Download The Place of Liver Transplantation in HIV-infected Patients

Reference Section
The Place of Liver Transplantation in HIV-infected Patients
a report by
Didier Samuel
Head, Intensive Care Unit and Liver Unit, Medical Director, Liver Transplant Program and
Consultant Hepatologist, Paul Brousse Hospital
Didier Samuel is Head of the
Intensive Care Unit and Liver Unit,
Medical Director of the Liver
Transplant Program and
Consultant Hepatologist at the outpatient clinic for liver transplant
patients and patients with
hepatobiliary disorders at the Paul
Brousse Hospital. Since 1997, he
has also been Professor of
Hepatology and Gastroenterology at
South Paris University (Paris 11).
He has been a practitioner in
hepatology since 1992, before which
he was Assistant Chief of Clinic in
the Centre for Liver Diseases at the
Paul Brousse Hospital. Dr Samuel is
a member of numerous scientific
societies, including the European
Association for the Study of the
Liver. He is currently Associate
Editor of Liver Transplantation and
was Associate Editor of the Journal
of Hepatology between 1999 and
2004. Dr Samuel is also Head of
an INSERM Research Unit at the
Centre Hepatobiliaire. His research
on liver disease and transplantation
has resulted in more than 200
written papers, many of which have
been published in top-rank
international journals. Dr Samuel
completed his PhD at Paris 11
University in 1995, having obtained
his medical degree from Paris VI
University in 1985.
The prognosis of infection due to HIV has been
improved dramatically since the advent of highly active
antiretroviral therapy (HAART). However, 20% to
40% of HIV-infected patients are co-infected with
hepatitis C virus (HCV) or hepatitis B virus (HBV).
The outcome of viral hepatitis in HIV-co-infected
patients is more rapid and severe than in patients
infected with HCV alone and/or HBV.1–8 A high
number of HIV-infected patients will die as a
consequence of viral hepatitis. There is, therefore, a
demand to offer liver transplantation to HIV-infected
patients with life-threatening viral liver disease.
Before the advent of HAART, results of liver
transplantation in HIV-infected patients were
poor.9–13 Moreover, a rapid progression of HIV
infection was noted in most of the patients,
suggesting a deleterious effect of immunosuppressive
treatments on the course of HIV infection. Thus, in
the absence of HAART, the risk of acceleration of
the spontaneous course of HIV infection after liver
transplantation was important.
The statement of the Jury of the Consensus
Conference on the Indications of Liver Transplantation
held in Paris in 1993 was that the presence of AIDS
was an absolute contraindication to liver
transplantation and that asymptomatic HIV infection
without AIDS was a relative contraindication.14 Since
then, a very limited number of patients infected with
HIV have been transplanted. Recently, with the
advent of HAART and the dramatic improvement of
the prognosis of HIV infection, the issue of liver
transplantation has been raised again in patients with
life-threatening liver disease.
Issues in Liver Transplantation for
HIV-infected Patients
Timing for the Indication of
Liver Transplantation
1
The ideal timing for liver transplantation is still
unknown. Most patients have a particularly
aggressive, rapidly evolving course. The evolution
towards cirrhosis and complications of cirrhosis are
more rapid than in non-co-infected patients.1–8
Many patients are referred too late and die before
transplantation or are too ill to receive liver
transplant and still have reasonable chances of
surviving. Several studies have shown that the
course of liver disease was significantly accelerated in
HIV with HBV or HCV co-infection in comparison
with those without HIV co-infection. The
prognosis criteria (e.g. Child-Pugh or model for
end-stage liver disease (MELD)) have not been
validated in HIV-infected patients.15 Transplantation
of patients with major denutrition and terminal liver
disease may impair the results of liver transplantation
in HIV patients. This is why the criteria of prognosis
of liver disease in HIV patients must be validated in
order to refer patients to transplant centres at an
earlier stage.
The Risk of HIV Transmission to
Healthcare Workers
The risk of HIV transmission to healthcare workers
should be discussed with physicians and nurses
within the medical team. This risk is low, but does
exist, and this should be explained and discussed
with the medical and nursing team. Liver
transplantation is a surgical intervention of long
duration (frequently performed overnight) that
places physicians and nurses at high risk of
needlestick injury. This risk is present during and
after transplantation, which is why it is important to
obtain the agreement of all healthcare workers
involved in the management of these patients. It is
also important to know in advance the sensibility of
the HIV strain to antiviral treatment in order to
immediately give an effective antiretroviral
prophylaxis in case of needlestick injury.16–17
The Problem of Drug Interaction
Between Calcineurin Inhibitors and
Antiretroviral Treatment
Calcineurin inhibitors are metabolised through the
cytochrome P450 3A enzymatic pathway. This
pathway is also used by most antiretroviral
treatments – non-nucleoside inhibitors of reverse
transcriptase and protease inhibitors. In case of
co-administration of protease inhibitor and
BUSINESS BRIEFING: EUROPEAN GASTROENTEROLOGY REVIEW 2005
The Place of Liver Transplantation in HIV-infected Patients
calcineurin inhibitor, there will be an interaction
with the cytochrome P450 pathway with
immediate accumulation of tacrolimus or
cyclosporine, leading to a risk of tacrolimus or
cyclosporine drug toxicity. This requires cautious
monitoring of tacrolimus and cyclosporine blood
levels. Particular attention should be paid in case of
introduction or discontinuation of a protease
inhibitor. In addition, very low doses of tacrolimus
or cyclosporine being administered over a long
time to avoid drug toxicity may lead to low
prevention of acute rejection risk with an
inadequate area under the curve of blood levels of
tacrolimus or cyclosporine.
The effect of calcineurin inhibitors on the risk of low
or high dosage of protease inhibitors is unknown.
The interaction is very strong with protease
inhibitors, less strong with non-nucleoside analogues
and weak with nucleoside analogues. Some protease
inhibitors, such as ritonavir, also have a stronger
interaction than others with anti-calcineurins.18–20
Accumulation of Treatments
Patients infected with HIV will receive a significant
amount of drugs after the transplantation, including
HAART, immunosuppressive drugs, anticytomegalovirus prophylaxis, prophylaxis against
pneumocystis carinii, anti-HBV or anti HCV antiviral
treatments and various other treatments
(antibiotics, anti-hypertensive drugs, etc.). This
accumulation of drugs increases the risk of poor
tolerance and may be the cause of a low
compliance to treatments. There is also a risk of
cumulative toxicity when ribavirin is added to
nucleoside analogues.
The Risk of Progression of HIV
Infection after Transplantation
Before the advent of HAART, the course of HIV
infection seemed accelerated compared with nontransplant patients.8 Since the advent of HAART,
the preliminary experiences of liver transplantation in
HIV-infected patients did not show any acceleration
of the course of HIV infection. In the preliminary
experience of several centres, with a follow-up
between one and three years, there was no
acceleration of HIV infection, no decrease in CD4
count and no opportunistic infection, and HIV
RNA level remained low or undetectable under
HAART.28–30 However, longer follow-up is required
to evaluate the risk of accelerated course of HIV
diseases after transplantation, particularly the risk of
opportunistic infection and lymphoproliferative
disorder. A few cases of lymphoma and Kaposi’s
sarcoma have been described, but the majority of
patients did not develop opportunistic infection and
liver transplantation did not seem to accelerate the
course of HIV infection. However, some authors
have shown a poorer outcome in transplanted
patients, with a CD4 count below 200/mm3.28 In
addition, the risk of HIV viral breakthrough should
be taken into account before transplantation. For
more than 10 years, patients with liver cirrhosis have
been frequently infected with HIV and have been
treated with several antiretroviral combinations. It
seems important to know the sensitivity of the HIV
strain to various antiretroviral treatments in order to
evaluate the risk of further virologic breakthrough
and therapeutical possibilities in case of breakthrough. Thus, it seems dangerous to propose liver
transplantation in patients with low therapeutic
alternatives against HIV and in patients with
uncontrolled HIV infection.
Mitochondria Toxicity of HAART
Nucleoside analogues administration may alter the
mitochondria DNA polymerase and lead to a
decrease of the content of DNA in mitochondria.
Nucleoside analogues affect the respiratory chain of
the mitochondria and are responsible for lesions
such as micro-vesicular steatosis, pancreatitis and
lactic acidosis.21 Some authors have suggested an
increased mitochondria toxicity in HCV-positive
patients through unknown mechanisms.22–25 In
addition, there is a link between the duration of
HAART treatment and the risk of mitochondria
toxicity. At present, there is no information
regarding the particular risk of mitochondria
toxicity after transplantation in patients with pretransplant mitochondria alterations such as
neuropathy or lypodystrophy; this should be further
studied. The administration of ribavirine may also
further increase the risk of HAART-related
mitochondria toxicity.26,27
Results of Liver Transplantation in
Patients Co-infected with HIV and HBV
Before transplantation, there is a risk of persistent
HBV replication secondary to emergence of the
tyrosine-methionine-aspartate-aspartate (YMDD)mutant HBV strain resistant to lamivudine. Indeed,
lamivudine has been widely used against HIV in HIVinfected patients, but the risk of HBV breakthrough is
extremely high in this population – approximately
100% at four years.31 Therefore, it seems important to
avoid the overuse of lamivudine in HIV–HBVco-infected patients. In case of viral B breakthrough,
adefovir, a nucleotide analogue that is a potent drug
against the HBV strain resistant to lamivudine, should
be added to the treatment before transplantation.32
Tenofovir, another nucleotide analogue, is efficient
against both the HBV strain resistant to lamivudine
and against HIV and is now widely used in the
armentarium in these patients.33 In short, the
BUSINESS BRIEFING: EUROPEAN GASTROENTEROLOGY REVIEW 2005
2
Reference Section
introduction of lamivudine and tenofovir in the
treatment of HIV–HBV-co-infected patients should
be discussed between physicians in charge of the
management of HIV infection and transplant
hepatologists. Many physicians in charge of HIVinfected patients are now well aware of the risk of
HBV escape mutation on lamivudine, and most
patients who need an antiviral treatment against HBV
are now on a combination therapy of tenofovir plus
lamivudine. After transplantation, it is possible to
control HBV re-infection by using a prophylaxis
combination with anti-HBs immunoglobulins
(HBIGs) and lamivudine and/or adefovir. This type of
prophylaxis is highly efficient and reduces the risk of
HBV recurrence to less than 10%.34 The preliminary
experience of liver transplantation in HIV–HBVco-infected patients showed excellent initial results
with good survival and low HBV recurrence risk. It
appears that the results of liver transplantation in
HIV–HBV-infected patients are similar to those
observed in mono-infected HBV patients.
Liver Transplantation in Patients
Co-infected with HIV and HCV
3
Liver transplantation in HIV–HCV-co-infected
patients currently represents the most difficult and
important issue. These patients represent a large
group of individuals; in some series, 30% of HIVinfected patients are also infected with HCV. In
addition, a lot of these patients already have a severe
liver disease with cirrhosis. Before transplantation,
the risk of rapid progression of liver cirrhosis is
particularly high. It has also been suggested that
HAART hepatic toxicity may be a deleterious
co-factor of HCV-related liver fibrosis progression.24
This emphasises again the need for a better
understanding of liver fibrosis progression in
HCV–HIV-co-infected patients and better criteria of
prognosis in HIV–HCV-infected patients. The result
of liver transplantation in these patients has been
better known for the past two years.28–30,35–37 The
problem of HCV re-infection of the graft appears as
a major issue in these patients. In a recent report in
the HAART era, the King’s College group reported
very disappointing results because five out of seven
patients who were transplanted for HIV–HCV-coinfection died of severe HCV recurrence 12 to 25
months after transplantation.35 These poor results
have not been confirmed by other groups. The
group from Miami and Pittsburgh reported better
results, with an 80% survival rate at a two-year
follow-up.28,29 In 2000, the transplant centre at the
Paul Brosse Hospital started a programme of liver
transplantation in HIV–HCV-co-infected patients
supported by the French Agency for Research
against AIDS (ANRS).30 The criteria for patient
selection were the presence of life-threatening liver
cirrhosis due to HCV and controlled HIV infection.
Currently, 23 patients have been transplanted and 18
are alive, with a two-year survival rate of 70%.
Among the five patients who died, three died of
severe HCV recurrence with combined HAART
toxicity. However, the medium-term survival can be
impaired due to HCV recurrence. The first results
showed that all patients developed HCV recurrence,
but in comparison with the group of patients infected
with HCV alone, the delay for recurrence seems
shorter, the post-transplant HCV viral load is higher
and the development of fibrosis on the liver graft
more rapid and severe. There is no clear explanation
for this more severe course of HCV graft infection in
HIV transplant patients, but it should be compared
with what was observed in the non-transplant
HIV–HCV-infected patients. A deleterious role of
HAART and, particularly, of some nucleoside
analogues is possible. It has been shown that some
patients developed a microvesicular steatosis on the
graft with deterioration of the mitochondrial
respiratory chain and of the mitochondrial DNA.30,38
For this reason, antiretroviral drugs, such as
didanosine (DDI), azidothymidine (AZT) and
stavudine (D4T), should be avoided. In addition, the
presence of microvesicular steatosis on the graft in a
patient may indicate that a change of antiretroviral
drugs is needed. The role of immunosuppressive
drugs on the severity of HCV recurrence is currently
being investigated.
Ethical Issues in Liver
Transplantation for HIV-infected
Patients
Liver transplantation in HIV-infected patients is a
new indication in the context of organ shortage.
Some may advocate the organs being used for less
risky patients. To limit the impact of this new
indication on the resource of liver organs, the use of
domino transplantation or living related liver
transplantation have been suggested. The ethical
committee of the French Agency for Organ
Distribution (Agence de la biomédecine), the French
Consensus Conference on the indications for liver
transplantation held in January 2005 and the
European Consensus Conference on the treatment of
chronic HBV and HCV in HIV-co-infected patients
concluded that there was no reason to refuse liver
transplantation in HIV-infected patients or to restrict
the grafts to domino grafts or grafts coming from
living related donors.39 It was, however,
recommended that the development of this
transplantation remain within experimented
transplant groups, with a multi-disciplinary approach,
and that transplantation be considered only in
patients with a controlled HIV infection. The postoperative care requires a multidisciplinary approach,
including transplant surgeons, hepatologists,
physicians in charge of HIV infection and virologists.
BUSINESS BRIEFING: EUROPEAN GASTROENTEROLOGY REVIEW 2005
The Place of Liver Transplantation in HIV-infected Patients
Conclusion
Liver transplantation in HIV-infected patients is
currently under evaluation. This is a demanding
procedure that should be developed within a multidisciplinary team, including hepatologists, transplant
surgeons, infectiologists, virologists and pathologists.
Liver transplantation in patients co-infected with HIV
and HBV give excellent results if efficient prophylaxis
against HBV is used before and after transplantation.
In contrast, liver transplantation in HIV–HCVco-infected patients is more difficult and several
problems need to be resolved in the future, such as the
ideal timing for transplantation, the prevention and
treatment of HCV recurrence post-transplantation,
and the prevention of HAART liver toxicity. ■
References
1. Zylberberg H, Pialoux G, Carnot F, Landau A, Brechot C, Pol S, “Rapidly evolving hepatitis C virus-related cirrhosis
in a human immunodeficiency virus-infected patient receiving triple antiretroviral therapy”, Clin. Infect. Dis.
(1998);27:1,255–1,258.
2. Benhamou Y, Di Martino V, Bochet M, Colombet G, Thibault V, Liou A et al., “Factors affecting liver fibrosis in human
immunodeficiency virus-and hepatitis C virus-coinfected patients: impact of protease inhibitor therapy”, Hepatology
(2001);34: pp. 283–287.
3. Di Martino V, Thevenot T, Colin J F, Boyer N, Martinot M, Degos F et al., “Influence of HIV infection on the response to
interferon therapy and the long-term outcome of chronic hepatitis B”, Gastroenterology (2002);123: pp. 1,812–1,822.
4. Soto B, Sanchez-Quijano A, Rodrigo L, Del Olmo J A, Garcia-Bengoechea M, Hernandez-Quero J et al, “Human
immunodeficiency virus infection modifies the natural history of chronic parenterally-acquired hepatitis C with an unusually
rapid progression to cirrhosis”, Hepatology (1997);26: pp. 1–5.
5. Di Martino V, Rufat P, Boyer N, Renard P, Degos F, Martinot-Peignoux M, Matheron S, Le Moing V, Vachon F,
Degott C, Valla D, Marcellin P, “The influence of human immunodeficiency virus coinfection on chronic hepatitis C in
injection drug users: a long-term retrospective cohort study”, Hepatology (2001);34: pp. 1,193–1,199.
6. Colin J F, Cazals-Hatem D, Loriot M A, Martinot-Peignoux M, Pham B N, Auperin A, Degott C, Benhamou J P,
Erlinger S, Valla D, Marcellin P, “Influence of human innmunodeficiency virus infection on chronic hepatitis B in
homosexual men”, Hepatology (1999);29: pp. 1,306–1,310.
7. Pol S, Lamorthe B, Thi N T, Thiers V, Carnot F, Zylberberg H, Berthelot P, Brechot C, Nalpas B, “Retrospective
analysis of the impact of HIV infection and alcohol use on chronic hepatitis C in a large cohort of drug users”, J. Hepatol.
(1998);28: pp. 945–950.
8. Vallet-Pichard A, Pol S, “Hepatitis viruses and human immunodeficiency virus co-infection. Pathogenesis and treatment”,
J. Hepatol. (2004);41: pp. 156–166.
9. Bouscarat F, Samuel D, Simon F, Debat P, Bismuth H, Saimot A, “An observational study (1985–1993) of 11 HIV1-infected liver transplant recipients”, Clin. Infect. Dis. (1994);19: pp. 854–859.
10. Samuel D, Castaing D, Adam R, Saliba F, Chamaret S, Misset J et al., “Fatal acute HIV infection with aplastic anaemia
transmitted by liver graft”, Lancet (1988);I: pp. 1,221–1,222.
11. Tzakis A, Cooper M H, Dummer J S, Ragni M, Ward J W, Starzl T E, “Transplantation in HIV Positive Patients”,
Transplantation (1990);49: pp. 354–358.
12. Erice A, Rhame F, Heussner R, Dunn D, Balfour H, “Human immunodeficency virus infection in patients with solidorgan transplants: report of five cases and review”, Rev. Infect. Dis. (1991);13: pp. 537–547.
13. Gordon F, Mistry P, Sabin C, Lee C, “Outcome of orthotopic liver transplantation in patients with hemophilia”, Gut
(1998);42: pp. 744–749.
14. Jury of The International Consensus Conference on Indications of Liver Transplantation, “Consensus statement on
indications for liver transplantation: Paris, June 22–23, 1993”, Hepatology (1994);20: pp. 63S–68S.
15. Wiesner R, Edwards E, Freeman R, Harper A, Kim R, Kamath P et al., “Model for end-stage liver disease (MELD)
and allocation of donor livers”, Gastroenterology (2003);124: pp. 91–96.
16. Le Grand R, Vaslin B, Larghero J, Neidez O, Thiebot H, Sellier P et al., “Post-exposure prophylaxis with highly active
antiretroviral therapy could not protect macaques from infection with SIV/HIV chimera”, AIDS (2000);14: pp.
1,864–1,866.
17. Baxter J D, Mayers D L, Wentworth D N, Neaton J D, Hoover M L, Winters M A et al., “A randomized study of
antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy”, AIDS
(2000);14: pp. F83–F92.
18. Sheikh A M, Wolf D C, Lebovics E, Golberg R, Horowitz H W, “Concomitant human immunodeficiency virus protease
inhibitor therapy markedly reduces tacrolimus metabolism and increases blood levels”, Transplantation (1999);68: pp.
307–309.
19. Jain A K B, Venkataramanan R, Shapiro R, Scantlebury V P, Potdar S, Bonham A et al., “The interaction between
antiretroviral agents and tacrolimus in liver and kidney transplanted patients”, Liver Transpl. (2002);8: pp. 841–845.
BUSINESS BRIEFING: EUROPEAN GASTROENTEROLOGY REVIEW 2005
4
Reference Section
20. Vogel M, Voigt E, Michaelis H-C, Sudhop T, Wolff M, Turler A, Sauerbruch T et al., “Management of drug-to-drug
interactions between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patients”
Liver Transpl. (2004);10: pp. 939–944.
21. Spengler U, Lichterfeld M, Rockstroh J K, “Antiretroviral drug toxicity. A challenge for the hepatologist?”, J. Hepatol.
(2002);36: pp. 283–294.
22. Sulkowski M S, Thomas D C, “Hepatitis C in the HIV infected person”, Ann. Intern. Med. (2003);138: pp.
197–207.
23. Vittecoq D, Jardel C, Barthélémy C, Escaut L, Cheminot N, Chapin S et al., “Mitochondrial damage associated with
long-term antiretroviral treatment: associated or causal disorder?”, J. Acquir. Immune Defic. Syndr. (2002);31: pp.
299–308.
24. Sulkowski M S, Thomas D L, Mehta S H, Chaisson R E, Moore R D, “Hepatotoxicity associated with nevirapine or
efavirenz-containing antiretroviral therapy: role of hepatitis B and C infections”, Hepatology (2002);35: pp. 182–189.
25. Carr A, Cooper D A, “Adverse effects of antiretroviral therapy”, Lancet (2000);356: pp. 1,423–1,430.
26. Lafeuillade A, Hittinger G, Chadapaud S, “Increased mitochondrial toxicity with ribavirin in HIV/HCV coinfection”,
Lancet (2001);357: pp. 280–281.
27. Guyader D, Poinsignon Y, Cano Y, Saout L, “Fatal lactic acidosis in a HIV-positive patientys treated with interferon and
ribavirin for chronic hepatitis C”, J. Hepatol. (2002);37: pp. 289–291.
28. Neff G, Bonham A, Tzakis A, Ragni M, Jayaweera D, Schiff E R et al., “Orthotopic liver transplantation in patients
with human immunodeficiency virus and end-stage liver disease”, Liver Transpl. (2003);9: pp. 239–247.
29. Ragni M V, Belle S H, Im K, Neff G, Roland M, Stock P, Heaton N, Humar A, Fung J F, “Survival of human
immunodeficiency virus-infected liver transplant recipients”, J. Infect. Dis. (2003);188: pp. 1,412–1,420.
30. Duclos-Vallée J C, Vittecoq D, Teicher E, Feray C, Roque-Afonso A M, Lombes A, Jardel C et al., “Hepatitis C viral
recurrence and liver mitochondrial damage after liver transplantation in HIV-HCV coinfected patients”, J. Hepatol.
(2005);42: pp. 341–349.
31. Benhamou Y, Bochet M, Thibault V, Di Martino V, Caumes E, Bricaire F et al., “Long-term incidence of hepatitis B
virus resistance in human innunodeficiency virus-infected patients”, Hepatology (1999);30: pp. 1,302–1,306.
32. Benhamou Y, Bochet M, Thibault V, Calvez V, Fievet M H, Vig P et al., “Safety and efficacy of adefovir dipivoxil in
patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open label study”, Lancet (2001);358: pp.
718–723.
33. Benhamou Y, Tubian R, Thibault V, “Tenofovir disoproxil fumarate in patients with HIV and lamivudine-resistant
hepatitis B virus”, N. Engl. J. Med. (2003);348: pp. 177–178.
34. Markowitz J S, Martin P, Conrad A J, Markmann J F, Seu P, Yersiz H et al., “Prophylaxis against hepatitis B recurrence
following liver transplantation using combination lamivudine and hepatitis B immune globulin”, Hepatology (1998);28:
pp. 585–589.
35. Prachalias A A, Pozniak A, Taylor C, Srinivasan P, Muiesan P, Wendon P et al., “Liver transplantation in adults
coinfected with HIV”, Transplantation (2001);72: pp. 1,684–1,688.
36. Stock P G, Roland M E, Carlson L, Freise C E, Roberts J P, Hirose R, Terrault N et al., “Kidney and liver
transplantation in human immunodeficiency virus-infected patients: a pilot safety and efficacy study”, Transplantation
(2003);76: pp. 370–375.
37. Fung J, Eghtesad B, Patel-Tom K, DeVera M, Chapman H, Ragni M, “Liver transplantation in patients with HIV
infection”, Liver Transpl. (2004);10: pp. S39–S53.
38. Antoniades C, Macdonald C, Knisely A, Taylor C, Norris S, “Mitochondrial toxicity associated with HAART following
liver transplantation in an HIV-infected recipient”, Liver Transpl. (2004);10: pp. 699–702.
39. Alberti A, Clumeck N, Collins S, Gehrlich W, Lundgren J, Palu G, Reiss P et al., “Short statement of the first European
consensus conference on the treatment of chronic hepatitis B and C in HIV co-infected patients”, J. Hepatol. (2005);42:
pp. 615–624.
5
BUSINESS BRIEFING: EUROPEAN GASTROENTEROLOGY REVIEW 2005