Need for liver transplant in HIV-positive patients: first results of a specific survey in Italy, Project HOST
Costigliola, Paolo; Tumietto, Fabio; Zagnoli, Alessandra; Chiodo, Francesco; for Project HOST
Department of Clinical and Experimental Medicine, Section of Infectious Diseases, University of Bologna, Bologna, Italy.
Sponsorship: This work was supported by grant no. 30D.23 (Programma Nazionale di Ricerca sull'AIDS), Istituto Superiore di Sanità, Rome, Italy.
Received: 30 January 2003; revised: 14 April 2003; accepted: 7 May 2003.
From 38 Italian infectious disease units, 135 HIV-positive patients with at least Child A grade cirrhosis were enrolled, to simulate a waiting list for liver transplantation. Clinical data were collected in order to calculate the Child–Turcotte–Pugh score, apply general exclusion criteria, gather united network organ sharing stratification criteria, and evaluate HIV clinical status. HIV infection selection criteria have great strength in reducing HIV-positive patients suitable for liver transplants and could be carefully considered when planning experimental protocols.
HIV infection has generally been considered an absolute criterion of exclusion for solid organ transplantation (SOT), which is well known to be the treatment of choice for the majority of end-stage organ diseases. Before highly active antiretroviral therapy (HAART), the main reason for exclusion was that individuals with HIV had a short lifespan, and in light of the shortage of organs, the utility of recipient survival should also be taken into account. Another reason for exclusion is the potential risk of progression of HIV infection, in the uncertainity of viral replication under iatrogenic immunosuppression used to prevent rejection.
This risk was frequently present in anecdotal experiences of the pre-HAART era [1,2]. However, this argument seems to be overcome by the advent of HAART combinations and the demonstration of a certain antiretroviral activity of several immunosuppressive agents .
Project HOST (HIV organ sharing and transplantation) is a national multicentric open study designed to evaluate several aspects close to the emerging issue of SOT for HIV-positive individuals. Particular aspects include: the incidence of end-stage organ diseases in HIV-positive individuals (HOST 1); the need for organs (HOST 2); a planning strategy to expand the pool of organ donors (so-called high-risk donors) (HOST 3); an evaluation of the outcome of the patients with HIV infection on the list (HOST 4); the monitoring of the pre and posttransplant phases (HOST 5); and the definition of specific guidelines regarding selection and clinical management (HOST 6).
HOST involves a high percentage of Italian infectious diseases units, which periodically report the cases of end-stage renal disease or cirrhosis occurring in HIV patients. Each centre provides simplified forms on which data regarding HIV infection (virological and immunological status, therapy, AIDS-defining illness, prophylaxis) and end-stage organ disease are collected.
From September 2001 to September 2002, 38 Italian centres of infectious diseases have taken part in the research, mostly in the middle and north of Italy.
The data received have been collected in an electronic database. Each reported patient has been listed, simulating a virtual waiting list for liver transplantation, according to the Child–Turcotte–Pugh score and united network organ sharing (UNOS) classification, which are the actual stratification criteria for waiting lists in Italy.
A further stratification of the virtual list based on clinical, immunological and virological parameters of HIV infection has been applied. From this point of view, patients have been selected on the basis of two arbitrary values: HIV-RNA level (< 50 copies/ml–undetectable or < 1 × 104 copies/ml) and CD4 cell count (> 200 or 350 cells/mm3).
The analysis has been conducted on the first 135 records for cirrhosis.
Intravenous drug addiction was the main risk for HIV infection, and hepatitis C virus infection represented more than 90% in aetiology.
Only 71 out of 135 patients (52.6%) met the UNOS listing criteria. The application of general clinical criteria of exclusion, alcohol and drug addiction, methadone treatment and AIDS-defining diseases reduced the number of patients to 27 (20%). Only one patient was listed in status 2A, 10 in status 2B, and 16 in status 3.
In the group of patients listed in status 2B, the adjunctive criteria based on immunological and virological status (CD4 cell count > 200 or 350 cells/mm3 and the HIV-RNA level) reduced the number of listed patients to eight (CD4 cell count > 200 cells/mm3; 5.9%) or five (CD4 cell count > 350 cells/mm3; 3.7%). Matching the CD4 cell count with the viral load determines a further reduction of the sample. Only four patients remained in status 2B, with a CD4 cell count greater than 200 cells/mm3 and HIV-RNA level less than 1 × 104 copies/ml, and two with an undetectable HIV-RNA level, but only two patients remained in status 2B with a CD4 cell count greater than 350 cells/mm3 and HIV-RNA level less than 1 × 104 copies/ml, and only one patient remained with a CD4 cell count greater than 350 cells/mm3 and an undetectable HIV-RNA level. The application of these two variables did not allow us to maintain patients in status 2A. The stand-by status (UNOS 7) comprised 19 or 22 patients, respectively.
In the HAART era, end-stage organ diseases (mainly of the kidney and the liver) have become the pressing quality of life and life-threatening issues for these patients. This is a result of the good multi-chemotherapeutic control of the clinical progression of HIV infection, which allows the progression of other latent infections and related damage to the liver (i.e. hepatitis C virus or hepatitis B virus), or the progression of other chronic diseases, as well as end-stage renal disease. Observing the ineluctable increase in the mortality rate for end-stage liver diseases, some authors proposed a re-evaluation of the reasons for the historical exclusion of HIV-positive individuals from transplant programmes [4–6].
Research conducted in the mid-1990s demonstrated that the use of the main immunosuppressive drugs that were actually available (cyclosporine A, tacrolimus, mycophenolate mofetil) was not an additional risk for an immunocompromised host, such as an HIV-positive individual [3,7]. Furthermore, existing protocols for SOT in HIV-positive individuals have clearly identified the interactions between antiretroviral and immunosuppressive drugs.
One of the emerging issues of SOT for HIV-positive patients is the unknown impact that the enrolment of these patients in normal liver transplant lists could have on waiting times. Our virtual waiting list for liver transplantation showed that by selecting patients with an optimal HIV-related condition (CD4 cell count > 350 cells/mm3) no individuals on UNOS status 2A were available, but five on UNOS status 2B and eight on UNOS status 3 (Child–Turcotte–Pugh score > 7) were. If we consider this good immunological pattern (CD4 cell count > 350 copies/mm3), only one patient showed an undetectable viral load, therefore reducing the risk of a supposed hard impact on a liver waiting list opened to HIV-positive patients with end-stage liver disease. Considering only this pattern (undetectable HIV-RNA level and CD4 cell count > 350 cells/mm3), four patients were on status 3 and 22 were on stand-by (UNOS 7).
These preliminary results seem to indicate that it is more than possible to determine a subgroup of patients with HIV infection who can be effectively evaluated for transplant in terms of a low risk of HIV progression towards AIDS and sufficient immune function. In addition, the experimental protocol ongoing in the United States discriminates against patients also on the basis of a lower CD4 cell count, considering patients eligible for kidney transplant with a count not lower than 200 cells/mm3, and not lower than 100 cells/mm3 for liver transplant. Our simulation is based on the selection of a smaller number of patients with better immunological and virological conditions, and it could be a good requirement in this new clinical challenge, considering previous reports [1,2].
However, more strict criteria based on HIV-related parameters could lead to a smaller number of candidates for orthotopic liver transplantation. This effect should be considered when defining entry criteria for experimental protocols, but more carefully in writing specific guidelines with regard to open waiting lists for including HIV-positive patients.
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Appendix: HOST Group
Gabriella Verucchi, Bologna, Italy; Evagelista Sagnelli, Cesare Nacca, Caserta, Italy; Alessandro Stagno, Stefano Brighi, Cesena, Italy; Elio Pizzigallo, Jacopo Vecchiet, Chieti, Italy; Gioacchino Angarano, Annalisa Saracino, Foggia, Italy; Alfredo Scalzini, Giorgio Perboni, Mantova, Italy; Adriano Lazzarin, Caterina Uberti Foppa, Milano, S. Raffaele, Italy; Roberto Esposito, Giovanni Guaraldi, Modena, Italy; Carlo Ferrari, Anna Degli Antoni, Parma, Italy; Lorenzo Minoli, Federica Poletti, Pavia, Italy; Giuliano Stagni, Francesco Di Candilo, Perugia, Italy; Francesco Alberici, Alessandro Ruggieri, Piacenza, Italy; Tiziano Zauli, Davide De Donà, Ravenna, Italy; Giacomo Magnani, Maria Alessandra Ursitti, Reggio Emilia, Italy; Massimo Arlotti, Andrea Boschi, Rimini, Italy; Vincenzo Vullo, Serena Dell'Isola, Roma, Pol. Umberto I, Italy; Fabio Branz, Nicoletta Dorigoni, Trento, Italy; Alberto Vaglia, Maria Cristina Rossi, Treviso, Italy; Paolo Grossi, Roberto Tambini, Varese, Italy; Paolo Fabris, Elena Pignattari, Vicenza, Italy; Enzo Raise, Pierangelo Chinello, Venezia, Italy; Peter George Stock, Transplant Division, Department of Surgery, University of California, San Francisco, USA; Lorenza Ridolfi, Regione Emilia Romagna, Centro Riferimento Trapianti, Italy.
© 2003 Lippincott Williams & Wilkins, Inc.