Drug–Drug Interactions Between Antiretroviral and Immunosuppressive Agents in HIV-Infected Patients After Solid Organ Transplantation: A Review

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drug level monitoring of calcineurin inhibitors, such as tacrolimus are necessary when PIs are (re)introduced or withdrawn in HIV-infected recipients.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.

Pretransplantation Pharmacokinetic Curves of Tacrolimus in HIV-Infected Patients on Ritonavir-Containing cART

“…In our patients on ritonavircontaining cART, the median advised loading and maintenance dose were 2.0 mg and 0.5 mg every 48 hours respectively, which is in agreement with the results from a other cohorts and case reports of posttransplantation HIV-infected recipients on PI-based cART previously described. (12,13). Furthermore, from the simulation of the pharmacokinetic curves as displayed by Figure 2, it can be concluded that patients on ritonavir-boosted cART the initial dose of tacrolimus needs to be strongly reduced to approximately 2 mg (0.025 mg/kg total body weight) in our population to reach therapeutic levels directly posttransplantation.…”

“…Tacrolimus is primarily metabolized by cytochrome (CYP) 3A in the liver and a substrate of P-glycoprotein (Pgp), an efflux pump, which is primarily localized in the liver and intestines (10,11). Many of the drugs included in cART have been reported to show clinically relevant interactions with CNIs (12). For instance, nonnucleoside reverse transcriptase inhibitors (NNRTIs) are well-known inducers of CYP3A enzymes that may affect tacrolimus pharmacokinetics and can cause underexposure but also have an overlapping iatrogenic profile regarding hepatoxiticity (13).…”

“…Furthermore, protease inhibitors (PIs) are very strong inhibitors of CYP3A enzymes and Pgp. Coadministration of PI's results in a major effect on the pharmacokinetics of tacrolimus and can cause serious overexposure, if the effect of the interaction is not anticipated by strongly reducing the tacrolimus dose (12,13). Ritonavir, which is added to PIs as a pharmacologic booster to increase bioavailability and reduce clearance, is currently by far the strongest commercially available CYP3A inhibitor.…”

Kidney Transplant in a Human Immunodeficiency Virus-Positive Patient: Case Report of Drug Interactions

“…With the inhibition of the CYP3A enzyme system, tacrolimus was recommended at 0.5 to 1 mg weekly to achieve a trough level of 8 to 12 ng/mL. [12][13][14][15] In conclusion, transplant is the best replacement therapy in HIV-positive end-stage kidney disease patients with controlled AIDS management under highly active antiretroviral therapy.…”

Outcomes of Renal Transplantation in HIV-1 Associated Nephropathy

“…Another possible explanation for higher rejection rates is inadequate immunosuppression. Calcineurin inhibitors (CNIs) are administered less frequently in HIV-infected kidney transplant recipients because of drug-drug interaction with protease inhibitors (PIs), which potently inhibit the cytochrome p-450 3A4 system [7]. One of our patients was only on 0.125mg of tarcolimus every other day compared to a total daily dose of 4–6 mg, which is normally used in non-HIV patients.…”