Omicron and COVID pills – the beginning of the end?

 Omicron variant

Omicron is the current dominant COVID-19 variant across the globe and in only a few weeks has even outcompeted Delta in the USA. As of January 4^th, 2022, omicron is now estimated to be 95% of new case counts. As the newest COVID variant blazes across the country and the world, by some metrics the pandemic is as out of control as ever. Average daily case counts are at an all-time high, with an exponential increase over the past few weeks. While it is still too early to tell because hospitalizations and deaths trail case counts by a few weeks, those figures have increased at a much slower rate.

This disconnect is consistent with the reporting out of South Africa, where the variant originated. Initial reports from South Africa identified a variant that was spreading extremely rapidly and had both mutations and clinical data indicating increased immune escape (aka less effective immunity based on prior infection or vaccination). While a recent study estimated that on average 86% of Americans had some form of prior immunity as of October 31^st, when accounting for waning over time true immunity was estimated at 77% against severe disease and only 50% against infection. Those results predate omicron, and therefore effective immunity is currently significantly lower than those estimates.

Despite those concerning factors, there were indications that omicron infection was resulting in less severe outcomes, and even hospitalized patients had much better outcomes compared to previous variants. The United Kingdom also reported observing the same relationship. Based on current data, the Institute for Health Metrics and Evaluation predicts that in the United States the hospitalization and death rate will be approximately half that of Delta. Scientific research has demonstrated that the reason why omicron is so contagious yet less deadly is that it preferentially replicates in the upper respiratory system – making it more easily spread – while reducing infectious damage to the deep lung.

While the rate of severe outcomes including hospitalization appears to be less among omicron cases, the overall number of hospitalizations is still overwhelming health systems as the daily case count has fluctuated as high as over 1 million cases per day. When combined with high incidence of staff who are either out sick, resigned, or fired due to vaccine mandates, many hospitals are unable to handle the surge and some have even been forced to ration care as was done in Spring 2020. Luckily, U.S. data as of the end of January demonstrates a similar pattern as was observed earlier in the U.K. and South Africa – the downside of the omicron peak appears to have arrived only 1 month after it started. Therefore, if hospitals can hold on just a few more weeks, the massive case count will have resulted in widespread immunity and a greatly reduced risk of serious outcomes moving forward (assuming a more dangerous variant does not emerge). Even more encouraging, preliminary research (on a small sample size) suggests that having both vaccination and natural infection may result in what is being called “superimmunity” – a more robust and long-lasting protection that may prove effective against a multitude of variants. Therefore, the surge in breakthrough cases may actually have a net protective effect long term. Of course, there are many anecdotal reports of triple-vaccinated individuals having caught omicron despite prior vaccination, so this optimistic outlook should be viewed with caution.

Pharmacological treatments

In addition to the indirect benefit of widespread immunity due to the omicron surge, a more straightforward positive development is the rollout of two oral treatment medications for COVID. Paxlovid, the trade name for the treatment developed by Pfizer, actually consists of two separate drugs (given as independent pills), nirmatrelvir and ritonavir. The primary, and novel, molecule is nirmatrelvir (PF-07321332), which blocks the function of a SARS-CoV2 (the COVID virus) protease that is necessary for viral function and reproduction. The other drug, ritonavir, was originally developed as an antiviral HIV protease inhibitor, however it was later discovered that at lower doses it inhibits a liver enzyme that degrades other protease inhibitors. It is therefore a useful co-treatment to increase the steady-state concentration and half-life of other protease inhibitor drugs. In clinical trials, COVID patients receiving Paxlovid within three days of symptom appearance demonstrated an astounding 89% decrease in hospitalization and death. Effectiveness remained strong at 85% when the window of treatment was extended to within five days of first symptoms.

Merck has also developed an antiviral drug, known as molnupravir (MK-4482, EIDD-2801). This drug is an analog for the traditional A, G, C, and U base pairs of RNA. This substitute results in random mutations upon RNA replication (either A or G can pair where only G should pair normally), leading to “error catastrophe”. Compared to paxlovid, molnupravir clinical trials demonstrated a much less effective but still statistically significant reduction in hospitalization of death of 30-50% (depending on the analysis). The Merck trial tested drug administration only within five days after the first symptoms. In addition to the reduced efficacy of molnupravir, some scientists are concerned that incomplete mutagenesis may promote the evolution of new COVID variants or even cancer and birth defects. While there was no evidence of any detrimental effects in the clinical trial, enrollees were advised to avoid unprotected sex and breastfeeding following treatment based on concern for birth/developmental defects.

Paxlovid received an emergency use authorization (EUA) on December 22, 2021. As a new drug, initial supplies have been limited, with only 180,000 doses available by the end of the year. Likely at least partially for this reason, the drug is only approved for high-risk individuals and demographics. Despite the reduce efficacy and concern of side effects, EUA approval of molnupravir for high-risk individuals shortly followed. In contrast with paxlovid however, molnupravir was approved only “for whom alternative COVID-19 treatment options authorized by FDA are not accessible or clinically appropriate.” There is strong optimism that these treatments could greatly diminish the hospitalization and death rate as distribution and accessibility increases over the coming months.

 

Conclusion

While the pandemic outlook has been bleak over the past two months, there is much reason for optimism. As more of the population gets boosted, omicron subsides, natural immunity increases, and treatment options become more readily available, the worst may hopefully (and finally, *fingers crossed*) be behind us. Until the next variant at least…