Drug treatments for covid-19: living systematic review and network meta-analysis

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Dear Editor:

Re: Drug treatments for covid-19: living systematic review and network meta-analysis

We have been following with interest the living systematic review and network meta-analysis of drug treatments for COVID-19 that Siemieniuk et al. have published with updates. (1) This work represents a valuable resource for guiding patient management by providing insight into the benefits that may potentially be derived from various interventions. However, we are not aware of recent updates that include anti-viral monoclonal antibodies (mAbs), of which two combination products, each consisting of two mAbs, have become available; casirivimab + imdevimab (REGEN-COV; Regeneron Pharmaceuticals, Inc.) and bamlanivimab + etesevimab (Eli Lilly and Company). These combination products have received Emergency Use Authorization from the United States Food and Drug Administration, (2,3) and the European Medicines Agency has issued advice on the conditions of use for these drugs (4,5); REGEN-COV has also received Emergency Use Authorization from the Central Drugs Standard Control Organisation (CDSCO) of India. (6)

Inclusion of mAbs in the living systematic review would be especially germane given that these mAbs are the only antiviral that specifically targets severe acute respiratory coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, and are the only pharmacologic intervention whose use for the treatment of COVID-19 is clearly supported by clinical trial data showing a range of benefits. These data provide evidence for a reduction in viral load and fewer medically attended visits in non-hospitalized patients. (7,8) In particular, REGEN-COV resulted in a 71% reduction in hospitalization or mortality among high risk COVID-19 patients treated in the outpatient setting. (9) While there have been logistical challenges to use of mAbs, an appropriate framework for patient identification and drug administration can enhance access to this intervention. (10)

A symposium presented at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) that further explored theoretical and practical implications of mAb treatment for COVID-19 (“Innovative Pharmacology to Health Economics Approach Using A Multi-Scale COVID-19 Transmission Model” (11)). Symposium presentations indicated that the benefits of the anti-viral mAbs are a function of access and utilization, with additional supply and full utilization leading to larger benefits. Projections of mortality from the Institute for Health Metrics and Evaluation (IHME)/University of Washington at Seattle indicate that while the number of deaths over the next several months will continue to decrease, 58,368 deaths are still expected to occur between April 13 and August 1 2021. (12) Model simulations (11) calibrated to the latest IHME mortality projections suggest that deployment of 1.25 million doses of REGEN-COV with prioritization to those ≥ 65 years old could avert 24,650 of these deaths (approximately 42%) during this time period, assuming deployment of 75% of the total drug supply during the first 50 days to temporally coincide with the peak of mortality.

The public health implications of mAbs for treatment of COVID-19 may be substantial, not only by reducing morbidity and mortality but also by potentially limiting transmission. For this reason, it is imperative that systematic reviews provide a comprehensive understanding of the therapies that should be considered for treating patients at various stages of COVID-19, including use of mAbs. We therefore look forward to an update by Siemieniuk et al. that reviews these important treatment modalities and can provide guidance on their appropriate use and expected benefits.

Andreas Kuznik (1), Patrick F. Smith (2), Mohamed A. Kamal (1), Meagan P. O’Brien (1), Mohamed Hussein (1), Vera Mastey (1)

1. Regeneron Pharmaceuticals, Tarrytown, NY, USA; 2. Certara; Princeton, New Jersey, USA

References
1. Siemieniuk RA, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. Bmj 2020;370:m2980.
2. U.S. Food & Drug Administration. Fact Sheet for Health Care Providers. Emergency Use Authorization (EUA) of Bamlanivimab and Etesevimab. https://www.fda.gov/media/145802/download. Accessed April 4, 2021. 2021; 2021(March 21). https://www.fda.gov/media/145802/download.
3. U.S. Food & Drug Administration. Fact Sheet for Health Care Providers Emergency Use Authporization (EUA) of Casirivimab and Imdevimab. https://www.fda.gov/media/143892/download. Accessed April 4, 2021. 2021; 2021(March 16). https://www.fda.gov/media/143892/download.
4. European Medicines Agency. EMA issues advice on use of antibody combination (bamlanivimab / etesevimab). https://www.ema.europa.eu/en/news/ema-issues-advice-use-antibody-combina.... Accessed May 9, 2021.
5. European Medicines Agency. EMA issues advice on use of REGN-COV2 antibody combination (casirivimab / imdevimab). https://www.ema.europa.eu/en/news/ema-issues-advice-use-regn-cov2-antibo.... Accessed May 9, 2021.
6. India approves Roche/Regeneron antibody cocktail to treat Covid-19. The Times of India. May 5,2021, http://timesofindia.indiatimes.com/articleshow/82407551.cms?utm_source=c.... Accessed May 17, 2021.
7. Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19. N Engl J Med 2020;384(3):238-51.
8. Gottlieb RL, Nirula A, Chen P, et al. Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial. Jama 2021;325(7):632-44.
9. Philley JV. Casirivimab With Imdevimab, a Cocktail of Two Antibodies Against SARS-CoV-2, in the Outpatient Setting: Phase 3 Efficacy and Safety Results. Presentation at: ATS 2021. American Thoracic Society International Conference; 17 May 2021-2 July 2021.
10. Razonable RR, Aloia NCE, Anderson RJ, et al. A Framework for Outpatient Infusion of Antispike Monoclonal Antibodies to High-Risk Patients with Mild-to-Moderate Coronavirus Disease-19: The Mayo Clinic Model. Mayo Clinic proceedings 2021;96(5):1250-61.
11. Innovative Pharmacology to Health Economics Approach Using A Multi-Scale COVID-19 Transmission Model. Symposium presented March 12, 2021 at the annual meeting of the American Society for Clinical Pharmacology and Therapeutics. https://www.eventscribe.net/2021/ASCPT/agenda.asp?startdate=3/12/2021&en... Accessed May 9, 2021.
12. Institute for Health Metrics and Evaluation. COVID-19 Projections. https://covid19.healthdata.org/united-states-of-america?view=cumulative-.... Accessed April 12, 2021.

Dear Editor,

We read with interest the systematic review focussing on drug treatments for Covid-19. We note with interest the plethora of studies and articles currently focussing on Covid-19. The National Institute for Health Research (NIHR) has also led a rapid implementation of research into COVID-19 [1,2,3]. Whilst COVID-19 studies have received swift review and approval, the consequences of focussing on COVID-19 studies on non-COVID-19 trials cannot be under-estimated. Many of these trials were paused by local trusts during the initial peak of the pandemic in the UK [4].

Whilst this policy may have been the correct response, the ‘collateral damage’ to musculoskeletal research cannot be under-estimated. Arthritis and musculoskeletal (MSK) conditions affect over 17 million people in the UK, with 20% of the population each year consulting their GP and 30 million working days lost each year due to MSK conditions [5]. Arthritis is the most prevalent condition in the population without a cure, and osteoarthritis (OA) has no disease modifying drugs.

Trial infrastructure: the NIHR produced a framework to guide the restart of research activities. Local trusts have begun to review their research portfolios, to determine which studies will be able to resume and when. Priority was given to COVID-19 studies. It is likely that studies involving group interventions or significant face-to-face contact will not be deliverable and may not resume.

Any change to a study’s design, such as virtual instead of a face-to-face follow up necessitates a protocol amendment, Ethics Committee approval, and local research approval. This is challenging with further delays for Health Research England (HRA) sign off as COVID-19 studies are prioritised [6].

Hospital restructuring: Trusts seeking to limit risk of contracting COVID-19 have reduced foot-fall. Masks have made communication difficult and more time consuming. Additionally most physiotherapy and other interventions are being delivered virtually which impacts on some musculoskeletal pathways and the ability to include physiotherapy interventions as part of a study. Patients now express additional anxiety in attending hospitals and may refuse to come for a face-to-face appointment, reducing the potential to recruit into studies [7].

Surgical pathways: The Royal College of Surgeons guidelines on prioritisation [8] has also affected treatment pathways with some patients likely to wait in excess of 3 months for their surgery, significantly delaying studies with a surgical intervention. This will impact on commercial device studies which risk early closure. Global predictive modelling has estimated that 72.3% of all operations will be cancelled during the pandemic with highest cancellation rates for benign diseases affecting recruitment [9].

Basic science studies: Basic science studies rely on access to university laboratories. Access in most has been reduced, with studies involving cell cultures affected.

Rheumatology studies: Further complexity for rheumatology research is due to many patients on immunosuppressants. In order to identify vulnerable patients that need protection from COVID-19, some rheumatology interventional studies that included immunosuppressants were unblinded, so that patients were aware of their risk. Guidance from the British Society of Rheumatology advised virtual appointments, delaying new DMARDs because of the potential risk with COVID-19, and only giving steroid injections if a patient has failed first-line measures and whose symptoms have a significantly negative effect on their health. Therefore, there will be a profound impact on trial delivery for any orthopaedic or rheumatology study requiring new drug therapies, steroids, imaging or pathology as part of the planned trial activity [10].

In summary, the profound effect of Covid-19 and a change in national prioritisation of clinical activity and clinical research, has resulted in a significant reduction of patients recruited to musculoskeletal research. The economic, societal and personal patient impact of the current shift in research prioritisation will not be fully determined for many years.

References
1. Wang L, Wang Y, Ye D, Liu Q. Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence. International Journal of Antimicrobial Agents 2020;https://doi.org/10.1016/j.ijantimicag.2020.105948
2. https://www.recoverytrial.net/
3. https://www.remapcap.org/
4. Thornton J. Clinical trials suspended in UK to prioritise covid-19 studies and free up staff. BMJ 2020;368 doi:https//doi.org/10.1136/bmj.m1172
5. Michael Ly, Justine Fitzpatrick, Benjamin Ellis and Tracey Loftis. Why are musculoskeletal conditions the biggest contributors to mortality? 2019. Health Profile for England
6. https://www.hra.nhs.uk/approvals-amendments/amending-approval/
7. https://w3.abdn.ac.uk/hsru/BSR-PsA/Public/Public/index.cshtml
8. Royal College of Surgeons. Specialty guides for patient management during the coronavirus pandemic. 11th April 2020
9. CovidSurg Collaborative, Nepogodiev D, Bhangu A. Elective surgery cancellations due to the COVID-19 pandemic: global predictive modelling to inform surgical recovery plans. British Journal of Surgery 2020;https//doi.org/10.1002/bjs.11746
10. Favalli EG, Ingegnoli F, De Lucia OD, Cincinelli G, Cimaz R, Caporali R. COVID-19 infection and rheumatoid arthritis: Faraway, so close! Autoimmunity reviews 2020;19:5:https://doi.org/10.1016/j.autrev.2020.102523

Dear Editor,

We read with great interest and little concern Siemieniuk et al. `Drug treatments for covid-19: living systematic review and network meta-analysis`.1 This living systematic review and network meta-analysis provides a comprehensive overview of the evidence for drug treatments of coronavirus disease of 2019 (COVID-19) up to 20 July 2020. We applaud the authors for assessing studies quality using both “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) and “Grading of Recommendations Assessment, Development and Evaluation” (GRADE).2 3 The authors report that the certainty of the evidence for most of the drug comparisons was very low. The only intervention that probably reduces mortality and the requirement of mechanical ventilation is glucocorticoids, a result entirely driven by the RECOVERY trial.4
The concern that we have relates to the lack of consideration on potential heterogeneity in therapy response between men and women. There is growing evidence that sex differences play a role in the immunological, hormonal, and cardiovascular pathophysiological responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).5 6 Furthermore, COVID-19 appears to affect men more severely than women.5 Also, comorbidities, with a worldwide higher prevalence among men than women, such as chronic lung disease, hypertension, and cardiovascular disease, are associated with more severe COVID-19 infection.5 7 8 These differences, are expected to affect the severity of the virus infection, disease course, and (side)-effects of initiated therapy differentially in men and women.6 9

Historically, in medical research, women were underrepresented in clinical trials, and data were rarely reported separately for men and women.5 6 9 Consequently, differences in disease presentation and progression between men and women have been understudied for decades and system-biological differences in (side-)effects of pharmacological therapy remained undetected.
The rigorous work by Siemieniuk et al., very elegantly reports the results of 20 clinical trials investigating potential effects of pharmacologic therapy on disease outcome. A sex specific meta-regression analysis would help to overcome the historic pitfalls of understudying sex differences. However, the lack of sex-sensitive analysis in the current manuscript is not surprising as only two out of the twenty clinical trials (Beigel et al. and Horby et al.)10 4 investigated sex-effect modification or showed stratified results by sex. Nevertheless, for several reasons we think that reporting the lack of sex-sensitivity analysis in current clinical trials on COVID-19 in the current manuscript is crucial. A large body of evidence shows that responses regarding pharmacokinetics of antiviral drugs differ between men and women and that women encounter adverse drug reactions to antiviral treatment more often than men, as shown for lopinavir/ritonavir.11 In fact, for the same dose administered, higher plasma concentrations of ritonavir have been reported in women. On the other hand, an atazanavir plus ritonavir regimen was associated with a higher risk of virologic failure in women than men.12
Moreover, chloroquine and hydroxychloroquine are known to trigger life-threatening polymorphic ventricular tachycardia (torsades de pointes) by prolonging the heart rate-corrected QT (QTc) interval.13 14 Previous reports indicate that women are more prone to develop drug-induced torsades de pointes than men, with 65–75% of drug-induced torsades de pointes occurring in women.15 Substantial sex differences in the electrocardiographic pattern of ventricular repolarization can be observed, with a longer QTc interval at baseline in women.16 17 Protective effects of testosterone have been suggested to account for the shorter QTc interval and the reduced incidence of drug-induced torsades de pointes in men. Also immune modulating drugs are expected to yield differences in outcome between sexes. Both the number and activity of innate immune cells, including monocytes, macrophages, and dendritic cells as well as downstream inflammatory immune responses in general, are higher in women than men.18 19 Moreover, when vaccinated, women develop higher antibody titres (i.e., a primary indicator of protection) and report more adverse reactions to vaccines than men.20 Both basal levels of immunoglobulin and antibody responses, are consistently higher in women than men.21 22 Data from inactivated influenza vaccines indicate that adult women (18–45 years of age) develop higher IL-6 and antibody responses than adult men, with less pronounced differences between the sexes among aged individuals (65+ years of age).23 In contrast, immunotherapies that suppress the immune response (cytokine or checkpoint inhibitors) are reportedly more efficacious in men.24 Therefore, a one-size-fits-all approach to immunotherapies is not expected to be effective, and sex may contribute to variable treatment success in clinical settings, also for COVID-19, as shown in the past for other diseases.

We expect that the lack of consideration of sex-biases in drug efficacy and reactivity for COVID-19 may lead to disparities in (side-) effects between men and women. To allow more personalized patient care, we call investigators developing and testing therapeutic and prophylactic approaches for COVID-19 to design studies that include sex-specific analyses and for already published studies to perform post-hoc sex-specific analysis. As for the study of Siemieniuk et al., the nature of their study allows future updates to report on the lack of sex-stratified data in current COVID-19 trials.

REFERENCES
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2. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097 [published Online First: 2009/07/22]
3. Puhan MA, Schunemann HJ, Murad MH, et al. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ 2014;349:g5630. doi: 10.1136/bmj.g5630 [published Online First: 2014/09/26]
4. Group RC, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med 2020 doi: 10.1056/NEJMoa2021436 [published Online First: 2020/07/18]
5. Gebhard C, Regitz-Zagrosek V, Neuhauser HK, et al. Impact of sex and gender on COVID-19 outcomes in Europe. Biol Sex Differ 2020;11(1):29. doi: 10.1186/s13293-020-00304-9 [published Online First: 2020/05/27]
6. Bischof E, Wolfe J, Klein SL. Clinical trials for COVID-19 should include sex as a variable. J Clin Invest 2020 doi: 10.1172/JCI139306 [published Online First: 2020/05/12]
7. Leung C. Clinical features of deaths in the novel coronavirus epidemic in China. Rev Med Virol 2020;30(3):e2103. doi: 10.1002/rmv.2103 [published Online First: 2020/03/17]
8. Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392(10159):1789-858. doi: 10.1016/S0140-6736(18)32279-7 [published Online First: 2018/11/30]
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10. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Preliminary Report. N Engl J Med 2020 doi: 10.1056/NEJMoa2007764 [published Online First: 2020/05/24]
11. Shiau S, Kuhn L, Strehlau R, et al. Sex differences in responses to antiretroviral treatment in South African HIV-infected children on ritonavir-boosted lopinavir- and nevirapine-based treatment. BMC Pediatr 2014;14:39. doi: 10.1186/1471-2431-14-39 [published Online First: 2014/02/14]
12. Smith KY, Tierney C, Mollan K, et al. Outcomes by sex following treatment initiation with atazanavir plus ritonavir or efavirenz with abacavir/lamivudine or tenofovir/emtricitabine. Clin Infect Dis 2014;58(4):555-63. doi: 10.1093/cid/cit747 [published Online First: 2013/11/21]
13. Giudicessi JR, Noseworthy PA, Friedman PA, et al. Urgent Guidance for Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus Disease 19 (COVID-19). Mayo Clin Proc 2020 doi: 10.1016/j.mayocp.2020.03.024 [published Online First: 2020/05/04]
14. Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia. Clin Toxicol (Phila) 2006;44(2):173-5. doi: 10.1080/15563650500514558 [published Online First: 2006/04/18]
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