Outcome in a hepatitis C (genotype 1b) single source outbreak in Germany - a 25-year multicenter study

Article (PDF Available)inJournal of Hepatology 43(4):590-8 · November 2005with77 Reads
DOI: 10.1016/j.jhep.2005.04.007 · Source: PubMed
Abstract
The natural course of the hepatitis C virus genotype 1b (HCV-1b) infection is still unclear but important for therapeutic decisions. There are few unbiased long-term follow-up studies with known dates of infection. Between August 1978 and March 1979, 14 HCV-1b contaminated batches of anti-D immunoglobulin had been administered to 2867 women for prophylaxis of rhesus isoimmunization throughout East Germany. We reexamined 1980 women, representing 70% of the total cohort of 15 centers. After application of the contaminated anti-D, 93% of the recipients developed an acute hepatitis C. After 25 years, 86% of the 1833 affected women still tested positive for hepatitis C virus antibodies and 46% for HCV RNA. Only nine (0.5%) had overt liver cirrhosis, 30 women (1.5%) developed pre-cirrhotic stages and one HCC was diagnosed. Ten (0.5%) died of HCV related complications, half of these related to additional comorbidity. In the last 5 years, a continuous, but low increase of fibrotic scores was observed. Young women without comorbidity may clear HCV (1b) infection in more than half of the cases, or develop mild chronic hepatitis C. We confirmed the low risk of progression to cirrhosis in this cohort within 25 years.
UNCORRECTED PROOF
Outcome in a hepatitis C (genotype 1b) single source outbreak
in Germany—a 25-year multicenter study
*
Manfred Wiese
1,
*
, Kurt Gru
¨
ngreiff
2
, Wolfgang Gu
¨
thoff
3
, Michael Lafrenz
4
, Ute Oesen
5
,
Heiner Porst
6
, For the East German Hepatitis C Study Group
1
University Affiliated Hospital St. Georg, Leipzig, Germany
2
Hahnemannstr, 39118 Magdeburg, Germany
3
Department of Infectious Diseases, Potsdam, Germany
4
Department of Internal Medicine, University of Rostock, Rostock, Germany
5
Hospital Kuchwald Chemnitz, Chemnitz, Germany
6
Hospital Friedrichstadt Dresden, Dresden, Germany
MS 1399
Background/Aims: The natural course of the hepatitis C virus genotype 1b (HCV-1b) infection is still unclear
but important for therapeutic decisions. There are few unbiased long-term follow-up studies with known dates of
infection.
Methods: Between August 1978 and March 1979, 14 HCV-1b contaminated batches of anti-D immunoglobulin had
been administered to 2867 women for prophylaxis of rhesus isoimmunization throughout East Germany. We
reexamined 1980 women, representing 70% of the total cohort of 15 centers.
Results: After application of the contaminated anti-D, 93% of the recipients developed an acute hepatitis C. After 25
years, 86% of the 1833 affected women still tested positive for hepatitis C virus antibodies and 46% for HCV RNA. Only
nine (0.5%) had overt liver cirrhosis, 30 women (1.5%) developed precirrhotic stages and one HCC was diagnosed. Ten
(0.5%) died of HCV related complications, half of these related to additional comorbidity. In the last 5 years, a
continuous, but low increase of fibrotic scores was observed.
Conclusions: Young women without comorbidity may clear HCV (1b) infection in more than half of the cases, or
develop mild chronic hepatitis C. We confirmed the low risk of progression to cirrhosis in this cohort within 25 years.
q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Keywords: Hepatitis C; HCV genotypes; Natural history; Outcome; Fibrosis; Liver cirrhosis; Anti-HCV; PCR;
Histology; Virology
Journal of Hepatology xx (xxxx) 1–9
www.elsevier.com/locate/jhep
DOCTOPIC: Viral Hepatitis
0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.jhep.2005.04.007
Received 21 December 2004; received in revised form 31 March 2005; accepted 4 April 2005
*
The study protocol is proved by the Study House of the German Network of Competence of Hepatitis ‘HepNet’.
*
Corresponding author. Address: Klinikum St. Georg, Delitzscher Str. 141, D-04129 Leipzig, Germany. Tel.: C49 341 9092606; fax: C49 341 9092637.
E-mail address: wiese@sanktgeorg.de (M. Wiese).
† Other participating members of the East German Hepatitis C Study Group include: U. Go
¨
bel (Cottbus), U. Kullig (Dresden), S. Luda (Leipzig), R. Markus
(Frankfurt/Oder), L. Schmidt (Halle), U. Schmidt (Erfurt), J. Seidel (Suhl); T. Seyfert, I. Schiefke (Leipzig) and M. Dollinger (Halle) from the Region East of
the German Network of Competence in Viral Hepatitis (Spokesman: W. Fleig), B. Tappe (Berlin), as well as the District Study Group of Mecklenburg-
Vorpommern, which includes G. Hauk, M. Knoke, and M. Schroeder.
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UNCORRECTED PROOF
1. Introduction
Hepatitis C virus (HCV) infection is rated by the World
Health Organization (WHO) and international consensus
conferences as a global health problem, based on its
prevalence, the high rate of chronicity, the rate of severe
complications such as cirrhosis and HCC as well as the high
costs of antiviral therapy and liver transplantation [1–3].
Screening measures by transfusion organizations as well as
preventive measures have indeed led to a decreasing
incidence of HCV infections in the industrialized world.
However, the prevalence of fully-developed illnesses
caused by HCV, and the subsequent mortality due to HCV
are rising [4]. An evaluation of the risk of progression to
cirrhosis and HCC is highly important in relationship to the
need for therapy, not only for the general welfare of society
but also for the individual patient. In order to make a
decision for the appropriate therapy, studies of the natural
course of the disease are necessary. This applies especially
to aggressive and very expensive forms of therapy which are
frequently burdened with side effects, e.g. interferon–
ribavirin-therapy for chronic hepatitis C.
Retrospective studies on the natural history of hepatitis C
assumed that HCV would lead to cirrhosis over the course of
20 years. However, more recent studies show that the
progression of hepatitis C is usually slow and that only a
proportion of cases develop rapidly into advanced forms of
liver disease [1,5–7]. Existing studies differ widely in design
with the particular concern that specialized clinics, which
are the sources of some of the studies, are more likely to see
patients with advanced chronic liver disease and less likely
to see those without any symptoms. International consensus
conferences have therefore called for further prospective
studies as well documented populations, indicating that
natural history studies should begin with the onset of HCV
infections. Especially interesting are the rare instances in
which infection begins at a known time, such as the hepatitis
C outbreak in East Germany in 1978/79 [8–12]. An earlier
report regarding this cohort [11] showed the lowest ever
reported cirrhosis rate of only 0.4% after 20 years.
2. Patients and Methods
2.1. Origin of the investigated cohort
During the period between August 1978 and March 1979 there was a
large outbreak of hepatitis C in East Germany involving a total of 2867
cases. This was due to HCV-contaminated anti-D immunoglobulin, given
to Rh-negative women to avoid Rhesus isoimmunization [8–12]. After
hepatitis index cases had been observed at the end of 1978, those women
who had received contaminated batches were identified through documen-
tation at the maternity clinics and were subsequently examined in regional
clinics for infectious diseases. Although, approximately 2/3 of the women
showed no or only mild clinical symptoms, many women had high ALT
values (up to 100 times normal) [9–12]. This population showing an onset
of disease marked by raised ALT values was examined prospectively.
2.2. Characteristics of the cohort
Compared with other published studies [13–18], the cohort analysed in
this paper has an advantage in the investigation of the natural course of
HCV infection: Through documentation of the batches, all recipients of
Anti-D immunoglobulin could be identified thus completely avoiding
selection bias. All received an inoculum contaminated with HCV genotype
1b from an identical source (‘single-source outbreak’). The fact that this
quantitatively large population of young healthy women (average age 24
years) had no competing injury and no severe comorbidity is of further
importance (see Table 1). Additionally, it is possible to analyse the number
of persons who, despite inoculation, did not develop hepatitis C, as
established through identification of normal ALT values and a negative
serologic test for hepatitis C.
2.3. Methods
We have already published the results of 1016 persons infected with
HCV after 20 years [11]. However, because there is concern that the benign
course of the disease described in the publication will not continue, we have
extended the study prospectively over 25 years with 1980 patients, which is
almost 70% of the entire population from 15 regional centres. In order to
avoid bias, all women who had been registered in 1978/79 in the relevant
regional centres, (those who did not develop the disease, those who had
recovered and those with chronic illnesses) were included in the analysis.
At least once a year all regional centres followed-up on the women
registered in 1978/9 (chronic cases were examined more frequently)
clinically, biochemically, serologically, molecularvirologically and
sonographically.
Serological examination for anti HCV was carried out using MEIA
(AxSYM; ABBOTT) and evaluation of HCV-PCR was carried out using
the qualitative test COBAS AMPLICOR HCV (Version 2.0; ROCHE
Diagnostics).
On indication (no clear ALT activity or no clear status, before therapy,
for diagnosing progression of fibrosis, or at the request of the patient), 1207
liver biopsies were carried out, 537 of them between 1995 und 2004. These
were evaluated uniformly according to the ISHAK score [19] by the
histologists assigned to the various centres.
High standards were set for establishing the actual diagnosis; no single
value was considered, only multiple evaluations of ALT and HCV-PCR
over a period of O5 years.
Table 1
Demographic and clinical data of the study population, exposed with a
HCV genotype 1b contaminated anti-D immunoglobulin
Number nZ1980
Sex and ethnic Female, caucasians
Age at HCV infection (median/range) 24 (16–38) years
Age at time of this study (median/
range)
49 (41–63) years
Coinfections
HBV: viremic cases nZ1 (0.05%)
HBV: nonviremic HBsAg positive nZ5 (0.25%)
HIV: None
Cofactors:
Alcohol consumption
a
None nZ831 (42%)
Sometimes (!20 g/d) nZ693 (35%)
O20 g/die nZ396 (20%)
O40 g/die nZ40 (2%)
O60 g/die nZ20 (1%)
Obesity (BMI O30) nZ192 (9.7%)
Diabetes mellitus nZ51 (2.55%)
Gallstones nZ77 (3.87%)
PBC simultaneously nZ1 (0.05%)
a
By declaration of the patients.
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UNCORRECTED PROOF
An informed consent was obtained from each patient, and the study
protocol conforms to the ethical guidelines of the 1975 Declaration of
Helsinki. The University Ethical Committee of Leipzig approved the study.
2.3.1. Statistical analysis
The database was constructed with Microsoft Access within the
German Network of Competence of Hepatitis. Data were summarized as
median and range. Comparison of PCR subgroups involved analysis of chi
square test and linear regression.
3. Results
3.1. Acute course and the early period of follow-up
In the acute stage, the patients showed (at that time
unknown) characteristics of an acute viral hepatitis C (see
Table 2). One thousand two hundred and twenty-one
patients (66.6%) had no, or only imperceptible complaints
and often polyphasic ALT pattern [9,10]. In 458 patients,
jaundice was evident; fulminant courses of hepatitis were
not observed. One hundred and forty-seven women (7%)
had not exhibited increased ALT levels after HCV
inoculation and tested negative for HCV markers so that
they were assessed as inoculated persons without signs of
hepatitis.
In 28% patients, ALT levels were persistently normal 1
year after infection serum, whereas the remaining 72% of
the cohort developed a biochemically and, mostly histo-
logically proved chronic hepatitis C (see [11]).
3.2. Outcome 25 years after HCV genotype 1b infection
3.2.1. Clinical data
After 25 years, 1141 patients (62%) of the patients
complained of constitutional symptoms such as reduced
exertional capacity, weakness and fatigue, abdominal disten-
tion, arthralgia, myalgia, or headaches in most cases in a
intermittent manner. Sonographic examination revealed an
enlargement of the liver (craniocaudal diameter O15 cm) and
a coarse structure on ultrasound in 343 (19%) of the cohort.
Serum ALT activity was normal in 1216 (61%) of the entire
cohort. Also in 176 (20%) chronic viremic women the ALT
was completely normal, but fluctuating in 138 (16%) and
permanently elevated in 554 (64%). Persistently normal ALT
levels and no clinical and histological evidence of liver disease
were presented in 14 viremicwomen (0.8%); they are regarded
Table 2
Acute course of hepatitis C virus (genotype 1b) infection in 1980 women
exposed with HCV contaminated anti-D immunoglobulin
Clinical course n (% of total) ALT (mIU/mL)
median (range)
Bilirubin
(mg/dL)
median (range)
Acute hepatitis
a
Fulminant 0 (–)
Icteric 458 (23) 765 (114–2305) 9.8 (1.6–20.3)
Anicteric 725 (37) 348 (50–1303) 0.7 (0.4–1.5)
Asymptomatic 628 (32) 390 (42–1500) 0.65 (0.3–1.0)
Unknown
b
22 (1) Unknown
No evidence of
hepatitis C
c
147 (7) 16 (5–20) Not determined
All with acute
hepatitis C
1833 (93) 26 (50–2305) 0.8 (0.3–20.3)
All exposed to
HCV
1980 (100)
a
Defined as ALT increase above the upper limit of normal (34 mU/mL)
within first 6 months.
b
Data of the years 1978/79 missing, but increase of ALT had been
certified.
c
Inoculated with HCV contaminated anti-D immunoglobulin without
subsequent increase in serum aminotransferases or markers of HCV
infection during follow-up.
Table 3
Clinical and biochemical outcome 25 years after infection with
hepatitis C virus genotype 1b in formerly healthy women
Patients (n) Percent rate
Of all After acute
hepatitis
1980 (nZ1980) (nZ1833)
Constitutional symptoms
a
1141 58 62
Minimal or intermittent 803 41 44
Substantial or permanent 338 17 18
Clinical findings
b
Liver below costal margin 682 34 37
Hepatosplenomegaly 14 0.7 0.8
Sonography
Coarse structure 343 17 19
Focal liver lesion
c
7 0.4 0.4
Markers for hepatocellular
carcinoma
Alpha-fetoprotein elevated
d
86 4 5
Biochemical findings
ALT (all exposed) 1980 100
Normal 1216 61
Fluctuating
e
210 11
Permanently elevated
f
554 28
ALT (chronic cases) 868 100
Normal 176 20
Fluctuating
e
138 16
Permanently elevated
f
554 64
Bilirubin elevated
f
119 6 7
GGT elevated
f
164 8 9
IgG IgG elevated
f
191 10 10
P III P elevated
f
166 8 9
Serology: anti-HCV positive 1573 79 86
a
Any of the following: abdominal distension, reduced physical
performance, increased body pain (myalgia, arthralgia or headaches), and
fatigue.
b
If liver was palpable O2 cm caudal to the costal margin (span O12 cm;
consistency grade I–II) or transverse craniocaudal diameter of the right lobe
was O15 cm on ultrasound.
c
Focal liver lesions as detected by ultrasound (benigne lesions included;
1 hepatocellular carcinoma).
d
One hepatocellular carcinoma with AFP 43.5; other values above the
upper limit (O7 mmol/l) were chronic hepatitis.
e
Sometimes above the upper limit.
f
Permanent above the upper limit.
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UNCORRECTED PROOF
as HCV carriers. Alpha-fetoprotein as marker for hepatocel-
lular carcinoma was elevated in 86 (5%) of the patients above
the upper limit of normal, but only one of these patients had a
HCC (AFP 43.5 mmol/l). Other biochemical parameters are
shown in Table 3.
Sixteen patients (0.8%) had died, in seven cases (0.35%)
as a result of hepatitis C complications, and in three cases
(0.15%) because of severe comorbidity or cofactors. In six
cases (0.3%), the HCV infection was cleared before death.
3.2.2. HCV infection status
One thousand five hundred and seventy-three (79%) of
the entire cohort were still positive for anti-HCV, and 835
(42%) for HCV RNA by PCR (see Table 4). Twenty-five
years after acute hepatitis C, 835 (46%) of all women with
documented acute hepatitis showed persistent viremia with
HCV genotype 1b, including 185 (10%) who had not
responded to treatment with interferon. Conversely, 1145
(54%) had cleared the virus, among them 883 (48%)
spontaneously, and 115 (6%) in response to treatment with
interferon. The sustained viral response to interferon
treatment was surprisingly high (115/300Z38%) compared
to a similar cohort [17].
Figs. 1 and 2 show the final results of the examined
population after 25 years. In the period from acute stage to
the 25th year, the viral clearance was much higher in
jaundiced acute hepatitis than in asymptomatic cases (66/
45%, resp.; P!0.001). Fig. 3 shows changes in the natural
course in the last 5 years in a subgroup of women (nZ907)
already studied in the 20th year [11]. In this subgroup, six
cases proceeded from chronic hepatitis of different stages to
cirrhosis, five chronic cases deteriorated to precirrhosis and
nine carriers developed to chronic hepatitis.
3.2.3. Liver histology
In the last 10 years (15–25 years after infection), liver
biopsy specimens had been obtained in 537 patients,
including 490 (59%) viremic women. Two hundred and
twenty-one liver biopsies were carried out in the last 5 years
(see Table 5). Inflammatory activity was absent in 14 (30%)
of the nonviremic women and minimal (grading 1–3) in 29
(63%) of the patients. All but one of them lacked any
evidence of advanced severe fibrosis. Among the 490
viremic women 254 (54%) showed chronic hepatitis of
minimal grade (score 1–3), 182 (37%) of mild grade (score
4–8), and 11 (2.2%) of moderate grade (score 9–13). Mild
portal fibrosis with no or rare short fibrous septa (staging
score 1 or 2) was present in 270 (55%), and discrete or
marked bridging fibrosis (staging 3 or 4) in 43 (9%) of the
viremic women. Development of incomplete or complete
cirrhosis (staging 5 or 6) was observed in 11 patients during
the last 5 years, compared to two patients in the previous
time. The trend of the fibrosis scores over time was
significant with linear regression (Fig. 4). Between the
10-year and the 5-year study period, only a slight increase in
precirrhotic and cirrhotic scores was noted.
Table 4
Virological outcome 25 years after infection with hepatitis C virus
genotype 1b in formerly healthy women
Patients (n) Percent rate
Of all After acute
hepatitis
Total 1980 (nZ1980) (nZ1833)
HCV infection
status
a
Serum HCV-RNA positive
a
835 42 46
Chronic infection
(untreated)
650 33 36
Non-responder to
interferon
b
185 9 10
Serum HCV-RNA negative
a
1145 58 54
c
No evidence of past
hepatitis C
d
147 7
Self-limited infection
e
883 45 48
Sustained responder to
interferon
b
115 6 6
Liver disease
f
None 1112 56 53
c
Recovered
spontaneously
836
g
42 46
HCV carrier
h
14 0.7 0.8
No evidence of past
hepatitis
i
147 7
Responder to interferon
b
115 6 6
Chronic cases totally 868 44 47
Chronic hepatitis 643 32 35
Precirrhotic stage 30 1.5 1.6
Cirrhosis
j
9 0.5 0.5
Hepatocellular carcinoma
in cirrhosis
k
1 0.05 0.05
Non-responder to
interferon
b
185 9 10
Death (all cases)
l
16 0.8 0.87
a
HCV RNA in serum positive or negative, respectively, by PCR
(COBAS AMPLICOR HCV
w
, Version 2.0, ROCHE Diagnostics)
independent to liver diagnosis.
b
Treated with interferon-alpha 3–6 MU t.i.w. or pegylated interferon
with or without ribavirin for up to 12 months.
c
Calculated as [(nK147)/1833]!100.
d
Women who had received HCV-contaminated batches of anti-D
globulin without consecutive rise in transaminases and who tested negative
for anti-HCV and HCV RNA later.
e
Defined as un-detectable HCV RNA in serum.
f
Categorized as: None, if persistently normal ALT over a period O5
years, no hepatomegaly, no splenomegaly, and sharp lower liver margins on
ultrasound or normal histology. Chronic hepatitis C, if intermittent or
permanent elevation of serum ALT and HCV viremia (without or with liver
biopsy). Cirrhosis (clinical diagnosis), in presence of palpable liver with
consistency grade III–IV and blunt margins or caput medusae, esophageal
varices, ascites.
g
Of them six patients are dead.
h
Chronic viremia (HCV RNA) with persistently normal ALT, without
evidence of liver disease.
i
Women who had received HCV-contaminated batches of anti-D
immunoglobulin without consecutive rise in ALT levels and who tested
negative for anti-HCV and HCV-RNA later.
j
Of them one primary biliary cirrhosis without HCV replication.
k
Histology: HCC of the infiltrative type, stage D; extension: entire
right lobe of the liver, extending on the left lobe and ascites; palliative
therapy.
l
See Table 5.
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3.2.4. Final diagnoses, clinical endpoints
After 25 years, 836 HCV infected women (46%) showed
a spontaneous recovery with viral clearance, normal ALT
levels and/or normal liver histology. One hundred and
fifteen women (6% of the total cohort) were cured
successfully with interferon/ribavirin in various therapeutic
schedules during the last decade.
In contrast, the rate of chronic hepatitis with persistent
viremia comprised 868 (47%) women after 25 years. An
apparent HCV carrier status was assessed in 14 cases
(0.8%). The rate of precirrhotic and cirrhotic stages
(1.6/0.5%, resp.) increased slightly in the last 5 years and
one hepatocellular carcinoma was diagnosed. Comparing
the results between the 20th and the 25th year in a subgroup
(nZ907) nine apparent carriers and 11 patients with chronic
hepatitis deteriorated. The HCV related mortality was
relatively low (nZ7Z0.35%). In additional three cases
(0.15%), with severe comorbidity the HCV infection was a
partial mortality factor (see Table 6).
4. Discussion
Not only patients but doctors as well need reliable
information regarding the natural course of HCV infection,
the former for planning their lives, the latter for a
substantiated decision on whether expensive therapy with
considerable side effects should be recommended to the
patient. Unfortunately, despite a considerable number of
publications—Freeman et al. [20] found in a metaanalysis
145 studies—a clear answer has still yet be given. After 20
years, progression rates to cirrhosis in studies of post-
transfusion hepatitis were 24 (11–37)%, in retrospective
studies in Hepatology Centers 22 (18–26)%, in community
based cohorts 7 (4–10)% and among blood donors 4 (1–7)%.
Seeff found a cirrhosis rate of 42% in retrospective studies,
of 11% in prospective studies, and of 2.1% in retrospective-
prospective cohort studies [7]. Within his own posttransfu-
sion study, there were 15% cirrhosis after 23 years, and in a
study among young men over a period of 45 years, the
cirrhosis rate was 5.9% [21]. An HCC was observed in 0–
1.3%, and liver-associated death in 1.6–6%, within a mean
follow up period of 8–14 years [22–25]. A WHO working
group estimated the proportion of infected persons who
develop chronic viraemic infection at 75%, the proportion
of chronically infected persons who develop cirrhosis w20
years after infection at 20–40% (younger than 40 or older)
and the annual rate of HCC among patients with cirrhosis at
1.6% [1]. How can such significant differences be
Recipients of HCV contaminated anti-
D immunoglobulin
n = 1980
Inocculatedbut no hepatitis
developed
n =147
Acute hepatitis C
n = 1833
Sustained responder
to IFN
n = 115
Follow-up
n = 1718
Chroniche patitisC
n = 868
Nonresponder to IFN
n = 185
Chronic hepatitis C
Natural course
n = 683
Chronic hepatitis
n = 643
Precirrhotic stage
n = 30
Cirrhosis
n = 9
HCC in cirrhosis
n = 1
Death from HCV or combination of
HCV and other diseases
n = 10
Spontaneous
recovery
n= 836
HCV carrier
n = 14
Fig. 1. Natural course of a HCV (genotype 1b) infection in young women from acute stage to clinical endpoints after 25 years.
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explained? Investigations so far show that there can be no
single answer on the prognosis of hepatitis C. Due to the fact
that the results depend strongly on the population examined,
on the study method and duration of follow up, as well as on
host factors (age at infection, sex), co-factors (coinfections,
alcohol), viral and transmission factors, and therefore, very
variable. In most studies on chronic hepatitis C, there was a
bias in favour of severe and progressive cases.
For a valid study on the natural course of hepatitis C, the
following demands were set: (1) known date of infection or
onset of hepatitis C, (2) inclusion of the full range of the
acute virus hepatitis C, (3) no therapy influences to interfere
with the natural course, (4) continuous follow-up results
until recovery or up to the endpoints death or liver
transplant, and (5) control group without hepatitis C.
Because of the mostly unclear onset of hepatitis C, and
the course without symptoms over decades, the postulates 1
and 2 are not realised in most studies, including the Irish
study on HCV infected women [13]. In contrast, the study
we are describing realizes those imperatives because the
exact inoculation date is known and the whole cohort
inoculated is documented, as well as the full clinical course
at the acute stage. The cohort includes w70% of the 2867
women exposed to contaminated anti-D immunoglobulin
and is, therefore, a representative study population. Ful-
filling the third postulate conflicts with ethical consider-
ations. Refusal of indicated antiviral therapy could not be
justified for ethical reasons. In our study, only 15% of the
population received treatment. We think the relatively small
group of patients treated only has a small influence on the
progression rate, so that the results presented here reflect the
natural course of HCV (1b) infection. Thirty-eight percent
of our patients treated have reached a permanent response
(SVR) to various interferon/peginterferon-(ribavirin) treat-
ments carried out over the last 15 years. In our patients, the
success of the therapy was significantly higher than in the
Irish study, in which none of the 11 women treated obtained
an SVR [17].
A complete follow up from the onset to the clinical end
points and a matched control group-according to demands 4
and 5—is usually impossible [7]. In our study, at least
the patients who have either recovered completely or have
died have been documented exactly from onset to the
clinical end points. This study shows, that in a representa-
tive female population with HCV (1b)-infection, the virus
has been eliminated spontaneously after 25 years in 48% of
Recipients of HCV contaminated
anti-D immunoglobulin
n = 1980
Inocculatedbut no hepatitis C developed
n =147
Acute hepatitis C
n = 1833
Unkown acute course
n = 22
Follow-up
n = 1811
Unjaundiced acute course
but symptoms of hepatitis
n = 725
PCR
positive
n = 143
PCR
negative
n = 283
= 66,4 %
Asymptomatic acute course
No symptoms but elevated
ALAT
n = 628
Jaundiced acute course
n = 458
Follow-up
n = 426
Follow-up
n = 582
Follow-up
n = 688
IFN responder
excluded
n = 32
IFN responder
excluded
n = 46
IFN responder
excluded
n = 37
PCR
positive
n = 368
PCR
negative
n = 320
= 46,5 %
PCR
positive
n = 318
PCR
negative
n = 264
= 45,4 %
Fig. 2. Natural course from acute stage (jaundiced—unjaundiced—asymptomatic acute pattern) to the 25th year. The highest viral clearance was
observed in icteric cases (66.4% compared with 45.4% in asymptomatic cases; P!0.001).
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all affected women. The virus elimination was significantly
higher in icteric cases (66%) compared with asymptomatic
courses (P !0.001; Fig. 2). This confirms that an icteric
acute course expresses a strong immune response, along
with a high degree of self limiting infections [16]. This
observation is important for deciding therapy in case of
acute icteric hepatitis C [26].
Among the clinical findings, it was noticeable that
62% of the women—regardless of the stage of their
illness subjectively still described more or less intense
symptoms.
In 61% of the women, ALT values were normal, among
these 20% of chronic cases of hepatitis. These data
correspond to recent studies of patients with persistently
normal ALT levels [27,28].
Persisting viraemia with chronic hepatitis C was now
documented in 46% of cases, clinically evident cirrhosis
in 0.5% of viraemic women, and an HCC in 0.05%.
Fig. 3. Evolution in the chronic stage between 20th and 25th year (subgroup (nZ482) from the study published in Hepatology 2000;32:91–96.
Recovered cases and inoculated cases without hepatitis (nZ425) were not shown.) In this published subgroup, six cases proceeded from chronic
hepatitis of different stages to cirrhosis, five chronic cases deteriorated to precirrhosis and nine carriers developed to chronic hepatitis.
Table 5
Liver biopsy findings in anti-HCV positive women in the 15–25th year (nZ537) and in the 20–25th year (nZ221) after infection with hepatitis C virus
genotype 1b
Histologic score
a
HCV RNA positive HCV RNA negative
15–25th year 20–25th year 15–25th year 20–25th year
(nZ490) (nZ196) (nZ47) (nZ25)
n (%) n (%) n (%) n (%)
Grading 0 33 (7) 12 (6) 14 (30) 4 (16)
1–3 264 (54) 102 (52) 29 (63) 20 (80)
4–8 182 (37) 73 (38) 4 (8) 1 (4)
9–12 10 (2) 7 (2.6) (–) (–)
13–18 1 (0.2) 1 (0.5) (–) (–)
Staging 0 164 (34) 39 (20) 25 (53) 5 (20)
1 173 (35) 66 (33) 16 (34) 14 (56)
2 97 (20) 52 (26) 5 (10) 5 (20)
3 30 (6) 21 (11) (–)
4 13 (3) 7 (4) (–)
5 6 (1) 5 (3) (–)
6 7 (2) 6 (3) 1
b
(2) 1
b
(4)
Total 490 (100) 196 (100) 47 (100) 25 (100)
a
Score of inflammatory grading (score 0–18) and fibrosis staging (score 0–6) according to Ishak et al.
b
Hepatocellular carcinoma in cirrhosis.
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UNCORRECTED PROOF
Liver-associated mortality was 0.5% in viremic women
(nZ10); more than half of them showed significant
comorbidity (chronic abuse of alcohol; one HBV super-
infection with fulminant course; vascular diseases). Fur-
thermore, most of these women were not in medical care of
liver centers. Further six nonviremic women died from other
causes (see Table 6). Up to now, no elevated HCV
associated mortality was registered.
Altogether, the rate of progressive liver disease was
astonishingly low. This is also shown by the histological
findings (Table 5). The results for our study population
match the findings of Poynard et al. [29], who showed in an
y = 0,011x + 2,63
y = 0,0674x - 0,2253
0
1
2
3
4
5
6
1 3 5 7 9 1113151719212325
Years of
Hepatitis C
Grading
0
1
2
3
4
5
6
Staging
Grading Staging Linear Regression (Grading) Linear Regression (Staging)
..
Biopsyn=112161021 812 5 3 7 137 9181865786574553642403441
Fig. 4. Liver histology (nZ699): number of biopsies per year and mean scores of grading and staging from acute stage to the 25th year. –––!––– mean
score of grading per year and trend of the scores over time
mean score of staging per year and trend of the scores over time line under the
diagram: number of biopsies per year from first to the 25th year.
Table 6
Clinical endpoints reached in the 25th year of follow-up
Patients (n) Percent rate (of all study
persons)
Spontaneously complete recovery
a
nZ836 (42.2)
Complete recovery by IFN-(RBV-)therapy
b
nZ115 (5.8)
Liver transplantation nZ2 (0.1)
All cases of death nZ16 (0.8)
Death from complications of HCV caused liver disease
c,d
nZ7 (0.35)
(e.g. Bleeding from esophageal varices or hepatic coma. None postmortem
examination available.)
Death cause: combination viremic Hepatitis C and other disease
e,d
nZ3 (0.15)
(other competitive causes of death existed, e.g. fulminant hepatitis by HBV
superinfection or bleeding to death during surgery as a result of gynecologic
cancer.)
Death from other diseases (previous HCV elimination)
f
nZ6 (0.3)
a
Categorized as: Spontaneously complete recovery, if HCV RNA in serum was below the lower limit by PCR (!50 IU/ml) and ALT was normal over a
period O5 years or the biopsy showed normal liver histology.
b
If after follow-up of O12 months HCV RNA in serum was below the lower limit by PCR (!50 IU/ml) and the ALT and/or the histology were normal.
c
HCV RNA in serum by PCR positive. Most of these women were not in permanent medical follow-up and had additional (suspected) chronic alcohol
abuse.
d
Five out of 10 viremic cases died between the 20th and the 25th year after HCV infection.
e
At time of death HCV RNA in serum by PCR positive.
f
At time of death HCV RNA in serum was below the lower limit by PCR (!50 IU/ml); other causes of death existed, e.g. cancer or cardiac insufficiency.
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extensive histological follow-up study, that the fibrosis
patterns in patients with chronic hepatitis C are very
heterogeneous: in this study there was one third of slow
fibrosers who would first suffer from cirrhosis after 50 years
(if at all). As in our study, this group consisted of women
who were infected before the age of 40 and did not drink
alcohol. The results of our study are certainly positively
influenced by the young age (median 24 years), the female
sex and a strong immunological response at the time of
infection. The absence of other risk factors or coinfections, a
low-risk lifestyle, and long-term medical care starting
immediately after screening may also have contributed to
the benign course. In our study population, there was still
only a slight increase in precirrhotic findings after 20 years
(see Fig. 3 and trend for fibrosis in Fig. 4). In addition to our
earlier study, the 25-year results after this quantitatively
high HCV outbreak show that a clear transition to a
progressive course of hepatitis C is not evident so far.
Acknowledgements
We are very gratefull to Dr med. H. Wedemeyer from the
German Network of Competence in Viral Hepatitis for
helpful discussions and much support. Moreover we thank
Prof. Dr med. R. Haupt, Leipzig, PD Dr med. G. Haroske,
Dresden, Dr med. habil. J.-O. Habeck, Chemnitz and Dr
med. B. Stengel (Rostock) for scoring of liver biopsies as
well as PD Dr E. Herrmann for statistical support.
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    • "About 20% or less of initial HCV infections causes acute viral hepatitis with a great severity enough for the patient to seek medical care, nevertheless, about 60-85% of all infections become persistent though diverse viral invasion strategies [16,17]. Chronically infected patients usually remain undiagnosed and asymptomatic for a long time before chronic hepatitis may lead to severe fibrosis, cirrhosis, hepatic failure, or hepatocellular carcinoma [18, 19] . HCV persistence is due to the imbalance between Thelper type 1 (Th1) and type 2 (Th2). "
    [Show abstract] [Hide abstract] ABSTRACT: Isoquinoline alkaloidal content of Berberis vulgaris L. (Berberidaceae) is regarded as the main source of pharmacological activity. Studies showed that berberine (BB) possesses cytotoxic and hepatoprotective properties. The aim of the study was to isolate BB from B. vulgaris and semisynthesis of berberrubine (M1) and diberberine sulphate (Di-BB), investigate their efficiency as cytotoxic, antihepatitis C virus (HCV) agents and acetylcholinesterase enzyme (AChE) inhibitors. M1 and Di-BB were semisynthesized from BB previously isolated from Berberis vulgaris methanolic extract. Structures of the three compounds were elucidated on basis of 1H- and 13C-NMR and LC/MS. Cytotoxicity activity was studied using both normal peripheral blood mononuclear cells as control and three different proliferating cancerous cell lines; HepG-2, Caco-2 and MCF-7. The capability to inhibit viral replication was evidenced by the disappearance of viral RNA-amplified products detected by RT-PCR after incubation for 96 h. In vitro study of cytotoxic activities showed that, B. vulgaris extract was the most efficient on Caco-2 (IC50 3.836 μg/mL) and HepG-2 (IC50 5.55 μg/mL) cells lines, while, BB was the most potent on MCF-7 (IC50 4.433μg/mL) at 48 h. Replication of HCV RNA was inhibited at 100 μg/mL of each of B. vulgaris extract, BB and Di-BB. Finally, Di-BB significantly inhibited AChE activity (IC50: 100 μg/mL). In conclusion, the alkaloids studied possessed potent hepato-protective properties. Furthermore, the AChE inhibiting activity of Di-BB makes it a point of interest for further study on treatment of Alzheimer's disease.
    Full-text · Article · Sep 2016
    • "Interestingly, significant associations between gender and relapse were observed in both the ITT and G3-infected populations. Although numerous reports have identified female gender as an independent predictor of spontaneous viral clear- ance3839404142, limited evidence is available for the association between gender and treatment outcomes: while Manns et al. have previously identified an association between gender and SVR [33], numerous publications have failed to identify gender as an independent predictor of response to peg-IFNα + RBV combination therapy [7,111213. However, in individuals with chronic HCV infection, more rapid rates of fibrosis progression have been found in men43444546, with evidence supporting beneficial effects of estrogen slowing the progression of liver fibrosis in women [47, 48]. "
    [Show abstract] [Hide abstract] ABSTRACT: The purpose of this investigation was to assess the real-life effectiveness of pegylated interferon (peg-IFN) α-2b with ribavirin (RBV) in a cohort of treatment-naïve patients with chronic genotypes 2 (G2) or 3 (G3) hepatitis C virus (HCV) infection. A post-hoc pooled analysis of two Canadian multicenter, observational studies, RediPEN and PoWer, was carried out. A total of 1242 G2- or G3-infected patients were included. The primary outcome was sustained virologic response (SVR). Secondary endpoints included early virologic response (EVR), end-of-treatment (EOT) response, and relapse. Multivariate logistic regression was used to identify independent predictors of treatment response. SVR in G2 and G3 was 74.4 % and 63.6 %, respectively. Relapse occurred in 12.7 % and 19.1 % of G2- and G3-infected patients achieving EOT response, respectively. Overall, G3 was found to independently predict reduced SVR [odds ratio (OR) = 0.20; p = 0.007] and increased relapse (OR = 6.84; p = 0.022). Among G3-infected patients, increasing fibrosis score was the most important factor predicting reduced SVR [F2 vs. F0/F1 (OR = 0.41; p = 0.009); F3 vs. F0/F1 (OR = 0.72; p = 0.338); F4 vs. F0/F1 (OR = 0.27; p = 0.001)]. Male gender (OR = 13.16; p = 0.020) and higher fibrosis score [F2 vs. F0/F1 (OR = 9.72; p = 0.016); F3/F4 vs. F0/F1 (OR = 4.23; p = 0.113)] were associated with increased relapse in G3 patients. These results support the real-life effectiveness of peg-IFN α-2b plus ribavirin in HCV G2- and G3-infected patients. Overall, genotype was identified as the most significant predictor of treatment outcome. Fibrosis score and gender were key outcome predictors in the G3-infected population. In clinical settings, peg-INF/RBV offers an alternative for patients without access to all oral direct-acting antivirals.
    Full-text · Article · Feb 2016
    • "of HCV. In HCV monoinfection without concurrent excess alcohol consumption , a minimum of 20–30 years is typically required for HCV to cause significant liver disease such as cirrhosis or hepatocellular carcinoma (HCC) [55][56][57][58][59]. HIV-infected individuals, when exposed to HCV, are less likely to be spontaneously clear of infection [60, 61]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background . Hepatitis C virus (HCV) coinfection occurs in 20–30% of Canadians living with HIV and is responsible for a heavy burden of morbidity and mortality. Purpose . To update national standards for management of HCV-HIV coinfected adults in the Canadian context with evolving evidence for and accessibility of effective and tolerable DAA therapies. The document addresses patient workup and treatment preparation, antiviral recommendations overall and in specific populations, and drug-drug interactions. Methods . A standing working group with HIV-HCV expertise was convened by The Canadian Institute of Health Research HIV Trials Network to review recently published HCV antiviral data and update Canadian HIV-HCV Coinfection Guidelines. Results . The gap in sustained virologic response between HCV monoinfection and HIV-HCV coinfection has been eliminated with newer HCV antiviral regimens. All coinfected individuals should be assessed for interferon-free, Direct Acting Antiviral HCV therapy. Regimens vary in content, duration, and success based largely on genotype. Reimbursement restrictions forcing the use of pegylated interferon is not acceptable if optimal patient care is to be provided. Discussion . Recommendations may not supersede individual clinical judgement. Treatment advances published since December 2015 are not considered in this document.
    Full-text · Article · Jan 2016
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