SHORT STATEMENT OF THE FIRST EUROPEAN CONSENSUS
CONFERENCE ON THE TREATMENT OF CHRONIC
HEPATITIS B AND C IN HIV CO-INFECTED PATIENTS*
Alfredo Alberti, Nathan Clumeck*, Simon Collins, Wolfram Gerlich, Jens Lundgren,
Giorgio Palu `, Peter Reiss, Rodolphe Thiebaut, Ola Weiland, Yazdan Yazdanpanah,
Stefan Zeuzem (The ECC Jury)
Despite recent advances in the management of hepatitis
and HIV co-infection, there is no clear consensus among
hepatology, infectious diseases and virology experts on
treatment of co-infections and patient management. This
encouraged the organisation of a European Consensus
Conference to review current knowledge on the treatment of
chronic hepatitis B and C in HIV co-infected patients, with
the view to developing this consensus statement.
An organising committee drafted questions to be
addressed at the conference, and following 2-days of
presentations and discussions, an independent Jury Panel
assessed the evidence and prepared this statement with the
aim of addressing eight questions:
† What are the reasons to treat viral hepatitis in HIV co-
infected patients in the HAART era?
† How should viral hepatitis be diagnosed and how should
disease severity be assessed in HIV-infected patients?
† What are the current treatment options?
† Which patients should be treated and when?
† How should co-infected patients be treated (treatment
† How should anti-hepatitis treatment be monitored?
† How should end-stage liver disease be managed?
† What are the most important areas for future research?
for preparing NIH Consensus Statements. This short version
of the consensus summarises the main conclusions and
publish a more detailed version of these recommendations
data. And in a supplement to Journal of Hepatology, articles
prepared by individual presenters will be published to
elaborate on the recommendations made here. Statements
and recommendations were graded for their strength and
quality using a grading system based on the Infectious
Diseases Society of America (IDSA) system (Table 1).
Globally, an estimated 370–400 million people are
chronic carriers of hepatitis B virus (HBV) and over 180
million people are chronic carriers of hepatitis C virus
(HCV). Overlapping routes of transmission of these
hepatitis viruses and HIV, result in a high frequency of
co-infection. Worldwide, several million people are
Journal of Hepatology 42 (2005) 615–624
0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
*In our strive to keep our readership aware of the developments on the
management of liver disease in patients co-infected with HIV, the Journal
of Hepatology endeavoured to publish a concise statement generated by
members of the Jury of the First European Consensus Conference on
treatment of HBV and HCV in HIV co-infected patients. This document
was distributed as a loose leaflet insert in the abstract book of the EASL
Annual Meeting and is published bound in the current issue of the Journal
of Hepatology for reference—Mario U. Mondelli, Co-Editor.
Endorsed by the European Association for the Study of the Liver
(EASL), the European AIDS Clinical Society (EACS), the European
Society of Clinical Microbiology and Infectious Diseases (ESCMID), the
European Federation of Internal Medicine (EFIM), the International AIDS
Society (IAS), the French Society of Infectious Diseases (SPILF) and the
European AIDS Treatment Group (EATG). Hosting societies include the
French Association for the Study of Liver Disease (AFEF) and the French
Society of Internal Medicine (SNFMI). Supported by the French Agency
for Research on AIDS (ANRS) and the French Ministry of Health.
*Corresponding author: Nathan Clumeck, Saint-Pierre University
Hospital, Division of Infectious Diseases, 322 Rue Haute, 1000 Bruxelles,
E-mail address: email@example.com (N. Clumeck).
co-infected with HBV and HIV or HCV and HIV.
Prevalence of HBV and HCV in HIV-infected patients in
Europe is high and estimated to be 40% for HCV and 8% for
HBsAg-positivity. The prevalence of co-infection is influ-
enced by geographic and ethnic origin.
Sexual activity and/or injection drug use are the most
common routes of transmission. Higher rates of HBV co-
infection are seen in men who have sex with men compared
to injection drug users and people with heterosexually-
acquired HIV infection. The primary modes of transmission
for both HCV and HBV are parenteral, sexual and vertical
from mother to child with a risk for HBVOHIVOHCV
for the latter setting. Although sexual transmission of HCV
occurs in !1% monogamous couples, there have been
increasing reports of sexual transmission between men who
have sex with men. Blood may contain up to 108K10950%
chimpanzees doses (CID50)/ml of HBV whereas HCV
reaches only 10650% CID50/ml. Both HBV and HCV may
survive drying in contrast to HIV—HBV is still infectious
after 7 days in the dry state, but HCV is infectious only for
All hepatitis B surface antigen (HBsAg)-positive and
HCV-RNA-positive patients are potentially infectious.
Infection with HBV or HCV and the related liver damage
is an important cause of mortality and morbidity among
In patients infected with HBV, HIV can lead to higher
rates of chronicity, decreased rates of anti-HBe and
anti-HBs seroconversion, and increased viral replication,
probably through the impairment of innate and adaptive
cellular and humoral immune responses. Similarly, in HCV-
infected patients, HIV accelerates the course of HCV-
associated liver disease progression, particularly in patients
who are more severely immune deficient. As a consequence,
both HBV/HIV and HCV/HIV co-infection is associated
with increased liver fibrosis progression and increased rate
of liver decompensation, cirrhosis, hepatocellular carci-
noma (HCC) and liver-related mortality. Therefore, it is
recommended to avoid the development of severe immune
deficiency (defined as !200 CD4 cells/mm3) in HBV or
HCV co-infected persons (BII).
There is no evidence that HBV affects HIV disease
progression. There is no evidence that HBV alters the
response of HIV to antiretroviral therapy (ART). But
starting ART may be associated with an increased risk
of transaminase flares. This may reflect both immune
restoration disease against HBV and/or drug toxicity.
Similarly, HCV has little or no effect on the response to
ART, or on immunological, virological and HIV-related
clinical disease progression.
At present in Europe, only a minority of HCV/HIV and
HBV/HIV co-infected patients are treated for their hepatitis.
Effort must be made, via multidisciplinary healthcare
infrastructures, to increase the applicability and availability
of treatment especially in the more vulnerable groups (such
as in immigrants, injection drug users, prisoners, people
with psychiatric illnesses and people with excessive use of
3. General recommendations for counselling
3.1. Alcohol consumption
Continued alcohol consumption increases HCV replica-
tion, accelerates fibrogenesis and liver disease progression
in hepatitis B and in hepatitis C, and also diminishes the
response and adherence to anti-hepatitis treatment
50 g/day). Therefore, psychological, social and medical
support should be made available to encourage patients with
a high alcohol intake to limit alcohol consumption and
preferably to stop drinking (AII).
3.2. Active drug users
Active drug use should not be an absolute exclusion
criteria since full benefits of HBV and HCV therapy are not
compromised when active drug users are successfully
retained in treatment. Patients who require treatment should
be offered opiate substitution therapy, including heroin
maintenance programmes, where medically available. If the
patient is not ready to stop drug use, any assessment for
initiation of HBV or HCV treatment should be made on a
case-by-case basis (AIII).
Substitution therapy as a step towards cessation should
be considered. Help provided (e.g. through needle- and
Grading scheme for recommendations
Strength of recommendation
Both strong evidence for efficacy and substantial clinical benefit
to support recommendation
Moderate evidence for efficacy—or strong evidence for efficacy
Evidence for efficacy is insufficient to support a recommendation
for or against use. Or evidence for efficacy might not outweigh
adverse consequences (e.g. drug toxicity, drug interactions) or
cost of the treatment under consideration
Moderate evidence for lack of efficacy or for adverse outcome
supports a recommendation against use
Good evidence for lack of efficacy or for adverse outcome
supports a recommendation against use
Quality of evidence
Evidence from at least one properly designed randomized,
Evidence from at least one well-designed clinical trial without
randomization, from cohort or case-controlled analytic studies
(preferably from more than one centre), or from multiple time-
series studies. Or dramatic results from uncontrolled experiments
Evidence from opinions of respected authorities based on clinical
experience, descriptive studies, or reports of expert committees
ECC statement / Journal of Hepatology 42 (2005) 615–624616
syringe-exchange programmes) reduces the risk of further
reinfection, including parenteral viral transmission (AIII).
3.3. Sexual transmission
Since HBV and HIV and, occasionally, HCV are
transmitted sexually, the use of condoms is recommended
HIV-infected patients should be screened for hepatitis A
and B. Patients lacking anti-HAV IgG antibodies or HBsAg
and anti-HBs antibodies should be offered vaccination for
the respective virus to prevent infection, regardless of their
CD4 count (AII).
The response to the vaccine is dependent on CD4 count
at the time of vaccination, and may be reduced in patients
with a CD4 cell count !500 cells/mm3. In all patients, the
anti-HBs antibody titre should be monitored 4 weeks after
the end of the HBV vaccination schedule. When there is
insufficient response (anti-HBs !10 IU/l) re-vaccination
should be considered (BIII). In patients eligible for highly
active antiretroviral therapy (HAART), vaccination should
be deferred until a clinically significant immune reconstitu-
tion has been achieved (AII). People who fail to seroconvert
after vaccination and remainat risk of HBV infection should
be annually monitored for serological markers of HBV
(HBsAg and antibodies to the hepatitis B core antigen (anti-
Isolated anti-HBc may be a marker of resolved HBV
infection where anti-HBs has disappeared. In such cases,
one dose of HBV vaccine may reveal an immune response.
Some experts believe that vaccination for HBV should be
recommended in HIV-infected patients with isolated anti-
HBc positivity (CIII). In the absence of anti-HBs response
one might consider HBV-DNA testing to assess occult HBV
infection (see below) (CIII).
3.5. Screening for late-stage complications
of hepatitis B or C
Patients with liver cirrhosis should be monitored for the
presence of oesophageal varices using upper-gastrointesti-
nal endoscopy every 1–2 years (AI).
Patients with advanced HBV- or HCV-associated
fibrosis/cirrhosis (F3/F4) have a high risk of developing
HCC, and therefore surveillance with ultrasound and serum
alpha-fetoprotein (AFP) is advised (AII). As the develop-
ment of HCC in co-infected patients may be faster,
monitoring intervals shorter than 6 month should be
In cases of decompensated cirrhosis, it may be necessary
to adjust the dose of antiviral drugs metabolised by the liver
(BII). When available, drug monitoring may be helpful.
4. HCV/HIV co-infection
4.1. Screening for HCV
All HIV-infected patients should be screened for HCV.
Screening for HCV in HIV-infected patients should be done
using a third generation anti-HCV antibody test (AII). A
positive result should be followed by evaluation for the
presence of HCV-RNA (AII). Detection of HCV-RNA
indicates active disease. A negative anti-HCV antibody test
excludes HCV infection—except if the patient has acute
HCV (diagnostic window) or has a blunted immune
response, in which case HCV-RNA should be measured to
document the infection (AIII).
4.2.1. Use of antiretroviral therapy
Initiation of treatment with nevirapine is associated with
a risk of hepatic toxicity, which manifests as significant
increases in ALT. This is more frequent in women who
commence therapy with a higher CD4 cell count (see
labelling for nevirapine). Most events are sub-clinical and
usually reverse spontaneously. In HCV/HIV co-infected
patients, nevirapine should be used with caution (AII).
Initiation of antiretroviral therapy in HIV/HCV co-
infected patients should follow the current recommendation
for initiation of antiretroviral in HIV mono-infected patients
(BII). However, for patients with CD4 cell count levels that
are just above the recommended threshold for initiation of
ART, commencement of ART should be considered before
the start of HCV therapy because of the risk of a decrease in
CD4 cell count during IFN-based anti-HCV therapy (BIII).
4.3. Liver biopsy and other evaluations
Liver biopsy provides information on histological
disease, extent of inflammation (grading), extent of fibrosis
(staging) and also about co-morbidities. The decision to
perform a liver biopsy should be individualized as the
resulting information about grading and staging will
influence the decision to treat (AIII). This is particularly
important in patients who are less likely to achieve a
sustained virological response (SVR), for example, patients
infected with genotype-1, when the risk-benefit of treatment
is doubtful (for example, when there is a high risk of adverse
events), and when patients’ motivation for treatment is low.
Several non-invasive methods to evaluate inflammation
and fibrosis are currently under investigation (for example,
serum fibrosis markers and tissue elastography) but their
usefulness in HCV co-infected patients requires validation.
The combination of PEG-IFN-a and ribavirin is the
treatment of choice for HCV infection.
ECC statement / Journal of Hepatology 42 (2005) 615–624617
4.4.1. Goals of therapy
The primary aim of anti-HCV treatment is sustained
virological response (SVR) defined as undetectable serum
HCV-RNA 24 weeks after the end of therapy—evaluated
using sensitive molecular tests (AI). Long-term follow-up
studies in HCV mono-infected patients indicate that SVR is
clinically related to viral eradication in a vast majority of
patients and improvement in histology, which is associated
with decreased risk of disease progression (cirrhosis,
decompensation and HCC).
4.4.2. When should treatment for HCV start?
Acute hepatitis C. Treatment of acute hepatitis C may
reduce the risk of chronicity. Therefore, if serum HCV-
RNA is not eliminated spontaneously within 3 months of
onset of disease (clinically and/or laboratory documented),
treatment should be offered (CIII). Treatment with PEG-
IFN is recommended for 6 months in HCV mono-infected
patients. Data in co-infected patients are limited—use of
monotherapy or combination therapy in this population
Chronic hepatitis C. If chronic hepatitis C is detected
early in the course of HIV infection (before initiation of
HAART is necessary), treatment for chronic hepatitis C is
advised (AIII). However, if a co-infected patient has severe
immune deficiency (CD4 count !200 cells/mm3), the CD4
cell count should be improved using HAART before
commencing anti-HCV treatment (AII).
4.4.3. Candidates for treatment
Treatment for HCV offers the possibility of eradicating
HCV within a defined treatment period. This is potentially
advantageous for the subsequent management of the patient
with HIV, and every patient should therefore be considered
for treatment when the benefits of therapy will outweigh the
There are several baseline parameters that can predict a
greater likelihood of achieving a SVR:
† Patients infected with genotypes 2 and 3.
† A low viral load (!800,000 IU/ml).
† Absence of cirrhosis.
† Age !40 years.
† Higher ALT levels (O3! ULN).
Conversely, low CD4 cell count can reduce the chance of
SVR. Several studies using standard IFN plus ribavirin
suggest a lower SVR in patients with a low CD4 count
evidence to conclude that SVR to PEG-IFN plus ribavirin
We recommend treatment, without liver biopsy or other
liver assessment, for patients infected with HCV genotypes
2 or 3, and patients infected with HCV genotype 1 if the
HCV viral load is low, if there are no major contra-
indications present and patients are motivated to undergo
therapy (AI). The SVR is in the order of 40–60% in these
patient groups. In case of the availability of a liver biopsy
demonstrating lower grades of liver fibrosis (F0-1), regard-
less of HCV genotype, treatment can be deferred (BIII). A
liver biopsy is especially important to perform for patients
with suspected low chance of SVR (either because of an a
priori low chance of response and/or excess risk of severe
In patients infected with HCV genotype 1 and with a high
HCV viral load, recommendation for treatment should also
take into account liver disease stage. In particular, patients
with histological evidence of advanced liver disease (fibrous
septa) should be considered for treatment (AII).
Because ALT levels do not necessarily reflect the stage
offibrosis—especially in HIV/HCV co-infected patients—a
‘normal’ ALT level alone should not be used as an argument
to defer treatment (AII). A biopsy in this situation can help
to make a more informed decision on whether to start or
Patients on opioid substitution therapy should not be
deferred from treatment. Psychological and social support in
a multidisciplinary team should be provided for these
patients. Initiation of anti-HCV therapy in active drug users
should be considered on a case-by-case basis (CIII).
Treatment with IFN can reveal and worsen depression.
Treatment for hepatitis C should therefore be deferred in
patients with moderate to severe depression until the
condition improves (EII). In patients with mild psychiatric
illness, treatment for hepatitis C should not be deferred and
support for the psychiatric condition (counselling and/or
antidepressant medication) should be offered (BIII).
IFN-based therapies are contraindicated in patients with
decompensated liver cirrhosis (Child Pugh stage B or C)
(EI). Liver transplantation, where feasible, should be the
primary treatment option for these patients (CII).
4.4.4. Management and therapeutic options
The standard dose for PEG-IFN 2a is 180 mg once
weekly, and for PEG-IFN 2b it is 1.5 mg/kg bodyweight,
Although clinical trials in HIV/HCV co-infected patients
used a fixed dose of 800 mg ribavirin once daily for all
genotypes, studies from HCV mono-infected patients
support the use of 1000–1200 mg ribavirin once daily for
treatment of infections with genotypes 1 and 4, and 800 mg
ribavirin once daily for genotypes 2 and 3. We therefore
recommend an initial ribavirin dose of 1000–1200 mg once
daily for HIV/HCV co-infected patients with a high HCV
genotype 1 or 4 viral load (BIII). For all other patients, a
dose of 800 mg once daily is recommended (AII).
Regardless of genotype, duration of treatment in co-
infected patients should be 48 weeks (BI).
4.4.5. Assessment of response
If an early virological response (EVR) of at least 2 log10
reduction in viral load compared to baseline is not achieved
ECC statement / Journal of Hepatology 42 (2005) 615–624618
at week 12, treatment should be stopped, because the
negative predictive value to achieve SVR is 99–100% (AII).
In patients who achieve at least a 2 log10reduction in
viral load at week 12, treatment should be continued. In
mono-infected patients testing for HCV-RNA at week 24 is
recommended, and in patients who remain positive for
serum HCV-RNA at week 24 (negative predictive value for
achieving SVR is 100%), treatment should be discontinued.
A similar algorithm applies for HIV/HCV co-infected
The population of non-responders is heterogeneous, non-
response is observed with any therapy for HCV, and can
range from ‘no viral decline during treatment’ to ‘end-of-
treatment virological response and subsequent virological
relapse’. The decision to retreat patients with PEG-IFN plus
ribavirin should be considered based on the type of
response/non-response and tolerability to the previous
treatment, the extent of liver damage and the HCV genotype
If the therapeutic aim in patients with biopsy-proven
advanced fibrosis/cirrhosis is to delay or prevent disease
progression in non-responders at week 12 and/or week 24,
continuation with PEG-IFN monotherapy can be considered
(CIII). Dose, duration and clinical benefits of such
maintenance therapy should be confirmed in clinical trials
in HIV/HCV co-infected patients (AIII).
4.4.6. Concomitant use of antiretroviral therapy
During PEG-IFN plus ribavirin combination therapy,
didanosine is contraindicated in patients with cirrhosis (EI)
and should be avoided in patients with less severe liver
disease (EII). Stavudine, especially in combination with
didanosine, is associated with an excess risk of lactic
acidosis and should be avoided (EII). In addition, the use of
zidovudine should be avoided due to an excess risk of
anaemia and neutropenia (DII).
A potential negative impact of protease inhibitor (PI) use
on SVR in patients with HIV/HCV co-infection treated with
PEG-IFN plus ribavirin has been suggested in a subgroup
analysis of one study—this requires clarification. The jury
do not recommend against the use of PIs (CIII).
4.4.7. Monitoring and follow-up
A full blood count and liver tests (transaminases and
bilirubin) should be performed during the first month of
therapy at weeks 1, 2 and 4, and thereafter on a monthly
basis. CD4 cell count should be monitored monthly.
Additional laboratory tests can then be carried out at the
physician’s discretion and should include assessment of
thyroid stimulating hormone (TSH) at least every 3 months.
Virological response should be monitored by serum
HCV-RNA quantification before initiation of treatment and
12 weeks after starting therapy using the same molecular
test. Patients who achieve a 2 log10drop but remain HCV-
RNA-positive should be tested again at week 24 by a
sensitive test with a lower limit of detection of 50 U/ml.
Assessment of SVR should be made 24 weeks after
completion of the therapeutic course by a qualitative test.
4.4.8. Management of adverse events
Effort should be made to keep patients on the optimal
dose of PEG-IFN plus ribavirin and to proactively manage
side effects of therapy. Such management should include
† Paracetamol (possibly combined with non-steroidal anti-
inflammatory drugs) for influenza-like syndrome (AII).
† Erythropoietin for severe anaemia (BI).
† Growth factors to correct severe neutropenia (CIII).
† Selective serotonin reuptake inhibitor antidepressants for
clinically-relevant depression (AII).
† Thyroid hormone substitution in hypothyroidism (AII).
† Beta-blockers to relieve symptoms of hyperthyroidism
5. HBV/HIV co-infection
5.1. Screening for HBV
All HIV-positive patients should be tested for HBsAg
and anti-HBc antibodies, and questioned about their HBV
vaccination history (AII).
If patients are negative for HBsAg and positive for anti-
HBc, they should be tested for anti-HBs (AII). In patients
with isolated anti-HBc positivity, a test for serum HBV-
DNA might be considered to assess occult HBV infection
(see below) (CIII).
All patients who are HBsAg-positive should be tested for
anti-HDV (AII). However, none of the currently available
nucleotide/nucleoside analogues are effective for the
treatment of HDV infection, and the only assessed treatment
is high dose interferon-a (IFN) (5 MU daily or 10 MU three-
times weekly for 12 months), which has limited efficacy and
often poor tolerability in the long term in HBV/HDV
patients without HIV and has not been assessed in HIV co-
In people who are HBsAg-positive, further evaluation of
the severity of HBV disease and the virological profile is
important (AII). Tests and evaluations may include those
listed below, but the extent of the examinations may be
different in different circumstances.
All patients should have:
† Examination for signs and symptoms of advanced liver
† Alanine aminotransferase (ALT) determination
B serial measurements are preferred as ALT may
fluctuate significantly, particularly when patients are
B although there is not an absolute correlation between
ALT levels and disease activity, the higher the ALT
ECC statement / Journal of Hepatology 42 (2005) 615–624 619
levels, the higher the likelihood of the presence of
significant disease and the faster the progression of
† HBeAg and anti-HBe
B HBeAg-positive patients almost invariably have high
HBV-DNA levels, independently of ALT levels
B anti-HBe-positive cases may or may not have high
virus replication, as defined by HBV-DNA testing
† HBV-DNA measurements
B results should be expressed in International Units (IU)
per millilitre, the universal, standardized HBV DNA
quantification unit (please refer to conversion tables
for calculation of IU/ml from non-standardised
copies/ml or genome equivalents/ml)
B the results should be expressed in decimal logarithm
(log) IU/ml, for precise assessment of baseline and
significant HBV DNA changes upon therapy
B serial measurements should be done if HBV-DNA is
initially found at low levels (%2000 IU/ml in anti-
HBe-positive patients with elevated ALT or other
signs of liver disease), as HBV-DNA may show wide
fluctuations in such cases
B only one type of assay should be used for monitoring
in the same individual, and if a change of assay is
planned, both tests should be used in parallel for at
least two subsequent samples
B tests should preferably be quantitative, have a high
sensitivity and cover a wide range of quantification
(80–1010IU/ml). Optimum tests are real-time nucleic
acid amplification tests
B tests should either be approved according to European
regulations or validated in a similar way using
internationally recognised standards, and should be
able to detect isolates of different HBV genotypes
B HBV-DNA assays should be performed in a labora-
tory that participates in external quality control
B different tests produce different absolute results and
this is why the thresholds given in these recommen-
dations are only indicative. The reason is that there is
no standardization of quantification units and the
dynamic ranges of quantification of the different
assays are only partially overlapping (theses issues
should be resolved with international units and real-
time PCR assays).
5.2. Liver biopsy and other evaluations
In specific circumstances, additional evaluation is
† Measurement of the stage of liver fibrosis and of
necroinflammatory activity is essential to define the
stage of disease and the risk of progression to clinically
significant liver complications and is most useful when a
decision to treat or not to treat has to be taken. The
current gold standard for assessment is liver biopsy (BII).
B liver stiffness measurements or measurement of non-
invasive markers of fibrosis can be considered alone
or in combination to avoid performing a liver biopsy
(CIII). These alternatives remain to be fully validated
in the setting of HBV/HIV co-infection.
† Ultrasound examination of the liver that can reveal
cirrhosis, steatosis and possibly early HCC.
5.2.1. Occult HBV infection
If only anti-HBc is present at the initial assessment, this
may be indicative of ‘occult’ HBV infection. Occult HBV is
usually assumed when HBV-DNA is detected at low levels
by highly sensitive techniques and in the absence of HBsAg.
Occult HBV is found more frequently in HIV-positive
patients than in HIV-negative people, but its clinical
relevance is uncertain. Currently, there is no evidence for
the need to routinely detect or treat occult HBV (CIII).
However, occult HBV may become relevant in specific
clinical settings. For example, if chemotherapy for cancer is
initiated and there is a risk of reactivation, pre-emptive anti-
HBV therapy may be considered (BIII). More research is
needed before the clinical relevance of occult HBV can be
5.3.1. Goals of therapy
The most ambitious goal of treatment for HBV is to
achieve HBsAg clearance with anti-HBs seroconversion,
but this endpoint can be reached only in a minority of
patients (less than 10% of HBV mono-infected patients
having received interferon treatment, and likely to be even
less among HIV/HBV co-infected patients). A more
realistic goal therefore is to efficiently and persistently
suppress HBV replication to reduce liver inflammation and
to stop or delay progression of fibrosis, thereby preventing
the development of end-stage complications such as
cirrhosis, decompensation, HCC and liver-related death
Drugs that are currently licensed in Europe for the
treatment of HBV include standard IFN-a 2a and 2b and
pegylated-IFN-a (PEG-IFN) 2a, lamivudine, and adefovir.
All these drugs have antiviral activity, and IFN has
additional immune modulatory effects. Tenofovir and
emtricitabine are approved for HIV and are also active
against HBV. Drugs under development with anti-HBV but
not anti-HIV activity include entecavir, clevudine, telbivu-
dine and a number of other compounds.
Data on the efficacy of some of these drugs in HIV/HBV
co-infected individuals are still very limited and no large-
scale randomised controlled trials have been conducted to
define their efficacy and safety when used alone or in
combination. Therefore, recommendations for the treatment
of HBV in HIV co-infected patients need to be derived from
what is known about the treatment of HBV mono-infected
ECC statement / Journal of Hepatology 42 (2005) 615–624620
patients, and from the limited data available in HBV/HIV
5.3.2. When should treatment for HBV start?
Most cases of acute hepatitis B resolve spontaneously
and do not need antiviral therapy (AII). In cases of acute
fulminant hepatitis B, lamivudine-therapy should be
considered despite the risk of selecting for lamivudine-
resistant HIV (AIII). As other drugs with sole anti-HBV
activity become available, these are likely to become the
preferred approach rather than using lamivudine. Therapy
with tenofivir or adefovir should be avoided because in most
such cases, liver failure is often accompanied with renal
In patients with HIV and chronic hepatitis B, the decision
to treat or not to treat shouldbe based as muchas possible on
an integrated evaluation of the diagnostic parameters
described in Section 5.3.1 (AIII).
5.3.3. Candidates for treatment
The criteria to decide whether to treat include:
† HBV-DNA level.
† Liver disease activity and stage (derived from ALT
profile, liver necroinflammatory activity and fibrosis
assessment, when indicated).
† Careful evaluation of the presence of cirrhosis.
In HBV-HIV co-infected patients, the HBV-DNA
threshold for starting therapy has not been defined.
In HBeAg-positive HBV mono-infected patients, HBV
DNA Oapproximately 20,000 IU/ml is the cut off to
indicate antiviral therapy, while a cut-off Oapproximately
2000 IU/ml is more often used for HBeAg-negative (anti-
HBe-positive) patients. These thresholds can also be applied
to co-infected patients (BIII).
5.3.4. Management and therapeutic options
The diagnostic algorithm and the treatment options vary
depending on different clinical scenarios that should take
into consideration: HBV-DNA levels, severity of liver
disease, CD4 count and indication for HAART, contra-
indications and previous treatments for HBV.
1. HBV/HIV co-infected patients with no immediate
indication for HIV treatment (Fig. 1)
The decision to start anti-HBV therapy should be taken
after obtaining evidence that liver disease is active and
When initiation of HAART is not indicated and HBV
disease is mild and not (or slowly) progressing, the best
current strategy may be to monitor the patients without
treatment intervention (BIII). More data and the approval of
new anti-HBV drugs without anti-HIV activity may, in the
near future, allow more informed treatment decisions in
In patients with high HBV-DNA levels (O20,000 IU/ml
for HBeAg-positive patients and O2000 IU/ml for HBeAg-
negative patients), the presence of liver inflammation and
stage of liver fibrosis should be assessed by liver biopsy or
*HBV DNA >20,000 IU/ml for HBeAg positive patients and >2000 IU/ml for HBeAg negative patients.
** Metavir<A2 and/or <F2.
*** Metavir ≥A2 and/or ≥F2.
No immediate indication
for HIV treatment
HBV DNA, ALT,
HBV disease active:
high HBV DNA levels*
Liver disease status
No evidence of active
and/or advanced disease**
Histological evidence of
active and/or advanced
CD4 ≥500 /mm3
CD4 < 500 /mm3
IFN / Peg IFN /
HAART including teno +
low HBV-DNA levels
Fig. 1. Management and therapeutic options in HBV/HIV co-infected patients with no immediate indication for HIV treatment.
ECC statement / Journal of Hepatology 42 (2005) 615–624 621
validated non-invasive markers, unless hepatic ultrasound is
clearly indicative of cirrhosis (BIII).
In the presence of histological evidence of active and/or
advanced disease (by liver biopsy this means moderate to
severe inflammation and/or fibrous septa—Metavir RA2
and/or RF2) therapy is indicated (AII).
In HBV mono-infected patients, HBeAg positivity,
elevated ALT, and/or infection with genotype A or B
virus predict a better response to treatment with IFN (AI).
IFN-based therapy may be an option for HBV/HIV co-
infected patients who do not need to start HAART (CD4
count O500 cells/mm3) (BII). As in the treatment of HBV
mono-infected patients, the recommended dose and dur-
ation depend on HBeAg/anti-HBe status. Most recently Peg
IFN has been licensed for hepatitis B and is becoming the
standard therapy. PEG-IFN 2a (180 mg once weekly) should
be given for 48 weeks independently of HBeAg/anti-HBe
status (BIII). When using standard (not pegylated) IFN,
5–6 MU/day or 10 MU three times weekly for 4–6 months
(BIII). HBeAg-negative patients should receive 3–6 MU
three times weekly for at least 12 months (BIII).
Although the benefit of IFN therapy is expected to be
higher in HBeAg-positive patients, anti-HBe-positive
patients can also be treated with IFN, particularly when
ALT levels are persistently elevated, but the likelihood of
sustained response is lower (BIII).
IFN-based therapy should be used as a finite course of
therapy and a favourable response defined by sustained (off
therapy) anti-HBe seroconversion in initially HBeAg-
positive patients, and by sustained (off therapy) ALT
normalisation and HBV-DNA suppression (!2000 IU/ml)
in initially HBeAg-negative patients (AII).
These recommendations are largely derived from data
obtained in HBV mono-infected patients due to the very
should be treatedwith
limited and incomplete information on the effect of IFN
therapy in HBV/HIV co-infected patients.
In patients with CD4 count O500 cells/mm3and with
contraindications to the use of IFN (including those with
advanced liver disease and cirrhosis, those who do not
tolerate IFN and IFN non-responders), adefovir at a dose of
10 mg daily (the dose currently used in the treatment of
HBV mono-infected patients and thought to have no activity
against HIV) may be an option. However, this is
controversial due to the theoretical risk of inducing HIV
resistance (CIII). In this scenario, the use of drugs with
potent antiviral activity solely against HBV and no activity
against HIV (such as entecavir, telbivudine) may be the best
solution when these agents become available.
In patients with a CD4 count lower than 500 cells/mm3
the best option is to consider earlier initiation of HAART
including two drugs with dual activity against both HBV
and HIV (tenofovir plus either lamivudine or emtricitabine)
Monotherapy using drugs with activity against HIV must
be avoided (AI).
Current research in HBV suggests that, as in HIV,
combination therapy reduces the risk of selecting for
resistance. Avoidance of monotherapy for HBV may thus
be equally important.
2. HBV/HIV co-infected patients with an indication for
anti-HIV therapy (Fig. 2)
In this scenario, the decision on how to treat should be
based mainly on HBV-DNA levels, without a stringent need
for measurement of the liver necroinflammatory activity and
stage of fibrosis. Liver biopsy may be useful to assess the
stage of disease at baseline to allow meaningful follow-up
of the disease course (CIII).
If HBV-DNA is high (O2,000 IU/ml), HAART includ-
ing two drugs with dual anti-HBV and anti-HIV activity is
*If feasible and appropriate from the perspective of maintaining HIV suppression.
Immediate indication for HIV treatment
High HBV DNA Low HBV DNA
Patient with cirrhosis
Patient without lamivudine
HAART regimen of choice
Patient with lamivudine
Substitute one NRTI by
tenofovir or add
HAART including teno +
lamivudine or emtricitabine
HAART including teno +
lamivudine or emtricitabine
Fig. 2. Management and therapeutic options in HBV/HIV co-infected patients with an indication for anti-HIV therapy.
ECC statement / Journal of Hepatology 42 (2005) 615–624622
In patients with low HBV-DNA levels (!2000 IU/ml),
the recommendation is to initiate the HAART regimen of
choice (it is optional to use a HAART regimen containing
two dual-activity drugs) (CIII).
3. HBV/HIV co-infected patients with lamivudine-
resistant HBV requiring HBV therapy
In the presence of suspected lamivudine-resistance, the
first step is to confirm the lamivudine resistance in HBV
If confirmed, we recommend a HAART regimen that
has maximal activity against both HIV and HBV. If HIV
is already controlled substitute one of the nucleoside
reverse transcriptase inhibitors (NRTIs) with tenofovir, if
feasible and appropriate from the perspective of main-
taining HIV suppression (BIII). If HIV is not controlled,
tenofovir can be added in the context of currently
accepted practices for management of HAART treatment
4. HBV/HIV co-infected patients with cirrhosis
In these cases, the HBV-DNA threshold for starting
therapy for HBV is lower (O200 IU/ml) (BIII). IFN-based
therapy is rarely indicated and often contraindicated due to
the very poor tolerability profile (DIII).
The risk of severe reactivation of hepatitis B during
immune reconstitution after starting HAART, with life-
threatening hepatitis flare, should be considered in this
setting, particularly when CD4 counts are !200 cells/mm3.
In this specific situation, and particularly in the presence of
high baseline HBV-DNA levels, reduction of HBV-DNA
levels may be preferred before starting HAART to reduce
the likelihood of immune reconstitution. However, given
the lack of available drugs with sole anti-HBV activity, this
cannot currently be done safely. Furthermore, an induction
treatment with two drugs with dual activity against HBV
and HIV carries the risk of selecting drug-resistance in HIV,
particularly in those with high HIV-RNA levels. For these
reasons, initiation for full HAART regimens in this setting
remains the preferred approach (BIII).
Some experts believe that adefovir (10 mg daily) should
be considered in these cases but this approach is
controversial, as stated above (CIII).
In this scenario, the use of drugs with potent antiviral
activity solely against HBV and no activity against HIV
may be the best solution in the near future.
In patients with decompensated liver cirrhosis (Child
Pugh stage B or C), (EI) liver transplantation, where
As the transmission of HIV, HBV and HCV continuesto expand across the European continent, there is a clear and important need to enhance efforts to prevent
and control these infections
Studies addressing the optimal time—during the course of chronic HIV infection—to commence antiretroviral therapy in HBV and HCV co-infected patient
should be initiated
Studies on the epidemiology and the social impact of HBV and HCV in patients infected with HIV should be actively investigated, with a special emphasis on
Phases II and III trials of new drugs should be performed in HIV/HBV and HIV/HCV co-infected patients as a priority due to the accelerated course of the
hepatitis infections in these populations
As the current therapies are suboptimal—in terms of efficacy, tolerability and quality of life—the development of new drugs to circumvent these issues should
be actively pursued
Studies to validate the utility of non invasive methods of liver disease progression should be performed
Studies on the use of maintenance therapy in patients with no SVR and with advanced liver disease are strongly recommended (including evaluation of optimal
dose and duration of treatment)
The optimal ribavirin dose for treatment of HCV genotype 1 and the potential benefits of prolonged treatment should be investigated
A shorter duration of treatment for patients with HCV genotype 2 and 3 should be investigated
Long-term follow-up studies of patients with and without SVR are strongly encouraged (to determine late relapses, duration of histological improvement, and
the effect of clinically relevant outcomes such as decompensation, HCC and death)
Studies on pathophysiology, including extrahepatic viral reservoirs and the specific immune response to HCV, should be conducted
The optimal treatment for acute HCV infection in HIV-infected patients should be investigated
Better understanding of the pathogenesis and mechanisms of HBV-related liver damage in HIV co-infected patients is needed
Prevalence, diagnosis and clinical significance of HBV genotypes and of occult HBV in HIV patients should be investigated
The significance and threshold (if any) of HBV-DNA serum levels in relation to liver disease activity and progression and indication for anti-HBV therapy
should be better defined in HIV co-infected cases
The efficacy, safety and tolerability of PEG-IFN and the optimal treatment schedule for HBV treatment in HIV co-infected patients need to be investigated in
clinical studies of adequate design and size
Correlates of disease progression and treatment response need to be identified—including the predictive value of viral load, the effect of anti-HBV therapy on
liver disease: biopsy or non-invasive markers, the impact of long-term treatment on HBsAg clearance and intrahepatic cccDNA, the impact of HBV drug
resistance on liver disease, and the role of cross-resistance testing in patients with HBV treatment failure
The value of combination versus monotherapy should be evaluated
The prevalence and natural history of HBeAg-negative chronic hepatitis C in HIV co-infected patients should be better defined
The impact of HBV treatments on liver-related morbidity and mortality in HIV patients receiving HAART needs to be understood
ECC statement / Journal of Hepatology 42 (2005) 615–624623
feasible, should be the primary treatment option for patients Download full-text
5.3.5. Monitoring and assessment of response
A clinically relevant response to anti-HBV therapy is
defined as a durable anti-HBe seroconversion in initially
HBeAg-positive patients, and as a durable normalisation of
ALT and adequate (!2000 IU/ml) and durable HBV-DNA
suppression in initially HBeAg-negative patients.
When using nucleotide and nucleoside analogues with
anti-HBV activity, an initial response is defined as at least 1
log10drop in HBV-DNA levels within 1–3 months. HBV-
DNA should then be measured every 3 months. The extent
of treatment efficacy is measured by the log10HBV DNA
reduction or by HBV DNA negativation below the lower
limit of detection of the assay.
Resistance should be suspected in compliant patients if
HBV-DNA levels increase by 1 log10 or more. Where
available, resistance testing should be performed.
5.3.6. Treatment discontinuation
Discontinuation of anti-HIV drugs with additional
activity against HBV has to be approached with caution.
Resistance of HIV and HBV are separate and indepen-
dent. Stopping the anti-HBV treatment can result in
potentially fatal hepatitis flares, particularly in patients
with more advanced liver disease, and should therefore be
avoided whenever possible (EII). Patient counselling is
important to avoid discontinuation of effective anti-HBV
6. Future studies and recommendations
A wide variety of unresolved issues exist in the
management of patients co-infected with hepatitis B or C
and HIV. During the conference, a number of potential areas
for future research were identified (Table 2).
7. Consensus Development Conference Committees
Presidents: Y. Benhamou (France), D. Salmon-Ceron
International Organising Committe: J.M. Pawlotsky
(France), J. Rockstroh (Germany), V. Soriano (Spain).
Local Organising Committe: Patrice Cacoub (France),
Gilles Pialoux (France).
Scientific Committe: M. Battegay (Switzerland), M.
Carneiro de Moura (Portugal), M. Colombo (Italy), M.
Dupon (France), G. Dusheiko (UK), R. Esteban (Sapin), B.
Gazzard (UK), A. Hatzakis (Greece), A. Horban (Poland),
C. Katlama (France), J. Lange (Netherlands), M. Manns
(Germany), P. Marcellin (France), S. Mauss (Germany), M.
Experts: M. Alter (USA), J.M. Pawlotsky (France), M.
Koziel (USA), T. Poynard (France), M. Puotti (Italie), S. Pol
(France), J. Rockstroh (Germany), A. Hatzakis (Greece), X.
Forns (Spain), N. Afdhal (USA), P. Yeni (France), M.
Nunez (Spain), A. Craxi (Italy), D. Thomas (USA), G.
Dusheiko (UK), V. Soriano (Spain), M. Sulkowski (USA),
F. Zoulim (France), R. Chung (USA), S. Mauss (Germany),
M. Buti (Spain), C. Perronne (France), M. Guarinieri (Italy),
G. Brook (UK), G. Gaeta (Italy), J.M. Miro (Spain), R.
Bruno (Italy), M. Manns (Germany).
Jury Panel: Alfredo Alberti (Italy) (President), Nathan
Clumeck (Belgium) (President), Simon Collins (UK),
Wolfram Gerlich (Germany), Jens Lundgren (Denmark),
Giorgio Palu ` (Italy), Peter Reiss (Netherlands), Rodolphe
Thiebaut (France), Ola Weiland (Sweden), Yazdan Yaz-
danpanah (France), Stefan Zeuzem (Germany).
Bibliographic group: C. Nuria (Spain), L. Piroth
(France), M. Rumi (Italy), M. Vogel (Germany).
ECC statement / Journal of Hepatology 42 (2005) 615–624624