Nirmatrelvir-ritonavir bests molnupiravir in COVID-19 patients with advanced kidney disease

In a retrospective observational study, nirmatrelvir-ritonavir trumps molnupiravir in reducing the risk of all-cause mortality at 90 days and hospitalization in COVID-19 patients with advanced kidney disease (chronic kidney disease [CKD] stage 4, ie, eGFR <30 mL/min/1.73 m²).

Compared with molnupiravir, absolute risk reduction (ARR) at 90 days with nirmatrelvir-ritonavir was 2.91 percent for all-cause mortality and 4.16 percent for hospitalization. The respective adjusted hazard ratios (HRs) for these two outcomes were 0.624 and 0.782. [eClinicalMedicine 2024;72:102620]

“Based on the estimated HR for all-cause mortality … the E-value was 2.59. This suggested that the estimated HR could be explained by unmeasured confounding variables, with a 2.59-fold stronger association with all-cause mortality. Hence, our conclusions are likely robust to potential unmeasured confounding,” the researchers explained.

As for the other outcomes, there were similar incidences of intensive care unit (ICU) admissions (ARR at 90 days, -0.09 percent), ventilatory support (ARR at 90 days, 0.13 percent), hepatic impairment (ARR at 90 days, 0.03 percent), ischaemic stroke (ARR at 90 days, -0.06 percent), and myocardial infarction (MI; ARR at 90 days, 0.07 percent) between the nirmatrelvir-ritonavir and molnupiravir arms.

Numerically, events were lower in the nirmatrelvir-ritonavir than the molnupiravir arm. These events were all-cause mortality (n=74 vs 273), ICU admissions (n=4 vs 6), ventilatory support (n=13 and 35), hospitalizations (n=218 vs 618), ischaemic stroke (n=3 vs 5), and MI (n=2 vs 7).

One of the notable side effects tied to nirmatrelvir use is hepatotoxicity. [https://www.fda.gov/media/155050/download, accessed July 3, 2024] “[H]ence, hepatic tolerance is one of the concerns when dosing in patients with advanced kidney disease,” the researchers noted. In the study, there were no cases of hepatic impairment in the nirmatrelvir-ritonavir arm. With molnupiravir, there was one case reported.

CKD patients have worse outcomes

During the fifth Omicron wave in Hong Kong, individuals undergoing peritoneal dialysis and haemodialysis had a high mortality (19.4 and 21.9 deaths/1,000 dialysis population, respectively). [Hong Kong Med J 2023;29:82-83] “[CKD patients] are likely to have worse outcomes, including a higher incidence of hospitalization. Early effective antiviral therapy is therefore crucial for this group of patients,” the researchers said. [J Nephrol 2021;34:173-183; J Nephrol 2022;35:69-85]

Nirmatrelvir-ritonavir is used in COVID-19 patients with normal or mild renal impairment (eGFR ≥30 mL/min/1.73 m²), but there is insufficient data regarding its use in individuals with advanced kidney disease, they pointed out.

The research team adopted target trial emulation using data from a territory-wide electronic health record database. They gathered data on 4,886 patients with advanced kidney disease (mean age 79 years, 54 percent women) who were infected with COVID-19 and were prescribed molnupiravir (n=3,424) or nirmatrelvir-ritonavir (n=1,462) within 5 days of infection between March 16, 2022 and December 31, 2022.

“[Our study] is the first territory-wide real-world study comparing nirmatrelvir-ritonavir and molnupiravir in advanced kidney disease,” said the researchers. “Our findings supplement further pieces of information on how the two antiviral drugs compare with each other in terms of effectiveness.”

They added that the large database confers high population representation. However, the information extracted from this database is not enough to sort out COVID-19-related hospitalizations and mortality, as well as severe COVID-19 infections.

“[Nonetheless, the findings suggest that] nirmatrelvir-ritonavir remains a favourable option for this group of patients,” the researchers concluded.

They called for further investigation on the effects of nirmatrelvir-ritonavir in dialysis and non-dialysis cohorts to establish pharmacokinetic (PK) differences and optimize dosing for these patient groups.

“Dialysis and non-dialysis patients are likely to have different drug elimination profiles. Moreover, PK is dependent on modalities and frequency of dialysis. Whether nirmatrelvir is dialysable or requires further dose adjustments remains to be an area to explore,” they said.