In a study conducted by Stanford Medicine investigators and their colleagues, it was found that Paxlovid, an antiviral drug combination targeting SARS-CoV-2, the virus that causes COVID-19, was safe for extended treatment but did not reduce specific symptoms of long COVID. This 15-day course of Paxlovid did not show benefits for long-COVID patients, but further research could explore different doses or effects on people with specific symptoms. The persistence or reappearance of COVID-related symptoms three months after initial infection was not improved by Paxlovid in this single-center study.
The results will be published in a paper on June 7 in JAMA Internal Medicine. Paxlovid is an effective antiviral drug approved for treating acute COVID-19. It is authorized by the Food and Drug Administration for use in adults who have recently contracted SARS-CoV-2, experience mild or moderate COVID symptoms, and are at high risk of complications due to age or underlying conditions. A five-day Paxlovid treatment has been proven to decrease the chances of hospitalization and death by over 85%.The Stanford trial found that while Paxlovid did not reduce long COVID symptoms, it was shown to be safe for use for more than two weeks. “We’ve demonstrated the overall safety of a 15-day course of Paxlovid — that’s three times as long as it’s being taken for acute COVID,” said Linda Geng, MD, PhD, clinical associate professor of primary care and population health, who was one of the trial’s co-principal investigators. Geng is the lead author of the paper, while the trial’s other co-principal investigator, Upinder Singh, MD, is the senior author. Singh is a professor and chief of infectious disease and geographic medicine and of microbiology.
Desperate people: “Although there are now improved therapies and treatment practices for acute COVID, there’s nothing FDA-approved for long COVID, people continue to suffer and the numbers keep piling up,” Geng said.
An estimated 10% to 20% of SARS-CoV-2-infected people — tens of millions in the United States alone — develop long COVID. That estimate is fuzzy, because the definition of long COVID is ambiguous. More than 200 separate symptoms have been ascribed to the syndrome. These symptoms are often shared by other conditions, making a definitive diagnosis challenging to define long COVID. It might be a combination of various illnesses triggered by acute COVID, each with different underlying mechanisms and effects, and therefore requiring different approaches for relief.
There are several potential causes of long COVID. These include changes in our gut bacteria caused by the virus, lingering inflammation, COVID-induced autoimmune reactions, and the activation of other dormant viruses that have integrated into our genes and lay dormant until our immune systems are preoccupied or weakened by SARS-CoV-2.An experimental phase 2 trial called STOP-PASC, which stands for Selective Trial of Paxlovid for Post-Acute Sequelae of COVID, or long COVID, was conducted to test the effectiveness of Paxlovid treatment. This trial is the first of its kind and was designed to investigate the viral-reservoir hypothesis of long COVID. This hypothesis suggests that even after the initial symptoms have subsided and viral counts have decreased, the virus or viral remnants may still be present in deep tissues, potentially replicating slowly. Some research indicates that viral particles and molecular debris may still be present.Singh stated that they believed Paxlovid might help relieve the ongoing symptoms experienced by long-COVID patients. Anecdotal reports have suggested that Paxlovid may provide relief for these symptoms, with patients at Stanford’s long-COVID clinic showing improvement after taking Paxlovid for new infections. Between November 2022 and September 2023, 155 trial participants who tested positive for SARS-CoV-2 were enrolled and followed by Geng, Singh, and their colleagues. All but two of the participants had been vaccinated.The demographic makeup of the participants in the study broadly represented the ethnic diversity of the San Francisco Bay Area. Their average age was 43, with approximately two-thirds falling between the ages of 34 and 54.
On average, the participants had been infected for over 16 months prior to joining the trial. Despite this, each participant reported experiencing moderate to severe cases of at least two of the six common “core” long-COVID symptoms, which included fatigue, brain fog, shortness of breath, body aches, and cardiovascular or gastrointestinal symptoms.
Half of the participants were randomly assigned to a 15-day treatment with Paxlovid, while the other half received a placebo.The combination drug Paxlovid includes low doses of two separate drugs. Both drugs are antiviral agents, but only one, nirmatrelvir, has been found effective against SARS-CoV-2. The other drug, ritonavir, does not directly fight the virus, but it does bind to certain liver enzymes that break down nirmatrelvir, increasing the concentration of nirmatrelvir in the body.
Ritonavir was added to the placebo formulation to make it difficult for recipients to distinguish between the placebo and the actual drug, as it can cause a distinct metallic taste in the mouth.The study involved switching some participants from the placebo to the active drug, and vice versa. Midway through the study, the data was sent to an independent group for initial analysis. The researchers found that there were no safety issues, but no clear benefits were observed, so they continued the trial but stopped enrolling new participants. At the 10-week mark, which was the scheduled time for the final comparison, there was no significant difference between the two groups in terms of the primary endpoint: a reduction in the severity of the six core symptoms. There were also no noticeable differences in various secondary outcomes such as seated and stand will maintaining blood pressure and heart rates, as well as performance on the one-minute “sit and stand” test (participants are instructed to sit in a chair, stand up and sit down repeatedly as quickly as possible for a minute).
The 15-day medication plan was found to be safe. There was one severe adverse event (hepatitis) possibly related to the trial among the placebo recipients, while the three cases of severe adverse events experienced by those taking Paxlovid (blood loss anemia, forearm fracture, and melanoma) were determined to be unrelated to the drug treatment.
“Our results suggest that Paxlovid can be safely administered for a longer period of time.”
During the recent trial, it was observed that there was no clinical response, but this does not necessarily mean that Paxlovid cannot reduce long-COVID symptoms in certain individuals.
Dr. Singh highlighted the need to address several unanswered questions such as the appropriate timing to begin treatment, the duration of treatment, and whether the right patients were included in the trial. These factors need to be further examined to determine the effectiveness of Paxlovid. For instance, it is possible that only specific symptoms may respond positively to the treatment.
Long COVID may not have a one-size-fits-all treatment, which means that different clusters of symptoms may require different approaches.
Testing for hidden SARS-CoV-2 in participants before or after treatment was not feasible due to the lack of simple, noninvasive, and affordable tests, according to Singh.
Interestingly, both the intervention and placebo groups showed overall symptom improvement during the study, which could be a positive outcome.
So, the lack of a universally effective antiviral treatment makes it a challenging condition to manage.
The article discusses the potential for a placebo effect in the treatment of long-COVID symptoms. It explains that the extra attention and care from healthcare providers, along with the hope of relief from medication, may lead to subjective or even objective improvement in patients. Additionally, the lack of validated objective biomarkers makes it challenging to measure the extent of improvement in individuals. The article also mentions the use of chemical tests, immunological tests, and wearable measurements to monitor the progress of patients.Stanford Medicine team is conducting a trial to determine the varying benefits of Paxlovid for different individuals. They aim to identify who may benefit more from the drug and how to distinguish them before treatment or participation in future trials. Singh stated that they expect to analyze the results in four to six months, which could influence ongoing and upcoming clinical trials for Paxlovid and other medications designed to alleviate long-COVID symptoms. These trials are funded by the National Institutes of Health and Pfizer, Inc., the developer, manufacturer, and marketer of Paxlovid. Kaiser researchers are also involved in the study.Permanente North California and Pfizer collaborated on the project. The study was financially supported by Pfizer.
