Therapeutic advances in COVID-19

Abstract

Over 2 years have passed since the start of the COVID-19 pandemic, which has claimed millions of lives. Unlike the early days of the pandemic, when management decisions were based on extrapolations from in vitro data, case reports and case series, clinicians are now equipped with an armamentarium of therapies based on high-quality evidence. These treatments are spread across seven main therapeutic categories: anti-inflammatory agents, antivirals, antithrombotics, therapies for acute hypoxaemic respiratory failure, anti-SARS-CoV-2 (neutralizing) antibody therapies, modulators of the renin-angiotensin-aldosterone system and vitamins. For each of these treatments, the patient population characteristics and clinical settings in which they were studied are important considerations. Although few direct comparisons have been performed, the evidence base and magnitude of benefit for anti-inflammatory and antiviral agents clearly outweigh those of other therapeutic approaches such as vitamins. The emergence of novel variants has further complicated the interpretation of much of the available evidence, particularly for antibody therapies. Importantly, patients with acute and chronic kidney disease were under-represented in many of the COVID-19 clinical trials, and outcomes in this population might differ from those reported in the general population. Here, we examine the clinical evidence for these therapies through a kidney medicine lens.

Fig. 1. Classes of therapies for COVID-19.

Therapies for COVID-19 can be broadly categorized as targeting the host response to infection (including inflammation, thrombosis, acute respiratory distress syndrome (ARDS) and renin–angiotensin–aldosterone system (RAAS) activation) or targeting the virus directly (including direct antivirals and antibody-based therapies). SARS-CoV-2 infection can lead to hyperinflammation characterized by abundant circulating levels of pro-inflammatory cytokines such as IL-6. Therapies targeting inflammation include immunosuppressive drugs such as glucocorticoids (for example, dexamethasone) and anti-IL-6 receptor antibodies (for example, tocilizumab). Several antithrombotic therapies have also been trialled to address the haemostatic and thrombotic complications associated with COVID-19, whereas different methods of oxygen delivery and intubation can be employed to treat patients with ARDS. COVID-19 can also disrupt RAAS homeostasis and drugs such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers are being investigated as potential therapies. Finally, therapies targeting SARS-CoV-2 directly include antivirals that disrupt viral replication and neutralizing antibody therapies that prevent virus entry into host cells.

Fig. 2. Timeline of publication of pivotal phase III randomized clinical trials of COVID-19 therapies.

Timeline of publication and key features of pivotal phase III randomized clinical trials of COVID-19 therapies. These trials are categorized into six treatment categories: anti-inflammatory agents, antivirals, renin–angiotensin–aldosterone system (RAAS) modification, antithrombotic agents, convalescent plasma and monoclonal antibody therapies. AC, anticoagulation; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; d, days; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; IMV, invasive mechanical ventilation; NIV, noninvasive ventilation; outpts, outpatients; pts, patients. This timeline reflects published data as of 29 May 2022.

Fig. 3. Anti-inflammatory and antiviral agents for COVID-19 including dose adjustment for kidney function impairment.

The immunosuppressive therapies dexamethasone and tocilizumab can be used without dose adjustments in patients with kidney disease, including those with kidney failure. However, the anti-inflammatory agent baricitinib must be administered at reduced doses in patients with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m². In the case of antivirals used to treat SARS-CoV-2 infection, molnupiravir can be used without dose adjustments and remdesivir, although currently not recommended for use in patients with eGFR < 30 ml/min/1.73 m², has been reportedly used in patients across the spectrum of kidney dysfunction, including in patients with kidney failure who require kidney replacement therapy (KRT). By contrast, nirmatrelvir–ritonavir is contraindicated in patients with eGFR <30 ml/min/1.73 m² and, given its potential to increase exposure to calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors, must be used with extreme caution in recipients of solid organ transplants, and only if CNI and/or mTOR levels can be monitored closely. The asterisk indicates that in patients with eGFR 30–59 ml/min/1.73 m², the dose of nirmatrelvir is reduced by 50% but the ritonavir dose remains unchanged.