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Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 May 7;382(19):1787-1799. doi: 10.1056/NEJMoa2001282. Epub 2020 Mar 18. (Original study)
Abstract

BACKGROUND: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2.

METHODS: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.

RESULTS: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events.

CONCLUSIONS: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).


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Ratings
Discipline Area Score
Hospital Doctor/Hospitalists 7 / 7
Internal Medicine 7 / 7
Intensivist/Critical Care 7 / 7
Infectious Disease 7 / 7
Tropical and Travel Medicine 6 / 7
Respirology/Pulmonology 6 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Comments from MORE raters

General Internal Medicine-Primary Care(US) rater

A well done study with disappointingly negative results.

Hospital Doctor/Hospitalists rater

In the time of COVID-19, many dubious cures are doing the rounds and this study is key to making sure that science remains valid in the time of an outbreak. This is a very important negative study.

Infectious Disease rater

Although the study showed that Lopinavir-Ritonavir was not better than standard care in time to clinical improvement (mortality and detectable viral RNA at various time points), 52% of patients were randomized more than 12 days after onset of symptoms. It is possible that earlier administration may be effective.

Infectious Disease rater

Conducting this trial in the middle of the outbreak is an admirable achievement. Unfortunately, the study didn't show a significant benefit.

Intensivist/Critical Care rater

This is important information about lack of therapeutic benefit from this anti-viral drug combination. It must be disseminated rapidly to avoid inappropriate use, motivate further studies, and avoid instilling false hope.

Intensivist/Critical Care rater

This article and its results are very important. Essentially, this informs us that we should not use ritonavir/lopinavir routinely in these critically ill patients. It isn't a perfect trial, but many of the biases should have favored the treatment, and with those biases, a negative trial is probably truly negative.

Internal Medicine rater

I can't imagine something more newsworthy now than a trial on a medication for COVID-19. This appears to be a well-done RCT on two protease inhibitors (commonly used in HIV therapy) that seemed to have some benefit in SARS patients. The trial followed clinical, virologic, and hospital parameters. In this trial, no benefit was shown. More than 30% of the patients in this trial received steroids; whether this negated effects of the drug is unknown. No LFT side effects or Qt prolongation was noted (that might be seen in HCQ/Azithro combos), so this might still be an alternative option in patients who cannot take these due to Qt or transaminitis.

Internal Medicine rater

Negative trials are of great value. They allow us to focus on caring for patients and remind us that there is more to patient care than the use of drugs.

Respirology/Pulmonology rater

This is a well-conducted study of lopinavir-ritonavir in Chinese adults with Covid-19. There was no benefit demonstrated but the severity of illness was low compared with U.S. ICU patients. This raises the question about whether benefit may still accrue for severely and critically ill Covid-19 patients.

Respirology/Pulmonology rater

Prospective, unblinded study of patients with mild COVID-19. This standard combination anti-HIV retroviral therapy had no positive impact on symptoms, viral load, recovery, or mortality. This combination should not be used for patients with COVID-19.

Respirology/Pulmonology rater

As a critical care physician, any study about SARS Co V-2 is absolutely relevant, even if it's negative.
Comments from EvidenceAlerts subscribers

Dr. Guillaume ROLLIN (3/30/2020 5:55 AM)

It is hard to disqualify completely lopinavir/ritonavir on the basis of this study. If results seem convincing and clearly advocating against the use of lopinavir/ritonavir late in critically-ill patients, the median time between symptoms onset and treatment was 12-days. It is not unlikely that at this point treating the virus is not enough, and most of the damage has already been done.
Studies are needed to assess the potential of lopinavir/ritonavir in preventing severe cases if administered earlier and/or to patients presenting less severe symptoms.

Dr. Fabian Jaimes (3/25/2020 6:56 AM)

I think we need a re-reading of this paper. The results did not confirm that the drugs are useless. Instead, it showed a non-statistical significant reduction in mortality of 6%. Moreover, three patients died before receiving the first dose of antiviral. So, I think we need a larger study before discarding this therapy. Indeed, vis-a-vis the multiple experimental treatments that are in consideration currently (plasma, interferon, hydroxicloroquine, esteroids), this is the more advanced design to study an effective pharmacological therapy