Weekly Articles 7/18/2021

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Zachary A Yetmar, Supavit Chesdachai, Tarek Kashour, Muhammad Riaz, Danielle J Gerberi, Andrew D Badley, Elie F Berbari, Imad M Tleyjeh, Prior Statin Use and Risk of Mortality and Severe Disease From Coronavirus Disease 2019: A Systematic Review and Meta-analysis, Open Forum Infectious Diseases, Volume 8, Issue 7, July 2021, ofab284, https://doi.org/10.1093/ofid/ofab284

This was a meta-analysis on the prior use of statin on outcomes of patients with COVID-19. Mortality outcomes, rate of severe COVID, and diagnosis of COVID were evaluated. 19 studies were included, of which all were cohort studies (16 retrospective, 3 case-control), and totaled 395,513 patients. Mortality was evaluated in 13 studies, with use of statins being associated with reduced mortality (pooled aRR 0.65, 95% CI 0.56-0.77) but this outcome had a fairly high degree of heterogeneity:

9 studies evaluated the rate of severe COVID-19 with prior statin use, with its use being associated with reduced risk of severe disease (aRR 0.73, 95% CI 0.57-0.94) with similar degree of heterogeneity. 

Further, prior statin use was also associated with reduced risk of COVID-19 in one study, while it was associated with higher risk in another. The former study, however, was fairly well designed with over 37,000 patients. I am always wary of meta-analysis of retrospective studies, as there are multiple outcomes, doses of drugs, and populations that go into that. I do not think anyone is stopping statins in those who need them once they hit the hospital with COVID, but at least there is no risk of worsened outcomes if someone is already on them. 

J Ryan Bariola, Erin K McCreary, Richard J Wadas, Kevin E Kip, Oscar C Marroquin, Tami Minnier, Stephen Koscumb, Kevin Collins, Mark Schmidhofer, Judith A Shovel, Mary Kay Wisniewski, Colleen Sullivan, Donald M Yealy, David A Nace, David T Huang, Ghady Haidar, Tina Khadem, Kelsey Linstrum, Christopher W Seymour, Stephanie K Montgomery, Derek C Angus, Graham M Snyder, Impact of Bamlanivimab Monoclonal Antibody Treatment on Hospitalization and Mortality Among Nonhospitalized Adults With Severe Acute Respiratory Syndrome Coronavirus 2 Infection, Open Forum Infectious Diseases, Volume 8, Issue 7, July 2021, ofab254, https://doi.org/10.1093/ofid/ofab254

More Bam-bam! This was an observational study evaluating the association of monotherapy with bamlanivimab in those who get outpatient therapy for COVID and who have risk factors for progression to severe COVID. 700mg dose was given in those who had symptoms within 10 days, age >65 or a medical condition associated with high risk of COVID-19. Primary endpoint was a composite of hospitalization or all-cause mortality, with patients being matched in a 1:5 ratio with those who did not receive the medication using propensity score matching. 636 patients received bamlanivimab, with 11,311 acting as controls. 232 study patients were matched with 1160 controls. The primary outcome occurred in 6.9% of the balanivimab group compared to 15.5% of the control group:

In other words, bamlnanivimab led to a 60% reduction of all cause mortality and hospitalization. There was no effect between treatment or BMI or age. Treatment within 4 days of a positive seems to have the most effect when it came to ED visits or hospitalizations, but not mortality:

This is a fairly reassuring study, despite its observational nature. While propensity score matching was used to minimize the differences between groups, there is still some possible confounding factors. I think the “high risk” group of patients is a reasonable population to try such expensive therapy, if the resources for infusion are available. Though whether or not this would lead to a lower overall cost as compared to an admission to the ICU remains to be seen. 

Yuani M Roman, MD, MPH, Paula Alejandra Burela, BSc, Vinay Pasupuleti, MD, PhD, Alejandro Piscoya, MD, Jose E Vidal, MD, PhD, Adrian V Hernandez, MD, PhD, Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials, Clinical Infectious Diseases, 2021;, ciab591, https://doi.org/10.1093/cid/ciab591

Ooh some controversy, maybe. Ivermectin has been making the rounds as a possible therapy for COVID-19 with several cohort studies finding possible benefit. This was a meta-analysis of 12 studies, 10 of the being RCT with primary outcome being all-cause mortality, length of hospital stay, and adverse events. The dose ranged from 12mg to 210mg as well as duration, ranging from 1 to 5 days. 5 studies used SOC while the rest used placebo. There was no decrease in risk of all-cause mortality, length of stay, and adverse events with ivermectin:

Notably, there is a trend towards IVM in terms of mortality benefit, based on the forest plot:

However, given the different doses, durations, and time to therapy, it is difficult to draw any meaningful conclusions here. Either way, there is more RCTs down the line, so hopefully this question gets resolved in the near future.

Tanner M Johnson, Amanda H Howard, Matthew A Miller, Lorna L Allen, Misha Huang, Kyle C Molina, Valida Bajrovic, Effectiveness of Bezlotoxumab for Prevention of Recurrent Clostridioides difficile Infection Among Transplant Recipients, Open Forum Infectious Diseases, Volume 8, Issue 7, July 2021, ofab294, https://doi.org/10.1093/ofid/ofab294

This was a retrospective study on the use of bezletoxumab + standard of care or standard of care for CDI in solid organ transplant or heme transplant patients. Recall that bezlotoxumab is a maB against C. diff toxin B. Primary endpoint was incidence of recurrent CDI at 90 days after completion of therapy. 39 patients were in the BEZ group while 56 were in the standard of care group. Notably, more patients in the bezlotoxumab group had solid organ transplant, had a higher mean of CDI episodes prior to enrollment (71% vs 35%), and a higher proportion of these patients had a hospitalization in the month prior.  Moreover, more patients in the standard of care group had severe CDI (13% vs 32%). Fidaxomicin was used more commonly in the bezlotoxumab group (34% vs 11%), while PO vanc and IV MTZ was used more commonly in the standard of care group (13% vs 41%). Unadjusted 30 day and 90 day recurrences were not statistically different between groups, though there was a trend towards the bezlotoxumab group:

Subgroup analysis that excluded those who were treated with MTZ monotherapy revealed similar outcomes (16% in the BEZ group vs 31% in the standard of care group with a trend towards the BEZ group). Notably, on multivariate analysis, the use of bezlotoxumab was associated with lower odds of recurrent CDI:

I find it difficult to draw conclusions here, mostly due to the small number of patients and the obvious imbalances between groups. Further, given that more patients in the BEZ group received fidaxomicin (an agent that prevents recurrences, to the point that in the latest guidelines, it is now a first line agent), I think it skews the results in my eyes. 

H Scheper, L M Gerritsen, B G Pijls, S A Van Asten, L G Visser, M G J De Boer, Outcome of Debridement, Antibiotics, and Implant Retention for Staphylococcal Hip and Knee Prosthetic Joint Infections, Focused on Rifampicin Use: A Systematic Review and Meta-Analysis, Open Forum Infectious Diseases, Volume 8, Issue 7, July 2021, ofab298, https://doi.org/10.1093/ofid/ofab298

A meta-analysis on the use of rifampin for Staphylococcal spp PJI that undergo a debridement and implant retention (DAIR) strategy. 64 studies, totaling 4380 patients were included, with all being cohort studies, with the exception of 2 RCTs. CoNS was the agent in 915 patients while Staph aureus was the organism in the rest. 21% of these were MRSA. There was no difference in success rate between MRSA  (58%) or MSSA (60%), however, CoNS knee PJI had better outcomes relative to S. aureus knee PJI, as did any type of hip PJI:

In studies where rifampin was used, the success rates were higher than those where it was not used (64% vs 44%), with pooled risk ratio favoring the use of rifampin for PJI:

Again, it is difficult to draw conclusions here due to the observational nature of these studies and possible survival bias (i.e. those who were more likely to do better were on rifampin and did better), however it seems reasonable to pursue rifampin if there is no contraindication. 

Sara Alosaimy, Abdalhamid M Lagnf, Taylor Morrisette, Sarah C J Jorgensen, Trang D Trinh, Evan J Zasowski, Marco R Scipione, Jing J Zhao, Ryan Mynatt, Shelbye Herbin, Sorabh Dhar, Teena Chopra, James Janisse, Nicholas Rebold, Jason M Pogue, Michael J Rybak, Standardized Treatment and Assessment Pathway Improves Mortality in Adults With Methicillin-resistant Staphylococcus aureus Bacteremia: STAPH Study, Open Forum Infectious Diseases, Volume 8, Issue 7, July 2021, ofab261, https://doi.org/10.1093/ofid/ofab261

More dual therapy for staph aureus bacteremia. This was a retrospective, single center study that evaluated the implementation of a treatment pathway for MRSA bacteremia. In short, dual therapy with an antistaphylococcal beta-lactam (usually cefazolin, though cefepime, CTX, and ceftaroline were also used) was given in conjunction with either vancomycin or daptomycin for at least 48hrs after blood culture sterilization along with mandatory ID consult. The period prior to the pathway implementation and post-implementation was compared. Primary outcome was 30 day mortality, which was performed in an interrupted time series analysis. 813 patients were evaluated, with more patients in the pre-pathway having diabetes, heart failure, liver disease, prior hospitalization, or surgery within 30 days of admission. Patients in the post-pathway cohort had a shorter time to ID consultation and lower rates of VAN MIC of 2 (2.2% in the post-pathway group vs 51% in the pre-pathway). Cefepime and cefazolin (47% and 29%, respectively) were the most commonly used beta-lactams upfront, with 45% of patients being on cefazolin within 48hrs. 30-day and 90-day mortality was higher in the pre-pathway period:

Patients who died within 30 days were older, had higher rates of AKI and chronic pulmonary disease, and were more likely to have MIs and pneumonia as a source of bacteremia and were less likely to have achieved source control. Notably, vancomycin MIC was distributed similarly between both groups. Multivariable regression found that the pathway was associated with lower mortality, though the p-value was barely statistically significant:

My experience with dual-therapy with a beta-lactam for MRSA usually involves ceftaroline, though the use of cefazolin and other anti-staph beta-lactams was explored in the camera 1 and 2 trials. A higher proportion of those in the pre-pathway cohort were sicker upfront, and a lot more (16%) had endocarditis compared to the post-pathway group (11%). I thought the higher vanc MIC was to play a role in the primary outcome, but this was not the case. The authors did adjust for confounding variables, including ID consultation, which is known to improve outcomes in staph aureus bacteremia. Overall, given what we know from RCTs and the fact this was a barely statistical significant result, I am still not thrilled about using dual therapy for MRSA bacteremia. 

Martin TCS, Abrams M, Anderson C, Little SJ. Rapid Antiretroviral Therapy Among Individuals With Acute and Early HIV. Clin Infect Dis. 2021 Jul 1;73(1):130-133. doi: 10.1093/cid/ciaa1174. PMID: 32777035; PMCID: PMC8246801.

This is a study evaluating the rapid initiation of ART in patients who had an acute and early diagnosis of HIV (AEH). Primary outcome was the time from estimated date of infection to viral suppression, duration from ART initiation to viral suppression, and proportion of patients with viral suppression at 12, 24, and 48 weeks. 84 patients were included, of which 39% had an acute infection (within 7 days). 96% started ART within 4 days of diagnosis, and in the ITT analysis, duration from EDI to suppression was 15 weeks, while duration from ART initiation to viral suppression was 7.5 weeks. Moreover, those who started ART within 7 days of diagnosis were more likely to achieve viral suppression by 24 weeks, compared to those who did not (86% vs 65%, p =0.03). 58 patients were included in the per-protocol analysis and these were patients who started ART within <7 days of diagnosis. Median time from EDI and ART initiation to suppression was similar to the overall cohort, but by week 48, the per protocol cohort had a higher proportion of viral suppression compared to the ITT cohort (98% vs 88%). Overall, it seems early initiation of ART is a fairly safe way to go. Though it is limited in its scope as there is no comparator group or long-term outcome to evaluate for possible resistances or other issues such as loss of follow up, I think starting ART ASAP is a fairly good idea. It may be the case, however, that those who get linked into care are more motivated patients, so keep that in mind. 

Orkin C, Squires KE, Molina JM, Sax PE, Sussmann O, Lin G, Kumar S, Hanna GJ, Hwang C, Martin E, Teppler H. Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (TDF) Versus Efavirenz/Emtricitabine/TDF in Treatment-naive Adults With Human Immunodeficiency Virus Type 1 Infection: Week 96 Results of the Randomized, Double-blind, Phase 3 DRIVE-AHEAD Noninferiority Trial. Clin Infect Dis. 2021 Jul 1;73(1):33-42. doi: 10.1093/cid/ciaa822. PMID: 33336698; PMCID: PMC8246893.

DRIVE-AHEAD! This is the 96 week point of the DRIVE-AHEAD trial, which was a randomized, active-controlled, double-blind, non-inferiority phase 3 trial evaluating 2 NNRTIs based regimen in treatment-naive adults with viral loads >1000 copies/mL. Doravarine, a new NNRT, was compared with efavirenz, the well known NNRTI that causes nightmares. DOR/3TC/TDF was compared with EFV/TDF/FTC (aka Atripla). Patients were randomized in a 1:1 fashion to either medication, with a matching placebo for the other medication (in other words, if someone was in the atripla group, they would get a DOR-style matching placebo and vice versa). Primary end point was proportion of patients with viral suppression at week 96. 734 patients were randomized, with both groups being fairly well balanced overall. At week 96, the proportion of patients with viral suppression (defined as <50 copies/mL) was 77.5% in the DOR group and 74% in the EFV group (treatment difference, 3.8%, 95% CI -2.4 to 10):

Notably, a lower percentage of patients discontinued DOR compared to EFV. Resistance was similar between groups:

65% of patients in the EFV had some sort of treatment related AE compared to 32% in the DOR group, with 59% of EFV patients having some sort of neuropsychiatric AE (vs 26%). There is a lot to talk about here; it seems that for patients who like their Atripla but have issues with the neuropsych issues can likely switch to this drug (though that wasn’t the outcome studied here). Notably, both components used TDF, which is known to cause some renal dysfunction and increased bone turnover (though TAF may cause some metabolic issues). How this regimen compares to an integrase-based regimen would be an interesting question going forward, as I tend to gravitate towards the latter. With the issue of possible metabolic syndrome and integrase-inhibitors, and HIV patients living longer, this may be a reasonable question to answer. DOR actually had pretty favorable lipid profiles compared to EFV:

Ellis RJ, Peterson S, Cherner M, Morgan E, Schrier R, Tang B, Hoenigl M, Letendre S, Iudicello J. Beneficial Effects of Cannabis on Blood-Brain Barrier Function in Human Immunodeficiency Virus. Clin Infect Dis. 2021 Jul 1;73(1):124-129. doi: 10.1093/cid/ciaa437. PMID: 32296832; PMCID: PMC8246839.

More on HIV. This is a weird one. There is evidence of possible blood-brain barrier dysfunction in patients with HIV as evidenced by their CSF-to-serum (CSAR) ratios and increased urokinase plasminogen activator in HIV patients. In other words, HIV patients may have a leaky BBB which may contribute to higher rates of AIDS dementia. Cannabis may actually help with this by stimulating tight junction proteins. This study evaluated the interaction of HIV serostatus and cannabis use by studying 45 patients with HIV and 30 controls who had used cannabis within the past month. Patients had their CSF urokinase plasminogen activator and albumin level measured as an assessment of BBB “leakiness” and a composite index of these markers was created using principal component analysis. Patients with HIV had higher CSF albumin levels (17.4 vs 12.2, p =0.03) and total protein (39 vs 29) compared to those without HIV. The log CSAR and log CSF SuPAR levels were highly correlated with each other. Using the principal components analysis of these 2 markers (with higher values = more BBB leakiness), there was a strong correlation between the 2 markers (CSAR r = 0.87, uPAR r = 0.87). Those with HIV had higher log10 CSAR values than those without HIV (3.79 vs 2.78), with these values being associated with lower nadir CD4 but not current CD4 count. In patients who had used cannabis within the past month, BBB index values were better in those with HIV but not in those without HIV:

As seen above, the closer to the latest date of use, the better the BBB indices were. Using CSF neurofilament light chain as a marker of axonal injury, worse BBB integrity factor was associated higher CSF NFL levels:

I guess this is another reason to go ahead with cannabis research. 

Jia-Hui Cheng, Ching-Wan Yip, Ying-Kui Jiang, Ling-Hong Zhou, Chun-Xing Que, Yu Luo, Xuan Wang, Hua-Zhen Zhao, Li-Ping Zhu, Clinical Predictors Impacting Cryptococcal Dissemination and Poor Outcome in Patients With Cirrhosis, Open Forum Infectious Diseases, Volume 8, Issue 7, July 2021, ofab296, https://doi.org/10.1093/ofid/ofab296

Do people with cirrhosis have higher risk of disseminated cryptococcus? Yes. This was a retrospective case series of 49 patients without HIV and cirrhosis who were diagnosed with cryptococcosis. Within this cohort, more than half had a CP classification of either B or C and 65% had another pre-disposing factor (25% had steroid use, 22% had an autoimmune disease). 18% had pulmonary crypto, while 78% had crypto meningitis. Notably, 91% of patients with CP B or C had extrapulmonary crypto compared to 65% of those with compensated cirrhosis. Overall, the CSF examination of these patients was fairly similar to that of non-cirrhotic patients, with 39% having elevated opening pressure of >300cm H2O and a median CSF CrAg of 1:1280 in the 27 patients with crypto meningitis. Overall mortality was 20% at one year, with the more decompensated group having a higher mortality:

Multivariate analysis found that a time to diagnosis of >120 days and CP class C were associated with higher mortality in those who were diagnosed with cryptococcal meningitis:

Given the degree of immunosuppression, and how often these folks get infections, it is not surprising they are also at risk for crypto, but certainly is not something I would be looking for on the regular. It should be noted, though, the diagnosis was not really subtle. Fever and headache accounted for 92% of the symptoms seen, with ⅓ having altered mental status. So you most likely won’t miss it, but if you find a cirrhotic with headache and AMS and not improving after lactulose, you should probably do an LP with opening pressure. 

Emily T Martin, Caroline Cheng, Joshua G Petrie, Elif Alyanak, Manjusha Gaglani, Donald B Middleton, Shekhar Ghamande, Fernanda P Silveira, Kempapura Murthy, Richard K Zimmerman, Arnold S Monto, Christopher Trabue, H Keipp Talbot, Jill M Ferdinands, HAIVEN Study Investigators, Low Influenza Vaccine Effectiveness Against A(H3N2)-Associated Hospitalizations in 2016–2017 and 2017–2018 of the Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN), The Journal of Infectious Diseases, Volume 223, Issue 12, 15 June 2021, Pages 2062–2071, https://doi.org/10.1093/infdis/jiaa685

This study evaluated the efficacy of the flu vaccine during the 2016-2017, and 2017-2018 flu seasons using the HAIVEN database. VE was calculated against RSV as a negative control outcome. Furthermore, the VE was also calculated based on the product of the vaccine, based on the idea that egg-produced vaccine may have lower efficacy. 7398 patients were enrolled, with 6129 being in the final analysis. Over 95% of patients had a high risk condition during both season. Overall efficacy against influenza-associated hospitalization was 33.5% (95% CI 24-42%), with the efficacy being lower for A(H3N2) than for B/Yamagata strain. VE comparing ICU patients with an without A(H3N2) was 24% (95% CI 075 to 66) in 2016-2017, and 27% (95% CI -56 to 66) in 2017-2018:

When looking at the vaccine type, 66 patients in the cohort got a non-egg based vaccine (Flucelvax and Flublok). While for flu A, the cell-based shot had a higher efficacy than the egg-based one, the CI were too wide for it to be statistically significant:

Further, prior vaccination seemed to confer a higher VE against flu A (30%) compared to those who were not vaccinated previously (5.7%). While reassuring that egg-based vaccines are not less efficacious than the cell-based ones (the number of the former in this study was fairly small), I think the bigger concern here is the degree of antigenic shift/drift that is seen with flu each year. 

Shiori Yoshikawa, Sachiyo Yoshio, Yuichi Yoshida, Yuriko Tsutsui, Hironari Kawai, Taiji Yamazoe, Taizo Mori, Yosuke Osawa, Masaya Sugiyama, Masashi Iwamoto, Koichi Watashi, Takumi Kawaguchi, Tomoyuki Akita, Junko Tanaka, Yoshimi Kikuchi, Masashi Mizokami, Shinichi Oka, Tatsuya Kanto, Hiroyuki Gatanaga, Impact of Immune Reconstitution-Induced Hepatic Flare on Hepatitis B Surface Antigen Loss in Hepatitis B Virus/Human Immunodeficiency Virus-1 Coinfected Patients, The Journal of Infectious Diseases, Volume 223, Issue 12, 15 June 2021, Pages 2080–2089, https://doi.org/10.1093/infdis/jiaa662

Does IRIS-induced hepatic flare in HIV patients lead to Hep B surface antigen loss? Yes. A functional cure for hepatitis B is defined as the loss of hepatitis B surface antigen (HBsAg), with the idea that a hepatic flare in the context of IRIS may lead to destruction of hep B infected hepatocytes. This single-center retrospective cohort evaluated 58 patients with treatment naive chronic hep B and HIV-co infected patients. IRIS-HF was defined as an elevation of ALT >5x ULN without elevation in HBV DNA or HBsAg at any point between ART initiation and 12 months. HBsAg loss was seen in 25% of patients at 3 years, 35% at 5 years, and 38% at 10 years of ART. When looking at the cohort of patients who had a hepatic flare, the rates of HBsAg loss was higher in the IRIS group:

As seen in figure 4B, the drop of HBsAg was much faster in the IRIS group, while in the non-IRIS group it plateaued. Multivariate analysis revealed that IRIS-HF, baseline HBsAg level, and HBV genotype A were independent predictors for HBsAg loss:

Age, baseline HBV DNA, and change in CD4 were significant predictors of HF in multivariate analysis. One thigh to note here is this cohort did not include patients with cirrhosis, which I would imagine would be a bigger population. Though I supposed at that point, even clearing hep B wouldn’t yield much benefit (outside of HCC) and an IRIS event may lead them to significant cirrhotic decompensation. I do not know if this leads to increased mortality in certain populations, so that is something to be concerned about, though outside of TB and crypto meningitis, this may be a moot point. 

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