We thank Dr Morrison and CHIMERIX Laboratory for their interest in these two case reports. Here we bring some complementary data to improve the understanding of the manuscript and to answer to the critical points that were highlighted by the letter from Dr Morrison.
In the first case, prolonged CMV infection may be not an explanation for deterioration of renal function. First, prolonged CMV infection leads to a progressive and long-term decline of renal function(1). In this case, decrease of GFR occurs rapidly (few days) after initiation of either FCV and BCV, suggesting acute tubular injury. Second, no recovery is observed after CMV-induced decline of renal function(2). In this case, patient 1 showed two reversible acute renal injury after treatment, followed by an early improvement of renal function after discontinuation of FCV (Creatinine: 42 mg/L à 37 mg/L) and after discontinuation of BCV (58 mg/L à 24 mg/L after 4 weeks), compatible with the diagnosis of acute tubular injury. The estimated GFR also returned to baseline. Moreover, after 2 years of follow-up, patient 1 does not show any decline of renal function (creatinine level at 31 mg/L in march 2017). But, according to the data, a potentiation of BCV-induced toxicity by FCV may not be excluded. Finally, observation of renal graft biopsy showed only an extended acute tubular injury(2,3). As previously published, prolonged CMV infection leads to long-term graft loss (3 years)(1). Two events are commonly observed: involvement of acute rejection, (Patient 1 did not present any graft rejection, even after 2 years), or observation of irreversible graft fibrosis(2,3) (high grade tubular atrophy and interstitial fibrosis) that were not observed in our biopsy. Moreover, as previously seen, in this case, acute renal injury was reversible.
As shown in Figure 1C, patient 2 was treated with FCV two times. At each time, patient 2 presented a FCV-mediated acute renal injury (creatinin level raised to 35 mg/L) which was reversible after discontinuation and rehydration (baseline creatinine level raised to 20-23 mg/L). Just after renal recovery of first FCV treatment, patient received BCV for persistent CMV viremia. Creatinin level raised from 22 mg/L to 30 mg/L (from 01/09/15 to 10/09/15) and BCV was discontinued. Although BCV was stopped, creatinine level continues to increase to 52 mg/L in a context of diarrhea and increase absorption of tacrolimus. In this context, patient presented concomitantly an overdosage of everolimus and tacrolimus responsible of secondary thrombotic micro-angiopathy (TMA). Although creatinine level increased after first introduction of BCV, in this context of drug-induced TMA, the responsibility of BCV cannot be clearly stated. Moreover, renal function was aggravated by a second FCV treatment (27/09/15).
After complete recovery of the episode (17/12/15), creatinin level decreased close to baseline (22-25 mg/L). A second BCV treatment for persistent CMV viremia led to a progressive increase of creatinine level (44 mg/L). Thus, BCV was discontinued in February 2016, also 4 months after last treatment using FCV and 3 months after recovery of the first episode. The kidney biopsy showed only extended tubular necrosis, that cannot be attributed to FCV treatment (prescribed 4 months before, in September 2015). Moreover, no TMA lesions were observed in the biopsy. Thus, during the reintroduction of BCV, at a distance from last FCV-mediated renal injury and TMA episode, without clinical event or treatment modification and without sequels of TMA in the biopsy, renal function declined. Discontinuation of BCV led to rapid improvement of renal function. We share the opinion that concomitant multidrug administration and nephrotoxic therapy (calcineurin inhibitor, foscavir) may contribute to increase the BCV-mediated renal toxicity.
The underlying mechanisms of BCV-mediated renal toxicity are unknown. As highlighted in the manuscript, BCV in not a substrate of OAT1. But several other transporters may be involved in BCV-mediated tubular toxicity such as OCT2, OCTN2, MRP2, MDR1, BCRP, MATE1, MATE2-K. Moreover, the presence of chronic kidney failure in patient may potent tubular toxicity(4).
Safety studies and clinical assays in healthy volunteers or in hematopoietic stem cells receivers assessing toxicity of BCV are reassuring. Indeed, patients showed great tolerance to BCV, particularly concerning the involvement of acute kidney injury. However, the previous published trials may not be representative of our two specific patients (solid organ transplant with previous severe chronic kidney failure and concomitant treatment with other nephrotoxic drugs):
Indeed, during CMX001-201 study(5), focusing on the prevention of CMV infection in hematopoietic stem cell receivers, patients with severe chronic kidney failure (eGFR < 30 mL/min) were excluded. Moreover, depending of the weekly dose, 40 to 78% of patients presented an elevation of creatinine level. Interestingly, the most common side-effect was diarrhea.
In CMX001-202 trial, realized in adults and pediatric population for the preemptive treatment of adenovirus in hematopoietic stem cell receiver, GFR analysis after treatment was not performed in adult subjects due to small number of patient(6). The same authors reviewed renal function from the 3 completed clinical studies using BCV for treatment of adenovirus infection. In total 72 kidney-related adverse events were reported in 62 patients who received BCV (total 420 patients). About 50% of renal adverse events were considered as moderate to severe. Five (7%) renal events led to discontinuation of BCV. Four (6%) renal failure events were considered possibly related to BCV by the reporting investigator(6).
In phase 3 studies, renal transplant receivers are poorly represented. In CMX001-304 study, an open-labeled phase 3 study to evaluate BCV in treatment of adenovirus infection, only one adult renal transplant receiver was recruited(7). In CMX001-350 study, an open-labeled trial to assess BCV efficiency during life threatening disease caused by dsDNA viruses, only 16% of patients receive a solid organ transplant without precision of organ (liver, renal, lung, heart or combine…) (7,8).
In summary, in previous published trials, BCV showed good renal tolerance but renal adverse events were already report in some patients and were considered as possibly related to BCV. Moreover, immunocompromised patients enrolled during phase 2 and 3 trials were mainly hematopoietic stem cell receivers without moderate or severe chronic kidney disease and may not be compared to our two patients. Thus, the concomitant presence of kidney allograft in adults with chronic kidney failure may contribute to BCV-mediated toxicity.
Concerning renal adaptation, we followed the recommendations of CHIMERIX laboratories, advising discontinuation of BCV when estimated GFR decreases under 15 mL/min/1,73 m2. For both patient, elevation of creatinine was followed by discontinuation of BCV when eGFR decrease under 15 mL/min/1,73 m2. But French national society of Nephrology and Dialysis edited evidence-based guidelines for renal adaptation of BCV in chronic kidney failure patients. We have to bring a correction in the manuscript (Paragraph 1.1 line 23-24, "In accordance with CHIMERIX" should be replaced by: " In accordance with French Society of Nephrology and Dialysis"). However, even with renal adapted doses, a renal toxicity was observed in both patients and for both patient, discontinuation of BCV led to improve renal function.
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