The difficulty in timing for liver transplantation in cirrhotic patients coinfected with HIV: In search for a prognosis score

Authors

  • Didier Samuel,

    Corresponding author
    1. Centre Hépatobiliaire Unite INSERM-Paris XI 785, Hôpital Paul Brousse, Villejuif, France
    • Centre Hépatobiliaire, Unité INSERM-Paris XI 785, AP-HP, Hôpital Paul Brousse, 14 av Paul-Vaillant Couturier, 94800, Villejuif, France
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    • Telephone: 33-1-45 59 34 03; FAX: 33-1-45 59 38 57

  • Jean-Charles Duclos-Vallee

    1. Centre Hépatobiliaire Unite INSERM-Paris XI 785, Hôpital Paul Brousse, Villejuif, France
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  • See Article on Page 801

The development of liver transplantation in human immunodeficiency virus (HIV) infected patients has created a new challenge in the field of liver transplantation.1 Liver transplantation has been considered, until recently, as a contraindication in HIV-infected patients.2 The main concern was the risk of HIV progression after liver transplantation, and as a consequence, a poor posttransplant survival and a waste of grafts. Recently, the outcome of HIV infection has been dramatically improved following the advent of highly active antiretroviral therapy (HAART) against HIV. Most HIV-infected patients now have a good long-term survival prognosis. However, 10% to 30%, respectively, of HIV-infected patients are coinfected with hepatitis C virus (HCV) or hepatitis B virus (HBV). This rate of coinfection is linked with the type of transmission. The coinfection with HCV is more frequent in patients transmitted through intravenous drug addiction, while the coinfection with HBV is more frequent in patients transmitted through sexual intercourse. The common aspect of both types of coinfections is the accelerated clinical course of hepatitis B and C in these coinfected patients.3–7 In some cohorts of HIV-infected patients, the main causes of death are liver failure and hepatocellular carcinoma.8, 9 For these reasons, several centres in the world have developed a liver transplantation program for HIV-infected patients.10–14 This new indication of liver transplantation raised several questions: What is the ideal timing for liver transplantation in HIV-HBV and HIV-HCV cirrhotic patients? What is the risk of HIV progression after liver transplantation? What is the interaction between calcineurin inhibitors and protease inhibitors? What is the risk of liver toxicity of the HAART? What is the risk of HBV or HCV recurrence after liver transplantation? The first reported results of liver transplantation in HIV-coinfected patients gave us some important information. The results of liver transplantation for HIV-HBV patients and for HIV-HCV infected patients are different. In HIV-HBV infected patients, the risk of HBV recurrence after transplantation is low using post-transplant combination prophylaxis with anti-HBs immunoglobulin (HBIG) and nucleos(t)ide analogues. The combination of HBIG plus lamivudine and/or tenofovir is very effective, with a risk of HBV recurrence below 10%. For this reason, patient and graft's survival appeared excellent and not different from that of HBV monoinfected patients.14 In contrast, the recurrence of HCV infection after liver transplantation is a major issue in HIV-HCV infected patients.12, 14 The first reports have shown universal graft reinfection with HCV, a particular severe course of HCV graft infection in some patients, and a lower patient survival rate after transplantation than in monoinfected HCV patients.10,14 Although this has not been clearly demonstrated, it seems that the HCV recurrence is more severe in HIV–HCV infected transplant patients than in monoinfected HCV transplant recipients. The severity of HCV recurrence seems to be related to a more rapid progression of fibrosis on the graft and to a higher rate of cholestatic hepatitis. The role of viral factors such as post-transplant serum and liver HCV RNA levels, quasispecies distribution, and of non-viral factors such as graft steatosis, age of the donor, and host immune response are under investigation.

The question discussed by the paper of Terrault et al. in this issue of the Liver Transplantation is the timing for liver transplantation in HIV-HBV coinfected patients.15 Terrault et al. reported that among 35 HIV-HBV coinfected patients referred for liver transplantation between 2000 and 2002, nine (26%) were listed, 10 (29%) were not listed due to contraindications (HIV-related: three; ongoing substances abuse: five; HCC: two), nine (26%) were referred too early for LT, three (9%) not listed as too sick, and four (11%) died during the evaluation process. Of the nine listed patients, four remained listed, one died 18 months post-referral and four (11% of the total) were transplanted. Thus at the end, 7/35 (20%) of evaluated patients and 7/26 (27%) (Excluding nine too early for LT) of potential candidates for transplantation died before transplantation could be performed. The conclusions of the authors was that the death rate was higher in potential HIV-infected candidates than in non-HIV-infected patients, and that patients were referred too late to their liver transplant centre. In addition, the authors noticed that the MELD score was of 14 in both survivors and non-survivors groups suggesting that the MELD score was not accurate to predict death during the waiting time period for liver transplantation in this population in contrast to the non-HIV cirrhotic population.16 This series is small and retrospective; however the message delivered by the authors is important. We have reported in our personal series of HIV-HBV and HIV-HCV coinfected cirrhotic patients, that 25% of the potential candidates for liver transplantation died either on the waiting list or during the evaluation process due to progression of liver failure and of hepatocellular carcinoma, this death rate were higher than that of non-HIV infected patients (10%).17 The cause of death was, in some cases, clearly due to a late referral. This is in particular to the cases of the patients who died a few days or weeks after the first day of transplant referral. The reason for this is that liver transplantation is a new option for these patients and the referral of HIV-infected patients to a liver transplant centre is still not a common practice among physicians caring for HIV-infected patients. This also reflects that some physicians caring for HIV-infected patients are not experts in liver disease management or in liver transplantation. A particular effort should be made to inform physicians caring for HIV patients of the possibility of liver transplantation in this patient population and the importance of a prompt referral to liver transplantation centers. The other aspect to be underlined is the lack of an accurate prognostic index in HIV-infected cirrhotic patients. In the paper of Terrault et al.15 the MELD score at admission was identical in surviving and non-surviving patients, suggesting that the MELD score is not an accurate prognostic marker for short-term survival in this population. The value of the MELD score in this specific population should, however, be studied in larger series of HIV-HBV and HIV-HCV coinfected cirrhotic patients before drawing any definitive conclusion. It is true that some HIV-infected cirrhotic patients have an extremely rapid course after the first episode of decompensation, while some others have a slower course. HCC seems to have a very aggressive course in some HIV patients. It has been recently shown that survival is dramatically poorer in HIV-HCV infected cirrhotic patients after the first episode of decompensation than in non-infected HIV patients.8,18 Pretransplant survival is shorter in HIV-positive than HIV-negative subjects with end-stage liver disease. These studies and others show an accelerated course of HIV-HBV and of HIV-HCV infected cirrhotic patients suggesting that the usual prognosis scores such as the MELD and the Child-Pugh scores are inaccurate to predict survival in this population. They also suggest that HIV cirrhotic patients should be referred to liver transplant centres at an earlier stage than non-HIV cirrhotic patients. For all these reasons, studies individualizing factors of poor prognosis in HIV cirrhotic patients are mandatory.

In their paper, Terrault et al. also pointed out the problem of HBV resistance to lamivudine (LAM) prior to transplantation in the HIV-HBV coinfected population. Lamivudine-resistant HBV infection was present in 67% of the patients referred to liver transplantation. In contrast, HBV recurrence post-transplantation was well prevented by the post-transplant combination of HBIG plus lamivudine/tenofovir. The problem of HBV resistance to lamivudine is an important issue that is well addressed by the first European Consensus Conference on the treatment of chronic hepatitis B and C in HIV coinfected patients.19 Lamivudine is an effective drug against HIV and was historically used first against HIV before being used against HBV. For this reason, many HIV-HBV infected patients treated with lamivudine have developed HBV resistant infection to lamivudine.20 The presence of HBV resistance to lamivudine at time of transplantation is a potential risk for HBV recurrence after transplantation despite the use of HBIG + lamivudine post-transplantation.21 In addition, the emergence of HBV resistance to lamivudine in a cirrhotic patient can be associated with the occurrence of severe liver failure that can be potentially fatal. For all these reasons, it seems essential to avoid the emergence of HBV mutation in HBV-HIV cirrhotic patients. Fortunately, the advent of adefovir and tenofovir, 2 nucleotide analogues effective against HBV lamivudine resistant strains, give new therapeutic options in the management of these patients.22,23 The current strategy recommended in HIV-HBV infected patients is to use the combination lamivudine plus adefovir in those patients who do not require a specific treatment against HIV, while the combination lamivudine (or emtricitabine) plus tenofovir is recommended in patients who need an antiviral treatment effective against both HBV and HIV.19 Anyway, in HBV-HIV coinfected cirrhotic patients, it is important to discuss a priori with the transplant physician, which anti-HBV treatment should be given.

In conclusion, liver transplantation for HIV patients is an emerging field with good preliminary results in HIV-HBV infected patients and pending results in evaluation for HIV-HCV patients. The death rate on the waiting list seems higher in the HIV-infected cirrhotic population, raising the question of the ideal timing for liver transplantation. Informing physicians caring for HIV-HBV and HIV-HCV coinfected patients on the management of HBV and HCV infections and the need of prompt referral for liver transplantation are mandatory. This should stimulate discussions among hepatologists, transplant physicians and HIV specialists regarding the optimal timing for liver transplantation and the choice of HAART in HIV-HBV infected patients in order to avoid the deleterious emergence of a HBV mutant virus. Thus, the management of HIV cirrhotic patients before and after liver transplantation requires a multidisciplinary approach.

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