Lopinavir/ritonavir/tocilizumab

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An event is serious (based on the ICH definition) when the patient outcome is:

• * death

• * life-threatening

• * hospitalisation

• * disability

• * congenital anomaly

• * other medically important event

In a real-world, retrospective, open-label, single-arm, uncontrolled study of COVID-19 pneumonia patients, who had been treated between 30 March 2020 and 11 April 2020 in Australia, 3 men aged 46−71 years were described, of whom, 2 men developed ventilator-associated pneumonia, myositis or Staphylococcus epidermidis bacteraemia during off-label treatment with tocilizumab; while a 71-year-old man developed hepatitis during off-label treatment with tocilizumab and lopinavir/ritonavir for COVID-19 pneumonia [not all dosages, routes times to reactions onsets and outcomes stated].

Patient 1: A 53-year-old man, who had hypertension, had been diagnosed with SARS-CoV-2 infection and COVID-19 pneumonia. He was admitted to a hospital in Australia with fever and rapid-onset type I respiratory failure secondary to COVID-19 pneumonia. Eventually, he required endotracheal intubation and mechanical ventilation to manage adequate gas exchange and noradrenaline [norepinephrine] to maintain mean arterial BP above 70mm Hg. On day 2 of hospitalisation, he started receiving off-label lopinavir/ritonavir and hydroxychloroquine for 6 days. On day 3 of hospitalisation, he received a single dose of off-label IV tocilizumab 400mg. He also started receiving methylprednisolone 70mg (1 mg/kg). After 6 hours of tocilizumab administration, norepinephrine was stopped. His ventilatory function improved after 2 days of tocilizumab treatment; however, he developed encephalopathy when sedation was weaned. Therefore, corticosteroids were stopped. The encephalopathy resolved quickly. After 3 days of tocilizumab administration, he was diagnosed with ventilator-associated pneumonia, and tocilizumab was suspected as a contributory factor. He was thus treated with piperacillin/tazobactam. Following 3 days of tocilizumab administration, he was extubated. He was discharged from the ICU after 5 days of tocilizumab administration. On the next day, oxygen therapy was also stopped. After further 4 days, he was discharged home.

Patient 3: A 71-year-old man was diagnosed with SARS-CoV-2 infection and COVID-19 pneumonia. His medical history was significant for dyslipidaemia, bioprosthetic aortic valve replacement and lacunar stroke. He presented to the hospital in Australia with fever and rapid-onset type I respiratory failure secondary to COVID-19 pneumonia. His PaO₂ was 56mm Hg and a PF ratio was 93mm Hg. He was thus immediately transferred to the ICU. He received two doses of off-label IV tocilizumab 400mg 8 hours apart. After 50 hours of first tocilizumab administration, his FiO2 requirement reduced to 36% while SpO₂ maintained at greater than 92%. He maintained conscious proning for 16 hours per day. Along with tocilizumab, he also received off-label lopinavir/ritonavir 400mg/100mg twice daily and off-label hydroxychloroquine. He exhibited prolonged corrected QT interval on ECG [aetiology not stated]. Thus, lopinavir/ritonavir and hydroxychloroquine were discontinued. Lopinavir/ritonavir was administered for three days and hydroxychloroquine was administered for six days. After 6 days of tocilizumab administration, he was shifted out of the ICU. After 12 days of tocilizumab administration, he developed hepatitis, which was suspected to be related to tocilizumab and lopinavir/ritonavir. The hepatitis resolved after 5 days, without any treatment. Subsequent screening for autoimmune and infectious hepatitis was found to be negative; while abdominal ultrasound revealed hepatic steatosis. On day 19 after tocilizumab administration, he remained admitted, requiring oxygen via nasal cannulae.

Patient 5: A 46-year-old man, with a significant history of asthma and obesity, had been diagnosed with SARS-CoV-2 infection, presented to the hospital with COVID-19 pneumonia, with SpO2 95% on room air. He was admitted to a hospital in Australia. On day 3 of hospitalisation, he developed type I respiratory failure. Therefore, on day 4, he underwent endotracheal intubation and mechanical ventilation. On day 5, he developed acute kidney injury, for which continuous renal replacement therapy was started on day 6. On day 6, his PF ratio was 69mm Hg and he exhibited clinical and biochemical features of cytokine release syndrome. He was advised for manual proning. He received a single dose of off-label IV tocilizumab 800mg and methylprednisolone. Subsequently, the methylprednisolone dose was tapered and eventually stopped. After the day of tocilizumab administration, his PF ratio improved to 193mm Hg. After 12 days of tocilizumab administration, he was extubated. After 15 days of tocilizumab administration, oxygen therapy was stopped. During hospitalisation, he developed myositis. On day 17 after tocilizumab administration, spinal MRI revealed inflammation of the left psoas and iliacus muscles and surrounding the left lumbar plexus. He also developed Staphylococcus epidermidis bacteraemia attributed to central venous catheterisation, for which he was treated with vancomycin and venous catheter was removed. He also exhibited eosinophilia (peak 1.9 x 10⁹cells/L). As of day 24 after tocilizumab administration, he remained hospitalised and dialysis-dependent. The tocilizumab therapy was suspected to be contributory agent in development of myositis and Staphylococcus epidermidis bacteraemia.