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Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19
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https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(20)30070-5?platform=hootsuite
Published , 4/11/2020
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
COVID-19 Guideline, Part 2: Diagnostics - Coming Soon
COVID-19 Guideline, Part 3: Infection Prevention - Coming Soon
Adarsh Bhimraj*, Rebecca L. Morgan**, Amy Hirsch Shumaker, Valery Lavergne**, Lindsey Baden, Vincent Chi-Chung Cheng, Kathryn M. Edwards, Rajesh Gandhi, William J. Muller, John C. O'Horo, Shmuel Shoham, M. Hassan Murad**, Reem A. Mustafa**, Shahnaz Sultan**, Yngve Falck-Ytter**
*Corresponding Author **Methodologist
Executive Summary
COVID-19 is a pandemic with a rapidly increasing incidence of infections and deaths. Many pharmacologic therapies are being used or considered for treatment. Given the rapidity of emerging literature, IDSA felt the need to develop living, frequently updated evidence-based guidelines to support patients, clinicians and other health-care professionals in their decisions about treatment and management of patients with COVID-19 infection.
Summarized below are the recommendations with comments related to the clinical practice guideline for the treatment and management of COVID-19. A detailed description of background, methods, evidence summary and rationale that support each recommendation, and research needs can be found online in the full text. In brief, per GRADE methodology, recommendations are labeled as "strong" or "conditional". The word "recommend" indicates strong recommendations and "suggest" indicates conditional recommendations. In situations where promising interventions were judged to have insufficient evidence of benefit to support their use and with potential appreciable harms or costs, the expert panel recommended their use in the context of a clinical trial. These recommendations acknowledge the current "knowledge gap" and aim at avoiding premature favorable recommendations for potentially ineffective or harmful interventions.
•Recommendation 1. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends hydroxychloroquine/chloroquine in the context of a clinical trial. (Knowledge gap)
•Recommendation 2. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends hydroxychloroquine/chloroquine plus azithromycin only in the context of a clinical trial. (Knowledge gap)
•Recommendation 3. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends the combination of lopinavir/ritonavir only in the context of a clinical trial. (Knowledge gap)
•Recommendation 4. Among patients who have been admitted to the hospital with COVID-19 pneumonia, the IDSA guideline panel suggests against the use of corticosteroids. (Conditional recommendation, very low certainty of evidence)
•Recommendation 5. Among patients who have been admitted to the hospital with ARDS due to COVID-19, the IDSA guideline panel recommends the use of corticosteroids in the context of a clinical trial. (Knowledge gap)
•Recommendation 6. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends tocilizumab only in the context of a clinical trial. (Knowledge gap)
•Recommendation 7. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends COVID-19 convalescent plasma in the context of a clinical trial. (Knowledge gap)
The panel expressed the overarching goal that patients be recruited into ongoing trials, which would provide much needed evidence on the efficacy and safety of various therapies for COVID-19. The panel determined that when an explicit trade-off between the highly uncertain benefits and the known putative harms of these therapeutic agents were considered, a net positive benefit was not reached and could possibly be negative (risk of excess harm). The panel acknowledges that enrolling patients in RCTs might not be feasible for many frontline providers due to limited access and infrastructure. Should lack of access to clinical trials exist, we encourage setting up local or collaborative registries to systematically evaluate the efficacy and safety of drugs to contribute to the knowledge base. Each clinician can play a role in advancing our understanding of this disease through a local registry or other data collection efforts.
Background
The first cases of coronavirus disease 2019 (COVID-19) were reported from Wuhan, China in early December 2019 [1], now known to be caused by a novel beta-coronavirus, named as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within a span of months COVID 19 has become pandemic due to its transmissibility, spreading across continents with the number of cases and deaths rising daily [2]. Although most infected individuals exhibit a mild illness (80%+), 14% have serious and 5% have critical illness. Approximately including invasive ventilation due to acute respiratory distress syndrome (ARDS) [3]. mortality appears to be more common in older individuals and those with comorbidities, such as chronic lung disease, cardiovascular disease, and diabetes, young people with no comorbidities also appear to be at risk for critical illness including multi-organ failure and death.
There has been an expanding number of studies rapidly published online and in academic journals; however, some of these may be of limited quality and are pre-published without sufficient peer-review. Critical appraisal of the existing studies is needed to determine if the existing evidence is sufficient to support currently proposed management strategies.
Given the rapid global spread of SARS CoV-2 and the difficulty for the overburdened front-line providers and policymakers to stay up to date on emerging literature, IDSA has recognized the necessity of developing a rapid guideline for the treatment of COVID-19. The guideline panel used a methodologically rigorous process for evaluating the best available evidence and providing treatment recommendations. Two additional guidelines on diagnostic testing and infection prevention are also under development. These guidelines will be frequently updated as substantive literature becomes available and will be accessible on an easy to navigate web and device interface:
http://www.idsociety.org/covid19guidelines.
These recommendations are intended to inform patients, clinicians, and other health professionals by providing the latest available evidence.
Recommendation 1. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends hydroxychloroquine/chloroquine in the context of a clinical trial. (Knowledge gap)
Recommendation 2. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends hydroxychloroquine/chloroquine plus azithromycin only in the context of a clinical trial. (Knowledge gap)
Summary of the evidence
Two RCTs of patients with confirmed COVID with mild pneumonia (e.g., positive CT scan without oxygen requirement) or non-severe infection admitted to the hospital treated with hydroxychloroquine (HCQ) reported on mortality at 14 days, clinical progression (radiological progression on CT scan), clinical improvement, failure of virologic clearance (PCR), and adverse events (both) [11, 12] (Table 1).
In addition, we identified four publications describing three trials of combination treatment with HCQ plus azithromycin (AZ) among hospitalized patients with COVID-19 reporting on the outcomes of mortality, failure of virologic clearance (assessed with PCR test), and adverse events (i.e., significant QT prolongation leading to treatment discontinuation) [13-16] (Table 2).
Benefits
The currently available best evidence failed to demonstrate or to exclude a beneficial effect of HCQ on clinical progression of COVID-19 (as inferred by radiological findings; RR: 0.61; 95% CI: 0.26, 1.43; see Figure s2), or on viral clearance by PCR tests (RR: 2.00; 95% CI: 0.02, 20.00; see Figure s2), although a somewhat higher proportion in the HCQ group experienced clinical improvement (RR: 1.47; 95% CI 1.02, 2.11). However, the certainty in the evidence was rated as very low mainly due to small sample sizes (sparse data), co-interventions, and risk of bias due to methodological limitations. In addition, the selected outcomes should be considered indirect, as important patient outcomes (e.g., mortality, rate of progression to ARDS and need for mechanical ventilation) were unavailable.
Studies evaluating the addition of azithromycin to HCQ provided indirect comparisons of failure of virologic clearance to historical controls. The observed risk of mortality among patients receiving HCQ+AZ during hospital stay was 3.4% (6/175 patients). However, an estimated mortality rate in an untreated cohort was not provided in the manuscript. When compared to a lack of viral clearance in historical controls (100% virologic failure), 12 symptomatic patients were compared at day 5 or 6 from a separate hospital in France. Patients receiving treatment with HCQ+AZ experienced numerically fewer cases of virologic failure (43% pooled virologic failure; 29/71 patients) (Figure s3). There is very low certainty in this comparison of treatment effect mainly due to very high-risk selection bias, making any claims of effectiveness highly uncertain. In addition, relying on intermediary outcomes, such as viral clearance to determine patient-important outcomes (including a reduction in development of pneumonia, hospital or ICU admission, or need for intubation) add another layer of imprecision.
Harms
Two studies described significant QT prolongation in 10 of 95 treated patients, either resulting in an QT increase to over 500 ms or discontinuation of the HCQ/AZ treatment, illustrating the high risk for clinically relevant arrhythmias for this treatment [15, 16]. In addition, several case reports of QT prolongation related to hydroxychloroquine have also been published [17-20].
In another prospective cohort study in 224 COVID uninfected patients with SLE who received either chloroquine or hydroxychloroquine for routine care, gastrointestinal side effects occurred in 7% of patients [21].
Several case reports have been published citing the risk of a prolonged QT prolongation, torsades de pointes, and ventricular tachycardia in patients receiving azithromycin alone. In a large cohort study, patients taking a five-day course of azithromycin had an increased risk of sudden cardiac death with a hazard ratio of 2.71 (1.58-4.64) vs. 0.85 (0.45-1.60), compared to patients receiving no antibiotic or amoxicillin, respectively [22]. Given the cumulative effect on cardiac conduction seen with hydroxychloroquine and azithromycin, if this combination was to be used in the context of a clinical trial, baseline and follow-up ECG monitoring would be indicated, as well as careful surveillance for other concomitant medications known to prolong the QT interval.
Renal clearance accounts for 15-25% of total clearance of hydroxychloroquine, however dose adjustments are not recommended according to package labeling. Chloroquine and hydroxychloroquine are metabolized by cytochrome P450 isoenzymes 2C8, 2D6, and 3A4 [23], therefore inhibitors and inducers of these enzymes may result in altered pharmacokinetics of these agents.
Providers are encouraged to visit resources such as the newly created website, https://www.covid19-druginteractions.org/ to aid in the evaluation and management of drug interactions with current and emerging investigational agents for COVID-19.
Azithromycin is low risk for cytochrome P450 interactions [24]; however additional pharmacologic adverse events including gastrointestinal effects and QT prolongation need to be carefully considered particularly in the outpatient setting where frequent ECG monitoring is not feasible.
Other considerations
The panel agreed that the overall certainty of evidence was very low due to concerns with risk of bias, inconsistency, indirectness, imprecision, and publication bias.
Conclusions and research needs for this recommendation
The guideline panel recommends that the use of HCQ or the HCQ+AZ combination only be used in the context of a clinical trial. This recommendation does not address the use of azithromycin for secondary bacterial pneumonia in patients with COVID-19 infection. Additional randomized controlled trials and prospective outcome registries are needed to inform research for treatment with HCQ alone or in combination with azithromycin for patients with COVID-19 (Table s2. Best practices/suggestions for research of treatments for patients with COVID-19).
Recommendation 3. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends the combination of lopinavir/ritonavir only in the context of a clinical trial.
(Knowledge gap)
Summary of the evidence
One RCT and two case studies reported on treatment with combination lopinavir/ritonavir for hospitalized patients with COVID-19 [25-27] (Table 3). Cao et al. randomized 199 hospitalized patients with severe COVID-19 to receive treatment with lopinavir/ritonavir in addition to standard of care (n=99) or standard of care alone (n=100) for 14 days. The trial reported on the following outcomes: mortality, failure of clinical improvement (measured using a 7-point scale or hospital discharge), and adverse events leading to treatment discontinuation.
Benefits
Based on a modified intention to treat analysis, treatment with lopinavir/ritonavir failed to show or exclude a beneficial effect on mortality (RR: 0.67; 95% CI: 0.38, 1.17) or on clinical improvement (RR: 0.78; 95% CI: 0.63, 2.20).
Harms
Nearly 14% of lopinavir/ritonavir recipients were unable to complete the full 14-day course of administration due primarily to gastrointestinal adverse events, including anorexia, nausea, abdominal discomfort, or diarrhea, as well as two serious adverse episodes of acute gastritis. Two recipients also had self-limited skin eruptions. The risk of hepatic injury, pancreatitis, severe cutaneous eruptions, QT prolongation, and the potential for multiple drug interactions due to CYP3A inhibition, are all well documented with this drug combination.
Other considerations
The panel elected to inform their decision based on the RCT [27]. The panel determined the Certainty of evidence to be very low due to concerns with risk of bias (lack of blinding) and imprecision. In the randomized clinical trial conducted by Cao et al, the group that received lopinavir/ritonavir and the group that did not had similar rates of viral decay. This finding suggests that lopinavir/ritonavir is not having a measurable antiviral effect, its purported mechanism of action.
Conclusions and research needs for this recommendation
The guideline panel recommends the use of lopinavir/ritonavir only in the context of a clinical trial. Additional clinical trials or prospective outcome registries are needed to inform research for treatment with lopinavir/ritonavir and other HIV-1 protease inhibitors for patients with COVID-19 (Supplementary Table s2
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