Monday Parallel Session 24, October 30, 2006
HCV Diagnosis, Natural History and Epidemiology
M. Danta; N. Semmo; D. Brown; C. A. Sabin; P. Fabris;
S. Bhagani; P. Klenerman;
G. M. Dusheiko.
Background:
HCV is associated with accelerated liver injury in HIV
co-infection. The outcome and natural history of HCV depends on early
host-viral interactions. We studied the acute phase HCV host-viral interactions
in a cohort of HIV co-infected individuals.
Methods:
Acute HCV was defined as seroconversion to anti-HCV ± ALT
>10x ULN and a positive serum HCV RNA. Clinical parameters were compared
before and after HCV infection. Serum and PBMCs
samples were collected over the first 12 weeks from diagnosis of acute HCV. The
E1/E2 region of the HCV genome was amplified and cloned using RT-PCR and TOPO
TA cloning in 8 co-infected patients (mean 9 clones at 2-3 time-points).
Diversity was calculated by pairwise comparison of
the clones and complexity was described by determining the number of variants
at each time-point, respectively. Selection pressure was assessed by
calculating dN/dS ratios for this region.
Cell-mediated responses were compared in 14 co-infected and 8 HCV mono-infected
patients. HCV-specific T-cell responses were assessed using an IFN-γ ELISpot for HCV core derived peptides (20mers overlapping
by 10aa) and HCV recombinant non-structural proteins (NS3-5).
Results:
A cohort of 55 individuals was identified (mean age 35.6, all
male, median peak ALT 389, median HCV viral load 6.0 log IU/ml, median CD4 554
cells/µl, HAART exposure 64%). Mono-infected individuals (n=8; 5 males, mean
age 32.5) were used for ELISpot comparison. HCV
persisted in 52 (95%) co-infected individuals. HCV had no impact on CD4/CD8
counts or detectable HIV viral load. In co-infected patients, there was a
significant increase in the HCV median genetic diversity (0.57% to 2.43%,
p=0.04) and a trend to increased complexity (4.5 to 8 variants, p=0.1) between
the first and subsequent time-points. All E1/E2 dN/dS
ratios were <1 at each time-point. Comparison of IFN-γ ELISpots for NS3-5 proteins revealed significantly reduced
responses in HIV co-infected versus HCV mono-infected individuals (1/10 vs.
5/6, p=0.008). No difference was seen for the core peptides (3/10 vs. 4/6,
p=ns).
Conclusions:
HIV co-infection is associated with increased rates of HCV
persistence. While there was evidence of increased HCV diversity and complexity
over time, the dN/dS ratios remained <1, implying
immune selection pressure was not driving the viral diversity. The paucity of
detectable CD4 T-cell responses, which were infrequent and limited in breadth,
supports a lack of immune pressure. While NS3-5 responses are particularly
associated with resolving HCV infection, these were specifically lost in the
co-infected group. HIV has a significant impact on the early HCV host-viral
interaction.
M.
Sulkowski; S. Mehta; M. Torbenson
; Y. Higgins; R. Moore; D. Thomas.
Background:
Current guidelines suggest that HCV treatment may be deferred
in persons with minimal fibrosis (Hepatology 2004;39:1147-71). To assess the
applicability of this recommendation to HIV-infected persons, we prospectively
examined the change in fibrosis stage between paired liver biopsies (bxs) among HIV/HCV coinfected pts attending an urban HIV
clinic
Methods:
177 pts underwent two liver bxs.
Paired bx were simultaneously evaluated by a single
pathologist blinded to bx sequence and scored
according to the Ishak criteria from F0 (no fibrosis) to F6 (cirrhosis).
Logistic regression analysis was used to identify non-histological and
histological correlates of progression of fibrosis (> 2 stages).
Results:
Of the 177 pts, 10 were excluded due to cirrhosis on the 1st bx. Characteristics at 1st bx
included: median age, 44 years (yrs); male, 78%; Black, 78%; CD4 < 200/mm3,
23%; HIV RNA < 400 c/mL, 59%; median BMI, 24.8; alcohol abuse, 27%;
persistently elevated AST, 31%; no steatosis, 68%. Between bxs,
82% and 12.5% received HIV and HCV treatment, respectively. Median time between
bxs was 2.91 yrs (IQR, 2.47 – 3.39 yrs). Fibrosis
increase ≥ 2 stages was observed in 37 (22%) of pts whereas a 1 stage
decrease occurred in only 11 (6.5%) pts (8, F1 at 1st bx
and 3 F2 at 1st bx). Among persons with mild fibrosis
(≤ F1) at 1st bx, 22% had evidence of 2-stage
progression. Compared to those with no progression, pts with a 2-stage fibrosis
increase were more likely to have persistently elevated (> 100 IU/L)AST
and/or ALT levels at bx 1 (p=0.01) and between bxs (P = .01). Additional analysis are planned to assess
the relationship of fibrosis progression and HIV or HCV treatment.
Conclusions:
Unexpectedly, 22% of coinfected pts with mild fibrosis on
initial liver bx had significant fibrosis on
subsequent bx. If confirmed by others, these data do
not support the application of current HCV treatment guidelines to HIV-infected
pts on the basis of a single liver biopsy, and suggest such pts should be
closely monitored for liver disease progression.
Comparison of Fibrosis
scores at Biopsy 1 and Biopsy 2
|
Fibrosis at Biopsy 1 (Column) |
|
|
|
|
|
|
|
|
|
Fibrosis at Biopsy 2 (Row) |
F0 |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
Total |
|
F0 |
42 |
20 |
12 |
2 |
2 |
3 |
1 |
82 |
|
F1 |
8 |
20 |
12 |
6 |
2 |
0 |
2 |
50 |
|
F2 |
1 |
2 |
11 |
2 |
0 |
0 |
0 |
16 |
|
F3 |
0 |
0 |
1 |
7 |
3 |
5 |
2 |
18 |
|
F4 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
1 |
|
Total |
51 |
42 |
36 |
17 |
7 |
8 |
6 |
167 |
B.
B. Borg; D. E. Kleiner; J. Liang; J. H. Hoofnagle.
Background:
Liver biopsy is the gold standard for determination of stage
of liver disease, but it cannot predict future progression. Attempts to develop
predictive models for fibrosis in chronic hepatitis C have used various
biochemical and clinical parameters. Since the linearity of progression of
fibrosis cannot be assumed, multiple liver biopsies are needed to strengthen
the predictive power of these models.
Aim:
To identify predictive factors of progression of fibrosis in
pts with chronic hepatitis C using multiple liver biopsies in a longitudinal
analysis using GEE models.
Methods:
1471 liver biopsies from 797 HCV-infected pts who were
followed by the Liver Diseases Branch at the
Results:
476 pts were treatment-naïve and 321 were enrolled in
different therapeutic protocols. 396 pts had one biopsy, and 401 had 2 to 7
biopsies each. The mean ± SD of time interval between biopsies was 3.0 ± 2.7
yrs. In the analysis of the first biopsies, 494 (62%) patients had no or mild
fibrosis, and 297 (37.2%) had moderate to severe fibrosis. Pts with severe
fibrosis were more likely to be male and to be African American. They were also
older, had higher BMI and longer duration of infection.
In the initial GEE model, increase in age, BMI, serum levels
of AST, IgA, AFP, ferritin,
and creatinine, and liver biopsy necro-inflammatory,
fat, Fe and Cu scores were significantly associated with advanced fibrosis. A
decreasing ALT and platelet count were also predictive of advanced fibrosis. In
the final optimized model, increase in BMI (OR=1.05 p=0.024), serum AST (OR=1.2
p=0.006), HAI scores (OR=1.19 p<0.0001) and hepatic Fe scores (OR=1.56,
p=0.008) and decrease in ALT (OR=1.08, p=0.025) and platelets (OR=1.04,
p<0.0001) were predictive variables of progression of fibrosis.
Conclusion:
Biochemical markers of liver disease can be used reliably as
predictors of progression of fibrosis. Prospective randomized controlled trials
will be needed to confirm these effects and the effect of therapy on fibrosis.
A.
N. Sofair; M. Fine; S. Huie-White;
S. Speers; A. Roome; N. Forbes; N. Hulten; S. Bialek; B. P. Bell.
Background
The assessment of hepatitis C virus (HCV) infection requires
confirmation of a positive anti-HCV test with a recombinant immunoblot
assay (RIBA) or detection of HCV RNA. In
Methods
Using information available on reported positive anti-HCV
laboratory reports for Waterbury residents, we contacted medical providers who
ordered these tests to determine the reason for testing, risk factors for
infection including intravenous drug use (IDU), contact with an individual with
hepatitis, or receipt of a blood transfusion prior to 1992. A provider data
form was completed either by the provider or Emerging Infections Program staff.
Results
In 2004, 376 positive anti-HCV reports were received. Patient
address or phone number were available for 350 (93%). The median age among
those reported as having a positive anti-HCV test was 41 years (range 2-67
years); 237 (63%) were male. Provider data were obtained for 326 (88%). Using
these data, the most commonly reported reasons for ordering anti-HCV testing
were to screen asymptomatic patients with risk factors for HCV infection (30%)
or evaluate patients with abnormal liver enzymes (21%). Information on risk
factors for HCV infection was available through physician report or chart
review in 205 (63%) patients and included IDU (41%), contact with a patient
with hepatitis (10%) and blood transfusion before 1992 (6%). Confirmation of
the initial positive anti-HCV tests was performed in 112/326 (34%) patients, of
whom 17 were positive by RIBA and 66 by detection of HCV RNA. Liver enzyme test
results were available for 168 (52%) patients in whom 62 (37%) were abnormal.
Conclusion
Over 65% of patients who tested positive for anti-HCV did not
receive additional testing to confirm the diagnosis. The lack of confirmatory
testing for HCV infection or evaluation of liver enzymes suggests that patients
may not receiving adequate evaluation for HCV infection.
S.
Currie; D. Tracy; J. Ryan; T. Belaye; M. Kim; A. Monto.
Introduction:
Injection drug use (IDU) is a primary and efficient route of
infection for the HCV virus. Recent NHANES survey data suggest that at least
48.4% of all persons with HCV antibodies have a history of IDU. However, many
persons with recent or active injection drug use who are chronically infected
with the hepatitis C virus (HCV) do not receive HCV antiviral treatment due to
a concern of possible HCV reinfection. Previously
reported studies in Chimpanzees suggest that clearance of HCV is associated
with immunologic resistance to reinfection. There are
limited studies investigating reinfection in these
patients.
Objective:
To determine whether persons with a history of IDU can get reinfected with HCV.
Methods:
Data were prospectively collected from 1997 to date on 427
persons with a current or history of drug use. Baseline and 6 month followup data were collected that included demographic,
socioeconomic and risk behaviors such as ongoing IDU,
alcohol and sexual behaviors. Serum samples were
collected and tested for HCV antibody and HCV RNA positivity.
Persons were included in this study if they were confirmed HCV antibody
positive with RNA levels undetectable by qualitative assay (Roche Cobas Amplicor 2.0) in serum
through spontaneous viral resolution or HCV antiviral treatment. Reinfection was defined by the presence of RNA positive
samples at > 2 visits preceded by documented HCV clearance. 43 HCV resolvers were included in this analysis.
Results:
The median age of the study group was 46 years (range of 30 –
71), 65% were male, 46.5% were Caucasian, 18.6% African American and 18.6% Latino.
26 (60.5%) of the 43 had baseline incomes < $10,000. 12 (28%) of the 43
persons continued to inject drugs for a total of 682 months or 56.83 person
years of potential HCV exposure to reinfection. Of
these persons, 0 (0%) were reinfected. Similarly, 0 (0%)
were reinfected in the non-IDU group.
Conclusion:
These data suggest that despite ongoing IDU risk and
potential ongoing exposure to the HCV virus, reinfection
is highly unlikely and should not be a barrier to initial HCV antiviral
treatment. Further study should be conducted to evaluate possible factors
associated with protective immunity
E.
Berkley; K. K. Leslie; C. R. Qualls; S. Arora; J. C.
Dunkelberg.
Objective:
To assess perinatal complications, documentation of hepatitis
C viral (HCV) antibody status, and postnatal referral of pregnant women and
neonates at high risk for hepatitis C infection.
Methods:
A prospective historical study was performed of pregnant
patients from Milagro, a drug dependence and
treatment program at the University of New Mexico Hospital. Multivariate
logistic regression statistical analysis was performed to assess the relative
contributions of multiple factors (HCV antibody status, drug use and methadone
use) to outcomes.
Results:
Three hundred and forty three women with a total of 351
pregnancies from the Milagro program received
prenatal care between January 2000 and January 2006. One hundred and fifty five
pregnant women (45.2%) were found to be HCV antibody positive, 137 (39.9%)
tested negative for HCV antibody, and 51 (14.9%) were not evaluated for
hepatitis C. Methadone use was highly associated with HCV antibody positivity (59.7% vs. 23.4%, p<0.001). The incidence of cholestasis of pregnancy was increased in mothers who were
HCV antibody positive (10/159 vs. 0/141, p=0.002). In women who used methadone
and were HCV antibody positive, there was a nine-fold increased risk of preterm
delivery (p=0.05, OR 9.27, CI 1-85.95). Neonates born to HCV antibody positive
mothers had a lower birthweight (2804 vs. 2943 g,
p=0.047) and were more likely to weigh less than 2500 g (40% vs. 18.4%,
p=0.003), an outcome associated with methadone use, not HCV antibody positivity. Neonates born to HCV antibody positive mothers
had an increased incidence of NICU admission (20.8% vs. 12.1%, p=0.045). Only
nine of 159 HCV antibody positive women were referred for evaluation for
chronic hepatitis C in the peripartum period. Only 3
of 159 neonates born to HCV antibody positive mothers received referral for
follow-up for chronic hepatitis C.
Conclusion:
HCV antibody positive pregnant women have an increased risk
for cholestasis of pregnancy. In pregnant women
involved in a drug dependence and treatment program, HCV antibody positivity is associated with methadone use, and neonates
born to these women are at increased risk for preterm birth, low birthweight, and NICU admission. Postnatal referral of
mother and infant for evaluation of hepatitis C is suboptimal.