Weekly Articles: 1/24/2021

Ditte Marie Kirkegaard-Klitbo, Magda Teresa Thomsen, Marco Gelpi, Flemming Bendtsen, Susanne Dam Nielsen, Thomas Benfield, Hepatic steatosis associated with exposure to elvitegravir and raltegravir, Clinical Infectious Diseases, 2021;, ciab057, https://doi.org/10.1093/cid/ciab057

This was an observational cohort study evaluating exposure to integrase inhibitors and subsequent hepatic steatosis. As it is known, integrase inhibitors are associated with increased weight gain. Using non-con CT scans and multivariate regression analysis, those with raltegravir were more likely to have hepatic steatosis (15%) compared to elvitegravir (10%) and dolutegravir (4%). Any exposure seems to be associated with increased hepatic steatosis in those who used raltegravir while cumulative exposure was associated with hepatic steatosis in the elvitegravir group:

Overall, another reason to avoid raltegravir. DTG is the GOAT. 

Monica L Nation, Robert Moss, Matthew J Spittal, Tom Kotsimbos, Paul M Kelly, Allen C Cheng, for the Influenza Complications Alert Network (FluCAN) Investigators, Influenza Vaccine Effectiveness Against Influenza-Related Mortality in Australian Hospitalized Patients: A Propensity Score Analysis, Clinical Infectious Diseases, Volume 72, Issue 1, 1 January 2021, Pages 99–107, https://doi.org/10.1093/cid/ciz1238

This multicenter Australian cohort study evaluated the impact of influenza vaccinations on influenza-related mortality by comparing influenza-related mortality in vaccinated with unvaccinated patients as well as non-influenza related mortality between similar groups. Propensity scores were calculated into a multivariate regression analysis using control patients (non-vaccinated) who were alive at the end of the study period. Adjusted odd ratios (aOR) were then calculated using logistic regression. Overall, the aOR for influenza-related mortality was 0.69 (95% CI 0.49-0.97), with an influenza-vaccine effectiveness of 31%. Notably, the severity of influenza was not attenuated.

The results seem to be driven by those who were at higher risk (elderly, pregnant women, people with comorbidities), however subgroup analysis of those who were >65 do not reveal any impact of vaccination on influenza-related mortality. The authors attribute this to immunosenescence, or perhaps the original antigenic sin. This topic still confuses me to no end, but I would still recommend influenza vaccination.  

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. Published online January 21, 2021. doi:10.1001/jama.2021.0202

Bam bam! You know what I like? Besides saying “bam bam”? Studies with non-patient centered primary outcomes and dozens of secondary outcomes (seriously, 3 whole pages of outcomes). This was a phase 2 and 3, randomized, double-blind, placebo controlled study evaluating bamlanivimab monotherapy with bamlanivimab/etesevimab dual therapy. Etesevimab binds to a different epitope from bamlanivimab (i.e. they work in different areas of the spike protein). Remember the BLAZE-1 trial? Yep this is a continuation, evaluating the “antibody cocktail” to prevent resistance. Here, patients with mild-moderate COVID-19 were randomized to receive either placebo, 700mg of bamlanivimab, 2800mg bamlanivimab, 7000mg bamlanivimab, and combination of 2800mg bamlanivimab/2800mg etesevimab. Primary outcome was change in viral load from baseline to 11 days. Plus a bunch of secondary outcomes. 592 patients were randomized, with roughly 100 patients per group. The groups were reasonably well matched (more patients in the 7000mg group had moderate disease while those in the 700mg group were generally younger). Overall, at day 11, there were not differences in terms of the change of viral load from baseline:

Further, only 10 out of 84 secondary outcomes were statistically significant. Patients in the 700mg group and 7000mg group had improvement in their symptoms that was statistically significant, but this was not seen in the 2800mg group nor the combination group. Make that what you will. Feel free to check out that massive list of secondary outcomes; I think these are statistical flukes (not the liver ones). I am not wowed yet with the mabs, though I am crossing my fingers.

Sippola S, Haijanen J, Grönroos J, et al. Effect of Oral Moxifloxacin vs Intravenous Ertapenem Plus Oral Levofloxacin for Treatment of Uncomplicated Acute Appendicitis: The APPAC II Randomized Clinical Trial. JAMA. 2021;325(4):353–362. doi:10.1001/jama.2020.23525

This was an open-label, randomized, non-inferiority trial evaluating PO moxifloxacin vs IV ertapenem for 2 days followed by PO levofloxacin + metronidazole (total antibiotic therapy 7 days) for the treatment of uncomplicated appendicitis. Patients were randomized in a 1:1 ratio, with primary outcome being treatment success at 1 year which included no recurrent appendicitis and no surgical intervention. 603 patients were randomized, with the oral antibiotic achieving a 70.2% treatment success at 1 year compared to 73.8% in the IV to PO group (absolute mean difference -3.6%, 95% CI -9.7 to infinity, p=0.26). Primary failure rate (appendectomy in initial hospitalization) was 6.1% in the PO group and 3.8% in the IV to PO group (2.3%, p=0.25). 

So yay antibiotics! Which I cannot say I am surprised; moxifloxacin may be a bit too broad spectrum but does the job fairly well (covers anaerobes and gram negatives that live in the gut). Perhaps an oral beta-lactam may suffice, but given the dose conversion from IV to PO, I think we are stuck with fluoroquinolones for the time being. One thing to note is this study excluded patients who were older than 60 years old, so those in internal medicine may have issues with applying this study to the older population we see. 

Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter JJ. Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019: The Ivermectin in COVID Nineteen Study. Chest. 2021 Jan;159(1):85-92. doi: 10.1016/j.chest.2020.10.009. Epub 2020 Oct 13. PMID: 33065103; PMCID: PMC7550891.

So Ivermectin is in the news. This was a retrospective study from a health system in Florida evaluating a one time dose of 200mg of ivermectin in all-cause mortality in patients admitted for COVID-19. 173 patients were treated with ivermectin while 107 were treated with standard of care at the time (including steroids, azithromycin, HCQ). Given the differences between the groups (more patients in the ivermectin group got steroids), 98 patients in each group were matched. Mortality was lower in the matched ivermectin gohort, 13.3% vs 24.5% (OR 0.47, 95% 0.22-0.99), which was driven mostly by the severe group (32% vs 81% in severe, p=0.002):

Ivermectin was associated with an absolute risk reduction of 11.2% (95% CI 0.38 to 22.1%) and a NNT of 8.9. I am hopeful for this. Unlike HCQ, you can give a one time dose with option of redosing in about a week, and side effects are minimal. I know that guidelines removed the recommendation against ivermectin, so it is reasonable to use. How it affects mortality may be difficult to tell at this time, but it doesn’t hurt to be hopeful. 

C. Chaccour et al., The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial, EClinicalMedicine (2021), https://doi. org/10.1016/j.eclinm.2020.100720

This was a pilot, randomized, placebo controlled single-center trial evaluating the maximum approved dose for ivermectin in Europe and its impact on SARS-CoV2 in viral load at day 7.  Adult patients with non-severe COVID who presented within 72hrs of symptoms were enrolled. 24 patients were randomized, with no difference in the proportion of PCR positive patients between groups. There was a trend towards ivermectin having lower viral load:

Those in the ivermectin group had fewer patient-days of any symptoms (171 vs 255), mostly in terms of cough and anosmia. Notably, however, when using a cycle threshold cutoff of 30 (the point above at which viral cultures did not grow), there was a difference in positivity between ivermectin and placebo:

Given that most of the PCR studies “flag” a cycle threshold below that number as positive (the cycle threshold is the number of cycles needed to amplify the sample. The lower the number, the more virus there is in the sample and thus, less cycles are needed to amplify this) which may have implications in viral transmission. This does not tell us much about clinical utility, but this is a small study so lets see how the data pans out. 

Shi C, Ye J, Xu R, et alEffect of the vancomycin minimum inhibitory concentration on clinical outcomes in patients with methicillin-susceptible Staphylococcus aureus bacteraemia: a systematic review and meta-analysisBMJ Open 2021;11:e040675. doi: 10.1136/bmjopen-2020-040675

This was a meta-analysis evaluating the impact of the MIC to vancomycin in MSSA in terms of mortality and complicated bacteremia, regardless of antibiotic therapy. Primary outcome was mortality. 15 studies involving nearly 2500 patients were included. All studies were observational studies. Mortality for patients with MSSA isolates with a high MIC was higher compared to those with low MIC (OR 1.44, 95% CI 1.12 to 1.84):

Higher MICs were also associated with increased likelihood of septic thrombophlebitis (OR 3.16, 95% CI 1.11 to 9.00) and a non-significant higher likelihood of persistent bacteremia. One of the things to note is different assays were used for MIC cut off, with different cut offs used, either >1.5 of >2. This makes a cutoff for therapy a bit difficult to discern. Why a high MIC to vancomycin plays a role in therapy for MSSA (vanco was only used in less than a quarter as definitive therapy). A few hypothesis include that vancomycin MIC is a surrogate marker to weak response to other antibiotics, or a marker of unfavourable bacterial or genetic factors. 

Elisa H Ignatius, Kunbo Wang, Andrew Karaba, Matthew Robinson, Robin K Avery, Paul Blair, Natasha Chida, Tania Jain, Brent G Petty, Zishan Siddiqui, Michael T Melia, Paul G Auwaerter, Yanxun Xu, Brian T Garibaldi, Tocilizumab for the Treatment of COVID-19 Among Hospitalized Patients: A Matched Retrospective Cohort Analysis, Open Forum Infectious Diseases, Volume 8, Issue 1, January 2021, ofaa598, https://doi.org/10.1093/ofid/ofaa598

Tocilizumab! The humanized monoclonal antibody against IL-6 used in rheumatology has also been used in COVID. This was a retrospective study of adult patients comparing patients who got  tocilizumab compared to patients who did not. Primary outcome was all-cause inhospital mortality at 28 days. 1914 patients were included (90 patients with tocilizumab and 1669 controls). Notably, those who got tocilizumab were more likely to have:

• Severe respiratory failure 
• Tachypnea
• Lower GFR
• Higher inflammatory markers (IL-6 >55, ferritin >800)

Using the marginal structural Cox model, patients who got tocilizumab had a lower risk of death at 28 days (aHR 0.38, 95%  CI 0.21 to 0.70), which was also the case in the 1:1 matched data set (aHR 0.47, 95% CI 0.25 to 0.88):

Male patients, those >55yo, those with normal vitals, as well as those with increased inflammatory markers (ferritin >800, WBC >12k, D-dimer >4, and IL-6 >55) had greater benefit. Of note, those with IL-6 >55 had an aHR 0.34 (95% CI 0.178 to 0.64) while those with ferritin >800 had an aHR 0.26 (95% CI 0.102 to 0.64). So there may be a benefit to this monoclonal antibody in those who are relatively young, stable, and have high inflammatory markers. I suspect this is because they may have not deteriorated yet and the high inflammatory markers are a tip off of something bad to happen, but that is just mere speculation.