COVID: early use of lopinavir/ritonavir with ribavirin and IFN beta-1b

 

A new study found that adding ribavirin plus interferon beta-1b to lopinavir/ritonavir over just taking lopinavir/ritonavir alone significantly decreased SARS-CoV-2 viral loads and hospital stays in patients with early/mild Covid-19 (see covid early triple therapy helps lancet2020 in dropbox, or doi.org/10.1016/S0140-6736(20)31042-4)

 

Details:

--127 patients in Hong Kong were randomized to a 14-day combo of lopinavir 400mg/ritonavir 100mg bid  (41 patients) vs that plus ribavirin 400mg bid and 3 doses of 8 million international units of interferon beta-1b (86 patients)

    --the interferon beta-1b was only used if patients were within 7 days of symptom onset, for fear of its proinflammatory effects

--all patients had to have NEWS2 score of at least 1 (see below) and symptom duration of <14 days

--median age 54, 54% male

--40% had underlying diseases: hypertension 32%, hyperlipidemia 27%, diabetes 15%, CAD 12%, all the rest were <3% (though BMI was not included)

--symptoms/signs: fever 80%, cough 56%, all the rest <33% [though only 2% had anosmia and 12% malaise: these are quite different numbers from other studies. Why??]

--labs: mostly normal CBCs, LFTs, renal function. But increased  ESR at 19 and CRP at 3 [only a little high]; abnormal CXR in 76%, mostly right lower zone infiltrate (44%)

--overall disease severity: mild, based on the NEWS2 and SOFA scores

--median time to hospital admission from symptom onset: 5 days

-- 52 of the 86 patients on combo therapy were admitted to the hospital <7days after symptom onset and got the full regimen; 34 were admitted later and received only the lopinavir/ritonavir plus ribavirin

--treatments: 55% got antibiotics (mostly amoxacillin-clavulanate in 40%); only 5 people total were on oxygen and only 1 on ventilator, mortality 0

--primary endpoint was time to a negative nasopharyngeal swab for SARS-CoV-2 PCR

Results:

--clinical outcomes (this is for patients treated within 7 days of symptom start, the combo group given interferon beta-1b):

    --NEWS2 scores: from a baseline score of 2:

        --combo group: decreased to 1 on day 1 and to 0 on day 3 and remained at 0

        --lopinavir/ritonavir control group: decreased to 1 on day 7

        --time to NEWS2 of 0: 4 days (3-8) vs 8 days (7-9), p<0.0001

    --SOFA scores: baseline 0

        --combo group: remained 0 throughout

        --lopinavir/ritonavir control group: increased to 1 on day 2 and remained at 1 thru day 7

        --time to SOFA of 0: 3 days (1-8) vs 8 days (6.5-9), p=0.041

    --duration of hospital stay, in days: 9.0 (7-13) vs 14.5 (9.3-16), p=0.016

 

--viral loads (log scale) at baseline: nasopharyngeal swabs 6.4, posterior oropharyngeal saliva 5.2, throat swab 4.6, stool 3.5 (no difference between combo and control groups)

   --SARS-CoV-2 viral loads decreased dramatically on combo therapy by day 1, with naropharyngeal swabs decreasing to 4+ log units and no change in control group. Similar for viral loads by other types of samplings

--time to negative viral loads, in days:

    --nasopharyngeal swabs: 7 (5-11) vs 12 (8-18) p=0.001

    --posterior oropharyngeal saliva: 6 (3-8) vs 8 (5.3-10.8), p=0.044

    --throat swab: 4.5 (1.3-6.8) vs 7.0 (3-12), P=0.039

    --stool:  5 (2-5) vs 7 (4-8), P=0.030

    --urine: all samples negative throughout

    --of note, there were significant differences by day 1 of therapies in the combo group

--IL-6 levels also decreased significantly by day 2 of combo therapy

    --the 76 patients who started therapy <7 days after symptoms had better clinical and virological outcomes in the combo group, with almost all outcomes in that later group not being statistically significant  [because treating early is better, or because this early group got the interferon-beta-1b??]         

    --a negative baseline CXR was also associated with negative day 7 nasopharyngeal samples for SARS-CoV-2, though less impressively than being assigned to the combo therapy group

 

--adverse events (no statistically significant differences):

    --only 1 serious one, in the control group

    --nausea: 33%, (average duration 2 days), diarrhea 42% (average duration 3 days), increased ALT 15%, hyperbilirubinemia 6%, sinus brady 3%, fever 38%

--post-hoc subgroup analysis: the only real difference they found was that those who started treatment within 7 days of symptom onset had better clinical and virological outcomes

 

Commentary:

--a few comments on study design:

    --they comment that this was not a placebo-controlled trial because “a placebo group was generally not accepted in Chinese culture”

    --at the time of this study, all patients with Covid-19 were required to be hospitalized in South Korea until nasopharyngeal swab viral loads were negative on 2 consecutive days. Hence, their ability to follow these patients with mild disease so well

    --they chose these drugs for several reasons:

        --they have in-vitro activity against SARS-CoV and MERS-CoV

        --an open-label study found that lopinavir/ritonavir with ribavirin reduced mortality and need for intensive respiratory support in SARS-CoV
        --SARS-CoV-2 acts more like influenza (high viral load early in disease), and triple therapy works better than single agents for flu: these researchers found previously that treatment with naproxen, clarithromycin (both having weak anti-influenza viral activity) along with oseltamivir were clinically superior to oseltamivir alone. Hence the design of this current study with triple therapy

--NEWS2 (National Early Warning Score 2): a combo of respiratory rate, hypercapneic respiratory failure, oxygen supplementation, temperature, systolic BP, pulse and consciousness; a respiratory rate >20 gets at least a score of 2, needing oxygen another 2, and a score of 7 means there should be prompt emergency assessment (see https://www.mdcalc.com/national-early-warning-score-news-2#use-cases ). the max score in this study was 2

--SOFA scale (Sequential Organ Failure Assessment): a scale reflecting oxygenation and need for supplemental oxygen, mechanical ventilation, platelet count, Glasgow Coma Scale, bilirubin, mean arterial pressure, and creatinine (see https://www.mdcalc.com/sequential-organ-failure-assessment-sofa-score)

--a prior Chinese study RCT found that lopinavir/ritonavir did not quite reach statistically significant benefit in patients with severe Covid-19 infection, though there were significant methodologic questions, and they did find that there was benefit if starting the lopinavir/ritonavir before 12 days after the onset of symptoms: http://gmodestmedblogs.blogspot.com/2020/03/covid-19-lopinavir-does-not-work-but-is.html 

--it would be really interesting to know if treating patients early with these (or other) meds alters the immune response: other studies have found less robust neutralizing antibody responses in those with mild vs severe disease. does aggressive early treatment further blunt the neutralizing antibody response?  and perhaps leave people more susceptible to recurrent infection later?

limitations of the study:

--open-label study, and not randomized placebo-controlled one (though does have the advantage of comparing the triple therapy with lopinavir/ritonavir which may have some anti-SARS-CoV-2 activity, especially if given early in the disease, and then showing incremental benefit of the combo therapy)

--it is unclear what the specific role of interferon beta-1b is, given that it was timed with early initiation of meds (which likely worked better in and of itself).

--this study involved only patients with mild disease and cannot be extrapolated to those with more serious disease

 

So, an interesting study targeting mild Covid-19 cases, suggesting that:

--early treatment of people with mild symptoms may have important benefits; and there may be profound social (as well as the individual) benefits in decreasing viral spreading by several days and theoretically decreasing further viral transmission

--this combination of meds used seems reasonable based on our mechanistic understanding, including the fact that they should work better earlier in the disease (which was also found in the other lopinavir/ritonavir RCT:  http://gmodestmedblogs.blogspot.com/2020/03/covid-19-lopinavir-does-not-work-but-is.html )

-- and, hopefully, there will soon be more studies of meds used in patients with early and mild symptoms of Covid-19, which is really likely to be a primary target for secondary prevention….

--it is also great to be able to repurpose older meds instead of trying to create new ones: they are available, they have some track record of their short-term and long-term adverse effects, and they (probably) are cheaper and more accessible to more people/countries

geoff

 

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