COVID-19 Therapy Options – 1

In this and the next article I will discuss the various therapy options presently available to us.  There is a lot of complicated science involved, geeks like me live for it.  But I will keep this simple so your eyes do not glaze over.  Where possible I have provided links to credible articles so you can read more of the details.  I will try to cover all the serious drugs, not the silly ones.  

Remdesivir

Remdesivir, an anti-viral drug, was developed by Gilead Sciences and emerged from a collaboration between Gilead, the U.S. CDC and the Army Medical Research Institute of Infectious Diseases. They were looking for antiviral drugs for treating RNA-based viruses that had global pandemic potential, such as Ebola, Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS).  Unlike many broad spectrum antibiotics we have in our arsenal that work on a number of bacterial infections, broad spectrum anti-viral drugs are hard to find.  So when COVID-19 came along, it made sense to see if remdesivir would be effective against it.

In October of last year the FDA approved the antiviral drug remdesivir (brand name “Veklury”) for use in adult and pediatric patients 12 years of age and older for the treatment of COVID-19 requiring hospitalization. The FDA specified remdesivir should only be administered in a hospital or in a healthcare setting capable of providing acute care comparable to inpatient hospital care.

We live in times of rapid change and often that means we and our doctors have to make judgement calls based on evolving information.  How well does remdesivir work?  Does it have special toxicity issues? 

Remdesivir for the treatment of Covid-19 – Final report

The New England Journal of Medicine

We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.

A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days, as compared with 15 days among those who received placebo.  The Kaplan–Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 . Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%).

Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection.

 New England Journal of Medicine is one of the most prestigious medical journals out there.  This is double-blind, placebo controlled trial, the gold standard of clinical trial designs.  The trial involved more than a thousand people – pretty robust size.  I have attached the link to the full article, please take the time to browse, if you are so inclined.

Cutting to the chase, patients given remdesivir, compared to a placebo, recovered sooner – 10 days compared to 15 days.   6.7% of the patients given remdesivir were projected to die, compared to 11.9% of  the control group.  I will be the first to acknowledge:  Both of those study finding are encouraging and surely beat a kick in the head!

Now for some of the not so clear details.  The patients involved in this study were drawn from the general population.  There is  no specific mention, but I am willing to bet they did not look into how CLL patients or other immune compromised people would respond to remdesivir. 

In addition to being immune compromised, our guys need to keep a sharp eye for potential adverse drug interactions.  Most CLL patients are older, treated with maintenance drug regimens to control CLL and other diseases.  An article from University of Cincinnati researchers published last month draws attention to  a potential side effect of remdesivir and raises concerns for adverse drug interactions.  Remdesivir interferes with the activity of an enzyme called CES-2, which is found in the intestine, liver and kidney.  Unfortunately, this very enzyme is needed for the breakdown of many other medications.  Does remdesivir change how your body absorbs, say, Ibrutinib or venetoclax?  How about high blood pressure medication?  Statins for cholesterol control?  “This enzyme normally breaks down and activates medicines in certain antivirals or inactivates other medicines such in certain anticoagulants,” says the author.  He also says it increases the toxicity of many more medications such as heart medicines and anticancer drugs.  

The manufacturer of remdesivir does not recommend the drug to those with kidney problems.  Of particular interest to our folks, it is also stated that remdesivir may cause increase in liver function tests.  Have you looked at your routine blood monitoring test results recently?  “ALT” and “AST” will be listed there, indicators of the health of your liver.  “Hepatomegaly” or swollen liver is one of the hallmarks of advancing liver damage due to CLL.  In fact, hepatomegaly is the classic feature that kicks CLL patients into high grade CLL, according to the Rai grading system.  A swollen liver often signals CLL has progressed beyond the “Watch & Wait” stage and needs to be treated.

How is remdesivir administered?  I wish it were a tablet that you swallow in the comfort (and safety) of your own home.  No such luck. Remdesivir is only administered through the veins in a hospital setting. FDA typically recommends a dose of once a day, for approximately 10 days.  Since the present FDA approval of remdesivir is limited to patients who have already been infected with COVID-19 virus, chances are good that your primary care physician or your local oncologist is not going to be the ones administering it to you in their safe and quiet out-patient clinics.  You will have to go to the hospital to get this treatment, one infusion per day for ten days.  Given the crowded hospitals and ER rooms across the country, this presents logistic challenges, not to mention possible risks.

Action Items:

• Are you on maintenance drugs for CLL and / or other health conditions? (Heart disease, high blood pressure, diabetes, liver damage, insufficient kidney function – that is a short list, not all-inclusive).  If so, you need to talk with your doctors to see if any of them are likely to have adverse effects in combination with remdesivir.
• If in spite of your best efforts you get infected with COVID-19, I urge you to ask if your present medications should be withheld while you get remdesivir.  This is not an easy decision, especially if the maintenance drugs are necessary for life threatening issues such as heart disease, diabetes, hypertension.  Damned if you do and damned if you don’t. 
• If you have compromised liver function (check your AST and ALT results on your latest blood test), the risk versus reward of remdesivir may not be in your favor.
• Bottom line, plan ahead of time!  Do not hope the over worked ER doc will be familiar with your particular medical needs as a CLL patient, or that he will be able to reach your personal doctor and have a detailed consult of all the drugs you are on already.  Therapy decisions will  be made in a matter of minutes, by medical personnel that do not have a detailed picture of your medical history.  I am willing to bet you probably know a lot more about CLL and its many requirements than most front-line physicians.

Convalescent Plasma

As the name implies, convalescent plasma uses blood from people who have recovered from COVID-19.  Blood donated by people who’ve recovered from COVID-19 has antibodies to the virus that causes it. The donated blood is processed to remove blood cells, leaving behind clear liquid (plasma) and the precious antibodies (“IgG”)cured patients developed to defeat the disease. These can be given to newly infected people to boost their ability to fight the virus.  If you have young and fit family members who have contracted COVID-19 and recovered, please convince them to volunteer, donate their blood so life saving convalescent plasma can be extracted from it.

One of the issues that complicates the use of convalescent plasma is a very simple one:  dosage.  You see, not every donor who recovered from COVID-19 has the same level of feisty anti-bodies (IgG) in their blood.  Right now, plasma from several donors is combined and the pooled product is administered to several patients needing it.  Will you get plasma from a bunch of super hero donors, whose blood is packed with zillions of the precious anti-bodies (“high titer IgG”), or will you be unlucky and get a watered down version from donors who had low levels of antibodies to begin with?  No way of telling, right now.

The second important question is when the convalescent plasma is administered.  In simple terms, if you think of this therapy as the cavalry coming in to rescue you when you are under attack, it obviously makes a huge difference when the cavalry arrives.  Sooner is obviously better, and you would want the cavalry to come in large numbers. Below is an  article from the New England Journal of Medicine that explores this question.

Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults

BACKGROUND

Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness.

METHODS

We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. 

RESULTS

A total of 160 patients underwent randomization. In the intention-to-treat population, 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), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed.

CONCLUSIONS

Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. 

Moral of the story – continuing our cavalry analogy – when / if we catch the COVID-19, we want lots of cavalry, strong and well trained troops,  rushing to our rescue at the first sign of trouble.  Problem is, there are not enough cavalry around, not all of them are equally capable of taking down the enemy, and there are too many of us waiting to be rescued.  Confusion reigns on when exactly patients should be administered convalescent plasma that is in chronic short supply.  Will you be one of the lucky ones?  Not without you doing your due diligence and planning ahead of time.  Negotiate, plan, get your ducks in a row.  I believe luck favors the prepared patient.

Editorial

My next article will discuss monoclonal antibody cocktail drugs as well as a couple of anti-malaria and anti-parasite drugs that have attracted attention as potentially useful in the fight against COVID-19.  I decided to set these aside for another article since they are a bit more controversial and I want to be sure to do justice to them.  In the meantime, please allow me to repeat for the record stuff that you can do, right now, while you stay safely cocooned against this pandemic.

• Quarantine, quarantine, then quarantine some more.  No kidding.  I cannot be more serious about this recommendation.
• Improve your communication skills. “Controversies in communication“, an older article on CLL Updates, may be worth a read.  Make sure your doctors (primary care physician, local oncologist, and CLL expert) are all on the same page and up to speed on your situation.  Please remember they are all over-worked and under-thanked right now.  Keep your communication pleasant, to the point and appreciative.  Don’t waste their time.
• It’s equally important that you bring your family and friends up to speed on your heightened risk.  You are only as safe as your first ring of contacts.  I heard from one poor CLL patient whose wife is a nurse on active duty.  She refused to get vaccinated when it was offered to her because of some conspiracy theory she saw online.
• Is it kosher to ask your doctor whether everyone in his / her office has been vaccinated?  Let me hear from your experiences on this one please.
• I am over whelmed too – with gratitude.  So many of you have welcomed me with such warmth back into your lives after my 6 year retirement.  Thank you from the bottom of my heart.
• There have been a few complaints.  One reader took me to task for scaring the living bejeezus out of him.  For starters, it is clearly his decision to read my article, or hit the delete button.  Second, if I really scared him that much and he is now more aware of the danger (man had to cancel some social / family outings, poor baby! It seems his wife read my article and insisted) and he is now taking it more seriously, good!!!  That was one of the objectives of my coming out of retirement – get you guys to take this situation seriously.  
• There is a good bit of information in the comment section following each article, which trickles in slowly over several days after publication.  You can spot my responses quickly because they are highlighted.  But I suggest you read all the comments.  We have a savvy group of readers with interesting responses.  May I suggest you revisit earlier published articles a couple of times and scroll down to the bottom to see if there are new comments?
• We have run into problems with sending out our usual email to announce a new article – so many email addresses in our data bank are no longer functioning.  If you want to get an email, make sure you are registered and that the email address listed in your account is up-to-date.  Talk to our webmaster about this if you need help. 
• Spread the word around if you want others to be aware of new stuff on our website.  

Stay safe, stay strong and survive.  I know this is hard, it is hard for all of us.  But with a little help from our families, friends, doctors, and patient community, we can do this.  I think we should make lemonade when we are pelted with lemons on a daily basis.  Take this opportunity to read, learn, be more compassionate and involved in our patient community and we will come out far better people at the other end of the tunnel.  A sense of humor helps.

Be well,

Chaya