Kenneth Bender, PharmD, MA

An investigation of the approximate 1 in 5 patients at a clinic who test positive for SARS-CoV-2 after being discharged in apparent recovery and with negative test results revealed few actually carried replicating virus, according to a 

Flora Liotti, PhD, Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy, and colleagues investigated the retested positive nasal/oropharyngeal swab samples from recovered patients with prior negative results for the presence of replicative SARS-CoV-2 RNA.

"Real-time PCR is not a viral culture and does not allow determination of whether the virus is viable and transmissible," Liotti and colleagues indicate, in explaining their rationale for re-analyzing the swab samples with both total (genomic) and replicative (subgenomic) real-time polymerase chain reaction (RT-PCR) assays to ascertain whether the positive result reflects active infection.

, Mitchell Katz, MD concurs that the high sensitivity of the RT-PCR assay for fragments of viral RNA can yield a positive result from detecting nonviable remnants of the virus.

"Unfortunately, the interpretation of positive results in patients who have previously recovered from COVID-19 is fraught," Katz observed.

Liotti and colleagues identified 176 recovered patients with COVID-19 who were admitted to the post-acute outpatient service of their clinic in Rome for follow-up between April 21 and June 18, 2020.These patients had discontinued isolation according to the clinic criteria, which included no fever for 3 consecutive days, improvement in other symptoms, and 2 negative RT-PCR results taken 24 hours apart.

At follow-up, the investigators found that 32 of the 176 patients had viral loads ranging from 1.6X101to 1.3X104 SARS-CoV-2 RNA copies per ml. One of the 32 samples (3.1%) was replicative.The samples obtained at diagnosis from these 32 patients were determined to all contain replicative RNA.The mean time from diagnosis to follow-up for these 32 patients was 48.6 days (SD 13.1).

"Only 1 of 32 patients retesting positive had replicating virus in the nasal/oropharyngeal sample, suggesting either recurrent infection or re-infection, which is impossible to separate because no whole-genome sequencing and phylogenetic analysis were performed," Liotti and colleagues concluded.

Katz suggested moderation in the application and interpretation of testing for those without symptoms given the absence of such investigational capacity in clinical settings.

"To avoid unnecessary quarantine for patients who have recovered from COVID-19, routine repeated PCR testing should not be done in the 90 days following infection," Katz advised.

Articles

Patients testing positive for SARS-CoV-2 after recovery and negative tests are re-examined to determine if they are reinfected and/or infectious.

Testing Positive for SARS-CoV-2 after Recovering from COVID-19

The final report of the phase 3 trial of remdesivir for COVID-19 confirms preliminary findings that supported the emergency use authorization, and provides the detail of potential benefit at different disease severity that informed the first FDA approval of treatment for COVID-19.

"Our overall findings were consistent with the findings of the preliminary report," John Beigel, MD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, and colleagues indicate in the study 

. "A 10-day course of remdesivir was superior to placebo in the treatment of hospitalized patients with COVID-19."

, Raphael Dolin, MD, Department of Medicine, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston MA, and Martin Hirsch, MD, Massachusetts General Hospital, Partners AIDS Research Center, Boston welcomed the report, characterizing it as an important first step in the development and approval of effective treatments for COVID-19.

"The report from Beigel et al shows that remdesivir provides moderate clinical benefit in the treatment of patients with COVID-19," Dolin and Hirsch commented."These findings are a step forward on the road to developing effective therapy for SARS-CoV-2 infections and, as such, are an important advance."

The trial enrolled participants from February 21, 2020 through April 19, at 60 trial sites in 10 countries. A total of 1062 patients were randomized 1:1 to receive either placebo or a 10-day course of remdesivir, administered intravenously with 200mg loading dose on day 1, and100mg maintenance doses daily from day 2 to 10. The trial was conducted with "adaptive-design" to allow participants to receive other therapies indicated by protocols at their respective treatment centers.

The investigators described numerous challenges in conducting the large, multlnational trial early in a pandemic with a novel virus, including inadequate supplies of personal protective equipment and trial-related supplies, such as swabs.

"The trial was implemented during a time of restricted travel, and hospitals restricted the entrance of nonessential personnel," Beigel and colleagues recount. "Training site initiation visits, and monitoring visits often were performed remotely.Research staff were often assigned other clinical duties, and staff illnesses strained research resources."

The trial was also designed when little was known about the course of COVID-19, and so the primary outcome was changed early in the trial, from a comparison of outcomes on day 15 to a comparison of time to recovery up to day 29. The apparent shortening of time to recovery led to an early unblinding of the protocol so that patients on placebo could elect for active treatment.

The investigators report that time to recovery with active drug was a median 10 days, compared to 15 days with placebo. Patients on active drug also achieved greater clinical improvement, on ordinal scale score measure, at day 15; a shorter time to improvement, on one of two ordinal scale categories; and shorter length of initial hospital stay (median 12 days vs 17). All cause mortality was 11.4% with remdesivir and 15.2% with placebo.

The investigators found the active drug associated with lower incidence of new oxygen use, and a lower proportion of patients needing higher levels of respiratory support. For patients receiving oxygen or ECMO at study entry, the active drug was associated with fewer days of subsequent oxygen, and shorter subsequent duration of mechanical ventilation or ECMO.

Beigel and colleagues found that benefit was most apparent in patients who needed only low-flow oxygen at study entry. They acknowledge, however, that this may reflect the larger sample of patients at this level of severity; and also noted that the follow-up period with more severely ill patients may have been too short to adequately determine their benefit from the drug.

"Cumulatively, these findings suggest that treatment with remdesivir may not only reduce the disease burden but may also decrease the use of scarce health care resources during this pandemic," Beigel and colleagues indicate.

The final report of remdesivir trial supports its approved treatment for COVID-19 after preliminary findings enabled emergency use authorization.

Final Report of Remdesivir Trial Supports First FDA Approval of Treatment for COVID-19

demonstrated persistent protection up to 4 years after a 3rd dose, and evaluation of a booster following the 3-dose regimen evidenced continued immunogenicity, safety and tolerability, according to reports at the 2020 IDWeek virtual conference.

Shon Remich, MD, Senior Director, Clinical Research and Development, Pfizer, Downingtown, Pennsylvania reported on the extension of a phase 2 study of a 3-injection regimen with two antigen dose levels,in which a 4th, booster injection was administered to some participants, and monitoring extended for up to 4 years after the 3-dose regimen, or 3 years after the booster.

vaccine candidate is highly immunogenic, well tolerated and demonstrates an acceptable safety profile in both dose groups," Remich reported, adding "antibody persistence remains stable from 12 months to 4-year post dose 3."

The first stage of the phase 2 trial was conducted from July 16 2015 to March 7, 2017, following "Fast Track" designation from the FDA on August, 2014.Approximately 850 health adults aged 65 to 85 years of age were enrolled and randomized to receive injections with either a 100μg or 200μg total dose of combined toxin A (TcdA) and B (TcdB), or placebo.The active agent or placebo was administered in one of two 3-dose regimens: on days 1, 8 and 30 or Months 0, 1 and 6.

Immunogenicity testing was conducted on samples obtained at each of 9 study visits through 12 months after the 3rd dose.At the conclusion of this portion of the trial, Kathrin Jansen, PhD, Senior Vice President and head of Vaccine Research and Development, Pfizer 

"We are very encouraged by these interim immunogenicity and safety results demonstrating robust increases in vaccine-elicited neutralizing antibodies to both toxins, that we believe could provide protection against 

disease," Jansen indicated in a press release.

In the extension stage of the trial, subjects who had received vaccine were re-randomized 12 months after the third dose, to receive either a booster dose or placebo in a 1:1 ratio.These subjects were then followed for immunogenicity for 3 years after the booster dose, which was 4 years after the 3rd dose.

Remich reported that peak antibody response to vaccination was observed between day 8 and 30 following booster administration."Both regimens demonstrated robust anamnestic responses with peak levels above the three-dose peak," he indicated.

Toxin A geometric mean concentrations (GMC) remained above pre-booster GMCs 3 years after the booster for both dose levels and regimens.Antibody persistence for both groups demonstrated stable antibody levels four years after the primary vaccination among those who did not receive the booster dose, according to Remich.

Remich indicated that adverse event rates were similar between both regimens and placebo, and there were no serious adverse events related to the vaccine at any dose or regimen.The safety profile was similar to what was found in the initial stage of the study.

The report is abstract 12 at the 2020 IDWeek conference: "Randomized Studies of Two 

An investigational vaccine for C difficile  demonstrates multiyear efficacy in trials reported at 2020 IDWeek Conference.

Progress Reported on Trials of Vaccine for C difficile

A novel, first-in-class antifungal, fosmanogepix, demonstrated efficacy in a phase 2 candidemia trial, and was well tolerated in a subset of patients with renal insufficiency, according to results presented at the 2020 IDWeek virtual conference.

“Fosmanogepix demonstrated high level treatment success with no evidence of drug-related nephrotoxicity, with no dose adjustments required,” reported Pierre Bulpa, MD, Head, Clinical Department, Mont-Godine University Hospital, Yvoir, Belgium.

Fosmanogepix is described by the manufacturer and sponsor of the phase 2 trial, Amplyx Pharmaceuticals, as a unique antifungal with a novel mechanism of action and broad spectrum activity, including against strains such as 

that are resistant to the 3 available antifungal classes of polyenes, azoles and echinocandins.

The mechanism of action of fosmanogepix involves inhibition of the fungal enzyme Gwt1 by the active moiety, manogepix. The manufacturer indicates that Gwt1 is highly conserved across fungal strains and is essential for trafficking and anchoring manoprotein to the outer cell wall in fungi; with mannoproteins integral to fungal cell wall integrity, adhesion, pathogenicity, and for evading host defenses.

As a substantial number of patients with candidemia also suffer from renal insufficiency, Bulpa and colleagues conducted a subset analysis of those patients from an open-label, non-comparative phase 2 trial of the safety and efficacy of the agent as first-line treatment.

All participants had a positive blood culture for 

spp within 96 hours prior to study entry, and had not received antifungal treatment within the previous 2 days.Patients with neutropenia, 

 infections, or those on hemodialysis were excluded.

Participants received fosmanogepix for up to 14 days, as 1000mg intravenously (IV) twice daily for 1 day, then 600mg IV daily for at least 2 days, followed by either 600mg IV or 700mg orally daily.Fluconazole was to be administered to any participants who required antifungal treatment beyond the 14 day regimen with fosmanogepix.

Of the 21 participants, 14 had some degree of renal insufficiency: 7 had mild insufficiency with glomerular filtration rate (GFR) of 60-89; 5 had moderate insufficiency with GFR 30-59; and 2 had severe renal insufficiency with GFR 15-29.

Twelve of the 14 (85%) with renal insufficiency completed the study treatment, and treatment was successful for each of the 12 at the end of the 14 day regimen.Successful outcome was defined as survival with clearance of 

from blood cultures with no additional antifungal treatment.

“Decline in renal function was not observed at end of study treatment,” Bulpa reported, and“there were no treatment-related adverse events.”

There was worsening of renal function observed in the follow-up period in 4 patients, however, although none required dialysis.Bulpa indicated that renal impairment had not increased “the exposure” (ie, increased serum levels) of fosmanogepix, and so no dose adjustments were required.

“These preliminary data support the continued evaluation of foxmanogepix in patients with candidemia and renal dysfunction as an alternative to potentially nephrotoxic antifungal agents,” Bulpa reported.

The results were reported at the 2020 IDWeek virtual conference, Poster 1157: “Clinical Safety, Efficacy, and Pharmacokinetics of Fosmanogepix, a Novel First-in-class Antifungal, in Patients with Renal Insufficiency: Subset Analysis from a Phase 2 Candidemia Trial.

Phase 2 trial demonstrates novel investigational antifungal Fosmanogepix is tolerated and efficacious in patients with renal Insufficiency.