Preliminary Clinical Experience of Molnupiravir to Prevent Progression of COVID-19 in Kidney Transplant Recipients : Transplantation

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Original Clinical Science—General

Preliminary Clinical Experience of Molnupiravir to Prevent Progression of COVID-19 in Kidney Transplant Recipients

Villamarín, Miguel MD1; Márquez-Algaba, Ester MD1; Esperalba, Juliana MD2; Perelló, Manuel MD3; Los Arcos, Ibai MD, PhD1; Campany, David MD4; Moreso, Francisco MD, PhD3; Len, Oscar MD, PhD1,5

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doi: 10.1097/TP.0000000000004306
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Abstract

INTRODUCTION

Kidney transplant recipients (KTRs) are a population group that is especially vulnerable to COVID-19, not only because they are immunosuppressed patients but also because they are patients with many other comorbidities.1 The administration of monoclonal antibodies or antivirals reduces the risk of COVID-19–related hospitalization and death.2 With the Omicron variant being the predominant one, options to treat COVID-19 reduced drastically. The monoclonal antibody sotrovimab retains efficacy to the original Omicron variant.3 However, it is often difficult to organize an ambulatory intravenous administration. This is also the case with remdesivir despite favorable studies.4,5 Fortunately, 2 oral options became available at the end of 2021: nirmatrelvir coadministered with ritonavir and molnupiravir. However, ritonavir is a potent cytochrome P450 inhibitor that hinders its concomitant use with anticalcineurin or mammalian target of rapamycin (mTOR) inhibitors that are essential to prevent rejection in KTRs. Thus, molnupiravir seems the only suitable option to treat COVID-19 in KTRs at early stages. Molnupiravir is an oral antiviral drug that inhibits replication of SARS-CoV-2 with an in vitro potency broadly similar to remdesivir avoiding hospitalization compared with placebo.6 Molnupiravir is administered BID for 5 d. It retains activity against Omicron variants of SARS-CoV-2.7 However, KTRs were not included in the study that assessed the efficacy of molnupiravir. So, the aim of our study was to describe the clinical evolution of KTRs with SARS-CoV-2 infection treated with molnupiravir and the possible interactions between molnupiravir and the immunosuppressive treatment.

MATERIALS AND METHODS

Population Under Study and Design

We conducted a prospective observational cohort study at our center, a tertiary referral hospital in which around 120 kidney transplants are performed every year. All adult KTRs diagnosed with COVID-19 and treated with molnupiravir or remdesivir from January 1, 2022, until April 30, 2022, were included. The baseline characteristics of the patients, laboratory data, treatments received, immunosuppression management, graft function, and clinical evolution were included in a specifically dedicated database. All patients were aware of the treatment‚ and written consent was obtained. All patients treated were included in the Pharmacy registry. This study adhered to the principles of the Declaration of Helsinki, formulated by the World Medical Association.

Inclusion Criteria

Following the medical indication authorized in Spain during the study time period, elegible KTRs were those patients older than 18 y that fulfilled inclusion criteria: patients diagnosed with SARS-CoV-2 infection within the first 5 d, with mild symptoms, who presented with renal (glomerular filtration measured by CKD-EPI <30 mL/min/1.73m2) or liver impairment (alanine aminotransferase above 5 times the upper limit of normal) that prevented the use of remdesivir and had antibodies against the spike protein that prevented the use of monoclonal antibodies.8 KTRs in whom outpatient intravenous administration was not feasible were also eligible. An individual application for medications in special situations was requested for each treatment.

Antiviral Treatment

The dose for molnupiravir was 800 mg every 12 h orally for 5 d. Remdesivir was administered intravenously for 3 d (200 mg on day 1 and 100 mg on days 2 and 3).

RESULTS

Nine KTRs with SARS-CoV-2 (Omicron variant) infection and mild symptoms received molnupiravir as shown in Table 1. Half of them were male‚ and median age was 49 y (IQR 30–59). Three of them were in the early posttransplant period and received a basiliximab (n = 2) or antithymocyte globulin (ATG)-based induction (n = 1). One of the patients had been treated with methylprednisolone bolus and ATG for an episode of acute rejection in the previous months and was also receiving eculizumab for a thrombotic microangiopathy at the time of SARS-CoV-2 infection. They were all vaccinated with mRNA vaccines‚ and all but 1 had serological response by means of positive antispike antibodies. Molnupiravir was initiated within the first 5 d after symptoms onset in all cases in an outpatient basis. The dose of mycophenolate was reduced or discontinued in 6 of 9 patients. Median time from molnupiravir initiation to tacrolimus or everolimus first control was 8 d (IQR 3–21 d). Only one of the patients experienced a worsening of his clinical condition despite molnupiravir treatment and developed pneumonia requiring hospital admission. However, the patient did not require high flow oxygen or intensive care unit admission (maximum FiO2 0.35). None of the patients suffered adverse effects attributed to molnupiravir‚ and no adjustment of tacrolimus or everolimus dose was needed. None of the 7 patients in the remdesivir cohort presented COVID-19 worsening (see Table 2). There were no differences between the 2 cohorts as shown in Table 3.

TABLE 1. - Kidney transplant recipients’ characteristics (molnupiravir)
Patient 1 2 3 4 5 6 7 8 9
Sex/age (y) F/54 M/35 M/49 F/57 F/20 M/30 M/30 M/62 F/72
Time since KT 7 d 4 mo 4 d 9 y 5 mo 29 mo 2 mo 5 y 20 d
IS BSX, TAC, MPA, PRED TAC, EVE, PRED. ATG (AR), eculizumab (TMA) BSX, TAC, MMF, PRED TAC, PRED TAC, MPA, PRED TAC, MPA, PRED TAC, MMF, PRED TAC, MMF, PRED ATG, TAC, MPA, PRED
SARS-CoV-2 vaccination 3 doses 2 doses 3 doses 3 doses 3 doses 3 doses 3 doses 4 doses 3 doses
SARS-CoV-2 serology (IgG anti-S protein) Positive Positive Positive Positive Positive Negative Positive Positive Positive
Time to molnupiravir initiation (d) 2 5 3 5 5 5 5 2 1
GF premolnupiravir initiation (mL/min) 78 33 18 18 >90 58 38 17 12
ALT premolnupiravir initiation (UI/L) 22 37 16 16 13 14 15 13 19
GF after molnupiravir treatment (mL/min) 85 38 29 20 >90 61 42 27 22
Time to immunosuppressive drug levels control from molnupiravir initiation (d) a 9 8 5 22 21 3 2
IS adjustment MPA dose reduction No MMF dose reduction No MPA discontinuation MPA discontinuation No MMF discontinuation MPA discontinuation
Progression to pneumonia No Yes (maximum FiO2 35%) No No No No No No No
Hospital admission No Yes (Already admitted) b No No No No (Already admitted) b (Already admitted) b
Adverse effects No No No No No No No No No
aClose immunosuppressive drug levels monitoring was only performed in patients who were hospitalized and those with recent kidney transplant who required close follow-up for this reason (n = 7). Immunosuppression control was not carried out in 2 patients because clinical evolution was correct and they had received kidney transplant >2 y ago.
bFor reasons other than COVID-19.
AR, acute rejection; ATG, antithymocyte globulin; BSX, basiliximab; EVE, everolimus; F, female; GF, glomerular filtration; IS, immunosuppression; KT, kidney transplantation; M, male; MMF, mycophenolate mofetil; MPA, mycophenolic acid; PRED, prednisone; TAC, tacrolimus; TMA, thrombotic microangiopathy.

TABLE 2. - Kidney transplant recipients’ characteristics (remdesivir)
Patient 1 2 3 4 5 6 7
Sex/age (y) M/37 F/35 F/46 F/39 M/61 F/54 M/37
Time since KT 4 mo 1 y 8 y 10 y 11 d 14 y 11 y
IS TAC, MMF, PRED TAC, MPA, PRED TAC, MMF, PRED TAC, MMF, PRED BSX, TAC, MMF, PRED TAC, MPA, PRED TAC, SRL, PRED
SARS-CoV-2 vaccination 2 doses 3 doses 3 doses 4 doses 3 doses 3 doses 4 doses
SARS-CoV-2 serology (IgG anti-S protein) Positive Negative Positive Unknown Positive Positive Positive
Time to remdesivir initiation (d) 4 3 1 3 1 4 1
GF preremdesivir initiation (mL/min) 53 56 87 87 73 46 53
ALT preremdesivir initiation (UI/L) 13 21 12 34 78 14 62
GF after remdesivir treatment (mL/min) 48 55 86 87 77 61 55
IS adjustment MMF discontinuation No MMF discontinuation MMF discontinuation No MPA discontinuation No
Treatment administration Inpatient HaH Inpatient HaH Inpatient HaH Inpatient
Progression to pneumonia (Already admitted) a No No No (Already admitted) a No No
Hospital admission No No No No No No No
Adverse effects No No No No No No No
aFor reasons other than COVID-19.
BSX, basiliximab; F, female; GF, glomerular filtration; HaH, hospital at home; IS, immunosuppression; KT, kidney transplantation; M, male; MMF, mycophenolate mofetil; MPA, mycophenolic acid; PRED, prednisone; SRL, sirolimus; TAC, tacrolimus.

TABLE 3. - Comparison between molnupiravir and remdesivir treatment
Molnupiravir (n = 9) Remdesivir (n = 7) P
Age, y (median [IQR]) 49 [30–59] 39 [34–54] 1.0
Male, n (%) 5 (56) 3 (43) 0.5
SARS-CoV-2 infection in early post-trasplantation period (<1 mo), n (%) 3 (33) 1 (14) 0.39
SARS-CoV-2 infection in the first 2 y from transplantation, n (%) 6 (67) 3 (43) 0.32
SARS-CoV-2 vaccination (>2 doses), n (%) 8 (89) 6 (87) 0.55
SARS-CoV-2 serology positive (IgG anti-S protein), n (%) 8 (89) 5 (71) 0.48
Time to SARS-CoV-2 treatment initiation, d (median [IQR]) 5 [2–5] 3 [1–4] 0.36
GF pretreatment initiation, mL/min (median [IQR]) 33 [17–68] 56 [53–87] 0.61
GF post-treatment, mL/min (median [IQR]) 38 [24–73] 61 [55–86] 0.61
ALT pretreatment initiation, UI/L (median [IQR]) 16 [13–26] 21 [13–62] 0.61
IS adjustment, n (%) 6 (67) 4 (57) 0.55
Progression to pneumonia, n (%) 1 (11) 0 0.56
Hospital admission due to SARS-CoV-2 pneumonia, n (%) 1 (11) 0 0.56
Adverse effects, n (%) 0 0
GF, glomerular filtration; IQR, interquartile range; IS, immunosuppression

DISCUSSION

Treatment of COVID-19 is rapidly evolving, and recently, different therapeutic lines have been tried in the initial stage of the disease, including molnupiravir. However, evidence about effectivity and safety of these therapies is largely uncharacterized in KTRs.

The present study describes the favorable evolution of a series of KTRs with COVID-19 treated with molnupiravir compared with a cohort of patients receiving remdesivir.

Molnupiravir has shown a decrease in the probability of admission compared with placebo when administered within the 5 d of infection.6 In our study, it was started a median of 5 d (2–5) d after symptoms onset. Only one of the patients (1/9, 11%) was admitted to the hospital because of a worsening in health condition related to COVID-19, similar to the 16% admission rate (8/49) published in a recent retrospective study on COVID-19 outpatient therapies in solid transplant recipients.9 The patient was 35 y old and had no other comorbidities, but he had been treated with methylprednisolone bolus and ATG for an episode of acute rejection in the previous months and was also receiving eculizumab for a thrombotic microangiopathy at the time of SARS-CoV-2 infection. In addition, molnupiravir was initiated at day +5 after the onset of symptoms. For this reason and based on the mechanism of antiviral activity of the drug (nucleoside analogue acting though induction of error catastrophe in virus replication),10 it would be expected that, the shorter the clinical course of the disease, the more effective the treatment with molnupiravir should be. It is also important to notice that the patient that progressed to pneumonia was only vaccinated with 2 doses of the vaccine. The administration of a booster dose is protective against the Omicron variant.11

The management of immunosuppression is a complex issue in the context of a possible severe infection, not only because of the infection itself but also because of the possible interaction with the drugs used to treat SARS-CoV-2 pneumonia. So, it is important to mention that, in our series, molnupiravir has not shown interactions with calcineurin or mTOR inhibitors. In our study, immunosuppression with antimetabolites was reduced or withdrawn in all patients at diagnosis as described elsewhere.12 Mycophenolate was reintroduced once treatment with molnupiravir finished‚ and none of them developed rejection after a 30-d follow-up.

Compared with remdesivir, both drugs were well tolerated‚ and recipients had no adverse events.

However, molnupiravir per oral administration instead of intravenous remdesivir may be more practical and patient friendly for nonhospitalized patients. This fact and the possibility of using it in patients with renal impairment are 2 advantages that make this drug a promising option in KTRs.

The main limitation of our study is the small size of the cohort. However, evidence on the efficacy and safety of molnupiravir in solid organ transplant patients is still scant, and we provide some real-life experience of molnupiravir outcomes in KTR.

In conclusion, our study suggests that KTRs with SARS-CoV-2 infection under treatment with molnupiravir have a good clinical evolution with a probable lower risk for hospitalization and no adverse effects. At the renal level, molnupiravir was well tolerated, with no evidence of nephrotoxicity secondary to the drug or interactions with the immunosuppressive therapy. However, although promising, further controlled studies with a larger number of patients are necessary to broaden the understanding of this drug in SARS-CoV-2 infection in kidney transplant patients.

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