The time to offer treatments for COVID-19

Figures & data

Figure 1. The Phases of COVID-19. SARS-Cov-2 infection begins with an asymptomatic period of viral incubation. As viral replication accelerates, an influenza-like illness may appear. Lung involvement begins the early inflammatory phase which can proceed to a late inflammatory phase with accompanying secondary infections and a coagulopathy. The viral load is typically falling while the inflammatory state intensifies. This phase often includes disease of multi-organ systems. Elevated cytokine levels suggest an autoimmune process as the cause. The pneumonia may lead to acute respiratory distress with severe hypoxia. In those patients who recover, there can occur a prolonged period of symptoms and disability. This “tail phase” can continue for many months

Table 1. Published studies of high impact as of 15 February 2021. Each agent is listed along with the country originating the publication. We have listed studies with 100 or more subjects. The type of control procedure: RCT: Randomized controlled study PLAC: Placebo, soc: standard of care which is variable depending on each location. AC: Active control: the control options are listed in parenthesis. OBS: retrospective observation study. LPV/R: lopanovir/ritonavir; HCQ: hydroxychloroquine; AZM: azithromycin; IFN: interferon; tocilizumab: TCZ. SEV: severe; CRIT: critical; MOD: moderate. WHO.: World Health Organization

TREATMENT	LOCATION	TYPE OF	NUMBER	SETTING	SEVERITY	RESULTS
		CONTROL	SUBJECTS
Remdesivir^13	China	RCTPLAC vs soc	273	HOSP	SEV	mortality in remdesivir group 14%, control 13%
						11% in remdesivir group with <10 days symptoms
						Vs 14% in placebo group, no difference in viral clearance
Remdesivir^14	U.S.A.	RCTPLAC	1062	HOSP	SEV,CRIT	29 day mortality 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03)
Remdesivir^17	W.H.O.	AC(10 day, vs soc)	5451	HOSP	MOD,SEV	Mortality Remdesivir RR = 0.95 (0.81–1.11, p = 0.50 301/2743 active vs 303/2708 control
FVP^19	China	AC (umifenovir vs favipiravir)	240	HOSP	MOD,SEV	Clinical recovery rate 56%umifenovir vs 71% fvp
HCQ^24	France	OBS(hcq+azm, noncomparable control group)	3737	MIXED	MILD,MOD	0.9% overall mortality, no sudden death, no cardiac arrythmias
HCQ^38	U.K.	RCT (HCQ vs soc)	1542	HOSP	MOD,SEV	no significant difference in28-day mortality (26.8% hydroxychloroquine vs. 25% usual care; hazard ratio 1.09 [95% confidence interval 0.96–1.23]; p = 0.18) (Mortality RR = 1.19 (0.89–1.59, p = 0.23; 104/947 HCQ vs 84/906 control
HCQ^17	W.H.O.	AC(HCQ vs soc)	1853	HOSP	MOD, SEV	Mortality RR = 1.19 (0.89–1.59, p = 0.23; 104/947 HCQ vs 84/906 control
HCQ^39	U.S.A.	OBS (hcq+azm +zinc vs hzq +azm)	932	HOSP	MOD,SEV	Reduction in mortality with addition of zinc OR 0.449, 95% CI 0.271–0.744).
HCQ^42	Spain	RCTPLAC	293	OUTPAT	MILD	no difference in viral load at 7 days after 6 days HCQ treatment nor risk of hospitalization compared to untreated patients
HCQ^43	Spain	RCTPLAC	2324	OUTPAT	HEALTHY	no significant difference in the primary outcome of PCR-confirmed, symptomatic Covid-19 disease (6.2% usual care vs. 5.7% HCQ; risk ratio 0.89 [95% confidence interval 0.54–1.46]), nor evidence of prevention of SARS-CoV-2 transmission (17.8% usual care vs. 18.7% HCQ)
HCQ^46	Canada	RCTPLAC	1483	OUTPAT	HEALTHY	3 month treatment with HCQ in hospital workers no significant difference in SARS-Cov-2 infection rate HCQ 0.27 events per person/year vs placebo 0.38% (p = 0.18)
LPV/r^49	U.K.	RCT(soc)	1596	HOSP	MOD,SEV	no significant difference in the primary endpoint of 28-day mortality (22.1% LPV/r vs. 21.3% usual care; relative risk 1.04 [95% confidence interval 0.91–1.18];(p = 0.58)
LPV/r^17	W.H.O.	AC(LPV/r vs soc)	2771	HOSP	MOD,SEV		Mortality LPV/r (RR = 1.00 (0.79–1.25, p = 0.97; 148/1399 vs 146/1372
LPV/r^50	Hong Kong	AC(lpv/r+ ribavirin+beta interferon vs lpv/r+ ribavirin)	127	HOSP	MOD.SEV	Triple combination of interferon beta-1b, lpv/r, and ribavirin yielded more rapid viral clearance but attributable primarily to interferon
IFN^17	W.H.O.	AC(vs soc)	4100	HOSP	MOD,SEV	Mortality IFNRR = 1.16 (0.96–1.39, p = 0.11; 243/2050 vs 216/2050)
IFN-α nasal drops^54	China	OBS	2944	OUTPAT	HEALTHY	No cases of COVID-19 compared to historical control
IFN- β-1a(nebulized)^56	U.K.	RCT(soc)	101	HOSP	MOD,SEV	OR for clinical improvement 2 · 32 (1 · 07–5 · 04)
Convalescent plasma^57	China	RCT(soc)	103	HOSP	SEV.CRIT	time to clinical improvement at 28 days was 4.9 days shorter (95% CI, −9.33 to −0.54 days) in convalescent plasma group (HR, 2.15 [95% CI, 1.07–4.32]; P = .03). No significant difference in critically ill patients. Mortality 28-day mortality (15.7% convalescent plasma vs 24.0% control; P = .30)
Convalescent plasma^62	U.S.A.	OBS	3,082	HOSP	MOD,SEV	adjusted 30–35 day mortality was 30% in patients treated with plasma with low antibody levels (IgG) 35 or more days after COVID-19 diagnosis. By contrast 30-day mortality was 20% in 353 patients treated within 3 days of diagnosis with plasma with high antibody levels.
Convalescent plasma^63	U.S.A.	OBS	160	HOSP	MOD,SEV	severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P = 0.03).
Convalescent plasma^64	U.S.A.	OBS	21,987	HOSP	MOD,SEV	7 day mortality 13%
LY-CoV555^66	U.S.A.	RCT(soc)	452	OUTPAT	MILD,MOD	6.2% of patients receiving placebo had emergency room visit or hospitalization vs 1.6% patients who received antibody
RGN-Cov2^67	U.S.A.	RCT(soc)	275	OUTPAT	MILD,MOD	Decreased viral load vs placebo; 6% medical visits for placebo patients vs 3% for those receiving monoclonal antibody cocktail
Fluvoxamine^70	U.S.A.	RCT(fluvoxamine vs soc)	152	OUTPAT	MILD,MOD	Clinical deterioration in 0 patients on fluvoxamine, 8.7% placebo (p < 0.009)
Ivermectin^71	India	Case Control (Ivermectin vs placebo)	115	OUTPAT	HEALTHY	Two doses of ivermectin yielded 73% reduction in COVID_19 cases
Dexamethasone^79	U.K.	RCT(soc)	6119	HOSP	MOD,SEV	Dexamethasone reduced 28-day mortality by 35% in patients receiving invasive mechanical ventilation (rate ratio 0.65 [95% CI 0.51 to 0.82]; p < 0.001) and by 20% in patients receiving oxygen without invasive mechanical ventilation (rate ratio 0.80 [95% CI 0.70 to 0.92]; p = 0.002
Methylprednisolone^80	Italy	RCT(soc)	173	HOSP	SEV	Mehtylprednisolone group had fewer deaths (6 vs. 21, adjusted HR = 0.29; 95% CI: 0.12–0.73) and more days off invasive mechanical ventilation (24.0 ± 9.0 vs. 17.5 ± 12.8; p = 0.001)
Anakinra^104 .	Greece	OBS(vs soc)	130	HOSP	SEV	Incidence of severe respiratory failure 22% anakinra patients vs 59% soc,, 30 day mortality 11.5% anakinra vs 22.3% soc).
TCZ^111	U.S.A.	RCTPLAC (TCZvs soc)	803	HOSP	SEV,CRIT	Mortality 28% tocilizumab vs 36% control
TCZ^112	U.K.	RCTPLAC (TCZvs soc)	4116	HOSP	SEV,CRIT	Mortality 29% tocilizumab vs 33% control
Colchicine^115	Greece	RCT(colchicine vs soc)	105	HOSP	MOD,SEV	The clinical primary end point rate was 14.0%in the control group (7 of 50 patients) and 1.8%in the colchicine group (1 of 55 patients) (odds ratio,0.11; 95%CI, 0.01–0.96; P = .02).
Colchicine^116	Canada	RCT(colchicine vs soc)	4159	OUTPAT	MILD,MOD	The clinical primary end point rate was 6% in the control group and 4% in the colchicine group ((odds ratio, 0.75; 95% CI, 0.57 to 0.99; P = 0.04)
Mesenchymal Stem Cells^120	China	RCTPLAC	101	HOSP	SEV WITH LUNG DAMAGE	Lesion volume decreased compared to placebo (p < 0.05)

Table 2. SARS-Cov-2 vaccines either currently or soon to be authorized

Vaccine	Commercial sponsor	Country	Vaccination Schedule	Vaccine Technology	Reported Effectiveness	Authorization for Use
BNT162b2 [122]	Pfizer/Biontech	U.S.A.	2 shots	mRNA	95%	U.S.A., European Union, U.K., Israel
mRNA1273 [123]	Moderna	U.S.A.	2 shots	mRNA	94%	U.S.A, U.K. E.U
Sputnik 5 [124]	Gamelaya Institue	Russia	2 shots	Adenovirus vector	91%	Russia
CHadOx1 [125]	Astra Zeneca	U.K.	2 shots	Adenovirus vector	70%	U.K., E.U.
Ad5-nCoV [126]	Cansino	China	One shot	Adenovirus vector	66%	China
Ad26.COV2.S [127]	Janssen	U.S.A.	One shot	Adenovirus vector	72%	South Africa
NVX-CoV2373 [128]	Novavax	U.S.A.	Two shots	Recombinant spike protein	89%	– – – –
BBIP B-CorV [129]	Sinopharm	China	Two shots	Alum precipitated inactivated virus	86%	China, Bahrain, United Arab Emirates, Egypt
Coronavac [130]	Sinovac	China	Two shots	Inactivated virus	50%	China, Brazil
Covaxin [131]	Bharat Biotech	India	2 shots	Inactivated virus	– –	India

Figure 2. Phase-specific treatment of COVID-19. The successive disease periods call for different treatments. Antiviral treatments, including convalescent plasma., monoclonal antibodies, and interferons are indicated during the period of viral replication, but are unlikely to be effective during the inflammatory process. Suppression of the immune response is indicated to combat the inflammatory events

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