The First Simultaneous Pancreas, Renal Transplant in a Patient with HIV in Australia

We report the first case of a simultaneous pancreas and renal transplantation, in Australia, in a 45 year old male with long standing human immunodeficiency virus infection, type 1 diabetes mellitus and diabetic nephropathy requiring haemodialysis. This patient experienced previous virological failure and subsequent resistance to most nucleoside and non-nucleoside reverse transcriptase inhibitors. However, using novel combinations of anti-retroviral agents, along with careful monitoring, successful outcomes were achieved during the peri and post transplantation period, with excellent pancreas and renal graft function at one year.


Introduction
Recent experiences suggest that transplantation can be safely conducted in patients with human immunodeficiency virus (HIV) infection. Balancing medication interactions between antiretroviral therapy and immunosuppressive therapy remains a challenge. Eight cases of simultaneous pancreas and kidney (SPK) transplantation in HIV patients with type 1 diabetes mellitus (T1DM) have been reported with good outcomes [1][2][3][4][5]. At transplantation, all patients were under the age of 50 years, with undetectable HIV RNA blood levels. Most were on nucleoside reverse transcriptase inhibitor (NRTI) based regimes. Here we report the first SPK transplantation case in Australia. We highlight that successful transplantation can be achieved in the context of viral resistance, with the use of novel anti-retroviral medications.

Case
A 45 year old male with HIV-1 infection was referred to our facility from a regional area, for SPK transplantation. T1DM was diagnosed aged 19 years, complicated by nephropathy requiring home haemodialysis in the three years leading up to transplantation. HIV was diagnosed, aged 24 years. Eight years later, lamivudine/zidovudine and efavirenz was commenced at a nadir CD4 count of 160 cells/mL. History was notable for coronary artery bypass grafting, previous seizures and fractured humerus.
Over twenty years, modifications to his anti-retroviral regime were necessary because of adverse effects and virological failure (Table 1). In 2011, mutations at positions M184V, K103N, M41L and T215CF were found, precluding the use of most NRTIs. In 2014, despite good virological control, anti-retroviral medications were modified in preparation for transplantation. Protease inhibitors (PI) and etravirine were avoided due to cytochrome P450 inhibition. Instead, a novel combination including subcutaneous enfuviritide was used, along with dolutegravir, maraviroc (CCR5 tropic virus) and renal-adjusted tenofovir disoproxil fumarate (TDF).
Twelve months later, at the time of transplantation, CD4 count was 518 cells/mL, HIV viral load was undetectable and CMV and EBV IgG were negative. The donor-recipient was 0/6 mismatched on HLA loci. Standard induction therapy included basiliximab, mycophenolate and prednisone. Maintenance immunosuppression was continued with mycophenolate, renally adjusted tacrolimus, a calcineurin inhibitor (CI) and prednisone. Valganciclovir prophylaxis was added.

Journal of HIV & Retro Virus ISSN 2471-9676
This Article is available in: http://hiv.imedpub.com Therapeutic drug monitoring (TDM) allowed gradual escalation of the CI dose, with the aim to achieve adequate, yet safe, immunosuppression to optimise graft survival. Renal function fully recovered over three weeks, allowing gradual escalation to standard doses of TDF (Figure 1).
Insulin was no longer required post operatively. At discharge, proton pump inhibitor was ceased and enfuviritide was changed to rilpivirine (absorbed in acidic environments). TDF was replaced by Tenofovir alafenamide combined with emtricitabine, a new agent with reduced nephrotoxicity. His general health improved, despite several admissions with psoas collection and a splenic infarct. His 12-month biopsy showed no evidence of acute rejection, with a BANFF score of 0 (t0, i0, g0, cg0, ah0, v0, vv0, ct0, mm0). However, there were signs of early glomerulopathy. HIV viral load remained undetectable.

Discussion
The current case demonstrates that the presence of complex antiretroviral drug resistance patterns, requiring thoughtful anti-retroviral treatment regimens, can be managed successfully to allow organ transplantation in HIV patients. The favourable outcome here was consistent with the other case reports ( Table  2). Only one patient has been reported as having died, after SPK transplantation, resulting from bacterial sepsis at nine months [1]. Graft failure has been reported in two cases [1,2]. The remaining five organ grafts have functioned at follow up between 5 and 84 months [2][3][4][5].
Despite recommendations [6] against anti-retroviral treatment interruptions, the peri and post-operative approaches to antiretroviral therapy in SPK transplantation have varied. In one case, anti-retrovirals were withheld, without virological failure, pre-operatively and seven years post [4]. In a case series, antiretrovirals were withheld in the pre and peri-transplantation period to avoid medication interactions. Reintroduction was at 25-58 days, with CD4 counts 71-195 [2]. Our recipient and two other cases received uninterrupted anti-retroviral treatment [3,5].
The challenges faced in managing such patients are diverse.
The primary challenge is that drug-drug interactions need to

Journal of HIV & Retro Virus ISSN 2471-9676
be considered. PIs inhibit the metabolism of CI, necessitating lower doses of CIs [6]. Conversely non-nucleoside reverse transcriptase inhibitors (NNRTI) can increase CI metabolism, necessitating higher doses of CIs [6]. Despite prior PI and NNRTI use, our recipient was prescribed TDF (a NRTI), regardless of risk of nephrotoxicity, as it has minimal interactions with immunesuppressive drugs [6,7] and has antiviral activity despite his resistance profile.
The ethical implications of transplantation in potential candidates with HIV must be considered. Simultaneous pancreas kidney transplantation is the treatment of choice for most patients with type 1 diabetes mellitus and ESKD because it saves lives, improves the quality of life and is cost-effective [9]. Recently, the advent of antiretroviral therapy, HIV positive patients with concurrent ESKD are expected to have similar expected graft survival as non-HIV patients [10]. However, the proposals to transplant HIV positive patients have also raised several ethical concerns. Apart from the interactions between antiviral agents and immunosuppression, the increased risk of acute rejection observed in HIV transplant recipients also poses major challenges balancing the dose and types of immunosuppression use and