Summary of Covid literature

Summary of literature - key points - updated 20th June 2020

• Favipiravir -20/06/2020 Approved (accelerated approval ) by DCGI for use in Mild/Moderate cases of Covid-19. Dosage 1800mg BD on day 1 followed by 800mg BD for 14 days. Tablet available as 200mg (Fabiflu) at the cost of 103 Rs per tablet, total pills 122 at the cost of 12500 Rs for whole course of therapy. RNAdependent RNA polymerase inhibitor like Remdesivir. Informed consent to be taken before administration. Contraindicated in pregnancy because of teratogenic effects seen in mice, though experience for usage in Influenza is good. Suggested to do UPT in child-bearing age group women before starting. Need to stop the drug for one week before conceiving.

        Can be given in Diabetes, interaction with Repaglinide.

        Not to be given in severe kidney dysfunction with GFR below 30 ml/min

        Not to be given in Liver dysfunction

        Effect of combination with other antiviral drugs not known.

        Likely to fasten conversion to negativity and recovery.

        Will it be useful to start it after 7-10 days of illness??

• Role of corticosteroids - Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19.

    RECOVERY Trial: (statement)

       A total of 2104 patients were randomised to receive dexamethasone 6 mg once per day (either by mouth or by intravenous injection) for ten days and were compared with 4321 patients randomised to usual care alone. Among the patients who received usual care alone, 28-day mortality was highest in those who required ventilation (41%), intermediate in those patients who required oxygen only (25%), and lowest among those who did not require any respiratory intervention (13%).

Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75; p=0.14).

Based on these results, 1 death would be prevented by treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone.

• Remdesivir: A small, underpowered study in China found no difference in 28-day clinical improvement or mortality, in contrast to as-yet unpublished data from a larger NIAID study.

       ACTT-1: Preliminary report of ACTT-1 published in NEJM on 22nd May 2020 - Multicentric, double blind, randomized, placebo controlled trial of IV Remdesivir in hospitalized adults, randomized 1063 patients into two arms. Findings - Remdesivir improves time to recovery (11 days Vs 15 days), best for those on oxygen therapy, observed a non-significant mortality benefit and no significant side effects. NIH sponsored study.

Remdesivir approved for use in India for severe cases of COVID as an infusion - 20/06/2020

• The benefit of IL-6 inhibitor therapy (Tocilizumab) is unknown; multiple randomized controlled trials (RCTs) are ongoing.
• Early studies suggested that viral RNA was rarely found in the blood. Now viremia/RNAemia with extrapulmonary infection is becoming more characterized, but it's still not clear whether it represents systemic infection with infectious virus.
• It's currently unknown what proportion of patients have a viremic phase of illness.
• The association between thrombosis and COVID-19 is becoming clearer, but the benefit of changing evidence-based anticoagulation strategies is unknown.
• Structural inequities around racism and impoverishment are associated with differential outcomes, and more data are urgently needed.
• Ivermectin - SAINT trial - Single dose in mild cases - results awaited

Single dose not likely to reach IC50 in lungs ( Clin Pharm Therap; Schmith et al)

• Convalescent Plasma Therapy - JAMA June 3 - RCT terminated early as no significant improvement was seen in severely ill patients.

      PLACID trial: ICMR has initiated a multi-center clinical trial, titled “A Phase II, Open Label, Randomized Controlled Trial to Assess the Safety and Efficacy of Convalescent Plasma to Limit COVID19 Associated Complications in Moderate Disease” (PLACID Trial). The PLACID trial protocol has been registered with the Clinical Trial Registry of India (CTRI) and the registration number is CTRI/2020/04/024775. The study has also received approval from the COVID-19 National Ethics Committee (CONEC), vide letter no. CoNEC 002/2020, dated 29th April 2020. The generic protocol for this study has also been approved by the DCGI, CDSCO vide letter no X.11026/78/2020-BD, dated 26th April 2020. The sample size of the study is 452. The clinical trial liability insurance has been bought centrally by ICMR. 

• SOLIDARITY Trial: The Solidarity trial for treatments is a multinational Phase III-IV clinical trial organized by the World Health Organization (WHO) and partners to compare four untested treatments for hospitalized people with severe COVID-19 illness.^[1][2] The trial was announced 18 March 2020,^[1] and as of 21 April, over 100 countries were participating.^[3]
  In May, the WHO announced an international coalition for simultaneously developing several candidate vaccines to prevent COVID-19 disease, calling this effort the Solidarity trial for vaccines.^[4]

The individual or combined drugs being studied in the Solidarity and Discovery projects are already approved for other diseases and recognized as safe.^[2] They are:^[2][6]

• Remdesivir
• Lopinavir/ritonavir combined
• Lopinavir/ritonavir combined with interferon-beta
• Hydroxychloroquine or chloroquine

Due to safety concerns and evidence of heart arrhythmias leading to higher death rates, the WHO suspended the hydroxychloroquine arm of the Solidarity trial in late May 2020.^[12][13] The WHO had enrolled 3,500 patients from 17 countries in the Solidarity trial.^[12]

On 3 June 2020, the WHO announced it would resume its global trial of hydroxychloroquine after its data safety monitoring committee found there was no increased risk of death for treating severe COVID‑19 infection.^[14]

• Cytokine filters to be used in an extracorporeal circuit (Cytosorb, oxyris) have been approved for emergency use in patients with cytokine storm. (extrapolation from sepsis patients)

• Nonpharmaceutical interventions are important for epidemic control and economic recovery.

  COVID-19 Therapy Randomized Trials

  
  

  Table 1. Major COVID-19 Randomized Treatment Trials to Date
  Ref	Drug Tested	Total N	Outcome	Notes/Limitations
  (1)	Lopinavir/ritonavir	199	No difference	Clinical improvement, mortality, and percentage of patients with detectable viral RNA similar; median of 13 days from illness onset to randomization
  (2)	Favipiravir versus umifenovir	240	For patients with moderate COVID, favipravir led to faster day 7 clinical recovery and resolution of fevers but no difference in need for mechanical ventilation	Preprint report
  (3)	Hydroxychloroquine	150	No difference	Primary outcome of viral clearance at 28 days may not be a good endpoint; randomized late in illness course
  (4)	Lopinavir/ritonavir versus umifenovir versus control	86	No difference for primary or secondary outcomes	Randomized 2:2:1; open-label trial with relatively small N; primary endpoint was time to negative RT-PCR, which may not be meaningful
  (5)	Remdesivir	237	No difference in primary outcome; trend toward mortality improvement for those started within 10 days of symptom onset	Outbreak controlled in Wuhan before prespecified enrollment goal could be met: underpowered; majority of patients received steroids in this cohort
• Table 2. Preliminary Data on COVID-19 Randomized Treatment Trials
  Ref	Drug Tested	Total N	Outcome	Notes/Limitations
  (1)	Remdesivir	1063	Remdesivir group: 31% faster recovery compared with placebo; trend toward improved mortality	Preliminary report of findings based on press release; formal report pending peer review
  (2)	Remdesivir	397	Similar improvement in severe-disease patients who received 5 or 10 days of remdesivir	Industry-sponsored trial (Gilead); no placebo arm
  (3)	Tocilizumab	129	Primary outcome was need for mechanical ventilation or death; "A significantly lower proportion of patients reached the primary outcome in the tocilizumab arm."	Open-label study (no placebo); preliminary report of findings based on press release; formal report pending peer review
  (4)	Sarilumab	457	"Negative trends" in severe-disease group in phase 2, with "positive trends" in critical group	Industry-sponsored trial (Regeneron/Sanofi); phase 3 trial continuing with sarilumab 400 mg versus placebo in critical group only

  Table 3. Key Findings in Mode of Transmission
  Source	RNA Detected?	Live Virus?	Mode of Transmission and Evidence
  Nasopharynx (1)	Yes	Yes	Droplet confirmed	Direct contact suspected
  Sputum (1) (2)	Yes	Yes	Airborne likely in some circumstances
  Saliva (3)	Yes	Yes	Direct contact suspected as above
  Stool (4) (5)	Yes	Yes	No evidence fecal-oral to date: Macaques challenged with intragastric SARS-CoV-2 were not infected (however, direct inoculation in oral mucosa suspected)
  Blood (6) (7)	Yes	No	No confirmed bloodborne transmissions to date
  Conjunctiva (8) (9)	Yes	Yes	Macaques with corneal inoculation develop infection
  Vertical	Yes	N/A	Several cases of fetal IgM, 1 case of neonate with RNA at 16 hours (10) (11); additionally, multiple reports of placental infection (12)
  Semen/vaginal fluids	Yes		SARS-CoV-2 RNA has been detected in semen, including after recovery (13); most reports have not found virus in vaginal fluids, but there is a signal report with positive vaginal swabs (14)
  Urine (15)	Yes	Yes
  Cats (16)	Yes	Yes	Cats can transmit SARS-CoV-2 between each other

  

Viral Shedding: Key Points

• Nasopharyngeal viral load peaks around 1 day prior to symptom onset, correlating to peak time of infectiousness.
• Saliva may become an important sampling site for diagnosis.
• SARS-CoV-2 is a descending infection; in later disease, viral loads are higher in the lower respiratory tract (especially in severe/critical illness).
• In mild cases, live virus is isolated up to day 8 after symptom onset.
• There can be prolonged shedding of viral RNA lasting many weeks, particularly after critical illness. Correlation with infectiousness is unknown.
• Studies differ on whether severity of illness correlates with viral load.
• In some cases, viral RNA has also been identified in the stool, blood, conjunctiva, urine, cerebrospinal fluid, and pleural fluid.

SARS-CoV-2 Seroprevalence

• Studies with (near) universal screening of various populations are increasingly available, finding a wide range of asymptomatic people with positive RT-PCR tests.
  • Pregnant women in NYC: 13.5% (87% of total infections)
  • Homeless shelter in Boston: 36% (great majority of infections)
  • Town in Italy: < 1% (41% of total infections)
  • Iceland: < 1% (43% of total infections)
  • Diamond Princess cruise ship: 9% (46% of total infections)
• Varying rates relate to local stage of epidemic, population and sampling, and mitigation strategies in place.
• Some asymptomatic people are likely to be presymptomatic given the variable and sometimes lengthy incubation period.

Viral Entry: Key Points

• ACE2 is an important receptor for viral cellular entry.
• TMPRSS2 primes the S protein and allows for efficient cellular entry.
• An interaction between SARS-CoV-2 and CD147 may facilitate invasion.
• Many unresolved questions remain regarding the exact role of CD147 in viral entry. Does it directly interact with the S protein or is the interaction mediated by CypA and the N protein, as was found for SARS-CoV?

What Else Have We Learned?

• Peak infectiousness is probably 1 day prior to symptom onset.
• In the absence of therapy/vaccine, intermittent social distancing is likely to be needed for years to avoid overwhelming critical care capacity.
• Emerging pathologic correlates of clinical presentations:
  • Multiple mechanisms of cardiac injury
  • Virus can cause systemic infection
  • Viral endotheliitis and possible complement activation as cause of micro/macro thromboses
• Obesity is a risk factor for severity of disease.
• Hypercoagulability is a key feature of the disease.
• Age-based sheltering is unlikely to be effective without social distancing.
• Epidemic control is feasible with contact tracing if minimal delay is achieved.
• Asymptomatic/presymptomatic transmission is substantial.
• The incubation period is highly variable (median, 5 days).
• Can we predict who is likely to get severe disease?