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Liver transplantation in HIV-infected recipients
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Liver Transplantation
Volume 11, Issue 1, January 2005
Santiago Moreno 1 *, Jesús Fortún 1, Carmen Quereda 1, Ana Moreno 1, Ma Jesús Pérez-Elías 1, Pilar Martín-Dávila 1, Emilio de Vicente 2, Rafael Bárcena 3, Yolanda Quijano 2, Miguel García 3, Javier Nuño 2, Adolfo Martínez 4
1Department of Infectious Diseases, Liver Transplant Unit, Hospital Ramón y Cajal, Universidad de Alcalá de Henares, Madrid, Spain
2Department of Liver-Gastroenterology, Liver Transplant Unit, Hospital Ramón y Cajal, Universidad de Alcalá de Henares, Madrid, Spain
3Department of General and Digestive Surgery, Liver Transplant Unit, Hospital Ramón y Cajal, Universidad de Alcalá de Henares, Madrid, Spain
4Department of Anesthesiology, Liver Transplant Unit, Hospital Ramón y Cajal, Universidad de Alcalá de Henares, Madrid, Spain
Abstract
Liver transplantation is being evaluated as a therapeutic option for human immunodeficiency virus (HIV)-infected patients with end-stage liver disease, but experience is still scarce. We describe the outcome of 4 HIV-infected patients who underwent liver transplantation in our hospital between July 2002 and April 2003.
HIV-infected liver transplant recipients meet the same standard criteria for transplantation as do HIV-negative candidates. In addition, HIV infected persons are required to have a CD4 T-cell count greater than 100/mL (CD4 T-cells are targets for HIV infection). Immunosuppressive regimens, perioperative surgical prophylaxis, and prophylaxis for opportunistic infections are standard in the Liver Transplantation Unit in our hospital.
Four patients, including 3 former intravenous drug users, received a liver transplant (2 from deceased donors and 2 from living donors), with a median follow-up of 510 days. Three patients (75%) are alive, with 1 death occurring 17 months posttransplantation in a patient who developed fibrosing cholestatic hepatitis. Rejection occurred in 1 patient, and was managed with no complications. Hepatitis C virus (HCV) recurrence occurred in 3 patients. HIV-infection has remained under control with antiretroviral treatment. A combination of 3 nucleoside analogs was used in 3 patients, with no need for drug adjustments.
No opportunistic infections or other significant infectious complications developed. In conclusion, orthotopic liver transplantation seems a safe therapeutic option in the short term for HIV-infected persons with end stage liver disease, including patients with a history of drug abuse. If indicated, an antiretroviral regimen consisting of 3 nucleosides could be used to avoid interactions with immunosuppressive drugs.
AUTHOR DISCUSSION
Our experience expands previous observations of the safety of liver transplantation in HIV-infected patients with end-stage liver disease, and supports the consideration of these patients as candidates for transplantation when established criteria are fulfilled.
There has been, and there is still, significant concern on the indication of liver transplantation in HIV-infected subjects, based both in medical and ethical considerations.[19-21] The initial most important medical consideration was that immunosuppressive therapy used in transplantation could accelerate the progression of HIV disease and the development of opportunistic infections, even when potent antiretroviral drugs were available. A uniform result in all the published reports, including ours, has been the lack of significant opportunistic complications during the 1st year after transplantation, when the risk of severe infections is greatest. Moreover, adequate immunological and virological control has been the rule in most transplanted patients.[9-17] The response to antiretroviral therapy has been good if, as is usually required for HIV-infected patients who are considered candidates for transplantation, there are active drugs to be used. As in other reports, we observed a mild to moderate decrease in the CD4 count during the first 3 months after transplantation, which has not been associated with clinical deterioration and from which all the patients recover within the following few months.[12-17]
A second major cause of concern is the potential interactions between antiretroviral and immunosuppressive agents. Protease inhibitors and nonnucleoside reverse transcriptase inhibitors may induce or inhibit specific cytochrome P-450 enzymes and thus modify blood concentrations of tacrolimus, cyclosporine, and other drugs frequently used in transplant recipients.[22-26] These interactions, however, can be managed by monitoring plasma drug levels, and, although potentially dangerous, they do not pose a real problem in most centers. Nucleoside-analog reverse transcriptase inhibitors (NRTI) are not metabolized by the P-450 enzymes and do not have interactions with the immunosuppressive agents. For this reason, we have used the combination of 3 NRTI in 3 of our patients. Recent reports have shown that the combination of 3 NRTI are not as efficacious as regimens that include a protease inhibitor or nonnucleoside reverse transcriptase inhibitors when used as initial therapy.[27] Therefore, its use as initial therapy should be limited to situations where other regimens cannot be used.[28] However, regimens with 3 NRTI have been shown to be highly efficacious and as good as regimens including nonnucleoside reverse transcriptase inhibitors in patients with previously suppressed viral replication.[29] This simplification strategy could then be considered adequate and convenient for HIV-infected patients after transplantation. Regimens that include tenofovir plus 2 NRTI deserve special mention, since they have been shown to be associated with a high failure rate when used both as initial therapy[30][31] and as simplification regimens.[32] Thus, it has been recommended that they should be avoided in any circumstance.[28] Exceptionally, some patients who begin therapy with 1 of these regimens may have an adequate response, in which case therapy can be continued. That was the case for 1 of our patients, who was given a combination of tenofovir and 2 NRTI, and who is still on this therapy due to the good tolerance and suppression of HIV replication. It will be important to see if the good response can be maintained in the long run in this patient and in other patients.
Coinfection with HIV and HCV is frequently acquired together through parenteral drug use. The use of illicit drugs has also been considered as an additional barrier for liver transplantation in coinfected patients, arguing both medical and ethical reasons.[21] In Spain, most HIV infected patients who may become candidates for liver transplantation have been former intravenous drug users and so this is a crucial point in our transplant programs. Our experience, and that of other centers in our country, with liver transplantation in drug users who fulfilled the inclusion criteria has been good.[33] These patients are required not to have used drugs for at least 2 years, although they can be in a methadone maintenance program. A total of 3 of the 4 patients evaluated in this report were former drug users and 1 of them was in a methadone program. There has been no medical or nonmedical problems with these patients related with this particular practice.
Having reached this point, the main issue with liver transplantation in HCV-HIV coinfected patients remains the long-term outcome for the graft and the patient. There seems to be important differences in the outcome between HIV infected patients who are transplanted for alcoholic liver disease or HBV infection, and those transplanted for HCV infection.[12-17] The latter universally develop reinfection with HCV, which could have a more rapid progressive course.[34] HCV reinfection is also universal in HIV-uninfected individuals who receive a liver for HCV-related end-stage liver disease, but there are at least theoretical bases to suspect a more indolent course in this patient population.[35][36] Three of our patients had reinfection with HCV after transplantation and 1 of them developed a severe sclerosing cholestatic hepatitis with a fulminant course despite therapy with pegylated interferon and ribavirin. The only patient who was not reinfected with HCV was a patient with a triple infection with HBV, HCV, and hepatitis D virus, who had undetectable HBV and HCV plasma load before transplantation. The suppressive effect of hepatitis D virus on HCV and HBV replication has been described in patients with dual or triple viral infection, and persists after transplantation.[37][38]
In summary, as we are accumulating experience with liver transplantation in HIV-infected patients, initial medical concerns are being resolved. Opportunistic infection and drug interactions are manageable, and do not seem to condition a worse evolution during the 1st year after transplantation. A 3-nucleoside regimen may be used in patients with previously suppressed HIV RNA. Patients who acquired the infection through intravenous drug use, including those in a methadone maintenance program, may be suitable for transplantation. Thus, the procedure is safe to this point and is associated with a good survival. The long-term outcome is still to be established. Special attention should be paid to effective ways of avoiding the progression of recurrent HCV infection.
Article Text
Liver disease has become a leading cause of morbidity and mortality in patients with human immunodeficiency virus (HIV) infection. Several recent reports have shown that, after introduction of highly active antiretroviral therapy (HAART), end-stage liver disease is the leading cause of death among HIV-infected persons in some industrialized countries.[1-4] Although new combination therapies may cure a significant number of patients with compensated chronic hepatitis C,[5][6] no pharmacological intervention is effective in patients with decompensated liver disease. Only supportive care and transplantation may be offered to patients at these stages.
Until a few years ago, HIV infection was an exclusion criteria for organ transplantation. Understandably, the poor prognosis, with an almost unavoidable fatal outcome, of patients with HIV infection / acquired immunodeficiency syndrome precluded the consideration of these patients as candidates to be transplanted.[7] More recently, however, the significant increase in life expectancy of HIV-infected persons with HAART, coupled with the consequent increase in the number of these persons that face end-stage organ disease and advances in the transplantation field has led researchers to readdress the issue.[8]
In the HAART era, a number of isolated case reports and articles including short series of patients have described the short-term outcome of HIV-infected patients who have been recipients of kidney, liver, or heart trasplants.[9-17] The results are encouraging so far, but experience is still scarce and the follow-up of transplanted patients has been short. However, given the early phase of the experience with transplantation in the context of HIV infection, all reports may be significant to establish recommendations at this point.[18]
We describe the outcome of 4 HIV-infected patients who underwent liver transplantation in our hospital, including 2 patients with living-related donors. We emphasize the management of antiretroviral therapy in the face of immunosuppressive drugs and some of the peculiarities of these patients after at least 1 year of follow-up.
Materials and Methods
The Liver Transplantation for HIV Infected Persons Program was initiated in our hospital in July 2001. The 1st patient was transplanted on July 9, 2002, and the last on April 2, 2003. To be included in the program, all liver transplant recipients had to meet the same standard criteria for transplantation as did HIV-negative candidates. In addition, HIV infected persons were required to have a CD4 T-cell count greater than 100/mL (CD4 T-cells are targets for HIV infection), and plasma HIV ribonucleic acid (RNA) levels lower than 50 copies/mL. However, patients who did not fulfill the CD4 and viral load criteria were possibly eligible to be included in the program if they could not receive adequate antiretroviral therapy due to liver toxicity, and a complete virological suppression and immune reconstitution posttransplantation could be predicted by the caring physician based on the availability of active drugs for a particular patient. Patients were excluded if they had acquired immunodeficiency syndrome-defining opportunistic infections and neoplasia, with the exception of those that may have developed in the absence of significant immunosuppression (e.g., localized skin Kaposi's sarcoma or pulmonary tuberculosis), or if they were active consumers of alcohol or illicit drugs. Former intravenous drug users were possibly eligible for transplantation if they had not consumed drugs for at least 2 years, including those in methadone maintenance programs.
Antiretroviral therapy was given until the day of transplantation, when it was discontinued, to be reinitiated between the 3rd and the 5th day posttransplantation. There was no standard antiretroviral regimen administered. The regimens varied depending on the drugs the patients were taking before transplantation. In some patients, HAART regimens were modified to include drugs for which fewer interactions with immunosuppressive therapy are predicted. Usually, antiretroviral therapy consisted of 3 drugs to optimize viral suppression, in accordance with the current guidelines.
Immunosuppressive regimens were those routinely used at the Liver Transplantation Unit in our hospital. No significant modifications were made in the standard immunosuppression protocol. All patients received tacrolimus and steroids. In addition, patients receiving a graft from living donors received basiliximab.
Perioperative surgical prophylaxis and prophylaxis of opportunistic infections were also used according to standard transplant protocols.[19] Postoperative prophylaxis included ampicillin and cefotaxime during the 1st 48 hours and was prolonged to 5 days in patients with allograft dysfunction. During the hospitalization period, all patients received oral fluconazole, 100 mg, 1 time per day, as fungal prophylaxis. During the 1st 6 months, all patients received cotrimoxazole as Pneumocystis carinii prophylaxis, which was maintained until CD4 counts were greater than 200/mL. Cytomegalovirus prophylaxis (ganciclovir 5 mg/kg, 2 times per day for 14 days, followed by oral ganciclovir 1 gm, 3 times per day for 3 months) was given to seronegative recipients of seropositive donors. For the rest of the patients, preemptive cytomegalovirus prophylaxis guided by cytomegalovirus antigenemia (pp65) was used. Ganciclovir was administered to patients with cytomegalovirus antigenemia values higher than 15 positive cells per 200,000 leukocytes until antigenemia values fell to 0.
RESULTS
A total of 4 liver transplantations were performed in our hospital from July 2002 through April 2003. Two of the patients received a living-related orthotopic liver transplant, and 2 received an organ from deceased donors. Patient demographics and baseline characteristics are shown in Table 1. Three of the 4 patients were former intravenous drug users and 1 of them was in a methadone maintenance program. All the patients were infected with HCV, and, in addition, 1 patient was coinfected with the hepatitis B virus (HBV) and the hepatitis D virus. Two patients had received unsuccessful combination therapy with pegylated interferon and ribavirin for HCV infection prior to transplantation.
At the time this article was written, all of the patients had been followed for at least 1 year (432, 480, 510, and 532 days, respectively). The 1st patient developed a severe histological recurrence of HCV 6 months after the procedure. Liver biopsy showed a pattern of severe sclerosing cholestatic hepatitis, and there was a marked increase in serum bilirubin (32 mg/dL) and HCV RNA (>2 × 106 IU/mL). A course of pegylated interferon plus ribavirin was initiated, with significant improvement in biochemical parameters (bilirubin levels fell to 2 mg/dL), but the patient discontinued therapy after 7 months due to poor tolerance (i.e., anemia, severe depression) with progressive worsening of liver function and death 17 months after liver transplantation. The other 3 patients remain alive. Biopsy-proven rejection was diagnosed in 1 patient, who was the recipient of a living donor transplant. The rejection episode was managed by increasing tacrolimus doses. Steroid boluses were not required.
Infectious complications were surprisingly low in our patients. One patient had positive cytomegalovirus antigenemia, which was treated with a 2-week course of intravenous ganciclovir with good response. The 2 patients with living donor grafts developed episodes of cholangitis. Noninfectious complications included biliary fistula in 2 patients, and diabetes that required insulin and a change from tacrolimus to cyclosporin A in 1 patient. Closure of the biliary fistula was delayed until months 3 and 12, respectively.
Three of the 4 patients developed recurrence of HCV at months 1, 2, and 6 after transplantation, respectively. HCV RNA plasma levels in the recurrence ranged from 2 × 103 to 4 × 106 IU/mL. Only 1 patient (patient 1), who developed fibrosing cholestatic hepatitis, received a course of anti-HCV combination therapy with pegylated interferon alpha 2b plus ribavirin. The only patient who did not develop recurrence of HCV was a 36-year-old female who was coinfected with HCV, HBV, and delta agent. Before transplantation, she had undetectable plasma HBV deoxyribonucleic acid as well as undetectable HCV RNA. She had been treated with lamivudine as a component of her antiretroviral regimen for the last 6 years. Since transplantation, she has received hepatitis B immunoglobulin. She continues on monthly hepatitis B immunoglobulin prophylaxis and lamivudine plus tenofovir, and her HBV and HCV viral load remain undetectable.
Plasma HIV RNA has remained undetectable in all the patients. Only patient 1 had a rebound of viral load prior to his death, when HAART was discontinued. A triple nucleoside regimen was chosen in 3 patients due to the low risk of interaction of these drugs with immunosuppressive agents. One of the patients was initiated with a combination of tenofovir, abacavir, and lamivudine. Results from a clinical trial advised against this combination due to an extremely high rate of virological failure. Since the patient had undetectable viral load, with good tolerance and no significant interactions, he was maintained with the same regimen, with close follow-up. The other 2 patients with nucleoside analog-based therapy were switched to their current regimens after having an undetectable viral load with other drugs. They have remained on their initial regimens with adequate virological control and with no need for dose adjustments of antiretroviral or immunosuppressive drugs. The remaining patient continued on a nelfinavir-based regimen that he was receiving prior to transplantation; he required an important reduction of tacrolimus dose and was managed by monitoring plasma drug levels.
CD4 counts have remained stable in the 1st year posttransplant. There was a significant decrease immediately posttransplant, with CD4 counts below 200/mm3 in all the patients. Immunological recovery began at month 3 and persisted, although slowly, during the 1st year. Despite the nadir of CD4 T lymphocytes and the slow recovery, no acquired immunodeficiency syndrome-defining or other opportunistic infections have been seen in these patients.
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