Characteristics of Adults in the Hepatitis B Research Network in North America Reflect Their Country of Origin and Hepatitis B Virus Genotype

Clinical Gastroenterology and Hepatology 2014;-:-–-

Characteristics of Adults in the Hepatitis B Research Networkin North America Reflect Their Country of Origin and Hepatitis BVirus Genotype

Marc G. Ghany,* Robert Perrillo,‡ Ruosha Li,§ Steven H. Belle,§ Harry L. A. Janssen,k

Norah A. Terrault,¶ Margaret C. Shuhart,# Daryl T.-Y. Lau,** W. Ray Kim,‡‡ Michael W. Fried,§§

Richard K. Sterling,kk Adrian M. Di Bisceglie,¶¶ Steven-Huy B. Han,##

Lilia Milkova Ganova-Raeva,*** Kyong-Mi Chang,‡‡‡ and Anna Suk-Fong Lok,§§§ for theHepatitis B Research Network

*Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,Bethesda, Maryland; ‡Hepatology Division, Baylor University Medical Center, Dallas, Texas; §Department of Epidemiology,University of Pittsburgh, Pittsburgh, Pennsylvania; kDivision of Gastroenterology, Toronto Western and General Hospitals,University Health Network, Toronto, Canada; ¶Division of Gastroenterology, University of California–San Francisco, SanFrancisco, California; #Viral Hepatitis and Liver Clinic, Harborview Medical Center/University of Washington, Seattle,Washington; **Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston,Massachusetts; ‡‡Division of Gastroenterology, Stanford University School of Medicine, Palo Alto, California; §§University ofNorth Carolina Liver Center, Section of Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina;kkSection of Hepatology, Virginia Commonwealth University Health System, Richmond, Virginia; ¶¶Department of InternalMedicine, Saint Louis University School of Medicine, St. Louis, Missouri; ##Pfleger Liver Institute Clinic, David Geffen School ofMedicine, University of California–Los Angeles, Los Angeles, California; ***Centers for Disease Control and Prevention/Divisionof Viral Hepatitis/Molecular Epidemiology and Bioinformatics Sequencing Laboratory, Atlanta, Georgia; ‡‡‡Penn Center for ViralHepatitis, University of Pennsylvania Perelman School of Medicine, Philadelphia Veterans Affairs Medical Center, Philadelphia,Pennsylvania; and §§§Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan

BACKGROUND & AIMS:

Abbreviations used in this papchronic hepatitis B; DCC, Dataantigen; HBRN, Hepatitis B Resantigen; HBV, hepatitis B virus;man immunodeficiency virus; NDigestive and Kidney Diseases

Chronic hepatitis B virus (HBV) infection is an important cause of cirrhosis and hepatocellularcarcinoma worldwide; populations that migrate to the United States and Canada might beaffected disproportionately. The Hepatitis B Research Network (HBRN) is a cooperativenetwork of investigators from the United States and Canada, created to facilitate clinical,therapeutic, and translational research in adults and children with hepatitis B. We describe thestructure of the network and baseline characteristics of adults with hepatitis B enrolled in thenetwork.

METHODS:
The HBRN collected data on the clinical characteristics of 1625 adults with chronic HBVinfection who are not receiving antiviral therapy from 21 clinical centers in North America.
RESULTS:
Half of the subjects in the HBRN are men, and the median age is 42 years; 72% are Asian, 15%are black, and 11% are white; with 82% born outside of North America. The most common HBVgenotype was B (39%); 74% of subjects were negative for the hepatitis B e antigen. The medianserum level of HBV DNA when the study began was 3.6 log10 IU/mL; 68% of male subjects and67% of female subjects had alanine aminotransferase levels higher than the normal range.
CONCLUSIONS:
The HBRN cohort is used to address important clinical and therapeutic questions for NorthAmericans infected with chronic HBV and to guide health policies on HBV prevention andmanagement in North America.
Keywords: HBeAg; Chronic Hepatitis B Virus Infection; USA; ALT.

er: ALT, alanine aminotransferase; CHB,Coordinating Center; HBeAg, hepatitis B eearch Network; HBsAg, hepatitis B surfaceHCC, hepatocellular carcinoma; HIV, hu-IDDK, National Institute of Diabetes and

; ULN, upper limit of normal.

Published by the AGA Institute1542-3565/$36.00

http://dx.doi.org/10.1016/j.cgh.2014.06.028

http://dx.doi.org/10.1016/j.cgh.2014.06.028

2 Ghany et al Clinical Gastroenterology and Hepatology Vol. -, No. -

Chronic hepatitis B virus (HBV) infection is acommon cause of morbidity and mortality in the

United States and throughout the world.1 Globally,cirrhosis ranks as the 12th leading cause of death,2 andchronic HBV infection accounts for approximately a thirdof cirrhosis cases and half of all hepatocellular carci-nomas (HCCs).3 Although conventional estimates havecited approximately 1.4 million persons in the UnitedStates to be infected with HBV,4 the number of infectedpersons may be as high as 3 million owing to under-sampling of immigrant populations.5

Despite the availability of an effective vaccine forprevention of hepatitis B and safe and effective therapy,many questions regarding the natural history and path-ogenesis of chronic HBV infection remain unanswered.With substantial racial and ethnic diversity, the UnitedStates and Canadian populations are ideal to study thefull breadth of the epidemiology, natural history, andclinical virology of chronic HBV infection.

The Hepatitis B Research Network (HBRN) is a coop-erative network of investigators from 28 geographicallydistinct clinical centers across the United States and inCanada (North America), a data coordinating center (DCC),and an immunology center funded by the National Instituteof Diabetes and Digestive and Kidney Diseases (NIDDK).The goal of the HBRN is to facilitate and conduct epide-miologic clinical virologic and therapeutic research in acuteand chronic hepatitis B (CHB) in both adult and pediatricpatients who reside in North America. This report de-scribes the structure of the HBRN and the baseline char-acteristics of the participants in the Adult Cohort Study.

Figure 1.Map indicating the location of clinical sites (blue circlesImmunology Center (yellow arrowhead) comprising the HBRN aInstitutes of Health [NIH] clinical center).

Methods

Establishment and Governance of theHepatitis B Research Network

The HBRN sites were selected through a process ofpeer review in response to a Request for Applicationissued by the NIDDK. Each Clinical Center Granteecomprises 1 to 3 clinical sites, resulting in a total of 21adult and 7 pediatric clinical centers in North America.The HBRN also includes a DCC and an ImmunologyCenter (Figure 1). The DCC is responsible for coordi-nating study operations and logistics, developing andimplementing data and other systems, maintaining thedatabase, and performing data analyses. The Immu-nology Center is responsible for designing and con-ducting immunologic studies to elucidate immuneresponses to HBV during different phases of CHB and inresponse to antiviral therapy. There are 2 centralvirology laboratories.

The HBRN is funded through cooperative U01 grants,with NIDDK officials participating in its design andexecution. A Steering Committee composed of the prin-cipal investigator of each U01 grant, the principal inves-tigator from the DCC, the principal investigator from theImmunology Center, and the NIDDK project scientist isresponsible for study oversight. Several subcommitteeshave been established to facilitate thework of the SteeringCommittee (Figure 2). An independent Data and SafetyMonitoring Board was appointed by the NIDDK to review

, orange diamonds, and green square), DCC (red balloon), andnd the funding agency (NIDDK, same location as the National

Figure 2.Organizationalstructure of the HBRN. TheHBRN consists of 21 clin-ical sites recruiting adults,a DCC, an immunologycenter, and the Liver Dis-ease Branch at the NIDDK.A Steering Committee isresponsible for studyoversight. Several com-mittees were established,and an independent Dataand Safety MonitoringBoard (DSMB), appointedby theNIDDK, reviewed theprotocols and the progressof the studies. CDC, Cen-ters for Disease Control.

- 2014 HBRN Cohort Description 3

the protocols and monitor the progress of the studies andparticipant safety.

The HBRN studies include 2 cohort studies (1 foradults and 1 for children), 2 clinical trials of antiviraltherapy in immune-tolerant participants (1 for adultsand 1 for children), and a randomized clinical trial ofantiviral therapy in immune active participants (adultsonly), all of which are ongoing. The designs of the cohortstudies and the clinical trials in immune-tolerant par-ticipants for adults and children are similar and areavailable on the HBRN Web site (http://www.hepbnet.org/). Currently, there are 14 approved ancillarystudies. All protocols were approved by the SteeringCommittee and the Institutional Review Boards(Research Ethics Board in the case of the Toronto site) ofthe participating sites, and all participants providedwritten informed consent.

Adult Cohort Study Design

This was an observational study of adult patientswith chronic HBV infection who were not on antiviraltreatment, with the exception of pregnant women. Theprimary aims of the study were to describe the charac-teristics of participants in a prospectively accrued cohortof chronic HBV infection in North America and to identifypredictors of disease activation and progression. A sec-ondary goal was to identify potential participants for theHBRN clinical trials. Hepatitis B surface antigen (HBsAg)-positive patients 18 years or older were eligible forenrollment after providing written informed consent.Patients with a history of hepatic decompensation, HCC,solid organ or bone marrow transplantation, or humanimmunodeficiency virus (HIV) co-infection, and thosewho were receiving antiviral therapy (with the exception

of women who were pregnant at the time of enrollment),were excluded. Participants were evaluated at enroll-ment, week 12, week 24, and every 24 weeks thereafter.Participants experiencing hepatitis flares, hepatitis B eantigen (HBeAg) or HBsAg loss, or who were pregnantwere seen at more frequent intervals.

Baseline and Follow-up Evaluation

The baseline evaluation included a detailed medicalhistory, physical examination, and laboratory tests. In-formation on risk factors for HBV infection, family historyof HBV, prior antiviral therapy, results of recent imagingtests, medical comorbidities, health behavior, and socio-economic indicators were recorded. Recommended labo-ratory tests included a complete blood count, liver panel,creatinine, international normalized ratio, a-fetoprotein,quantitative HBV DNA level, HBsAg, antibody againstHBsAg, HBeAg, antibody against HBeAg, antibody againstHIV, antibody against hepatitis C virus, antibody againsthepatitis D virus, autoimmune markers, and fastingglucose and lipid panels. Evaluations at follow-up visitsinclude an updated medical history, use of HBV antiviraltherapy whichmay have been initiated after entry into thecohort, physical examination, laboratory testing for HBVDNA and a liver panel, and results of recent imaging tests.

Collection and Storage of Biospecimens

Serum and plasma samples for future research weredrawn at each visit, stored frozen at each clinical center,and sent regularly to the NIDDK central repositorywhere they were stored at -80�C. Samples are sent by therepository in batches to central laboratories for testing.One sample of whole blood for extracting host DNA was

http://www.hepbnet.org/

http://www.hepbnet.org/


collected from all consenting participants for genetictesting. Liver biopsy slides, either historical or from astandard-of-care biopsy, and a sample of liver tissuestored in RNALater (Ambion, Life Technologies, GrandIsland, NY) if a biopsy was performed during the study,were collected from all consenting participants. Datawere collected at each clinical site and entered into apassword-protected electronic database by trainedpersonnel. The DCC regularly monitors the data to assessthe accuracy and timeliness of data collection. Eleven ofthe 21 clinical sites enrolling adults also are engaged inancillary immunology studies. Participants eligible forthe immunology studies are enrolled after providingseparate written consent.

Enrollment Process and Criteria

The study set out to enroll consecutive, eligible,HBsAg-positive patients at each clinical site with anaggregate target sample size of 2500 subjects. At each site,a screening log was kept to record reasons for non-enrollment. The first participant was enrolled on January14, 2011. After enrolling approximately 1500 partici-pants, the Steering Committee reviewed revised powercalculations and changed from consecutive to targetedenrollment, focusing on the following groups: (1) poten-tial candidates for the clinical trials, (2) patients whowerepregnant, (3) individuals who experienced flares of CHB,(4) patients with acute hepatitis B, (5) those with knownhepatitis D virus infection, and (6) patients who wereeligible for the immunology study. The protocol amend-ment was approved at all sites in 2013. Only participantswith chronic HBV infection enrolled before switching totargeted enrollment were included in the current analysis.

Monitoring and Testing

Standardized cut-off levels for the upper limit of normal(ULN) for an alanine aminotransferase (ALT) level of 30 U/L for men and 20 U/L for women were used, regardless ofthe normal range at the laboratory fromwhich results wereobtained. HBV DNA levels from the Central Virology Lab-oratory were based on the results of the Roche real-timepolymerase chain reaction assay (COBAS Ampliprep/COBAS TaqMan HBV Test, v2.0; Roche Molecular Di-agnostics, Branchburg, NJ), which has a lower and upperlimit of quantification of 20 IU/mL and 1.7 � 108 IU/mL,respectively. HBV genotype data were based on massspectrometry, performed at the Molecular Epidemiologyand Bioinformatics Laboratory in the Division of ViralHepatitis at the Centers for Disease Control and Preven-tion.6 If there were insufficient research blood samples forbaseline HBV DNA testing or HBV genotyping to be per-formed in the central laboratories, historical results fromthemedical recordwere used, if available. Because this wasan observational study with study visits conducted inconjunctionwith clinical practice, laboratory testswere not

always performed on the same day as the study visits.Often, they were performed before the visit, therefore awindow of up to 12 months was accepted for baseline ALTand HBVDNA levels, and a window of up to 24months wasaccepted for HBeAg status. However, reported resultstypically were more recent (ie, 99% of ALT and HBV DNAlevels were obtained within 3 months of entry, and 91% ofHBeAg levels were obtained within 12 months of entry).

Assignment of Chronic Hepatitis B Phenotype

Investigators were asked to assign a phenotype foreach participant on the day of enrollment. The guidelineswere as follows: (1) immune tolerant: HBeAg-positive,ALT levels �ULN on 2 or more occasions at least6 months apart and HBV DNA levels �106 IU/mL; (2)immune active CHB; (a) HBeAg-positive: ALT levels morethan 2 times the ULN on 2 or more occasions at least6 months apart and HBV DNA levels �104 IU/mL; or (b)HBeAg-negative: ALT levels more than 2 times the ULNon 2 or more occasions at least 6 months apart and HBVDNA levels �103 IU/mL; (3) inactive carrier: HBeAg-negative, ALT levels �ULN and HBV DNA levels lessthan 103 IU/mL on 2 or more occasions at least 6 monthsapart; and (4) indeterminate: individuals who did not fitinto one of these categories.

Statistical Analysis

Baseline characteristics were summarized via fre-quencies and percentages for categoric variables and viamedians and quartiles for continuous variables. To testwhether distributions of categoric variables differedacross racial groups, the Pearson chi-square test or itsexact version were used, as appropriate. Because theresults are descriptive, pairwise comparisons were notadjusted for multiple testing. The same method was usedto examine the association between genotype distribu-tions and birthplace. The Kruskal–Wallis test was used totest whether the distributions of continuous variablesdiffered across racial groups. For all statistical tests, asignificance level of 0.05 was used to establish statisticalsignificance. The statistical analyses were conducted inSAS (version 9.2; SAS Institute, Cary, NC).

Results

Baseline Demographics and ClinicalCharacteristics of the Adult Cohort

Among 7118 adults screened for entry into theobservational study before targeted enrollment, 1653(23%) were enrolled between January 2011 and August2013. The major reasons for nonenrollment includedcurrent antiviral therapy (n ¼ 3013), refusal to consent(n ¼ 924), inability to comply with follow-up evaluation(n ¼ 419), and ineligibility because of HIV co-infection


(n ¼ 194), HCC (n ¼ 188), hepatic decompensation(n ¼ 180), liver transplantation (n ¼ 62), or other rea-sons (n ¼ 951). Twenty-eight subjects with acute hepa-titis B were excluded from the current analyses, resultingin 1625 subjects with chronic HBV infection in the

Table 1. Demographic and Clinical Characteristics by Race

Characteristics

All Wh

(N ¼ 1625) (N ¼Age, ya N ¼ 1623 N ¼

42 (33–52) 48 (35Age group, yb N ¼ 1623 N ¼

18 to <30 264 (16.3) 27 (1430 to <40 452 (27.8) 37 (2040 to <50 405 (25) 37 (2050 to <60 324 (20) 48 (26�60 178 (11) 35 (19

Sexb N ¼ 1625 N ¼Male 829 (51) 111 (60

Hispanicb N ¼ 1612 N ¼Yes 18 (1.1) 10 (5.5

Place of birthb N ¼ 1615 N ¼United States/Canada 294 (18.2) 118 (64Other North America and South America 27 (1.7) 10 (5.4Europe 47 (2.9) 44 (23Asia/Australia 1077 (66.7) 10 (5.4Africa 170 (10.5) 2 (1.1

Presumed mode of transmissionb N ¼ 1210 N ¼Vertical 724 (59.8) 27 (22Horizontal/household 325 (26.9) 20 (16Sexual 73 (6) 33 (27Medical exposures 62 (5.1) 25 (20Drug use 17 (1.4) 13 (10Other 9 (0.7) 2 (1.7

Estimated duration of HBV, ya N ¼ 1168 N ¼31 (20–43) 25 (13

Ever received HBV treatmentb,c N ¼ 1623 N ¼Yes 235 (14.5) 24 (13

Genotypeb N ¼ 1379 N ¼A 247 (17.9) 84 (55B 531 (38.5) 7 (4.6C 450 (32.6) 4 (2.6D 106 (7.7) 50 (32E 35 (2.5) 2 (1.3F/G/H/multiple 10 (0.7) 5 (3.3

HBeAgb N ¼ 1386 N ¼Positive 365 (26.3) 31 (19

HBV DNA, log10 IU/mLa N ¼ 1592 N ¼3.6 (2.5–5.6) 3.0 (2.0

ALT level, U/L, mena N ¼ 800 N ¼38 (27–61) 46 (30

ALT level, U/L, womena N ¼ 764 N ¼26 (19–39) 29 (22

Albumin level, g/dLa N ¼ 1516 N ¼4.3 (4.1–4.6) 4.3 (4.1

Total bilirubin level, mg/dLa N ¼ 1544 N ¼0.6 (0.4–0.8) 0.6 (0.4

Platelet level 103/mm3a N ¼ 1389 N ¼217 (179–256) 208 (17

aContinuous variables were summarized by N of observed data and medians (intbCategoric variables were summarized by N of observed data and percentagesappropriate.cPatients currently on antiviral therapy were excluded from enrollment with the e

cohort. The median age was 42 years (range, 18–80 y),51% were men, and the median physician-estimatedduration of infection was 31 years (range, 1–76 y). Asshown in Table 1, the majority of subjects were Asian(72%), followed by black (15%), white (11%), and mixed

ite Black Asian Mixed/other

P value184) (N ¼ 237) (N ¼ 1158) (N ¼ 38)

184 N ¼ 237 N ¼ 1157 N ¼ 38 <.001–58) 43 (34–54) 41 (32–51) 39 (28–47)184 N ¼ 237 N ¼ 1157 N ¼ 38.7) 31 (13.1) 194 (16.8) 11 (28.9).1) 64 (27) 341 (29.5) 8 (21.1).1) 67 (28.3) 287 (24.8) 14 (36.8).1) 44 (18.6) 227 (19.6) 3 (7.9)) 31 (13.1) 108 (9.3) 2 (5.3)184 N ¼ 237 N ¼ 1158 N ¼ 38 <.001.3) 132 (55.7) 569 (49.1) 13 (34.2)183 N ¼ 235 N ¼ 1150 N ¼ 38 <.001) 1 (0.4) 4 (0.3) 1 (2.6)184 N ¼ 237 N ¼ 1150 N ¼ 37 <.001.1) 57 (24.1) 97 (8.4) 22 (59.5)) 11 (4.6) 3 (0.3) 1 (2.7).9) 1 (0.4) 0 (0.0) 1 (2.7)) 2 (0.8) 1048 (91.1) 13 (35.1)) 166 (70) 2 (0.2) 0 (0.0)120 N ¼ 179 N ¼ 875 N ¼ 33 <.001.5) 40 (22.3) 626 (71.5) 29 (87.9).7) 97 (54.2) 205 (23.4) 2 (6.1).5) 24 (13.4) 15 (1.7) 1 (3).8) 15 (8.4) 22 (2.5) 0 (0.0).8) 2 (1.1) 1 (0.1) 1 (3)) 1 (0.6) 6 (0.7) 0 (0.0)101 N ¼ 154 N ¼ 875 N ¼ 32 <.001–35) 15 (6–32) 34 (23–45) 30 (21–42)184 N ¼ 237 N ¼ 1157 N ¼ 38 .02) 20 (8.4) 183 (15.8) 8 (21.1)152 N ¼ 162 N ¼ 1023 N ¼ 35 <.001.3) 105 (64.8) 50 (4.9) 6 (17.1)) 7 (4.3) 510 (49.9) 6 (17.1)) 3 (1.9) 420 (41.1) 23 (65.7).9) 12 (7.4) 40 (3.9) 0 (0.0)) 31 (19.1) 2 (0.2) 0 (0.0)) 4 (2.5) 1 (0.1) 0 (0.0)156 N ¼ 189 N ¼ 1003 N ¼ 32 <.001.9) 19 (10.1) 305 (30.4) 9 (28.1)178 N ¼ 234 N ¼ 1136 N ¼ 38 <.001–4.2) 3.0 (2.0–3.9) 4.0 (2.7–6.1) 3.4 (2.5–4.5)109 N ¼ 127 N ¼ 548 N ¼ 13 .06–68) 36 (26–63) 37 (26–58) 46 (33–91)71 N ¼ 101 N ¼ 564 N ¼ 24 <.001–44) 20 (16–27) 27 (19–40) 27 (16–46)175 N ¼ 219 N ¼ 1079 N ¼ 36 <.001–4.6) 4.2 (3.9–4.4) 4.4 (4.1–4.6) 4.3 (4.0–4.6)179 N ¼ 225 N ¼ 1096 N ¼ 37 <.001–0.8) 0.5 (0.4–0.7) 0.6 (0.5–0.9) 0.5 (0.4–0.7)167 N ¼ 209 N ¼ 974 N ¼ 34 .20–257) 208 (170–263) 219 (184–255) 216 (186–263)

erquartile range). The P values were based on the Kruskal–Wallis test.. The P values were based on the chi-square test or its exact version when

xception of pregnant women.


or other race (2%). Less than one fifth (18%) of thesubjects were born in North America. For the 1210(74%) participants for whom a route of transmissionwas determined by the investigator, it was categorizedbroadly as vertical in 60% and horizontal in 40%. Thedistribution of HBV genotypes were as follows: A, 18%;B, 39%; C, 33%; D, 8%; E, 3%; and other, 1%. At baseline,74% of the subjects were negative for HBeAg. The me-dian serum HBV DNA level was 3.6 log10 IU/mL; 36%had a level less than 103 IU/mL, 21% had a level of 103

to 104 IU/mL, 25% had a level of 104 to 107 IU/mL, and18% had a level of 107 IU/mL or more. The distributionof serum ALT levels was �1 times the ULN in 33%, >1 to�2 times the ULN in 43%, and more than 2 times theULN in 24%. Physician-assigned phenotype at studyentry was reported as immune tolerant in 10%, HBeAg-positive CHB in 14%, HBeAg-negative CHB in 26%,inactive carrier in 37%, and indeterminate in 13%. Mostparticipants (86%) had never received treatment forHBV infection.

Analysis by Race

There were marked differences in almost all of thedemographic, clinical, and laboratory features among themajor racial groups (Table 1). Compared with Asians,whites and blacks were older, more likely to be men, andhave a shorter estimated duration of infection. Verticaltransmission was the predominant source of infectionamong Asians, whereas horizontal transmission wasmore common among whites and blacks, with sexualtransmission and medical exposure being the most

Figure 3. (A) Distribution of serum ALT level (categorized by ULtimes the ULN, >1 to 2 times the ULN, and >2 times the ULN, w(B) Distribution of serum HBV DNA level by race. Serum HBV DN104 IU/mL, 104 to 107 IU/mL, and 107 IU/mL or higher.

common modes of horizontal transmission. The majorityof all races were HBeAg negative, including 70% ofAsians, 80% of whites, and 90% of blacks. The distri-bution of HBV genotypes varied markedly among the 3major racial groups. The predominant genotypes amongAsians were B (50%) and C (41%), among whites were A(55%) and D (33%), and among blacks were A (65%)and E (19%). The majority of whites in the cohort (65%)were born in North America compared with only 24% ofblacks and 8% of Asians.

ALT levels also were different across racial groups(P ¼ .01) (Table 1 and Figure 3A). A higher percentage ofblacks (42%) than Asians (32%; P ¼ .01) or whites(24%; P ¼ .001) had a normal ALT level, and propor-tionally more whites (31%) had an increased ALT levelmore than 2 times the ULN compared with Asians (24%;P ¼ .05) and blacks (20%; P ¼ .02). HBV DNA levels werehighest among Asians (Table 1 and Figure 3B). Physician-assigned phenotype differed by race (Figure 4). AmongAsians, 13% were designated as having immune-tolerantdisease, 29% had HBeAg-negative CHB, 15% had HBeAg-positive CHB, and 30% were inactive carriers. Incontrast, among whites and blacks, immune-tolerantdisease was uncommon (1% and 2%) and the inactivecarrier phenotype was the most common (47% and 66%,respectively), followed by HBeAg-negative CHB (25%and 14%, respectively). Notably, 13% (10%–15% byrace) of all participants had an indeterminate phenotype.Among participants with an indeterminate phenotype forwhom each characteristic was known, 57% were men,74% were Asian, and 83% were HBeAg negative. Therewas a broad spread of HBV DNA levels: 33% had a level

N) by race. Serum ALT level was categorized as follows: �1ith the ULN defined as 30 U/L for men and 20 U/L for women.A level was categorized as follows: less than 103 IU/mL, 103 to

Figure 4. Distribution ofphases of chronic HBVinfection by race. Eachslice of the pie representsthe percentage of pheno-type distribution.


less than 103 IU/mL, 27% had a level of 103 to <104

IU/mL, 34% had a level of 104 to <107 IU/mL, and 5%had a level greater than 107 IU/mL, and ALT levels: 28%had an ALT level �ULN, 54% had a level >1 to 2 timesthe ULN, and 18% had a level more than 2 times the ULN.

Analysis by Continent of Birth

There were also racial and genotype differences withrespect to immigration status. Nearly three quarters ofthe participants in the HBRN adult cohort were Asians, ofwhom 92% were born outside North America. In addi-tion, 15% of the cohort was black, of whom 70%reported Africa as their birthplace. The genotype distri-bution differed significantly (P < .001) by continent ofbirth (Figure 5). The most common genotypes were Aand C among those born in the United States and Canada,B and C for those born in Asia, A and E for those born inAfrica, A and D for those born in Europe, and A andothers (F, G, and H) for those born in South America andMexico.

Discussion

The objectives, organizational structure, and initialfindings of the NIDDK-sponsored HBRN are described.The HBRN is a large research program in North Americacreated to study the epidemiology, natural history, andtreatment of CHB. During a period of 32 months, 1625adults with chronic HBV infection were enrolled from 21

clinical centers in the United States and Canada. Thepotential importance of the HBRN is owing to its widecatchment distribution, the racial and ethnic diversity ofthe participants, the planned long-term follow-up eval-uation of study participants, and the breadth of data andbiosamples collected that will enable investigators tostudy a wide range of topics related to hepatitis B. Effortswill continue to enroll targeted patient groups for studiesof specific aspects of natural history of chronic HBVinfection and treatment trials. Information on pediatricparticipants enrolled in the HBRN cohort studies will beanalyzed and published separately.7

Although it generally is accepted that chronic HBVinfection can be classified into 4 phases, 13% of subjectsin the HBRN did not meet criteria for any of these phases.Intriguingly, using recent definitions of normal ALTinstead of laboratory reference ranges, 43% of ourcohort displayed low-level increases in ALT level (1–2 �ULN) that may not be categorized neatly into commonlyaccepted immune active, inactive, or tolerant phases ofchronic HBV infection. Further follow-up evaluation willdetermine the natural history of these participants.Furthermore, virtually all of the immune-tolerant pa-tients were Asian and were born abroad.

One of the phases, HBeAg-negative CHB, formerly wasconsidered relatively rare in North America and has beenobserved more commonly in the Mediterranean, EasternEurope, and Asia, where it may constitute as much as90% of all patients with chronic HBV infection.8,9 Ourstudy showed that in North America, HBeAg-negativeCHB is far more common than HBeAg-positive CHB

Figure 5. Distribution of subjects in the HBRN Cohort Study by continent of birth and HBV genotype. The size of each pierepresents the proportion of enrollees who were born in each continent (with the exception of Europe and South America,which were enlarged slightly to facilitate viewing), and each slice of the pie represents the percentage of genotype distribution.N. America, North America; S. America, South America.


among all racial groups. The largest group of HBeAg-negative participants was classified as inactive carriers;excluding patients who were receiving antiviral therapymay have skewed the HBRN cohort toward this group.

Determining HBV genotypes is an important goal ofthe HBRN because it has been postulated that certaingenotypes are associated with a higher incidence of long-term complications including HCC.10 A broad range ofgenotypes (A–H) are represented in the HBRN cohort,with genotypes A to D constituting more than 90% ofcases. Compared with a previous study performed adecade ago, the most striking difference of the currentanalysis was the markedly lower prevalence of genotypeA (a decrease from 35% to 18%) and an increase ingenotype B (from 22% to 39%).11 This could be becausethe study was conducted at different sites than per-formed previously or because of participant selection,but also could be explained by changes in immigrationpatterns over the past decade.

The adult cohort study provides a unique opportunityto examine the natural history of hepatitis B across manyraces and ethnicity. The data on country of birth confirmsthat the burden of chronic HBV infection is dispropor-tionately large among immigrant populations residing inNorth America, the size of which differs by race. Thesefindings from the HBRN are well aligned with a recentreport from the Centers for Disease Control and Preven-tion highlighting the impact that changing immigrationpatterns has had on the epidemiology of chronic HBVinfection in the United States. It is estimated that morethan 90% of people with chronic HBV infection in theUnited States today immigrated from other countries.12

During the period from 1974 to 2008, nearly 30 millionimmigrants have entered the United States, of whom 63%were born in countries of intermediate or high HBVprevalence (range, 2%–31%).12 Thus, it is estimated that1.3 million new HBsAg carriers entered the United Statesduring this period. The true burden of HBV infection in theUnited States has been underappreciated because immi-grant minorities are sampled inadequately in population-based studies such as the National Health and NutritionExamination Survey IV study.13 The high frequency ofimported CHB has important implications for developingpublic health strategies to educate and control the spreadof HBV infection in the community.

There were several limitations of the HBRN worthnoting. Subjects enrolled in the HBRN may not be repre-sentative of those in the community. Patients who arecurrently on antiviral therapy (>40% of those screenedfor enrollment), those who do not have access to special-ized liver centers, and those who do not speak a languagefor which data can be collected by the HBRN were notincluded. Furthermore, more than half of the potentiallyeligible participants were not enrolled, primarily becausethey refused to consent orwere considered to be unable tocomply with follow-up evaluation. Subjects with HIV wereexcluded from the main cohort but are being studied aspart of a parallel NIDDK R01-funded ancillary study.

In summary, the NIDDK-sponsored HBRN is a largeprospective cohort study in North America, and includesa diverse racial distribution and the full spectrum ofdisease phenotypes.5,14 Longitudinal assessments ofparticipants should provide meaningful insights into thenatural history and disease burden of chronic HBV


infection in North America. With the large size of thepopulation under study, the HBRN should provide reli-able estimates of transitions from one phase of chronicHBV infection to another and the virologic and immu-nologic basis behind those transitions. Collectively, im-migrants with chronic HBV infection constitute thelargest group of patients with hepatitis B in NorthAmerica. A better understanding of the epidemiology andnatural history could improve management, delay dis-ease progression, and save lives.

References
1. Lavanchy D. Worldwide epidemiology of HBV infection, disease
burden, and vaccine prevention. J Clin Virol 2005;34(Suppl 1):S1–S3.

2. Lozano R, Naghavi M, Foreman K, et al. Global and regionalmortality from 235 causes of death for 20 age groups in 1990and 2010: a systematic analysis for the Global Burden of Dis-ease Study 2010. Lancet 2012;380:2095–2128.

3. Perz JF, Armstrong GL, Farrington LA, et al. The contributions ofhepatitis B virus and hepatitis C virus infections to cirrhosis andprimary liver cancer worldwide. J Hepatol 2006;45:529–538.

4. McQuillan GM, Coleman PJ, Kruszon-Moran D, et al. Prevalenceof hepatitis B virus infection in the United States: the NationalHealth and Nutrition Examination Surveys, 1976 through 1994.Am J Public Health 1999;89:14–18.

5. Kowdley KV, Wang CC, Welch S, et al. Prevalence of chronichepatitis B among foreign-born persons living in the UnitedStates by country of origin. Hepatology 2012;56:422–433.

6. Ganova-Raeva L, Ramachandran S, Honisch C, et al. Robusthepatitis B virus genotyping by mass spectrometry. J ClinMicrobiol 2010;48:4161–4168.

7. Schwarz KB, RosenthL P, Murray KF, et al. Phenotypes of NorthAmerican children with hepatitis B virus (HBV) infection. Hep-atology 2012;56:635A.

8. Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negativechronic hepatitis B. Hepatology 2001;34:617–624.

9. Funk ML, Rosenberg DM, Lok AS. World-wide epidemiology ofHBeAg-negative chronic hepatitis B and associated precore andcore promoter variants. J Viral Hepat 2002;9:52–61.

10. Liu CJ, Kao JH. Global perspective on the natural history ofchronic hepatitis B: role of hepatitis B virus genotypes A to J.Semin Liver Dis 2013;33:97–102.

11. Chu CJ, Keeffe EB, Han SH, et al. Hepatitis B virus genotypes inthe United States: results of a nationwide study. Gastroenter-ology 2003;125:444–451.

12. Mitchell T, Armstrong GL, Hu DJ, et al. The increasing burden ofimported chronic hepatitis B–United States, 1974-2008. PLoSOne 2011;6:e27717.

13. Wang SH, Pong P, Pollack H. Hepatitis B virus in the UnitedStates. Ann Intern Med 2011;155:204–205; author reply 5–6.

14. Rotermann M, Langlois K, Andonov A, et al. Seroprevalence ofhepatitis B and C virus infections: results from the 2007 to 2009and 2009 to 2011 Canadian Health Measures Survey. HealthRep 2013;24:3–13.

Reprint requestsAddress requests for reprints to: Marc G. Ghany, MD, MHSc, Liver DiseasesBranch, National Institute of Diabetes and Digestive and Kidney Diseases,National Institutes of Health, Bdg 10, Room 9B-16, 10 Center Drive, MSC 1800,Bethesda, Maryland 20892-1800. e-mail: [email protected]; fax: (301)402-0491.

AcknowledgmentsThe Hepatitis B Research Network comprised the following: Harvard Consortium:Raymond T. Chung, MD (Massachusetts General Hospital, Boston, MA); Minne-sota Alliance for Research in Chronic Hepatitis B Consortium: Lewis R. Roberts,MB,ChB,PhD (MayoClinicRochester,Rochester,MN), andColeman I.Smith,MD(University of Minnesota, Minneapolis, MN); Saint Louis Midwest Hep B Con-sortium: Mauricio Lisker-Melman, MD (Washington University, St. Louis, MO);University of Toronto Consortium: David K. Wong, MD, Joshua Juan, MD, JordanFeld, MD, MPH, Colina Yim, and Jenny Heathcoate, MD (Toronto Western andGeneral Hospitals, Toronto, Ontario, Canada); HBV Clinical Research NetworkNorth Texas Consortium: William M. Lee, MD (Division of Digestive and LiverDiseases, University of Texas Southwestern Medical Center at Dallas, Dallas,Texas), and Son Do, MD (University of Texas Southwestern, Dallas, TX); LosAngeles Hepatitis B Consortium: Tram T. Tran, MD (Cedars Sinai Medical Center,Los Angeles, CA); San Francisco Hepatitis B Research Group Consortium: Man-dana Khalili, MD, MAS (Department of Medicine, University of California–SanFrancisco, San Francisco, CA), and Stewart L. Cooper, MD (California PacificMedical Center, Research Institute, Sutter PacificMedical Foundation, Division ofHepatology,SanFrancisco, CA);MichiganHawaii Consortium:Robert J. Fontana,MD (University of Michigan, Ann Arbor, MI), and Naoky Tsai, MD (The Queen’sMedical Center, Honolulu, HI); Chapel Hill, NCConsortium: Keyur Patel, MD (DukeUniversity Medical Center, Durham, NC), and Donna Evon, PhD (University ofNorth Carolina at Chapel Hill, Chapel Hill, NC); Pacific Northwest/Alaska ClinicalCenter Consortium: Robert C. Carithers, MD (University of Washington MedicalCenter, Seattle,WA),Kris V.Kowdley,MD (VirginiaMasonMedicalCenter, Seattle,WA), and Chia C. Wang, MD (Harborview Medical Center, Seattle, WA); LiverDiseases Branch, National Institute for Diabetes and Digestive and Kidney Dis-eases,National Institutes of Health: T. Jake Liang,MD; ImmunologyCenter: Jang-June Park, PhD (University of Pennsylvania Perelman School of Medicine, Phila-delphia, PA); Data Coordinating Center: Abdus Wahed, PhD (Graduate School ofPublic Health, University of Pittsburgh, Pittsburgh, PA); and Central Pathology:David Kleiner, MD, PhD (Center for Cancer Research, National Cancer Institute,National Institutes of Health, Bethesda, MD).

In addition to the authors, the Hepatitis B Research Network would like toacknowledge the contributions of the following: Harvard Consortium: NezamAfdhal, MD, Asad Javaid, MBBS, Jianghe Niu, Johanna Han, and Imad Nasser,MD (Beth Israel Deaconess Medical Center, Boston, MA); Minnesota Alliancefor Research in Chronic Hepatitis B: Alisha C. Stahler, and Linda Stadheim, RN(Mayo Clinic Rochester, Rochester, MN), and Mohamed Hassan, MD (Univer-sity of Minnesota, Minneapolis, MN); Saint Louis Midwest Hep B Consortium:Debra L. King, RN, and Rosemary A. Nagy, MBA, RD, LD (Saint Louis Uni-versity School of Medicine, St. Louis, MO, and Washington University, St.Louis, MO); University of Toronto Consortium: Danie La, RN, and Lucie Liu(Toronto Western and General Hospitals, Toronto, Ontario, Canada); HBV CRNNorth Texas Consortium: Stacey Minshall, RN, BSN (Division of Digestive andLiver Diseases, University of Texas Southwestern Medical Center at Dallas,Dallas, TX), and Sheila Bass (University of Texas Southwestern, Dallas, TX); LosAngeles Hepatitis B Consortium: Samuel French, MD, and Velma Peacock, RN(David Geffen School of Medicine, University of California–Los Angeles, LosAngeles, CA); San Francisco Hepatitis B Research Group Consortium: AshleyUngermann, MS, Claudia Ayala, MS, Emma Olson, BS, and Ivy Lau, BS (Uni-versity of California–San Francisco, San Francisco, CA), Veronika Podolskaya,BS, NCPT, and Nata DeVole, RN (California Pacific Medical Center, ResearchInstitute, San Francisco, CA); Michigan Hawaii Consortium: Barbara McKenna,MD, Kelly Oberhelman, PAC, Sravanthi Kaza, Bpharm, and Cassandra Rodd,BS (University of Michigan, Ann Arbor, MI), Leslie Huddleston, NP, and PeterPoerzgen, PhD (The Queen’s Medical Center, Honolulu, HI); Chapel Hill, NCConsortium: Jama M. Darling, MD, A. Sidney Barritt, MD, Tiffany Marsh, BA,Vikki Metheny, ANP, and Danielle Cardona, PA-C (University of North Carolinaat Chapel Hill, Chapel Hill, NC); Virginia Commonwealth University MedicalCenter: Velimir A. Luketic, MD, Paula G. Smith, RN, BSN, and Charlotte Hof-mann, RN (Virginia Commonwealth University Health System, Richmond, VA);Pacific Northwest/Alaska Clinical Center Consortium: Terri Mathisen, RN, BSN,and Susan Strom, MPH (University of Washington Medical Center, Seattle,WA), Jody Mooney, and Lupita Cardona-Gonzalez (Virginia Mason MedicalCenter, Seattle, WA); Liver Diseases Branch, National Institute for Diabetes andDigestive and Kidney Diseases, National Institutes of Health: Nancy Fryzek,RN, BSN, MBA, Elenita Rivera, RN, BSN, Nevitt Morris, RN, BSN, BS, andVanessa Haynes-Williams, RN, BSN, MSN; Immunology Center: Mary E.Valiga, RN, Keith Torrey, BS, Danielle Levine, BS, James Keith, BS, andMichael Betts, PhD (University of Pennsylvania, Philadelphia, PA), and Luis J.Montaner, DVM, DPhil (Wistar Institute, Philadelphia, PA); Centers For DiseaseControl and Prevention: Chong-Gee Teo, MD, PhD, Yury Khudyakov, PhD, LiliT. Punkova, MSc; Data Coordinating Center: Yona Cloonan, PhD, MichelleDanielson, PhD, Tamara Haller, Geoffrey Johnson, MS, Stephanie Kelley, MS,Sharon Lawlor, MBA, Ruosha Li, PhD, Manuel Lombardero, MS, Joan M.MacGregor, MS, Andrew Pelesko, BS, Donna Stoliker, Barbara Walters, andElla Zadorozny, MS (Graduate School of Public Health, University of Pittsburgh,Pittsburgh, PA).

Conflicts of interestThese authors disclose the following: Robert Perrillo had received lecture feesfrom Bristol Myers Squibb and Gilead Sciences, and consultant fees fromNovartis; Harry Janssen has received consultant fees and grant support fromBristol Myers Squibb, Gilead Sciences, Novartis, Roche, and Merck; MargaretShuhart has received grant funding from Gilead Sciences; W. Ray Kim has

http://refhub.elsevier.com/S1542-3565(14)00976-8/sref1

























































mailto:[email protected]


received consultant fees from Gilead Sciences; Michael Fried has receivedconsultant fees from Genentech, Merck, Vertex, AbbVie, Janssen, BMS, andGilead Sciences; Richard Sterling has received consultant fees from BMS, GileadSciences, Roche, and Genentech, and research support from BMS, Gilead Sci-ences, Roche, Genentech, and RocheMolecular Diagnostics; Adrian Di Biscegliehas received consultant fees and grant support from Gilead Sciences and BristolMyers Squibb; Steven-Huy Han has received lecture fees from Gilead Sciences,and grant support from Gilead Sciences, Bristol Myers Squibb, and Idenix Phar-maceuticals; Kyong-MiChang reports her spouse is an employee of BristolMyersSquibb and her spouse has received consultant fees from Bristol Myers Squibb;and Anna Lok has received consultant fees from Gilead Sciences, Glax-oSmithKline, Merck, and Roche, and grant support from Bristol-Myers Squibb,Gilead Sciences, and Merck. The remaining authors disclose no conflicts.

FundingThe Hepatitis B Research Network was funded by grants from the NationalInstitute of Diabetes and Digestive and Kidney Diseases to the followinginvestigators: U01 DK082872 (W.L.), DK082864 (S.B.), DK082874 (H.J.), U01

DK082944 (N.T.), DK082943 (R.C.), DK082919 (D.T.-Y.L.), DK 082843(L.R.R.), DK082867 (M.W.F.), DK082923 (R.K.S.), DK082871 (A.D.B.),DK082927 (S.-H.B.H.), DK082866 (K.-M.C.), and DK082863 (A.S.-F.L.); aninteragency agreement with the National Institute of Diabetes and Digestiveand Kidney Diseases: A-DK-3002-001 (L.M.G.-R.); and support from theintramural program, National Institute of Diabetes and Digestive and KidneyDiseases, National Institutes of Health (M.G.G.). Additional funding for thisstudy was provided by the Immunology Center (National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, Center ofMolecular Studies in Digestive and Liver Diseases: P30DK50306; and aNational Institutes of Health Public Health Service Research grant: M01-RR00040 to K.-M.C.), by the National Center for Advancing TranslationalSciences, National Institutes of Health (UL1TR000058 to R.K.S.); and Clinicaland Translational Science Awards grants: UL1TR000004 (N.A.T.),UL1TR001111 (M.W.F.), and UL1RR024986 (A.S.-F.L.). Additional supportwas provided by Gilead Sciences, Inc, and Roche Molecular Systems via aCooperative Research And Development Agreement through the NationalInstitute of Diabetes and Digestive and Kidney Diseases.

Characteristics of Adults in the Hepatitis B Research Network in North America Reflect Their Country of Origin and Hepatitis B Virus Genotype

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