HBV and HCV
related HCC were 83.3% and 70.3% respectively. CONCLUSIONS: The seroprevalence of HBV and HCV in HCC was
significantly higher in our cohort (26% vs. 70%) than the national average (18%
vs. 29%). African Americans were over represented in our cohort whereas
Hispanic
Americans
were under represented. There were no Caucasians or Asians in our cohort. The
HBV related HCC patient was more likely to be young, non- cirrhotic, and have
thrombocytosis than the HCV patient. A significant proportion of HCV patients
had evidence of prior HBV exposure. We conclude that there is increased need
for HCC surveillance among HBV and HCV patients in the African American
population.
HCC in HCV patients without cirrohis:
absence of associated NASH. B.K.
Kutala, P. Bedossa, T. Asselah, L. et al. ABSTRACT FINAL ID: 1008
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) in
absence of cirrhosis in chronic hepatitis C is rare and risks factors are not
well known. Recently only 6 cases of HCC in the absence of cirrhosis related to
VHC have been reported (Kathryn et al, World J Gastroenterol 2010). The aim of
this study was to characterize the clinicopathological features of
characteristics and frequency of patients with HCV-HCC without cirrhosis. We
report here 15 cases. METHODS: The
records of consecutive patients admitted for HCC with a positive HCV RNA and
hospitalized in the hepatology or digestive surgery between January 2000 and
December 2010 were identified by our registry hepalist and reviewed
retrospectively with collection of 96 variables (data demographics, history and
etiology of cirrhosis, circumstances of diagnosis, therapeutic management and
survival). Inclusion criteria HCC and cirrhosis or noncirrhosis diagnosed by
liver biopsy. Criteria of exclusion: (HCC and cirrhosis or non-cirrhosis
diagnosed by other method than liver biopsy), patient treated for HCV
infection, had other coexistent causes of cirrhosis or liver disease than HCV
or Coinfection HBV or HIV.
RESULTS: 437 patients have been admitted for
HCV-HCC during the period 2000-2010. Only 15 patients have HCVHCC without
cirrhosis and 46 patients had HCV-HCC with cirrhosis satisfied to inclusion
criteria. Finally 61 patients were studied (80% men). The median follow-up was
28 months (range: 1-143). The median age at diagnosis of HCC was 62 years in
Cirrhosis group vs 69 in Non-Cirrhosis group. Abnormal AST, albumin, bilirubin
total, platelets count,
were more
frequent in cirrhosis group than in non-cirrhosis group (2.7 vs 1.5 xN, 35 vs
42 g/l, 22 vs 13 μmol/L, 114 vs 218 x10*/L (0.0006, 0.0002, 0.002,
<0.0001). Steatosis and NASH were significantly more frequent in cirrhosis
group than non-cirrhosis group (48% vs 13% and 19% vs 0% respectively
P=<0.0001 and <0.0001). Markers of HBV active infection were
significantly less frequent in cirrhosis group than in non-cirrhosis group (
Anti Hbc and Anti Hbs 5% vs
33% and 5% vs
26% p=<0.0001) CONCLUSIONS:
Clinicopathological characteristics of HCV-infected patients with HCC with or
without cirrhosis are different. Risk factors such as NASH, steatosis or
overload hemosiderin was not found in patients without cirrhosis.
These results
suggest a possible occult infection to HBV virus or a past infection to HBV
virus may induce the HCC in the setting of HCV without cirrhosis that requires
further investigation in the future.
Post-Transplant
Efficacy and safety of aggressive
antiviral treatment for recurrent hepatitis C after liver
transplantation.Influence of Receptor
and Donor Interleukin 28B Polymorfisms in virological response. J.
Pascasio, J. Sousa, M. Ferrer, et al. ABSTRACT FINAL ID: 702
AIMS:
To evaluate sustained virological response (SVR) and safety of antiviral
treatment in liver transplant (LT) recipients with recurrent hepatitis C virus
(HCV) infection, following a schedule starting with full doses of Pegylated
interferon alpha-2a (PEG2a) plus ribavirin (RBV) and prolonging therapy in
patients without rapid virological response (RVR) and to assess the influence
of receptor and donor interleukin-28B (IL28B) polymorfisms in response. METHODS: Retrospective study of all
liver recipients with histologically proven recurrent hepatitis C treated with
full doses of PEG2a plus RBV for 48 (genotypes 1-4) or 24 (genotypes 2-3)
weeks.We offered to prolong the therapy to 72 (genotypes 1-4) or 48 weeks
(genotypes 2-3) to patients without RVR.There were 71 cases [(5 severe acute hepatitis
and y 66 chronic hepatitis, 50% of which had advanced fibrosis (stage F3-F4)],80%
genotype 1 and 69% with HCV-RNA≥800.000 IU/mL. 22 patients (19 genotype
1) received prolonged treatment. Genotyping
of L28Brs12979860 was performed by TaqMan 5 allelic discrimination assay in 68
recipients and 66 donors (in liver biopsies obtained before initiating
antiviral treatment). RESULTS: 29%,62%,68%
and 58% (56% in genotype 1) of patients achieved HCV-RNA (-) at 4 weeks
(RVR),12 weeks,end-of-treatment and SVR, respectively.SVR was associated to
HCV-RNA (-) at 4 (90% vs 47%;p=0,001) and 12 weeks (84% vs 17%;p<0,0001) and
to early virological response (70% vs 9%;p<0,0001).In patients without RVR, prolonged
treatment tended to enhance SVR (82% vs 50%;p=NS) and reduce relapse (18% vs
33%;p=NS). RVS was associated to low virological load (82% vs 47%;p=0,009),but
not to the severity of fibrosis. SVR was higher in recipients with IL28B CC and
CT genotypes as compared with those carrying TT (67 and 69% vs 25%; p=0,016 and
p=0,01,respectively) and also in donors (in liver biopsies) with IL28B CC and CT
genotypes as compared with those carrying TT (66 and 62% vs 29%;p=0,01 and
p=NS,respectively). Anemia, neutropenia, thrombocytopenia and rejection were
observed in 83%, 60%, 24% and 22% of patients, respectively.Filgastrim,
erythropoietin and transfusion were administered to 11%, 62% and 22%,
respectively.21% of patients had to discontinue treatment for adverse events
and this was associated to lower SVR (33% vs 64%;p=0,041). CONCLUSIONS: The aggressive treatment of recurrent hepatitis C
after LT starting with full doses of PEG2a plus RBV and prolonging therapy in
patients without RVR improves SVR as compared with previous reports.IL28B
rs12979860 TT genotype in recipients and donors (in liver biopsies) are
associated to lower SVR, without differences between CC and CT genotypes.
Efficacy and safety of protease
inhibitors for hepatitis C recurrence after liver transplantation: a first
multicentric experience. A.
Coilly, B. Roche, T. Antonini, D. et al. ABSTRACT FINAL ID: 9
BACKGROUND: Protease inhibitors (PI), telaprevir
and boceprevir, in combination with peginterferon/ribavirine improved sustained
virological response rate in HCV genotype 1 patients (pts), naive or previously
treated with dual therapy. We describe for the first time their use after liver
transplantation (LT) for HCV recurrence on the graft. Patients and METHODS: This cohort study enrolled 25
liver transplant pts (male: 92%, mean age 54±11 years [31-75]),
with an
active genotype 1 hepatitis C, in 5 centers between March 2011 and February
2012 and treated with boceprevir (n=14) or telaprevir (n=11) immediately or
after a 4-weeks lead-in phase (n=21). The meantime between LT and PI initiation
was 49.5±52.3 months [1.6 to 180]. Indication for therapy was HCV recurrence
defined by ≥ F2 in the METAVIR scoring system (n=21) or a cholestatic
hepatitis (n=4). Eleven (44%) pts were naive and 11 (44%) nonresponders
to a previous
course of dual therapy after LT. Fifteen pts received cyclosporine (60%), 10
tacrolimus (40%). RESULTS: The mean
follow-up was 20.3±8.8 weeks [2-40]. At baseline, HCV viral load, total
bilirubin and hemoglobin levels were 6.86±1.17 log10 IU/mL [3.11 to 8.49],
50.9±95.7 μmol/L [5-372], 13.2±1.8 g/dL [8.7-16.3] respectively. After 4
weeks of PI, a rapid virological response was obtained for 6 (43%) boceprevir
pts and 5 (45%) telaprevir pts.
After 12
weeks of PI, a complete early virological response was obtained for 11 (79%)
boceprevir pts and 8 (73%) telaprevir pts. 6 pts experienced an early
discontinuation of therapy, 5 for a virological breakthrough (boceprevir n=2, telaprevir
n=3) and a null non-responder in the boceprevir group. Three severe infections
occurred, leading to death in two pts (boceprevir: 1 at week 20; telaprevir: 1
at week 2). The most common side effect was anemia in 64% of pts:
92% and 91%
in boceprevir and telaprevir groups received erythropoietin (EPO) alone or
combined with ribavirin reduction and 4 pts received red blood cell
transfusions. The cyclosporine dose was reduced by 1.5±0.4 fold [1.0 to 2.0]
and 2.8±1.1 fold [1.3-4] with boceprevir and telaprevir, respectively. The
tacrolimus dose was reduced by 5.8±2.8
fold
[3.1-9.5] and 40.0±14.8 fold [21.4-57.1with boceprevir] and telaprevir,
respectively.
CONCLUSION: A complete early virological response
after 12 weeks of triple therapy was observed in 76% of liver transplant pts in
our cohort. More than 90% pts used EPO for anemia which was the most common
adverse event. Interactions between PI and calcineurin inhibitors were constant
but easily managed thanks to a close monitoring. Final results will be
presented.
Multicenter Preliminary Experience
Utilizing Boceprevir with Pegylated Interferon and Ribavirin for Treatment of
Recurrent Hepatitis C Genotype 1 after Liver Transplantation.
B. Aqel, E.J.
Carey, T.J. Byrne, et al. ABSTRACT FINAL ID: 706
BACKGROUND: Hepatitis C virus (HCV) recurrence
after liver transplant is universal and causes significant reduction in both
graft and patient(pt) survival. The use of protease inhibitors combined with
pegylated interferon (PEG) and RBV significantly improve sustained virological
response in non-LT patients. There is limited experience regarding their use
post LT. AIM: To describe our
experience with boceprevir-based triple therapy for recurrent HCV post LT
METHODS: Multicenter study describing the
outcome of HCV treatment post LT, utilizing a strict and standardized clinical
protocol. All pts were converted to cyclosporine based immunosuppression (IS)
regimen prior to treatment. cyclosporine dose was halved and levels were
closely monitored once boceprevir was initiated. All pts had a lead-in phase
with PEG and RBV for 4 weeks followed by addition of boceprevir. Demographic,
clinical, biochemical and
virological
data was collected at baseline and during therapy. Ribavirin levels were
monitored every 4 weeks RESULTS:
Total of 23 patients with genotype 1 recurrent HCV were treated with boceprevir
bases regimen between 06/11-04/12. Treatment characteristics are shown in
table-1. Ten patients (43%) achieved complete early virological response; four
of them continue to be negative at week 24. Six (26%) met the futility rules
with inadequate virological
response.
Treatment was stopped in four patients (17%)due to adverse events. All patients
required growth factors support on treatment. CONCLUSIONS: Boceprevir based triple therapy can be used post LT
but requires close clinical monitoring. Antiviral efficacy of this regimen is
better than standard therapy in difficult to treat population. Patients should
be closely
monitored for
adverse events. Ongoing follow up will provide additional data regarding safety
and efficacy of this regimen.
First ever successful use of
Daclatasvir and GS-7977, an Interferon-free oral regimen, in a liver transplant
recipient with severe recurrent Hepatitis C. R.J.
Fontana, M.Bifano, D. Dimitrova, et al. ABSTRACT FINAL ID: 694
BACKGROUND: Recurrent HCV infection is nearly
universal in liver transplant (LT) recipients and associated with an
accelerated rate of allograft injury and fibrosis. Daclatasvir (DCV), a potent
oral NS5A replication complex inhibitor, has synergistic antiviral activity and
a favorable safety profile when combined with GS-7977, a potent oral nucleotide
polymerase inhibitor. The aim of our study is to describe the first ever use of
DCV and GS-7977 combination therapy in a LT recipient with severe recurrent
HCV. METHODS: DCV 60 mg QD and
GS-7977 400 mg QD were given for 24 weeks. Serum HCV RNA levels were assessed
at weeks 0, 1, 2, 3, 4, 8, 12, 24 and at weeks 4, 8, 12, and 24 post-therapy
(Roche Cobas Taqman, llod < 43 IU/ml). RESULTS:
A 56 year old African-American male with diabetes and HCV genotype 1b failed to
respond to IFN monotherapy as well as pegIFN and ribavirin combination therapy.
Due to progressive liver failure, he underwent LT with a MELD score of 24. He
initially did well
but at month
4 postLT developed elevated serum ALT and alk phos levels while on tacrolimus
and prednisone. A liver biopsy at 6 months postLT demonstrated moderate chronic
active hepatitis with cholestatic features and an Ishak fibrosis score of 4. He
then developed ascites with serum AST 178 IU/ml, alk phos 316 IU/ml and
bilirubin 4.1 mg/dl but normal creatinine. ERCP and inferior venocavagram were
negative, HCV RNA was 12,000,000 IU/ml and IL28-B
genotype was
CT. At month 8 postLT, DCV and GS-7977 were initiated and HCV RNA became
undetectable along with normalization of liver biochemistries at week 4. By
week 8, ascites had resolved and he remained HCV RNA negative throughout treatment.
At post-treatment week 12, HCV RNA remains undetectable and liver
biochemistries are normal. The tacrolimus dose and trough levels were unchanged
during and after therapy. CONCLUSIONS:
An interferon free regimen of DCV and GS-7977 led to rapid suppression of serum
HCV RNA and sustained clearance of HCV in an immunosuppressed LT recipient who
had previously failed pegIFN /ribavirin therapy. The potent antiviral efficacy
and favorable safety profile of this Interferon-free oral combination regimen as
well as the low potential for drug-drug interactions with calcineurin
inhibitors make it an attractive regimen worthy of further study in LT
recipients
Early and End of Treatment Virologic
Responses in Patients with Hepatitis C (HCV) genotype I Recurrence After Liver
Transplant Treated with Triple Therapy using Telaprevir: A Single Center
Experience. P.S. Mantry, C. Wu, J.S. Weinstein, et
al. ABSTRACT FINAL ID: 712
BACKGROUND: We report the first experience of
treating a cohort of patients with HCV genotype I recurrence after liver
transplant using off label telaprevir (TVR) based triple therapy in patients on
Tacrolimus (TAC) based immunosuppression. METHODS:
Since June 2011, we have treated 17 patients with genotype 1 HCV infection
recurrence post liver transplant using combination therapy with pegylated
interferon alpha 2a or 2b, Ribavirin (RBV), and TVR folowed by PEG/RBV
combination therapy for additional 12 or 36 weeks. All patients were on TAC at
a stable dose prior to start of the antiviral regimen. At the start of therapy,
the TAC dose was reduced to approximately half the pre-treatment dose and the
frequency was reduced to once a week with frequent level checks . After
completing TVR, TAC was reintroduced slowly to pre-TVR dosing. CBC, Chemistry,
HCV RNA, TAC levels and clinic evaluation of patients was
performed
once a week during the first 4 weeks of Rx and every 2 weeks there after. RESULTS: There were 9 male and 8 female
patients in the cohort who were from 6 months to 8 years out post transplant.
11/17 patients were genotype 1a. Of the 17 patients, 6 had rapid virologic
response and extended (e)RVR; additionally 6 patients became aviremic at
32,33,40,55,62 84 and 90 days and had complete early virologic response. 4
patients were non responders and 1 patient had a breakthrough during treatment.
4 patients received response guided therapy and stopped at 24 weeks; the other
6 patients are still on therapy. Anemia was the most prominent side effect of
treatment with all patients requiring growth factor support and 8 of them
needing blood transfusions despite lower doses of RBV. CONCLUSIONS: We report the first experience of treating HCV
recurrence in post liver transplant recipients with TVR based triple therapy in
setting of TAC based immunosuppression. We observed robust virologic responses
in a majority of patients and TAC/TVR interactions and side effects were
manageable. Our preliminary data show that this treatment shows promising
virologic responses in patients and merits prospective evaluation.
Liver transplant center focused
experience with peginterferon alfa-2a, ribavirin and telaprevir therapy in
patients with genotype 1 hepatitis C cirrhosis. J.F. Gallegos-Orozco, A.E. Chervenak,
E.J. Carey, et al. ABSTRACT FINAL ID: 53
AIM:
To describe our experience with direct acting antiviral (DAA) therapy for HCV
genotype 1 cirrhotics, and to assess baseline features that may help identify
patients at risk of severe adverse events. METHODS:
Retrospective review of HCV-cirrhotic patients (baseline MELD ≤15)
treated with telaprevir-based DAA. Demographic, clinical, biochemical and
virologic data was collected at baseline and during therapy. Statistical
analysis included descriptive statistics, chi square for categorical variables,
T test or Wilcoxon test for continuous variables. Results reported as
mean±standard deviation or median with interquartile range (IQR). P <0.05
defined statistical significance. RESULTS:
39 patients (9 on the liver transplant wait-list) with genotype 1 HCV-cirrhosis
treated with telaprevir-based DAA between 6/1/2011-5/31/2012 at our liver
transplant center. Gender: 27 men (69%)/12 woman (31%); mean age 55.3±6.4
years. HCV genotype: 1a 41%, 1b 28%, 1 without subtype 31%. IL28B polymorphism:
CC 21%, CT 63%, TT 16%. Prior therapy experience: naïve 33%, relapser 23%,
non-responder 38%, unknown 5%. Use of growth factors: erythropoietin 67%,
filgrastim 46%. Treatment duration: mean 19.4±9.8 weeks. Thirty patients have
completed 12 weeks of therapy, 24 have attained complete early viral response
(80%), and 10 met criteria for extended rapid virologic response (33%).
Currently 17 patients have completed 24 weeks of treatment, 10 (59%) have
maintained undetectable HCV RNA. In 9/39 patients (23%) therapy was
discontinued due to severe adverse events, including 4
patients with
infectious complications requiring hospitalization (1 each: spontaneous
bacteremia, severe bacterial pneumonia, renal abscess, diskitis with
paravertebral abscess). No deaths have been recorded, but 1 patient suffered severe
decompensation requiring liver transplant. In comparison with patients who did
not develop severe complications, those who did had a higher baseline MELD
(median 10, IQR 9-10 vs. 8, IQR 7-9, p=0.04) and lower platelet count (72±17
vs. 114±55, p=0.001). Other clinical, laboratory and viral features were
similar between groups.
CONCLUSIONS: DAA treatment of cirrhotic patients is
feasible but at the risk of increased frequency of serious adverse events, in
particular severe infectious complications, requiring hospital admission and/or
discontinuation of antiviral therapy. Cirrhotic patients in whom therapy is
being considered require close clinical monitoring and high index of suspicion
for bacterial infection if clinical decompensation occurs while on treatment.
Our observations support that these patients should be treated in the context
of a liver transplant center.
Dose Reduction Of Ribavirin To 200 mg
Is Associated With Treatment Failure In The Treatment Of Null Responders Post
OLT With Advanced Fibrosis/Cholestatic Hepatitis C With Telaprevir Plus PEG
Interferon/Ribavirin. P.Y.
Kwo, M. Ghabril, M.A. Lacerda, R. ABSTRACT FINAL ID: 719
Aggressive
recurrence of hepatitis C remains problematic post OLT with low SVR rates with
PEGIFN/RBV
(PR). There are limited data on treatment of G1 HCV infection with DAA therapy
with PR post OLT and there are substantial drug-drug interactions with telaprevir(TVR)/ calcineurin inhibitors.Our AIM was to review our experience
with TVR addition to PR in treatment of aggressive hepatitis C in null
responders to PR post OLT. METHODS:
Adult patients with recurrent HCV infection post OLT with null response to PR
for 12 weeks (< 2 log
reduction)
received 4 week lead-in PEG-IFN alfa-2b (1.0 μg/kg/wk) plus RBV (600-1000
mg/day) followed by addition of telaprevir 750 q8. All patients not on
cyclosporine (CYA) were converted to CYA from tacrolimus prior to initiation of
HCV therapy. On day 1 of TVR, patients received 25 mg CYA with trough levels
titrated to 100 ng/ml. HCV RNA measured every 4 weeks by Cobas TaqMan HCV Test.
RESULTS: Seven patients (3 M, 4 F),
mean age 56 years, have been treated. 3 were < 1 year post-OLT, 6 had
cirrhosis/1 bridging fibrosis. Treatment parameters are described in table. All
patients required RBV dose reduction, 6/7 required EPO, 5/7 required G-CSF, 2/7
required eltrombopog for platelets <25,000 μl. Mean PRBCs transfused
per patient was 8 over 12 weeks of TVR, mean PRBCs after TVR is 4. 2/7
individuals required hospitalization for severe anemia. All patients who
achieved futility during TVR treatment or
breakthrough
post TVR required RBV dose reduction to 200 mg due to anemia. One patient who
reached futility at week 4 of TVR therapy continued PR with undetectable HCV
RNA at week 28. No supra/sub-therapeutic CYA levels encountered, no episodes of
renal insufficiency due to CYA toxicity. CONCLUSIONS:
Conversion to CYA followed by four week
PR lead-in with addition of telaprevir can lead to significant clearance rates
at week 24 in null responders with advanced fibrosis though high rates of
anemia/RBV dose reduction, growth factor, and transfusion require-ments were noted.
Dose reduction of RBV to 200 mg was associated with treatment failure. CYA
Interactions were easily managed by CYA dose adjustment. EOT results will be
available for ¾ individuals who are HCV RNA undetected at week 24 by 11/2012.