consensus conference on chronic viral hepatitis and hiv infection: updated spanish recommendations
TRANSCRIPT
Consensus conference on chronic viral hepatitisand HIV infection: updated Spanish recommendationsV. Soriano,1 J. M. Miro,2 J. Garcıa-Samaniego,1 J. Torre-Cisneros,3 M. Nunez,1 J. del Romero,4
L. Martın-Carbonero,1 J. Castilla,5 J. A. Iribarren,6 C. Quereda,7 M. Santın,8 J. Gonzalez,9
J. R. Arribas,9 I. Santos,10 J. Hernandez-Quero,11 E. Ortega,12 V. Asensi,13 M. A. del Pozo,14
J. Berenguer,15 C. Tural,16 B. Clotet,16 M. Leal,17 J. Mallolas,2 J. M. Sanchez-Tapias,2
S. Moreno,7 J. M. Gatell,2 M. J. Tellez,18 R. Rubio,19 E. Ledesma,20 P. Domingo,21 P. Barreiro,1
J. Pedreira,22 M. Romero,1 J. Gonzalez-Lahoz,1 and E. Lissen17 1Hospital Carlos III, Madrid, Spain; 2Hospital
Clınic-IDIBAPS, University of Barcelona, Barcelona; 3Hospital Reina Sofıa, Cordoba; 4Centro de Salud Sandoval, Madrid; 5Plan Nacional del SIDA,
Madrid; 6Hospital Virgen de Aranzazu, San Sebastian; 7Hospital Ramon y Cajal, Madrid; 8Hospital de Bellvitge, L’Hospitalet de Llobregat; 9Hospital La
Paz, Madrid; 10Hospital La Princesa, Madrid; 11Hospital Clınico, Granada; 12Hospital General, Valencia; 13Hospital General de Asturias, Oviedo;14Hospital Clınico, Valladolid; 15Hospital Gregorio Maranon, Madrid; 16Hospital Germans Trias i Pujol, Badalona; 17Hospital Virgen del Rocıo, Seville;18Hospital Clınico San Carlos, Madrid; 19Hospital Doce de Octubre, Madrid, Spain; 20BMS, Waterloo, Belgium; 21Hospital de Sant Pau, Barcelona; and22Hospital Juan Canalejo, A Coruna, Spain
Received March 2003; accepted for publication May 2003
SUMMARY. Chronic hepatitis B and C represent a leading
cause of morbidity and mortality among human immuno-
deficiency virus (HIV)-infected patients worldwide. New
treatment options against both hepatitis B (HBV) and C
(HCV) viruses have prompted us to update previous recom-
mendations for the management of coinfected individuals.
Fifteen topics (nine related to HCV, five to HBV and one to
both viruses) were selected for this purpose. A panel of
Spanish experts in the field was invited to review these areas
and propose specific recommendations, which were scored
according to the Infectious Disease Society of America (IDSA)
grading system. These guidelines represent a comprehensive
and updated overview on the management of hepatitis B and
C in HIV-infected patients.
Keywords: hepatitis B, hepatitis C, human immunodeficiency
virus, interferon, lamivudine, ribavirin, tenofovir.
INTRODUCTION
Liver disease because of chronic hepatitis B and C is now a
leading cause of morbidity and mortality among human
immunodeficiency virus (HIV)-infected patients in the
developed world, where classical opportunistic complications
of severe immunodeficiency have declined dramatically as a
result of the widespread use of potent antiretroviral therap-
ies. Over the last few years, several consensus reports have
addressed the issue of viral hepatitis and HIV infection [1–3].
In Spain, the first consensus conferences on this topic took
place in 2000 and 2001 [4,5]. Two years later, the large
amount of new information in this field prompted us to
organize another consensus conference, which was held in
Madrid on 27 November 2002. Following international
recommendations for the development of clinical guidelines
[5], the meeting was planned as a full 1-day workshop in
which around 25 experts in the field of HIV and viral
hepatitis discussed a total of 15 questions, which were
selected in advance as the most relevant and currently
conflicting topics in the management of chronic viral
hepatitis in the setting of HIV infection. The workshop was
open and many other people, including persons from non-
governmental organisations, industry, health care adminis-
trators and physicians, attended it.
For practical purposes, it was agreed that the conference
should be focussed on hepatitis B and C alone. International
recommendations on the management of viral hepatitis in
the setting of HIV infection were taken into account [3] and
particular features of coinfected patients in Spain were the
basis of the discussion. Nine questions were mainly related to
the hepatitis C virus (HCV), another five were focussed on
hepatitis B virus (HBV), and the very last question addressed
the issue of liver transplantation in these patients. Two
Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; HIV,
human immunodeficiency virus; IFN, interferon; RBV, ribavirin.
Correspondence: Vincent Soriano, Service of Infectious Diseases,
Hospital Carlos III, Calle Sinesio Delgado 10, Madrid 28029, Spain.
E-mail: [email protected]
Journal of Viral Hepatitis, 2004, 11, 2–17
� 2004 Blackwell Publishing Ltd
different experts were invited to discuss each topic, and a
group of 10 different people constituted a permanent panel
which reviewed the data presented and graded their evi-
dence according to the IDSA scoring system [6]. Briefly, the
quality of evidence for any statement was graded as 1 (based
on properly randomised, controlled trials), 2 (other kind of
publications) and 3 (expert opinion). The strength of the
recommendation was categorised as A (good), B (modest) or
C (poor). Herein, we summarise the major conclusions of the
meeting.
Is sexual transmission of HCV more frequentin HIV-infected persons?
Background
Hepatitis C virus shares the same routes of transmission as
HIV. However, it is transmitted parenterally more efficiently
than HIV, according to data derived from surveys conducted
in blood transfusion recipients, intravenous drug users and
health care providers [7–9]. Conversely, transmission of
HCV through sexual contact seems to be rare [10,11],
whereas is more frequent for HIV, particularly through
homosexual relationships. The claim of a higher vertical
transmission of HCV in newborns from HIV-HCV coinfected
mothers [12,13] has hinted on a possibly higher risk of
sexual transmission of HCV in the setting of HIV coinfection.
However, preliminary data from several studies of HIV-pos-
itive homosexual men and/or individuals infected hetero-
sexually does not support this convincingly [14], although
the prevalence of HCV antibodies is below 2% in the general
population in Western countries, and rises to 5–10% among
HIV-positive persons infected by sexual contacts [15].
Moreover, the higher the number of contacts, the greater the
chances of HCV infection [10].
The presence of HCV has been demonstrated in semen and
vaginal secretions, but the titres were lower than in blood
[16–18]. A critical review of studies conducted so far
examining whether there is an increased risk of sexual
transmission of HCV among HIV-positive carriers does not
support this convincingly (Table 1) [19–22].
Panel recommendation
Hepatitis C virus is found in genital secretions and can be
transmitted through sexual contact. Although the efficiency
of sexual transmission of HCV is low, it may account for a
large number of HCV infections at the population level.
There is no evidence to support a higher transmission of
HCV among HIV-coinfected persons, despite higher HCV
loads frequently seen in such individuals. Specific practices
(i.e. sexual promiscuity) might favour a greater chance of
exposure to HCV among HIV-infected persons, which could
account for the slightly greater prevalence of HCV infection
among those infected through sexual contact, particularly
homosexual men. Score: B.II.
Can HCV accelerate HIV disease progressionand/or partially blunt the immune reconstitutionthat follows antiretroviral therapy?
Background
The state of permanent immune activation provided by
chronic HCV infection might act deleteriously in HIV-posit-
ive persons, favouring HIV replication within infected cells
and more rapid destruction of CD4+ T lymphocytes [23]. On
the contrary, the immune recovery seen after beginning
effective antiretroviral therapy could be partially blunted in
subjects with HCV infection because of similar mechanisms,
or through infection of immune cells by HCV itself [24].
Clinical studies which have examined whether there is an
influence of HCV on HIV disease progression show conflict-
ing results. Whereas some have demonstrated an association
between HCV infection and faster HIV disease progression,
others have not [25–41] (Table 2). In only a few of these
studies was HIV progression analysed following adjustment
for potential confounding factors, such as low access to
antiretroviral therapy, given that many HCV-HIV coinfected
Table 1 Sexual transmission of hepatitis
C virus (HCV) in serodiscordant couples
and effect of human immunodeficiency
virus (HIV) co-infection
Study
HCV-pos/HIV-pos
index case
HCV-pos/HIV-neg
index case
P-value*Cases
HCV-pos
partner no. (%) Cases
HCV-pos
partner no. (%)
Eyster et al. [19] 164 5 (3.0) 30 0 (0) 0.428
Soto et al. [20] 120 11 (9.2) 22 0 (0) 0.146
Wyld et al. [21] 30 0 (0) – – –
Marincovich et al. [22] 171 0 (0) – – –
Total 485 16 (3.3) 52 0 (0) 0.191
*Comparison of the rate of HCV-positivity among partners of HIV-pos and HIV-neg
index cases with chronic hepatitis C.
� 2004 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 11, 2–17
Consensus conference on chronic viral hepatitis and HIV infection 3
persons were drug addicts, or lower compliance with their
medication, for similar reasons. In the Swiss cohort [35],
HIV-positive individuals with HCV infection progressed faster
to AIDS and death than those HCV negative. Table 3 sum-
marises the main features of studies which have examined
the effect of HCV on HIV mortality [42–44].
Overall, the available data support a direct negative
impact of HCV on HIV disease progression, although to a
slight extent. In addition, HCV may influence negatively HIV
disease through indirect ways, such as making antiretroviral
treatment discontinuation more frequent due to an
increased risk of liver toxicity [3,4].
Panel recommendation
The HCV might act as a cofactor for HIV disease progression
by several mechanisms. First, nonspecific immune stimula-
tion driven by chronic HCV infection might enhance HIV
replication. Secondly, infection of immune cells by HCV
could favour CD4 T cell depletion and partially blunt the
immune recovery which follows successful antiretroviral
therapy. Thirdly, HCV could compromise the benefit of
antiretrovirals as a result of a higher incidence of liver tox-
icity and treatment discontinuation. Score: C.II.
Who should be treated for hepatitis C and who should not?
Background
All HIV-infected individuals should be screened for HCV
antibodies in serum or plasma. Those seropositive with
repeatedly elevated aminotransferase levels should be tested
for HCV load and HCV genotype, in order to take steps to-
wards anti-HCV therapy.
All HIV positive persons with chronic HCV infection should
be considered as candidates for anti-HCV therapy, given their
higher risk of progression to end-stage liver disease and their
higher risk of liver toxicity after beginning antiretroviral
therapy, compared with HIV negative ones [3,4]. As the
response to anti-HCV therapy is dependent of the CD4 count
[3], it should be prescribed only when the CD4 count is above
350 cells/lL, a threshold which is relatively easy to obtain in
most instances when antiretroviral therapy is properly used.
In subjects with CD4 counts between 200 and 350 cells/lL,
Table 2 Influence of hepatitis C virus (HCV) on human immunodeficiency virus (HIV) disease progression
Study Year Design HCV-pos/HCV-neg Follow-up (months) Influence HCV on HIV
Pre-HAART era
Llibre et al. [25] 1993 Transverse 71/21 – No
Quan et al. [26] 1993 Transverse 18/195 – No
Wright et al. [27] 1993 Retrospective 74/438 84 Yes
Dorrucci et al. [28] 1995 Longitudinal, prospective 214/208 30 No
Sabin et al. [29] 1997 Haemophilic cohort 79/32 – Yes (HCV-1)
Piroth et al. [30] 1998 Prospective cohort 119/119 36 Yes
Lessens et al. [31] 1999 Observational 22/59 17 (years) Yes
Piroth et al. [32] 2000 Longitudinal, prospective 89/723 11 (years) Yes
HAART era
Haydon et al. [33] 1998 Cohort 240/268 – No
Staples et al. [34] 1999 Observational cohort 122/228 141 No
Greub et al. [35] 2000 Prospective cohort 1157/1954 28 Yes (HCV-3)
Martın et al. [36] 2001 Cohort 119/119 36 Yes
Chung et al. [37] 2002 Retrospective 40/129 12 No
Moreno et al. [38] 2002 Prospective cohort 185/101 24 Yes
Sulkowski et al. [39] 2002 Prospective cohort 873/1082 24 No
De Luca et al. [40] 2002 Prospective cohort 729/600 37 Yes
Macıas et al. [41] 2002 Retrospective 323/169 46 No
Table 3 Increased mortality among
human immunodeficiency virus (HIV)-
infected individuals with hepatitis C virus
(HCV) coinfection
Study year Design
HCV-pos/
HCV-neg
Follow-up
(months) RR
Darby et al. [42] 1997 Hemophilic cohort – – 16.7
Greub et al. [35] 2000 Prospective cohort 1157/1954 28 2.2
Soriano et al. [43] 2000 EuroSIDA cohort 1092/2161 30 1.5
Klein et al. [44] 2001 Cohort 78/104 42 1.6
RR, relative risk.
� 2004 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 11, 2–17
4 V. Soriano et al.
and already under long-term antiretroviral therapy, the
decision to treat HCV might be considered having taken into
account other factors, such as the estimated length of HCV
infection, the severity of liver disease, the extent of control of
HIV replication, and classical predictors of response to anti-
HCV therapy such as HCV genotype and HCV viraemia.
Finally, anti-HCV therapy should be deferred in individu-
als with <200 CD4 cells/lL as the response rate is very low
in this subgroup of patients [3]. Moreover, the risk of
opportunistic infections in the short-term is high and may
worsen with anti-HCV therapy [45,46]. Therefore, they
should be treated with antiretroviral therapy and receive
prophylaxis for opportunistic infections as a priority. Later
on, when their CD4 counts have risen and their plasma HIV-
RNA level is under control, the prescription of anti-HCV
therapy should be assessed again.
Patients with prior liver decompensation (ascites, gastroin-
testinal bleeding, hepatic encephalopathy, etc) should not be
treated, given the higher risk of serious side effects with the
current drugs, pegylated interferon (peg-IFN) and ribavirin
(RBV), and should be assessed for liver transplantation. How-
ever, patients with compensated cirrhosis (Child-Pugh class A)
must be treated. On the contrary, individuals with prior history
of severe neuropsychiatric disorders should not be treated as
IFN can exacerbate these conditions. Individuals currently
engaged in heavy alcohol intake and/or illegal drug addiction
practices should delay treatment, whereas all efforts should be
devoted to entering them into detoxification programmes.
Following the recent NIH Consensus Conference Recom-
mendations [2], subjects with repeated normal liver enzymes
might benefit from current anti-HCV therapy, particularly those
infected with HCV genotypes 2 or 3. However, more data on
liver damage in this subgroup of HCV-HIV coinfected patients
are needed to balance the cost-benefit of anti-HCV therapy.
In drug-naıve individuals with HCV-HIV coinfection,
chronic hepatitis C should be treated first if the CD4 count
does not warrant initiation of treatment. However, in pa-
tients with CD4 counts >350 cells/lL but high plasma HIV-
RNA (i.e. above 50 000 copies/mL), it is not clear whether
suppression of HIV replication should be done at first defer-
ring anti-HCV therapy until undetectable HIV viraemia is
attained. A greater efficacy of anti-HCV therapy in this set-
ting should be balanced with a higher risk of interactions
between anti-retrovirals and anti-HCV drugs.
Panel recommendation
All HIV-infected individuals should be screened for HCV
antibodies. Those with positive HCV serology should be tes-
ted for HCV-RNA. All individuals with positive HCV-RNA
should be considered as candidates for anti-HCV treatment.
HCV-RNA quantitation in serum and genotyping should be
requested prior to start of therapy. Treatment should first be
provided to patients with repeated elevated alanine amino-
transferase (ALT) levels, CD4 counts >350 cells/lL, relative
low plasma HIV-RNA (i.e. <50 000 copies/mL), no active
use of illegal drugs or high alcohol intake, and no prior
severe neuropsychiatric conditions. Treatment in patients
with normal ALT levels should be provided in the context of
study protocols. Treatment in patients with CD4 counts be-
low 350 cells/lL should be provided cautiously. The treat-
ment of choice is the combination of peg-IFN plus RBV,
following doses and schedules used for HCV-monoinfected
patients. Score: A.II.
How important is liver biopsy before recommendingtreatment?
Background
Liver histology allows staging of HCV hepatic damage and
predicts in the short-mid term who will develop cirrhosis. At
the same time, it may rule out other causes of liver damage,
such as haemochromatosis, alcohol-related steatosis, Wil-
son’s disease, autoimmune hepatitis, etc., although these
conditions may also be recognized by other noninvasive
means [47–49].
The value of liver biopsy before prescribing anti-HCV
therapy in HIV-positive patients is still under discussion. The
proportion of HCV-HIV coinfected patients with significant
liver fibrosis is much higher than in HCV-monoinfected pa-
tients (see Table 4) [50–55]. Therefore, anti-HCV therapy is
almost always justified considering the extent of histological
damage in HIV/HCV-coinfected patients [55]. Moreover,
nearly half of HCV/HIV-coinfected patients may show
unexpected cirrhosis or precirrhosis [50–53]. The main pre-
dictor of advanced fibrosis is the estimated duration of HCV
infection [52]. On average, nearly half of patients will have
cirrhosis 25 years after HCV exposure. If we consider that the
mean age of HCV/HIV-coinfected patients in Spain is cur-
rently 40 years old, and that most are former i.v. drug users
Table 4 Stage of liver fibrosis in patients
with chronic hepatitis C according to
human immunodeficiency virus (HIV)
status
Study
No. of
patients HIV
F0
(%)
F1
(%)
F2
(%)
F3
(%)
F4
(%)
Berenguer et al. [50] 104 Pos 4 25 24 29 18
Quereda et al. [51] 99 Pos 6 38 18 26 12
Martın-Carbonero
et al. [52]
492 Pos 13 35 19 21 12
Fuster et al. [53] 157 Pos 30 22 – 42 6
Forns et al. [54] 476 Neg 51 24 10 10 5
� 2004 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 11, 2–17
Consensus conference on chronic viral hepatitis and HIV infection 5
who began to exchange needles when they were
15–20 years old, it should be expected that many of them
currently show significant liver fibrosis and that, if not trea-
ted, a rapid growth of liver disease complications among HIV-
infected persons in Spain should occur over the next decade.
Those in favour of a liver biopsy before treating chronic
hepatitis C in HIV-coinfected patients argue that side effects,
risk of interactions with antiretrovirals and relatively low
efficacy of current anti-HCV therapy in this population are
major limitations that only justify the medication for those
who histologically really need it. However, given that liver
damage is a dynamic process and fibrosis progression rate is
accelerated in HCV/HIV-coinfected patients, supporters of
this point of view should remember that if treatment is not
offered to patients with none or minimal fibrosis, liver biopsy
should be repeated at 2–3-year intervals. However, this op-
tion would face opposition among many patients and may
increase the costs significantly [47]. Accordingly, a recent
analysis has pointed out the cost-effectiveness of therapy in
all coinfected individuals with moderate or advanced HCV-
related liver disease [56].
Panel recommendation
The role of liver biopsy for treatment decision purposes is
controversial in HIV/HCV-coinfected patients. Patients’
reluctance to accept it and/or other difficulties should not
defer the prescription of anti-HCV therapy once considered
appropriate, given the faster progression to end-stage liver
disease in coinfected patients. When the histological infor-
mation becomes available, treatment could be deferred in
patients with no fibrosis (F0). In those with minimal portal
fibrosis (F1), controversy exists on whether treatment should
be provided or deferred. Score: C.III.
Efficacy of anti-HCV therapy in HIV-coinfected patients.How to improve response rates
Background
Available data from interim analysis of large clinical trials
and from a few studies already completed show that response
rates to anti-HCV therapy are lower in HIV-coinfected patients,
even using the new pegylated IFN formulations (Table 5)
[57–63]. Overall, sustained response rates are in the range of
20–35% [57–59,63], approximately half of the responses
seen in HIV-negatives. It should be noted that early virolo-
gical response and end-of-treatment response are equally
much lower in HIV/HCV-coinfected patients. Moreover,
relapses seem to be more frequent as well [58].
The reasons why anti-HCV therapy results in worse
response rates in the setting of HIV infection may be varied.
Since both peg-IFN and RBV act, at least partially, as im-
munomodulatory agents, subtle immune defects derived from
HIV infection might negatively impact on the performance of
these drugs, even in patients with high CD4 counts and
undetectable HIV-RNA on antiretroviral therapy.
In addition, there is a high rate of anti-HCV treatment dis-
continuation in some of the trials conducted in HIV-coinfected
patients, often surpassing 25% of subjects recruited
[59,61,62]. Although it may reflect a higher rate of adverse
events in this population compared with HIV-negatives [64],
it might also reflect a lack of expertise of physicians taking
care of these patients. Thus, efforts to minimise side effects
with pre-emptive symptomatic treatments and appropriate
management of complications are critical to ensure com-
pletion of anti-HCV therapy in most patients.
Panel recommendation
The overall response to anti-HCV therapy is lower in patients
coinfected with HIV. Sustained response rates of 40–50% are
seen in subjects with HCV genotypes 2 or 3, and lower than
25% in those with HCV genotypes 1 or 4. Both early viro-
logical responses and relapses are less and more frequent,
respectively, in coinfected patients compared with HCV-
monoinfected individuals. The benefit of extending therapy
(more than 6 months for HCV genotypes 2 or 3; and more
than 12 months for HCV genotypes 1 or 4) in early virolo-
gical responders should be examined in clinical trials. More-
over, treatment adherence should be considered a critical
factor for the attainment of response and must be encouraged
actively over the whole treatment period. Score: A.II.
Table 5 Response to pegylated interferon plus ribavirin in hepatitis C virus (HCV)-human immunodeficiency virus (HIV)
coinfected patients
Study No.
HCV-1/4
(%)
Neg HCV-RNA at
12–24 weeks (%)
SR
(%)
HCV-1/4
response (%)
HCV-2/3
response (%)
Discontinuation because
of side effects (%)
Goelz et al. [57] 25 45 36 20 ? ? 32
Perez-Olmeda et al. [58] 68 65 50 35 24 52 15
Perrone et al. [59] 100 69 ? 38 25 42 28
Rockstroh et al. [60] 30 73 57 ? ? ? 13
Hopkins et al. [61] 16 37 45 ? 0 62 6
Chung et al. [62] 133 ? 44 ? 33 80 ?
Quereda et al. [63] 35 65 ? 31 18 58 ?
SR, sustained response.
� 2004 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 11, 2–17
6 V. Soriano et al.
Early predictors of sustained response to anti-HCV therapy.Are they also applicable to HIV-coinfected patients?
Background
Almost all subjects who will clear HCV with anti-HCV
treatment show an early virological response after beginning
therapy [3,64]. Therefore, an early assessment of serum or
plasma HCV-RNA titres after starting treatment may identify
who would benefit from prolonging therapy and who would
not. In HIV-negative patients, those who show a decline in
HCV-RNA >2 logs or have a undetectable levels at 12 weeks
of therapy are those who will achieve eventually a sustained
response [64]. In contrast, almost none of those who show
an HCV-RNA decline of <2 logs at 12 weeks achieve that
goal. Therefore, anti-HCV therapy may be discontinued at
12 weeks considering this virological criteria in early non-
responders [2]. This principle to guide HCV therapy might
spare side effects and costs in individuals with no chance of
cure. In HIV-HCV coinfected patients these considerations
should be deemed even more crucial, as interactions
between antiretrovirals and anti-HCV therapy are frequent
and issues related to poor compliance in subjects under
polymedications are of much relevance.
Kinetic studies suggest that HCV clearance after beginning
therapy with interferon may be delayed in the setting of HIV
infection [65] (Fig. 1a). Therefore, these are concerns about
the reliability of the principle of 2 log reduction in HCV-RNA
at 12 weeks: it might not work in HCV-HIV coinfected
patients. However, preliminary reports suggest that despite a
slower decay in HCV-RNA seen in HIV-coinfected patients
after beginning anti-HCV therapy, all subjects who will
reach a sustained response show a decline >2 logs at
12 weeks on therapy [66]. Therefore, the principles guiding
anti-HCV therapy in HIV-negative may also apply to HIV-
coinfected patients (Fig. 2).
There is a second phase of clearance of HCV-RNA in
subjects on prolonged anti-HCV therapy, which accounts for
the steady destruction of infected cells (hepatocytes). The
slower decay recognised in the setting of HIV infection
(Fig. 1b) and early discontinuation of therapy might result
in higher relapse rates in virological responders. Recent data
support this notion, and therefore one needs to reconsider for
how long anti-HCV therapy should be extended in early
virological responders [57]. This observation seems to apply
particularly to HCV genotype 3, as relapses are uncommon
in HIV-negative subjects infected with this genotype while it
occurs in up to one-third of HIV/HCV-coinfected patients
who receive anti-HCV therapy for only 6 months, following
what is recommended in HIV-negatives [2]. Further studies
examining extended periods of anti-HCV therapy (i.e.
12 months in HCV genotypes 2 and 3, and up to 18 months
in HCV genotypes 1 and 4) should be conducted to examine
whether such regimens can reduce the relapse rate.
Panel recommendation
Early virological response during anti-HCV therapy can
predict the likelihood of a sustained response in HIV-coin-
fected patients as it does in HCV-monoinfected individuals.
1st phase
(clearance of virions)
2nd phase (clearance of infected cells)
HIV
(a) Early phase
Time
Time
HCV-RNA
HCV-RNA
1st phase
(clearance of virions )
2nd phase (clearance of infected cells)
(b) Late phase
HIV
Fig. 1 HCV dynamics under interferon. Influence of HIV
infection at different phases [3].
Peg IFN + RBV
Week 12 HCV-RNAmeasurement
>2log ↓ <2log ↓
Week 24 HCV-RNA Stopqualitative
Neg Pos
Continue untilmonth 12 (HCV-1/4)
Fig. 2 HCV treatment algorithm [2].
� 2004 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 11, 2–17
Consensus conference on chronic viral hepatitis and HIV infection 7
Moreover, the use of an early time-point for treatment
decision making seems to be equally appropriate in coinfected
patients. Only those patients who show a decline in serum
HCV-RNA >2 logs at 12 weeks on therapy will have a chance
of reaching a sustained response. Therefore, treatment might
be discontinued in the rest. This is of particular relevance
given the risk of toxicity derived from interactions between
anti-HCV therapy and antiretroviral drugs. Score: C.II.
Adverse effects of anti-HCV therapy in the settingof HIV infection. How to manage it?
Background
Side effects of anti-HCV medications are common, and may
be grouped in five main categories: influenza-like symptoms
(headache, fever, asthenia, myalgias, decreased appetite),
haematologic abnormalities (mainly anaemia), neuropsy-
chiatric disorders (depression, irritability, insomnia), gastro-
intestinal symptoms (nausea, diarrhoea), and inflammation
at injection sites. In addition, other adverse events may
develop more rarely, such as alopecia and thyroid dysfunc-
tion [2,67]. Overall, they lead to treatment discontinuation in
around 15% of HCV-monoinfected patients, and to dose
reductions of either peg-IFN and/or RBV in another 20–25%
[64,67]. Higher treatment discontinuation rates have been
recorded in some studies conducted in HIV-coinfected per-
sons [58,60,61]. The lack of expertise in the management of
HCV treatment-related side effects by the doctors in charge as
well as insufficient information given to patients may have
contributed to the high drop-out rates. These aspects should
therefore be properly addressed in the future.
The haematologic abnormalities may be due to peg-IFN
and/or RBV. Anaemia due to RBV is typically mild and due to
extravascular haemolysis and is accompanied by an increase
in reticulocytes. Although erythropoietin has been success-
fully used in some cases of RBV-associated anaemia, RBV
dose reductions are more appropriate to manage anaemia in
this setting [2]. The dose of RBV should be reduced to half
when Hb drops below 10 g/dL, and it needs to be discon-
tinued if Hb goes below 8.5 g/dL. However, in subjects
developing anaemia and having low reticulocyte counts,
anaemia because of medullar depression by IFN should be
suspected, and the use of recombinant erythropoietin could
be considered before reducing or discontinuing RBV.
Leukopoenia, specially neutropoenia and less frequently
lymphopoenia, may develop with peg-IFN. In particular,
patients should be informed in advance on the risk of a drop in
their CD4+ count. In most instances they affect the absolute
CD4 number but not the percentage of these cells. However,
such effects reverse after discontinuing IFN therapy [1].
Panel recommendation
Anti-HCV therapy causes fever, malaise, asthenia, depres-
sion, etc. in the majority of cases. Patients should be
informed in advance about these side effects and how to
prevent and manage them (paracetamol for influenza-like
symptoms, etc.). Treatment of depression should be consid-
ered as soon as symptoms begin to develop. Peg-IFN may
produce significant CD4 T cell declines and neutropoenia,
which are reversible after discontinuing it. RBV may cause
anaemia within the first 12 weeks of therapy. Doctors
should improve their expertise in the management of these
side effects, trying to keep patients on therapy as long as no
serious toxicities develop. Score: A.I.
Toxicity due to interactions between antiretroviral drugsand anti-HCV therapy. How to avoid it?
Background
As anaemia is a frequent side effect of RBV use, attention
should be paid to those patients who are taking azido-
thymidine (AZT), known also to produce anaemia. Thus, in
patients with AZT-related anaemia this drug should be dis-
continued before prescribing RBV. Alternatively, close
monitoring of Hb values over the first 6 weeks of therapy is
warranted.
Mitochondrial damage results from the inhibition of mito-
chondrial polymerase gamma by nucleoside analogues [68].
RBV can enhance the intracellular concentrations of phos-
phorylated didanosine (ddI) metabolites, and result in a
higher risk of toxicity [69–71]. Several cases of pancreatitis
and/or lactic acidosis have been reported, and a warning of
the FDA has been released advising on the risk of giving RBV
and ddI concomitantly. Therefore, subjects who begin
treatment with RBV should avoid the use of ddI. Alternat-
ively, close monitoring of serum lactate and amylase levels
are warranted, and patients should be informed in advance
of any symptoms potentially associated to lactic acidosis
(abdominal discomfort, fever, malaise, nausea, vomiting).
More recently, cases of hepatic decompensation, some of
them fatal, have been reported in subjects receiving RBV
with ddI plus/minus d4T [72]. All were cirrhotics, and
hypothetically ddI and RBV acted synergistically leading to
liver failure. Therefore, the administration of ddI and RBV
should be contraindicated in subjects with advanced liver
fibrosis.
Finally, several observations have highlighted that RBV
could potentiate subcutaneous fat loss when used concom-
itantly with some nucleoside analogs, mainly d4T [73]. In
this form, severe weight loss mimicking progression of lipo-
atrophy could be another characteristic side effect derived
from the interaction of RBV and antiretroviral drugs.
Patients should be informed in advance on the risk of this
complication and, when possible, drugs with lower lipodys-
trophic profile should be prescribed.
Panel recommendation
Interactions between antiretrovirals and RBV may be
harmful. Given the higher risk of pancreatitis and lactic
acidosis, ddI should be avoided when taking RBV. In patients
� 2004 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 11, 2–17
8 V. Soriano et al.
with liver cirrhosis, ddI should be used cautiously as it may
lead to liver decompensation. On the contrary, AZT should
be used with caution when RBV is given, as both may pro-
duce anaemia. Patients should be advised on the possibility
of experiencing severe weight loss, mimicking a rapid pro-
gression of lipoatrophy, most likely as a result of a potenti-
ation of mitochondrial damage in the subcutaneous fat
tissue, when taking RBV and some nucleoside analogues.
Score: A.II.
Hepatotoxicity of antiretroviral drugs. How to predictand how to manage them?
Background
Significant liver enzyme elevations occur on average in 5–
10% of patients who start triple antiretroviral therapy [74].
The rate is significantly higher in patients with underlying
chronic hepatitis C (Table 6) [3,75–88]. Moreover, some
drugs (i.e. nevirapine, ritonavir at full doses) cause hepato-
toxicity more frequently than the rest [74]. Thus, liver
function tests should be closely monitored in subjects who
initiate antiretroviral treatment, particularly when some of
the drugs mentioned above are administered to patients with
chronic hepatitis C.
Cumulative toxicity may explain steady liver enzyme ele-
vations when using some drugs. If not apparent shortly after
beginning therapy, it may become manifest much later,
often after 4–6 months on therapy [85,87]. This has been
seen with drugs like nevirapine.
Liver enzyme elevations following antiretroviral treatment
may occur by other mechanisms than direct injury by the
drug(s) prescribed. Immune reconstitution phenomena and
hypersensitivity reactions may account for some additional
cases [3]. In patients with low CD4 counts and/or high HIV-
RNA titres, successful anti-HIV therapy may enhance
immune responses to a degree that hepatic cells harbouring
HCV antigens may be recognised and destroyed massively.
As long as the patient remains asymptomatic and transa-
minase levels do not rise above 10-fold the limit of normal
values (grade 4 toxicity), treatment could be continued with
close monitoring of laboratory values, as return of liver
enzymes to baseline values occurs in most cases [89]. These
episodes of immune-related hepatitis, however, are quite rare
[90]. On the contrary, allergic phenomena which may
develop shortly after exposure to nevirapine, abacavir or
amprenavir may be accompanied by liver enzyme elevations
in the context of a more generalised reaction. The presence
of underlying chronic hepatitis C does not seem to play a role
in the occurrence of this phenomenon [3].
Liver toxicity may also occur as consequence of mitoch-
ondrial damage in patients receiving nucleoside analogs,
particularly d4T and ddI. Histological features of hepatic
steatosis are frequent in this setting and more common in
women and obese individuals [68,91].
Table 6 Hepatotoxicity of antiretroviral therapy
Study No. of patients HAART modality Liver toxicity grade 3–4 Predictors
Rodrıguez-Rosado et al. [75] 187 with PI 14% HCV
Saves et al. [76] 748 with PI 9% HCV, HBV, ›ALT
1249 Two nucleosides 6% idem
Sulkowski et al. [77] 211 with PI 12% HCV, HBV, › CD4, RTV
87 Two nucleosides 6% HCV, HBV, › CD4
Den Brinker [78] 394 With PI 18% HCV, HBV
Saves et al. [79] 1080 With PI 2% HCV, HBV
Nunez et al. [80] 222 Any triple 9% HCV, older age, alcohol
Bonfanti et al. [81] 1477 With PI (OR: 2.7) HCV, RTV, ›ALT
D’Arminio et al. [82] 1255 Any triple 5% HCV, HBV, ›ALT
Aceti et al. [83] 1325 With PI 3% HCV, HBV, RTV
Wit et al. [84] 560 Any triple 6% HCV, HBV, ›ALT, RTV,
NVP, female gender
Martinez et al. [85] 610 With NVP 12.5% HCV
Palmon et al. [86] 141 With NVP 1.4% –
91 With EFZ 1.1% –
40 With DLV 0% –
Sulkowski et al. [87] 256 With NVP 15.6% HCV, HBV, › CD4
312 With EFZ 8% idem
Martın-Carbonero et al. [88] 162 With NVP 12% HCV, female gender, alcohol
136 With EFZ 4% idem
HCV, hepatitis C virus; HBV, hepatitis B virus; ALT, alanine aminotransferase; PI, protease inhibitor; idem, equal; RTV:
ritonavir; NVP, nevirapine; EFZ, efavirenz; DLV, delavirdine.
� 2004 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 11, 2–17
Consensus conference on chronic viral hepatitis and HIV infection 9
Panel recommendation:
Liver enzyme elevations after beginning antiretroviral ther-
apy are more frequent in patients with underlying chronic
hepatitis B and C. Thus, drugs with more hepatotoxic profiles
(i.e. nevirapine, ritonavir, indinavir) should be used cau-
tiously in coinfected patients. Treatment should be discon-
tinued in patients with symptoms or grade 4 increase in
aminotransferase levels. In certain cases, immune reconsti-
tution phenomena may lead to rises in transaminases after
starting potent anti-HIV therapy. Close monitoring of these
patients during the first weeks may keep them on therapy, as
they experience a progressive resolution of liver abnormal-
ities without discontinuing treatment. Score: A.II.
Is HBV-related liver disease acceleratedin HIV-coinfected patients?
Background
Hepatitis B virus is a noncytopathic virus. Thus, liver dam-
age in HBV infection is mainly immune-mediated. Cytotoxic
CD8+ T cells recognise HBV antigens in the context of HLA
class I exposed on the surface of infected hepatocytes, and
destroy them. The killing of these cells results in elevated
aminotransferase levels and over time may lead to liver
cirrhosis. The presence of HIV infection increases the risk of
chronicity after exposure to HBV, is associated with higher
HBV-DNA titres, and reduces the rate of spontaneous HBsAg
and HBeAg seroconversion [92]. However, as HBV-related
liver damage is mainly immune-mediated, initial reports
claimed that liver enzyme elevations and hepatic necro-
inflammation could be milder in the setting of HIV infection
[93]. A recent report, however, has demonstrated that this is
not always the case, and that enhanced replication levels of
HBV in HIV-coinfected subjects may result in more severe
liver damage [94]. Moreover, in some clinical studies, the
risk of end-stage liver disease was significantly increased in
HIV-infected patients with chronic hepatitis B [95–98], as
occurs in those with HCV infection. Most likely, the risk of
more rapid liver disease should be considered in HIV-infected
subjects with positive HBsAg and detectable HBV-DNA, with
or without HBeAg. In contrast, in HIV-positive patients with
HBV chronic infection but no evidence of active HBV repli-
cation (inactive carrier state), this risk could be negligible
[98,99] (Fig. 3).
The possibility that diminished immune responses in HIV-
infected persons might lead to higher rates of HBV escape
has been a matter of controversy over the last few years
when considering subjects lacking HBsAg [100,101]. These
‘silent’ or ‘occult’ HBV infections, as defined by the presence
of significant titres of serum HBV-DNA in subjects lacking
HBsAg, might have clinical implications. Hypothetically,
they might enhance the risk of hepatotoxicity using anti-
retroviral drugs, reduce the response to anti-HCV treatment,
and even lead to liver damage in a hidden fashion
[101,102]. However, a recent study has not found evidence
of such ‘occult’ HBV infections in HBsAg-negative HIV-
infected patients with markers of prior HBV exposure [103],
and therefore the potential impact of this condition should be
reassessed.
Panel recommendation
The HIV infection enhances HBV replication in subjects with
chronic hepatitis B, although liver enzyme elevations are
frequently milder in coinfected patients. HBeAg-positive
chronic hepatitis B is more frequent in HBV/HIV-coinfected
patients than in HBV-monoinfected individuals. Liver disease
may be more severe, leading to more rapid progression to
cirrhosis in these patients. Score: B.II.
Is HBV a cofactor for HIV disease progression?
Background
A persistent state of chronic immune activation occurs in
subjects with chronic HBV replication, as occurs in chronic
HCV carriers. This circumstance as well as putative direct
effect of some HBV factors on HIV transcription [104] may
favour a higher HIV replication and might lead to faster
CD4+ T cell decline in HIV-coinfected persons. The majority
of clinical studies conducted so far have examined the
influence of HBV on HIV disease progression considering just
HBsAg as the marker for chronic HBV infection. They have
provided conflicting results [98,99]. However, as chronic
replicative HBV infection requires the presence of substantial
amounts of HBV-DNA in serum or plasma besides HBsAg,
further studies examining specifically the outcome in sub-
jects with HBsAg and high HBV-DNA titres should be con-
ducted to determine to what extent HBV exerts a deleterious
effect on the natural history of HIV infection. In the mean-
time, indirect evidence suggest that active chronic hepatitis
B should be considered as a cofactor for HIV disease pro-
gression (Fig. 4).
Panel recommendation
Chronic hepatitis B with replicative markers (high HBV-DNA
levels) might act as cofactor for HIV disease progression.
HBsAg+, HBV-DNA+
No chronic hepatitis B
HBsAg+
Years
Cirr
hosi
s ris
k
Fig. 3 Hepatitis B virus – related liver disease in HIV coin-
fection.
� 2004 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 11, 2–17
10 V. Soriano et al.
HBV may accelerate HIV disease progression indirectly
through inducing state of immune stimulation. Score: C.II.
Is there a greater risk of hepatotoxicity of antiretroviraldrugs in subjects with underlying chronic hepatitis B?
Background
Significant liver enzyme elevations are frequently seen after
beginning antiretroviral therapy, and overall may lead to
treatment discontinuation in up to 10% of patients,
depending on the drugs in use and the prevalence of chronic
liver disease in the study population [3]. Whereas there is no
doubt that underlying chronic hepatitis C favours the
development of liver enzyme elevations after beginning
antiretroviral therapy, less agreement exists for the role of
chronic hepatitis B (Table 6). A review of recent studies
however, suggest that chronic hepatitis B should be con-
sidered as a predictor of hepatotoxicity using antiretroviral
drugs [76–79,82–84,87]. This fact becomes even more
apparent when drugs with a more hepatotoxic profile, such
as ritonavir or nevirapine, are used.
Another situation which needs to be considered is the
occurrence of liver enzyme flare-ups in subjects with chronic
hepatitis B while taking antiretroviral therapy. Multiple
reasons may explain this (Table 7). For instance, discon-
tinuation of lamivudine (3TC) or tenofovir for any reason or
development of 3TC resistance by HBV (which occurs in
30–50% of HIV-infected patients after 12 months of
therapy) [105] may be accompanied of abrupt transaminase
flares, which may be wrongly interpreted as hepatotoxicity
of current antiretroviral drugs.
Panel recommendation
The HIV-infected patients with chronic hepatitis B are more
prone to develop liver enzyme elevations after beginning
antiretroviral therapy. Score: B.III.
Treatment and prophylaxis of hepatitis B in the settingof HIV infection. When and how?
Background
As in HIV-negatives, the goals of anti-HBV therapy in the
setting of HIV infection should pursuit the suppression of
HBV replication, HBeAg seroconversion (and eventually also
HBsAg seroconversion), normalisation of liver enzymes, and
improvement of liver damage [106,107].
All HIV-infected patients with chronic hepatitis B and
elevated transaminase levels should be considered as candi-
dates for anti-HBV therapy. In patients with HBeAg-positive
chronic hepatitis B, better responses are seen with higher
ALT levels and lower HBV-DNA titres. Treatment with
nucleoside analogues (lamivudine and/or tenofovir) should be
considered in patients who need to be treated with antiret-
roviral therapy. The most promising results so far have been
obtained with tenofovir (Table 8) [108–113], which results in
mean HBV-DNA reductions of nearly 4 logs; moreover, this
response lasts for many months without apparent selection of
resistance by HBV. On the contrary, in subjects in whom
antiretroviral drugs are not prescribed, treatment with IFN
(or pegylated IFN) may be considered. However, the response
to IFN in HBV/HIV-coinfected patients is poor [97]. If treat-
ment of HBV is to be prescribed to HIV-positive subjects never
exposed to antiretroviral therapy and having CD4 counts
greater than 350 cells/lL, lamivudine with tenofovir should
be preferred, but a third drug with anti-HIV activity should be
added. A compound with high genetic barrier for resistance
and few side effects should be preferred (i.e. abacavir).
At this time, the role of adefovir, the other only approved
orally given drug for the treatment of HBV, is controversial in
HIV-coinfected patients. At doses of 10 mg daily, adefovir
HBsAg+, HBV-DNA+
No chronic hepatitis B
HBsAg+
Years
CD
4 co
unt
Fig. 4 HIV disease progression in patients with chronic
hepatitis.
Table 7 Causes of liver enzyme elevations in HBsAg-positive
HIV-infected patients
Lamivudine (or tenofovir) discontinuation
Development of 3TC resistance
HBeAg or HBsAg seroconversion
HBV reactivation
Immune reconstitution syndrome
Delta superinfection
Table 8 Treatment of chronic hepatitis B with tenofovir
Study
No. of
patients
Week
12*
Week
24*
Nelson et al. [108] 15 )2.47 )3.15
Bochet et al. [109] 11 )3.11 )3.67 (week 16)
Cooper et al. [110] 12 – )4.40
Nunez et al. [111] 12 – )3.78
Ristig et al. [112] 6 )3.10 )4.30
Portsmouth et al. [113] 20 – )4.00
*Serum HBV-DNA decline (logs).
� 2004 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 11, 2–17
Consensus conference on chronic viral hepatitis and HIV infection 11
seems to be safe and active against HBV, and might be con-
sidered in HIV-infected patients not taking antiretroviral
drugs who cannot receive or who failed a previous course of
IFN; however, development of HIV resistance mutations
(K65R) is of much concern after long periods of therapy [114].
The role of HBV genotypes in pathogenesis and their
influence on treatment response are so far unknown in HIV-
coinfected patients. In HIV-negatives, HBV genotype A is the
most frequently found in Spain [115]; however, no data are
available from HBV/HIV coinfected patients.
In summary, screening of serum HBV markers should be
requested after first HIV diagnosis. Individuals lacking HBV
markers should be vaccinated. In patients with more
advanced immunodeficiency, extra doses are often needed to
obtain protective anti-HBs titres (>10 IU/mL) [116]. More-
over, periodic monitoring of these antibodies is warranted as
they may decline progressively over time. Repeated vaccina-
tions should be considered in subjects with no protective titres,
given that they might acquire HBV in case of exposure [117].
Panel recommendation
Treatment of hepatitis B should be considered in all HIV-
infected patients harbouring HBsAg, detectable HBV-DNA
and elevated transaminase levels. Peg-IFN might be consid-
ered in subjects not taking antiretroviral drugs, having CD4
counts >350 cells/lL and plasma HIV-RNA below
50 000 copies/mL. In contrast, 3TC, tenofovir or both in
combination should be considered as first choice in patients
already on antiretroviral therapy. Lamivudine should be used
at doses of 300 mg (and not 100 mg) once a day. Score: B.II.
New anti-HBV therapies and their use in HIV-coinfectedpatients
Background
Entecavir and emtricitabine (FTC) are among the new drugs
coming soon into the market with promising anti-HBV
activity. Entecavir is specific for HBV and does not show any
anti-HIV activity. It is the most potent anti-HBV agent
examined so far and was a safe profile [118]. Phase 3 trials
are ongoing worldwide. FTC will be soon available as a new
anti-HIV agent. Its similarity with 3TC makes it appropriate
in terms of tolerance and dosing as long as no 3TC resistance
has been selected by either HIV and/or HBV, given that these
compounds share cross-resistance [119].
Panel recommendation
New nucleoside analogs represent the most attractive drugs
for the treatment of HBV infection. Entecavir is a promising
specific anti-HBV agent with high potency against HBV and
safety profile, which is currently under assessment in HIV-
coinfected patients. Given the risk of selecting drug resistant
variants, the success of HBV therapy most likely will be
enhanced using combination therapy. Score: C.II.
Liver transplantation in HIV-coinfected patients
Background
The HIV-infected patients with end-stage liver disease
develop classical complications of decompensated cirrhosis,
including ascites, jaundice, gastrointestinal bleeding, spon-
taneous peritonitis and encephalopathy. The only treatment
available at this stage is orthotopic liver transplantation
(OLT). Initial attempts before the introduction of HAART
regimens provided very poor results [4]. Those reports
showed that only a small percentage of transplanted HIV-
positive recipients maintained good organ function while
most experienced an accelerated course to AIDS [4]. Since
the introduction of HAART, HIV-infected liver transplant
recipients have improved their short- and mid-term survival.
Now, the outcome of transplantation is no longer compro-
mised as long as HIV infection is controlled with HAART in
the post-transplant period. Table 9 summarises the experi-
ence with OLT in HIV-infected patients during the HAART
era [120–130]. Although cases came from different institu-
tions, the criteria used for liver transplantation were quite
similar. In general, candidates did not have prior history of
opportunistic infections, CD4 counts >100–200 cells/lL and
undetectable plasma HIV-RNA on HAART (or available
drugs for successful treatment in the post-OLT period). There
were at least seven patients with end-stage liver disease
because of chronic hepatitis B who underwent OLT and all
remained alive, in some cases up to 3 years. In respect to
HCV, at least 17 cases underwent OLT and 12 (70.5%) re-
mained alive, some of them up to 2 years. In Spain, the first
HIV-infected patient was transplanted in January 2002
[130]. During the last two years, 15 HIV-infected patients
underwent OLT in Spain. Up to 73% were former iv drug
users and all but one had end-stage liver disease caused by
HCV. Only one patient died after a median (range) follow-up
of 6 (1–21) months [131]. Roland et al. [128] are coordi-
nating a prospective study in which 18 cases from eight
centres in the USA are being followed up, some of them
already published. He has reported a survival rate at 1 year
in HIV-positives similar to that found at the United Network
for Organ Sharing (UNOS), 92% vs 87.9%, respectively.
Similar rates were seen for graft survival, 83% vs 81.4%.
The main conclusions of these studies are the following:
(1) The risk of opportunistic infections in the post-transplant
period is very low when HIV replication is well controlled
with HAART, most cases remaining with undetectable viral
load. Furthermore, CD4 cell counts remain stable or even
increase with HAART. Therefore, the use of standard
immunosuppressive therapy in patients with well-controlled
HIV-infection does not increase their susceptibility to
opportunistic infections or malignant conditions. (2)
Cyclosporin and tacrolimus can inhibit HIV replication and
mycophenolate mofetil may potentiate abacavir. The benefit
of these interactions is currently being explored. (3) There
� 2004 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 11, 2–17
12 V. Soriano et al.
are important pharmacokinetic interactions between some
antiretrovirals protease inhibitors (PIs) and non-nucleosides
(NNRTIs) and immunosuppressive agents, mainly cyclospo-
rin and tacrolimus. PIs may increase the levels of cyclosporin
and tacrolimus whereas NNRTIs may reduce their levels,
because of their opposing effects on cytochrome p450. These
interactions have caused some episodes of acute rejection in
patients who stopped PIs while taking calcineurin-inhibitor.
Therapeutic drug monitoring of immunosuppressive agents
is mandatory when taking antiretroviral drugs. (4) Hepato-
toxicity associated with HAART regimens can also be
observed in liver allografts and liver function should be
closely monitored. (5) HCV and HBV recurrence may occur
after OLT. HBV recurrence is dramatically reduced using
immunoglobulins and 3TC (and most likely tenofovir). In
contrast, HCV reinfection occurs in most patients and results
in cirrhosis in nearly 20% of cases within 5 years. Rapid
progression of HCV-related liver disease in HIV-infected
recipients represents a major drawback and is the main
reason for a shortened life expectancy of these patients.
Standard anti-HCV therapy must be prescribed as early as
possible (1–3 months after OLT) following the recommen-
dations stated in point 3. In addition, other approaches as
pre-emptive therapy (i.e. using interferon shortly before
transplantation in the case of living donors) should be
explored. (6) As survival in the waiting list seems to be much
shorter in HIV-coinfected patients, strategies to make liver
transplantation available sooner after the patient’s assign-
ment to this procedure should be underlined.
With respect to HBV, the outcome is much better.
Recurrence is very rare as long as HBV is suppressed at the
time of transplantation with hepatitis B immunoglobulin
and/or lamivudine. However, selection of 3TC-resistant HBV
can be a problem, but now most of these patients can be
controlled with tenofovir.
Panel recommendation
All HIV-infected patients with end-stage liver disease should
be considered as candidates for liver transplantation as long
as they have not advanced HIV disease. In those with severe
immunodeficiency (<100 CD4 cells/lL), the control of HIV
replication and immune restoration should be prioritised. The
evaluation and the pre- and postoperative medical manage-
ment of HIV-positive candidates for OLT must include an
interdisciplinary team composed of a hepatologists, infectious
disease physicians, surgeons, psychologists, social workers
and members of alcohol, heroin and cocaine detoxification
programs. HIV-positive candidates should have no prior
history of opportunistic infections (except tuberculosis and
perhaps oesophageal candidosis), current CD4 counts
>100 cells/lL, plasma HIV-RNA below 200 copies/mL and
drugs for successful treatment in the future. Moreover, they
should have abstained from consumption of alcohol and/or
illegal drugs for at least 6 months. Score: B.II.
ACKNOWLEDGEMENTS
The workshop was organized by AIES and FIT. Funds were
provided in part by grants from RIS (Red de Investigacion en
Sida, no. 173) y RTIC (G03/015). Dr JM Miro was a recipient
of a Research Grant from the IDIBAPS (Barcelona, Spain).
Several pharmaceutical companies collaborated in the event:
Roche Pharma, Schering-Plough, Gilead, Roche Diagnostics,
Abbott Diagnostics and Bristol-Myers-Squibb.
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Table 9 Liver transplantation in human immunodeficiency virus-infected patients during the HAART era
Author year No. of cases Virus Follow-up (months) Status
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Schliefer et al. [121] 2000 1 HBV 27 Alive
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6 (1–21) 1 death, 14 alive
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