An ongoing dialogue on HIV/AIDS, infectious diseases,
December 20th, 2021
Believe It or Not, We Already Have a Highly Effective Outpatient Antiviral Treatment for COVID-19
And that treatment is … (drum roll) … remdesivir.
What’s the truth here?
For that, let’s turn to what gets my vote for the most unheralded highly favorable clinical trial result since the start of the pandemic, the PINETREE study.
The trial randomized 562 outpatients with an increased risk for severe COVID-19 to daily intravenous remdesivir for 3 days or placebo. None had vaccination or treatment with monoclonal antibodies.
The results were unequivocally positive — remdesivir-treated patients had an 87% reduction in the risk of hospitalization or death, with no significant treatment-related toxicities. Key figure from the IDWeek 2021 late breaker presentation:
The contrast with the so-so results of the drug in hospitalized patients is striking, and underscores the importance of early antiviral treatment for this disease. By the time the immune-mediated organ damage kicks in — which is when most hospitalizations take place — it’s often too late for antivirals to have any effect.
Note that remdesivir given early in the course of illness to outpatients yields comparable results to the monoclonal antibodies and nirmatrelvir plus ritonavir (Paxlovid), and better results than molnupiravir. (Yes, caveats about cross-study comparisons understood.) Furthermore, remdesivir has been available for months, and is the only fully FDA-approved treatment for COVID-19 — which means clinicians can prescribe it in whatever setting they deem useful.
But it’s hard — OK, nearly impossible — to find anyone who has actually used remdesivir in a nonhospitalized patient:
The PINETREE study showed that remdesivir daily for 3 days in nonhospitalized, high-risk individual with Covid19 reduced the risk of hospitalization by 87%.
Have you or anyone you know used it this way outside of a research study? https://t.co/o9e0IBPH0F
— Paul Sax (@PaulSaxMD) December 19, 2021
The reasons so few have adopted this treatment are obvious. Setting up outpatient intravenous therapy urgently is a challenge even under the best of circumstances — and doing so for patients who are acutely ill and have a highly contagious infectious disease only makes it more challenging.
The study sponsors recognized these hurdles and stopped the study early because of the availability of single-infusion monoclonal treatment and vaccine availability, both of which seemed destined to make the study results of limited clinical utility.
But with Omicron’s arrival, the results of PINETREE instantly become quite relevant. Omicron is so highly contagious and vaccine evasive that many people who have been “fully vaccinated” (time to retire that phrase, by the way) will contract COVID-19. My (very funny) British ID colleague Neil Stone describes it as follows:
Forget airborne, this thing seems to spread by telepathy — feels like you can catch it just by THINKING about it.
Furthermore, the most widely used monoclonal antibodies in current use — casirivimab and imdevimab and bamlanivimab and etesevimab — don’t neutralize Omicron. Sotrovimab, which is predicted to retain some activity, is in very short supply. The oral antivirals nirmatrelvir and molnupiravir are not yet available, and even once they get approved, supplies will be severely limited. Note again that molnupiravir reported lower efficacy than remdesivir, and furthermore has mutagenesis concerns.
My late colleague Francisco Marty — a brilliant clinical researcher — proposed studying remdesivir as a single IV dose, analogous to the one-dose baloxavir and peramivir treatments for influenza. This would greatly facilitate outpatient and emergency room treatment. Remdesivir infusions don’t take long, and require no post-treatment observation. Unfortunately, the study never went forward.
Maybe it’s time to revive the idea? Start a clinical trial now comparing 1 vs. 3 doses, using a noninferiority design?
Regardless, we’re going see a lot of COVID-19 in the next few weeks. Since most PCR assays do not report “spike gene target failure” — a hallmark of Omicron — clinicians will not know in real time whether these cases are Omicron or Delta, and hence whether the currently available monoclonal antibodies will work.
But based on other regions where Omicron appeared, the dominance of this variant is all but inevitable and will occur rapidly. This experience in Houston is typical, one we’re seeing in multiple areas in the United States right now:
Sunday Update: The Omicron variant is now in Houston in full force, accounting for 82% of new symptomatic Houston Methodist #COVID-19 cases as of earlier this week.
#Omicron became the cause of the supermajority of new Houston Methodist cases in less than three weeks. pic.twitter.com/XL5C31P4As
— S. Wesley Long (@drswlong) December 19, 2021
Why not prepare for this change by shifting the resources we’ve developed for intravenous monoclonal antibodies to intravenous remdesivir? Let’s offer this first to our highest risk patients — people who are B-cell depleted, transplant recipients, other severely immunocompromised.
It won’t be easy, but it will be worth it. Let’s use all the effective tools we have to treat this disease, and that includes remdesivir for high-risk outpatients.