Brit: Welcome to emDocs.net podcast. The goal of this podcast is for us to briefly review some of the high-yield posts from the site, which we hope you will read in more detail below.
This episode covers therapies in COVID, first looking at antivirals, and second, at hydroxychloroquine (HC) and chloroquine (CQ). The original antiviral post was released on March 30 and the HC and CQ post on April 6. However, there have been some major updates in the literature concerning these agents. Today, we are going to focus on these and provide some more insights. Please go to the accompanying post for the podcast, as we have more information with references for all of the studies we discuss today.
Manny: Antiviral medications have become one of the main focuses of potential treatment options. Remdesivir is a nucleotide analogue RNA polymerase inhibitor that has previously been tested in a limited number of patients with Ebola, SARS-CoV-1, and MERS. One of the first studies evaluating remdesivir was an industry-sponsored[BL1] case series of 61 patients, which found clinical improvement in 36 patients. But, there were some significant limitations, including no control group, unclear patient selection (and inclusion of what seems to be healthier patients), very poor information about the patients included, and no clear primary endpoint. A randomized controlled trial of admitted[BL2] patients with COVID-19, which included 158 receiving remdesivir versus 79 receiving placebo, found no difference in clinical improvement and no impact on viral load. This study was also stopped early.
The IDSA states remdesivir should not be used outside of a clinical trial. While it may be promising, we need further high-quality RCT data that includes patients earlier in the disease course when viral replication occurs.
Brit: Great points Manny. And for that RCT data, ask and you shall receive! The preliminary report of the Adaptive COVID-19 Treatment Trial (ACTT-1), a multi-center, placebo-controlled RCT on remdesivir is here!
Patients were recruited from 60 sites in several countries. Inclusion criteria were patients who were hospitalized due to COVID-19 with evidence of lower respiratory tract infection, defined in terms of meeting at least one of the following criteria:
Important exclusion criteria are as follows. These are stealthily hidden in the supplemental appendix, so they may be widely overlooked:
The primary endpoint was the time to clinical recovery (defined as either discharge from the hospital or remaining in the hospital solely for the purpose of isolation). Median time to recovery was 11 days in the remdesivir group versus 15 days in the placebo group (p<0.001).
So it looks like remdesivir accelerates recovery, which is nice. Getting out of hospital earlier is good. However, a much more important endpoint is whether or not patients recover (regardless of timing). The latest numeric data point provided within the study is absolute recovery by day 14. More patients in the remdesivir group did recover within that 14 day period (334/538 (62%) in the remdesivir group versus 273/521 (52%) in the placebo group; p= 0.002).
The key question is then whether this benefit in recovery rates is durable over time, or whether it is a short-lived phenomenon. This is important to sort out:
Without additional data it’s impossible to distinguish between these possibilities. The curves shown above seem to start converging, suggesting that benefit may be lost over time. However, some data is still missing (because many patients had not been followed up for 28 days), so it’s impossible to tell.
The study reports the mortality numbers at 14 days, a rather early timepoint. Depending on how you crunch these numbers, it may look like remdesivir caused a mortality benefit. However, the authors were appropriately careful not to make any claims about mortality benefit. The reason not to get excited about these mortality numbers at 14 days is that this looks like a time-limited anomaly. Examining the mortality curve from the supplemental data suggests that mortality curves diverge around 14 days, but then converge at around 25 days. So, when the 28-day mortality numbers are finalized, it’s likely that there won’t be any sustained mortality benefit. Unfortunately, it’s too soon to be sure.
Of course, absence of mortality benefit doesn’t indicate that a medication isn’t beneficial. It’s extremely difficult to achieve proven mortality benefit in critical care trials (discussed here and here). Mortality may not be a terrific outcome to use in COVID-19 patients, because it lumps together patients who truly recover with those who require tracheostomy and chronic ventilation.
Subgroup analysis
Remdesivir hastened recovery in mildly ill patients. There was no signal for benefit among patients on high-flow oxygen, noninvasive ventilation, or invasive ventilation. This is consistent with the concept that later-phase COVID-19 is largely an immunopathological phenomenon (so anti-viral therapy may not help patients with advanced illness very much).
These subgroup analyses are under-powered and ultimately inconclusive. Thus, this data shouldn’t be interpreted to mean that intubated patients shouldn’t be treated with remdesivir. However, this does cast shade on the popularized strategy of allocating limited stores of remdesivir to the sickest patients.
Safety data
There are no signals of harm due to remdesivir. This is consistent with the prior trial in the Lancet.
Missing data
The trial design at clinicaltrials.gov lists 28 secondary endpoints. The supplemental appendix describes collection of blood tests and nasopharyngeal swabs for viral load:
Much of this data is conspicuously absent from the manuscript, including:
The absence of any data on creatinine or renal function is particularly bothersome. Patients with renal insufficiency were excluded from the trial (apparently without any well-defined GFR cutoff?). Lack of a GFR cutoff or information about patients’ GFR values makes it difficult to know which patients can safely receive remdesivir. Enthusiasm about remdesivir will inevitably lead to its administration among patients with renal insufficiency who would have been excluded from the trial, among whom the safety of remdesivir is unknown.
Bottom line?
The presented data to date suggests that remdesivir hastens recovery by a few days. It remains unclear whether remdesivir has a durable effect to increase the number of patients who recover. Available evidence suggests that remdesivir probably has no impact on mortality.
The next agent is a combination of lopinavir, a protease inhibitor for HIV, and ritonovir (a CYP inhibitor to increase lopinavir bioavailability). This combination drug has typically been used to treat HIV and has demonstrated in vitro effects on MERS and SARS-CoV-1. An open-label, single center RCT published in the the New England Journal of Medicine including 199[BL3] patients failed to demonstrate an improvement against standard care in time to clinical improvement, mortality, or percentage of patients with detectable viral RNA at various time points. Authors were also able to exclude patients if they thought the combination was not in the patient’s best interest, the study was not blinded, and most importantly, patients were not treated until day 13 of illness. In this point of a COVID-19 infection, cytokine storm is a more pressing matter, and antiviral s likely will not work. In addition, there were 4 cases of serious GI adverse events in the treatment group, including acute gastritis and lower GI bleeding. This study had a mortality rate of almost 23%, which is significantly higher than the current reported mortality rate in other studies of hospitalized patients with COVID-19.
Manny: The third medication in this class under evaluation is the combination of interferon alpha and ribavirin. Interferon-alpha inhibits viral infection by inducing host immune responses, while ribavirin is a guanosine analog that disrupts replication of multiple RNA viruses.
A study released in May in The Lancet evaluated the combination of interferon beta-1b, lopinavir-ritonavir (Kaletra), and ribavirin versus lopinavir-ritonavir, with no placebo group. This multicenter, open label RCT recruited 127 patients who presented within 14 days of symptoms. The primary outcome was time to negative nasopharyngeal swab, with secondary outcomes including time to resolution of symptoms, hospital length of stay, mortality at 30 days, daily viral load changes in the first 7 days, and frequency and duration of adverse events (specifically nausea and diarrhea). The median time from symptom onset to the start of treatment was 5 days. For the most part, patients were only mildly ill. The combination treatment group demonstrated shorter time to negative nasopharyngeal swab, time to alleviation of symptoms, hospital length of stay, and time to negative viral load. There was no difference in adverse events. However, there was no placebo group, there was unclear consecutive enrollment, the primary outcome was not patient centered, it was open label, and there were no critically ill-patients. The important aspect of this study is that patients were treated relatively early compared to other studies, but patients overall were generally well. Further study is needed, but the medication combination is promising.
Brit: The bottom line is that the IDSA does not recommend these medications outside of a clinical trial. We need more study regarding treatment within the timeframe of viral replication, including blinded RCTs.
There was initially a great deal of support for HC and CQ. These medications alter intracellular endosomal pH and are thought to reduce viral replication. Initial studies released in preprint form suggest promising findings. A study released[BL6] in March stated CQ was safe and effective in China. Two observational studies released in France found improved viral clearance, but[BL7] as discussed in the emDocs post released on April 6, there are some major issues. The first observational study primarily looked at viral clearance on day 6, with no patient centered outcomes, and the second had no control group. Basically, significant bias, lack of adequate controls, and poor blinding among many other problems severely limit the clinical implications.
Manny, have there been any RCTs published?
Manny: In late March a pilot, prepublication RCT was released[BL8] that compared 30 patients receiving HC to standard care, but it found no real difference in viral swabs or patient outcomes. A second[BL9] RCT that was released in pre-publication format included 62 adults with COVID-19. This study was non-blinded and included patients with mild disease, with primary outcome of time to clinical recovery. This meant no fever and no cough for 72 hours. Authors found HC decreased times by about 1 day, but when evaluating the trial registration, there are some major problems. There was supposed to be a placebo group, and the study was stopped early. While the study was single center, the authors stated randomization was to “stratified by site” in the registration, suggesting it was supposed to be multicenter. While it was declared “positive”, there are again too many problems to declare a positive trial.
Since these questionable “positive” studies, several higher quality studies have been released. A multicenter, open label trial of 150 patients with mild[BL10] COVID-19 found no difference in symptoms or rates of negative conversion. However, there were significant increases in adverse events in those receiving treatment, at 30% vs. 9%.
Brit, what have you found in the literature?
Brit: A double blind RCT in Brazil[BL11] compared 2 doses of CQ (600mg BID for 10 days vs. 450 mg BID on day 1 and then 450mg daily for 4 days). While authors were supposed to enroll 440 patients, they stopped at 81 because mortality was higher in the CQ group. A chart review of[BL12] 368 patients admitted in the U.S. also found higher rates of death in patients receiving HC compared to those who were not, at 28% vs. 11%. Another observation study including 1376 patients in New[BL13] York City found those receiving HC did worse, but with propensity matching, authors did not find a difference in time to death or intubation.
Currently, the IDSA only recommends use in the setting of a clinical trial. However, it’s tough to discount the significant[BL14] harms found in several of the higher quality studies, with really no demonstrable positive outcome.
Manny: This rounds out our summary of the key emDOCs posts. Thanks for joining us, and stay tuned for our next episode. Feel free to comment on our site and let us know if you have any feedback. Stay safe and healthy everyone!
References:
[BL1]Grein J, Ohmagari N, Shin D, Diaz G. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl Journ Med. Published April 10, 2020. DOI: 10.1056/NEJMoa2007016
[BL2]Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. April 2020. doi:10.1016/s0140-6736(20)31022-9
[BL3]Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19 [published online ahead of print, 2020 Mar 18]. N Engl J Med. 2020;10.1056/NEJMoa2001282. PMID: 32187464
[BL4]Hung IF-N, Lung K-C, Tso EY-K, et al. 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. The Lancet. Published online May 2020. doi:10.1016/s0140-6736(20)31042-4
[BL5]Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 Infection. Published April 11, 2020. Available at https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
[BL6]Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020 Mar 16;14(1):72-73.
[BL7]Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar 20.
S6. Gautret P, Lagier J, Parola P, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study. Available at https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf
[BL8]Jun C, Danping L, Li L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). JOURNAL OF ZHEJIANG UNIVERSITY. Available at http://subject.med.wanfangdata.com.cn/UpLoad/Files/202003/43f8625d4dc74e42bbcf24795de1c77c.pdf
[BL9]Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. doi: https://doi.org/10.1101/2020.03.22.20040758. Available at https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v3
[BL10]Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. 2020. Not published. Available preprint here.
[BL11]Borba MGS, Val FFA, Sampaio VS, et al. Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study). 2020. Not published. Available preprint here.
[BL12]Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. 2020. Not published. Available preprint here.
[BL13]Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19 N Engl J Med. 2020; [article]
[BL14]Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 Infection. Published April 11, 2020. Available at https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/