CME INDIA Presentation by Dr N K Singh, Admin.

Solidarity Trial, co-ordinated by WHO and executed by ICMR in India is able to answers some critical questions about COVID-19 Therapeutics. Take a case – asymptomatic /mild / moderate /severe /critical – interim analysis showed no benefits of Remdesivir in any groups of COVID-19. There were 26 actively randomizing sites with 937 participants in India too, so these data have got significance to Indian patients as India contributed one tenth of the participants. Worth to note, this was world’s largest global randomized controlled trial spanning 30 countries. It is now said that mankind has found the answer that Remdesivir does not work.

Practice changing impact – is it there?

CME INDIA tried to understand the Impact

Dr Richard Russell, PhD, FRCP, UK:

(Personal message to Dr N K Singh)

Consultant Physician at Lymington New Forest Hospital and is the Clinical Director of the Hampshire Community Integrated Respiratory Service, PI in Experimental Medicine in the Respiratory Medicine Department at Oxford, founding Editor of the International Journal of COPD.

• While the Solidarity data are robust, they may not address whether certain patients are helped by the drug.
• The trial wasn’t designed to answer whether there may be a benefit for patients treated early after symptoms begin, as opposed to early after hospitalisation. Treatment early in the course of infection may avoid the inflammation that precedes the need for ventilation.
• It’s always better to stop a fire from happening than put one out.
• The problem is that for all the results were negative. So, you need to look at the characteristics of potential responders and use their phenotype to target who to treat.

Dr Anupam Gupta, Asansol:

By “Sooner the Better” I meant as soon as respiratory distress sets in. If the patient is symptomless it should NOT be given. No medicine should be given other than Zinc, Vitamin C.  We are still UTTERLY CONFUSED. Trying to decipher the Pandemic. No drug seems to work nicely in my experience.

Dr P R Parthsarathy, Chest Physician,Chennai:

• No treatment is required in the initial phase after RTPCR +vity, except paracetamol SOS, monitoring of patient, for symptom development, SPo2 monitoring, periodic investigation of inflammatory biomarkers, treatment as required. Zinc, Vit. C has not been found to be of any value. Anecdotal data of usefulness of HCQS, Ivermectin is there.
• O2, steroids at the correct time are the only thing which have been found to be useful.
• Steroids should not be given in the early phase (viral replication phase) when the body’s immunity is taking care of the virus. As an immune modulator, when given early, will affect the natural defence mechanism which will allow the virus to multiply faster – producing more damage. Ideally, steroids should be given when the patient is in hypoxic state (on oxygen).

Dr Murali Mohan, Pulmonologist, Bengaluru:

• Frankly, we are still using Ivermectin/ Doxycycline or Favipiravir in mild cases and Remdesivir in admitted patients. We think there is a definite benefit and this is echoed by many practising clinicians.
• If we do not have any anti-viral, then the only really proven treatment – steroids could actually be counterproductive. Absolutely – early antivirals and steroids only if hypoxia – at rest or a 3%+ drop on exercise (6-minute walk) – is demonstrated.

Dr T Rekha, MD Med, Salem, TN:

Agreed, we have treated many patients with antivirals (favipiravir in mild cases – opd & Remdesivir in i.p patients with & without steroids based on CT severity score & hypoxia. They have recovered well.

If antiviral not useful, how they became alright? Natural course🤔

Of course, nothing works out including steroids in critical cases; had a fatal outcome.

Dr Gaurabh Gupta, New Delhi:

Dr Murali’s comment resonates with me. In my practice, we are doing the same. Only change over time is early timely use of Remdesivir and steroids only in cases of hypoxia.

Dr M Pavan Kumar, Prof. Med., MGM Hospital, Warangal:

I agree with Dr Murali.

Dr Anil Motta, Sr. Consultant Medicine, Max, Delhi:

I think ICMR needs to think & not act like Trump! I really think now every place & person is going to go by personal/anecdotal experience.

Dr Ambrish Mithal, DM Endo., Delhi:

• That is true for every condition before evidence accumulates. I will ask the same question again – do viral fevers respond to medication? It’s ok to try when we are not sure, but as more evidence is gathered we have to modify our protocols.
• While personal experience is very important, once we have data we should modify. Why do we follow ADA guidelines or spend hours debating ESC vs ADA vs EASD? Because we believe they are backed by science. Top infectious disease specialists in the US have changed their protocols rapidly.
• Remedesivir is still ok till more data appears. On a case by case basis. But HCQ, Ivermectin, Azithromycin, all have very little role. Of course, we may use them if we prefer to. We are not bound by anything or anyone. We are doing the best for our patients as we think fit. That is our right as physicians. I am just discussing the science. And how clinical practice will reflect it. Maybe it will take time to reach clinic.

Dr Kiran Shah, Diabetologist, Mumbai:

We continue to use Remdesivir. Double edged sword:

1. Despite many evidences showing no major benefit, there have been patients who have responded dramatically to treatment, but the number is small to very few.
2. If one does not use it despite being available and if the question is raised, be ready to answer not only the mob, but also to the task force and government authorities.

  There is no clear consensus – many would say it is a learning curve.

Dr B K Thakur, Pulmonogist, Physician, Dhanbad, Jharkhand:

• An obese diabetic case, 5th day of fever PRCR positive, HRCT-CORAD 5, SpO2-93%……I am strongly in favour of giving Remdesivir, leave apart Solidarity data and ICMR press note.
• Hypoxic high-risk patients, at present, not using only available experienced drug could be a mistake.
• Illusion is dense but physicians need to apply consensus opinions at desperate time not only dry and hard guidelines. With Remdesivir, we have something positive with Recovery and ACTT post hoc data.

 Dr Anand Malani MD, Sangli, Maharashtra:

• We always consider RCTs as ‘Gold’ standard in our field.
• Guidelines and Protocols get modified accordingly. But this doesn’t immediately translate into paradigm shifts in personal practices.
• Opposite is true for PERSONAL EXPERIENCES, which is a ‘bad word’ in the field of Medicine as far as scientific practices are considered.
• Nonetheless we continue to bank on them and use in our practice.
• Same will be true for Remdesivir.  Due to WHO SOLODARITY trial, it may go OFF Guidelines and OFF SHELVES in INDIA, leaving us with nothing specific to treat.
• But many, INCLUDING ME AND MY COLLEAGUES, AND MANY IN THIS GROUP AS WELL will continue TO SHOW THEIR SOLIDARITY WITH REMDESIVIR RATHER THAN THE TRIAL!
• The trial itself which is being branded as a ‘very large trial’ ‘DOESN’T HOLD TRUE.’ 
• Total patients included were 11266 and those allocated to Remdesivir were 2750. Well this is a very small number considering the magnitude of the Pandemic.
• Even my city with a population of 6-7 lakhs had significantly more total number of patients and also those who received Remdesivir.
• It’s time to be ATMANIRBHAR and conduct our own RCTs as well as RETROSPECTIVE ANALYSIS of all the patients who were admitted and received various treatment modalities.
• The pooled data will be a huge and factual one and will definitely guide us for the present and the upcoming SECOND WAVE!

Dr Atri Gangopadhyay, Pulmonologist, Ranchi:

• Prior to results of SOLIDARITY and statement by ICMR, the first option for moderate COVID (any patient with abnormal CT) was always REMDESIVIR. Placebo or not, I was fruitfully rewarded by majority early presentations getting better.
• Now again, I am back to absolutely no specific options for moderate to severe COVID, and its very tough convincing patients that “you need to get admitted, but I don’t have any specific options for you.”

Dr Ravi Kirti, HoD Med., AIIMS, Patna:

• Lopinavir (with ritonavir) had been discredited long ago. Interferon was never used widely in the treatment of COVID-19.
• Most of the world stopped using HCQS once the findings of the recovery trial became known. In India, it is still being used due to the insistence of ICMR (and inclusion in the MoHWF guidelines). As ICMR has proudly (and rightly) taken credit for participating in the SOLIDARITY trial, I hope these guidelines will be revised soon now.
• So, that leaves us with Remdesivir. We should stop believing that it is a wonder drug. But I feel that it will stay in clinical practice for now. A subgroup analysis in the earlier trial had demonstrated some mortality benefit in patients requiring oxygen but not needing high flow oxygen or ventilatory support. It would be interesting to know if any such effect was seen in the SOLIDARITY trial. In the absence of other alternatives and more data, we may continue to use it in patients with a relatively low but increasing oxygen requirement.

Dr Rajkamal Chaudhary, Asso. Prof. Med., Bhagalpur:

However, even as the Solidarity trial found that Remdesivir was ineffective in reducing mortality or duration of hospital stay, the ICMR also revolted to the anti-viral drug on 19th October 20.

For me it was no Surprise as around 1200 Patients of COVID-19 have been admitted in ICU Of JLNMCH BHAGALPUR while we had 100 Deaths which is quite high (Admitted of Adjoining District about half a dozen also) Altogether Remdesivir was given in 150 Patients by 6 Units of the Medicine Department but severe cases did not survive. I knew the fate of this drug so we did not try, only in VIP Patients so that they could not say that this drug was not given to my patients. So, this is not going to give impact on my Practice and I never wrote this drug in my Private Practice.

Dr Suresh Kumar, Infectious diseases specialist, Apollo Hosp., Chennai: Shares…

• I will use Remdesivir in high risk patients presenting within 3 days. Others and late (up to. 5 days) – optional.

Dr Arvind Ojha, Internist, Kolkata:

We are waiting for ICMR to change guideline and suggest future course. The problem of those who are treating the patients are totally different. Unless, it is mentioned in clear terms I am afraid it will be used due to social pressure, peer pressure. And above all, if one patient dies today without these agents, you are doomed in so many ways.

Forget about Remdesivir, tocilizumab, plasma, people are using high dose pulse steroid, ulinastatin and what not? All these are simply increasing the cost of therapy and doing no good for pt.

As long as it is there in guideline, I am bound to use it?

Dr Basab Ghosh, Internist, Agartala:

Where is the recommendation to stop these drugs? Why don’t they bell the cat?

Dr Akash Singh, Internist, Baroda:

• Though Solidarity trial and ICMR have suggested no benefit of Remdesevir, it will be difficult to cease using it suddenly in our practice. As per our experience, we cannot say that it is not effective.
• Many patients have improved after Remdesevir along with steroids and LMWH. Maybe another trial or meta-analysis may be needed. Or maybe we have to look in to study again.
• Moreover, it has created an impression that it is very useful in minds of the general public and it will take time to change the public perception where it may ultimately land up like Tocilimab. Hence as we watch the roller coaster ride of Ramdesivir as more and more data emerge, I would continue to use it as of now.

Dr R K Misra, Diabetologist, Physician, Jamshedpur:

• Today primary medications are not antiviral but anti-inflammatory and drugs controlling thrombo embolic hence steroids and LMWH with antibiotics remain the most important.
• Antivirals like Remdesivir or Fevipiravir have no place after 10 days hence if patients come early in a day or 2 give benefit of doubt by using them no harm along with other supportive like Ivermectin or Zinc or VitC. I think drugs like modulating IL 10 may have a role or IL6 modulators also may have a role or even…
• Methotrexate 25mg SC weekly as we give in Rheumatoid or even Biologics seems exciting but I am worried about their toxicity or even newer one Iguratimod 25mg o d or b d may play a role but difficult to experiment, though I have used this for Rheumatoid in around 28 patients till now and found very safe pathology is very similar to ILD or UIP.

Dr Himalaya Jha, Sr. Physician, CMO, CGHS, Ranchi:

• Since last 1 month, we have been getting mostly asymptomatic or mild symptomatic cases of COVID 19:
  • 95 percent of mild cases presented with c/o mild fever may be associated with body ache and throat irritation.
  • Their investigations showed normal neutrophils with borderline low lymphocyte
  • CRP varied from 5 to 24.
  • Normal d – Dimer.
  • I used to prescribe doxycycline 100 mg twice daily for 5 days with ivermectin 12 mg for 3 days or Azithromycin with HCQS. along with vit. C, D zinc.
  • Few patients were put on Favipiravir 200 mg, 9 tabs twice daily for 1 st day then 4-tab bd for 7 to 14 days after assessing LFT.
  • Few patients were on dexamethasone when they   developed low saturation (less than 94 percent) or having breathlessness. Usually after 5 to 7 days illness.
  • Asymptomatic patient was put on zinc, Vit D, and Vit C. Most of these patients were recovered from their illness within 5 to 10 days. Those who had high d- Dimer were put on apixaban 2.5 mg bd. Chronic diabetic COVID 19 pts were put on aspirin and atorvastatin (75 + 10) since day first with onset of symptoms. I had never used remdesvir for our mild to moderate OPD cases. Severe and critical cases were advised admission. For cough, used to advise Mucinac 600mg twice daily for 3 days then cough suppressant.

Dr Nishith Kumar, Pulmonologist, Ranchi:

It’s definitely a big blow to Remdesivir post Solidarity Trial result which clearly showed that Remdesivir appeared to have little or no effect on mortality or length of hospital stays among Covid-19 patients with pneumonia.

We as treating physicians should revisit the way we treat & manage Covid-19 related pneumonia. The message is loud and clear that Remdesivir is no magic bullet & has miserably failed in preventing death & clinical outcome.
Post The PLACID Trial result which clearly showed that Convalescent Plasma Offers No Benefit in Reducing Mortality or Disease Progression I had stopped using Convalescent Plasma in my patients. Now I am very hesitant to use Remdesivir in my patients.

Their remains an unprecedented challenge to identify effective drugs for prevention and treatment of Covid-19. Overall the cornerstone of care still largely remains supportive & symptomatic therapy along with use of Dexamethasone in Hypoxemic cases & LMWH in selected high risk cases.

Dr Bhanu Pratap Singh, Internist, Siwan, Bihar:

I have experience of using Remdesivir in only one patient and favipiravir in two patients only. The pt who was put on Remdesivir was father in law of my batchmate (a surgeon). The pt was aged 68 yrs, a diabetic with moderate to severe COVID and there was marvelous recovery in that pt. Pt was kept on methyl prednisolone, insulin and remdesivir. Drugs were administered at due time and there was a marvelous response. Now pt is fine. Though it is a miniscule observation, what I inferred is that Remdesivir reduces both duration of illness as well as mortality, particularly in moderate and severe cases (but those not requiring ventilatory support).

Dr B K Shukla, Bihar:

But, I am not using Remdesivir, but advised some doctors admitted elsewhere seeking my opinions, I told them if you have spo2 without supplemental oxygen > 94% and afebrile in 3 to 5 days less than 25% involvement in HRCT then avoid the Remdesivir (supposed to reduce viral load and severity?). Even with comorbidities, I feel that as in most of the cases treated by us it is second week which is lethal & dangerous (by which time most of the cases have negligible or undetectable SARS cov2 virus. And inappropriate hyperinflammatory state (cytokines mediated) causes most of the complication. This can be managed with steroids, LMWH and as per need O2.

In fist week, we focus (in mild to moderate cases) on monitoring and treating only fever with paracetamol/ mefenamic acid along with Doxycycline and ivermectin symptomatic cough syp etc. Occasionally azithromycin (many times patient come to us self-primed with one to two doses already taken. Neither Remdesivir nor favipiravir has been in our choice before this trial except for VIP and some panic stricken googlites and few insisting and arguing doctor family as we have nothing to show them that despite worldwide popularity, there is no strong evidence. But certainly, ICMR exclusion will strengthen our stand to convince the demanding one to limit the use of Remdesivir to a very few (inconvincible one or Elite ones, or who want everything available on drug buffets of corona – costlier/with high TRP more preferable)

So far, I have managed only mild to moderate cases. Not treated severe cases (all referred to institution where in time of need ventilators Available).

SOLADARITY AND ICMR are certainly going to boost our confidence and power of perusal to suggest and omit these antiviral and I am confident that within a month or two 80% doctors and institutions will change their practicing protocol by excluding Remdesivir.

CME INDIA Learning Points:

• Indiscriminate use of Remdesivir needs to be stopped.
• Solidarity data has dampened the zeal of using Remdesivir.
• Exert opinions point towards a very pragmatic approach to use Anti-viral, as told by Dr Richard Russel, we need to look at the characteristics of potential responders and use their phenotype to target who to treat.
• Till date, no modifications in guidelines. In new Rapid Living Practice Points, the American College of Physicians (ACP) says that evidence points toward a net benefit with the use of Remdesivir for patients with COVID-19. The ACP Practice Points provide clinical advice based on the best available evidence on the benefits and harms of the use of Remdesivir for COVID-19 patients. The Practice Points are based on a rapid systematic review conducted by the VA Evidence Synthesis Program (10^th October 2020).
• At present, Remdesivir seems to remain in status quo for use in COVID-19 in appropriate situations.

CME INDIA Tail Piece:

• Newer antiviral drugs, immunomodulators and anti-SARS COV-2 monoclonal antibodies are now being considered for evaluation.
• The European Union might renegotiate a 1 billion-euro ($1.2 billion) contract it sealed last week with Gilead for a six-month supply of the COVID-19 drug Remdesivir after this trial.
• If nothing works in COVID, what is the utility of Indian Ayush Mantralaya Protocol for ayush practioners, recently released by health minister of India criticized by IMA. It says apart from general measures such as drinking herb-infused warm water or turmeric milk, steam inhalation, gargling and moderate exercise in the form of several yogic postures, the protocol also recommends a set of medicines to be used for prophylaxis and treatment. They have used two herbs— guduchia (Tinospora cordifolia or heart-leaved moonseed) and ashwagandha (Withania somnifera or Indian ginseng).

• Immunity Boosters are the king, so do you think, Intermittent Fasting can be used for prevention and Fasting for treatment. There is science behind this?

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