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Liver Transplantation Update for HIV & IVDUs
 
Reported by Jules Levin
 
  The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients
 
Solid organ transplantations have been performed successfully in selected HIV-positive patients with highly active antiretrovirus therapy (HAART). However, some of the medications in the HAART regimen require metabolism via the cytochrome P4503A, the same enzyme complex responsible for clearance of the calcineurin inhibitors cyclosporine and tacrolimus. Several case reports have described significant interactions between the agents used in HAART and immunosuppressive drugs. The goal of this report is to examine the extent of potential drug interactions between antiretroviral agents and tacrolimus after liver and kidney transplantation. Seven liver transplant (LTx) patients (M = 6, F = 1) and four kidney transplant (KTx) patients (M = 4) infected with HIV underwent surgery between September 1997 and January 2001. Initial immunosuppression consisted of tacrolimus and steroids for LTx patients or tacrolimus, steroids, and mycophenolate mofetil for KTx recipients. Their current baseline immunosuppression and HAART regimen were examined retrospectively. Of the seven liver recipients, one (case 4) died 2 weeks after LTx and never received HAART therapy posttransplantation. The remaining six patients were placed on a regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTI) and one protease inhibitor (PI) (nelfinavir in 5, indinavir in 1) based on known viral sensitivities or history of a previous clinical response. Kidney recipients received NRTI and nonnucleoside reverse transcriptase inhibitors (NNRTI). The mean dose of tacrolimus in liver recipients was 0.6 mg/d, with mean trough concentration of 9.7 mg/mL. Compared with historic controls (liver transplant patients not on HAART), the average tacrolimus dose was 16-fold lower in patients on HAART. In contrast to liver recipients, HIV-positive kidney recipients not on PI therapy required a mean tacrolimus dose of 9.5 mg/d to maintain a mean trough concentration of 9.6 ng/mL. Of the two protease inhibitors used, nelfinavir seems to have a more profound effect than indinavir. When patients on nelfinavir alone (n = 5) were compared with a control group not on antiretroviral therapy, the need for a tacrolimus dose was 38 times lower (mean dose, 0.26 mg/d). Profound drug interactions between PI and tacrolimus have been observed requiring up to 50-fold reductions in dosage. This effect seems to be most pronounced with the use of nelfinavir as opposed to indinavir, although further experience is required to confirm this observation. In contrast, HAART using NRTI and NNRTI without the use of PI, as shown in kidney recipients, produces less significant effects on tacrolimus metabolism. Great caution and frequent drug level monitoring are necessary when HAART is introduced or withdrawn in HIV-positive recipients of organ transplants. (Liver Transpl 2002;8:841-845.)
 
Nelfinavir, a protease inhibitor, increases sirolimus levels in a liver transplantation patient: A case report
 
With the increasing success of liver transplantation and the proven effectiveness of highly active retroviral therapy in HIV-positive patients, liver transplantation has been performed successfully in selected HIV-positive recipients with CD4 and an HIV viral load response to highly active antiretroviral therapy. In these patients, an interaction between a protease inhibitor (nelfinavir) and tacrolimus has been shown. The effect of nelfinavir on the pharmacokinetics of sirolimus, a newer immunosuppressive drug, is currently not known. The goal of the present case report is to document the interaction between sirolimus and nelfinavir in a liver transplantation patient. A 40-year-old woman who was HIV positive underwent a cadaveric liver transplantation for acute fulminant liver failure secondary to nevirapine (a nonnucleoside reverse transcriptase inhibitor). Postoperatively, she was treated with tacrolimus and steroids. She experienced steroid-resistant rejection and was started on sirolimus on the 17th postoperative day. Kinetic parameters were determined after a 2-mg oral dose of sirolimus and 250 mg of nelfinavir by collecting multiple peripheral venous blood samples before and after sirolimus administration. The kinetic parameters were compared with parameters from three liver transplantation patients on sirolimus who were not on nelfinavir. After normalizing the kinetic parameters to sirolimus dose of 1 mg/d, 0-hour and 24-hour trough sirolimus concentrations were nine-fold and five-fold higher for the patient who was on nelfinavir, compared with those who were not on nelfinavir. The maximum concentration was 3.2 times higher, the area under the concentration curve was 1.6 times higher, and the terminal disposition half-life was prolonged by 60%. The time to reach the peak concentration was 1 hour in all patients. Increase in trough concentration, peak concentration area under the curve concentration, and prolongation of half-life of sirolimus has been shown in a patient who was on a low dose (one fifth the recommended dose) of nelfinavir. The authors concluded that even with one fifth of the recommended dose of nelfinavir, a nine-fold increase in sirolimus trough concentration, three-fold increase in peak concentration, and 60% increase in area under the concentration curve 0 to 24 hours has been observed in a liver transplantation patient, compared with patients who were not on nelfinavir. Caution is suggested when these drugs are used together until additional kinetic studies are performed and a better understanding of the interaction between the agents emerges. (Liver Transpl 2002;8:838-848.)
 
Liver transplantation for patients on methadone maintenance
 
Most transplant programs require abstinence of at least 6 months from alcohol and illicit drugs before orthotopic liver transplantation (OLT). However, there are no published data regarding OLT outcomes in patients who are currently on methadone maintenance treatment (MMT) as part of the treatment of their heroin addiction at the time of OLT. The objective of this study is to evaluate our experience regarding the outcome of OLT in patients with end-stage liver disease (ESLD) who were on MMT at the time of OLT. Between March 1993 and May 1999, a total of 185 patients with ESLD underwent OLT at our center. Five transplant recipients (2.7%) had a history of heroin abuse and had undergone drug and alcohol rehabilitation, but could not be weaned off methadone. Pre-OLT status, drug history, perioperative course, compliance with medical therapy, post-OLT follow-up, and patient and allograft survival were analyzed in detail in these patients. All patients on MMT underwent uneventful OLTs. Their compliance with medications and follow-up was excellent. One patient was weaned completely off methadone after OLT. Post-OLT mean hospital stay in this group was 43 25 days. Although the number of patients was small, long-term outcome of liver transplant recipients on MMT appears similar to that of patients not on MMT who underwent OLT during this period. Our results suggest cirrhotic patients on MMT should be considered for OLT if they meet the same psychosocial requirements as patients with alcohol abuse. Furthermore, it is not necessary for patients to be weaned off methadone before OLT. (Liver Transpl 2002;8:778-782.)
 
EDITORIAL: Methadone is a medication, not an addiction (authors: Monica Koch and Peter Banys)
 
Methadone is a medication, not an addiction. Although methadone is most certainly an opioid that can produce physical dependence, its use by MMT patients is not best conceptualized as an addiction, but as a replacement medication. It is difficult to get high on it, it is not injectable, and the evidence for its long-term efficacy is overwhelming. Properly prescribed methadone is neither intoxicating nor sedating. It does not impair motor activities such as driving. Methadone suppresses narcotic withdrawal and drug craving for 24 to 36 hours, but patients still perceive pain and have emotional reactions. Adequate doses, usually above 60 mg per day, competitively block heroin effects and make "chipping" a waste of time and money. Above all, when used in a structured treatment program, it leads to greatly improved social functioning and not to the impaired functioning associated with heroin use.
 
MMT patients should not be excluded from transplant consideration. Methadone should not be a proxy for other kinds of psychosocial evaluations. Psychosocial factors remain important in eligibility assessment, but many methadone maintenance patients meet criteria for adequate psychosocial support. By complying with the very stringent rules of methadone programs, they have shown their capacity to comply with complex requirements to an extent that can rarely be matched by other transplant candidates. Requiring abstinence from illicit substances before transplant is likely to increase compliance and stability and has been shown to be an acceptable prerequisite. Belle et al report that criteria for recipient and donor selection change as centers gain experience. It seems important to distinguish between MMT patients who have turned their lives around from those who continue to use other illicit drugs, participate in criminal or antisocial activities (such as domestic violence), and remain psychosocially unstable. It is important that methadone not be considered a proxy for these aspects of a psychosocial evaluation. In our opinion, there are many MMT patients who should not be qualified for waiting lists because of chaotic, criminal, drug-using lifestyles or other psychosocial factors. Rather, it is that these factors need to be assessed in their own right. Mandatory discontinuation of methadone should not be required. Discontinuation of methadone, particularly when unsupported by a residential treatment program such as a therapeutic community, is very likely to produce heroin relapse in previously stable patients and thus disqualify them for transplantation. The American Society for Addiction Medicine position paper of 1990 states, "for the majority of opioid dependent patients, methadone maintenance is the most effective long term modality. Withdrawal from methadone carries a substantial risk associated with relapse to intravenous drug use. Withdrawal should only be attempted when strongly desired by the patient and with adequate supervision and support."
 
The 1997 NIH consensus statement reports that "it is now generally agreed that opiate dependence is a medical disorder and that pharmacologic agents are effective in its treatment" and "continuity of treatment is crucialand most, if not all, patients require continuous treatment over a period of years, and perhaps for life."
 
An evidence base needs to be developed for MMT patients who undergo transplantation. The experience with alcohol dependent patients shows that substance abuse disorders per se are no reason for exclusion for liver transplants. The implicit assumption that substance abusers will be noncompliant or will simply relapse remains prevalent. It is also possible that judgments of social value, which occurred in the alcoholic population, are even more salient in the opiate addicts. They have a higher likelihood of criminal history, lower social status, unemployment, and antisocial behaviors. It is, of course, entirely possible that these patients are at higher risk for noncompliance, as it was possible that alcoholics would resume drinking after transplant. At this point, however, these reservations remain speculative and have no supporting evidence in the literature. On the contrary, the few available reports, including the small sample reported in this issue, indicate that outcomes for MMT patients are no different than those fo the rest of the population.
 
Studies are needed to examine several kinds of outcomes-tolerance levels for opioid analgesics postoperatively, medication compliance, misuse of opioid analgesics, long-term graft outcomes, and overall compliance with medical regimens. Because most of these patients will have liver failure caused by hepatitis C, outcomes for MMT patients need to be compared with other cohorts of similarly infected patients.
 
 
 
 
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