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Liver Transplantation in HIV
 
 
  Below are 2 articles discussing interactions between HAART medications and the drugs required for immunosuppression to perform the transplant. The first article below also repors on the outcomes and followup of 7 liver transplant patients and 4 kidney transplant patients, all who had HIV. The transplants were performed between 1997 and 2001. The authors discuss the viability of conducting transplants. It is accepted today that liver transplants in HIV-infected individuals can be successfully performed. But there are several bariers for patients. Insurance reimbursement is not easily forthcoming. There is a shortage of donor livers and HIV-infected individuals, persons who used alcohol, and IVDUs may receive lower priority. One way to overcome the organ donor shortage is to request that people authorize the use of their organs for transplantation after they die. But this has been very controversial.
 
The problem of coinfection with HIV and hepatitis receives little attention and funding support. These problems include the need for programs addressing testing and counseling, vaccinations for hepatitis A and B, access to treatment for hepatitis, patient and provider education, and reimbursement. But HCV and associated liver disease is the leading cause of death in HIV. Where's the money!!
 
Larry Kramer is a well known AIDS activist of long-standing who recently received a successful liver transplant, he had hepatitis B and HIV. He tells his story here:
 
My New Liver
http://www.natap.org/2002/Oct/102102_2.htm
 
In this article by Larry he discusses the need for consent by individuals to provide their organs after death, and the controversy surrounding this:
 
Liver Transplants: we must have presumed consent
http://www.natap.org/2002/Oct/102102_1.htm
 
The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients
 
Liver transplantation, Sept 2002, V 8, number 9. Authors: Ashok Kumar B. Jain et al including John Fung, Margaret Ragni, and Thomas Starzl. From the Department of Surgery, Department of Pharmaceutical Sciences, Department of Pathology, and Department of Medicine, Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA.
 
The increasing success of liver and kidney transplantation has led to a broadening of their indications. In selected HIV-positive patients, liver and kidney transplantation have been successfully performed. This requires continued use of highly active antiretrovirus therapy (HAART) after transplantation along with careful immunosuppressive management. As with other liver and kidney recipients, HIV-positive patients typically receive calcineurin inhibitors (cyclosporine or tacrolimus), which are primarily eliminated by cytochrome P450 3A (CYP3A)-mediated metabolism. They also receive a HAART regimen that usually consists of a combination of nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zalcitabine, and so on), protease inhibitors (indinavir, nelfinavir, saquinavir, ritonavir), and/or nonnucleoside reverse transcriptase inhibitors (delavirdine, efavirene, nevirapine, zidovudine). Several of the antiretroviral agents have significant drug-drug interactions. There have been a few case reports documenting the interaction between immunosuppressive drugs and antiretroviral agents. Here we report a drastic reduction in the dose of tacrolimus that was necessary in HIV-positive transplant patients who were on concomitant antiretroviral therapy that included protease inhibitors. In contrast, the HIV-positive transplant patients who were on antiretroviral therapy that did not include protease inhibitors received conventional doses of tacrolimus.
 
Between September 1997 and January 2001, seven HIV-positive patients underwent orthotopic liver transplantation (OLTx) for end-stage liver failure and four patients underwent kidney transplantation. All received tacrolimus-based immunosuppression. The liver transplant patients received 1 g methylprednisone on reperfusion of the liver and a 600-mg methylprednisone taper over the next 6 days. Kidney transplant patients also received mycophenolate mofetil. Trough tacrolimus blood concentrations were measured in all the patients by a microparticulate enzyme immunoassay using the IMx analyzer (Abbott Laboratories, Abbott Park, IL). In liver transplant patients, trough tacrolimus concentrations were maintained between 12 to 15 ng/mL during the first month, 10 to 12 ng/mL during the second and third months, 8 to 10 ng/mL during the third to sixth months, and 6 to 8 ng/mL after 6 months posttransplantation. Kidney transplant patients were maintained at approximately 30% higher concentrations of tacrolimus as compared with the liver transplant patients. HAART was instituted postoperatively (with return of normal liver function in the case of liver recipients) based on preoperative viral sensitivity or history of clinical response.
 
Liver transplant patients
 
The 7 liver transplant patients were 44, 41, 41, 43, 40, 33, and 53 years of age. The 4 kidney transplant patients were 47, 48, 33, and 59 years old. Only 1 patient of the 11 was a female. Six of 7 liver transplantation patients had HCV. Five patients were hemophiliacs. One patient's diagnosis had drug-induced (nevirapine) fulminant hepatic failure. Patient 1 follow-up was 19.5 months, patient 2 48.5 months, patient 3 33.5 months, patient 4 0.5 months (he died), patient 5 16.4 months, patient 6 11.6 months, and patient 7 8.5 months. The 4 kidney transplants have been followed for 41, 37.9, 7.3, and 7.26 months, respectively. ALT ranged from 17 and 18 in 2 patients to 169 in 1 patient. The other patients ranged from 45 to 82. AT ranged from 27 to 836. But most were within 99 to 27.
 
One liver transplant patient (case 4) died within 2 weeks after transplantation and did not receive any antiretroviral therapy. All other liver transplant patients received a combination of two nucleoside reverse transcriptase inhibitors and one protease inhibitor. Nelfinavir, 1.5 to 2.5 g/d, was used in divided doses except in case 5, in which the initial dose of nelfinavir was 250 mg twice daily and was increased to 1250 mg twice daily over 4 months because this patient had an acute fulminant hepatic failure from nevirapine, and in case 6, in which indinavir 800 mg three times daily was used. None of the kidney transplant patients happened to have been on any protease inhibitors before transplantation and continued on their nucleoside and nonnucleoside reverse transcriptase inhibitors after transplantation.
 
The extent of the interaction between tacrolimus and protease inhibitors was evident in case 1. In the third postoperative week, the patient was on a tacrolimus dose of 2 mg/d with a trough concentration of 11.1 ng/mL. When nelfinavir was resumed at a dose of 750 mg three times daily, the trough concentration of tacrolimus increased to 30 ng/mL on the fourth day. Tacrolimus was discontinued for 10 days and then reintroduced at 1 mg twice per week; this was subsequently readjusted to 1 mg every sixth day to achieve a trough target level of about 10 ng/mL.
 
At week 39, the patient discontinued the protease inhibitor without our knowledge; this led to undetectable tacrolimus blood concentrations and moderate-to-severe acute rejection of the liver allograft. His tacrolimus dose was increased to 5 mg twice daily (60 times increased from baseline) to achieve a concentration of 6.5 ng/mL. Rapamycin was added to his immunosuppressive regimen. Unfortunately, this patient eventually developed chronic rejection progressing to liver failure 19 months after his liver transplantation and died.
 
The mean dose of tacrolimus in liver recipients was 0.6 mg/d with mean trough concentration of 9.7 ng/mL. In a large HIV-negative liver transplant patient population not on antiretroviral therapy, the mean dose of tacrolimus necessary to maintain a trough blood concentration of 10 ng/mL was 10 mg/d. A 16-fold lower dose of tacrolimus was necessary in patients who were on protease inhibitors to achieve comparable blood concentrations of tacrolimus. Of the two protease inhibitors used in our institution, nelfinavir seems to have a more profound effect on the trough tacrolimus blood concentrations. When case 6, receiving indinavir and on 2 mg/d of tacrolimus, was excluded from the analysis, the mean tacrolimus dose required in patients on nelfinavir was only 0.26 mg/d, 38 times less than the historical controls.
 
Kidney transplant patients
 
All four kidney transplant patients are alive with satisfactory renal function. The mean and median tacrolimus dose in these patients was 9.5 and 10 mg/d with a trough blood concentration of 9.6 ng/mL. Two of the patients who were on nevirapine required a lower tacrolimus dose (4 mg/d) compared with the other two (6 and 24 mg/d).
 
HAART Regimens
 
These are the HAART regimens patients received after the transplant. Two liver transplant patients received AZT and 3TC. Two of the 3 received standard AZT dose of 300 mg bid, but 1 patient received AZT 1 mg bid, perhaps that was a misprint. 2 patients received 3TC standard dose of 150 mg bid with d4T 40 mg bid. 1 patient was receiving 3Tc with ddC 0.75 mg bid. 5 of the liver transplant patients received nelfinavir but at various doses: 750 mg tid in 3 patients, 500 mg tid for 1 patient, 1250 mg bid in 1 patient. And 1 patient received indinavir 800 mg tid.
 
Three of the 4 kidney transplant patients received nevirapine or efavirenz. One patient received nevirapine 100 mg bid and a second patient received nevirapine 200 mg bid. All 4 received 3TC. Two received d4T, one 20 mg bid, the other patient 40 mg bid. One patient received a triple nuke regimen of 3TC, abacavir 300mg bid, and AZT 300 mg bid. One patient received efavirenz 600 mg qd.
 
Discussion by authors
 
Several drugs are known to induce or inhibit the metabolism of tacrolimus. Drugs such as phenytoin, phenobarbital, and rifampin are known to decrease the blood concentration of tacrolimus. Drugs such as ketoconazole, itraconazole, fluconazole, and verapamil are known to increase tacrolimus blood concentrations. In the cases presented here, we observed the need for drastic reduction in the dose of tacrolimus to maintain therapeutic concentrations of tacrolimus in liver transplant patients who received protease inhibitors. Such a profound interaction has rarely been observed between tacrolimus and other drugs. These observations can be explained by the profound inhibition of CYP3A enzyme system by protease inhibitors. On the other hand, in kidney transplant patients who were taking reverse transcriptase inhibitors only, the mean dose of tacrolimus required to achieve therapeutic levels was similar to that of the HIV-negative recipients.
 
It is important to realize that some of the protease inhibitors act both as an inducer and an inhibitor of CYP3A4. When coadministered, the inhibitory effect of protease inhibitors predominates. However, after a sudden withdrawal of the protease inhibitor, there will be no more inhibition, but the CYP3A4 system may remain induced for a few days, resulting in a sudden decrease of tacrolimus concentration, as observed in case 1. When nelfinavir was discontinued without our knowledge, the patient developed irreversible acute rejection with undetectable tacrolimus levels. Despite the 60-fold increase in the tacrolimus dose and adding rapamycin, the allograft eventually was lost.
 
It is extremely important to appreciate protease inhibitors-tacrolimus interactions both when starting and when discontinuing the protease inhibitor. Based on our experience, we recommend at least a four-fold reduction in the dose of tacrolimus when nelfinavir is used, and following up on the trough concentration twice per week for further dosage adjustment. It is also important to increase the dose of tacrolimus if protease inhibitors are withheld. Frequent monitoring of tacrolimus trough blood concentrations is mandatory in patients on agents that are known to induce or inhibit the metabolism of tacrolimus.
 
Summary by authors
 
A profound interaction between protease inhibitors, particularly nelfinavir and tacrolimus, has been shown in HIV-positive liver transplant patients. They require a 10- to 50-fold tacrolimus dosage reduction to maintain therapeutic concentrations. Such an extent of drug interaction was not observed in KTx patients who did not receive protease inhibitors. Between the two protease inhibitors used, nelfinavir and indinavir, nelfinavir seems to have more profound drug interactions than indinavir. Nucleosides and nonnucleosides may have even fewer drug interactions compared with a protease inhibitor. However, great caution is required when protease inhibitors are added or discontinued in patients on tacrolimus after transplantation to prevent toxicity or rejection, respectively. A further kinetic study detailing the precise extent of drug interactions between immunosuppressive agents and HAART therapy is essential for better understanding of the drug interaction.
 
Nelfinavir, a protease inhibitor, increases sirolimus levels in a liver transplantation patient: A case report
 
Liver Transplantation. Sept 2002, V 8, Number 9. Authors: Ashok Kumar B. Jain et al. University of Pittsburgh.
 
Successful liver transplantation has been performed in HIV-positive patients. However, these patients must continue highly active antiretroviral therapy after transplantation to manage their HIV infections. Because the use of antiretroviral drugs has been associated with significant drug interactions,3 caution is required in the management of the immunosuppressive drug therapy in these patients. The protease inhibitor nelfinavir has recently been documented to drastically decrease the dose of tacrolimus required to maintain adequate trough blood concentrations in a liver transplantation patient. Sirolimus is a newer immunosuppressive drug that seems to be beneficial in liver transplantation patients. The potential effect of nelfinavir on the blood concentrations of the sirolimus is not known. In the present case report, we document an interaction between nelfinavir and sirolimus in a liver transplantation patient.
 
A 40-year-old woman who was diagnosed with HIV on routine testing had a CD4 count of 68 and a low viral load. She received azidothymidine, lamivudine, and nevirapine. She responded well initially, with a CD4 count of 103. However, 4 weeks later she presented with acute fulminant liver failure. A liver biopsy showed massive hepatic necrosis. She underwent successful orthotopic liver transplantation on May 2000. Her antiretroviral therapy was withheld perioperatively. Her initial immunosuppressive therapy consisted of one gram intravenous methylprednisolone on reperfusion of the liver followed by a 6-day steroid taper from 200 to 20 mg/d. She also received tacrolimus (0.3 mg/kg/d) intravenously for a few days, and then was switched to oral tacrolimus 0.15 mg/kg/d. On the 17th postoperative day, she experienced mild-to-moderate acute cellular rejection, which was treated with steroids, and she was started on sirolimus (5 mg/d). Her antiretroviral therapy was also reinitiated with lamivudine, zidovudine, and nelfinavir. Nelfinavir was started at a dose of 250 mg twice per day (one fifth of the regular dose), which was increased to 750 mg three times per day by 3 months, and currently she is on 1250 mg twice per day. Three weeks after the initial low dose of nelfinavir, her platelet count decreased from 321 ? 106 L to 144 ? 106 L; the white cell count decreased from 12.4 ? 106 L to 2.9 ? 106 L; and the hematocrit decreased from 34.9% to 29.1%. At this time, the 24-hour trough blood concentration of sirolimus was 24.7 ng/mL. The dose of sirolimus was decreased to 3 mg/d and then to 2 mg/d. The pharmacokinetics of sirolimus were evaluated 5 days later by collecting 3 mL of blood at 0 (before the dose of sirolimus), 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 hours after the 2-mg oral dose of sirolimus. A similar pharmacokinetics evaluation of sirolimus was performed in three other liver transplantation patients who were on a stable dose of 5 to 7 mg/d sirolimus who were not receiving nelfinavir. Sirolimus levels were measured by the high-pressure liquid chromatography-mass spectrometry/massspectrometry method. Sirolimus pharmacokinetics parameters including trough concentrations (0-hour and 24-hour), maximum blood concentrations, time to reach maximum concentration, the terminal disposition half-life, and the area under the concentration curve from 0-24 hours were compared between the patient on nelfinavir therapy and those not on nelfinavir.
 
Results
 
The liver and renal function were normal in the patient who received nelfinavir on the day of the pharmacokinetic evaluation (total bilirubin, 0.6 mg/dL; alanine aminotransferase, 30 /L; alkaline phosphatase, 18 /L; alkaline phosphatase, 70 /L; -glutamyltransferase, 69 /L; blood urea nitrogen, 15 mg/dL; creatinine, 0.9 mg/dL). The three other patients not receiving nelfinavir had bilirubin levels of 1.4, 1.7, and 2.1 mg/dL. The whole blood concentration versus time profile for sirolimus in the patient on nelfinavir is shown in Figure 1 along with the median blood concentration versus time profile in the three patients not receiving nelfinavir therapy, after normalizing the values to a 1-mg dose of sirolimus.
 
The 0-hour and 24-hour trough blood concentrations were 5.3 ng/mL and 4.6 ng/mL for the study patient versus the mean concentration of 0.58 0.4 (median, 0.57) and 0.94 0.8 ng/mL (median, 0.94) for the control group (nine-fold and five-fold higher, respectively). The time to reach maximum concentration (1-hour) was not different in the study patient and the control group. The maximum concentration was 12.5 ng/mL in the study patient compared with 3.87 1.97 ng/mL in the control group (3.2-fold higher). The terminal disposition half-life in the patient was 22 hours, and that for control group was 12.4 hours (median half-life) or 15.6 hours (mean half-life). The area under the concentration curve 0 to 24 hours was 49 ng/mL/h/mg in the study patients versus 30.5 11.6 ng/mL/h/mg (60% higher for study patient) in the control group.
 
Discussion
 
Multiple drug interactions have been reported with the use of antiretroviral drugs. Nelfinavir is a substrate for the P4503A4/5 system and is known to inhibit the metabolism of several other drugs. Nelfinavir is a substrate and inhibitor of p-glycoprotein efflux pump. In clinical use, increased concentrations of coadministered drugs are often observed in patients on nelfinavir because of inhibition of CYP3A4/5 enzyme and/or p-glycoprotein efflux pump.
 
Tacrolimus is metabolized by the cytochrome P4503A4/5 system and is a substrate for p-glycoprotein.14-16 Nelfinavir has been observed to inhibit the metabolism of tacrolimus and substantially decrease the dose of tacrolimus required in a liver transplantation patient.4 Sirolimus is a substrate for CYP3A4/5 and p-glycoprotein. Therefore, we also anticipated a nelfinavir-mediated increase in sirolimus levels in our patient. In the present report, even with one fifth of the recommended dose of nelfinavir, there was a significant increase in the blood concentrations of sirolimus in our patient compared with three other patients who were not on nelfinavir. The present case report provides a basis for further kinetic studies to evaluate the interaction between nelfinavir and sirolimus and to establish an appropriate dosing regimen of sirolimus in patients on drugs such as nelfinavir. In the meantime, frequent monitoring of the trough concentrations of sirolimus is recommended to avoid sirolimus-mediated toxicity in patients who simultaneously receive nelfinavir.
 
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.
 
 
 
 
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