#217 COVID Cakes the Fourth: ACTT-1, Triple Therapy, PCR, Serology

June 1, 2020 | By Deb Gorth

Helping you keep up with the hot COVID science

Stay current with the emerging COVID-19 research including: ACTT-1 (remdesivir), triple therapy with interferon, and conundrums  about SARS-CoV-2 PCR and serologic testing. We’re led by the one and only Curbsider/internist/epidemiologist, Rahul Ganatra MD MPH (@rbganatr). And…just in case you live outside of the habitat for murder hornets and your anxiety about the pandemic had begun to abate, we touch on the CDCs guidance to beware of hungry aggressive rats. Gross!

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Credits

Written and Produced by: Rahul Ganatra MD, MPH, Deborah J. Gorth ScM, Emi Okamoto MD, Sarah P. Roberts MPH, and Matthew Watto MD

Cover Art: Deborah J. Gorth ScM

Hosts: Matthew Watto MD, Rahul Ganatra MD MPH, Emi Okamoto MD, and Sarah P. Roberts MPH

Editor: Matthew Watto MD (written materials); Clair Morgan of nodderly.com

Sponsor

Join the American College of Physicians today! Post-training physicians can take advantage of an exclusive limited-time $100 dues discount. Visit acponline.org/member and use the code ACPDISCOUNT. Discount is only available until June 30, 2020.  

We are excited to announce that the Curbsiders are now partnering with VCU Health Continuing Education to offer continuing education credits for physicians and other healthcare professionals. Check out curbsiders.vcuhealth.org for more information.

Time Stamps

• 00:00 Sponsors
• 00:30 Intro, disclaimer
• 02:40 Fomites, groceries and killer rats
• 08:22 Sponsor
• 09:22 ACTT-1 trial of remdesivir
• 18:22 Triple therapy with lopinavir/ritonavir, ribavarin and interferon
• 33:10 Background on PCR testing for SARS-CoV-2; How common are false negative PCR tests?
• 44:25 Serologic testing for SARS-CoV-2; Utility of antibody testing; Test characteristics
• 50:30 Outro

COVID Cakes #4 Pearls

1. You do not need to bleach your bread when you get home from the supermarket. 
2. Beware of studies that change their primary outcome. This could increase the likelihood of a type I error (false positive), inappropriately rejecting the null hypothesis. Historic information about clinical trials can be found at clinicaltrials.gov in the tabular view. 
3. Triple therapy with Lopinavir/Ritonavir, Ribavirin and IFN-beta in hospitalized patients with a mild COVID-19 presentation reduces the time to a negative nasopharyngeal swab. 
4. Active control trials compare a new intervention to an existing intervention, not placebo, with the goal of showing that the new intervention is superior. 
5. There is a high false negative rate of SARS-CoV-2 PCR testing. The most sensitive period for testing appears to be 3 days after symptom onset.
6. Abbott’s SARS-CoV-2 IgG nucleocapsid serologic test becomes sensitive and specific two weeks after symptom onset.

COVID Cakes #4 Show Notes

Fomites and Aggressive Rats 

Both JAMA and the CDC have issued statements deemphasizing the spread of SARS-CoV-2 on fomites. JAMA’s new patient education page gives guidance about grocery shopping, so we can now stop bleaching our bread. The CDC re-organized its COVID advisory information page to seemingly downplay the risk of contracting COVID via contact with surfaces. However, per the CDC, the change was made simply to streamline content, and no new CDC guidelines have been issued regarding fomites and COVID transmission. The CDC did, however, recently issue a warning about the effect of COVID-19 on rodents, noting an increase in aggressive rat activity. 

ACTT-1 Trial Update

The ACTT-1 trial is a randomized, double-blind,  placebo controlled trial testing the efficacy of intravenous remdesivir for hospitalized adults with COVID-19.  The primary outcome for this study was positive; the remdesivir group recovered in 11 days (95% CI, 9 to 12) compared to 15 days (95% CI, 13 to 19) in the control group. 

Triple Therapy 

Hung et al investigates the effect of triple therapy with Lopinavir/Ritonavir, Ribavirin and interferon-beta on hospitalized patients with COVID-19. This is a multicenter, randomized, open-label, active controlled superiority trial with the primary outcome of time to negative nasopharyngeal swab. Patients in this study were not critically ill; only 15% of the patients were on supplemental oxygen, <5% were on non-invasive ventilator support,  and only one patient in the study was intubated. In contrast with placebo-controlled trials, in an active-controlled trial, the control group receives another treatment, which was lopinavir/ritonavir in this study. The time to negative nasopharyngeal swab was 6.5 days for the triple therapy group and 12.5 days for the group treated only with lopinavir/ritonavir (p <0.0001). There was no difference in adverse events or mortality between the groups.

Bottom line:  

This trial provides evidence that treating patients hospitalized with mild COVID-19 with triple therapy reduces time to negative nasopharyngeal swab. As Rahul points out, this is only a surrogate endpoint, but it may have public health implications by reducing transmission of infection. 

PCR Testing and Viral Shedding

A polymerase chain reaction (PCR) is a method of selectively amplifying and measuring small portions of DNA using multiple cycles of warming and cooling to denature the DNA and a heat-tolerant DNA polymerase to copy the material. Real-time PCR (RT-PCR) is a quantitative PCR that uses the number of cycles to approximate the starting quantity of genetic material in relation to a reference. The PCR itself is specific and sensitive, but this test is limited by the quality of sample collected. 

Kucira et al looked at 7 different studies and found that 67% of patients will test negative 4 days after exposure (i.e. one day prior to symptom onset), approximately 38% percent of patients will be negative on the first day of symptoms, and the lowest false negative rate is 3 days after symptom onset (20%). Prolonged viral shedding has been reported for up to 6 weeks, but no replication competent virus has been isolated after 10 days. The South Korean CDC released a report that suggests that individuals who have recovered from COVID-19, but still have a positive SARS-CoV-2 PCR did not infect new individuals. 

Bottom line:

False negative PCR testing for SARS-CoV-2 is common! Each patient must be evaluated based on symptoms, timing, and other relevant/available clinical information. Don’t assume that a negative PCR means the patient is free from infection. 

Serological Testing

Serological testing for the presence of antibodies is important for establishing prior exposure to SARS-CoV-2, verifying immune response for the development of vaccines, and potentially identifying individuals for plasma donation. A study by Bryan et al published in the Journal of Clinical Microbiology offered a promising characterization of an IgG antibody test. This test produced by Abbott for IgG antibodies against the SARS-CoV-2 nucleocapsid protein shows peak sensitivity and specificity of 100% for both at 14 days after PCR positivity and 17 days after symptom onset. 

Bottom Line:

We believe that serologic testing will play an important role as we move forward during the pandemic, but at this time their clinical use is challenging since there are many different tests with different performance characteristics, antibody types and antigenic targets.

Goal

Listeners will practice their critical appraisal skills as they update themselves on the latest COVID-19 research.

Learning objectives

After listening to this episode listeners will…

1. Describe the quality of evidence put forth by and the implications of the recent Lancet paper on triple therapy for COVID-19
2. Be familiar with the results of the ACTT-1 trial or remdesivir for COVID-19
3. Appreciate the complexities of PCR in testing for SARS-CoV2
4. Gain insight into the role of serological testing for SARS-CoV2

Disclosures

The Curbsiders report no relevant financial disclosures.

Citation

Gorth DJ, Ganatra RB, Okamoto E, Roberts SP, Watto MF. “#217 COVID Cakes 4 the Fourth”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list. June 1, 2020.