Kidney Res Clin Pract > Volume 42(2); 2023 > Article
Dufour, Devresse, Scohy, Briquet, Georgery, Delaey, Greef, Goffin, and Labriola: Safety and efficiency of molnupiravir for COVID-19 patients with advanced chronic kidney disease
Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is particularly life threatening in patients who are immunocompromised, including those with advanced chronic kidney disease (CKD) [1,2]. Despite the implementation of a third dose of a messenger RNA (mRNA) vaccine, the efficacy of SARS-CoV-2 vaccination on humoral and cellular immunities is reduced in the population with CKD, resulting in an increased incidence of severe infection and mortality, including in fully vaccinated patients [3].
In this context, several antiviral therapies or monoclonal antibodies are being investigated for treatment of COVID-19. These drugs prevent viral replication through various mechanisms, including neutralization, blocking SARS-CoV-2 entry, and inhibiting RNA polymerase or proteases activity [4,5]. However, patients with CKD are frequently excluded from clinical trials evaluating new drugs.
Although sotrovimab and casirivimab/imdevimab have been shown to confer satisfactory protection against the COVID-19 Delta variant, they have limited neutralizing activity against the Omicron variant [4]. Remdesivir, nirmatrelvir/ritonavir, bebtelovimab, and molnupiravir seem to be effective against the Omicron variant [5]. U.S. Food and Drug Administration product labels do not recommend remdesivir or nirmatrelvir/ritonavir in patients with an estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m2 due to a lack of data concerning the risk of drug accumulation in this population. Indeed, nirmatrelvir and one of the excipients contained in remdesivir (betadex sulfobutyl ether sodium) are renally cleared and can accumulate in patients with abnormal kidney function. The appropriate dose for patients with severe renal impairment has not been determined. Bebtelovimab is only available in the United States. Thus, molnupiravir is the only antiviral drug that could potentially be used for CKD patients with the COVID-19 Omicron variant outside of the United States. Molnupiravir is an inhibitor of the RNA-dependent RNA polymerase of SARS-CoV-2. Although a phase III double-blind, placebo-controlled study of molnupiravir as an oral treatment for COVID-19 in nonhospitalized adults (MOVe-OUT) showed good efficacy, patients with eGFR of <30 mL/min or on dialysis were excluded [6]. To our knowledge, this is the first report on the efficacy and safety of molnupiravir in advanced CKD patients.
Three patients were on maintenance hemodialysis, one had received a transplant and had CKD G4 (eGFR, 18 mL/min/1.73 m2), and one had CKD G5 (eGFR, 11 mL/min/1.73 m2) (Table 1). Patients 1, 2, and 4 were under immunosuppressive therapy (heart transplantation, renal transplantation, and treatment of minimal change disease, respectively). All five were fully vaccinated (four doses of the mRNA BNT162b2 vaccine [Pfizer-BioNTech]). They received molnupiravir at a dosage of 800 mg twice daily for 5 days (given after hemodialysis on dialysis day) for mild-to-moderate COVID-19. Quantitative reverse transcription polymerase chain reaction was performed on nasopharyngeal swabs at diagnosis, on day 6 or 7 to evaluate the time to clearance of the virus, and on day 13 for patients 4 and 5 (Fig. 1). Three patients showed <1,000 copies/mL at day 6 or 7. Patients 4 and 5 had results of 1,685 and 2,071 copies/mL on day 13, respectively, and rapid symptom resolution. No adverse effects were observed in any patient. Renal function remained stable in the two CKD patients who were not on dialysis (Table 1). One month after treatment, four patients were entirely asymptomatic and feeling well. Patient 1 still reported tiredness and loss of appetite. None of the five patients experienced delayed immune events or early recurrence of SARS-CoV-2 infection.
Molnupiravir is a prodrug that is metabolized to the ribonucleoside analogue N-hydroxycytidine (NHC). NHC is distributed into cells where it is incorporated into viral RNA by the viral RNA polymerase, which inhibits replication [7]. NHC is eliminated by cellular metabolism to uridine and/or cytidine through the same pathways involved in endogenous pyrimidine metabolism [8]. Renal clearance is not a meaningful route of elimination for NHC. For these reasons, no dose adjustments in patients with any degree of kidney impairment are recommended on the product label [7,8].
Molnupiravir is a safe drug with no contraindications (except during pregnancy and in patients aged <18 years because it may affect bone and cartilage growth). Side effects are limited; the most common (incidence ≥ 1%) include diarrhea, nausea, and dizziness [6]. No drug interactions have been identified (unlike for nirmatrelvir-ritonavir); although ritonavir is a potent CYP3A4 inhibitor and an inducer of other cytochrome p450 substances, oral administration allows treatment outside the hospital, while remdesivir or bebtelovimab requires an intravenous route.
In conclusion, this real-life observational study reported the safety of molnupiravir use in advanced CKD and its relative effectiveness on symptoms and virus clearance.

Notes

Conflicts of interest

All authors have no conflicts of interest to declare.

Data sharing statement

The data presented in this study are available on request from the corresponding author.

Authors’ contributions

Conceptualization: AD, LL

Data curation: ID

Investigation: ID, HG, PD

Formal analysis: ID, AD, EG, LL

Supervision and validation: LL, AD, EG, JDG

Ressources: AS, CB

All authors read and approved the final manuscript.

Figure 1.

Evolution of the SARS-CoV-2 viral load on nasopharyngeal swabs.

SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
j-krcp-22-194f1.jpg
Table 1.
Baseline and COVID-19 characteristics of patients treated with molnupiravir.
Characteristic Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
Age (yr) 56 71 46 60 57
Sex Male Male Female Male Male
Cause of CKD CNI toxicity MPGN FSGS MCD Tubulo-interstitial disease
Dialysis modality (CKD stage) In-center HD (CKD G5D) No dialysis (CKD G4) Home HD (CKD G5D) No dialysis (CKD G5) In-center HD (CKD G5D)
Immunosuppressive therapy Tac/MMF Tac/Cs No Csa No
Reason for immunosuppressive therapy Cardiac transplant Renal transplant No MCD No
Cardiovascular disease Cardiac transplant Aortic valve stenosis No No Atrial fibrillation
Ischemic cardiomyopathy
Hypertension Yes No Yes Yes No
Diabetes mellitus Type II No No No No
Body mass index (kg/m2) 30 22 25 24 29
Chronic liver disease Liver cirrhosis due to NASH Nodular regenerative hyperplasia
Chronic pulmonary disease No No No No No
Other relevant comorbidities CML CLL Failed kidney transplant Spina bifida
Symptom
  Fever Yes No Yes Yes No
  Cough Yes Yes Yes Yes Yes
  Dyspnea No No No No No
  Diarrhea Yes No No No No
  Time between symptom onset and molnupiravir administration (day) 2 4 3 3 5
Vital sign at presentations
  Blood pressure (mmHg) 98/52 135/80 151/93 138/89 73/33
  Heart rate (beats/min) 106 85 110 99 82
  Oxygen saturation (%) 93 100 100 98 98
  Need for supplemental oxygen No No No No No
Baseline laboratory test results
  hsCRP (mg/L) 34 16 7 224 46
  Platelets (×103/µL) 125 118 129 131 150
  Lymphocytes (µL–1) 630 1370 410 770 770
  eGFR (mL/min/1.73 m2) Dialysis 18 11 Dialysis
  Serum albumin (g/L) 30 27 40 43 34
  Glucose level (mg/dL) 190 99 80 159 NA
  SARS-CoV-2 variant Omicron BA.5.1 Omicron BA.5.1.3 NA Omicron BA.5.2.1 Omicron BA.5.1.3
SARS-CoV-2 viral load on nasopharyngeal swabs
  Day 0 (copies/mL) 20,335,411 18,222,021 4,700 1,761,144 43,275,421
  Day 6 or 7 (copies/mL) <1,000 <1,000 <1,000 250,722 348,467
  Day 13 (copies/mL) NA NA NA 1,685 2,071
Long-term prognosis
  eGFR after treatment (mL/min/1.73 m2) NA 24 NA 19 NA
  Remaining symptoms Tiredness No No No No
Loss of appetite

CKD, chronic kidney disease; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CNI, calcineurin inhibitor; COVID-19, coronavirus disease 2019; Cs, corticosteroid; Csa, cyclosporin A; eGFR, estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; HBP, high blood pressure; HD, hemodialysis; hsCRP, high sensitivity C-reavtive protein; MCD, minimal change disease; MMF, mycophenolate mofetil; MPGN, membranoproliferative glomerulonephritis; NA, not available; NASH, nonalcoholic steatohepatitis; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Tac, tacrolimus.

References

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