Antiviral activity of sirolimus in an HIV-positive kidney transplant recipient

Introduction

Sirolimus (SIR) is an immunosuppressive agent frequently used in kidney transplantation. ¹ SIR exerts its action through inhibition of mammalian target of rapamycin (mTOR), a ubiquitous serine/threonine kinase that regulates multiple intracellular pathways involved in cellular growth, proliferation, differentiation and metabolism. ² Interestingly, SIR has been shown to determine in vitro ³ and in vivo^4,5 down-regulation of C-C chemokine receptor type 5 (CCR5), one of two co-receptors commonly used by HIV-1 to enter and infect CD4-expressing immune cells. ⁶ Based on these results, SIR may be a potential alternative immunosuppressive agent in the treatment of HIV-infection in solid organ transplant recipients.^3–5

In this case report, we describe for the first time the use of SIR to control low-level HIV-1 replication in an HIV⁺ kidney transplant (KT) recipient.

Clinical case

A 36-year-old Caucasian woman with a diagnosis of HIV infection since 1993 developed end-stage renal disease over the next ten years likely due to HIV-associated nephropathy. She never experienced an AIDS-defining illness and her nadir CD4+ T-cell count was 166 cells/mm³ in February 2005.

After three years of peritoneal dialysis, she received a kidney transplant in June 2008. Prior to transplantation, HIV-viral load (VL) was undetectable and CD4+ T-cell count was 396 cells/mm³. Her peak panel-reactive antibodies (PRA) was 38% but repeat testing revealed a PRA of 0% before transplantation.

Following basiliximab and steroid induction, she was started on cyclosporine (CyA) and steroids for maintenance immunosuppression. Monitoring of HIV-1 VL was performed by a reverse transcription-polymerase chain reaction with a cut-off of 40 copies/mL. According to the Italian National Kidney Transplant Program guidelines, CD4+ T-cell count and HIV VL were monitored every 15 and 30 days, respectively, for the first year and every six months thereafter. On postoperative day 21, everolimus (EVR) was administered in combination with low-dose CyA. Her graft had an immediate function without the need for renal replacement therapy.

Pre-transplant antiretroviral therapy (ART), consisting of abacavir/lamivudine/saquinavir (ABC/3TC/SQV), was switched to abacavir/lamivudine/enfuvirtide (ABC/3TC/T20) in order to reduce pharmacological interferences between protease inhibitors (SQV) and immunosuppressive agents. Because T20 was poorly tolerated, ART was subsequently converted to abacavir/lamivudine/raltegravir (ABC/3TC/RAL).

Four months post-transplantation, she developed low-level viremia with a median VL of 163 copies/mL lasting about nine months. HIV-1 drug resistance testing was negative. Despite awareness of considerable potential for interaction with immunosuppressive agents, her ART regimen of ABC/3TC/RAL was reinforced in an attempt to control HIV replication, first with ritonavir-boosted SQV (SQV/r) and then with ritonavir-boosted darunavir (DRV/r). As a result, these changes led to a long-term virologic suppression interrupted only by a single episode of intermittent viremia (VL of about 60 copies/mL) in March 2011. Development of wound-healing complications after gynecologic surgery performed in August 2010 prompted EVR withdrawal and continuation of full-dose CyA.

In May 2013, in the absence of HIV-resistance to ABC, 3TC, and RAL, her DRV/r was discontinued, and ART was simplified to ABC/3TC/RAL. After five months from this change, she experienced low-level viremia (median VL of 82 copies/mL) that was not suppressed by restoring the previous antiretroviral regimen ABC/3TC/RAL/DRV/r. Recognition of low-level resistance to ABC along with persistent viral replication led to drug withdrawal and the addition of rilpivirine (RPV) to the antiretroviral regimen. The administration of 3TC/RAL/RPV/DRV/r did not improve the control of viral replication and HIV-1 remained steadily detectable in plasma despite therapeutic drug monitoring showed normal plasma drug concentrations of antiretroviral agents at two different time-points.

In October 2014, CyA was switched to SIR for its antiviral proprieties. The profile of viral replication improved consistently although two virologic blips were detected (0.5 and 1.5 years, respectively) after the administration of the immunosuppressive agent (Figure 1). Since May 2016, her HIV-1 RNA remained undetectable until the end of follow-up.

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Figure 1.

Schematic representation of antiretroviral and immunosuppressive therapies, plasma HIV-1 viral load (copies/mL), CD4+ T cell (cells/mm³) and serum creatinine (mg/dL) after kidney transplantation.

After 3.3 years from the administration of SIR, renal function remained stable with the last value of creatinine of 1.08 mg/dL corresponding to an estimated GFR of 59 mL/min. She was exposed to a mean SIR trough level of 5.67 ± 2.42 mg/dL. SIR was well tolerated and no side effects such as heavy proteinuria, edema, dyslipidemia, oral aphthous ulcers, and pneumonitis were recorded. De novo donor-specific HLA antibodies without clinical significance (mean fluorescence intensity <1000) were detected but no episodes of allograft rejection developed during the observation period.

Discussion

In our study, we report data on a successful experience of SIR in one HIV⁺ KT recipient who developed low-level HIV-1 replication. Conversion from calcineurin inhibitor (CNI)-based to SIR-based therapy was not previously planned but was performed in response to the specific needs of the patient. SIR was chosen from among all immunosuppressive agents for its well-known antiviral activity.^7–9

In this case, the patient, despite perfect adherence to medications and in the absence of antiviral drug resistance, experienced an episode of low-level viremia that was not responsive to numerous changes in her ART. The administration of SIR favored the challenging control of HIV-1 replication as well as the maintenance of virologic suppression and of normal CD4+ T-cell count. SIR was also able to efficiently prevent graft rejection despite its use as monotherapy.

SIR possesses anti-viral proprieties in the setting of HIV infection. ³ Similarly, to a new class of antiretroviral drugs termed entry inhibitors, SIR reduces the expression of CCR5 on lymphocytes by interfering with IL-2 signaling. A study showed that SIR reaches this effect at blood concentrations lower than those used in KT recipients; therefore, patients treated with SIR may theoretically benefit from its antiretroviral effects without any increases in the total dose of the drug. ¹⁰ To date, few studies reporting the use of SIR among HIV⁺ solid organ transplant recipients have been published in the literature.^11,12 Di Benedetto et al. ¹³ showed significantly better control of HIV replication in liver transplant recipients with SIR monotherapy compared with CNI-based regimens. Stock et al. ¹² demonstrated that HIV⁺ KT recipients on SIR had significantly lower levels of persistent cell-associated HIV DNA and/or RNA compared to those receiving CNIs. Likely, the immune-modifying action of SIR resulting from inhibition of T-cell proliferation, decrease of CCR5 expression and enhancement of antigen-specific memory T-cell formation is capable of reducing the size of the HIV reservoir in the infected population. Based on these findings, a study that investigates the efficacy of SIR as a reservoir-modifying agent is ongoing in non-transplanted patients on ART. (ClinicalTrials.gov number: NCT02440789).

The administration of SIR in HIV⁺ KT recipients is not without side effects. Recent data show that SIR is associated with an inferior overall and graft survival compared to other immunosuppressive agents.^14,15 Furthermore, SIR leads to important pharmacological interactions when it is used in combination with PIs and NNRTIs. ¹⁶ For these reasons, SIR is warranted only in particular conditions and its use in monotherapy should be exceptional because it may further increase the risk of graft rejection in these patients.^17–20

It is unknown if the anti-HIV activity of SIR is drug-specific or a class effect. A recent study showed that EVR – an analogue of SIR – was unable to inhibit the expression of CCR5 on subsets of CD4+ T-cells. ²¹ Further data on this issue will be released by an ongoing trial aiming to assess the impact of EVR on HIV persistence in CD4+ lymphocytes in transplant recipients (ClinicalTrials.gov number: NCT02429869).

Conclusion

This case report supports the growing evidence of SIR as an immunosuppressive agent with immunomodulatory properties among HIV⁺ patients. Although we cannot exclude spontaneous virological clearance of HIV-1 under ART, the administration of SIR allowed a better control of viral replication in a KT recipient that experienced low-level viremia not responsive to multiple changes of ART.

However, the use of SIR (as first-line or add-on therapy to CNI) should be judicious because it is associated with an inferior outcome compared to other antirejection drugs. On the other hand, further studies should be encouraged by the pressing need for the development of new antiretroviral and immunosuppressive agents with minimal toxicity, emergence of strain-resistant HIV-1 and challenging adherence to complex treatment regimens.