Effects of immunosuppressive drugs on HIV infection: implications for solid-organ transplantation

With the advent of highly active antiretroviral therapy (HAART), HIV infection has become a chronic disease. Various end-stage organ failures have now become common co-morbidities and are primary causes of mortality in HIV-infected patients. Solid-organ transplantation therefore has been proposed to these patients, as HIV infection is not anymore considered an absolute contraindication. The initial results of organ transplantation in HIV-infected patients are encouraging with no differences in patient and graft survival compared with non-HIV-infected patients. The use of immunosuppressive drug therapy in HIV-infected patients has so far not shown major detrimental effects, and some drugs in combination with HAART have even demonstrated possible beneficial effects for specific HIV settings. Nevertheless, organ transplantation in HIV-infected patients remains a complex intervention, and more studies will be required to clarify open questions such as long-term effects of drug interactions between antiretroviral and immunosuppressive drugs, outcome of recurrent HCV infection in HIV-infected patients, incidence of graft rejection, or long-term graft and patient survival. In this article, we first review the immunological pathogenesis of HIV infection and the rationale for using immunosuppression combined with HAART. We then discuss the most recent results of solid-organ transplantation in HIV-infected patients.     

HIV in the dialysis population: Current issues and future directions

Antiretroviral therapy has significantly reduced mortality due to HIV infection, but the aging HIV‐positive patient population now faces a growing burden of comorbidity. This review describes the changing epidemiology of chronic kidney disease and end‐stage renal disease in this population, and highlights recent advances in antiretroviral therapy and kidney transplantation that directly impact the care of patients with HIV infection and end‐stage renal disease.     

Living-related donor renal transplantation in HIV+ recipients using alemtuzumab preconditioning and steroid-free tacrolimus monotherapy: a single center preliminary experience

BACKGROUND: End-stage renal disease (ESRD) is an increasing problem in patients infected with the human immunodeficiency virus (HIV). The use of highly active antiretroviral therapy (HAART) has decreased the morbidity associated with HIV and has prompted renewed interest in renal transplantation. METHODS: We performed four cases of deceased donor renal transplantation in HIV+ recipients and three cases where laparoscopic live donor nephrectomy (LLDN) was utilized to obtain the kidney for transplantation into living-related HIV+ recipients. In the four deceased donor cases, conventional tacrolimus-based immunosuppression, without antibody induction was used. In the three living-related cases, the immunosuppressive regimen was based on two principles: recipient pretreatment and minimal posttransplant immunosuppression. Alemtuzumab 30 mg (Campath 1-H) was used for preconditioning followed by low-dose tacrolimus monotherapy. RESULTS: Of the four deceased donor cases, one patient continues to have good graft function, and another is not yet on dialysis but has significant graft dysfunction. Rejection was observed in three patients (75%). Infectious complications occurred in one patient (25%), all non-acquired immunodeficiency syndrome (AIDs) defining. In the three living-related cases, all had good graft function, and none have experienced acute rejection. HIV viral loads remain undetectable. CD4 counts are slowly recovering. No infectious or surgical complications occurred. There were no deaths in either group. CONCLUSIONS: These data suggest that living-related donor renal transplantation with steroid-free tacrolimus monotherapy in a "tolerogenic" regimen can be efficacious. However, long-term follow-up is needed to confirm this observation.     

Safety and success of kidney transplantation and concomitant immunosuppression in HIV-positive patients

BACKGROUND: Human immunodeficiency virus-associated nephropathy (HIVAN) has become the third leading cause of end-stage renal disease (ESRD) in African Americans, and is expected to grow exponentially. Highly active antiretroviral therapy (HAART) has significantly prolonged the survival of patients with HIV infection. Despite the growing number of HIV-positive dialysis patients with prolonged life expectancy, kidney transplantation with immunosuppression has been declined because it is considered a waste of scarce donor kidneys due to potential increases in morbidity and mortality. METHODS: The institutional review board of Drexel University College of Medicine and Hahnemann University Hospital approved this prospective study. The aim was to find out safety and success of kidney transplantation, and the effect of immunosuppression on HIV infection. Forty HIV-positive dialysis patients received kidney transplantation between February 2001 and January 2004. Patient inclusion criteria were maintenance of HAART, plasma HIV-1 RNA of <400 copies/mL, absolute CD4 counts of 200 cells/muL or more. Immunosuppression was basiliximab induction and maintenance with cyclosporine, sirolimus, and steroids. HAART was continued post-transplant. Acute rejections were diagnosed by biopsy and treated with methylprednisolone. Surveillance biopsies were completed at 1, 6, 12, and 24 months, and evaluated for subclinical acute rejection, chronic allograft nephropathy, and HIVAN. RESULTS: One- and 2-year actuarial patient survival was 85% and 82%, respectively, and graft survival was 75% and 71%, respectively. Plasma HIV-1 RNA remained undetectable, and CD4 counts remained in excess of 400 cells per muL with no evidence of AIDS for up to 2 years. CONCLUSION: One- and 2-year graft survival is comparable to other high-risk populations receiving kidney transplantation. One- and 2-year patient survival is higher than HIV patients maintained on dialysis. Immunosuppression does not adversely affect HIV recipients maintained on HAART in the short term.     

Kidney transplantation in HIV-infected patients

Human immunodeficiency virus (HIV) infection has traditionally been considered an absolute contraindication to solid organ transplantation. With improvements in survival and increases in the prevalence of end-stage liver and kidney disease in HIV-positive patients treated with highly active antiretroviral therapy, many transplant centers have begun to reconsider the role of transplantation in patients with well-controlled HIV infection. This article reviews the literature on transplantation in HIV-infected patients, with a focus on kidney transplantation in the era of highly active antiretroviral therapy.     

Kidney transplantation for HIV-positive patients

HIV+ patients are at increased risk for end-stage renal disease, but HIV infection was once considered a contraindication to renal transplantation. However, contemporary studies from the United States and Europe have now demonstrated that renal transplantation is a safe and effective treatment for end-stage renal disease in HIV patients, with equivalent patient and allograft survival to those uninfected. Broader experience in transplantation in HIV+ patients has identified unique challenges including high rates of acute rejection, delayed graft function, and significant drug–drug interactions. Kidney transplantation in HIV-infected patients is an active area of clinical research and trials of HIV+ to HIV+ transplantation in the United States are underway.     

An Update on Heart Transplantation in Human Immunodeficiency Virus–Infected Patients

Cardiovascular diseases have become a significant cause of morbidity in patients with human immunodeficiency virus (HIV) infection. Heart transplantation (HT) is a well‐established treatment of end‐stage heart failure (ESHF) and is performed in selected HIV‐infected patients in developed countries. Few data are available on the prognosis of HIV‐infected patients undergoing HT in the era of combined antiretroviral therapy (cART) because current evidence is limited to small retrospective cohorts, case series, and case reports. Many HT centers consider HIV infection to be a contraindication for HT; however, in the era of cART, HT recipients with HIV infection seem to achieve satisfactory outcomes without developing HIV‐related events. Consequently, selected HIV‐infected patients with ESHF who are taking effective cART should be considered candidates for HT. The present review provides epidemiological data on ESHF in HIV‐infected patients from all published experience on HT in HIV‐infected patients since the beginning of the epidemic. The practical management of these patients is discussed, with emphasis on the challenging issues that must be addressed in the pretransplant (including HIV criteria) and posttransplant periods. Finally, proposals are made for future management and research priorities.     

Incidence and etiology of acute renal failure among ambulatory HIV-infected patients

BACKGROUND: Acute renal failure (ARF) is a cause of renal dysfunction in human immunodeficiency virus (HIV)-infected patients. Its incidence and causes have not been studied since the introduction of highly active antiretroviral therapy (HAART) in HIV ambulatory patients. METHODS: This is a prospective cohort study of 754 HIV patients, 18 years or older, seen at a university-based infectious disease clinic between 2000 and 2002. ARF was identified using proportional increases in serum creatinine from baseline and by chart review. Clinical conditions were assessed at the time of the ARF event. ARF incidence rates (IR) were calculated by dividing the number of events by person time at risk. To compare patients with and without ARF, t test or chi-square test were used. RESULTS: Patient's mean age was 40 years; 68% were male and 61% were black. One hundred-eleven ARF events occurred in 71 subjects (IR 5.9 per 100 person-years; 95% CI 4.9, 7.1). ARF was more common in men, in those with CD4 cell count <200 cells/mm(3), and HIV RNA levels >10,000 copies/mL. These patients more often had acquired immunodeficiency syndrome (AIDS), hepatitis C infection (HCV), and have received HAART. ARF was mainly community-acquired, due to prerenal causes or acute tubular necrosis, and associated with opportunistic infections and drugs. Liver disease was a cause of ARF in HCV-infected patients. CONCLUSION: ARF is common in ambulatory HIV patients. Immunosuppression, infection, and HCV are important conditions associated with ARF in the post-HAART era.     

Long‐term follow‐up of beta cell replacement therapy in 10 HIV‐infected patients with renal failure secondary to type 1 diabetes mellitus

The approach to transplantation in human immunodeficiency virus (HIV)‐positive patients has been conservative due to fear of exacerbating an immunocompromised condition. As a result, HIV‐positive patients with diabetes were initially excluded from beta cell replacement therapy. Early reports of pancreas transplant in patients with HIV described high rates of early graft loss with limited follow‐up. We report long‐term follow‐up of islet or pancreas transplantation in HIV‐positive type 1 diabetic patients who received a kidney transplant concurrently or had previously undergone kidney transplantation. Although 4 patients developed polyoma viremia, highly active antiretroviral therapy and adequate infectious prophylaxis were successful in providing protection until CD4+ counts recovered. Coordination with HIV providers is critical to reduce the risk of rejection by minimizing drug‐drug interactions. Also, protocols for prophylaxis of opportunistic infections and strategies for monitoring and treating BK viremia are important given the degree of immunosuppression required. This series demonstrates that type 1 diabetic patients with well‐controlled HIV and renal failure can be appropriate candidates for beta cell replacement, with a low rate of infectious complications, early graft loss, and rejection, so excellent long‐term graft survival is possible. Additionally, patients with HIV and cardiovascular contraindications can undergo islet infusion.     

HIV-positive renal recipients can achieve survival rates similar to those of HIV-negative patients

BACKGROUND: Although patients positive for HIV were once thought to be unsuitable candidates for kidney transplantation, their increasing numbers with end-stage renal disease (ESRD) and the introduction of highly active antiretroviral therapy has indicated that they should no longer be excluded for transplantation. To counteract suggestions that human immunodeficiency virus (HIV) patients received suboptimal kidneys, we provide studies of kidneys transplanted from the same donor into patients with and without HIV. METHODS: United Network for Organ Sharing kidney transplant data between 1997 and 2004 were analyzed. Graft and patient survival of 38 HIV patients who had received a renal transplant were compared with the survival of 38 recipients who had received a graft from the same donor. RESULTS: The 38 HIV-positive recipients were younger (49.0 vs. 52.3 years, P=0.14) and had lower peak panel-reactive antibodies (PRA; 5.1% vs. 15.6%, P=0.07) when compared with their bilateral donor to HIV-negative recipients. Sirolimus was used more frequently in HIV patients than in non-HIV patients (36.8% vs. 23.7%, P=0.09). The serum creatinine at 1, 3, and 5 years posttransplantation were higher in HIV patients when compared to non-HIV patients. Although not statistically significant, graft survival was higher among HIV-positive patients compared with their negative controls (76.1% vs. 65.1% at 5 years, P=0.21), as was patient survival (91.3% vs. 87.3% at 5 years, P=0.72). More grafts failed due to death with a functioning graft than rejection in HIV-positive patients. CONCLUSION: This study supports the position that there is no longer an ethical question surrounding the use of kidneys for HIV-positive patients.     

Liver transplantation in HCV/HIV positive patients

Since the introduction of highly active antiretroviral therapy (HAART) in 1996 for human immunodeficiency virus (HIV)-infected patients, the incidence of liver diseases secondary to co-infection with hepatitis C has increased. Although data on the outcome of liver transplantation in HIV-infected recipients is limited, the overall results to date seem to be comparable to that in non-HIV-infected recipients. Liver transplant centers are now accepting HIV-infected individuals as organ recipients. Post-transplantation HIV replication is controlled by HAART. Hepatitis C re-infection of the liver graft, however, remains an important problem because cirrhotic changes of the liver graft may be more rapid in HIV-infected recipients. Interactions between the HAART components and immunosuppressive drugs influence drug metabolism and therefore meticulous monitoring of drug blood level concentrations is required. The risk of opportunistic infection in HIV-positive transplant patients seems to be similar to that in HIV-negative transplant recipients.     

Kidney transplantation and waiting list for renal transplantation for human immunodeficiency virus patients

Introduction

The aim of this study was to evaluate the experience of a renal transplantation unit in the management of human immunodeficiency virus (HIV)-infected patients with end-stage renal disease (ESRD).

Methods

A prospective study was performed between 2005 and 2010 among 23 patients with ESRD.

Results

In this study 83% of HIV- infected patients with ESRD were included on the waiting list for renal transplantation with 4 patients in a clinical evaluation phase. During the follow-up, 52% of waiting list patients (n = 11) received a renal transplant, and 1 patient underwent a simultaneous kidney-pancreas transplantation. Among the waiting list group we observed a significant later exclusion (43%; n = 3). Among the transplanted group there was a high but clinically inconsequential prevalence of acute tubular necrosis (36%; n = 4) and acute rejection episodes (36%; n = 4). The renal function showed a serum creatinine of 1.1 mg/dL at a follow-up of 24 + 12 months. All patients on the waiting list and after the transplantation are prescribed combined antiretroviral treatment (cART) with a low viral load <50 with CD4 >200.

Conclusions

HIV-infected patients with ESRD should be considered to be candidates for renal transplantation if they meet the HIV inclusion criteria. Renal transplantation in adequately selected HIV-infected patients is a safe procedure with acceptable patient and graft survivals.     

Human immunodeficiency virus infection in end-stage renal disease patients

Human immunodeficiency virus (HIV) infection in patients with end-stage renal disease (ESRD) offers many diagnostic and therapeutic challenges to nephrologists. Renal failure may be a direct consequence of viral infection (HIV-associated nephropathy), or intrinsic renal diseases may occur in previously infected individuals. Patients receiving renal replacement therapy (RRT) may acquire HIV infection from blood transfusions, renal allografts, sexual contacts, or needle sharing by drug addicts. In the early 1980s, the overall prognosis of patients with the acquired immunodeficiency syndrome (AIDS) was very poor, and survival of those with ESRD was dismal. Consequently many even questioned the value of providing maintenance dialysis to patients with AIDS. With advances in diagnostic techniques in serologic and viral markers of disease, and deployment of highly effective antiretroviral agents, the prognosis of HIV-infected patients has dramatically improved. Over the past two decades, experiences in the management of HIV patients with ESRD is accumulating. Both peritoneal dialysis and hemodialysis are effective modes of therapy and many centers are now beginning to perform renal transplantation in HIV-infected patients. This article deals with various aspects of HIV infection in patients with ESRD.     

Kidney-Pancreas Transplantation in a Long-Term Non-Progressor HIV-Infected Recipient

With the introduction of highly active antiretroviral therapy (HAART), HIV infection has become a chronic disease with more frequent end-stage organ failures. As a result, the question of transplantation in HIV patients is raised more often. Although still subject to controversies, HIV infection is no longer an absolute contraindication to solid organ transplantation. We report a case of combined kidney-pancreas transplantation in a HIV recipient. HIV has remained stable without any antiviral therapy for up to 2 years after transplantation and has reached criteria for inclusion in the long-term nonprogressor (LTNP) group. Grafted organs demonstrated good function without rejection. This case emphasizes the need to consider LTNP HIV patients as a specific subgroup, when discussing solid organ transplantation. HAART is not required, thus sparing drug interactions and their unique immunological features, such as CCR5 mutation, might prevent rejection. This subgroup of HIV patients should be offered less restricted access to transplantation.     

Deceased Donor Kidney Transplantation in a Human Immunodeficiency Virus–Infected Recipient: A Case Report

Human immunodeficiency virus (HIV) infection has traditionally been considered an absolute contraindication for transplantation because immunosuppression will accelerate the disease progression and increase mortality. New antiretroviral agents have given rise to new perspectives and transplantation practices. Now renal transplantation is the gold standard treatment for end-stage renal disease in HIV-infected patients, but increased rejection and toxicity rates and compliance with treatment are important issues. Therefore, patient selection and follow-up should be done carefully in this patient group. Here we present a 51-year-old, male, HIV-infected patient who was diagnosed with HIV at his routine serologic investigation at 2015. Highly active antiretroviral therapy was initiated. One haplotype-matched kidney transplantation from a deceased donor was performed on October 19, 2016. Induction therapy was not administered, and the immunosuppressive regimen included tacrolimus, mycophenolate mofetil, and prednisolone. After 26 months, serum creatinine was 1.1 mg/dL and proteinuria 0.1 g/day. There was no development of donor-specific antibodies. The patient's current HIV viral load remains undetectable (and had been the entire time post-transplantation) while his CD4⁺ T-cell count currently is 543/mm³.     

The clinical characteristics of HIV-infected patients receiving dialysis in France between 1997 and 2002

BACKGROUND: In 1997, 0.38% of dialysis patients in France were infected by human immunodeficiency virus (HIV). No prevalence data were available in France since the widespread introduction of highly active antiretroviral therapy. METHODS: This was a cross-sectional epidemiologic survey. A questionnaire was sent to all French dialysis centers in July 2002. The centers that did not respond were sent 3 additional mailing reminders. Finally, the nonresponding centers were called early in 2004. RESULTS: Of the 27,577 patients on hemodialysis and 587 patients on peritoneal dialysis, 190 patients (0.67%) were infected by HIV. HIV-associated nephropathy was the cause of renal failure in 39.8% patients. Mean age was 44.6 +/- 10.9 years, the mean duration of dialysis was 4.9 +/- 5.9 years, the mean known duration of HIV infection was 8.9 +/- 5.6 years. Eighty-two percent of patients received antiretroviral therapy (ART). Fifty-eight percent of ART-treated patients had an undetectable HIV plasma viral load with a median CD4+ T-cell count 303/mm(3). CONCLUSION: The prevalence of HIV infection among French dialysis patients was 0.67% in late 2002, a 79% increase since 1997. Possible reasons for this large increase include increased access to dialysis, better general status of HIV dialysis patients, and increasing proportion of patients originating from Africa and the Caribbean. The current efficacy of ART makes renal transplantation a realistic option for these young patients.     

Liver transplantation in HIV-infected recipients.

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.     

Management of chronic viral hepatitis before and after renal transplantation

Hepatitis C virus (HCV) infection is present in 2-50% of renal transplant recipients and patients receiving hemodialysis. Renal transplantation confers an overall survival benefit in HCV positive (HCV+) hemodialysis patients, with similar 5-year patient and graft survival to those without HCV infection. However, longer-term studies have reported increased liver-related mortality in HCV-infected recipients. Unfortunately, attempts to eradicate HCV infection before transplant have been disappointing. Interferon is poorly tolerated in-patients with end-stage renal disease and ribavirin is contraindicated because reduced renal clearance results in severe hemolysis. Antiviral therapy following renal transplantation is also poorly tolerated, because of interferon-induced rejection and graft loss. Although the prevalence of hepatitis B virus (HBV) infection has declined in hemodialysis patients and renal transplant recipients since the introduction of routine vaccination and other infection control measures, it remains high within countries with endemic HBV infection (especially Asia-Pacific and Africa). Renal transplantation is associated with reduced survival in HBsAg+ hemodialysis patients. Unlike interferon, lamivudine is a safe and effective antiviral HBV treatment both before and after renal transplantation. Lamivudine therapy commenced at transplantation should prevent early posttransplant reactivation and subsequent progression to cirrhosis and late liver failure. This preemptive therapy should also eradicate early liver failure from fibrosing cholestatic hepatitis. Because cessation of treatment may lead to severe lamivudine-withdrawal hepatitis, most patients require long-term therapy. The development of lamivudine-resistance will be accelerated by immunosuppression and may result in severe hepatitis flares with decompensation. Regular monitoring with liver function tests and HBV DNA measurements should enable early detection and rescue with adefovir. Chronic HCV and HBV infections are important causes of morbidity and mortality in renal transplant recipients. The best predictor for liver mortality is advanced liver disease at the time of transplant, and liver biopsy should be considered in all potential HBsAg+ or HCV+ renal transplant candidates without clinical or radiologic evidence of cirrhosis. Established cirrhosis with active viral infection should be considered a relative contraindication to isolated renal transplantation.     

Single dose of Rituximab plus plasmapheresis in an HIV patient with acute humoral kidney transplant rejection: a case report

Before the highly active antiretroviral therapy (HAART) era, kidney transplantation was not considered an option for patients infected with human immunodeficiency virus (HIV) because of its poor outcome. However, recent studies have demonstrated results comparable to those of recipients without HIV infections. They have shown that HIV-positive patients maintained on HAART mount an immune response. Immunosuppressive agents are chosen to minimize aggravation of HIV infection, bearing in mind the potential side effects of the combination of HAART and immunosuppressive drugs. Herein we have reported the case of a 43-year-old HIV- and hepatitis C virus-infected woman with preserved immune function who received a cadaveric kidney transplant and developed an acute humoral rejection, which was successfully treated with Rituximab.     

Prevalence of human polyoma virus (BK virus and JC virus) infection in patients with chronic renal disease

Background Polyoma virus infection in renal transplant patients is sometimes critical in graft survival. But, to date, polyoma virus infection or reactivation has not been checked before renal transplantation. The prevalence of polyoma viruses (BK virus and JC virus) was investigated in 45 patients with renal disease who were future candidates as renal graft recipients.Methods Because these viruses are excreted in urine, the urine of these 45 patients was analyzed by polymerase chain reaction (PCR). The urine of 37 age-matched normal subjects (control group) was also investigated.Results In the control group, 13.5% of the normal subjects were positive for BK virus and 24.3% were positive for JC virus. In the patients with renal disease, 33.3% were positive for BK virus and 33.3% were positive for JC virus; the prevalence of BK virus infection was significantly higher than that in the normal subjects. Patients with renal disease with corticosteroid therapy revealed an especially high prevalence of BK virus infection (55.6%), indicating the possibility of viral reactivation by corticosteroid therapy.Conclusions More attention should be paid to polyoma virus infection in candidates for renal transplantation with a previous therapeutic history of corticosteroid administration.