COVID-19: lopinavir does not work, but is that true??

A open-label randomized controlled trial in Wuhan, China showed no significant benefit for lopinavir/ritonavir in hospitalized patients with severe COVID-19 infection (see covid lopinavir not help nejm2020 in dropbox, or DOI: 10.1056/NEJMoa2001282)

Details:
--199 patients with laboratory confirmed SARS-CoV-2 infection and documented pneumonia, an oxygen saturation of <94% on room air or a ratio of the partial pressure of oxygen/fraction of inspired oxygen of <300 mmHg, randomized to lopinavir/ritonavir 400mg/100mg twice daily for 14 days vs standard care
-- mean age 58, male 60%, fever 92%, respiratory rate>24 in 19%, white count normal 70%/low 10%/high 20%, lymphocytosis 37%
-- diabetes 12%, cerebrovascular disease 7%, cancer 3%
-- not requiring oxygen supplement 14%/requiring it 70%/requiring high flow or noninvasive mechanical ventilation 16%, <12 days from symptom onset 45%, mean viral load 10,000 per mL, days from illness to randomization 13
-- about 35% of patients in both groups were on systemic glucocorticoids, days of steroid therapy 6
-- randomization was stratified on the basis of respiratory support methods at the time of enrollment, in an attempt to equalize the 2 groups
--primary endpoint was time to clinical improvement, defined as time from randomization to either improvement by 2 points in the 7 categories scale (see below) or discharge from the hospital, whichever came first

Results:
--Comparing lopinavir/ritonavir to standard care:
    -- time to clinical improvement: 15 days in lopinavir/ritonavir vs 16 days in standard therapy, HR 1.24 (0.90-1.72)
    -- mortality at 28 days: 19.2% vs 25.0%, (-17.3 to 5.7) [ie, a pretty strong trend to benefit]
    -- detectable viral RNA was similar between the treatments, as measured by PCR, though they were unable to sample lower respiratory tract secretions
    -- by modified intention-to-treat analysis: lopinavir/ritonavir led to a median time to clinical improvement that was shorter by one day, HR 1.39 (1.00-1.91)
        -- in reviewing their graph of time to clinical improvement in the intention-to-treat population: there was clear and consistent separation of the graphs with improvement in lopinavir/ritonavir (i.e., there was no apparent regression to the mean)
 -- secondary outcomes:
    -- those started on lopinavir/ritonavir within 12 days after the onset of symptoms had a definitively shorter time to clinical improvement, HR 1.25 (1.77-2.05) vs a lack of clinical improvement statistically in those who started after 12 days [i think there was a typo in this HR, given that the intervals did not include th HR...]
    -- those on lopinavir/ritonavir also had significant decreases in:
        -- ICU stay of 6 days vs 11 days
        -- the duration from randomization to hospital discharge was 12 days vs 14 days
        --percentage of patients with clinical improvement at day 14 was higher in the lopinavir/ritonavir group than in the standard care group (45.5% vs 30.0%)
    -- however, there was no evident benefit in terms of time to clinical deterioration (a one category increase the 7 categories scale) or when clinical improvement was assessed by the NEWS2 scale: National Early Warning Score 2, as stratified by greater or less than 5
-- adverse events: overall, about 49% in both groups had adverse events, and grades 3 to 4 serious adverse events were actually less with lopinavir/ritonavir at 18% vs 31% with standard care. Though there are more treatment interruptions, in 14% of patients in the lopinavir/ritonavir group, due primarily to G.I. side effects

Commentary:
-- lopinavir has documented in vitro inhibitory activity against SARS-CoV as well as against MERS-CoV, as well as suggestive evidence in humans: in open label trials, compared to historical control groups, lopinavir/ritonavir seemed to decrease the risk of adverse clinical outcomes (ARDS or death) as well as viral load in patients with SARS, and also with MERS. These were not randomized controlled trials, and confounded by use of ribavirin in the first case and ribavirin plus interferon alpha in the second case.
    --it should be noted, however, that SARS-CoV-2 is genetically quite dissimilar to the other human coronaviruses, so we should not assume that a med working in SARS/MERS would work with the current virus
-- It is also important to remember that in looking at viral load, as they did above, this can persist after viral viability seems to have ended, as noted in http://gmodestmedblogs.blogspot.com/2020/03/covid-19-update-31120.html. However, as pointed out by Anna Wald, MD in a response to me, there is a logical/factual leap to assume that lack of ability to grow on an artificial culture medium is directly translatable to viral infectivity in humans

--The 7 category ordinal scale used to assess outcomes, (requiring a 2 point change to be considered significant):

1. not hospitalized with a resumption of normal activities
2. not hospitalized, but unable to resume normal activities
3. hospitalized, not requiring supplemental oxygen
4. hospitalized, requiring supplemental oxygen
5. hospitalized, requiring nasal high flow oxygen therapy, noninvasive mechanical ventilation, or both
6. hospitalized, requiring ECMO, invasive mechanical ventilation, or both
7. death

    -- I would argue that improving one category is actually a significant improvement, though even looking at 2 categories there was very close to statistically significant improvement with lopinavir/ritonavir

    -- limitations of the study include the fact that it was actually not blinded, those taking care the patient knew what the patient was getting, and they do not present granular data on the effect of those randomized to glucocorticoids was in terms of outcome

--An interesting sideline here is that I do have a patient who wants to become pregnant, has been on lopinavir/ritonavir for HIV for years with good effect, and does not want to change. However I just found out from the pharmacy that within 2 months lopinavir/ritonavir will no longer be available. Not sure if this has to do with people using it for COVID-19, or just that it is an old drug that has been supplanted by new ones.

--their conclusion to the study was “in hospitalized adult patients with a severe COVID-19, no benefit was observed with lopinavir/ritonavir treatment beyond standard care.”

BUT, if I were in this unfortunate situation with COVID-19, I would certainly opt for taking lopinavir/ritonavir if there were no better options because:
--their overall analysis was dependent on a large improvement (2 points in the 7 categories scale), which seem to override the seemingly significant benefit of only a 1 point improvement (going from requiring oxygen to not, or hospitalized to not both seem like real improvements to me...). Of note, when they looked at deterioration, they required only a 1 point deterioration to be important…
--for many outcomes, in secondary analysis, there seem to be pretty clear benefit: decreasing ICU stays a lot, discharging a couple of days earlier, percentage of patients with clinical improvement at day 14, strong trend to mortality benefit
--and, as noted in their study, it does seem to be beneficial to start the lopinavir/ritonavir earlier, as in before 12 days after the onset of symptoms. I would suspect that even earlier might be even better. Maybe even before infected????????
--Clearly, it would be very useful to have a true randomized controlled trial.
    --However, given where we are at now, I would opt for therapy with lopinavir/ritonavir at first signs of pulmonary involvement unless something better came along… [after all, once one has ARDS, one is predisposed to intersititial pulmonary fibrosis and the long-term sequelae of that….

geoff​

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