Laurie Carlson

HIV-infected liver and kidney transplant recipients: 1- and 3-year outcomes.

Improvements in human immunodeficiency virus (HIV)‐associated mortality make it difficult to deny transplantation based upon futility. Outcomes in the current management era are unknown. This is a prospective series of liver or kidney transplant recipients with stable HIV disease. Eleven liver and 18 kidney transplant recipients were followed for a median of 3.4 years (IQR [interquartile range] 2.9–4.9). One‐ and 3‐year liver recipients’ survival was 91% and 64%, respectively; kidney recipients’ survival was 94%. One‐ and 3‐year liver graft survival was 82% and 64%, respectively; kidney graft survival was 83%. Kidney patient and graft survival were similar to the general transplant population, while liver survival was similar to the older population, based on 1999–2004 transplants in the national database. CD4+ T‐cell counts and HIV RNA levels were stable; and there were two opportunistic infections (OI). The 1‐ and 3‐year cumulative incidence (95% confidence intervals [CI]) of rejection episodes for kidney recipients was 52% (28–75%) and 70% (48–92%), respectively. Two‐thirds of hepatitis C virus (HCV)‐infected patients, but no patient with hepatitis B virus (HBV) infection, recurred. Good transplant and HIV‐related outcomes among kidney transplant recipients, and reasonable outcomes among liver recipients suggest that transplantation is an option for selected HIV‐infected patients cared for at centers with adequate expertise.

Kidney and liver transplantation in human immunodeficiency virus-infected patients: a pilot safety and efficacy study.

Background. Human immunodeficiency virus (HIV)-infected patients have historically been excluded from consideration for transplantation out of concern for 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 reevaluation of transplantation as a treatment option for HIV-infected patients with end-stage kidney and liver disease. Methods. Eligible patients met standard transplant criteria. They had undetectable plasma HIV-1 RNA levels (viral load) for 3 months (kidney) or were predicted to achieve viral load suppression posttransplantation if unable to tolerate HAART (liver); a CD4+ T-cell count of more than 200 cells/&mgr;L (kidney) or more than 100 cells/&mgr;L (liver) for 6 months; and no history of opportunistic infections and neoplasm. Standard immunosuppression included prednisone, mycophenolate mofetil (CellCept, Roche Pharmaceuticals, Basel, Switzerland), and cyclosporine (Neoral, Novartis, East Hanover, NJ). Results. Fourteen patients received transplants (10 kidney transplants, mean follow-up 480 days; four liver transplants, mean follow-up 380 days). All of the kidney transplant recipients (100%) are alive and with functioning grafts, and three of four liver transplant patients (75%) are alive and well with functioning grafts (all liver transplant patients with normal liver function tests). The one death occurred 445 days posttransplantation in a liver recipient coinfected with hepatitis C virus, who died as the result of its rapid reoccurrence. Rejection occurred in 5 of 10 kidney transplant recipients but did not occur in any of the four liver transplant recipients. HIV viral loads have remained undetectable in all patients maintained with HAART. CD4 counts have remained stable in patients not treated for rejection. Patients receiving protease inhibitors require 25% of the dose of cyclosporine compared with patients receiving nonnucleoside reverse transcriptase inhibitors. Conclusions. There has been no evidence of significant HIV progression and no adverse effect of HIV on allograft function. Rejection is a concern in kidney transplant recipients, as is the possible poor outcome in hepatitis C virus-coinfected liver transplant recipients. Preliminary data are encouraging and indicate that transplantation should be a treatment option for individuals with well-controlled HIV disease.

Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection

Hepatitis C virus (HCV) is a controversial indication for liver transplantation (LT) in human immunodeficiency virus (HIV)–infected patients because of reportedly poor outcomes. This prospective, multicenter US cohort study compared patient and graft survival for 89 HCV/HIV‐coinfected patients and 2 control groups: 235 HCV‐monoinfected LT controls and all US transplant recipients who were 65 years old or older. The 3‐year patient and graft survival rates were 60% [95% confidence interval (CI) = 47%‐71%] and 53% (95% CI = 40%‐64%) for the HCV/HIV patients and 79% (95% CI = 72%‐84%) and 74% (95% CI = 66%‐79%) for the HCV‐infected recipients (P < 0.001 for both), and HIV infection was the only factor significantly associated with reduced patient and graft survival. Among the HCV/HIV patients, older donor age [hazard ratio (HR) = 1.3 per decade], combined kidney‐liver transplantation (HR = 3.8), an anti‐HCV–positive donor (HR = 2.5), and a body mass index < 21 kg/m2 (HR = 3.2) were independent predictors of graft loss. For the patients without the last 3 factors, the patient and graft survival rates were similar to those for US LT recipients. The 3‐year incidence of treated acute rejection was 1.6‐fold higher for the HCV/HIV patients versus the HCV patients (39% versus 24%, log rank P = 0.02), but the cumulative rates of severe HCV disease at 3 years were not significantly different (29% versus 23%, P = 0.21). In conclusion, patient and graft survival rates are lower for HCV/HIV‐coinfected LT patients versus HCV‐monoinfected LT patients. Importantly, the rates of treated acute rejection (but not the rates of HCV disease severity) are significantly higher for HCV/HIV‐coinfected recipients versus HCV‐infected recipients. Our results indicate that HCV per se is not a contraindication to LT in HIV patients, but recipient and donor selection and the management of acute rejection strongly influence outcomes. Liver Transpl 18:716–726, 2012.

Immunosuppressant pharmacokinetics and dosing modifications in HIV-1 infected liver and kidney transplant recipients

Solid organ transplantation in human immunodeficiency virus (HIV)‐infected individuals requiring concomitant use of immunosuppressants (IS) (e.g. cyclosporine [CsA], sirolimus [SrL], tacrolimus [FK]) and antiretrovirals (ARVs) (e.g. protease inhibitors [PIs] and/or nonnucleoside reverse transcriptase inhibitors [NNRTIs]) is complicated by significant drug interactions. To assist in appropriate clinical management, we describe the pharmacokinetics and dosing modifications in 35 patients (20 kidney, 13 liver and two kidney‐liver HIV‐infected subjects with end‐stage kidney or liver disease), on both IS and NNRTIs, PIs, and combined NNRTIs + PIs, in studies done at weeks 2–4 and/or 12 weeks after transplantation or after a change in IS or ARV drug regimen (n = 97 studies). CsA, SrL and FK concentrations were measured in whole blood by LC/MS. HIV‐infected transplant recipients using PIs with IS had marked increases in CsA, FK or SrL trough levels compared to those on NNRTIs alone or to patients not on ARVs, necessitating either a reduction in dose or an increase in dosing interval. Subjects on efavirenz (EFV) and CsA required much higher doses of CsA than those using any other ARV. Changes in antiretroviral therapy should be carefully managed to avoid insufficient immunosuppression or toxicity due to drug interactions.

Thymoglobulin‐Associated Cd4+ T‐Cell Depletion and Infection Risk in HIV‐Infected Renal Transplant Recipients

HIV‐infected patients are increasingly referred for kidney transplantation, and may be at an increased risk for rejection. Treatment for rejection frequently includes thymoglobulin. We studied thymoglobulins effect on CD4+ T‐cell count, risk of infection and rejection reversal in 20 consecutive HIV‐infected kidney recipients. All patients used antiretroviral therapy and opportunistic infection prophylaxis. Maintenance immunosuppression consisted of prednisone, mycophenolate mofetil and cyclosporine. Eleven patients received thymoglobulin (7 for rejection and 4 for delayed/slow graft function) while 9 did not. These two groups were similar in age, gender, race, donor characteristics and immunosuppression. Mean CD4+ T‐cell counts remained stable in patients who did not receive thymoglobulin, but became profoundly suppressed in those who did, decreasing from 475 ± 192 to 9 ± 10 cells/μL (p < 0.001). Recovery time ranged from 3 weeks to 2 years despite effective HIV suppression. Although opportunistic infections were successfully suppressed, low CD4+ T‐cell count was associated with increased risk of serious infections requiring hospitalization. Rejection reversed in 6 of 7 patients receiving thymoglobulin. We conclude that thymoglobulin reverses acute rejection in HIV‐infected kidney recipients, but produces profound and long‐lasting suppression of the CD4+ T‐cell count associated with increased risk of infections requiring hospitalization.

Outcome of patients with hepatitis B virus and human immunodeficiency virus infections referred for liver transplantation

The outcome of patients with hepatitis B virus (HBV) and human immunodeficiency virus (HIV) referred for liver transplantation (LT) is unknown. A high frequency of lamivudine‐resistant (LAM‐R) HBV infection may increase the risk of liver‐related death pre‐transplantation and prophylaxis failure post‐transplantation. We evaluated the association of LAM‐R HBV on pre‐transplant survival and post‐transplant outcomes in 35 consecutive HIV‐HBV coinfected patients referred for LT between July 2000 and September 2002. At the time of referral, the median CD4 count was 273/mm, MELD was 14, and LAM‐R HBV infection was present in 67%. Among these referred patients, 26% were listed, 29% not listed due to relative/absolute contraindications; 26% not listed as too early for LT; 9% not listed as too sick for LT; and 11% died during transplant evaluation. Of the 9 listed patients, 4 remained listed, 1 died 18 months post‐referral, and 4 were transplanted (11% of total) 3 to 40 months after listing. Of 17 evaluated but not listed patients, 5 died (p=0.38 compared to listed group) and all deaths were liver‐related. All the HBV‐HIV coinfected patients, who were transplanted, are HBsAg negative and have undetectable HBV DNA levels on prophylactic therapy using hepatitis B immune globulin (HBIG) plus lamivudine, with and without tenofovir or adefovir, with median 33.1 months follow‐up. Late referral and the presence of LAM‐R HBV pre‐transplantation are common in referred HIV‐HBV patients. In HIV‐HBV coinfected patients undergoing LT, HBV recurrence is successfully prevented with combination prophylaxis using HBIG and antivirals. Liver Transpl 12:801–807, 2006.

Kidney and Liver Transplantation in HIV-Infected Patients: Case Presentations and Review

Until recently, HIV-infected patients have been excluded from consideration for solid organ transplantation. The relatively high mortality rates among HIV-infected transplant recipients observed in the era prior to the use of highly active antiretroviral therapy (HAART), coupled with long waiting times for cadaveric organs, made it difficult to support organ transplantation in this patient group. However, in response to the marked reductions in morbidity and mortality associated with HIV infection, several transplant centers have developed pilot studies or revised their clinical criteria to allow transplantation in this group of patients. We describe two cases, one kidney and one liver transplant recipient, and review the major clinical and research issues related to this topic. Reports of transplantations in the pre-HAART era highlight two important findings. First, some HIV-infected transplant recipients did very well with long survival periods. However, overall progression to AIDS and death appeared accelerated. We recently reported on our preliminary experience with 45 selected transplant recipients in the HAART era. One-year patient survival rates were similar to unmatched survival data from the United Network for Organ Sharing (UNOS) database. Median CD4+ T-cell counts remained stable in the follow-up period compared to pretransplant. HIV-1 RNA nearly uniformly continued to be suppressed below the limits of detection. Preliminary data are promising and support the current efforts to evaluate patient and graft survival among HIV-infected transplant recipients and to explore the mechanisms underlying the many potential complications of transplantation in this population.

Changes in clearance, volume and bioavailability of immunosuppressants when given with HAART in HIV-1 infected liver and kidney transplant recipients

Solid organ transplantation in human immunodeficiency virus 1 (HIV)‐infected individuals requiring the concomitant use of immunosuppressants (IS) [e.g. cyclosporine (CsA) or tacrolimus (TAC)] and antiretrovirals (ARVs) [e.g. protease inhibitors (PIs) and/or non‐nucleoside reverse transcriptase inhibitors (NNRTIs)] is complicated by significant drug interactions. This paper describes the pharmacokinetics of CsA and TAC in 52 patients on both IS and NNRTIs, PIs or combined NNRTIs + PIs, in studies conducted at 2 weeks, 3, 6, 12 and 24 months after transplantation. Cyclosporine and TAC blood concentrations were measured by LC/MS/MS. This multisubject, varied ARV–IS drug combination, longitudinal observational patient study provided a unique opportunity to examine the effect of different ARV drugs on IS pharmacokinetics (PK) by comparing the ratios of parameters over time and between PK parameters. Subjects taking concomitant PIs exhibited increases in CsA and TAC exposure (AUC/dose) due to the increased apparent oral bioavailability and decreased apparent oral clearance. Those subjects taking CsA and concomitant efavirenz (EFV) showed time dependent increases in exposure due to ~30% increases in the apparent oral bioavailability over time as well as a decreased apparent oral clearance, while subjects on TAC and EFV showed time‐dependent changes in all PK parameters. The increased bioavailability was not observed in patients on CsA and nevirapine (NVP). These differences between IS drugs and the changes in PK parameters are not easily predicted, illustrating the importance of continued therapeutic drug monitoring in patients on these complex medication regimens. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Sofosbuvir, simeprevir, and ribavirin for the treatment of hepatitis C virus recurrence in human immunodeficiency virus/hepatitis C virus–coinfected liver transplant recipients

TO THE EDITORS: For human immunodeficiency virus (HIV) patients coinfected with hepatitis C virus (HCV), poor graft survival after liver transplantation (LT) has prompted concerns about their suitability for LT.1 The availability of oral direct-acting antiviral drugs for HCV offers new opportunities for managing HCV disease in LT recipients with HCV and HIV and potentially improving long-term survival,2 as shown by the 2 patients reported here.

Staff Responsibility to Exercise

Recent attention has been focused on the importance of exercise for improving the physical functioning of renal patients. The involvement of the dialysis staff in encouragement and implementation of programs is critical to the success of patient efforts in improving physical functioning. Staff responsibility initially consists of various developmental steps that are focused on gaining staff support and developing a plan that matches the needs and the resources available to the unit. Each staff member plays a critical role in the development, implementation, and evaluation of the exercise program. A concerted effort from all staff to incorporate exercise as a routine part of the patient care will enhance the potential of success and patient participation.