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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