During a median period of 22.8 years after HBeAg seroclearance, 40 66% patients became inactive carriers, whereas the remaining 21 34% showed alanine aminotransferase elevation: one 1% h
Trang 1doi:10.1136/gut.2007.128496 2008;57;84-90; originally published online 22 Aug 2007;
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G Fattovich, N Olivari, M Pasino, M D’Onofrio, E Martone and F Donato
Caucasian patients: mortality after 25 years Long-term outcome of chronic hepatitis B in
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Trang 2Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years
G Fattovich,1 N Olivari,1 M Pasino,1 M D’Onofrio,2 E Martone,2 F Donato3
1 Department of
Gastroenterology, University of
Verona, Verona, Italy;
2 Department of Radiology,
University of Verona, Verona,
Italy; 3 Institute of Hygiene,
Epidemiology and Public Health,
University of Brescia, Brescia,
Italy
Correspondence to:
Dr G Fattovich, Unita ` Operativa
di Gastroenterologia,
Dipartimento di Scienze
Chirurgiche e
Gastroenterologiche, Universita `
di Verona, Piazzale L.A Scuro n.
10, 37134 Verona, Italy;
giovanna.fattovich@univr.it
Revised 5 August 2007
Accepted 15 August 2007
Published Online First
22 August 2007
ABSTRACT Objective: To assess risk factors for liver-related death,
we re-evaluated, after a median follow-up of 25 years, a cohort of 70 Caucasian patients with hepatitis B e antigen (HBeAg) positive chronic hepatitis (CH) at presentation
Methods: Follow-up studies included clinical and ultra-sound examinations, biochemical and virological tests, and cause of death
Results: Sixty-one (87%) patients underwent sponta-neous HBeAg seroconversion During a median period of 22.8 years after HBeAg seroclearance, 40 (66%) patients became inactive carriers, whereas the remaining 21 (34%) showed alanine aminotransferase elevation: one (1%) had HBeAg reversion, nine (15%) detectable serum HBV DNA but were negative for HBeAg, eight (13%) concurrent virus(es) infection and three (5%) concurrent non-alcoholic fatty liver disease Liver-related death occurred in 11 (15.7%) patients, caused by hepatocellular carcinoma in five and liver failure in six The 25-year survival probability was 40% in patients persistently HBeAg positive, 50% in patients with HBeAg negative CH
or HBeAg reversion and 95% in inactive carriers Older age, male sex, cirrhosis at entry and absence of sustained remission predicted liver-related death independently The adjusted hazard ratios (95% CI) for liver related death were 33 (3.01–363) for persistently HBeAg positive patients and 38.73 (4.65–322) for those with HBeAg negative CH or HBeAg reversion relative to inactive carriers
Conclusion: Most patients with HBeAg seroconversion became inactive carriers with very good prognosis The risk of liver-related mortality in Caucasian adults with CH
is strongly related with sustained disease activity and ongoing high level of HBV replication independently of HBeAg status
Chronic hepatitis B virus (HBV) infection is an established cause of liver-related morbidity and mortality and represents a major global public health problem.1 2 Studies conducted in Asian regions of high HBV endemicity have estimated that up to 40%
of individuals with chronic HBV infection will progress to liver cirrhosis, end-stage liver disease or hepatocellular carcinoma (HCC) during their life-time and that HBV-related liver disease contribute to approximately 20 deaths per 100 000 population each year.3 4
The long-term liver-related morbidity and mortality of chronic hepatitis B in untreated Caucasian patients and predictors of survival deserve further evaluation In fact, the prognostic value of sustained high levels of HBV replication on survival
in untreated Caucasian patients is limited to cohorts
of patients with cirrhosis.5–7
We conducted this longitudinal study to eluci-date the long-term survival according to virological
pattern in a cohort of north Italian patients with chronic hepatitis B who had high levels of HBV replication (HBeAg positive) at diagnosis, during a median period of 25 years
PATIENTS AND METHODS Patients
A longitudinal study began in Padova, northern Italy, enrolling between 1972 and 1984 seventy consecutive hepatitis B surface antigen (HBsAg) and HBeAg positive patients, 49 male and 21 female with a median age of 29 years and with biopsy proven chronic hepatitis (8 (11.4%) with cirrhosis) at presentation The clinical, virological and histological details of the study population at entry and the natural history of the disease during
a mean follow-up period of 5.0 years (SD 2.3 years) were described previously.8 The follow-up of this cohort of patients has been performed at the Department of Gastroenterology at Verona University Hospital in northern Italy and updated through June 2006
Follow-up data were obtained during regular clinical controls, on average every 6 months for patients who remained HBeAg positive or sero-converted from HBeAg to anti-HBe, but main-tained or developed abnormal ALT levels and on everage every 12 months for inactive HBsAg carriers By 1986 it became clear that HBeAg seroclearance with ALT normalisation is usually associated with histology improvement,8 thus in the subsequent years follow-up liver biopsies were performed only in patients with active hepatitis Patients who did not undergo the regular controls were traced through the municipality registries and were phoned and asked to attend again the clinic for evaluation People who refused to attend the clinic again were interviewed by phone and asked
to provide laboratory and liver ultrasound exam-inations with the consent of their family doctors Data on patients’ liver-related or other diseases that had been collected through the phone inter-views were cross-checked with the archives of their family doctors The causes of death for those deceased were ascertained by retrieving the death certificates We were able to trace all patients except two (97.1%) from the initial cohort The current study was approved by the Verona Hospital Ethics Committee
Definition of clinical events The time of observation was calculated from the date of entry into the study until death, liver transplantation or the last observation The primary outcome was liver related mortality The occurrence of cirrhosis during follow-up was
Trang 3defined by histology or ultrasonography features suggestive of
cirrhosis based on a quantitative scoring system derived from
the appearance of the liver margins, parenchymal echotexture,
portal vein calibre and spleen diameter,9 10supplemented with
the presence of oesophageal varices or ascites HCC diagnosis
was based on the following criteria: a histopathological
examination; a positive lesion detected by at least two different
imaging techniques (abdominal ultrasonography, computerised
tomography, or angiogram); a positive lesions detected by one
imaging technique and a-fetoprotein levels exceeding 400 mg/l
Biochemical remission was defined as the normalisation of
serum ALT levels on at least two consecutive determinations
obtained at least 3 weeks apart and persisting at last
observa-tion After HBeAg seroclearance with anti-HBe seroconversion,
patients were defined as inactive HBsAg carries when ALT
values were persistently normal and HBV DNA was persistently
negative according to non-polymerase chain reaction (PCR)
assays (detection limit, 1.46105 copies/ml) Active hepatitis,
after HBeAg seroclearance, was defined as ALT elevation over
twice the upper normal value on at least two consecutive
determinations obtained at least 3 weeks apart HBeAg negative
hepatitis was diagnosed when abnormal ALT and HBV DNA
seropositivity by non-PCR assays persisted continuously or
recurred intermittently after HBeAg seroclearance
Laboratory procedures
HBsAg, antibody to HBsAg (anti-HBs), HBeAg, antibody to
HBeAg (anti-HBe), hepatitis delta virus (HDV) and hepatitis C
virus (HCV) antibodies, hepatitis A virus IgM antibodies were
detected by conventional serological assays Serum HBV DNA
was first tested by homemade spot hybridisation with a
detection limit of 0.1 pg/ml,8then the Digene Hybrid Capture
System assay (Digene, Beltsville, MD) was used, with a
detection limit of 0.5 pg/ml (1.46105copies/ml) More recently
HBV DNA was tested with a commercial PCR assay (Cobas
Amplicor HBV Monitor, Roche, Basel, Switzerland) with a
detection limit of 200 copies/ml
Serum HDV RNA was detected by an ‘‘in-house’’
reverse-transcriptase PCR (RT-PCR) in the virology laboratory of the
University Hospital of Verona Briefly, HDV RNA was
extracted from 200 ml of serum, reverse transcribed and
amplified by one-step RT-PCR in a final volume of 50 ml using
a set of primers derived from the carboxyterminal portion of the
genomic region coding for the HDV antigen (primers 59 R 39,
position 886–909 and 1331–1310, respectively) The
amplifica-tion products were visualised on a 2% agarose gel stained with
ethidium bromide For each test sample a negative and a
positive control were included in parallel throughout the entire
procedure Serum HCV RNA was first measured by an
‘‘in-house’’ nested RT-PCR with a detection limit of 100 copies/
ml,11then was assessed using a commercial PCR assay (Cobas
Amplicor HCV Monitor, Roche, Basel, Switzerland)
Histological diagnosis was defined according to international
criteria.12 13
Statistical analysis
The Mann–Whitney and x2 and exact tests were used for
comparison of continuous and categorical variables between
two independent groups p values lower than 0.05 in two-tailed
tests were considered as significant
The cumulative probabilities of survival were analysed by the
Kaplan–Meier method14 and comparison between groups was
performed by using the log-rank test.15Patients who died from
causes that were not related to liver disease or were lost to follow-up or responded to antiviral therapy were censored at the time of death, drop out or response to antiviral therapy, respectively Multivariate analysis was also performed by fitting the Cox proportional hazard models in order to evaluate the role
of each prognostic factor when controlling for the others The assumption of proportionality of hazards functions was assessed using graphical methods as suggested.16
Statistical analyses were performed using the STATA soft-ware (Stata Statistical Softsoft-ware release 8.0, 2003; Stata Corporation, College Station, Texas)
RESULTS Serological outcome HBeAg seroconversion Our cohort of 70 HBeAg positive patients was followed for a median period of 25.3 years (range, 1.3–33.1) for a total of 1564 person-years During this observation period nine (12.8%) patients remained persistently HBeAg positive and 61 (87.2%) underwent spontaneous HBeAg seroclearance with anti-HBe seroconversion (fig 1) The cumulative probabilities of HBeAg seroconversion were 64%, 93% and 97% at 5, 10 and 25 years of follow-up, respectively Most patients underwent HBeAg seroconversion during the first 10 years of the study (58 of 61, 95.1%), with an incidence rate of 18.7 per 100 person-years At enrolment, patients who remained persistently HBeAg positive were older (median age, 51 vs 27 years) and had a higher prevalence of cirrhosis (44% vs 6.6%) as compared with those who underwent spontaneous HBeAg seroclearance (table 1) At the time of HBeAg seroconversion, their median age was 30 years (range, 16–65) and 11 (18%) had histological evidence of cirrhosis The 61 patients with HBeAg seroclearance were followed for
a median period of 22.8 years (range, 0.5–28.4) after HBeAg seroconversion Forty (66%) out of the 61 patients had sustained ALT normalisation and undetectable HBV DNA by non-PCR tests and were considered inactive carriers; more recently HBV DNA was tested by PCR assay in 15 (37.5%) out
of the 40 inactive carriers and was detectable in all cases ranging from 700 to 9800 copies/ml The remaining 21 (34%) out of the
61 patients experienced active hepatitis; among these 21 patients, ALT elevation was associated with HBeAg reversion
in one (1%), detectable serum HBV DNA but HBeAg negative (HBeAg negative hepatitis) in nine (15%), concurrent HCV and/
Figure 1 Study flow diagram NAFLD, non-alcoholic fatty liver disease
Trang 4or HDV infection in eight (13%) and concurrent non-alcoholic
fatty liver disease (NAFLD) in three (5%) cases (fig 1) Of the
three patients with NAFLD, two had histological features of
non-alcoholic steatohepatitis (NASH) and one was obese (BMI
38 kg/m2) with fatty liver diagnosed by ultrasound All three
cases with NAFLD were seronegative for both HBeAg and HBV
DNA by non-PCR tests; at the last visit HBV DNA was
detectable by PCR ranging from 300 to 8750 copies/ml
The clinical and biochemical features of the 61 patients with
spontaneous HBeAg seroconversion according to clinical and
serologic categories during follow-up (40 with sustained
remission and 21 with active hepatitis) are given in table 2
The patients who developed HBeAg negative hepatitis or
HBeAg reversion had a higher prevalence of cirrhosis at the
time of HBeAg seroconversion compared to patients with
sustained remission (50% vs 17.5%, respectively; p = 0.04)
(table 2)
HBsAg loss
Eighteen (45%) of the 40 inactive carriers and one (12.5%) of the
eight patients with viral concurrent infections lost their HBsAg
and developed the related antibody (table 2) The incidence of
HBsAg loss was 2.1 per 100 person-years in inactive carriers
Among the 18 inactive carriers with HBsAg loss the median
interval between HBeAg seroconversion and HBsAg clearance
was 13.8 years (range, 1.1–26.9)
Clinical outcome
Patient survival
A total of 50 patients were alive at the end of the follow-up:
among them, 30 (60%) were checked into the hospital, 18 (36%)
were interviewed by phone and two were lost at the follow-up
Liver-related death occurred in 11 (15.7%) patients, caused by
HCC in five and liver failure in six, and one patient underwent OLT for end-stage liver disease (table 1)
The cumulative probability of survival among all patients was 90% and 86% at 10 and 25 years of follow-up, respectively The cumulative probability of survival at 25 years was significantly lower in the nine patients who remained HBeAg positive (40%) and in patients developing HBeAg negative hepatitis or HBeAg reversion (50%) as compared to inactive carriers (95%) (p,0.0001) (fig 2) None of the patients with concurrent HCV and/or HDV infection or patients with concurrent NAFLD died during the 25 years of observation The cumulative probability of survival at 25 years was significantly lower in eight patients with cirrhosis at entry (22.5%) and in 17 patients who developed cirrhosis during follow-up (59%) as compared to 45 patients without cirrhosis (100%) (p,0.0001)
Cox proportional hazard regression model showed that older age at diagnosis, male sex, the presence of cirrhosis at enrolment and the absence of sustained remission during follow-up were significantly associated with an increased risk for liver related death or OLT (table 3) In a subgroup analysis excluding patients with concurrent HCV and/or HDV infection or NAFLD, the risk of liver related mortality or OLT was increased 33-fold in patients with HBeAg persistence and 38-fold in those with HBeAg negative hepatitis or HBeAg reversion as compared
to patients with sustained remission (inactive carriers) (table 3)
Antiviral therapy Ten patients with evidence of high levels of HBV replication (two HBeAg positive and eight with HBeAg negative hepatitis) were still alive in the late 1980s when interferon (IFN) therapy became available and three of them (one HBeAg positive and two HBeAg negative) were treated with IFN An additional four out of the eight patients with concurrent viral concurrent
Table 1 Demographic and clinical features of different subsets of the study population at enrolment and during follow-up
All patients HBeAg persistence HBeAg seroclearance
Features at entry Age (years) (median, range) 29 (15–64) 51 (26–64) 27 (15–62)
ALT 6 normal (median, range) 2.9 (2–16) 2.7 (2–4.2) 3.0 (2–16) Previous acute hepatitis 30 (42.9) 4 (44.4) 26 (42.62) Presumed source of infection
Medical occupation 13 (18.6) 0 13 (21.3) Household contact 17 (24.3) 0 17 (27.9)
Presence of cirrhosis 8 (11.4) 4 (44.4) 4 (6.6) Features during follow-up
Cirrhosis occurrence 17 (24.3) 4 (44.4) 13 (21.3)*
Total number of deaths 19 (27.1) 7 (77.8) 12 (19.7) Liver-related deaths 11 (15.7) 5 (55.6) 6 (9.8)
Non-liver related deaths 8 (11.4) 2 (22.2) 6 (9.8)
Data expressed as number (%).
ALT, alanine aminotransferase; OLT, orthotopic liver transplantation.
*Seven patients developed cirrhosis before HBeAg seroclearance and six patients after HBeAg seroclearance.
Trang 5infections received antiviral therapy Among the seven treated
patients, two (one HBeAg positive and one HBV/HCV
co-infected patient) responded to antiviral therapy and were
censored from follow-up The details of IFN schedule and
reasons for not treating the remaining patients are provided in
the following sections
Clinical outcome of HBeAg positive patients
Among the nine patients who remained HBeAg positive during
a median follow-up period of 6.8 years (range, 1.3–25), eight had
histologically documented cirrhosis (four diagnosed at entry and
four during follow-up) One patient (with cirrhosis diagnosed during follow-up) responded to lymphoblastoid IFN at the dose
of 8 million units thrice weekly for 6 months in the year 1989 The remaining seven patients with cirrhosis died: four for decompensated cirrhosis, one for HCC and two for liver unrelated causes Among these seven patients, six died in the early 1980s before antiviral therapy became available and one did not receive IFN therapy due to ischaemic heart disease which was the cause of unrelated death in 1999 Only one (1.4%) of the 70 initially HBeAg positive patients is still HBeAg positive and alive without clinical and/or serological evidence of
Table 2 Clinical and biochemical features in 61 patients with spontaneous HBeAg seroconversion according to clinical and serological categories during follow-up (40 with sustained remission and 21 with active hepatitis)
Sustained remission
HBeAg-/HBV-DNA+
or HBeAg reversion
HDV and/or HCV concurrent infection NAFLD
Features at entry
Age (years) (median, range)* 29.5 (15–52) 24 (15–62) 23.5 (15–39) 15 (13–21)
ALT 6 normal (median, range)* 3.4 (2–10.9) 2.5 (2–9.2) 3.1 (2–16) 2.1 (2–2.4) Features during follow-up
Follow-up after HBeAg seroconversion (years) (median, range){ 23.0 (3.2–28.2) 18.2 (2.8–25.9) 19.4 (0.5–28.4) 20.8 (20.8–24.3) Age at HBeAg seroconversion (year) (median, range)* 33 (17–59) 28 (17–65) 30.5 (19–31) 22 (16–25)
Clinical and laboratory assessment 15 (37.5) 4 (40) 6 (75) 3 (100)
Data are expressed as number (%).
HDV, hepatitis delta virus; HCV, hepatitis C virus; NAFLD, non-alcoholic fatty liver disease; ALT, alanine aminotransferase; HCC, hepatocellular carcinoma; OLT, orthotopic liver transplantation.
Comparison between 40 patients with sustained remission and 10 patients with HBeAg negative hepatitis (HBeAg2/HBV DNA+) or HBeAg reversion (HBeAg+/HBV DNA+): *Not significant; {p = 0.05; {p = 0.04; 1p = 0.002.
Figure 2 Cumulative probability of
survival in the three subsets of patients:
inactive carriers, patients with HBeAg
negative hepatitis or HBeAg reversion and
patients persistently HBeAg positive
(p,0.0001, log-rank test)
Trang 6cirrhosis at the last observation in June 2006; the patient had
ALT fluctuating from normal to 1.5 times the upper normal
value during follow-up and remained untreated
Clinical outcome of inactive carriers
The clinical outcome of the 40 inactive carriers during a median
follow-up period of 23 years (range, 3.2–28.2) after HBeAg
seroconversion is shown in fig 3 Seven patients had
histolo-gically documented cirrhosis, three at enrolment and four
progressed to cirrhosis during the HBeAg positive phase before
HBeAg seroconversion Of these seven inactive carriers with
cirrhosis, two died from HCC 7.7 and 9.4 years after HBeAg
seroconversion, respectively, three died of liver-unrelated causes,
one is alive and one was lost to follow-up Of the 33 inactive
carriers without cirrhosis, three died of liver unrelated causes
and the remaining 30 are alive
Clinical outcome of patients with active hepatitis after HBeAg
seroclearance
The clinical outcome of the 21 patients with HBeAg
seroclear-ance and active hepatitis is illustrated in fig 4
One patient with cirrhosis at enrolment showed HBeAg
reversion associated with persistent ALT elevation 15 months
after HBeAg seroconversion and died of liver failure 3.9 years
after sustained HBeAg reversion
Among the nine patients who progressed to HBeAg negative
hepatitis two had histologically documented cirrhosis at the
time of HBeAg seroconversion and two developed clinical
cirrhosis 3 and 13 years after HBeAg seroconversion,
respec-tively Among the four patients with cirrhosis, one died of liver
failure in the year 1981, one did not respond to lymphoblastoid
IFN (8 million units thrice weekly for 6 months) in the year
1987 and underwent OLT 11 years later and the remaining two
patients remained untreated because of advanced cirrhosis with
low platelet levels at the time IFN therapy became available and
died of HCC All five patients with HBeAg negative hepatitis
without cirrhosis are alive All five patients underwent
follow-up liver biopsies after development of HBeAg negative hepatitis
showing mild to moderate chronic hepatitis without cirrhosis
and none showed liver surface nodularity or other
ultrasono-graphic markers of advanced liver disease at follow-up
ultrasound examination One patient failed to respond to
lymphoblastoid IFN (8 million units thrice weekly for
6 months) and the other four remained untreated because of mild histology and no clinical evidence of progressive disease
Of the eight patients with concurrent viral infections, five developed cirrhosis (histologically confirmed in four cases) during follow-up (one during the HBeAg positive phase and four after HBeAg seroconversion) and three had no clinical, liver ultrasonographic and/or biochemical evidence of cirrhosis at the last observation Of the five patients with cirrhosis, one HBV/ HCV infected patient responded to standard combination treatment with pegylated IFN-a and ribavirin, two anti-HDV/ anti-HCV positive (HCV RNA negative) patients failed to respond to recombinant IFNa2a (10 million units thrice weekly for 12 months), one anti-HDV/anti-HCV positive (HDV RNA, HCV RNA and HBV DNA negative by PCR at last observation) patient admitted alcohol abuse and was advised to abstain from alcohol intake and the remaining anti-HDV positive (HDV RNA negative at last observation) patient showed intermittently slightly elevated ALT and remained untreated Of the three patients without cirrhosis, one anti-HDV positive patient was lost to follow-up, one HBV/HCV infected patient lost HBsAg and refused antiviral therapy for HCV and the remaining HBV/ HCV infected patient failed to respond to standard combination therapy with recombinant IFN-a and ribavirin Excluding one anti-HDV positive patient lost to follow-up and one anti-HCV positive patient who responded to antiviral therapy and censored from follow-up, the remaining six patients are alive and without evidence of hepatic complications in those with cirrhosis
None of the patients with active hepatitis after HBeAg seroclearance received nucleoside or nucleotide therapy
DISCUSSION The major aim of this longitudinal study was to assess the prognostic significance of sustained high HBV replication levels
on the risk of liver-related death in a cohort of 70 Caucasian patients with HBsAg and HBeAg positive chronic hepatitis at diagnosis who were followed for a median period of 25 years with a very low drop-out rate The number of patients is relatively small, but the study population consists of a well-defined cohort of consecutive patients previously described,8
thus minimising the risk of selection bias Data on liver-related
Table 3 Hazard ratios (HR) and 95% confidence intervals (CI) for liver related death by Cox proportional hazard regression models (all variables included in the model)
No liver-related deaths/OLT HR (95% CI) p Age at entry (years) 70 12 1.10 (1.06 to 1.16) ,0.001 Sex
Duration of HBeAg positive phase (years) 70 12 0.84 (0.63 to 1.10) n.s.
Cirrhosis at entry
HBeAg2/HBV DNA+ or HBeAg reversion 10 5 38.73 (4.65 to 322.9) 0.001 HBeAg persistence 9 5 33.06 (3.01 to 363.0) 0.004 n.s., not significant.
*The model included the 40 patients with sustained remission (reference category), the 10 patients with HBeAg2/HBV DNA+
chronic hepatitis or HBeAg reversion and the nine patients with HBeAg persistence, and adjusted for age, sex and cirrhosis at entry.
Trang 7mortality were accurately obtained in the great majority (97%)
of patients After 25 years, survival was significantly worse in
patients who remained HBeAg positive, developed HBeAg
negative hepatitis or HBeAg reversion, as compared with
inactive carriers (40%, 50% and 95%, respectively) It is of note
that the adjusted hazard ratios for liver-related death were
33-fold higher in patients who remained HBeAg positive and
38-fold higher in HBeAg negative hepatitis who had HBV DNA
positivity or HBeAg reversion with respect to inactive carriers
To our knowledge, data regarding the relationship between
ongoing HBV replication and liver related mortality in the West
are limited to patients who have already progressed to
cirrhosis.5–7 Studies conducted in tertiary care centres in
Europe among patients with compensated cirrhosis showed
that those with persistently high levels of HBV replication, as
indicated by HBeAg positivity, have increased liver related death rates, of about 2-fold, as compared to those who clear HBeAg with biochemical remission.5 Early studies on the natural history of chronic hepatitis B in Caucasian patients do not provide information whether HBeAg seroconversion leads to a decreased risk of liver-related adverse events and mortality, due
to the too short follow-up period of 5 years at most8 17 18
A prospective population-based cohort study in HBsAg positive Chinese patients has reported that high viral load at baseline (>105 copies/ml) is significantly associated with increased mortality from HCC and chronic liver disease over a 11-year period.19
However, these findings should be considered with caution because only baseline measures of HBV DNA level were tested, which are poorly related with the levels of HBV replication and disease activity during the whole follow-up of an individual Only one prospective study from Asia monitored serum HBV DNA over time and showed that patients with sustained elevation of HBV DNA had the highest HCC risk,20
but data on the risk of liver-related mortality were not reported This is the first long-term longitudinal study in untreated adult Caucasian patients with chronic hepatitis B (89% without cirrhosis at diagnosis) showing that ongoing high level of HBV replication during follow-up is associated with significantly increased risk of liver-related mortality In our study the inactive carrier was defined by sustained normal ALT and HBV DNA persistently negative by non-PCR assays, thus including a heterogeneous group of patients who may have up
to 1.46105 copies/ml of HBV DNA Nevertheless we showed that HBeAg negative patients with sustained normal ALT and HBV DNA levels of less than 1.46105 copies/ml have a very good prognosis with long life expectancy Our data suggest that recent findings from cohort studies in Chinese subjects in their 40s with perinatally or early childhood acquired HBV infection (85% of cohort HBeAg negative, 94% with normal ALT) that serum HBV DNA levels above 104copies/ml increase the risk for cirrhosis and HCC regardless of serum ALT levels and HBeAg status20 21 can not be directly referred to Caucasian patients
Figure 3 Flow diagram of the clinical outcome of 40 inactive carriers
HCC, hepatocellular carcinoma.aThree patients had cirrhosis at
enrolment and four developed cirrhosis before HBeAg seroclearance
Figure 4 Flow diagram of the clinical
outcome of 21 patients with active
hepatitis after HBeAg seroclearance
NAFLD, non-alcoholic fatty liver disease;
NASH, non-alcoholic steatohepatitis;
HCV, hepatitis C virus; HDV, hepatitis
delta virus; OLT, orthotopic liver
transplantation; HCC, hepatocellular
carcinoma.aCirrhosis at enrolment.bTwo
of the four patients developed cirrhosis
after HBeAg seroclearance.cFour of the
five patients developed cirrhosis after
HBeAg seroclearance.dResponder to
pegylated interferon and ribavirin
Trang 8Differences in long-term outcomes between Asian and
Caucasian patients should be taken into account in current
recommendations for management and treatment of chronic
hepatitis B.1 22
Notably, our data are in accordance with a recent longitudinal
study of 91 HBeAg positive Italian children showing that 81
(95%) of 85 children without cirrhosis at enrolment and who
underwent spontaneous HBeAg seroconversion remained
inac-tive carriers after 29 years follow-up and none died.23
However,
of the four children with cirrhosis two remained inactive
carriers and two developed HCC 9 and 16 years after HBeAg
seroconversion.23 In our study two inactive carriers who had
already developed cirrhosis during the HBeAg positive phase,
died of HCC 8 and 9 years after HBeAg seroconversion These
findings underline the clinical relevance of HBeAg
seroconver-sion with virological and biochemical remisseroconver-sion early in the
course of the liver disease before cirrhosis occurrence
In addition to the main findings on survival, this study
provides some data on the long-term rates of serological events
The incidence of HBeAg seroconversion was 18.7 per 100
person-years in the first 10 years of the follow-up and the
incidence of HBsAg seroconversion was 2.1 per 100 person-years
in accordance with previous studies from Western countries in
adults patients.1 2 18 24–26
Our study shows that 34% of patients developed active
hepatitis despite HBeAg seroconversion: nine patients (15%)
showed HBeAg negative hepatitis and one (1%) showed HBeAg
reversion The patients who developed HBeAg negative
hepa-titis had a significantly higher prevalence of cirrhosis at the time
of HBeAg seroconversion as compared with inactive carriers
These results are in agreement with an Asian study by Hsu
et al,27
reporting that 33% of patients with spontaneous HBeAg
seroconversion experienced ALT elevation during a median
follow-up period of 8.6 years, associated with HBeAg negative
hepatitis in 24% of cases and with HBeAg reversion in 4% In
the same study, the patients with liver cirrhosis at the time of
HBeAg seroconversion had a 10-fold increased risk of developing
HBeAg negative hepatitis Overall these data support the view
that HBeAg negative chronic hepatitis represents a late phase in
the natural history of chronic HBV infection
Concurrent HCV and/or HDV infection was found in a small
proportion (13%) of our patients with active hepatitis after
HBeAg seroconversion and did not seem to affect the natural
history of chronic hepatitis B The complex viral interplay in
cases of dual or triple infection28may provide an explanation to
the clinical evidence in longitudinal studies that HBV/HDV
co-infection is not always associated with a more severe disease
than HBV infection alone6 and that HBV/HCV concurrent
infection is not always associated with a higher risk of HCC
than in either infection alone.29
In conclusion, the present long term study in Caucasian
patients with chronic hepatitis B shows that most patients
become inactive carriers after spontaneous HBeAg
seroconver-sion and this condition confers survival benefit with regard to
liver disease mortality, particularly if present before the onset of
cirrhosis HBeAg reversion or progression to HBeAg negative
chronic hepatitis occurs in a relatively small proportion of
patients following HBeAg seroconversion The risk of
liver-related mortality is strongly associated with sustained high level
of HBV replication and disease activity during follow-up,
independently of HBeAg status Older age, male gender and
cirrhosis also strongly predict disease-related mortality
Funding: This study was partially supported by the MURST 60% 2005 of the University of Verona (GF, 2005)
Competing interests: None.
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