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: vsoriano@dragonet.es

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.

REFERENCES

1 Soriano V, Garcıa-Samaniego J, Rodrıguez-Rosado R,

Gonzalez J, Pedreira J. Hepatitis C and HIV infection:

biological. Clinical, and therapeutic implications. J Hepatol

1999; 31 (Suppl. 1): 119–123.

Table 9 Liver transplantation in human immunodeficiency virus-infected patients during the HAART era

Author year No. of cases Virus Follow-up (months) Status

Ragni et al. [120] 1999 1 HCV 5 Alive

Schliefer et al. [121] 2000 1 HBV 27 Alive

Gow et al. [122] 2001 1 HCV 12 Alive

Prachalias and Boyd 2001 4 HCV 3–25 (range) All deaths

[123,124] 3 HBV 3–33 (range) All alive

Bonham et al. [125] 2001 6 HCV, 5 cases FHF

(PI), 1 case

18 (mean) 2 deaths, 4 alive

Didier et al. [126] 2002 7 HCV 12.8 (mean) 1 death, 5 alive

Neff et al. [127] 2002 3 3 HBV HCV 21, 27, 38 12, 19, 20 All alive

Radecke et al. [128] 2002 5 HCV, 3; HBV, 1;

HCV+HBV+HDV, 1

15.6 (mean) 1 death, 4 alive

Roland et al. [129] 2002 19 Most HCV 10.5 (mean) 4 deaths, 15 alive

Spanish experience [130, 131] 2002–2003 15 HCV 12, HCV+HBV 2,

HBV 1

6 (1–21) 1 death, 14 alive

HBV, hepatitis B virus; HCV, hepatitis C virus; FHF, fulminant hepatic failure; HDV, hepatitis delta virus.

� 2004 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 11, 2–17

Consensus conference on chronic viral hepatitis and HIV infection 13

2 NIH Consensus Panel, NIH Consensus Development Con-

ference Statement: management of hepatitis C. Gastroen-

terology 2002; 123: 2082–2099.

3 Soriano V, Puoti M, Sulkowski M et al. Care of patients with

chronic hepatitis C and HIV co-infection: updated recom-

mendations from the HIV-HCV International Panel. AIDS.

(in press).

4 Garcıa-Samaniego J, Soriano V, Miro JM et al. Spanish

Consensus Conference on Hepatitis C and HIV infection.

HIV Clin Trials 2002; 3: 99–114.

5 Gonzalez J, Guerra L, Amela C et al. Coinfection with HIV

and hepatitis A, B and C viruses in adults. Review and

recommendations from GESIDA/PNS. In: Antiretroviral

therapy and HIV-associated diseases. Madrid: Ediciones

Doyma, 2002: 173–225.

6 Kish MA. Guide to development of practice guidelines. Clin

Infect Dis 2001; 32: 851–854.

7 Mitsui T, Iwano K, Masuko K et al. Hepatitis C virus

infection in personnel after needlestick accident. Hepatology

1992; 16: 1109–1114.

8 Hernandez M, Bruguera M, Puyuelo T, Barrera JM, San-

chez-Tapias JM, Rodes J. Risk of needle-stick injuries in the

transmission of hepatitis C virus in hospital personnel.

J Hepatol 1992; 16: 56–58.

9 Sulkowski M, Ray S, Thomas D. Needlestick transmission

of hepatitis C. JAMA 2002; 287: 2406–2413.

10 Terrault N. Sexual activity as a risk factor for hepatitis C.

Hepatology 2002; 36 (Suppl. 1): 99–105.

11 Tor J, Llibre JM, Carbonell M et al. Sexual transmission of

HCV and its relation with hepatitis B virus and HIV. BMJ

1990; 301: 1130–1133.

12 Roberts E, Yeung L. Maternal-infant transmission of

hepatitis C virus infection. Hepatology 2002; 36 (Suppl. 1):

106–113.

13 Tovo P, Palomba E, Ferreris G et al. Increased risk of

maternal-infant HCV transmission for women coinfected

with HIV-1. Clin Infect Dis 1997; 25: 1121–1124.

14 Bonacini M, Puoti M. Hepatitis C in patients with HIV

infection: diagnosis, natural history, meta-analysis of sex-

ual and vertical transmission, and therapeutic issues. Arch

Intern Med 2000; 160: 3365–3373.

15 Filippini P, Coppola N, Scolastico C et al. Does HIV infection

favor the sexual transmission of hepatitis C? Sex Transm Inf

2001; 28: 725–729.

16 Manavi M, Baghestanian M, Watkins Riedel T et al.

Detection of HCV-RNA in normal cervical smears of

HCV-seropositive patients. Clin Infect Dis 2002; 35: 966–

973.

17 Debono E, Halfon P, Bourliere M et al. Absence of HCV

genome in semen of infected men by PCR, bDNA and in

situ hybridization. Liver 2000; 20: 257–261.

18 Leruez-Ville M, Kunstmann J, De Almeida M, Rouziouz C,

Chaix M. Detection of HCV in the semen of infected men.

Lancet 2000; 356: 42–43.

19 Eyster M, Alter H, Aledort L, Quan S, Hatzakis A, Goedert J.

Heterosexual co-transmission of hepatitis C virus (HCV)

and HIV. Ann Intern Med 1991; 115: 764–768.

20 Soto B, Rodrigo L, Garcia-Bengoechea M et al. Heterosexual

transmission of hepatitis C virus and the possible role of

coexistent HIV infection in the index case. A multicentre

study of 423 pairings. J Intern Med 1994; 236: 515–519.

21 Wyld R, Robertson J, Brettle R, Mellor J, Prescott L, Sim-

monds P. Absence of hepatitis C virus transmission but

frequent transmission of HIV-1 from sexual contact with

doubly-infected individuals. J Infection 1997; 35: 163–166.

22 Marincovich B, Castilla J, delRomero J et al. Absence of

hepatitis C virus transmission in a prospective cohort of

heterosexual serodiscordant couples. Sex Transm Inf 2003;

79: 160–162.

23 Daar E, Lynn H, Donfield S et al. HCV load is associated

with HIV-1 disease progression in hemophiliacs. J Infect Dis

2001; 183: 589–595.

24 Di Campli C. Evaluation of recent thymic emigrants

(TRECs) in patients affected by HCV chronic hepatitis.

J Hepatol 2002; 36 (Suppl. 1): 222.

25 Llibre JM, Garcıa E, Aloy A, Valls J. HCV infection and

progression of infection due to HIV. Clin Infect Dis 1993;

16: 182.

26 Quan C, Krajden M, Grigoriew G, Salit I. HCV infection in

patients with HIV. Clin Infect Dis 1993; 17: 117–119.

27 Wright TL, Hollender H, Puo X et al. Hepatitis C in HIV-

infected patients with and without AIDS, prevalence and

relationship to patients survival. Hepatology 1994; 20:

1152–1158.

28 Dorrucci M, Pezzotti P, Phillips A, Cozzi-Lepri A, Rezza G.

Coinfection of HCV with HIV and progression to AIDS.

J Infect Dis 1995; 172: 1503–1508.

29 Sabin C, Telfer P, Phillips A, Bhagani S, Lee C. The

association between HCV genotype and HIV disease pro-

gression in a cohort of hemophiliacs. J Infect Dis 1997;

175: 164–168.

30 Piroth L, Duong M, Quantin C et al. Does HCV co-infection

accelerate clinical and immunological evolution of HIV-

infected patients? AIDS 1998; 12: 381–388.

31 Lesens O, Deschenes M, Steben M, Belanger G, Tsouks C.

Hepatitis C virus is related to progressive liver disease in HIV-

positive hemophiliacs and should be treated as an oppor-

tunistic infection. J Infect Dis 1999; 179: 1254–1258.

32 Piroth L, Grappin M, Cuzin L et al. HCV coinfection is a

negative prognostic factor for clinical evolution in HIV-

positive patients. J Viral Hepatitis 2000; 7: 302–308.

33 Haydon G, Flegg P, Blair C, Brettle R, Burns S, Hayes P.

The impact of chronic hepatitis C virus infection on HIV

disease and progression in intravenous drug users. Eur J

Gastroenterol Hepatol 1998; 10: 485–489.

34 Staples C, Rimland D, Dudas D. Hepatitis C in the HAVACS:

the effect of coinfection on survival. Clin Infect Dis 1999;

29: 150–154.

35 Greub G, Ledergerber B, Battegay M, Grob P, Perrin L,

Furrer H et al. Clinical progression, survival, and immune

recovery during antiretroviral therapy in patients with

HIV-1 and HCV coinfections. Lancet 2000; 356: 1800–

1805.

36 Soriano V, Martın JC, Gonzalez-Lahoz J. HIV-1 progression

in hepatitis C-infected drug users. Lancet 2001; 357:

1361–1362.

37 Chung R, Evans S, Yang Y et al. Immune recovery is

associated with persistent rise in HCV RNA, infrequent

� 2004 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 11, 2–17

14 V. Soriano et al.

liver test flares, and is not impaired by HCV in co-infected

subjects. AIDS 2002; 16: 1915–1923.

38 Moreno S, Moreno A, Dronda F et al. Immune recovery

during antiretroviral therapy in patients infected with HIV-

1 and HCV coinfection: a cohort study. Ninth Conference

on Retroviruses and Opportunistic Infections. Seattle,

February 2002 [abstract 638-M].

39 Sulkowski M, Moore R, Mehta S, Chaisson R, Thomas D.

Hepatitis C and progression of HIV disease. JAMA 2002;

288: 199–206.

40 De Luca A, Bugarini R, Lepri A et al. Coinfection with

hepatitis viruses and outcome of initial antiretroviral reg-

imens in previously naıve HIV-infected subjects. Arch

Intern Med 2002; 162: 2125–2132.

41 Macıas J, Melguizo I, Fernandez-Rivera F et al. Mortality

due to liver failure and impact on survival of hepatitis virus

infections in HIV-infected patients receiving potent anti-

retroviral therapy. Eur J Clin Microbiol Infect Dis 2002; 21:

775–781.

42 Darby S, Ewart D, Giangrande P et al. Mortality form liver

cancer and liver disease in hemophiliac men and boys in

UK given blood products contaminated with hepatitis C.

Lancet 1997; 350: 1425–1431.

43 Soriano V, Kirk O, Antunes F et al. The influence of

hepatitis C on the prognosis of HIV: the EuroSIDA study.

XIIIth International AIDS Conference. Durban 2000 [ab-

stract ThOrB655].

44 Klein C, Lalonde R, Suissa S. HCV coinfection is associated

with increasing morbidity and mortality among HIV-

infected patients. Eighth Conference on Retroviruses and

Opportunistic Infections. Chicago 2001 [abstract 569].

45 Vento S, Di Perri G, Cruciani M, Garofano T, Concia E,

Bassetti D. Rapid decline of CD4+ cells after interferon

treatment in HIV-1 infection. Lancet 1993; 341: 958–959.

46 Pesce A, Taillan B, Rosenthal E. Opportunistic infections

and CD4 lymphocytopenia with interferon treatment in

HIV-1 infected patients. Lancet 1993; 341: 1597.

47 Wong J, Bennett W, Koff R, Pauker S. Pre-treatment

evaluation of chronic hepatitis C. Risks, benefits, and costs.

JAMA 1998; 280: 2088–2093.

48 Spinzi G, Minoli G. To biopsy or not to biopsy. Hepatology

2001; 34: 438–439.

49 Andriulli A, Mangia A, Niro G, Caturelli E. To biopsy or not

to biopsy. Hepatology 2001; 34: 438.

50 Berenguer J, Miralles P, Di Martino B et al. Liver fibrosis in

HIV-HIV patients candidates for anti-HCV therapy. 42nd

Interscience Conference on Antimicrobial Agents and Che-

motherapy, San Diego, October 2002 [abstract H-1276].

51 Quereda C, Moreno L, Navas E et al. Features and bio-

chemical markers of histological severity in HIV-HCV

coinfected patients. 42nd ICAAC, San Diego, Sept 2002

[abstract H-1722].

52 Martın-Carbonero L, Soriano V, Benhamou Y et al. Histo-

logical damage in liver biopsy specimens from 492 HIV-

HCV co-infected patients: a European collaborative study.

Tenth Conference on Retroviruses and Opportunistic

Infections. Boston, February 2003 (abstract 830).

53 Fuster D, Tural C, Tor J et al. Factors associated with liver

fibrosis in HIV-HCV coinfected patients on antiretroviral

therapy. Ninth Conference on Retroviruses and Opportun-

istic Infections. Seattle, February 2002 [abstract 646-M].

54 Forns X, Ampurdanes X, Llovet J et al. Identification of

chronic hepatitis C patients without hepatic fibrosis by a

simple predictive model. Hepatology 2002; 36: 986–992.

55 Soriano V, Martın-Carbonero L, Garcıa-Samaniego J.

Treatment of chronic hepatitis C virus infection: we must

target the virus or liver fibrosis? AIDS 2003; 17: 751–753.

56 Kuehne F, Bethe U, Freedberg K, Goldie S. Treatment for

hepatitis C virus in HIV-infected patients: clinical benefits and

cost-effectiveness. Arch Intern Med 2002; 162: 2545–2556.

57 Goelz J, Klausen G, Moll A et al. Efficacy and tolerance of

therapy with IFN-alpha/RBV and pegIFN-alpha/RBV in

HIV-/HCV-coinfected IVDUs. XIV World AIDS Conference;

July 7–12, 2002; Barcelona, Spain [abstract MoPeB3258].

58 Perez-Olmeda M, Nunez M, Romero M et al. Pegylated

interferon alpha 2b plus ribavirin as therapy for chronic

hepatitis C in HIV-infected patients. AIDS 2003; 17: 1023–

1028.

59 Perrone C, Carrat F, Bani S et al. RIBAVIC trial (ANRS

HCo2): a controlled randomized trial of pegylated-inter-

feron alfa-2b plus ribavirin versus interferon alfa2b plus

ribavirin for the initial treatment of chronic hepatitis C in

HIV co-infected patients: preliminary results. XIV World

AIDS Conference; July 7–12, 2002; Barcelona, Spain [ab-

stract LbOr16].

60 Rockstroh J, Schulz C, Mauss S, Klausen G, Voigt E, Golz J.

Pegylated interferon-alpha and ribavirin therapy for

hepatitis C in HIV-coinfected patients: 24 weeks results.

XIV World AIDS Conference; July 7–12, 2002; Barcelona,

Spain [abstract WePeB6025].

61 Hopkins S, Lyons F, Brannigan E, Mulcahy F, Bergin C.

Tolerability of pegylated interferon and ribavirin in the

HIV/HCV co-infected population. XIV World AIDS Con-

ference; July 7–12, 2002; Barcelona, Spain [abstract

ThPeC7531].

62 Chung R, Andersen J, Alston B et al. A randomized, con-

trolled trial of pegylated interferon alpha 2a with RBV vs

interferon alpha 2a with RBV for the treatment of chronic

hepatitis C in HIV coinfection. Ninth Conference on Ret-

roviruses and Opportunistic Infections. Seattle, February

2002 [abstract LB15].

63 Quereda C, Moreno L, Moreno A et al. Early prediction of

response to pegylated interferon alfa-2b plus ribavirin in

patients coinfected with HIV and HCV. 42nd ICAAC, San

Diego, Sept 2002 [abstract H-1724].

64 Fried M, Shiffman M, Reddy R et al. Peginterferon alfa-2a

plus ribavirin for chronic hepatitis C virus infection. N Engl

J Med 2002; 347: 975–982.

65 Torriani F, Ribeiro R, Gilbert T et al. Early HCV viral

dynamics in HIV/HCV-infected patients on HCV treatment.

Ninth Conference on Retroviruses and Opportunistic

Infections. Seattle, Feb 2002 [abstract 121].

66 Perez-Olmeda M, Martın-Carbonero L, Rios P, Nunez M,

Gonzalez-Lahoz J, Soriano V. Predictive value of early

virological response (12 weeks) to pegylated interferon

plus ribavirin in HIV-HCV coinfected patients. Tenth Con-

ference on Retroviruses and Opportunistic Infections.

Boston, Feb 2003 [abstract 842].

� 2004 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 11, 2–17

Consensus conference on chronic viral hepatitis and HIV infection 15

67 Manns M, McHutchison J, Gordon S et al. Peginterferon

alfa-2b plus ribavirin compared with interferon alfa-2b

plus ribavirin for initial treatment of chronic hepatitis C: a

randomised trial. Lancet 2001; 358: 958–965.

68 Moyle G. Hyperlactatemia and lactic acidosis during anti-

retroviral therapy: causes, management and possible eti-

ologies. AIDS Reviews 2001; 3: 150–156.

69 Lafeuillade A, Hittinger G, Chapadaud S. Increased mit-

ochondrial toxicity with ribavirin in HIV/HCV coinfection.

Lancet 2001; 357: 280–281.

70 Kakuda T, Brinkman K. Mitochondrial toxic effects of rib-

avirin. Lancet 2001; 357: 1803.

71 Salmon-Ceron D, Chauvelot-Moachon L, Abad S, Silber-

mann B, Sogni P. Mitochondrial toxic effects of ribavirin.

Lancet 2001; 357: 1803.

72 Mauss S, Larrey D, Valenti W et al. Risk factors for hepatic

decompensation in cirrhotic patients with HIV-HCV coin-

fection treated with PEG interferon or interferon and rib-

avirin or placebo. Sixth International Congress on Drug

Therapy in HIV Infection. Glasgow, Nov 2002 [abstract

PL12.4].

73 Garcıa-Benayas T, Blanco F, Soriano V. Weight loss in HIV-

infected patients. N Engl J Med 2002; 347: 1287–1288.

74 Bonnet F, Lawson-Ayayi S, Thiebaut R et al. A cohort study

of nevirapine tolerance in clinical practice: French Aquitaine

Cohort, 1997–1999. Clin Infect Dis 2002; 35: 1231–1237.

75 Rodriguez-Rosado R, Garcıa-Samaniego J, Soriano V.

Hepatotoxicity after introduction of highly active antiret-

roviral therapy. AIDS 1998; 12: 1256.

76 Saves M, Vandentorren S, Daucourt V et al. Severe hepatic

cytolysis: incidence and risk factors in patients treated by

antiretroviral combinations. Aquitaine Cohort, France,

1996–1998. AIDS 1999; 13: F115–F121.

77 Sulkowski M, Thomas D, Chaisson R, Moore R. Hepato-

toxicity associated with antiretroviral therapy in adults

infected with HIV and the role of hepatitis C or B virus

infection. JAMA 2000; 283: 74–80.

78 Den Brinker M, Wit F, Wertheim-van Dillen P et al.

Hepatitis B and C virus co-infection and the risk for

hepatotoxicity of highly active antiretroviral therapy in

HIV-1 infection. AIDS 2000; 14: 2895–2902.

79 Saves M, Raffi F, Clevenbergh P et al. Hepatitis B or

hepatitis C virus infection is a risk factor for severe hepatic

cytolysis after initiation of a protease inhibitor-contained

antiretroviral regimen in HIV-infected patients. Antimicrob

Agents Chemother 2000; 44: 3451–3455.

80 Nunez M, Lana R, Mendoza JL, Martın-Carbonero L, Sori-

ano V. Risk factors for severe liver toxicity following the

introduction of HAART. J Acquir Immune Defic Syndr 2001;

27: 426–431.

81 Bonfanti P, Landonio S, Ricci E et al. Risk factors for he-

patotoxicity in patients treated with highly active antiretro-

viral therapy. J Acquir Immune Def Syndr 2001; 27: 316–318.

82 D’Arminio Monforte A, Bugarini R, Pezzotti P et al.

Low frequency of severe hepatotoxicity and association with

HCV coinfection in HIV-positive patients treated with

HAART. J Acquir Immune Def Syndr 2001; 28: 114–123.

83 Aceti A, Pasquazzi C, Zechini B, De Bac C, The LIVERHA-

ART Group. Hepatotoxicity development during antiret-

roviral therapy containing protease inhibitors in patients

with HIV. The role of hepatitis B and C virus infection.

J Acquir Immune Def Syndr 2002; 29: 41–48.

84 Wit F, Weverling G, Weel J, Jurrians S, Lange J. Incidence

and risk factors for severe hepatotoxicity associated with

antiretroviral combination therapy. J Infect Dis 2002; 186:

23–31.

85 Martınez E, Blanco J, Arnaiz J et al. Hepatotoxicity in HIV-

infected patients receiving nevirapine-containing antiret-

roviral therapy. AIDS 2001; 15: 1261–1268.

86 Palmon R, Koo B, Shoultz D, Dieterich D. Lack of hepato-

toxicity associated with nonnucleoside reverse transcriptase

inhibitors. J Acquir Immune Def Syndr 2002; 29: 340–345.

87 Sulkowski M, Thomas D, Mehta S, Chaisson R, Moore R.

Hepatotoxicity associated with nevirapine or efavirenz-

containing antiretroviral therapy: role of hepatitis C and B

infections. Hepatology 2002; 35: 182–189.

88 Martın-Carbonero L, Nunez M, Gonzalez-Lahoz J, Soriano

V. Incidence of liver injury after beginning antiretroviral

therapy with efavirenz or nevirapine. HIV Clin Trials 2003;

4: 115–120.

89 Diaz B, Martın-Carbonero L, Perez-Olmeda M, Soriano V.

Normalization of liver enzymes in an HIV-HCV coinfected pa-

tient after potent antiretroviral therapy. AIDS 2002; 16: 1193.

90 Martın-Carbonero L, Nunez M, Rios P, Perez-Olmeda M,

Gonzalez-Lahoz J, Soriano V. Liver injury after beginning

antiretroviral therapy in HIV/HCV co-infected patients is

not related to immune reconstitution. AIDS 2002; 16:

1423–1425.

91 Lonergan J, Behling C, Pfander H, Hassanein T, Mathews

W. Hyperlactatemia and hepatic abnormalities in 10 HIV-

infected patients receiving nucleoside analogue combina-

tion regimens. Clin Infect Dis 2000; 31: 162–166.

92 Hadler S, Judson F, O’Malley P et al. Outcome of hepatitis B

virus infection in homosexual men and its relation to prior

HIV infection. J Infect Dis 1991; 163: 454–459.

93 Rector W, Govindarajan S, Horsburgh C, Penley K, Cohn

D, Judson F. Hepatic inflammation, hepatitis B replication,

and cellular immune function in homosexual males with

chronic hepatitis B and antibody to HIV. Am J Gastroenterol

1988; 83: 262–266.

94 Colin J, Cazals-Hatem D, Loriot M et al. Influence of HIV

infection on chronic hepatitis B in homosexual men. Hep-

atology 1999; 29: 1306–1310.

95 Puoti M, Spinetti A, Ghezzi A, Donato F, Zaltron S, Putzolu V

et al. Mortality for liver disease in patients with HIV infection:

a cohort study. J Acquir Immun Def Syndr 2000; 24: 211–217.

96 Thio C, Seaberg E, Skolasky R et al. HIV-1, hepatitis B virus,

and risk of liver-related mortality in the MACS. Lancet

2002; 360: 1921–1926.

97 Di Martino V, Thevenot T, Colin J et al. Influence of HIV

infection on the response to interferon therapy and the

long-term outcome of chronic hepatitis B. Gastroenterology

2002; 123: 1812–1822.

98 Puoti M, Airoldi M, Bruno R et al. Hepatitis B virus co-infection

in HIV-infected subjects. AIDS Reviews 2002; 4: 27–35.

99 Gilson R, Hawkins A, Beecham M et al. Interactions between

HIV and hepatitis B virus in homosexual men: effects on the

natural history of infection. AIDS 1997; 11: 597–606.

� 2004 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 11, 2–17

16 V. Soriano et al.

100 Brechot C, Thiers V, Kremsdorf D, Nalpas B, Pol S, Paterlini-

Brechot P. Persistent hepatitis B virus infection in subjects

without hepatitis B surface antigen: clinically significant or

purely ‘‘occult’’? Hepatology 2001; 34: 194–203.

101 Cacciola I, Pollicino T, Squadrito G, Cerenzia G, Orlando M,

Raimondo G. Occult hepatitis B virus infection in patients

with chronic hepatitis C liver disease. N Engl J Med 1999;

341: 22–26.

102 Nunez M, Rios P, Perez-Olmeda M, Soriano V. Lack of oc-

cult hepatitis B virus infection in HIV-infected patients.

AIDS 2002; 16: 2099–2101.

103 Gomez-Gonzalo M, Carretero M, Rullas J et al. The hepatitis

B virus X protein induces HIV-1 replication and tran-

scription in synergy with T cell activation signals. J Biol

Chem 2001; 276: 35 435–35 443.

104 Sinicco A, Raiteri R, Sciandra M et al. Co-infected and

superinfection of hepatitis B virus in patients infected with

HIV: no evidence of faster progression to AIDS. Scand

J Infect Dis 1997; 29: 111–115.

105 Benhamou Y, Bochet M, Thibault V et al. Long-term inci-

dence of hepatitis B virus resistance to lamivudine in HIV-

infected patients. Hepatology 1999; 30: 1302–1306.

106 Shaw T, Bowden S, Locarnini S. Chemotherapy for hepatitis

B: new treatment options necessitate reappraisal of tradi-

tional endpoints. Gastroenterology 2002; 123: 2135–2140.

107 Lok A. Perspective: chronic hepatitis B. N Engl J Med 2002;

346: 1682–1683.

108 Nelson M, Porstmouth S, Stebbing J et al. An open-label

study of tenofovir in HIV-1 and hepatitis B virus coinfected

individuals. AIDS 2003; 17: F7–F10.

109 Bochet M, Tubianan R, Benhamou Y et al. Tenofovir dis-

oproxil fumarate suppresses lamivudine-resistant HBV

replication in patients coinfected with HIV/HBV. Ninth

Conference on Retroviruses and Opportunistic Infections.

Seattle 2002 [abstract 675].

110 Cooper D, Cheng A, Coakley D et al. Anti-HBV activity of

tenofovir disoproxil fumarate in lamivudine-experienced

HIV/HBV coinfected patients. Ninth Conference on Retro-

viruses and Opportunistic Infections. Seattle 2002 [ab-

stract 124].

111 Nunez M, Perez-Olmeda M, Diaz B, Rios P, Gonzalez-Lahoz

J, Soriano V. Activity of tenofovir on hepatitis B virus

replication in HIV-coinfected patients failing or partially

responding to lamivudine. AIDS 2002; 16: 2352–2354.

112 Ristig M, Crippin J, Aberg J et al. Tenofovir dipivoxil fumarate

therapy for chronic hepatitis B in HIV/HBV-coinfected

individuals for whom interferon alpha and lamivudine

therapy have failed. J Infect Dis 2002; 186: 1844–1847.

113 Portsmouth S, Stebbing J, Barr A et al. An open label study

of tenofovir in HIV-1 and hepatitis B co-infected individu-

als. Sixth International Congress on Drug Therapy in HIV

Infection. Glasgow, November 2002 [abstract P280].

114 Delaugerre C, Marcellin A, Thibault V et al. HIV-1 reverse

transcriptase resistance mutations in HBV/HBV coinfected

patients treated for HBV chronic infection once daily with

10 mg of adefovir dipivoxil combined with lamivudine.

Antimicrob Agents Chemother 2002; 46: 1586–1588.

115 Sanchez-Tapias JM, Costa J, Mas A, Bruguera M, Rodes J.

Influence of hepatitis B virus genotype on the long-term

outcome of chronic hepatitis B in Western patients. Gas-

troenterology 2002; 123: 1848–1856.

116 Welch K, Morse A. Improving screening and vaccination

for hepatitis B in patients coinfected with HIV and hepatitis

C. Am J Gastroenterol 2002; 97: 2928–2929.

117 Diaz B, Nunez M, Soriano V. Acute hepatitis B in a previ-

ously vaccinated patient infected by HIV. Med Clin (Barc)

2001; 117: 518–519.

118 Lai C-L, Rosmawati M, Lao J et al. Entecavir is superior to

lamivudine in reducing hepatitis B virus DNA in patients

with chronic hepatitis B infection. Gastroenterology 2002;

123: 1831–1838.

119 Papatheodoridis G, Dimou E, Papadimitropoulos V. Nucleo-

side analogues for chronic hepatitis B: antiviral efficacy and

viral resistance. Am J Gastroenterol 2002; 97: 1618–1628.

120 Ragni M, Dodson S, Hunt S, Bontempo F, Fung J. Liver

transplantation in a hemophilia patient with acquired

immunodeficiency syndrome. Blood 1999; 93: 1113.

121 Schliefer K, Paar W, Aydermir G et al. Orthotopic liver

transplantation in a 33-year-old patient with fulminant

hepatitis B and HIV infection. Dtsch Med Wochnschr 2000;

125: 523–526.

122 Gow P, Mutimer D. Liver transplantation for an HIV-pos-

itive patient in the era of highly active antiretroviral

therapy. AIDS 2001; 15: 291–292.

123 Praschalias A, Pozniak A, Taylor C et al. Liver transplan-

tation in adults coinfected with HIV. Transplantation 2001;

72: 1684–1688.

124 Boyd A, Taylor C, Norris S et al. Liver transplantation and

HIV-A case series of 7 patients. Eighth Conference on

Retroviruses and Opportunistic Infections. Chicago, IL.

February 4–8, 2001. Abstract no. 577.

125 Bonham C, Dodson S, Ragni M, Costa G, Fung J. Liver

transplantation of HIV positive patients in the era of HA-

ART. American Society of Transplantation. Chicago, IL.

2001. Abstract 1029.

126 Didier S, Vittecoq D, Duclos-Vallee JC et al. Liver trans-

plantation for HCV cirrhosis in HIV-HCV coinfected

patients. Evaluation of antiretroviral toxicity and of HCV

recurrence. Hepatology 2002; 36: 231A.

127 Neff G, Jayaweera D, Tzakis A. Liver transplantation for

HIV-infected patients with end-stage liver disease. Curr Op

Organ Transplantation 2002; 7: 114–123.

128 Radecke K, Miller M, Ross B, Treichel U, Gerken G. Short

term outcome in five HIV infected patients with terminal

liver disease after orthotopic liver transplantation. Hepa-

tology 2002; 36: 190

129 Roland M, Carlson L, Ragni M et al. Solid organ trans-

plantation in HIV-infected recipients: 47 cases in the HA-

ART era. XIV International AIDS Conference. Barcelona,

Spain. July 7–12, 2002. Abstract MoOrB1060.

130 Rafecas A, Rufi G, Fabregat J, Xiol X. Liver transplantation in

a patient infected with HIV. Med Clin (Barc) 2002; 119: 596.

131 Rufı G, Barcena R, Vargas V, Valdivieso A, Miro JM,

Banares R et al. Orthotopic liver transplantation (OLT) in

15 HIV-infected recipients: evaluation of Spanish experi-

ence in the HAART era (2002–03). 11th Conference on

Retroviruses and Opportunistic Infections. San Francisco,

CA. February 8–11, 2004. [Abstract 827].

� 2004 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 11, 2–17

Consensus conference on chronic viral hepatitis and HIV infection 17