Annals of Internal Medicine
Serologic and Clinical Outcomes of 1536 Alaska Natives Chronically
Infected with Hepatitis B Virus
Brian J. McMahon, MD; Peter Holck, PhD; Lisa Bulkow, MS; and Mary Snowball, RN
Background: Knowledge of the outcome of chronic hepatitis B
virus (HBV) infection is limited.
Objective: To determine the incidence of and risk factors for
adverse events (hepatocellular carcinoma and end-stage liver dis-
ease) and clearance of hepatitis B e antigen (HBeAg) and surface
antigen (HBsAg) in carriers of HBV.
Design: Population-based cohort study of hepatitis B carriers
who were observed for a median of 12.3 years as part of an active
surveillance program to detect carriers with hepatocellular carcinoma.
Setting: 126 communities in Alaska.
Patients: 1536 Alaska Natives with chronic hepatitis B.
Measurements: Bivariate comparisons, multivariable models, and
other statistical methods were used to examine the relationships
of risk factors to outcomes and clearance of HBeAg and HBsAg.
Results: 1536 chronic HBV carriers were followed up for 19 430
person-years from their first HBsAg-positive test result. At the first
A n estimated 350 000 000 persons worldwide are
chronically infected with hepatitis B virus (HBV)
(1). Carriers of HBV are at increased risk for hepatocel-
lular carcinoma and end-stage liver disease (2).
Most persons infected with HBV recover from the
acute infection, as manifested by clearance of hepatitis B
surface antigen (HBsAg) and development of antibody
to hepatitis B surface antigen (anti-HBs). Initially,
chronic carriers of HBV have high levels of HBV DNA
in their sera and usually remain positive for hepatitis B e
antigen (HBeAg) for several years (3). Most carriers
eventually clear HBeAg and develop antibody to hepa-
titis B e antigen (anti-HBe) (4 7). Hepatitis B surface
antigen is sometimes cleared after many years of contin-
uous positivity (8). Because population-based studies
that have followed carriers for prolonged periods are
lacking, the proportion of carriers who clear HBeAg and
HBsAg over time is not known. Antiviral therapy in
chronic hepatitis B can result in accelerated clearance of
HBsAg and HBeAg in some carriers. However, the
long-term benefit of antiviral therapy is unclear (9). In-
formation on the clearance of these markers over a
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Article
serologic test, 641 were HBeAg positive and 893 were anti-HBe
positive. Older carriers were more likely than younger carriers to
clear HBeAg (P < 0.001). The observed probability of clearing
HBeAg within 10 years of diagnosis was 72.5%. Clearance of
HBsAg occurred in 106 (7%) of all carriers and was positively
associated with older age and positive result on initial anti-HBe
test. The incidence of adverse events was 2.3 per 1000 carrier-
years, and the incidence of hepatocellular carcinoma was 1.9 per
1000 carrier-years (2.3 in men and 1.2 in women). Risk for hep-
atocellular carcinoma increased with age, among those of Yupik
Eskimo ethnicity, and among carriers who reverted from anti-HBe
to HBeAg.
Conclusion: In HBsAg-positive carriers, observed clearance of
HBeAg was more than 70% during the first 10 years of follow-up.
Ann Intern Med. 2001;135:759-768. www.annals.org
For author affiliations, current addresses, and contributions, see end of text.
See related article on pp 796-800 and editorial comment on pp
835-836.
longer period in untreated patients would be helpful and
could be used to compare with results observed in per-
sons who have received antiviral therapy and are fol-
lowed over a long period.
Infection with HBV is hyperendemic in Alaska Na-
tives. In this group, HBV infection is primarily trans-
mitted horizontally in early childhood, with some acqui-
sition in adulthood (10). Serologic surveys beginning in
the early 1970s identified carriers of HBV, and a registry
of carriers was established in 1978 (11, 12). Between
1983 and 1987, 52 000 personsapproximately 70%
of the entire Alaska Native populationwere screened
for seromarkers of HBV, and 3.1% were found to be
HBsAg positive; rates were more than 8% in southwest
Alaska. Seronegative persons and all newborns were of-
fered hepatitis B vaccine in an effort to control the
spread of the infection (13, 14). Since 1987, screening
and vaccination have continued; at this time, more than
90% of the population has participated.
This program has identified 1536 persons chroni-
cally infected with HBV who have now been observed
for an average of 12.6 years (19 430 carrier-years). We
6 November 2001 Annals of Internal Medicine Volume 135 Number 9 759
 Article Sequelae and Serologic Outcome in Hepatitis B Carriers
report the outcome of chronic HBV infection in this
cohort, including clearance rates of HBeAg and HBsAg,
and the incidence of and risk factors associated with
hepatocellular carcinoma and end-stage liver disease.
METHODS
Participants
The Alaska Native population includes persons of
Eskimo, Indian, and Aleut descent. In 1998, an esti-
mated 104 305 Alaska Natives were living in Alaska.
Nearly all Alaska Natives receive their health care
through a three-tiered integrated health care system,
with primary care given in villages, secondary care in
regional hospitals, and tertiary care at the Alaska Native
Medical Center in Anchorage. The Hepatitis B Carrier
Registry contains records of all Alaska Natives who have
had at least one positive test result for HBsAg. All per-
sons who were HBsAg positive on consecutive speci-
mens obtained at least 12 months apart, determined
either retrospectively or prospectively, were defined as
hepatitis B carriers and were included in the analysis.
When newly HBsAg-positive persons were identified,
the serum bank located at the Arctic Investigations Pro-
gram of the Centers for Disease Control and Prevention
in Anchorage, which contains several hundred thousand
serum specimens stored since the early 1970s, was
searched, and if serum specimens from these persons
were found, they were tested for HBV seromarkers to
attempt to establish time of infection and duration of
carriage.
Permission to store carriers blood and test for HBV
markers was obtained from the Institutional Review
Boards of the Alaska Native Medical Center and the
Indian Health Service. Approval was also obtained from
Alaska Native Regional Health Boards. Individual pa-
tients signed consent forms agreeing to have their serum
specimens stored and tested.
Since 1982, all carriers and their health care provid-
ers have been sent reminders to have blood drawn for
HBsAg and -fetoprotein testing every 6 months as part
of an ongoing program to attempt to detect hepatocel-
lular carcinoma at an early resectable stage (15). Serum
specimens from these carriers are also tested annually for
HBeAg and anti-HBe. Testing for HBsAg, anti-HBs,
antibody to hepatitis B core antigen (anti-HBc),
HBeAg, and anti-HBe was performed by radioimmuno-
assay or enzyme-linked immunoassay, using commercial
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assays (Abbott Laboratories, Abbott Park, Ilinois). For
purposes of analysis, persons simultaneously positive for
both HBeAg and anti-HBe were counted as HBeAg-
positive. Carriers who cleared HBsAg continued to be
followed in the same manner as the rest of the cohort.
Hepatitis B virus DNA was not measured.
The approximate date of HBV infection was known
in 95 carriers because they were enrolled in a prospective
incidence study of HBV conducted in the mid-1970s
(10), before hepatitis B vaccine was available, or because
they had a previously stored serum specimen available
that subsequently was found to be negative for all sero-
markers of HBV. We used the midpoint between the
last HBsAg-negative specimen and the first HBsAg-pos-
itive specimen to estimate date of infection.
Alaska Natives reside in 189 communities, most of
which are isolated and inaccessible by road. Most com-
munities have a clinic in which primary care is provided
by village community health aides who are trained in
phlebotomy. Because it can take up to 1 week for serum
samples drawn in a village to arrive at the Alaska Native
Medical Center or the nearest hospital laboratory and
because hepatic enzymes are unstable over time when
clotted tubes are used to transport blood specimens,
liver aminotransferase levels are not routinely measured.
Outcomes
Statewide computerized medical records for Alaska
Natives and death certificates issued by the state of
Alaska were reviewed to determine cause of death in
carriers who died and to identify carriers who developed
hepatocellular carcinoma or end-stage liver disease. In
our study, an adverse outcome of HBsAg carriage was
defined as hepatocellular carcinoma; end-stage liver dis-
ease (defined as the presence of ascites, hepatic enceph-
alopathy, esophageal varices, or coagulopathy); or death
due directly to liver disease or death in which a mani-
festation of end-stage liver disease was listed as a con-
tributing cause, such as pneumonia in a carrier with
decompensated cirrhosis. Medical records of carriers
with end-stage liver disease as a primary or possible con-
tributing cause of death were reviewed.
Statistical Analysis
Analysis was performed to examine rates and de-
scribe characteristics of three outcomes: carrier clearance
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 Sequelae and Serologic Outcome in Hepatitis B Carriers Article

of HBsAg, loss of HBeAg, and hepatocellular carcinoma Table 1. Hepatitis B e Antigen and anti-HBeAg Serologic
and liver diseaserelated deaths. Both simple bivariate Outcome over Time of 1534 HBsAg-Positive Carriers*
comparisons and multivariable models were used to ex-
Group Participants Median Age at Median Median
amine relations between risk factors and outcomes. First HBsAg- Duration of Tests
Times to clearance of HBsAg and HBeAg were calcu- Positive Test Follow-up
Result
lated on the basis of time from initial HBsAg-positive
n (%) y n
test result (rather than time of infection, which was un-
A 100 (7) 7.7 11.9 12
known) and were analyzed by using KaplanMeier sur- B 432 (28) 8.3 12.8 16
vival curves. Risk factors for carrier clearance of HBsAg C 109 (7) 6.9 14.4 19
D 802 (52) 27.6 12.0 13
and loss of HBeAg were examined by using tables of E 91 (6) 27.6 12.5 15
observed frequencies of clearance rates by risk factor and Total 1534 19.9 12.4 15
were analyzed by using Cox proportional hazards mod-
* Two persons were not tested for HBeAg/anti-HBe. Both were tested twice for
els. Two time-dependent covariates were considered HBsAg, 1 year apart in one person and 3 years apart in the other. Both died of
nonliver-related causes. HBeAg hepatitis B e antigen; HBsAg hepatitis B
during model fitting: presence or absence of HBeAg and surface antigen.
the number of times that the measured value had changed. Group A, persons who were persistently HBeAg positive throughout follow-up;
group B, persons who seroconverted from HBeAg to anti-HBe; group C, persons
Hepatocellular carcinoma and liver diseaserelated death who seroconverted from HBeAg to anti-HBe, then had reactivation of HBeAg one
outcomes were modeled by using Cox proportional haz- or more times; group D, persons who were persistently HBeAg negative and
anti-HBe positive; group E, persons who were initially anti-HBe positive, then had
ards models after initial bivariate examination of out- reactivation of HBeAg one or more times.
comes with frequency distributions and contingency ta-
bles. For much of the analysis, change in HBeAg status
was categorized as one of five groups based on initial ethnicity (Yupik Eskimo or other Alaska Native),
HBeAg status and the number of switches: initial HBeAg- HBeAg status at first HBsAg detection, and pattern of
positive result with no switches, initial HBeAg-positive HBeAg switching (number of switches and HBeAg
result with one switch, initial HBeAg-positive result switching category). Variables in the multivariate mod-
with more than one switch, initial HBeAg-negative re- els presented were chosen by using forced-entry regres-
sult with no switches, and initial HBeAg-negative result sion to control for confounders. Two-way interactions
with one or more switches. This categorization permit- and nonlinear terms were added when their addition
ted more accurate description of the natural course of substantially improved the model.
HBeAg clearance than that afforded by specification of A separate analysis was performed for the subgroup
the number of switches only. of 95 people for whom an approximate date of hepatitis
We used two methods to explore factors contribut- B infection could be determined. A known approximate
ing to clearance of HBeAg. By defining an outcome as date of infection permits a more accurate estimate of
clearance of HBeAg within 5 years of initial diagnosis, years infected and time to clearance.
we could cross-classify outcomes by suspected influenc- Two-sided statistical tests were used; P values of
ing factors and note the variation in observed frequency 0.05 or less were considered significant. S-Plus software,
of clearance as levels of these factors change. In addition, version 4.0, or S-PLUS 2000 software (MathSoft, Inc.,
with time until conversion of HBeAg as an outcome, we Seattle, Washington) was used for all analyses.
used a Cox proportional hazards model to examine fac-
tors influencing conversion of HBeAg. RESULTS
We defined a favorable serologic outcome over time Demographic Characteristics
as conversion from HBeAg positivity to HBeAg negativ- We identified 1536 hepatitis B carriers, of whom
ity on the last two determinations or as being HBeAg 908 (59.1%) were male and 628 were female. Ninety-
negative/anti-HBe positive throughout follow-up (Table five persons were negative for all HBV seromarkers at
1, groups B and D). An unfavorable outcome was de- the time of first determination, and their serum speci-
fined as being persistently HBeAg positive or as having mens were found to be HBsAg positive on subsequent
one or more reversions to HBeAg (groups A, C, and E). testing. The remaining 1441 carriers were HBsAg posi-
The risk factors for these outcomes include age, sex, tive at first serologic testing. Of the 1536 carriers, the
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 Article Sequelae and Serologic Outcome in Hepatitis B Carriers
Figure 1. Time until seroconversion from hepatitis B
e antigen (HBeAg) positivity to negativity.
Data shown for carriers of hepatitis B surface antigen who were persis-
tently HBeAg positive throughout follow-up (solid line); those who sero-
converted from HBeAg positivity to anti-HBe positivity (dashed line);
those who seroconverted from HBeAg to anti-HBe, then had reactiva-
tion of HBeAg (dotted line); and those who were initially anti-HBe neg-
ative, then had reactivation and tested HBeAg positive (smaller dashed
line). Those who were persistently HBeAg negative and anti-HBe posi-
tive (group D in Table 1) are not shown.
median age at time of first HBsAg-positive test result
was 19.9 years (range, 1 to 87 years). The ethnic distri-
bution of the cohort was 865 (56.3%) Yupik Eskimo,
327 (21.3%) other Eskimo groups, and 344 (22.4%)
other Alaska Native groups (Athabaskan, Southeast In-
dian, or Aleut). Median duration of follow-up for the
cohort was 12.6 years (range, 1 to 33.4 years; 25th and
75th percentiles, 10.5 and 14.6); total duration of
follow-up was 19 430 person-years. The median num-
ber of HBeAg and anti-HBe determinations was 15
(range, 0 to 47).
Only 9 carriers had ever received antiviral therapy; 5,
all of whom were HBeAg positive, received interferon-,
and 4, 3 of whom were anti-HBe-positive, received
lamivudine. All 5 carriers who received interferon cleared
HBeAg within 1 year of treatment; the serologic status
of the patients receiving lamivudine did not change.
Clearance of HBeAg
At the first HBsAg-positive serologic measurement,
641 carriers (41.7%) were HBeAg positive and 893
(58.1%) had anti-HBe. Two carriers (0.1%) were not
tested for HBeAg and anti-HBe. Serologic test results
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for the 1534 carriers are shown in Table 1. Of the 641
persons who were initially HBeAg positive, 100 (15.6%)
remained HBeAg positive throughout follow-up (group
A), 432 (67.4%) seroconverted from HBeAg to anti-
HBe and remained HBeAg negative but anti-HBe pos-
itive thereafter (group B), and 109 (17%) had one or
more reactivations (that is, reversion back to HBeAg)
(median, 3 reactivations [range, 2 to 7 reactivations])
after initial seroconversion to anti-HBe (group C). Of
this last group, 70 persons were HBeAg negative on the
last two determinations and remained HBeAg negative
and anti-HBe positive for a median of 6.2 years (range,
0.9 to 10.5 years), whereas 39 were HBeAg positive on
the last serologic determination.
Of the 893 participants who were anti-HBe positive
and HBeAg negative on their first serologic test, 802
(90%) remained anti-HBe positive for the entire follow-up
period (group D) and 91 (10%) had one or more rever-
sions to HBeAg (median, 2 reactivations [range, 1 to 7
reactivations]) (group E). Of the latter group, 76 per-
sons were HBeAg negative and anti-HBe positive on
the last two measurements (median time from first
HBeAg-negative test result to last HBeAg-negative re-
sult, 7.4 years [range, 0 to 23.7 years]) and 15 were
HBeAg positive on the last test date. Figure 1 shows
the time until clearance of HBeAg in groups A through E.
A log-rank test indicated that the groups differed signif-
icantly (P 0.01).
Among the 532 persons whose first test was HBeAg
positive and who were followed for at least 5 years and
had at least two HBeAg measurements, the observed
probability of clearing HBeAg within 5 years was 0.39
(95% CI, 0.34 to 0.43) in carriers 0 to 18 years of age,
0.56 (CI, 0.43 to 0.68) in those 19 to 30 years of age,
and 0.45 (CI, 0.32 to 0.58) in those 31 to 78 years of
age; the overall probability of clearing HBeAg within 5
years was 0.41 (CI, 0.37 to 0.45). In a multivariable
Cox proportional hazards model, predicted clearance of
HBeAg over 5 years was 0.33, 0.52, and 0.76 for per-
sons 0 to 18 years of age, 19 to 30 years of age, and 31
to 78 years of age, respectively; these values are in rea-
sonable agreement with the observed results.
Figure 2 shows predicted survival curves (time to
first HBeAg-positive result) at 10, 20, and 50 years of
age. Significant covariates included in the model are age
at diagnosis of HBsAg (including a nonlinear effect), an
interaction of initial recorded status of HBeAg (positive
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 Sequelae and Serologic Outcome in Hepatitis B Carriers Article

or negative) and age, and the number of HBeAg mea- Figure 2. Estimated survival curve showing time to loss
surements recorded. The curve for a 20-year-old carrier of hepatitis B e antigen (HBeAg) from first HBeAg-
most closely approximates the predicted clearance of positive determination at 10, 20, and 50 years of age.
HBeAg in the cohort as a whole. The observed proba-
bility of clearing HBeAg within 10 years was 72.5%. In
those who cleared HBeAg, the median time to clearance
was 5.6 years (range, 1 to 29.4 years). Older carriers
were significantly more likely than younger ones to clear
HBeAg (P 0.001).
A favorable outcome occurred in 1208 (80.1%) of
the carriers: 798 of the carriers in group D (4 persons
had only one determination) and 410 carriers in group
B (22 persons had just converted to anti-HBe on last
determination). Three hundred carriers had an unfavor-
able outcome.
Carriers who had stable serologic status (groups A
and D) and were HBeAg positive or anti-HBe positive
for the entire duration of follow-up had fewer determi-
nations (P 0.01) than carriers who had one or more
changes in HBeAg/anti-HBe status during follow-up positivity at least once after clearing HBeAg. Four of the
(groups B, C, and E) (Table 1). 28 persons who were initially anti-HBe positive reverted
Of the 95 persons for whom the approximate time to HBeAg positivity at least once.
of infection was known, 67 (70.5%) were HBeAg posi-
tive and 28 (29.5%) were HBeAg negative and anti- Clearance of HBsAg
HBe positive on first determination of their HBe status During 19 430 person-years of follow-up, 106
(Table 2). Those who were HBeAg positive on first de- (6.9%) of 1536 HBsAg-positive carriers cleared HBsAg,
termination were significantly younger than those who yielding an average clearance rate of 0.5% per year.
were HBeAg negative (P 0.01). Of the 67 persons who Hepatitis B surface antigen was cleared in 9 (9.5%) of
were HBeAg positive at the time of their first HBsAg- the 95 carriers whose approximate date of infection was
positive result, 9 remained HBeAg positive throughout known and in 97 (6.7%) of the 1441 carriers who were
follow-up, 47 cleared HBeAg during follow-up and HBsAg positive on initial determination. Time to clear-
remained anti-HBe positive, and 11 reverted to HBeAg ance of HBsAg was shorter among carriers who were

Table 2. Long-Term Follow-up of 95 HBsAg-Positive Carriers Whose Approximate Date of Infection Was Known*

Status at First Participants Median Age at Median Median Serologic Course Status at Last Follow-up
HBsAg-Positive First HBsAg- Duration of Determinations
Result Positive Result Follow-up
n (%) y n
HBeAg positive 9 (13) 4.6 11.1 12.0 Remained HBeAg positive HBeAg-positive
HBeAg positive 47 (70) 7.8 16.6 17.0 Cleared HBeAg Anti-HBe positive
HBeAg positive 11 (16) 12.5 14.8 20.0 Cleared, then reactivated 8 anti-HBe positive, 3 HBeAg
positive
Anti-HBe-positive 24 (86) 22.2 13.0 14.5 Remained anti-HBe positive Anti-HBe positive
Anti-HBe positive 4 (14) 18.7 20.5 18.5 Had reactivation of HBeAg 4 anti-HBe positive
Total 95 13.4 15.5 16.0 83 anti-HBe positive, 12
HBeAg-positive

* HBeAg hepatitis B e antigen; HBsAg hepatitis B surface antigen.

Percentage of 67 persons who were HBeAg positive at first HBsAg-positive result.
Percentage of 28 persons who were anti-HBe positive at first HBsAg-positive result.

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 Article Sequelae and Serologic Outcome in Hepatitis B Carriers
Figure 3. Survival curve showing years to seroconversion
to hepatitis B surface antigen (HBsAg ) negativity in
carriers, by hepatitis B e antigen (HBeAg )/anti-HBe
status.
Line patterns represent carriers who seroconverted from HBeAg to anti-
HBe; those who seroconverted from HBeAg to anti-HBe, then had re-
activation of HBeAg; those who were persistently HBeAg negative and
anti-HBe positive; and those who were initially anti-HBe positive, then
had reactivation of HBeAg.
HBeAg negative on first determination than among
those who were HBeAg positive (Figure 3). Multivari-
able analysis that adjusted for the number of measure-
ments in an individual participant suggested that older
carriers, carriers of Yupik ethnicity, and carriers who are
initially HBeAg negative clear HBsAg most quickly. Fig-
ure 4 shows survival curves for HBsAg in carriers 20
years of age or older or younger than 20 years of age at
first determination. After 5 years of follow-up, the 95%
CIs of these two groups do not overlap. The median
follow-up period for carriers who lost HBsAg (n 106)
was 12.5 years (mean, 14.3 years) compared with 12.4
years (mean, 12.5 years) for carriers who remained
HBsAg positive. Two patients developed hepatocellular
carcinoma 3 years and 6.5 years after they cleared
HBsAg; neither had cirrhosis in the uninvolved liver.
Incidence of Hepatocellular Carcinoma and End-Stage
Liver Disease
One hundred eighty-four persons identified as car-
riers died during follow-up. Liver-related deaths oc-
curred in 25 persons; 8 had end-stage liver disease and
17 had hepatocellular carcinoma. An additional 19 car-
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riers developed hepatocellular carcinoma and are cur-
rently alive. The 44 adverse events (36 hepatocellular
carcinoma and 8 end-stage liver disease) yielded an in-
cidence of 2.3 adverse events per 1000 carrier-years of
follow-up (2.5 in men and 1.9 in women). The inci-
dence of hepatocellular carcinoma was 1.9 per 1000
carrier-years (2.3 in men and 1.2 in women). In a Cox
proportional hazards model, Yupik ethnicity (vs. other
ethnicity) (hazard ratio, 2.6 [CI. 1.3 to 5.3]), older age
(each 1-year increase, tempered by interaction with the
number of measurements obtained in a participant)
(hazard ratio, 1.04 [CI, 1.0 to 1.07]), and reversion to
HBeAg positivity or multiple switches in HBeAg status
(hazard ratio, 2.6 [CI, 1.3 to 5.4]) were associated with
increased risk for hepatocellular carcinoma, after adjust-
ment for potential confounders. Similar analysis for on-
set of end-stage liver disease was not done owing to the
small number of cases.
Inclusion of eight persons with end-stage liver dis-
ease and modeling of the probability of hepatocellular
carcinoma or end-stage liver disease by using a multiva-
riable logistic model indicated similar risk factors (all
P 0.01; adjustments were made for duration of fol-
low-up and number of measurements obtained on an
Figure 4. Survival curves showing years to seroconversion
from hepatitis B surface antigen (HBsAg ) positivity
to HBsAg negativity in carriers, by age at the start of
the study.
The center solid line represents participants 20 years of age or older; the
center dotted line represent participants younger than 20 years of age.
The lines on either side of the center lines are 95% CIs, which are largely
nonoverlapping.
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individual). Results of the HosmerLemeshow test were
nonsignificant (P 0.2), indicating a plausible fit of the
logistic model. The area under the receiver-operator
characteristic curve was 0.83.
DISCUSSION
Previous studies of the natural history of HBsAg
carriers have primarily been clinic-based, consisting
mainly of carriers with significant liver disease (6, 16
19). A few population-based studies have been reported
that have examined the incidence of hepatocellular car-
cinoma in HBsAg carriers but not the relationship be-
tween serologic events and the incidence of adverse
events (20 24). We estimate that more than 90% of all
HBsAg-positive carriers in our sample have been identi-
fied; this is the largest sample and the longest follow-up
reported to date.
Two thirds of carriers who were initially HBeAg
positive cleared HBeAg and developed anti-HBe during
the first 12 years of follow-up, with no evidence of re-
version to HBeAg positivity state (Table 1, group B).
The observed clearance of HBeAg, as well as the results
of two statistical models, generally agree in predicting
that approximately 50% of HBeAg-positive carriers will
lose HBeAg within 5 years and more than 70% will
clear HBeAg within 10 years. Since only nine carriers
had received antiviral therapy, five of whom were
HBeAg positive at the time, our results suggest that
most carriers clear HBeAg without antiviral therapy.
Of carriers who were initially HBeAg negative and
anti-HBeAg positive, 90% remained so throughout
follow-up. In addition, 80% of carriers who cleared
HBeAg remained HBeAg negative, suggesting that once
HBeAg is cleared, most carriers remain HBeAg negative
and anti-HBe positive. A study conducted in Italy dem-
onstrated that most carriers who remained anti-HBe
positive had normal liver enzyme levels and little or no
hepatitis on liver biopsy (25). Other studies have shown
that carriers who clear HBeAg, either with or without
antiviral therapy, have a significant reduction in risk for
end-stage liver disease compared with carriers followed
for a similar period who do not clear HBeAg (26, 27).
Approximately 20% of carriers had a less favorable
course, characterized by persistence of HBeAg positivity
or reversion to HBeAg positivity after previous loss of
this marker. Reversion from HBeAg-negative/anti-HBe
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Sequelae and Serologic Outcome in Hepatitis B Carriers Article
positive to HBeAg-positive status in untreated carriers
has been associated with elevated aminotransferase levels
and histologic exacerbation of hepatitis (28, 29). In our
study, 14% of carriers (200 of 1433) who cleared
HBeAg or were initially anti-HBe positive had reversion
to HBeAg, similar to the 13% rate of reversions in a
study of carriers who cleared HBeAg after interferon
therapy (30). These events could conceivably cause sig-
nificant liver damage. Our data also suggest that carriers
experiencing reversions are at a significantly higher risk
for hepatocellular carcinoma. Carriers who have rever-
sions or fail to clear HBeAg over a prolonged period
may benefit from antiviral therapy.
Hepatitis B surface antigen was lost in 106 (6.9%)
of the carriers during follow-up, or 0.5% per year. This
rate is consistent with the loss of HBsAg reported in two
other studies from Japan and Taiwan, in which the an-
nual clearance of HBsAg ranged between 0.5% and
0.8% (8, 31). Carriers who were older and initially anti-
HBe positive in our study had a higher clearance rate of
HBsAg, similar to the findings of the study from Tai-
wan. Chronic HBV carriers who clear HBsAg may still
have HBV DNA present in both the serum and liver (8,
3133). In a previous study, we found HBV DNA in 17
of 33 (52%) carriers who were tested a median of 5 years
after clearance of HBsAg (34). Hepatocellular carci-
noma developed in 2 of our carriers who cleared HBsAg,
and hepatocellular carcinoma has been reported to occur
in some carriers who clear HBsAg (31, 32).
Two patterns of chronic HBV infection have been
observed. One pattern is seen in persons who acquire
HBV through perinatal infection, 90% of whom be-
come chronically infected. This pattern is frequently
seen in Asia and Oceania and in Asian persons living in
the United States (35, 36). These carriers develop im-
mune tolerance to HBV; most remain HBeAg positive
throughout childhood, with normal aminotransferase
levels and little or no active hepatitis in their livers. The
other pattern, seen predominately in Africa but also in
Asia and Oceania, occurs in children who are infected
after birth and adults who become chronic carriers (37).
These carriers usually have elevated aminotransferase
levels during the time they are HBeAg positive but ap-
parently convert sooner to anti-HBe than do persons
infected at birth (38). In our study group, perinatal in-
fection is infrequent and the presence of HBeAg has
been significantly associated with elevation of liver ami-
6 November 2001 Annals of Internal Medicine Volume 135 Number 9 765
 Article Sequelae and Serologic Outcome in Hepatitis B Carriers
notransferase levels (39). Thus, the course of HBV in
our sample is similar to the second pattern described
above, and our findings probably apply to other groups
with similar patterns of transmission.
Treatment of HBeAg-positive carriers with interfer-
on- or lamivudine has been shown to result in signifi-
cantly higher clearance of HBeAg, HBV DNA, and
HBsAg during the 6 to 12 months after initiation of
therapy compared with untreated controls (9, 40). Over
longer follow-up, it is unclear whether HBeAg is cleared
in a higher proportion of carriers who received antiviral
therapy than in carriers who remain untreated, or
whether antiviral therapy merely accelerates clearance in
the short term. This uncertainty is primarily due to lack
of studies with long-term follow-up comparing treated
participants with untreated controls. Long-term con-
trolled trials are needed to answer this question.
In our study, the most frequent complication of
chronic HBV infection was the development of hepato-
cellular carcinoma. Seroconversion from HBeAg to anti-
HBe, and even loss of HBsAg, did not protect carriers
from development of hepatocellular carcinoma. In addi-
tion, no evidence indicates that antiviral treatment sig-
nificantly reduces the risk for hepatocellular carcinoma
(41). We found older age to be a risk factor for hepato-
cellular carcinoma, similar to findings of a population-
based study in men from Taiwan (20) and findings of a
study from Toronto (24).
Several caveats in the interpretation of our findings
are warranted. Whereas our cohort appears to be similar
to other groups of carriers who have not acquired HBV
through perinatal infection, the mean age of our cohort
was 20 years at the start of the study; the risk for com-
plications, including hepatocellular carcinoma, may
change as the cohort ages. The rates of clearance of
HBeAg and HBsAg may not pertain to carriers who are
infected during the perinatal period (35, 36). The fre-
quency of testing may have differed among participants
and may have affected serologic outcome. Exclusion of
the nine treated carriers would inconsequentially affect
the results of clearance of HBeAg and HBsAg, since
these participants account for only 1% of the persons
who cleared those markers. However, had we excluded
them, it would have influenced the incidence of adverse
events, since two of these carriers developed hepatocel-
lular carcinoma and one developed liver failure before
treatment. Carriers with reversion to HBeAg positivity
766 6 November 2001 Annals of Internal Medicine Volume 135 Number 9
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had more HBe and anti-HBe determinations than did
those without reversions, suggesting that we may have
underestimated the number of carriers who experienced
this phenomenon. The frequency of testing did not dif-
fer between carriers living in urban areas and those liv-
ing in rural areas. Since we found a difference in the
incidence of hepatocellular carcinoma between Yupik
Eskimos and other Native groups in our sample, differ-
ences in the incidence of hepatocellular carcinoma and
other complications of chronic HBV in our population
could differ from that of other populations. Persons who
developed hepatocellular carcinoma were more aggres-
sively followed after diagnosis. Differences among indi-
viduals in the frequency of testing could have resulted in
earlier detection of hepatocellular carcinoma at a small
and asymptomatic stage, thus influencing the incidence
rates. Finally, certain assumptions that we made before
performing statistical analysis might have affected the
findings, such as defining clearance of HBeAg as two
consecutive HBeAg negative results instead of one and
defining HBsAg carrier status as HBsAg positive for 12
months rather than 6 months.
From Viral Hepatitis Program, Alaska Native Medical Center, and Arctic
Investigations Program, National Center for Infectious Diseases, Centers
for Disease Control and Prevention, U.S. Public Health Service, Depart-
ment of Health and Human Services, Anchorage, Alaska.
Grant Support: By the U.S. Public Health Service, Indian Health Ser-
vice Viral Hepatitis Program for Alaska Natives.
Requests for Single Reprints: Brian J. McMahon, MD, Viral Hepatitis
Program, Alaska Native Medical Center, c/o Arctic Investigations Pro-
gram, Centers for Disease Control and Prevention, 4055 Tudor Centre
Drive, Anchorage, AK 99508-5932.
Current Author Addresses: Dr. McMahon: Viral Hepatitis Program,
Alaska Native Medical Center, c/o Arctic Investigations Program, Cen-
ters for Disease Control and Prevention, 4055 Tudor Centre Drive,
Anchorage, AK 99508-5932.
Dr. Holck: Alaska Native Health Board, 4201 Tudor Centre Drive,
Suite 105, Anchorage, AK, 99508
Ms. Bulkow: Arctic Investigations Program, Centers for Disease Control
and Prevention, 4055 Tudor Centre Drive, Anchorage, AK 99508-5932.
Ms. Snowball: Viral Hepatitis Program, Alaska Native Medical Center,
4315 Diplomacy Drive, Anchorage, AK 99508.
Author Contributions: Conception and design: B.J. McMahon, L.
Bulkow.
Analysis and interpretation of the data: B.J. McMahon, P. Holck, L.
Bulkow.
www.annals.org

Drafting of the article: B.J. McMahon, L. Bulkow.
Critical revision of the article for important intellectual content: B.J.
McMahon, L. Bulkow, M. Snowball.
Final approval of the article: B.J. McMahon, P. Holck, L. Bulkow, M.
Snowball.
Provision of study materials or patients: B.J. McMahon, M. Snowball.
Statistical expertise: P. Holck, L. Bulkow.
Administrative, technical, or logistic support: B.J. McMahon.
Collection and assembly of data: B.J. McMahon, L. Bulkow, M. Snow-
ball.
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Hattan died almost immediately, so there wasnt anything I could really have
done, but that didnt prevent me from blaming myself. It sometimes seems that Ive
spent half of my life sunk to the eyebrows in self-recrimination. Thats one of the
drawbacks of the study and practice of healing. Healers are always shocked and
outraged when they discover something else they cant heal. No one has come up
with a way to heal death, however, so a physician has to learn to accept losses and
move on.

David and Leigh Eddings

Polagara
New York: Del Rey; 1997:412
Submitted by:
John Fornace, DO
Norristown, PA 19401

Submissions from readers are welcomed. If the quotation is published, the senders name will be
acknowledged. Please include a complete citation (along with page number on which the quotation was
found), as done for any reference.The Editor

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