Drug-Drug Interactions Between Antiretroviral and Immunosuppressive Agents in HIV-Infected Patients After Solid Organ Transplantation: A Review.
ABSTRACT Abstract Since the introduction of combination antiretroviral therapy (cART) resulting in the prolonged survival of HIV-infected patients, HIV infection is no longer considered to be a contraindication for solid organ transplantation (SOT). The combined management of antiretroviral and immunosuppressive therapy proved to be extremely challenging, as witnessed by high rates of allograft rejection and drug toxicity, but the profound drug-drug interactions between immunosuppressants and cART, especially protease inhibitors (PIs) also play an important role. Caution and frequent drug level monitoring of calcineurin inhibitors, such as tacrolimus are necessary when PIs are (re)introduced or withdrawn in HIV-infected recipients. Furthermore, the pharmacokinetics of glucocorticoids and mTOR inhibitors are seriously affected by PIs. With the introduction of integrase inhibitors, CCR5-antagonists and fusion inhibitors which cause significantly less pharmacokinetic interactions, have minor overlapping toxicity, and offer the advantage of pharmacodynamic synergy, it is time to revaluate what may be considered the optimal antiretroviral regimen in SOT recipients. In this review we provide a brief overview of the recent success of SOT in the HIV population, and an update on the pharmacokinetic and pharmacodynamic interactions between currently available cART and immunosuppressants in HIV-infected patients, who underwent SOT.
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ABSTRACT: Liver transplantation (LT) is an accepted mode of treatment for patients with chronic liver disease. Historically, patients with HIV were excluded from LT programs, but with the introduction of highly effective antiretroviral regimens, HIV is no longer a contraindication. LT outcomes for some liver diseases in HIV-positive patients are equivalent to those observed in non-HIV-positive patients. This is not the case for patients coinfected with HIV and HCV, however, where results at 5 years have led to suggestions that LT for coinfection should be abandoned. This article examines the role of LT for HIV/HCV and identifies groups of patients where transplantation is associated with good outcomes. We believe that the application of existing knowledge to patient selection and organ allocation could improve outcomes further, and with the advent of directly acting antivirals for HCV, LT for HIV/HCV coinfection will no longer be controversial.Future Virology 07/2013; 8(7):639-648. DOI:10.2217/fvl.13.51 · 1.00 Impact Factor
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ABSTRACT: Combination antiretroviral therapy has resulted in longer life expectancies in persons living with HIV; however, end organ disease and death from organ failure have become growing issues for this population. With effective therapies for viral suppression, HIV is no longer considered an absolute contraindication to organ transplantation. Over the past decade, studies of transplantation in patients with HIV have had encouraging results such that patients with organ failure are pursuing transplantation. This review focuses on the current status of organ transplantation for HIV-infected persons.Current Infectious Disease Reports 10/2013; 15(6). DOI:10.1007/s11908-013-0381-x
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ABSTRACT: The calcineurin inhibitor tacrolimus is the backbone of immunosuppressive drug therapy after solid organ transplantation. Tacrolimus is effective in preventing acute rejection but has considerable toxicity and displays marked inter-individual variability in its pharmacokinetics and pharmacodynamics. The genetic basis of these phenomena is reviewed here. With regard to its pharmacokinetic variability, a single nucleotide polymorphism (SNP) in cytochrome P450 (CYP) 3A5 (6986A>G) has been consistently associated with tacrolimus dose requirement. Patients expressing CYP3A5 (those carrying the A nucleotide, defined as the *1 allele) have a dose requirement that is around 50 % higher than non-expressers (those homozygous for the G nucleotide, defined as the *3 allele). A randomised controlled study in kidney transplant recipients has demonstrated that a CYP3A5 genotype-based approach to tacrolimus dosing leads to more patients reaching the target concentration early after transplantation. However, no improvement of clinical outcomes (rejection incidence, toxicity) was observed, which may have been the result of the design of this particular study. In addition to CYP3A5 genotype, other genetic variants may also contribute to the variability in tacrolimus pharmacokinetics. Among these, the CYP3A4*22 and POR*28 SNPs are the most promising. Individuals carrying the CYP3A4*22 T-variant allele have a lower tacrolimus dose requirement than individuals with the CYP3A4*22 CC genotype and this effect appears to be independent of CYP3A5 genotype status. Individuals carrying the POR*28 T-variant allele have a higher tacrolimus dose requirement than POR*28 CC homozygotes but this association was only found in CYP3A5-expressing individuals. Other, less well-defined SNPs have been inconsistently associated with tacrolimus dose requirement. It is envisaged that in the future, algorithms incorporating clinical, demographic and genetic variables will be developed that will aid clinicians with the determination of the tacrolimus starting dose for an individual transplant recipient. Such an approach may limit early tacrolimus under-exposure and toxicity. With regard to tacrolimus pharmacodynamics, no strong genotype-phenotype relationships have been identified. Certain SNPs associate with rejection risk but these observations await replication. Likewise, the genetic basis of tacrolimus-induced toxicity remains unclarified. SNPs in the genes encoding for the drug transporter ABCB1 and the CYP3A enzymes may relate to chronic nephrotoxicity but findings have been inconsistent. No genetic markers reliably predict new-onset diabetes mellitus after transplantation, hypertension or neurotoxicity. The CYP3A5*1 SNP is currently the most promising biomarker for tailoring tacrolimus treatment. However, before CYP3A5 genotyping is incorporated into the routine clinical care of transplant recipients, prospective clinical trials are needed to determine whether such a strategy improves patient outcomes. The role of pharmacogenetics in tacrolimus pharmacodynamics should be explored further by the study of intra-lymphocyte and tissue tacrolimus concentrations.Clinical Pharmacokinetics 11/2013; 53(2). DOI:10.1007/s40262-013-0120-3 · 5.49 Impact Factor