624 • CID 2007:45 (1 September) • HIV/AIDS
H I V / A I D SM A J O R A R T I C L E
Impact of Highly Active Antiretroviral Therapy
(HAART) on the Natural History of Hepatitis B
Virus (HBV) and HIV Coinfection: Relationship
between Prolonged Efficacy of HAART and HBV
Surface and Early Antigen Seroconversion
Patrick Miailhes,1,3,4Mary-Anne Trabaud,2,3Pierre Pradat,1,3,4Bertrand Lebouche ´,1,3,4Miche `le Chevallier,5
Philippe Chevallier,2,3Fabien Zoulim,1,3,4and Christian Trepo1,3,4
1Ho ˆtel-Dieu, Service d’He ´patologie et de Gastroente ´rologie, and
2Ho ˆpital de la Croix-Rousse, Laboratoire de Virologie, Hospices Civils de Lyon,
5Laboratoire Marcel Me ´rieux, Lyon, France
4Universite ´ Lyon 1, and
(See the article by Gaglio et al. on pages 618–23 and the editorial commentary by Tillman on pages 633–6)
Coinfection with hepatitis B virus (HBV) in human immunodeficiency virus (HIV)–infected
patients is common. However, little is known about the natural history of chronic hepatitis B in HIV-infected
populations, especially the impact of highly active antiretroviral therapy (HAART) on the outcome of HBV early
antigen (HBeAg) and HBV surface antigen (HBsAg) status.
The characteristics of 92 patients coinfected with HIV and HBV were retrospectively assessed before
and after HAART and lamivudine treatment to determine the impact of treatment on chronic hepatitis B and
factors associated with HBeAg and/or HBsAg seroconversion.
During follow-up, 82 patients received antiretroviral therapy, 79 of whom received HAART. Twenty-
eight of the 76 patients who were administered lamivudine therapy developed lamivudine resistance mutations.
While receiving antiretroviral therapy, 10 of 59 HBeAg–positive patients developed antibody to HBeAg, 3 of 10
cleared HBsAg, and 2 of 3 developed antibody to HBsAg. Two of 23 HBeAg-negative patients cleared HBsAg and
developed antibody to HBsAg. HBeAg and/or HBsAg seroconversion combined with an undetectable HBV DNA
level (i.e., an HBV response) correlated with a sustained HIV response (
therapy ( ), and more-severe disease, as evaluated by Centers for Disease Control and Prevention stagingP p .058
(for stage B vs. stage A,; for stage C vs. stage A,P p .029
aminotransferase levels, the HBV response correlated significantly with a greater increase in CD4 cell count while
In HIV-HBV–coinfected patients, HBV response correlated with a sustained HIV response to
antiretroviral therapy, usually HAART including lamivudine.
), shorter durationofantiretroviralP p .001
). For patients with elevated baseline alanineP p .069
Coinfection with hepatitis B virus (HBV) and HIV is
frequent, because both viruses have the same routes
of transmission. In western Europe and the United
States, chronic HBV infection has been found in 7%–
Received 30 December 2006; accepted 1 April 2007; electronically published
30 July 2007.
Reprints or correspondence: Dr. Patrick Miailhes, Service d’He ´patologie et de
Gastroente ´rologie, Ho ˆtel-Dieu, 1 Place de l’Ho ˆpital, 69288 Lyon Cedex 02, France
Clinical Infectious Diseases2007;45:624–32
? 2007 by the Infectious Diseases Society of America. All rights reserved.
10% of HIV-infected patients, with a higher preva-
lence in men who have sex with men [1–3]. Before
the HAART era, Ockenga et al.  revealed that, in
HIV-infected patients, coinfection with either HBV or
hepatitis C virus (HCV) correlated with a reduced
survival rate. As HAART improved the survival of
HIV-infected patients, it became obvious that HIV
worsened the outcome of chronic hepatitis B and in-
creased the risk of liver-associated morbidityandmor-
tality [4–7]. Therefore, the aim of our study was to
describe the natural history of chronic hepatitis B in
HIV-infected patients and to assess the impact of
HAART on chronic hepatitis B.
HIV/AIDS • CID 2007:45 (1 September) • 625
PATIENTS AND METHODS
who were referred to our viral hepatitis and HIV infection
reference center (Department of Hepatogastroenterology, Ho ˆ-
tel-Dieu Hospital, Lyon, France) from January 1990 through
December 2002 and were followed-up for at least 6 months
were retrospectively assessed. Inclusion criteria were positive
serologic examination results for HIV and seropositivity for
hepatitis B surface antigen (HBsAg). Patients entered the study
before HAART and lamivudine treatment was initiated. The
following baseline (defined as entrance in the study) infor-
mation was collected: age, sex, ethnicity, HIV risk factors, HIV-
related illnesses, classification according to the Centers for Dis-
ease Control and Prevention (CDC) 1993 guidelines , HIV
RNA and HBV DNA levels, CD4 cell count, alanine amino-
transferase (ALT) level, hepatitis early antigen (HBeAg) status,
HBV genotype, and duration of follow-up for HIV and HBV
infections. The impact of HAART, especially of lamivudine
to the initial HBeAg profile was assessed, as were other factors
associated with HBeAg and HBsAg seroconversion. Becausethe
long-term follow-up involved changes in antiretroviral therapy
regimens, a sustained HIV response was defined as an unde-
tectable HIV RNA level (!50 copies/mL) during at least 80%
of the duration of antiretroviral therapy. An HBV response was
defined as HBeAg and/or HBsAg seroconversion combined
with an undetectable HBV DNA level (!100 copies/mL). Dur-
ing follow-up, HIV and HBV biological and virological tests
were performed every 3–4 months for most patients.
HBV serological tests included the
detection of HBsAg (Monolisa Ag HBs PLUS kit; Bio-Rad),
antibody to HBsAg (anti-HBs) and antibody to HBV core an-
tigen (Architect kits; Abbott), and HBeAg or antibody to
HBeAg (anti-HBe; AxSYM HBe 2.0 and anti-HBe 2.0 kits; Ab-
bott). Antibodies to HCV were tested using the Monolisa anti-
HCV PLUS 2.0 kit (Bio-Rad). When the results were positive,
a second test was performed using the Ortho HCV 3.0 ELISA
kit (Ortho-Clinical Diagnostics). Total antibodies to hepatitis
D virus were detected using the Eti-AB-Deltak-2 ELISA kit
(DiaSorin). For most patients, 2 commercial ELISA kits were
used for HIV antibody detection: Genscreen HIV 1/2 (Bio-
Rad) and Vironostika HIV Uni-Form II (Organon). However,
because HIV infection was diagnosed over a 15-year period,
other commercial assays may also have been used. The
NewLavBlot kit (Bio-Rad) was used to confirm HIV
During follow-up, for routinege-
nomic quantification, branched DNA technology was used to
quantify HIV RNA levels (Versant HIV RNA 3.0 kit; Bayer;
detection limit, 50 copies/mL) and HBV DNA levels (Versant
Quantiplex HBV DNA 1.0; Bayer; detection limit, 700,000 cop-
All patients coinfected with HIV and HBV
ies/mL) according to the manufacturer’s instructions. When
HBV DNA levels were below the threshold of the Versant kit,
real-time PCR (detection limit, 100 copies/mL) was performed
on frozen serum samples as described elsewhere, using primers
in the C gene region .
HBV genotype and resistance to lami-
vudine were retrospectively determined from frozen serum
samples using commercial line probe assays (INNO-LiPA HBV
genotyping kit and INNO-LiPA HBV resistance; Innogenetics)
according to the manufacturer’s instructions. Discrimination
between the genotypes or resistance mutations was made pos-
sible by hybridization with specific oligonucleotide sequences
immobilized on membrane-based strips after amplification in
the HBV B-C domains of the pol gene . The presence of
polymerase mutations at codons 173, 180, and 204, associated
with lamivudine resistance, was explored when HBV load was
detectable (1700,000 copies/mL) after a period of undetecta-
bility during treatment with lamivudine. This was performed
using the first serum sample with a detectable HBV load or, if
unavailable, the following sample before a second anti-HBV
drug was addedto thetreatmentregimenorlamivudinetherapy
Statistical analysis was performed us-
ing SPSS, version 11.5.1 for Windows (SPSS). Dichotomous
variables were compared using Fisher’s exact test, and other
categorical variables were compared using the Pearson x2test.
For continuous variables, Student’s t test was used (with cor-
rection if variances were not equal), and the Mann-Whitney U
test was used when the number of cases was small. Multivariate
Cox regression analysis, with data censored at the time of
HBeAg and/or HBsAg seroconversion, was conducted to check
for factors that might be related to the HBV response. ORs
and 95% CIs were calculated.
was considered to beP ! .05
Baseline characteristics of patients.
coinfected with HIV and HBV were evaluated (table 1). There
was no difference between the median baseline HBV DNA
level, irrespective of whether the patient’s CD4 cell count was
!200 cells/mL or 1200 cells/mL (8.9 log10copies/mL vs. 8.4
log10copies/mL;). ALT levels were normal in 57 pa-
P p .80
tients (62%) but elevated in 35 (38%). HBV genotyping was
performed for 80 patients (87%) (table 1). Most white pa-
tients had genotype A or D, and sub-Saharan Africans had
equally genotype A or E.
At baseline, 1 patient had isolated antibody to HBV core
antigen and then experienced HBV reactivation, with the reap-
pearance of HBsAg and HBeAg. Among the 91 HBsAg-positive
patients, 61 (67%) were also HBeAg-positive, 29 (32%) were
anti-HBe positive, and 1 was repeatedly negative for both
A total of 92 patients
626 • CID 2007:45 (1 September) • HIV/AIDS
HIV and hepatitis B virus (HBV) before HAART and lamivudine
Baseline characteristics of 92 patients coinfected with
Age, median years (range)
Risk factor for HIV infection
CD4 cell count, median cells/mL (range)
Nadir CD4 cell count, median cells/mL (range)
HIV RNA level,amedian log10copies/mL (range)
HCV RNA positive
ALT level, median IU/L (range)
HBV DNA level,cmedian log10copies/mL (range)
A + G
anine aminotransferase; anti-HCV, antibody to hepatitis C virus; anti-HDV, an-
tibody to hepatitis D virus; CDC, Centers for Disease Control and Prevention;
HBeAg, HBV early antigen; IDU, intravenous drug use; MSM, men who have
sex with men; ULN, upper limit of normal (57 IU/L).
aData are for 64 patients.
bData are for 91 patients.
cData are for 86 patients.
dData are for 80 patients.
Data are no. (%) of patients, unless otherwise indicated. ALT, al-
HBeAg and anti-HBe. Anti-HBe status was linked to African
origin (19 [90%] of 21 patients), and HBeAg-positive status
was linked to white race (61 [87%] of 70 patients). HBeAg
status was not correlated with CDC stage: 67% of patients with
CDC stage A or B HIV infection were HBeAg positive versus
71% of patients with CDC stage C HIV infection (
The median serum HBV DNA level was significantly higher in
HBeAg-positive patients than in anti-HBe–positive patients
(8.98 log10copies/mL vs. 4.27 log10copies/mL;
elevated ALT level also correlated with an HBeAg-positive
).P p .80
). AnP ! .001
status: 30 (49%) of 61 HBeAg-positive patients had elevated
ALT levels versus 4 (14%) of 29 anti-HBe–positive patients
(). The median (?SE) ALT levels were
P p .002
and IU/L, respectively, in these 2 groups (
baseline, only 10 patients (11%) were receiving antiretroviral
therapy, and the remaining 82 (89%) had not previously re-
ceived treatment (figure 1).
HBV disease classification.
initiated, 90 of 91 patients who were HBsAg positive were clas-
sified into 3 groups according to chronic hepatitis B disease
status. Thirty-four patients (37%) had chronic active hepatitis
B (CAHB), which was characterized by an ALT level greater
than the upper limit of normal and an HBV DNA level 15 log10
copies/mL. Forty-one patients (45%) were immunotolerant,
with repeatedly normal ALT levels and HBV DNA levels 15
log10copies/mL. Finally, 16 patients (18%) were considered to
be inactive HBsAg carriers (i.e., inactive carriers), with both
repeatedly normal ALT levels and HBV DNA levels !5 log10
copies/mL. The median baseline CD4 cell counts did not differ
among these 3 groups. One patient could not be classified,
because the patient had chronic hepatitis B with prolonged
HBsAg antigenemia (11 year) combined with elevated ALT
levels and undetectable HBV DNA levels (!100 copies/mL).
Treatment and outcome during follow-up.
2002 (the end of the study period), the median duration of
follow-up was 5 years (range, 0.5–13.3 years). Four patients in
the cohort died during follow-up; 2 died because of uncon-
trolled HIV infection with an AIDS event (1 had severe pneu-
mocystosis, and the other developed HIV encephalopathy),and
the other 2 died of end-stage liver disease. During follow-up,
82 patients (89%) received antiretroviral therapy, of whom 79
received HAART and 76 received lamivudine therapy (figure 1
and table 2). Twenty-eight (37%) of the 76 patients who re-
ceived lamivudine therapy developed lamivudine resistance
mutations (table 3), correlating significantly with longer du-
ration of lamivudine therapy (median, 62 months for patients
with the mutation vs. 24 months for patients without the mu-
tation;), higher baseline HBV DNA level (median, 9.06
P ! .001
log10copies/mL vs. 7.80 log10copies/mL;
baseline CD4 cell count (median, 398 cells/mL vs. 235 cells/mL;
). Lamivudine resistance was seen onlyin patientswith
P p .019
CAHB and immunotolerance. The median duration of lami-
vudine treatment was significantly shorter in the 10 treated
inactive carriers than in those with CAHB or immunotolerance
(18 months vs. 45 months;
P p .003
in the inactive carrier group had an HBV DNA level !3 log
copies/mL. Although the others had higher baseline HBV DNA
levels (up to 4.50 log copies/mL), no lamivudine resistancewas
observed. Lamivudine was the only anti-HBV drug used for
most of our patients and was the first antiviral administered
for 95% of them. Only 3 patients initiated treatment with a
P ! .001
), and higher
P p .001
). One-half of the patients
HIV/AIDS • CID 2007:45 (1 September) • 627
Characteristics of the cohort at the end of follow-up
Type of therapy
Duration of therapy, median months (range)
Presence of lamivudine resistance mutationsb
aAmong 82 patients receiving antiretroviral therapy.
bAmong 76 patients receiving lamivudine therapy.
Data are no. (%) of patients, unless otherwise indicated.
with HIV and hepatitis B virus (HBV) from baseline through December 2002. Data are duration of therapy, shown as median months (range). In total,
82 patients received ART (median duration, 65 months; range, 1–155 months), 79 received HAART (median duration, 43 months; range, 1–93 months),
and 76 received lam (e.g., Epivir, Combivir, and Trizivir; median duration, 36 months; range, 1–83 months). CHB, chronic hepatitis B; lam-R, lam
resistance; mo, months; pt, patient.
and IFN therapy was administered for 22 months.
History of antiretroviral therapy (ART; mono- or binucleoside ART), HAART, and lamivudine treatment (lam) among 92 patients coinfected
aFor this particular case, HAART including lam was unmodified, because it was effective against HIV infection,
combination of lamivudine and tenofovir, for a median period
of 4 months (range, 2–7 months). Thirteen others received
tenofovir as a component of an HIV treatment regimen that
was administered for a median of 6 months (range, 1–20
months). Eight (62%) of these 13 patients also had lamivudine
resistance. Finally, only 2 subjects received adefovir therapy,for
12 and 13 months, because of the emergence of lamivudine
Characteristics of patients who experienced HBeAg and/or
Of the 82 patients receiving antiret-
roviral therapy, 10 (17%) of the 59 HBeAg-positive subjects
acquired anti-HBe. Three of these 10 patients cleared HBsAg,
and 2 of them acquired anti-HBs. Two (9%) of the 23 HBeAg-
negative patients cleared HBsAg, and both seroconverted to
anti-HBs. At the time of HBeAg and/or HBsAg seroconversion,
all patients were receiving antiretroviral therapy. Ten were re-
ceiving HAART including lamivudine, 1 was receiving HAART
without any anti-HBV drug, and 1 was receiving zidovudine
and didanosine combination therapy (table 4). HBsAg or
HBeAg seroconversion was neither observed during tenofovir
or adefovir therapy nor in patients who did not receive treat-
ment for HIV infection. Overall, HBeAg or HBsAg serocon-
version combined with an undetectable HBV DNA level (i.e.,
an HBV response) was achieved in only 12 patients.
Factors associated with HBV response during antiretroviral
In univariate analysis (table 5), an HBV response
correlated significantly with a sustained HIV response (P p
). In addition, an HBV response correlated significantly.001
with a shorter duration of antiretroviral therapy (18 months
vs. 69 months; ), lamivudine therapy (20 months vs.P p .044
31 months;), and HAART (16 months vs. 48 months;P p .018
). Other factors, including the baseline and nadir CD4P p .003
cell counts, baseline HBV DNA and HIV RNA levels, and HBV
genotype, were not related to HBeAg and/or HBsAg serocon-
version (table 5).
related to the CDC stage at baseline (3% for stage A, 19% for
stage B, and 29% for stage C;). Moreover, patientsP p .014
628 • CID 2007:45 (1 September) • HIV/AIDS
tients treated with lamivudine.
Factors associated with the lamivudine resistance mutation among 76 pa-
(n p 28)
(n p 48)
Duration of lamivudine therapy, months
Baseline HBV DNA level,alog10copies/mL
Baseline HIV RNA level,blog10copies/mL
Baseline CD4 cell count, cells/mL
Nadir CD4 cell count, cells/mL
aData were available for 71 patients (25 with lamivudine resistance and 46 without lamivudine
bData were available for 50 patients (16 with lamivudine resistance and 34 without lamivudine
Data are median (range). HBV, hepatitis B virus.
with elevated baseline ALT levels had a 4-times greater chance
of achieving an HBV response than did patients with normal
ALT levels (26.5% vs. 6.3%;P p .023
patients with CAHB, we observed a greater increase in the CD4
cell count during HAART in those who experienced an HBV
response than in those who did not experience an HBV re-
sponse (median increase, 232 cells/mL vs. 48 cells/mL; P p
). Conversely, 7 patients with CAHB who experiencedfailure .03
of HAART developed immunotolerance. In these patients, we
observed a median decrease in CD4 cell count of 72 cells/mL
(range, ?403 cells/mL to +58 cells/mL).
Using multivariate Cox regression analysis (table 6), with
correlated significantly with HBsAg and/or HBeAg serocon-
version: median duration of antiretroviral therapy (OR, 0.41;
95% CI, 0.16–1.03; ) and CDC stage ( for stage B vs.P p .058
stage A,; for stage C vs. stage A,P p .029
response could not be included in this model, because none
of the patients who did not experience this response had an
HBV response, and therefore, the OR could not be calculated.
). In addition, among 34
). HIVP p .069
Despite the widespread use of lamivudine since 1996, HBeAg
and HBsAg seroconversion has been observed only in a mi-
nority of patients initiating HAART regimens [10–13]. In our
study, we described 12 instances of HBeAg and/or HBsAg se-
roconversion during antiretroviral therapy. Most of these se-
roconversions occurred during HAART including lamivudine
and correlated significantly with a sustained HIV response and
a shorter duration of antiretroviral therapy. Interestingly,
HBeAg or HBsAg seroconversion was not observed in patients
who did not receive treatment for HIV infection, in patients
who experienced failure of HAART, or in carriers of mutations
conferring lamivudine resistance, which suggests that a sus-
tained HIV response to antiretroviral therapy is necessary to
control HBV infection. Our study also confirms that powerful
and brief, active antiretroviral therapy, combined with anti-
HBV drugs, triggers HBeAg and HBsAg seroconversion in pa-
tients coinfected with HIV and HBV. Efficient and prolonged
HIV therapy after such an HBV response probably hampers
the reversibility of HBeAg and/or HBsAg seroconversion.
Unlike the results of 2 small studies evaluating the effects of
antiretroviral therapy regimens including lamivudine [10, 12],
the results of our study indicate that baseline CD4 cell count
and HIV RNA and HBV DNA levels are not associated with
either a better outcome during HAART or a higher HBeAg
seroconversion rate. Nevertheless, our study suggests that pa-
tients in more advanced CDC stages of HIV infection have
more chance of seroconverting to anti-HBe or anti-HBs. This
finding may suggest that immunorestoration during HAART,
even without lamivudine (as noted for 2 of our patients) (table
4), plays a major role in controlling chronic hepatitis B and
favors HBeAg and HBsAg seroconversion. Thus, in a subgroup
of patients with a CAHB profile, we revealed that immuno-
restoration during HAART was predictive of HBeAg or HBsAg
seroconversion. In the study by Carton et al. , 5 patients
seroconverted to anti-HBe while receiving HAART including
lamivudine, and their CD4 cell counts increased significantly
more than did those of patients who did not experienceHBeAg
seroconversion. Consequently, immunorestoration after the
initiation of HAART, together with active anti-HBV therapy,
might play a major role in suppressing HBV replication and,
thus, enhance the specific immune response to achieve HBeAg
or HBsAg seroconversion.
A previous immunologic study involving 5 patients coin-
fected with HIV and HBV found evidence of the reconstitution
of a functionally active HBV-specific CD8 cell response when
HAART was combined with an anti-HBV drug . More
HIV/AIDS • CID 2007:45 (1 September) • 629
Characteristics of the 12 patients who experienced hepatitis B early antigen (HBeAg) and/or hepatitis B surface antigen
Type of HBV
CD4 cell count, cells/mL
At time of
AZT, ddI, SQV
d4T, ddI, 3TC,
IDV; then d4T,
ddI, 3TC, EFV
AZT, 3TC; then
AZT, 3TC, SQV
AZT, ddI, 3TC,
AZT, 3TC, IDV
AZT, 3TC, SQV
AZT, 3TC; then
d4T, 3TC, IDV
d4T, 3TC, NFV
3 Positive266C Anti-HBe (30)Yes 648+382 Yes
4 Positive53C Anti-HBe (2)Yes 271+218 Yes
HBV, hepatitis B virus; IDV, indinavir; NFV, nelfinavir; NVP , nevirapine; SQV, saquinavir; 3TC, lamivudine.
aUndetectable HIV RNA level (!50 copies/mL) during at least 80% of the duration of antiretroviral therapy.
bThis patient had a “flare” in transaminase levels after 50 months of 3TC treatment because of emergence of 3TC resistance. The patient was then treated
with the same ART plus IFN-a therapy and experienced HBeAg seroconversion after 22 months of IFN-a therapy.
anti-HBe, antibody to HBeAg; anti-HBs, antibody to HBsAg; ART, antiretroviral therapy; AZT, zidovudine; d4T, stavudine; ddI, didanosine; EFV,efavirenz;
recently , the same group demonstrated that an HBV-spe-
cific CD8 cell response had been reconstituted in 50% of the
HIV-infected patients receiving HAART.
Information on the natural history of chronic hepatitis B in
patients coinfected with HIV and HBV is still limited and
mostly comes from studies conducted during the HAART era
involving patients previously treated with lamivudine (many of
them with lamivudine resistance) [10, 11, 16–18]. In our study,
before HAART and lamivudine treatment, most of our patients
were HBeAg positive (68%) and had normal ALT levels (62%).
Our results are similar to those of previous studies involving
both lamivudine-naive  and lamivudine-pretreated coin-
fected patients [17, 20] but differ from the results of a French
study involving HBV-monoinfected patients , in which a
higher prevalence of anti-HBe positivity was reported. In our
cohort, the higher prevalence of HBeAg-positive patients was
clearly because of the fact that most of the white subjects ac-
activity or injection drug use . Conversely, anti-HBe status
occurred more frequently among African subjects, possibly be-
cause chronic HBV infectionmostlyoccurredduringchildhood
or even earlier, during the perinatal period. This difference was
not reported in previousstudies [4,23],becausetheyconcerned
only white men who have sex with men or injection drugusers.
As noted, with regard to HBV monoinfection , the HBV
DNA level was higher in HBeAg-positive patients than in anti-
HBe–positive patients. As reported by Colin et al. , HBV
DNA level was not related to CD4 cell count or CDC stage.
Immunodepression induced by HIV infection is usually asso-
ciated with an immunotolerant anti-HBV phase, defined by a
normal ALT level and a high HBV DNA level. Nevertheless, in
the present study, the baseline median CD4 cell counts were
similar in patients with immunotolerance and in those with
CAHB. Colin et al.  found similarresults,withnostatistically
significant difference in transaminase levels according to CDC
stage. However, in some of our patients, evolutions of the im-
mune system and changes in CD4 cell count were clearly as-
sociated with different phases of chronic hepatitis B. Thus, the
profiles of 7 patients shifted from CAHB to immunotolerance,
because their CD4 cell counts decreased because of failure of
HAART. Therefore, in certain subjects, there is a dynamic evo-
lution of the chronic hepatitis B pattern that is dependent on
changes in the immune system.
In populations coinfected with HIV and HBV, monotherapy
630 • CID 2007:45 (1 September) • HIV/AIDS
response among 82 patients.
Univariate analysis of factors associated with hepatitis B virus (HBV)
Median baseline ALT level, IU/La
Median baseline HBV DNA level, copies/mLc
Median baseline HIV RNA level, copies/mLd
Median baseline CD4 cell count, cells/mL
Median increase in CD4 cell count,ecells/mL
Median nadir CD4 cell count, cells/mL
Median duration of HAART, monthsg
Median duration of antiretroviral therapy, monthsg
Median duration of lamivudine treatment,g
Sustained HIV responseh
HBeAg or HBsAg
(n p 12)
(n p 70)
20 31 .018
as either hepatitis B early antigen (HBeAg) or hepatitis B surface antigen (HBsAg) serocon-
version combined with an undetectable HBV DNA level duringantiretroviraltherapy.ALT,alanine
aminotransferase; CDC, Centers for Disease Control and Prevention.
aData are for 80 patients.
bData are for 37, 21, and 24 patients with CDC stages A, B, and C HIV infection,respectively.
cData are for 76 patients (11 patients who experienced seroconversion and 65 patientswho
did not experience seroconversion).
dData are for 54 patients.
eChanges from baseline to the end of follow-up.
fData are for 52 patients with genotype A and 19 patients with a non-A genotypes.
gDuration of treatment is censored at the time of HBeAg and/or HBsAg seroconversion.
hData are for 47 patients who had a sustained HIV response (defined as an undetectable
HIV RNA level [!50 copies/mL] during at least 80% of the duration of antiretroviral therapy)
and 35 who did not have this response.
Data are no. (%) of patients, unless otherwise indicated. HBV responsewasdefined
with lamivudine for chronic HBV infection is often associated
with a rapid appearance of lamivudine resistance [16, 25, 26],
with higher risk associated with long-term therapy. Werevealed
that other factors, such as higher baseline HBV DNA level and
both higher baseline and nadir CD4 cell counts, correlated
significantly with the occurrence of lamivudine resistance. As
with HBV monoinfection, a higher pretreatment HBV DNA
level was an important factor explaining this fact . Our
routine HBV DNA level quantification method had a detection
limit of 700,000 copies/mL, and wecould notexcludethatsome
patients had a weaker reduction in HBV DNA level, with per-
sistent low replicative HBV load (10,000–700,000 copies/mL)
while receiving lamivudine therapy, which explains the later
appearance of lamivudine resistance. However, all of the pa-
tients who had prolonged undetectable HBV loads had real-
time PCR performed on frozen serum samples (detectionlimit,
100 copies/mL), which confirmed that HBV DNA levels were
!10,000 copies/mL for this subgroup and !100 copies/mL for
all 12 HBV seroconverters.
In our study, a low HBV DNA level before lamivudine treat-
ment limited the risk of lamivudine resistance. Consequently,
lamivudine resistance was seen only in patients with CAHBand
immunotolerance and not in any of the 10 inactive carriers. In
the latter group, the median duration of lamivudine treatment
was 18 months, which was significantly shorter than that for
the other 2 groups. This result should be underlined, because
in previous studiesinvolvingHIV-HBV–coinfectedpatients,the
rates of lamivudine resistance usually exceeded 20% and 50%
HIV/AIDS • CID 2007:45 (1 September) • 631
ciated with hepatitis B virus (HBV) response among 82 patients.
Multivariate Cox regression analysis of factors asso-
FactorOR (95% CI)P
B vs. A
C vs. A
Elevated baseline ALT
Duration of HAARTa
Duration of lamivudine therapya
Duration of antiretroviral therapya
(HBeAg) or hepatitis B surface antigen (HBsAg) seroconversioncombinedwith
of antiretroviral therapy are censored at the time of HBeAg or HBsAg sero-
conversion for HBV responders. The sustained HIV response could not be
included in the model, because none of the patients who did not have a
sustained HIV response exhibited an HBV response. Therefore, the OR could
not be calculated for this variable. Only variables with
analysis were kept in a Cox model. ALT, alanine aminotransferase; CDC, Cen-
ters for Disease Control and Prevention.
HBV response was defined as either hepatitis B early antigen
in univariateP !.10
at 1 and 2 years, respectively [16, 25, 26]. Here, none of the
patients with a baseline HBV DNA level !5.50 log copies/mL
developed lamivudine resistance. Moreover, in other studies
[10, 16, 18, 25, 26, 28], this lowreplicativesubgroupwasusually
In summary, our results indicate that HBeAg or HBsAg se-
roconversion correlates with a sustained HIV response during
antiretroviral therapy, which was mostly HAART including la-
mivudine. Moreover, for patients with an elevated baselineALT
level, the HBV response correlated significantly with immu-
norestoration following HAART. In practice, our resultssuggest
that a HAART regimen exhibiting dual activity against HIV
and HBV is necessary for the majority of patients coinfected
with HIV and HBV to optimize the HBV response [1, 29, 30].
We thank Eva Garcia and the HIV Database Team, for their help with
data collection; Corinne Brochier and Valerie Thoirain, for technical as-
sistance; and Dr. Jean Jacques Jourdain, for his contribution to data
Potential conflicts of interest.
All authors: no conflicts.
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