|Year : 2017 | Volume
| Issue : 3 | Page : 160-162
A challenging male patient with retroviral infection on highly active antiretroviral therapy issues with re-transplantation
George Joseph Kavalam, Priya Haridas, Deepu S George, Milly Mathew, Saravanan Sundararajan, Georgi Abraham
Department of Nephrology, Madras Medical Mission Hospital, Chennai, Tamil Nadu, India
|Date of Web Publication||20-Dec-2017|
Dr. Georgi Abraham
Madras Medical Mission Hospital, 4A, Dr. Jayalalithaa Nagar, Mogappair, Chennai - 600 037, Tamil Nadu
Source of Support: None, Conflict of Interest: None
A 44-year-old African male with chronic kidney disease Stage V due to hypertension underwent a live related renal transplant in 2005. He was on triple immunosuppression postoperatively. Subsequently, he developed metastatic Kaposi sarcoma requiring reduction in immunosuppression and switching over to rapamycin. He was found to be retrovirus positive on a follow-up visit. His graft function progressively deteriorated requiring dialysis while continuing on highly active antiretroviral therapy. He had multiple infective episodes including acute bacterial endocarditis. He received a second renal transplant from a live-related donor in 2017. Despite repeated dosage adjustments, tacrolimus levels were persistently elevated due to drug-drug interaction with diltiazem and anti-retroviral drugs, despite good allograft function.
Keywords: Calcineurin inhibitor induced allograft dysfunction, Kaposi sarcoma, re-grafting, retroviral infection
|How to cite this article:|
Kavalam GJ, Haridas P, George DS, Mathew M, Sundararajan S, Abraham G. A challenging male patient with retroviral infection on highly active antiretroviral therapy issues with re-transplantation. Indian J Transplant 2017;11:160-2
|How to cite this URL:|
Kavalam GJ, Haridas P, George DS, Mathew M, Sundararajan S, Abraham G. A challenging male patient with retroviral infection on highly active antiretroviral therapy issues with re-transplantation. Indian J Transplant [serial online] 2017 [cited 2021 Apr 15];11:160-2. Available from: https://www.ijtonline.in/text.asp?2017/11/3/160/221194
| Introduction|| |
The advent of active retroviral therapy in the year 1996 prolonged the life of many chronic kidney disease (CKD) patients enabling them to undergo successful renal transplantation. Triple immunosuppressive therapy with CNIs along with thymoglobulin induction is not an uncommon practice in retroviral patients undergoing transplantation. Commonly used anti-retroviral drugs such as lamivudine (nucleoside analog reverse-transcriptase inhibitor [NRTI]), abacavir (NRTI) along with protease inhibitors like ritonavir can have significant interactions with CNI's producing very high serum levels and hence toxicity. Immunosuppression leads to activation of HHV-8 and Kaposi sarcoma, which is an infrequent complication. Other opportunistic pathogens including bacterial, viral, and fungal are a threat to CKD patients on dialysis and those who undergo transplantation. Retroviral multiplication leading to high viral counts along with low CD4 count is a contraindication for renal transplantation. Appropriate retroviral therapy with multiple agents to eliminate the virus and sustain viral remission for 6 months is mandatory before undertaking a renal transplantation. Here, we report a patient who following a failed allograft transplant and appropriately treated Kaposi sarcoma with low viral load who underwent a successful regrafting 12 years after the first allograft.
| Case Report|| |
Currently 56-year-old, African male, married with 3 children, incidentally diagnosed with CKD, diabetes mellitus, and systemic hypertension in the year 2004. He was initiated on hemodialysis in Tanzania and came to our center for renal transplant. Preoperative investigations such as human leukocyte antigen (HLA) typing, hemoglobin electrophoresis, and serology were performed. Both donor and recipient were negative for hepatitis B, hepatitis C, and HIV in 2005. CMV status of both the donor and recipient were IgG positive and IgM negative. The patient underwent his first renal transplant from his brother as a donor in the year 2005 at our center in Chennai. He was inducted with single dose basiliximab 20 mg following which; he was initiated on triple immunosuppressive therapy. In 2006, he was seen with a large mass in the right thigh, which was progressively enlarging, and biopsy showed Kaposi sarcoma Stage IV with metastasis. His graft function at the time was good, blood urea level of 53 mg/dL and serum creatinine of 1.4 mg/dL. He was treated with chemotherapy for Kaposi sarcoma with 5 cycles of doxorubicin. His cyclosporine and prednisolone levels were being tapered and switched over to rapamycin monotherapy. The patient had complete remission from the disease following the treatment, which was confirmed by a PET scan. In the year 2009, due to an unknown illness, the patient was transfused with 2 units of unscreened blood in his home country. During a routine follow-up in 2010, the patient was diagnosed with retroviral infection and was initiated on highly active antiretroviral therapy (HAART). His anti-retroviral regimen included a combination of lamivudine 75 mg once daily, abacavir 600 mg once daily and efavirenz 600 mg once daily. Since 2011, his creatinine levels showed an increasing trend and biopsy done in 2015 revealed chronic tubulointerstitial nephritis with interstitial fibrosis and tubular atrophy [Figure 1]. C4D was negative. He was initiated on dialysis thrice-weekly regimen through right IJV catheter. In view of multiple failed access for dialysis, a PTFE graft was made between the left brachial artery and left axillary vein. A year later in view of a large aneurysm, the brachial artery was resected and a reverse saphenous vein was used as an interposition graft. In 2016, he presented with fever and signs of cardiac failure and was diagnosed with infective endocarditis of aortic valve caused by Pseudomonas aeurginosa and was treated using piperacillin and tazobactam 2.25 g, 8th hourly. The patient received routine dialysis for 2 years before he opted for a retransplant. Pretransplant workup included confirmation of the remission status of Kaposi, CMV status of the recipient and donor, monitoring of HIV viral load and CD4 count. His Viral load status was 55 copies IU/L with a CD4 count of 272 cells/μL. CMV status of both the donor and recipient were IgG positive and IgM negative. The patient underwent his second renal transplant following induction with thymoglobulin 50 mg in view of poor HLA match, from a live related donor on June 26, 2017.
Postoperatively, his graft function was good. By the 3rd postoperative day, his serum creatinine level was 1.21 mg/dL, and by the 11th postoperative day, his serum creatinine values were 0.94 mg/dL. [Figure 2] shows the serial decrease in serum creatinine. His antiretroviral drugs were restarted on postoperative day 8, with anzavir R200/100 mg single daily dose and a combination of abacavir and lamivudine 600/300 mg single daily dose. The patient was also started on valganciclovir 450 mg on alternate days. His blood pressure was controlled with clonidine 100 mcg thrice daily and diltiazem 90 mg twice daily. Trough levels of tacrolimus were measured every 3rd day. Tacrolimus levels continued to be elevated with values ranging >30 ng/dl even with serial adjustments of tacrolimus doses. In view of alterations in blood pressure, regular adjustments were made to his antihypertensive regimen. The patient's high serum trough levels are depicted in [Figure 3]. His creatinine levels were stable within a range of 0.9–1.2 mg/dL until about 3 weeks since surgery when there was a rise in creatinine >1.5 mg/dL in view of which allograft biopsy was done which showed normal findings with <5% interstitial fibrosis and tubular atrophy [Figure 4]. Tacrolimus dosages are now adjusted to 0.25 mg once daily, every 4 days, and thus serum tacrolimus dose is being maintained in the range of 8–9 ng/ml. Postoperatively, his viral load was <40 copies/ml and CD4 count of 735 cells.
| Discussion|| |
Drug-drug interactions are becoming an important area of research as newer agents are becoming available. Understanding the drug-drug interactions between immunosuppressive therapy and anti-retroviral therapy will be critical to patient care and management. Since the use of antiretroviral drugs has been associated with significant drug-drug interactions, caution is required in the management of patients with HIV undergoing organ transplantation.
This was a challenging case due to numerous factors. His previous history of Kaposi sarcoma and the retroviral status were some of the complex issues we faced. Recurrence of Kaposi sarcoma after renal transplant has been documented in studies conducted by Doutrelepon et al. Recurrence is associated with the increase in immunosuppression and remission attained only with decrease dosages of immunosuppressant at the cost of allograft failure. The retroviral status proved a constant strain on management with the current indications for renal transplant emphasizing on the need for CD4 count more than 200 cells/ml and undetectable viremia for 6 or more months., The viral load in our patient was 55 cell/mm 3 with a CD4 >200 cells for more than 6 months as per guidelines.
Tacrolimus which has a narrow therapeutic index makes regular monitoring quintessential for appropriate serum trough levels. Studies have been conducted by Pulzar et al. regarding dose finding before renal transplant to achieve early therapeutic blood levels postoperatively. Numerous interactions between tacrolimus and several other drugs have been documented previously. In our patient, tacrolimus dosage was initially used at 0.15 mg/kg/day. Tacrolimus has a half-life of 12–18 h which suggests that approximately 2.5 days should elapse to assess the effect of a dosage adjustment on the levels. The patient's serum tacrolimus levels showed a constant level >30 ng/ml. All protease inhibitors that exhibit anti-HIV activity are metabolized by the CYP3A4 isoenzyme pathway. Since cyclosporine, tacrolimus, and sirolimus share the same metabolic pathway, significant drug-drug interactions can be expected as observed in our patient. Renal transplant recipients on protease inhibitor therapy require a tacrolimus dose reduction 38 times lower than the mean for a transplant recipient not on antiretroviral therapy. Profound drug interactions have been noted in previous studies often requiring up to 50-fold reductions in dosage., Regimens without protease inhibitors such as the combinations of NRTI and NNRTI require significantly less tacrolimus dosage adjustments. Therefore, it is of utmost importance to take into account those potential pharmacokinetic and pharmacodynamics of drug-drug interactions between drugs for immunosuppression and anti-retroviral therapy to avoid drug toxicity and lack of efficacy. Among other interactions that added to the challenge was between tacrolimus and diltiazem, which is also metabolized by CYP3A pathway., Diltiazem inhibits tacrolimus metabolism and hence can dramatically increase tacrolimus concentration. This patient illustrates the complexities of managing renal transplantation in a retrovirus-infected patient with previous malignancy and comorbidities.
| Conclusion|| |
We are presenting an adult male patient with second successful live related renal transplant who is retrovirus positive with disease in remission on triple HAART regimen who has good allograft function. He required constant monitoring and adjustment of tacrolimus dosage to very low levels to avoid drug toxicity and maintain well-being.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bhagani S, Sweny P, Brook G, British HIV Association. Guidelines for kidney transplantation in patients with HIV disease. HIV Med 2006;7:133-9.
Abbott KC, Swanson SJ, Agodoa LY, Kimmel PL. Human immunodeficiency virus infection and kidney transplantation in the era of highly active antiretroviral therapy and modern immunosuppression. J Am Soc Nephrol 2004;15:1633-9.
Doutrelepont JM, De Pauw L, Gruber SA, Dunn DL, Qunibi W, Kinnaert P, et al
. Renal transplantation exposes patients with previous Kaposi's sarcoma to a high risk of recurrence. Transplantation 1996;62:463-6.
Pulzer A, Seybold U, Schönermarck U, Stangl M, Habicht A, Bogner JR, et al
. Calcineurin inhibitor dose-finding before kidney transplantation in HIV patients. Transpl Int 2013;26:254-8.
Spencer CM, Goa KL, Gillis JC. Tacrolimus. An update of its pharmacology and clinical efficacy in the management of organ transplantation. Drugs 1997;54:925-75.
Erice A, Rhame FS, Heussner RC, Dunn DL, Balfour HH Jr., Human immunodeficiency virus infection in patients with solid-organ transplants: Report of five cases and review. Rev Infect Dis 1991;13:537-47.
Mahesh E, John MM, Konana GC, Parampalli RM, Bande SR, Suryadevara S, et al
. Renal transplantation in HIV-positive patients - No more a scare! Saudi J Kidney Dis Transpl 2017;28:1106-11.
Stock PG, Roland ME, Carlson L, Freise CE, Roberts JP, Hirose R, et al.
Kidney and liver transplantation in human immunodeficiency virus-infected patients: A pilot safety and efficacy study. Transplantation 2003;76:370-5.
Izzedine H, Launay-Vacher V, Baumelou A, Deray G. Antiretroviral and immunosuppressive drug-drug interactions: An update. Kidney Int 2004;66:532-41.
Moreno M, Latorre A, Manzanares C, Morales E, Herrero JC, Dominguez-Gil B, et al
. Clinical management of tacrolimus drug interactions in renal transplant patients. Transplant Proc 1999;31:2252-3.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]