CLINICAL MATTERS

Hindsight, they say, is always 20/20. It is easier to look back and point out things that should have been done once the event is over. The Covid-19 pandemic isn’t quite over since the World Health Organization (WHO) hasn’t said so, but now that we can breathe, it is always useful to take stock of what we have learned and what mistakes were made. As the first pandemic that played out in a hyperconnected society, there was so much misinformation that would go viral and was so difficult to correct. In addition, the science (along with the virus) was rapidly evolving leading to virulent attacks on scientists and doctors who were trying to make sense of the data and doing their best to respond. Here are five facts that are now much easier to understand as we review the latest data on Covid-19 three years after it arrived.

COVID-19 vaccines work. All of them.

One of the most contentious issues early in the pandemic is whether some Covid-19 vaccines worked better than others. The most frequently maligned vaccines were the Chinese-made ones. Part of the confusion came from many people misunderstanding the original intent of vaccines as defined by the WHO. At the start of the pandemic, the WHO set a minimum vaccine efficacy of 50 percent for preventing severe disease. The reasoning was that a vaccine that decreases severe disease by at least 50 percent will potentially save millions of lives and should be deployed as soon as possible. Sinovac, the first vaccine that became available in the Philippines, was shown to be 78 percent effective against moderate disease and 100 percent effective against severe disease in its initial clinical trials. This already hurdled the WHO’s minimum requirements and it subsequently received WHO prequalification and emergency use listing. It was only 51 percent effective in preventing symptomatic disease, which was never the WHO-specified endpoint. This initial finding was confounded by two things: the circulating variant in Brazil at the time of the trial was the Gamma variant, which is considered more transmissible and virulent; and the population tested was the highly exposed healthcare workers. Real-world studies involving over 10 million people eventually showed over 80 percent efficacy in preventing symptomatic disease and these confirmed the over 90 percent efficacy in preventing severe disease. Sinovac performed just as well, if not better, than the single dose Janssen vaccine. The wider antigen repertoire of inactivated vaccines may also increase protection against severe disease from different variants. Unfortunately, this data was compared head-to-head with the initial results from the mRNA vaccines. mRNA vaccines had similar efficacies against severe disease compared to inactivated vaccines. But these were also more than 90 percent effective in preventing symptomatic disease. This very high number against symptomatic disease came down to earth when the variants of concern emerged, but the mRNA vaccines did retain good efficacy against severe disease. Presently, the efficacy of all vaccines against severe disease remains high while efficacy against symptomatic disease is below 50 percent even for the mRNA vaccines against Omicron. Fortunately, updated bivalent boosters against Omicron seem to increase symptomatic disease protection. Most vaccine makers are now developing updated vaccines as Covid-19 further evolves. Interestingly, when the emergence of Omicron necessitated the use of boosters, some people ended up with heterologous (mixed vaccine types) vaccination. People who were vaccinated with a non-mRNA vaccine and subsequently received an mRNA booster showed more robust immune responses compared to those who got a homologous (same vaccine type) booster. Since many Filipinos had been vaccinated with inactivated vaccines and boosted with mRNA ones, this may have helped the Philippines do better than most Western countries when the variants of concern arrived.

Masks work.

I’ve tackled the evidence supporting this before in a previous column ([https://mb.com.ph/2023/01/31/masking-makes-sense/](https://mb.com.ph/2023/01/31/masking-makes-sense/)). There are very clear prospective studies showing efficacy against Covid-19 transmission and acquisition of infection. There continues to be some contentious issues on how robust the evidence is, and a recent meta-analysis failed to show efficacy of masks when looking at combinations of studies, including different mask types against not just Covid-19 but also influenza and other respiratory viruses. Unfortunately, this negative study was misconstrued by many as proof that masks do not work when it only included very few studies on Covid-19 and did not consider adherence as an important confounder. A US CDC study has shown that both N95 respirators and surgical masks can reliably decrease the risk of Covid-19 provided they are worn correctly and consistently. Otherwise, the effect disappears due to the nature of the pathogen. While N95 respirators tended to have a higher degree of protection, the result was not statistically significant compared to surgical masks and this probably reflects the multifactorial nature of protection, including adherence to masking and levels of exposure. From a real-world standpoint, the continued use of masks in our country has kept our daily cases in the low hundreds compared to over tens of thousands of new cases in the US and other countries where masks are no longer regularly worn.

Remdesivir and nirmatrelvir/ritonavir (Paxlovid) work. Molnupiravir isn’t as good.

After initially recommending against the use of remdesivir, the WHO has quietly reversed course and now recommends the use of remdesivir for patients with severe Covid-19 and in mild to moderate Covid-19 patients who are at risk for progression to severe disease. The initial recommendation against the use of remdesivir was quite puzzling to many scientists, including those who review medical evidence on a regular basis. The US FDA initially granted Emergency Use Authorization to remdesivir early in the pandemic based on a randomized, placebo-controlled trial that clearly showed a decrease in recovery time among patients with severe Covid-19, albeit without a decrease in mortality. Nevertheless, this was seen as a positive outcome as people got out of the ICU and the hospital earlier. Unfortunately, the WHO panel only looked at mortality benefit, which neither this study nor the initial results of the WHO Solidarity trial showed. Compounding this was that most patients with severe Covid-19 were already receiving steroids, which had a clear mortality benefit and may have diluted remdesivir’s effect on the risk of death from Covid-19. When the WHO Solidarity trial was finally completed, it did show a small mortality benefit with remdesivir. This finding, coupled with new evidence that remdesivir decreases the risk of progression to severe Covid-19 leading to hospitalization by 87 percent in at risk populations led to WHO finally giving the greenlight to remdesivir as a proven treatment for Covid-19. Paxlovid, on the other hand, is only useful for patients with mild or moderate disease who are at risk for progression. It decreases the risk of progression of disease leading to hospitalization by 88 percent. Unlike remdesivir, it is not indicated for severe disease. The most recent data for molnupiravir indicates that it decreases risk of hospitalization in unvaccinated patients by 31 percent, but it has no effect on disease progression in vaccinated persons. For this reason, molnupiravir is recommended only as an alternative therapy when neither Paxlovid nor remdesivir is available.

Ivermectin is useless for prevention and treatment of Covid-19.

No drug for Covid-19 has courted as much controversy as ivermectin. Unfortunately, most of the studies that showed some sort of benefit with ivermectin were either flawed or outright spurious and made up. The most recent rigorous studies have all shown that ivermectin has no significant clinical effect against Covid-19 whether used as medicine for prevention, prophylaxis, or treatment. Ivermectin at the high doses prescribed by its proponents can cause significant side effects, and there is no benefit in continuing to take this drug for any Covid-19 indication.

Mass testing is not useful for decreasing Covid-19 transmission.

RT-PCR has always been a difficult test to use. It is expensive, difficult to scale, and does not distinguish current from past infection. When governments started to use RT-PCR for disease screening, most scientists were concerned that it was not sustainable. When different groups started demanding indiscriminate mass testing, we were horrified that emergent newly infected cases would be missed while people who had already recovered would still be flagged as positive. This did happen. The best use of RT-PCR is for targeted testing to guide Covid-19 management. Compelling evidence has shown that the potential impact of mass RT-PCR testing on transmission is less than five percent, due to the long turn-around time and imperfect characteristics of the test. Antibody tests (as opposed to antigen tests, which can be helpful when used properly) were even more useless, since most people infected with Covid-19 do not show positive Ig and IgG until at least the seventh day of illness and most only turn positive on the 14th day when they are no longer contagious. The DOH refused to procure rapid antibody tests precisely because HTAC