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Liver & Kidney Transplants in HIV: selected HIV-related abstracts from Intl Congress on Transplantation Conference, Aug 25-30, 2002, Miami, FL.
Reported by Jules Levin
D. Samuel1, C. Feray1, D. Vittecoq1, D. Azoulay1, E. Teicher2, F. Saliba1, P. Ichai1, A.M. Roque-Afonso3, D. Castaing1, R. Adam1, E. Dussaix3, C Guettier4.1 Centre Hepato-Biliaire, Hopital Paul Brousse, Villejuif, France. 2UMIT, Hopital Paul Brousse-Villejuif, France. 3 Service de Virologie, Hopital Paul Brousse-Villejuif, France. 4 Service d'Anatomie Pathologique, Hopital Paul Brousse-Villejuif, France. [0569]
HIV infection is considered as a contraindication for liver transplantation (LT). The prognosis of HIV infection has dramatically improved with antiretroviral treatment. Many of these patients have severe life-threatening HCV liver disease. Aim: Evaluate the feasibility of LT in HIV-HCV coinfected patients. Six patients (5 M, 1 F) mean age 39 years underwent LT from December 1999 to October 2001. All patients have Child C cirrhosis and controlled HIV replication. HIV and HCV serum viral load were performed before and after LT, liver biopsy was performed at 6, 12 and 24 months post-LT. Immunosuppression was a combination of Tacrolimus and steroids. Results: 3 patients received a domino graft (from a donor transplanted for familial amyloidotic polyneuropathy); 2 a living related donor graft and 1 a cadaver graft. All but one patients are alive, mean follow-up 12 months (6-28). Protease inhibitors and tacrolimus interaction was responsible for acute rejection by low tacrolimus level in 1 and for toxic levels of tacrolimus in 1. After LT, all patients but one have undetectable or low level of HIV RNA, and all have high level of serum HCV RNA with hepatitis. One patient developed an unexplained episode of jaundice, one developed microvesicular steatosis probably related to antiretroviral treatment, one developed a severe chronic hepatitis C requiring combination therapy of interferon plus ribavirine, which was successful (HCV RNA negative) and one patient died of liver failure from mixed causes. Significant improvement of quality of life and gain of weight was observed in 4/6 patients.
Conclusion: Liver transplantation in HIV-HCV coinfected patients is feasible but require a cautious monitoring of HCV reinfection, of drug interactions and of antiretroviral toxicity.
Leslie Z. Benet, M. Baluom, C-Y. Wu. San Francisco, USA. [0731]
The immunosuppressive agents cyclosporine, tacrolimus and sirolimus are all substrates for the metabolic enzyme cytochrome P450 3A (CYP3A) as well as the efflux transporter, P-glycoprotein (P-gp). Recently it has been recognized that intestinal metabolism is the major source of variability for these immunosuppressives via CYP3A, but that access to the enzyme is controlled by the P-gp transporter. Variability of intestinal P-gp appears to be a better predictor of bioavailability than intestinal CYP3A. Since recent evidence suggests that CYP3A and P-gp are coregulated in humans and animals, it is not surprising that inducers of the enzyme would also induce the transporter. The anti TB drug rifampin, as well as the herbal remedy St. John's wort, are inducers of both CYP3A and P-gp leading to potentially non-efficacious immunosuppressive drug levels. The azole antifungal agents and certain macrolides such as erythromycin are substrates and inhibitors of the enzyme, as well as the transporter. Following oral immunosuppressive dosing, these interacting drugs have their major impact on intestinal bioavailability, rather than on hepatic elimination. With the advent of highly active antiretroviral therapy (HAART), HIV+ patients are now receiving organ transplants. Protease inhibitors (PIs) can compete with, as well as inhibit, both CYP3A and P-gp, requiring marked decreases in immunosuppressive drug dosing to prevent toxic reactions. The non-nucleoside reverse transcriptase inhibitors (NNRTIs) are also substrates for CYP3A, but unlike the Pis have little interactive effect with P-gp. In contrast to CYP3A, where little differences in activity are noted based on genotypic variables, P-gp exhibits a wide variety of genotypes leading to different levels of P-gp and different activities of the transporter variants. It appears that the immunosuppressive pharmacokinetic differences observed in African Americans can be explained on the basis of genotypic differences in P-gp and the interactive nature of P-gp and CYP3A. Recent advances in understanding the characteristics of drug metabolism of immunosuppressive agents should allow clinicians to more rationally select and adjust dosage regimens in various patient populations.
A. Jain, R. Venkataramanan, R. Shapiro, V. Scantlebury, B. Eghtesad, S. Potdar, M. Ragni, J. Fung.University of Pittsburgh Thomas E. Starzl Transplantation Institute.United States. [0172]
Solid organ transplants have been performed successfully in selected HIV+ patients with highly active anti-retrovirus 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 and Rapamycin. The aim of the present report is to examine the extent of potential drug interactions between anti-retroviral agents and immunosuppressive drug agents after LTx and KTx. Patients and Method: Seven (LTx) patients and four KTx patients were HIV+. At the time of transplantation, all patients received tacrolimus and steroids. Rapamycin was used for steroid-resistant rejection in one LTx patients. Their current base line immunosuppression and HAART regimen were examined retrospectively. Kinetic parameters were determined after a 2 mg oral dose of Rapamycin and 250 mg of nelfinavir by collecting a peripheral venous blood sample at 0 (before sirolimus) 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 hours after the sirolimus dose. These kinetic parameters were compared with three other post-LTx patients, who were not on nelfinavir.
Results: Protease inhibitor and tacrolimus: Of the seven LTx, 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). Kidney recipients received NRTI and non-nucleoside 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 to 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+ 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. Protease inhibitor and Rapamycin: Kinetic parameters to sirolimus 1 mg/day, 0 hour and 24 hour trough Rapamycin concentrations were 9-fold and 5-fold higher. (Cmax) was 3.2 times higher, the area under the concentration curve (AUC) was 1.6 times higher, and the terminal disposition half life was prolonged by 60% in the patient who was on nelfinavir compared to control.
Conclusion: Profound drug interactions between PI and tacrolimus have been observed requiring up to 50-fold reductions in dosage. In contrast, HAART utilizing NRTI and NNRTI without the use of PI, as demonstrated in kidney recipients, produces less significant effects on tacrolimus metabolism. Similarly, an increase in trough concentration, peak concentration area under the curve concentration and prolongation of half life of Rapamycin has been demonstrated in a patient who, on low dose (one-fifth the recommended dose) nelfinavir.
P.G. Stock, L. Carlson, C. Freise, M. Roland, S.J. Tomlanovich, L.A. Frassetto, T. Coates, J.P. Roberts, R. Hirose, N. Ascher.University of California San Francisco, San Francisco CA, United States. [0567]
Background: HIV infected patients (pts) have historically been excluded from consideration for transplantation (tx) out of concern about the effects of immunosuppression on the progression of HIV disease. Improvements in HIV related morbidity and mortality with the use of highly active antiretroviral therapy (HAART) have prompted a re-evaluation of tx as a treatment option for HIV infected people with end-stage kidney and liver disease.
Methods: Eligible pts met standard transplant criteria; had undetectable plasma HIV-1 RNA levels (VL) for 3 months (kidney) or were predicted to achieve VL suppression post tx if unable to tolerate HAART (liver); CD4+ T-cell count of > 200 cells/ÁL (kidney) or >100 cells/ÁL (liver) for 6 months; and no history of opportunistic infection/neoplasm (OIs). Outcome measures include: survival, graft function, incidence of OIs, changes in CD4 counts, HIV viral load, anogenital human papilloma virus (HPV) disease progression, HHV8 infection, and pharmacokinetic analysis of protease inhibitors (PI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and immunosuppressive drugs.
Results: Eleven pts have received transplants, 7 kidney and 4 liver. Standard immunosuppression included prednisone, mycophenolate mofetil and cyclosporine. Ten recipients are alive and well (median survival 331 days, range 37-637 days as of 1/14/02) with functioning grafts (Cr range 0.9-3.1 mg/dL; all liver tx pts with normal LFTs). The one death occurred 445 days post tx in a liver recipient co-infected with hepatitis C, who died due to rapid reoccurrence of HCV. He also developed CMV esophagitis just prior to his death with a CD4 count of 200, the only OI observed so far. Rejection occurred in 4/7 kidney tx recipients, but in 0/4 liver tx recipients. CD4 counts have remained acceptable (median 514, range 363-828/ÁL) in pts not treated for rejection. CD4 counts are lower (median 84, range 74-104/ÁL) in three pts treated for rejection with thymoglobulin and sirolimus. HIV viral loads have remained undetectable in all pts maintained on HAART. One pt developed high grade anal dysplasia at 18 months post tx requiring treatment. Pts on PIs require 25% of the dose of cyclosporine compared to pts on NNRTIs.
Conclusions: There has been no evidence of significant HIV progression and no adverse effect of HIV on allograft function. Rejection is concerning in kidney tx recipients as is the possible poor outcome in HCV co-infected liver tx recipients. Preliminary data are encouraging and suggest that transplant should be a treatment option for individuals with well-controlled HIV disease.
In report by Michelle Roland at Barcelona more details are available. HCV+ liver transplant recipients do not appear to do as well as others:
A. Kobryn, E.J. Smit, R. Pool, S. Ndlovu, M. Bondo, M.C.M. Modiba.Medical University of Southern Africa, Republic of South Africa. [3635]
HIV transmission through Tx has been reported in the past. The cause and timing of progression to AIDS are not well understood. Long-term asymptomatic recipient's survival was also reported. Typically, HIV antibodies were first detected after seroconversion (40-50 days after Tx). Kumar et al. (Ann.Int.Med.,N2,V106,Feb.1987), reported low titers of HIV antibodies detected 5 days after kidney Tx and suggested a passive transfer of antibodies from the donor. 36 hours after LR haploidentical kidney Tx a high MEIA (Abbot Axsym HIV-1/2 gO) reactivity was detected in African recipient. There was a further rise in sample Rate/Cut off Rate (S/CO) in the first week after Tx. Both, donor and recipient were screened for HIV prior to Tx. In retrospect, the donor was found serologically and RNA positive 5 days before Tx. The recipient was HIV-1 RNA and serologically negative the day before Tx. 2 units of PRBCs, routinely screened for HIV serology by central blood service, were transfused during Tx. Harvesting and preservation procedures were standard.
Immunosuppression consisted of AZA+PRED and FK506 was started on day 3 post Tx. An acute clinical seroconversion syndrome was observed on D16-18, accompanied by the upregulation of CD4, CD8, CD3, CD19 (148%,418%,218%,115%) and followed by an increase in NK cells (from 252% to 750%) for the next 15 days. ART was commenced on D28 (HIV RNAvl >500 000 c/mL). HIV-1vl dropped to 310c/mL after 10 weeks on Combinavir and Nelvinavir. ART implementation was followed by a rapid increase (17x) in FK Co. At the time of writing this report (235 days after Tx) the recipient is well, with s.Cr.170 umol/L, and undetectable HIV-1vl (<50 c/mL).
CONCLUSIONS: HIV EIAs detects passively transferred HIV antibodies within hours of Tx. The case demostrates that, in spite of extensive preservation perfusion, still remains a parenchyma bound HIV antibodies fraction which can not be eluted from the kidney but is rapidly released from the allograft to the recipient's blood soon after Tx. Therefore, serological testing of recipients for HIV antibodies immediately after Tx may help to identify organ transmitted (missed in a donor) HIV infection and to start ART. Due to a strong reactivity of passively transmitted antibodies we were not able to establish how many days after Tx the recipient seroconverted and started producing his own HIV antibodies. The interpretation of post Tx FC immunophenotype is difficult due to possible interference of alterations in immunosuppression and subclinical, undetected rejection responses.
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