A recent study published in The New England Journal of Medicine tested the “benefits” of treating severe Covid-19 cases with Lopinavir-Ritonavir.
The authors of the study concluded that there was no observed benefit to treating adults with sever Covid-19 with Lopinavir-Ritonavir.
As of December 2019, a new Coronavirus, designated SARS-CoV-2, has caused an international outbreak of respiratory disease called Covid-19. The full spectrum of Covid-19 ranges from mild, self-limiting disease of the respiratory tract to severe progressive pneumonia, multiple organ failure, and death.
So far, there are no specific therapeutic agents for Coronavirus infections. After the onset of severe acute respiratory syndrome (SARS) in 2003, screening for approved drugs identified lopinavir, a human immunodeficiency virus (HIV) type 1 protease aspartate inhibitor, which has in vitro inhibitory activity against SARS-CoV, the virus that causes SARS in humans.
Ritonavir is combined with lopinavir to increase its plasma half-life by inhibiting cytochrome P450. An open study published in 2004 suggested, compared to a historical control group receiving ribavirin alone, that the addition of lopinavir-ritonavir (400 mg and 100 mg, respectively) to ribavirin reduced the risk of adverse clinical outcomes (acute respiratory however, the lack of randomization and a contemporary control group and the concomitant use of glucocorticoids and ribavirin in that study hindered the effect of lopinavir – ritonavir.
Similarly, lopinavir has activity, both in vitro and in an animal model, against the Middle East respiratory syndrome Coronavirus (MERS-CoV), and case reports have suggested that the combination of lopinavir – ritonavir with ribavirin and Alpha interferon resulted in virological clearance and survival.
However, due to a lack of convincing data on the efficacy of this approach in humans, a clinical trial (with recombinant interferon beta-1b, for MERS (ClinicalTrials.gov number, NCT02845843) is currently underway.
This randomized trial found that lopinavir – ritonavir treatment added to standard supportive care was not associated with clinical improvement or mortality in critically ill patients with Covid-19 other than that associated with standard care alone. However, in the modified intention-to-treat analysis, which excluded three patients with early death, the difference between groups in the median time to clinical improvement (median, 15 days vs. 16 days) was significant, albeit modest.
It is noteworthy that the overall mortality in this trial (22.1%) was substantially higher than the 11% to 14.5% mortality reported in the initial descriptive studies of hospitalized patients with Covid-19,1,2, which indicates that we include a seriously ill population.
The finding is consistent with studies showing that patients with SARS-CoV-2 viral pneumonia have progression in the second week of illness1 and with the effects of treatment time observed in previous antiviral studies in SARS20 and severe influenza21-23.
Furthermore, we found that the number of lopinavir – ritonavir recipients who had severe complications (acute kidney injury and secondary infections) or who required invasive or noninvasive mechanical ventilation for respiratory failure was lower than in those who received no treatment. These observations generate hypotheses and require additional studies to determine if treatment with lopinavir – ritonavir administered at a certain stage of the disease can reduce some complications in Covid-19.
Almost 14% of lopinavir-ritonavir recipients were unable to complete the full 14-day course of administration. This was mainly due to gastrointestinal adverse events, such as anorexia, nausea, abdominal discomfort, or diarrhea, as well as two serious adverse events, both acute gastritis. Two recipients had self-limited skin rashes.
Such side effects, including the risks of liver injury, pancreatitis, more severe skin rashes, and QT prolongation, and the potential for multiple drug interactions due to CYP3A inhibition, are well documented with this drug combination.
The side effect profile observed in the current trial raises concerns about the use of higher or longer lopinavir-ritonavir dose regimens in an effort to improve outcomes.
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