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Many people are saying...


...maybe some cytokines are okay?
This piece is courtesy of Dr. Tiara Calhoun.
The FLARE Four:
  1. There is an intense need for antiviral therapies targeted against SARS-CoV-2, but positive results so far are limited to observational reports and a press release (with no published data) describing a shorter time to recovery with remdesivir. 
  2. Given the negative results for antiviral therapies to date, many have wondered if combination therapy might be more effective.
  3. A recent report, described tonight, explores the results of interferon beta-1b in combination with antiviral therapies.
  4. Despite a complicated trial design, the report by Huang and colleagues suggests that such an approach speeds recovery in COVID-19.  
As of today, May 11, 2020, over 285,000 people worldwide have died from SARS-CoV-2 infection. The magnitude of the pandemic has created an intense need to develop effective therapies. A staggering 1358 studies on COVID-19 have been registered on, and a whopping 2320 publications are listed in the “Treatment” section of LitCovid alone. A few randomized trials have been published, and a few more non-randomized, observational, and pre-print reports have caught the attention of the press and clinicians alike. There is a lot left to learn, and a lot to sift through. In tonight’s FLARE, we review a promising new trial that studied a three-drug combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin vs. lopinavir-ritonavir alone for the treatment of COVID-19 in Hong Kong (Hung et al., 2020).
What do we know so far about
therapies for COVID-19?
To date, the results of five noteworthy randomized trials have been published: lopinavir-ritonavir vs. supportive care (Cao et al., 2020), hydroxychloroquine vs. supportive care (Chen et al., 2020b), remdesivir vs. supportive care (Wang et al., 2020), high- vs low-dose chloroquine (which was interrupted for safety concerns) (Borba et al., 2020), and the one we discuss today -- the first with a positive result. Several more non-randomized (H & A, anyone? March 22nd FLARE) (Gautret et al., 2020), observational (May 8th FLARE) (Cavalli et al., 2020; Paranjpe et al., 2020), and pre-print (Chen et al., 2020a) reports of therapies for COVID-19 have surfaced. Most are limited by flaws in study design and lack of peer review. Therapies ranging from IL-6 inhibitors like tocilizumab (March 25th FLARE), convalescent plasma (March 27th FLARE), to stem cells (April 25th FLARE), remain in earlier phases of trial design and recruitment (see Figure 1 below). The NIH has touted the effectiveness of remdesivir (compared to placebo) in decreasing illness duration in a press release on the ACTT trial on April 29th, but as of this writing has yet to release any detailed data or reports that have been subject to peer review.
Figure 1.  A recent Lancet Digital Health article released the above graphic representation of clinical trials of therapies currently in progress for COVID-19. Lines between nodes indicate head-to-head comparisons of two therapies. Circular arrows indicate trials of a therapy vs. control. Numbers on lines and arrows indicate the number of total trials in progress for this specific comparison. This figure is up to date as of April 21, 2020 (Thorlund et al., 2020).
What's the new trial about?
Hung and colleagues describe and report their study: Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial” (Hung et al., 2020).
What is the biological rationale and prior clinical data available for these study drugs?
Lopinavir, a protease inhibitor initially designed for use in HIV, was identified by in vitro screening to have activity against SARS-CoV (Chen et al., 2004; Wu et al., 2004). The plasma half-life of lopinavir increases when combined with ritonavir through inhibition of cytochrome P450. Lopinavir also has activity in vitro (de Wilde et al., 2014) and in vivo against MERS-CoV (Chan et al., 2015). This drug combination has been studied in SARS-CoV-2, and investigators found no difference in time to clinical improvement or change in viral load (Cao et al., 2020).
Ribavirin is a guanosine nucleoside analog which interferes with viral replication by multiple mechanisms though chiefly through inhibition of faithful viral RNA replication. Notably, ribavirin does not have activity against coronavirus RNA-dependent RNA polymerases as these enzymes possess a 3’->5’ “proofreading” exonuclease activity which can allow excision of such nucleoside analogues
(Ferron et al., 2018). Thus, antiviral effects of ribavirin in CoVs, as in DNA viruses, likely reflect indirect modulation of intracellular nucleotide pools. Nevertheless, ribavirin has been combined with lopinavir-ritonavir in prior studies in SARS-CoV and MERS with modestly promising results (see “combined therapies” below).
Interferon beta-1b
Interferons are important signaling molecules of the innate immune response upon viral infection (Perry et al., 2005). Studies evaluating the antiviral activity of interferons have reported interferon-beta as the most potent in reducing MERS-CoV replication in vitro (Chan et al., 2013; Hart et al., 2014). Interferon beta-1b has been studied in a primate model of MERS-CoV, where it demonstrated improved outcomes, including reduced viral loads (Chan et al., 2015).

SARS-CoV-2 may not induce adequate host expression of interferons, which may be related to poor outcomes. In a recent study by Chu and colleagues (Chu et al., 2020), human lung explants were obtained from six donors who were not infected with SARS-CoV-2 at the time of surgical lung resection. Subsequently, lung explants were infected with SARS-CoV or SARS-CoV-2 ex vivo to compare viral replication and immune activation. Although SARS-CoV and SARS-CoV-2 have similar cell tropism (type I and II pneumocytes, alveolar macrophages), infection and viral replication was more efficient for SARS-CoV-2 than SARS-CoV. However, SARS-CoV-2 essentially failed to induce expression of any interferons (type I, II or III) in the infected human lung tissue, whereas SARs-CoV induced interferon expression as expected. These data support a possible therapeutic role for interferon beta-1b in SARS-CoV-2 infection.
Prior Studies of Combination Therapy
During the 2003 SARS epidemic, the same research group that published the current study conducted an open-label trial of lopinavir-ritonavir plus ribavirin (n = 41) compared to historical controls treated with ribavirin alone (n = 111) (Chu et al., 2004). The lopinavir-ritonavir group experienced a lower rate of adverse outcomes (ARDS and death) at 21 days from symptom onset compared to the historical controls.

In MERS, two observational studies of ribavirin plus interferon (interferon alpha-a1 and recombinant interferon, respectively) failed to show a benefit (Arabi et al., 2020; Omrani et al., 2014). However, case reports show successful use of triple antiviral therapy including lopinavir-ritonavir, ribavirin, and interferon in MERS (Kim et al., 2016; Min et al., 2016; Spanakis et al., 2014).
Back to the current study
Similar to influenza, and unlike SARS-CoV and MERS-CoV, viral load of SARS-CoV-2 peaks around the time of symptom onset (To et al., 2020). Based on this, the authors of the present study hypothesized that early triple therapy may be useful to rapidly suppress viral load before development of severe disease, as well as decrease viral shedding and thus risk to health workers and other people. Of note, in the recent, negative trial of lopinavir-ritonavir in SARS-CoV-2 infection (Cao et al., 2020), the median time from symptom onset to start of treatment was 13 days, when viral shedding was likely much lower.

To test this, the researchers designed a multicenter, prospective, open-label, randomized controlled trial of adults in six hospitals across Hong Kong, which serve 75% of the population of the city-state. Inclusion criteria were age 18 or over, national early warning score 2 (NEWS2, see Figure 2 below) of at least 1, and symptom duration of 14 days or less upon recruitment. Simple randomization was used.
Figure 2. The NEWS2 scoring system was designed by the UK Royal College of Physicians to standardize assessment and response to clinical deterioration in patients with acute illness. It is used in the UK and several other countries similarly to the SOFA score. Aggregate scores of 0 to 4 warrant general care assessments, and scores of 5 or greater warrant urgent assessment by the medical team. Scores of 7 or more trigger assessment by critical-care trained providers. A score of 3 in any single parameter triggers a multidisciplinary discussion to determine if escalation of care is necessary. Chart reproduced from The Royal College of Physicians.
Treatment was started within 48 hours of hospital admission (note: in Hong Kong, all SARS-CoV-2 positive individuals are hospitalized regardless of COVID-19 symptoms) and patients otherwise received standard of care (including oxygen, non-invasive or invasive ventilatory support if indicated, antibiotics for concern for bacterial superinfection and other supportive therapy). Hospital admission, however, occurred at variable times after symptom onset leading to some variation in the time of treatment initiation with respect to symptom onset. Oddly, “standard care” also included stress dose steroids (hydrocortisone 50 mg every 8 h IV tapered over 7 days) in any patient with desaturation or hypoxemia necessitating oxygen support; only a small number of patients were actually sick enough to meet those criteria.

The primary outcome was time to achieve a negative nasopharyngeal swab RT-PCR for SARS-CoV-2. Secondary outcomes included time to resolution of symptoms (defined as a NEWS2 of 0 for 24 hours or more), daily NEWS2 and SOFA score, length of hospital stay, and 30-day mortality. Outcomes were assessed in an intention-to-treat analysis.
Testing "triple therapy"...sort of
The authors divided the patients into a “control group” and a “combination group.” However, there were effectively three treatment groups. The control group of 41 patients received 14 days of lopinavir-ritonavir alone, starting up to 14 days from symptom onset (“single therapy”). Within the “combination group,” there were two separate subgroups: one included 34 patients with ≥7 days of symptoms who received lopinavir–ritonavir and ribavirin only (“double therapy”); another subgroup included 52 patients with <7 days of symptoms, who received lopinavir–ritonavir, ribavirin, and 1 to 3 doses interferon beta-1b, depending on the number of days from symptom onset (“triple therapy”). Thus, 31 patients in the treatment group received no interferon (i.e. got the same treatment as the control group, plus ribavirin).

Most of the analysis presented in the main text compared the “control group” to the “combination group.” However, given the difference in actual provided therapy, a subgroup analysis was done to compare the group that actually received “triple therapy” to the control group which recieved lopinavir–ritonavir alone.
The study populations were pretty well matched
Encouragingly, baseline characteristics between the study groups were roughly equivalent, including age (median 51 and 52 years in study and control), sex (52 and 56% male), medical comorbidities (diabetes, hypertension, hyperlipidemia, etc.), symptoms of COVID-19 (fever, chills, cough, etc.), disease severity (NEWS2 of 2 and SOFA score of 0 at baseline in both groups), and baseline laboratory and radiographic findings. Median days from symptom onset to start of study treatment were 5 and 4 days in treatment and control groups, respectively. 

Overall, patients in both groups had mild symptoms. 17 total patients required oxygen therapy, 5 required non-invasive ventilatory support (both similar proportions between treatment and control), and one patient in the control group required mechanical ventilation. Similar numbers of patients in both groups received antibiotics and stress dose steroids (thankfully, this number was small--7 patients across both groups).  
The study group (encompassing both “double therapy” and “triple therapy” groups, analyzed together) had significantly shorter median time from start of treatment to negative nasopharyngeal swab (7 days, IQR 5-11) compared to the control group (12 days, IQR 8-15). All secondary endpoints, except 30-day mortality (as no deaths occurred in either group), were significantly better in the treatment group, including: shorter time from treatment initiation to resolution of symptoms by NEWS2 score of 0 (average 4 days in the combination group vs. 8 days in the control group). shorter time to SOFA score of 0 (3 days vs. 8 days) and shorter median hospital stay (9.0 days vs. 14.5 days). There was no difference in adverse events (mild nausea and diarrhea reported in approximately equal proportions in both) and one patient discontinued lopinavir-ritonavir in the control group due to elevated transaminases. The authors also analyzed serum cytokines for the first 84 recruited patients: IL-6 was significantly lower than in the control group on days 2, 6, and 8, but TNFα and IL-10 were not significantly different between the groups.
Given the odd distribution of treatments in the treatment group - how do we know what worked?
We don’t know for sure. 

The authors performed a post-hoc subgroup analysis of 76 patients (52 treatment, 24 control) who started treatment within 7 days of symptom onset (and thus received interferon - the “early” subgroup) and the 51 patients (34 treatment, 17 control) who started treatment 7 or more days after symptom onset (“late” subgroup) and as such did not receive interferon beta-1b. They found similar results to the overall, intention-to-treat analysis in the early subgroup. However, no significant differences were found in the late subgroup. With appropriate caveats given that this was a post-hoc subgroup analysis, this suggests some component of the triple therapy was responsible for the benefits seen in the composite treatment group. Which component? Given that both groups (treatment and control) received lopinavir and ritonavir, it seems reasonable to conclude that either interferon, ribavirin, or a synergistic effect between the three drugs led to improved outcomes. This is illustrated in Figure 3, adapted from data in the supplement, in which nasopharyngeal swab viral load was plotted against days from symptom onset. There is a clear, steep decrease in viral load in the interferon + lopinavir/ritonavir + ribavirin early subgroup compared to the lopinavir/ritonavir early control subgroup, while the decrease in viral load is similar between the lopinavir/ritonavir and lopinavir/ritonavir + ribavirin late subgroups.
Figure 3. Nasopharyngeal swab viral load plotted over time in the four subgroups analyzed. Not the steep decrease in viral load in the interferon + lopinavir/ritonavir + ribavirin early subgroup compared to lopinavir/ritonavir alone, while the decrease in viral load is similar between the lopinavir/ritonavir and lopinavir/ritonavir + ribavirin late subgroups. Adapted from Hung et al., 2020.
A rough comparison with the prior results from (Cao et al., 2020), which compared lopinavir-ritonavir to standard care, does suggest a more rapid decrease in viral load in the current study (Figure 4 below). However, readers should note that the Cao and colleagues measured viral load from oropharyngeal swabs, which may have different test characteristics than nasopharyngeal swabs, and patients were started on therapy on median day 13 from symptom onset.
Figure 4. Comparison of viral load in the early “triple therapy” subgroup with early “single therapy” from the current study. Also provided is viral load over time in the lopinavir-ritonavir vs. standard care groups (Cao et al., 2020).
In addition to the problem of the “double” and “triple therapy” groups as described above, the study has several other limitations. As the authors report, their trial was open label, had no placebo group, and was confounded by a subgroup within the treatment group that omitted interferon beta-1b due to late recruitment after symptom onset. The study also had very few critically-ill patients (only one intubated during the study period) and no patients were critically ill at the time of randomization. This severely limits the generalizability in a disease that is distinguished by its high rates of critical illness. 
With vaccines still months to years away, and hundreds of thousands of fatalities to date, there is an urgent need for drug therapies targeted against COVID-19. Few randomized trials have been published thus far, and tonight’s represents the first with a positive result. Despite a complicated trial design, this study by Huang and colleagues suggests that immune modulation with interferon, in combination with antiviral agents, speeds recovery in COVID-19. Generalizability is limited by a lack of critically ill patients and haphazard treatment with interferon. More studies are needed to further elucidate the relative importance of each of the drugs tested in combination in this trial.
FLARE is a collaborative effort within the Pulmonary and Critical Care Division and the Department of Medicine at Massachusetts General Hospital. Its mission is to appraise the rapidly evolving literature on SARS-CoV-2 with a focus on critical care issues.

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