COVID-19 Therapies in Non-Hypoxemic Patients – A Work in Progress

No comments

COVID-19 is still among us. I had actually predicted it would be an endemic virus, similar to influenza, where we would have to get annual “flu+covid” shots each year to avoid disaster. I have a lot of issues with the initial response, not to mention the amount of useless COVID-related papers that have been published. One neat thing is the rapid response to find a reasonable therapeutic for COVID, with steroids + remdesevir being standard of care for acute hypoxemic respiratory failure due to COVID-19. This is fairly standard now, so I would like to focus on the thing I am not familiar with: what to do with symptomatic COVID where they are not hypoxic. I am running into the issue of patients showing up to the hospital with something, perhaps a heart failure exacerbation, and ending up testing positive for COVID despite not having any symptoms. What to do with these? In short, depends:

  1. Symptomatic and admitted but not hypoxemic = remdesivir OR some monoclonal antibodies
  2. Symptomatic but not admittable i.e. “walking flu” = Paxvlovid or Molnuperavir 
  3. PEP = monoclonal antibodies 

Remdesivir

I ain’t going to lie, I am still shocked this thing actually works. Considering our record with oseltamivir, you cannot blame me. Regardless, most of the data on remdesivir tends to focus on more critically ill-patients, with these making up the bulk of enrolled patients. For instance, the ACTT-1 trial enrolled 1062 hospitalized patients and randomized them 1:1 to remdesivir or placebo (1). Primary endpoint was time to recovery at day 28. Of the over 1000 patients enrolled, 138 did not require any supplemental oxygen. Overall, the time to recovery was shorter in the remdesivir group than in the placebo group (rate ratio 1.29, 95% CI 1.12 to 1.49). When looking at those who did not require oxygen the ratio of recovery was still higher than in the placebo group, but this did not reach statistical significance (rate recovery 1.29, 95% CI 0.91 to 1.83). An open-label randomized trial compared a 5-day and a 10-day remdesivir with standard of care in a cohort of hospitalized patients (2). 584 patients were enrolled, of which over 80% of patients were not requiring supplemental oxygen. At day 11, patients in the 5-day remdesivir group had higher odds of better clinical outcome based on a 7-point ordinal scale (OR 1.65, 95% CI 1.09-2.48):

By day 28, the clinical status in patients who received remdesivir was better than those in the standard of care group. The SOLIDAIRTY trial specifically looked at hospitalized COVID-19 patients, however within the over 11,000 participants enrolled at least 3200 did not use supplemental oxygen (3). Overall, in the primary endpoint of in-hospital mortality, there was no difference between placebo and Remdesivir:

Similarly, there was no mortality benefit of remdesivir when looking at a meta-analysis of 4 trials:

It is difficult to draw any meaningful conclusions when it comes to its utility in non-hypoxemic patients given the lack of robust data, but at least there is some noise to suggest its use here.

Antivirals

I’ll be discussing 2 major ones: molnupiravir and nirmatrelavir. One early study recruited 204 patients and randomized them 1:1 to 200mg of molnupiravir or matching placebo or 3:1 to molnupiravir (400mg or 800mg) or placebo (4). Primary endpoint was time to viral RNA clearance via nasopharyngeal RT-PCR. Rate of viral clearance at day 3 were significantly higher in the experimental group when compared to the placebo group:

A phase 3, double-blind trial evaluated 800mg of molnupiravir twice per day over 5 days compared with placebo in non-hospitalized patients (5). 1433 patients were randomized, with nearly 45% having moderate disease and 58% having the delta variant. At day 29, the rate of hospitalization or death was lower in the molnupiravir group when compared to the placebo group (7.3% vs 14.1%, treatment difference -6.8, 95% CI -11.3 to -2.4) in the pre-specified mITT analysis. Pooling all randomized patients showed lower rate of death or hospitalization in the molnupiravir group (difference -3.0, 95% CI -5.9 to -0.1):

Ritonavir-boosted nirmatrelvir aka Paxvlovid was evaluated in a double-blind, randomized trial in non-hospitalized COVID patients at risk of progression (6). Patients were randomized in a 1:1 fashion to either combination therapy every 12 hours for 5 days or placebo. Primary endpoint was the percentage of patients hospitalized for COVID or all-cause mortality at 28 days. 2246 patients were randomized, with patients in the experimental group having lower incidence of hospitalization or death at 28 days when compared to placebo:

This held true regardless if therapy was started within 3 or 5 days of symptom onset. A multivariate Cox Regression analysis of nearly 4750 patients who received Paxlovid found that receipt of the medication was associated with lower rates of severe COVID or COVID-related mortality (7): 

One thing to note here is these drugs were evaluated in outpatients rather than inpatients, so its clinical utility in the hospital setting remains to be seen. Think of these as “Tamiflu” where you may give them to those ambulatory patients who are symptomatic but not needing oxygen.

Monoclonal Antibodies

These are a bit more difficult to talk about, as the type of strain affects their utility. For instance, sotrovimab has no activity against Omicron BA.2 (8). It may be these will have a niche in critical care depending on the prevalent strain. Nevertheless, most of the data have focused on prevention of severe COVID in high-risk patients. A phase 3, multicenter, randomized trial evaluated a single infusion of 500mg of sotrovimab with placebo in non-hospitalized patients with mild to moderate COVID-19 (9). Primary outcome was the percentage of patients who were hospitalized through day 29 after randomization. 583 patients were randomized, with sotrovimab being associated with a significant reduction in disease progression (relative risk reduction 85%, 95% CI 44 to 96%). 

In the ACTIV-3 trial, sotrovimab and BRII-196 + BRII-198 were compared with placebo in patients hospitalized with COVID-19 (10). Think of it as two trials into one, where in one part patients were randomized in a 2:1 fashion to sotrovimab:placebo and in the other in a 2:1 fashion to 196/198 and placebo. Patients in the sotrovimab group received one dose of 500mg, while those in the combination group received one 1g dose of each. Primary outcome was time to sustained clinical recovery up to day 90 based on a 7-point pulmonary ordinal scale. 546 patients were enrolled, and at day 5 neither experimental group had significant odds of more favorable outcomes over placebo (aOR 1.07, 95% CI 0.74-1.56 for sotrovimab; aOR 0.98, 95% CI 0.67-1.43 for 196/198). By day 90, sustained clinical recovery was seen in 85% of patients in the placebo group compared to 88% in the sotrovimab group and 88% in the 196/198 group. 

A randomized, open-label trial evaluated casirivimab/imdevimab (aka REGEN-COV)  in comparison with standard of care of convalescent plasma (11). Primary outcome was 28-day all-cause mortality, with nearly 10,000 patients being randomized. Of these, only 11% did not require any oxygen on admission. Overall, combination monoclonal antibodies was associated with reduction in primary outcome when compared to standard of care (RR 0.79, 95% CI 0.69-0.91). This effect was more pronounced in seronegative patients:

Notably, in secondary analysis, those who did not receive oxygen did not get any benefit from the infusion:

In the REGEN-COV trial, patients were randomized in a 1: 1:1 ratio to receive either the IV antibiotic cocktail at a dose of 2400 mg or 8000 mg or placebo (12). The primary endpoint was the percentage of patients with at least 1 COVID-19 related hospitalization or death from any cause through day 29.  For the primary outcome, Covid related hospitalization or death occurred in 1.3% of the 2400 mg group, compared to 4.6% of dose who were in the placebo group. Similarly 1% of the patients were randomized to the 1200 mg group as she had the primary endpoint compared to 3.2% and the corresponding placebo the relative risk reduction was 71.3% in the 2400 mg group and 70.4% in the 1200 mg group. The time to resolution of symptoms was the same in both antibody cocktail doses and was significantly shorter than the placebo. 

Bamlanivimab was evaluated in a multi-stage, double blind trial in hospitalized patients (13). Primary outcome was sustained clinical recovery, measured as an ordinal outcome. 314 patients were enrolled, with 86 not requiring any oxygen therapy. Overall, there was no difference in the rate of sustained recovery between the therapy (82%) or the placebo (79%) groups (RR 1.06, 95% CI 0.77 to 1.47). Again, if these agents are available it wouldn’t be an unreasonable therapy however, given most of the time we do not know what strain is infecting someone upfront, I do not see these as being widely used.

References:

  1. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC; ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 – Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826. doi: 10.1056/NEJMoa2007764. Epub 2020 Oct 8. PMID: 32445440; PMCID: PMC7262788.
  2. Spinner CD, Gottlieb RL, Criner GJ, Arribas López JR, Cattelan AM, Soriano Viladomiu A, Ogbuagu O, Malhotra P, Mullane KM, Castagna A, Chai LYA, Roestenberg M, Tsang OTY, Bernasconi E, Le Turnier P, Chang SC, SenGupta D, Hyland RH, Osinusi AO, Cao H, Blair C, Wang H, Gaggar A, Brainard DM, McPhail MJ, Bhagani S, Ahn MY, Sanyal AJ, Huhn G, Marty FM; GS-US-540-5774 Investigators. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2020 Sep 15;324(11):1048-1057. doi: 10.1001/jama.2020.16349. PMID: 32821939; PMCID: PMC7442954.
  3. WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Abdool Karim Q, Alejandria MM, Hernández García C, Kieny MP, Malekzadeh R, Murthy S, Reddy KS, Roses Periago M, Abi Hanna P, Ader F, Al-Bader AM, Alhasawi A, Allum E, Alotaibi A, Alvarez-Moreno CA, Appadoo S, Asiri A, Aukrust P, Barratt-Due A, Bellani S, Branca M, Cappel-Porter HBC, Cerrato N, Chow TS, Como N, Eustace J, García PJ, Godbole S, Gotuzzo E, Griskevicius L, Hamra R, Hassan M, Hassany M, Hutton D, Irmansyah I, Jancoriene L, Kirwan J, Kumar S, Lennon P, Lopardo G, Lydon P, Magrini N, Maguire T, Manevska S, Manuel O, McGinty S, Medina MT, Mesa Rubio ML, Miranda-Montoya MC, Nel J, Nunes EP, Perola M, Portolés A, Rasmin MR, Raza A, Rees H, Reges PPS, Rogers CA, Salami K, Salvadori MI, Sinani N, Sterne JAC, Stevanovikj M, Tacconelli E, Tikkinen KAO, Trelle S, Zaid H, Røttingen JA, Swaminathan S. Repurposed Antiviral Drugs for Covid-19 – Interim WHO Solidarity Trial Results. N Engl J Med. 2021 Feb 11;384(6):497-511. doi: 10.1056/NEJMoa2023184. Epub 2020 Dec 2. PMID: 33264556; PMCID: PMC7727327.
  4. Fischer W, Eron JJ, Holman W, Cohen MS, Fang L, Szewczyk LJ, Sheahan TP, Baric R, Mollan KR, Wolfe CR, Duke ER, Azizad MM, Borroto-Esoda K, Wohl DA, Loftis AJ, Alabanza P, Lipansky F, Painter WP. Molnupiravir, an Oral Antiviral Treatment for COVID-19. medRxiv [Preprint]. 2021 Jun 17:2021.06.17.21258639. doi: 10.1101/2021.06.17.21258639. Update in: Sci Transl Med. 2022 Jan 19;14(628):eabl7430. PMID: 34159342; PMCID: PMC8219109.
  5. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V, Martín-Quirós A, Caraco Y, Williams-Diaz A, Brown ML, Du J, Pedley A, Assaid C, Strizki J, Grobler JA, Shamsuddin HH, Tipping R, Wan H, Paschke A, Butterton JR, Johnson MG, De Anda C; MOVe-OUT Study Group. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022 Feb 10;386(6):509-520. doi: 10.1056/NEJMoa2116044. Epub 2021 Dec 16. PMID: 34914868; PMCID: PMC8693688.
  6. Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W, Baniecki M, Hendrick VM, Damle B, Simón-Campos A, Pypstra R, Rusnak JM; EPIC-HR Investigators. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022 Apr 14;386(15):1397-1408. doi: 10.1056/NEJMoa2118542. Epub 2022 Feb 16. PMID: 35172054; PMCID: PMC8908851.
  7. Najjar-Debbiny R, Gronich N, Weber G, Khoury J, Amar M, Stein N, Goldstein LH, Saliba W. Effectiveness of Paxlovid in Reducing Severe COVID-19 and Mortality in High Risk Patients. Clin Infect Dis. 2022 Jun 2:ciac443. doi: 10.1093/cid/ciac443. Epub ahead of print. PMID: 35653428; PMCID: PMC9214014.
  8. US Food and Drug Administration. FDA updates Sotrovimab emergency use authorization: Update: Sotrovimab is no longer authorized to treat COVID-19 in any U.S. region due to increases in the proportion of COVID-19 cases caused by the Omicron BA.2 sub-variant. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-sotrovimab-emergency-use-authorization 
  9. Gupta A, Gonzalez-Rojas Y, Juarez E, Crespo Casal M, Moya J, Falci DR, Sarkis E, Solis J, Zheng H, Scott N, Cathcart AL, Hebner CM, Sager J, Mogalian E, Tipple C, Peppercorn A, Alexander E, Pang PS, Free A, Brinson C, Aldinger M, Shapiro AE; COMET-ICE Investigators. Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab. N Engl J Med. 2021 Nov 18;385(21):1941-1950. doi: 10.1056/NEJMoa2107934. Epub 2021 Oct 27. PMID: 34706189.
  10. ACTIV-3/Therapeutics for Inpatients with COVID-19 (TICO) Study Group. Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial. Lancet Infect Dis. 2022 May;22(5):622-635. doi: 10.1016/S1473-3099(21)00751-9. Epub 2021 Dec 23. PMID: 34953520; PMCID: PMC8700279.
  11. RECOVERY Collaborative Group. Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2022 Feb 12;399(10325):665-676. doi: 10.1016/S0140-6736(22)00163-5. PMID: 35151397; PMCID: PMC8830904.
  12. Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, Xiao J, Hooper AT, Hamilton JD, Musser BJ, Rofail D, Hussein M, Im J, Atmodjo DY, Perry C, Pan C, Mahmood A, Hosain R, Davis JD, Turner KC, Baum A, Kyratsous CA, Kim Y, Cook A, Kampman W, Roque-Guerrero L, Acloque G, Aazami H, Cannon K, Simón-Campos JA, Bocchini JA, Kowal B, DiCioccio AT, Soo Y, Geba GP, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD; Trial Investigators. REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19. N Engl J Med. 2021 Sep 29. doi: 10.1056/NEJMoa2108163. Epub ahead of print. PMID: 34587383.
  13. ACTIV-3/TICO LY-CoV555 Study Group, Lundgren JD, Grund B, Barkauskas CE, Holland TL, Gottlieb RL, Sandkovsky U, Brown SM, Knowlton KU, Self WH, Files DC, Jain MK, Benfield T, Bowdish ME, Leshnower BG, Baker JV, Jensen JU, Gardner EM, Ginde AA, Harris ES, Johansen IS, Markowitz N, Matthay MA, Østergaard L, Chang CC, Davey VJ, Goodman A, Higgs ES, Murray DD, Murray TA, Paredes R, Parmar MKB, Phillips AN, Reilly C, Sharma S, Dewar RL, Teitelbaum M, Wentworth D, Cao H, Klekotka P, Babiker AG, Gelijns AC, Kan VL, Polizzotto MN, Thompson BT, Lane HC, Neaton JD. A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. N Engl J Med. 2021 Mar 11;384(10):905-914. doi: 10.1056/NEJMoa2033130. Epub 2020 Dec 22. PMID: 33356051; PMCID: PMC7781100.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s