Important aspects of this case involve treatment with combination therapy of dual direct-acting antivirals, the use of an extended course of 10 days, and the crushing of nirmatrelvir to allow administration via a nasogastric tube. This case suggests the combination of Paxlovid and remdesivir may act synergistically as antivirals, as seen in pre-clinical studies.
During this illness hypoxia worsened requiring intubation, SARS-CoV-2 RNA cycle threshold values progressively decreased, and chest CT imaging progressively worsened prior to treatment with dual DAAs. Notably, disease progressed despite treatment with both agents as monotherapy and nMAbs. This suggests that during persistent infection a significant pathology is caused by ongoing viral replication. For this reason, antivirals may be needed to prevent direct pathology from viral replication during persistent infection. In this case, immunomodulation mediated by steroids likely offered additional benefit in reducing immunopathology caused by immune stimulation from the ongoing presence of viral antigen.
Experience from other viral pathogens suggests dual therapy may have benefit in reducing chance of emergent resistance, as recognised by expert opinion [10]. As the two antiviral agents have different targets, which are not present in humans, we believe co-administration poses little theoretical risk of additive or synergistic toxicity. Renal and hepatic function was monitored with regular biochemistry testing with no adverse effect identified.
Prolonged courses of antivirals in COVID-19 have previously been studied. Whilst Paxlovid is licensed in North America and Europe as a 5 day course [11], in a phase 2/3 study of Paxlovid as post-exposure prophylaxis, one arm received 10 days of Paxlovid [12] with no adverse safety signals after interim analysis [13]. The safety of remdesivir courses of 10 days is known from large randomised controlled trials [14].
The monograph for Paxlovid states tablets should be swallowed whole and not chewed, broken, or crushed [11]. Crushing tablets may alter the pharmacokinetics and therefore impact on drug absorption of either components, nirmatrelvir or ritonavir. This is seen with tablets containing related drug combination, lopinavir/ritonavir, with reduction in the bioavailability of ritonavir [15] Therefore, ritonavir tablets were substituted with ritonavir sachets for suspension, which is licensed for NG administration [16]. The use of crushed nirmatrelvir was supported by a previous publication documenting the pharmacokinetics of an oral suspension [17]. As noted by British Columbia COVID-19 Treatment Committee, crushed nirmatrelvir is unlikely to have any significant differences to those reported in the nirmatrelvir tablet monograph [18]. Indeed, nirmatrelvir tablets are film-coated for ease of swallowing and aesthetic purpose, rather than for pharmacokinetic reasons (Personal communication with Pfizer Medicines Information team, 09-Sep-22). The multidisciplinary team felt there was sufficient pharmacokinetic data to support crushing of nirmatrelvir and use of suspended ritonavir instead of Paxlovid tablets. TDM may be valuable for confirming differences in pharmacokinetics caused by crushing, but is not currently commercially available.
There is a theoretical concern around the safety of crushing nirmatrelvir tablets, due to evidence of teratogenicity from animal studies [11]. As such Paxlovid is not recommended in pregnancy [11]. Healthcare workers may be inadvertently exposed whilst crushing, and patients may have increased exposure from altered pharmacokinetics. However these animal studies were conducted at much higher doses, achieving plasma concentrations much higher than would be achieved in humans through accidental exposure during crushing [11]. Risk to staff was considered to be low, and further mitigated by use of personal protective equipment (gloves, gowns and FFP3 masks) during the care of SARS-CoV-2 positive patients.
This case report suggests dual DAA therapy may have utility in treating chronic COVID-19. In our experience, immunosuppressed patients with chronic COVID-19 often have poor outcomes, and clinical trials are urgently needed to confirm the efficacy, safety, optimum regimen and duration of treatments for persistent SARS-CoV-2 infection.