Weekly Articles 6/6/2021

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Some isavuconazole news, a PJI trial, a few HIV-related articles, and therapies for COVID that won’t die.

Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, Bow EJ, Rahav G, Neofytos D, Aoun M, Baddley JW, Giladi M, Heinz WJ, Herbrecht R, Hope W, Karthaus M, Lee DG, Lortholary O, Morrison VA, Oren I, Selleslag D, Shoham S, Thompson GR 3rd, Lee M, Maher RM, Schmitt-Hoffmann AH, Zeiher B, Ullmann AJ. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016 Feb 20;387(10020):760-9. doi: 10.1016/S0140-6736(15)01159-9. Epub 2015 Dec 10. PMID: 26684607.

I do not know how this one got past me earlier in the year. This is a phase 3, double blind, multicenter, non-inferiority, randomized control trial evaluating isavuconazole versus voriconazole for the treatment of invasive mould disease. Patients who had either proven, probable, or possessive invasive mould disease by EORCT/MSG criteria with a positive serum galactomannan were included. Patients were randomized in a 1:1 fashion, with isavuconazole being given at a 372mg IV TID for 2 days followed by isavuconazole 200mg daily and placebo, while voriconazole was dosed as 6mg/kg IV twice daily on day 1 followed by 4mg/kg twice daily on day 2. They would go on to receive either 4mg/kg twice daily or 200mg twice daily. Maximum duration was 84 days. Primary endpoint was all-cause mortality from first dose to day 42 in the ITT. There was also a mITT analysis (using or probable/proven disease) and the mycological ITT that evaluated those with aspergillus. 527 patients were randomized, of which 516 were included in the ITT population. There were no obvious differences between groups, though the voriconazole group was more likely to have an active malignancy and AML. 13% had proven mould disease while 40% had probable disease. Both were treated for approximately the same amount of time. For the primary efficacy end point, all-cause mortality was not statistically different between the 2 groups:

This also held true for the mITT and the myITT population. The study demonstrated non-inferiority. In the per protocol analysis, the all cause mortality at day 42 was 15% for isavuconazole while it was 18% for voriconazole (adjustment treatment difference, -2.6%, 95% CI -10.3 to 5.1). In terms of safety, roughly there was the same number of adverse events between the two groups, with more patients in the voriconazole group having eye issues, skin issues, and hepato biliary issues:

Drug-related events, as considered by the investigators, were lower for the isavuconazole groups compared to voriconazole (42% vs 60%). I do not think this was a huge surprise, considering that isavuconazole is non-inferior to voriconazole. It has a better safety profile, less drug-drug interactions, and a broad spectrum of activity against invasive moulds. While there may be an issue in terms of only around half having some degree of proven/possible IFI, I think in the grand scheme of things it doesn’t matter as in the vast majority of patients, the antifungal would be started empirically anyway. 

Bose P, McCue D, Wurster S, Wiederhold NP, Konopleva M, Kadia TM, Borthakur G, Ravandi F, Masarova L, Takahashi K, Estrov Z, Yilmaz M, Daver N, Pemmaraju N, Naqvi K, Rausch CR, Marx KR, Qiao W, Huang X, Bivins CA, Pierce SA, Kantarjian HM, Kontoyiannis DP. Isavuconazole as Primary Antifungal Prophylaxis in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome: An Open-label, Prospective, Phase 2 Study. Clin Infect Dis. 2021 May 18;72(10):1755-1763. doi: 10.1093/cid/ciaa358. PMID: 32236406; PMCID: PMC8130026.

This was a single-institution, prospective, phase 2 trial evaluating isavuconazole for antifungal prophylaxis in patients with AML/MDS. Patients were enrolled if they were or were anticipated to become neutropenic. Isavuconazole was dosed as 372mg every 8 hours for the first 2 days followed by 372mg daily, administered until recovery of neutropenia and attainment of complete remission. Patients were treated for a maximum of 12 weeks, with the primary endpoint being the occurrence of proven/probable IFI up to 30 days from the last dose. 75 patients were enrolled, but only 65 received prophylaxis. The incidence of probable and possible IFI was 15% (10), with all patients being profoundly neutropenic and not in  clinical remission. 9 of the patients who developed IFI received either venetoclax-based regimens or high-intensity regimens (cladribine, cytarabine + idarubicin), with 38/55 who did not receiving similar regimens. 

7 additional patients discontinued the medication, 2 due to physicians discretion, 3 due to elevated aminotransferases and 2 due to transition to another azole prophylaxis.While this study is helpful in letting us know that isavuconazole may be useful for prophylaxis, do not expect for people to reach it over posaconazole until an RCT comparing both comes out. One of the reasons for isavuconazole over posaconazole is due to the amount of drug-drug interactions that occur with posaconazole and certain regimens, including venetoclax, as well as its ability to prolong the QTc. Be on the lookout for further, well designed trials here. 

Hurt WJ, Tenforde MW, Molefi M, Mitchell HK, Milton T, Azama MS, Goercke I, Mulenga F, Tlhako N, Tsholo K, Srivastava T, Leeme TB, Simoonga G, Muthoga C, Lechiile K, Mine M, Jarvis JN. Prevalence and Sequelae of Cryptococcal Antigenemia in Antiretroviral Therapy-Experienced Populations: An Evaluation of Reflex Cryptococcal Antigen Screening in Botswana. Clin Infect Dis. 2021 May 18;72(10):1745-1754. doi: 10.1093/cid/ciaa356. PMID: 32236414; PMCID: PMC8130030.

This was a prospective study of patients who had CD4 testing at a Botswana reference lab, evaluating the utility of reflex serum CrAg in an ART-experienced population. Over 140,000 CD4 tests were performed in over 59,000 patients, of which CD4 counts <200 were seen in 9.5% of the cohort and counts <100 seen in 3.2% of the cohort. 2108 samples whose CD4 count was <100 had a sequential blood samples tested for CrAg (which was done in during the period study for those who had CD4 <100), with 5.8% of samples (123/2108) being positive. These corresponded to 1645 patients, of which 463 had repeat tests . 55.2% of patients were ART naive, with 13.6% having defaulted on their ART and 31.2% being ART-experienced. 6.3% of this cohort (104/1645) were CrAg positive, with prevalence being higher in the inpatient compared to outpatient (21.9% vs 4.8%). Of 339 patients who tested negative initially and had repeat CrAg done, 10 (2.9%) tested positive. Variables associated with cryptococcal antigenemia included male gender and low CD4 count, with ART status being not significantly different. There was no statistical difference in ART status when comparing those who were CrAg positive or negative:

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6 month mortality in the outpatient cohort was 23.3% in those who were CrAg-positive and 8.6% in CrAg negative individuals (HR 2.95, 95% CI 1.7-4.9), with mortality increasing to 27.8% of Cr-Ag positive and 11.9% in CrAg negative if those who were lost to follow-up were counted as deaths (HR 2.53, 95% CI 1.6 to 4). Positive CrAg at baseline, CD4 <50, and not taking ART at baseline were associated with higher mortality at 6 months:

The prevalence of cryptococcal meningitis was higher in the ART-naive CrAg positive group (34%) when compared to the defaulters (9%) and those on ART (4%, or 1/25) with the latter having a viral load of >400,000 copies/mL. Not surprisingly, titers were significantly higher in those who died compared to those who didn’t, with a cut-off of 1:80 yielding a sensitivity/specificity of 82.4% and 53.1%, respectively, to predict mortality. PPV and NPV were 48 and 85, respectively. 

This may have been confusing, but I think I can kind of break it down here. Screening with serum CrAg is useful for those who are ART naive, as it allows us to screen for cryptococcal meningitis and treat prior to starting ART, since IRIS is a concern. How this factors in those who are already on ART is unknown. Here, there was no difference in rate of CrAg positivity when taking into account those who are and are not taking ART, but those on ART at the time of screening had better odds of surviving, with 26 CrAg positive patients on ART surviving at 6 months compared to 26/46 of those who were not on ART. Reflex screening in those who were initially negative identified an additional 10 cases of cryptococcal antigenemia. I think reflex CrAg testing in those whose CD4 <100 is helpful for both ART-naive and ART-experienced individuals and it is helpful to risk stratify those who are positive. 

Nolan NS, Adamson S, Reeds D, O’Halloran JA. Bictegravir-Based Antiretroviral Therapy-Associated Accelerated Hyperglycemia and Diabetes Mellitus. Open Forum Infect Dis. 2021 Apr 16;8(5):ofab077. doi: 10.1093/ofid/ofab077. PMID: 33981777; PMCID: PMC8103800.

A few case reports that I found interesting. This one reports on 3 patients with chronic HIV who were switched to a TAF/FTC/BIC regimen (one was switched from RPV/TDF/FTC, another one was switched from EFV/TDF/FTC, and the third was switched from ABC/3TC/DTG). Here, following the switch, all presented with sudden onset diabetic ketoacidosis after having a fairly well controlled A1c, and requiring admission with insulin administration and significantly elevated A1c:

It was been reported that several integrase inhibitors may have a negative effect on metabolism, mainly leading to insulin resistance and weight gain. The authors do note that all of the patients were switched from TDF to TAF, with one being transitioned from one integrase inhibitor to another, raising the possibility that either 1) the TAF was responsible or 2) this was due to BIC. 

Adams SH, Mahapatra R. Rat bite fever with osteomyelitis and discitis: case report and literature review. BMC Infect Dis. 2021 May 26;21(1):479. doi: 10.1186/s12879-021-06172-x. PMID: 34039283; PMCID: PMC8153095.

This one is on Streptobacillus moniliformis, a pleomorphic gram negative rod. A middle-aged man presented to the ED with a 6 week history of lower back pain that worsened over that same time frame, anorexia and a 15lb weight loss. He underwent an MRI that revealed an abnormal enhancement of the lower endplate of the L2 vertebral body and diffuse enhancement of L3 vertebral body with enhancement in the intervertebral disc, suggesting discitis and possible OM. He had a CT-guided aspiration with gram stain revealing gram variable rods. He was started on cephalexin and linezolid, and the cultures were sent to a reference lab where a MALDI-TOF identified the organism as Streptobacillus moniliformis. The patient revealed he had 2 pet rats and had numerous bites. 

The authors review 9 cases of rat-bite fever associated with OM or discitis, with only 7 cases acknowledging rat exposure. Their review of 65 cases of rat-bite fever noted the most common symptoms were fever, arthralgias, and rash along with nausea/vomiting. 

Haas DW, Acosta EP. Implications of Efavirenz Pharmacogenetics When Switching From Efavirenz- to Dolutegravir-containing Antiretroviral Regimens. Clin Infect Dis. 2021 May 18;72(10):1820-1822. doi: 10.1093/cid/ciaa975. PMID: 32667979; PMCID: PMC8130017.

This study deals with the interaction between efavirenz (EFV) and dolutegravir (DTG). Efavirenz is the NNRTI component in Atripla, which is the first line therapy in many low income areas of the world. Dolutegravir is increasingly being used as an alternative to Atripla (usually seen as Descovy + Tivicay or Triumeq) either as first line or second line agent. Efavirenz induces hepatic drug metabolizing enzymes (P450 2B6) which decreases plasma dolutegravir levels. Those who are CYP2B6 slow metabolizers have significantly greater hepatic enzyme induction when exposed to efavirenz. Here, 12 HIV-negative volunteers received 50mg dolutegravir daily for 5 days, followed by 50mg of dolutegravir plus 600mg of efavirenz for 14 days. 5 patients had normal CYP2B6, one had intermediate CYP2B6 activity and 3 were slow metabolizers. The degree of minimum concentration for dolutegravir in normal metabolizers decreased by 60%, from 812ng/mL to 323 ng/mL following efavirenz, while the mean dolutegravir minimum concentration decreased by 85% in the slow/intermediate metabolizer group (941ng/mL to 145ng/mL). The CYPB26 genotype correlated with efavirenz, with the half-life of efavirenz being 2.7 times greater (half life 39.1hrs) in the slow metabolizers (half-life in normal metabolizers 14.3hrs):

The authors note that the safest strategy would be to switch from an EFV-containing regimen to DTG if patients are well controlled, and if this is not the case, either switch directly or add an additional 50mg of dolutegravir for 2 weeks after the switch. While testing for CYP2B6 is not feasible, one thing to note is that black Africans and Southeast Asians are more likely to be slow metabolizers, with 1 in 4 being slow metabolizers compared to 1 in 20 of white Europeans. 

Bernard L, Arvieux C, Brunschweiler B, Touchais S, Ansart S, Bru JP, Oziol E, Boeri C, Gras G, Druon J, Rosset P, Senneville E, Bentayeb H, Bouhour D, Le Moal G, Michon J, Aumaître H, Forestier E, Laffosse JM, Begué T, Chirouze C, Dauchy FA, Devaud E, Martha B, Burgot D, Boutoille D, Stindel E, Dinh A, Bemer P, Giraudeau B, Issartel B, Caille A. Antibiotic Therapy for 6 or 12 Weeks for Prosthetic Joint Infection. N Engl J Med. 2021 May 27;384(21):1991-2001. doi: 10.1056/NEJMoa2020198. PMID: 34042388.

This is a multicenter, open-label, non-inferiority, randomized control trial evaluating 6 weeks vs 12 weeks of antibiotics in patients with prosthetic joint infections. Patients who had either hip or knee prosthetic joint infection with appropriate surgical therapy were included. Patients with mycobacterial/fungal/actinomyces/brucella infection were excluded. Patients were randomized in a 1:1 fashion to either 6 weeks or 12 weeks of antibiotic therapy. Primary outcome was persistent infection within 2 years after the end of antibiotic therapy, which was validated by an adjudication committee of 3 doctors blinded to the group assignments. This was done in the modified ITT population that included all patients who underwent randomization. No suppressive or chronic therapy was given. 410 patients were randomized, with both groups being fairly well balanced though the 6 week therapy group had more cases of staph aureus (38% vs 30%) and the 12 week group had more cases of CoNS (35% vs 30%). Both groups had a median of 9 days of IV therapy. In the mITT, primary outcome occurred in 18.1% of the 6 week group compared to 9.4% of the 12 week group (difference 8.7%, 95% CI 1.8 to 15.6), meaning it did not meet the criterion for non-inferiority. The same held true in the per-protocol analysis:

In all subgroups, the 12 week group was consistently favored with statistical differences seen in the debridement subgroup and in the first prosthetic joint infection subgroup:

Other interesting things to note here: more patients in the 6 week group received either rifampin or fluoroquinolones, as well as the combination of fluoroquinolones/rifampin:

Further, persistent infections in the 6 week group were more likely to be due to Staph aureus (58% vs 47%) and the 6 week group had a few more MDR bugs, but the small numbers are likely just by chance:

This is somewhat surprising, as I would have guessed surgical intervention would have resulted in no difference between the 2 groups. I do not think the type of organisms played a role, as the numbers were not that different. One surprising tidbit was that the one and two-stage revisions did not show any difference in outcomes between the groups, with most of the difference being driven by the DAIR group, suggesting possible role of biofilms, but given that all subgroups favored the 12 week group, this is unlikely. 

Nel A, van Niekerk N, Van Baelen B, Malherbe M, Mans W, Carter A, Steytler J, van der Ryst E, Craig C, Louw C, Gwetu T, Mabude Z, Kotze P, Moraba R, Tempelman H, Gill K, Kusemererwa S, Bekker LG, Devlin B, Rosenberg Z; DREAM Study Team. Safety, adherence, and HIV-1 seroconversion among women using the dapivirine vaginal ring (DREAM): an open-label, extension study. Lancet HIV. 2021 Feb;8(2):e77-e86. doi: 10.1016/S2352-3018(20)30300-3. PMID: 33539761.

This was an extension of the Ring study, which evaluated the use of a silicone matrix vaginal ring with 25mg of dapivirine in the prevention of HIV. This was a phase 3B, multicenter, open label extension trial in healthy women who were HIV-negative who were originally randomized in a 2:1 fashion. The primary objective was the safety profile of the vaginal ring and to assess the adherence of its use when inserted at monthly intervals. The secondary objectives were the incidence of HIV-1 seroconversion. Adherence was assessed by self-reporting and a residual value <23.5mg. 941 patients from the Ring study were enrolled in the follow up study, of which 649 were assigned to the DVR ring. Patients who were enrolled in the follow up study were more likely to be married, be older, and had a partner that had knowledge of ring use. There was a total of 616 adverse events reported, with 37 being grade 3 or 4, most of them being urogenital adverse events:

The one death in the DVR group was due to cardiomyopathy. Most participants that were enrolled in the follow up study had lower DVR residual concentrations compared to the larger ring study, suggesting better adherence:

18 participants who were on DVR seroconverted out of 938, for an incidence of 1.8 (95% CI 1-2.6) per 100-person years. Using bootstrap sampling in the placebo group from the Ring Study, an incidence of 4.7 (95% CI 3.7 to 5.8) per 100-person years would be expected in the absence of DVR use. This corresponded to a 62% lower incidence rate in the DVR group. I think this is an interesting idea for HIV prevention and it seems this is a fairly safe device. One thing to note is that there was a lag between the original Ring study and the DREAM follow up, meaning there could have been different background HIV transmission rates between the studies. Further, only those who were HIV negative at the end of the Ring study could participate, meaning there was likely a selection bias (indeed, those in the DREAM study were older and more likely to be married).

Youngmok Park, Yea Eun Park, Byung Woo Jhun, Jimyung Park, Nakwon Kwak, Kyung-Wook Jo, Jae-Joon Yim, Tae Sun Shim, Young Ae Kang, Impact of susceptibility to injectable antibiotics on the treatment outcomes of Mycobacterium abscessus pulmonary disease, Open Forum Infectious Diseases, 2021;, ofab215, https://doi.org/10.1093/ofid/ofab215

This was a multicenter, retrospective Korean cohort study evaluating the impact of in vitro testing of susceptibility to intravenous antibiotics on the treatment outcomes in patients with M. abscessus subs abscessus pulmonary disease. This is because the guidelines recommend the use of 3 or 4 active drugs guided by in vitro susceptibility, with the initial phase requiring at least 2-3 IV drugs. Unfortunately, M. abscessus susceptibility testing is kind of a crapshoot. 

Primary outcome was culture conversion and microbiological cure according to susceptibility to injectable antibiotics. Patients received a three to four week course of IV amikacin, IV beta-lactam (cefoxitin in one center) and an oral macrolide OR combination of FQ/doxycycline and macrolide. In one center, an oral regimen was maintained for at least 12 months after sputum culture conversion, with another center using IV amikacin 3-5 times per week and an oral macrolide. 82 patients were evaluated, of which 65 had clarithromycin-inducible resistance strains. All were treated with IV amikacin and beta-lactams for at least 4 weeks along with an oral macrolide. One third took either clofazimine or moxifloxacin. Most strains were susceptible to amikacin (82%), followed by linezolid (61%):

Culture conversion and microbiological cure rates were similar regardless of the susceptibility of injectable antibiotics. 

Despite this, the numbers of resistant strains were fairly small, especially for amikacin so it is certainly possible these results were by chance. Further, cefoxitin’s results were less than ideal with 38% achieving culture conversion if the strain was resistant compared to 67% in the susceptible category. Imipenem’s numbers in the resistant category were better, but again it is difficult to draw any conclusions based on the relatively small numbers. 

In those with inducible clarithromycin resistance, treatment outcomes were same regardless of whether the strains were susceptible to amikacin, cefoxitin, imipenem, or moxifloxacin:

Again, a careful look at the numbers reveals these are quite small. Overall, while it would have been nice to not worry about susceptibility, unless a larger trial validates these results, color me skeptical. It is certainly possible all these results were due to chance, especially when it comes to amikacin resistant strains. Some conclusions could be drawn about the amikacin-intermediate strains and the results here look ok. 

COVID-19 Articles

RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial. Lancet. 2021 May 29;397(10289):2049-2059. doi: 10.1016/S0140-6736(21)00897-7. Epub 2021 May 14. PMID: 34000257; PMCID: PMC8121538.

Another arm of the RECOVERY trial is in the books. This one was for the convalescent plasma arm. As before, this was a randomized controlled, open-label, adaptive trial that evaluated multiple treatments for patients admitted for COVID-19. These therapies include HCQ, Remdesevir, dexamethasone, and tocilizumab. Any patients who were felt to get any benefit from convalescent plasma were eligible to participate. Patients were randomized in a 1:1 fashion to either convalescent plasma (two units, one immediately and the other one 12hrs later) or usual care. Given the design of the trial, patients could also get any of the other therapies (HCQ, dexamethasone, azithromycin, colchicine, or kaletra) as well as tocilizumab if the patients deteriorated later on (see the last article summaries for more information on this arm of the trial). Plasma donations with a cut-off of >6 on the EUROIMMUN IgG ELISA were obtained. Primary outcome was all-cause mortality at 28 days after randomization, and statistical analysis was done in an ITT comparison. A post-hoc analysis was done in patients randomized after December 1, 2020 to asses the efficacy of convalescent plasma after the emergence of B.1.1.7 variant. Similar to the tocilizumab paper, the authors pooled the results of this trial with other randomized trials for convalescent plasma to generate a meta-analysis comparing it to usual care. 11558 patients were randomized with 5% getting mechanical ventilation and 87% receiving some sort of oxygen therapy. 92% got some sort of corticosteroids. Both groups were fairly well balanced, and there was almost no crossover (only <1% of patients in the usual care group got any convalescent plasma). There was no significant difference in 28-day mortality between the two groups, 24% in the convalescent plasma group vs 24% in the usual care group (RR 1, 95% CI 0.93-1.07), with no difference in any of the subgroups evaluated:

When limited to patients with a positive SARS-CoV2 test, there is no difference either. When pooling all studies together, there was again no difference in mortality between either group (mortality RR 0.95, 95%CI 0.91 to 1.06). When looking at patients not on mechanical ventilation, the proportion of those who progressed to invasive mechanical ventilation or death was similar between the two groups, 29% and 29%, RR 0.99, 95% CI 0.93 to 1.05). The meta-analysis, which pooled a total of 11 trials, failed to show any significant difference:

I think the guidelines from IDSA or CDC had dropped the recommendation for convalescent plasma. I think with the addition of this fairly well designed and large trial (which increased the number of patients in the meta-analysis 8-fold), I think it may be time to drop this experiment going forward. Speaking of things that we need to drop and won’t go away…

Reis G, Moreira Silva EADS, Medeiros Silva DC, Thabane L, Singh G, Park JJH, Forrest JI, Harari O, Quirino Dos Santos CV, Guimarães de Almeida APF, Figueiredo Neto AD, Savassi LCM, Milagres AC, Teixeira MM, Simplicio MIC, Ribeiro LB, Oliveira R, Mills EJ; TOGETHER Investigators. Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial. JAMA Netw Open. 2021 Apr 1;4(4):e216468. doi: 10.1001/jamanetworkopen.2021.6468. PMID: 33885775; PMCID: PMC8063069.

This was a randomized, multicenter, clinical trial evaluating HCQ and Kaletra (lopinavir-ritonavir) to prevent progression of COVID-19 in outpatients with documented SARS-CoV2. Patients who had symptoms for less than 8 days or CT consistent with COVID-19 were eligible. Patients also needed at least one criteria for high risk. Patients were randomized in a 1:1:1 manner to HCQ, Kaletra, and placebo. Those who got HCQ got a loading dose of 900mg at time of randomization, and then 400mg daily for 9 days. Those in kaletra got a loading dose of 800/200 at the first 2 intakes followed by 400/100 twice per day. Matching placebos were use for all groups. Primary outcome was COVID-associated hospitalization and death at 90 days after randomization. 685 patients were randomized, with all 3 groups being fairly well balanced. When compared to placebo, there was no difference in the risk of hospitalization for either Kaletra or HCQ in both the ITT and the per protocol population:

Moreover, clearance for HCQ (OR 0.91, 95% CI 0.82-1.02) and Kaletra (OR 1.04, 95% CI 0.94-1.16) was no different when compared to placebo. Interestingly, the rate of serious adverse events was higher for Kaletra (8.6%) compared to HCQ (5.3%), with 9 of those in the Kaletra group having to stop the medication, compared to only 1 in the HCQ group. Given the lack of efficacy for pre-exposure prophylaxis, post-exposure prophylaxis, and now with another study for outpatients, where the bulk of the benefit would theoretically have been seen, I think it is reasonable to once and for all drop HCQ as a viable treatment. Apologists may look at the time to randomization as a weakness, arguing that it needs to be started as soon as possible. Looking at how the real world works, I think this may be a better reflection of how things would work if such therapies were to be implemented, especially in a broad scale, as it takes a while to get diagnosed and then get a medication written for. Further, the fact that it does not seem to work even in the earliest possible exposures suggests that clinically, HCQ and Kaletra may not have a role here. 

Sing CW, Tan KCB, Wong ICK, Cheung BMY, Cheung CL. Long-term Outcome of Short-course High-dose Glucocorticoids for Severe Acute Respiratory Syndrome (SARS): A 17-Year Follow-up in SARS Survivors. Clin Infect Dis. 2021 May 18;72(10):1830-1833. doi: 10.1093/cid/ciaa992. PMID: 32671407; PMCID: PMC7454482.

Not quite COVID, but still related. This was a study evaluating the outcomes in SARS survivors who received corticosteroids after 17 years. Patients who received a very-high dose of steroids (>100mg prednisone equivalent per day) were compared to those who got low to high dose regimen (<100mg prednisone equivalent per day. 1142 SARS survivors were included. The median amount of prednisone equivalents in the VHD group was 625mg per day compared to the 35mg for the LTHD group, respectively. Propensity score matching was done. The only outcome that had a significantly higher incidence was avascular necrosis, with a 7.5-fold increased risk in the VHD group. This remained true after adjusting for other risk factors for avascular necrosis:

Considering we are only using around 6mg of dexamethasone for most patients nowadays (which is 40mg daily), I do not think we will see such outcomes in the future following this COVID-19 pandemic.

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