With influenza season under way, primary care physicians may be seeing more patients with serious symptoms who could potentially benefit from antiviral treatment. However, a recent analysis raises questions about the relative benefits versus risks of oseltamivir phosphate (Tamiflu)—the most commonly prescribed antiviral. How should physicians proceed?
“The study identified 15 different randomized controlled trials and found no reduced risk of hospitalization in all groups, which came as a bit of a surprise to most of us,” said Gregory Poland, MD, MACP, professor of medicine and head of the Vaccine Research Group at Mayo Clinic in Rochester, Minn. “It calls into question the utility of prescribing a medication like oseltamivir, particularly in low-risk people.”
The review, published June 12 in JAMA, included more than 6,000 patients with the flu in trials that compared oseltamivir to placebo or standard of care. Antiviral treatment was not associated with reduced risk of hospitalization compared with control, including in a subgroup of high-risk patients. Incidences of nausea and vomiting were higher in the oseltamivir group.
“Healthy, middle-aged adults comprise the bulk of the data, so we are most confident of the results in that population,” said the study's senior investigator, Emily McDonald, MD, MSc, of McGill University Health Centre in Montreal. “While we did include immune-suppressed older adults in a subgroup analysis, we have less confidence in those results because there were fewer participants overall.”
Based on the findings, an expert review of the data leading to oseltamivir's approval is needed, said Dr. Poland. In the meantime, oseltamivir remains the best option for patients at high risk of hospitalization, such as those with serious chronic conditions.
“Oseltamivir is not expensive and the risk of taking it is relatively low,” he said. “It's worth suggesting to patients at high risk of complications.”
Flu, RSV, or COVID-19?
As flu season progresses, experts stress the importance of promoting vaccines as the best way to avoid serious illness. The CDC currently recommends annual flu vaccination for all adults starting in September and October and throughout the season as long as viruses are circulating, typically until early spring. Adjuvanted or high-dose vaccines are recommended for those ages 65 years and older.
“The No. 1 tool we have is the vaccine, especially more advanced formulations of vaccine for older or high-risk patients,” said Amesh Adalja, MD, FACP, senior scholar at Johns Hopkins Center for Health Security in Baltimore. “We need to make sure we get the right vaccines to the right people.”
Before treatment, experts said patients should be tested to determine whether their symptoms stem from influenza versus respiratory syncytial virus (RSV) or SARS-CoV-2. An at-home diagnostic test can be used as a first step. Earlier this year, the FDA issued an emergency use authorization for the first over-the-counter test capable of differentiating between the flu and SARS-CoV-2. Similar to existing COVID-19 test kits, the Lucira COVID-19 & Flu Home Test works by analyzing a nasal swab sample, with results available in less than 30 minutes.
According to the FDA, the Lucira test demonstrates very high accuracy in ruling out disease. In people with symptoms, the home test correctly identified 99% of negative and 90% of positive influenza A samples and 100% of negative and 88.3% of positive COVID-19 samples.
“At-home testing is the wave of the future,” said Dr. Adalja, who noted that he has received honoraria from Pfizer and is a member of the speaker's bureau for GlaxoSmithKline. “It speeds diagnosis, links people to correct treatments, and avoids unnecessary treatment and visits to physician offices and the ED.”
However, patients have so far been slow to use home testing, said Gopi Patel, MD, professor of medicine and medical director of the Antimicrobial Stewardship Program at the Icahn School of Medicine at Mount Sinai in New York, N.Y.
“We are unfortunately seeing some testing avoidance, likely due to the ramifications of a positive test for mild symptoms in terms of absence from work or school or missing events,” she said. “There are several other circulating respiratory viruses that also can account for respiratory symptoms, so testing for COVID-19 and flu at home is helpful.”
Keep in mind that a negative test may not mean someone isn't infectious, added Dr. Patel. In the presence of flu-like symptoms, people should still exercise caution to avoid putting a child, coworker, or immunocompromised adult at risk for a serious infection.
It's not usually necessary for healthy adults to see their physician following a home test, said Sean Liu, MD, PhD, assistant professor of medicine and microbiology and director of the COVID-19 clinical trials unit at Mount Sinai. However, those with complicated medical histories or those who are immunocompromised may consider an in-person visit.
Virtual visits are a good option for follow-up care and have the added benefit of limiting the spread of disease, he said. Many patients became comfortable with telehealth during the pandemic and may prefer this form of care.
In-person visits are sometimes recommended for older patients or those at higher risk of complications, said Mana Rao, MD, FACP, director of infection control at Archcare, a continuing care facility in Saddle River, N.J. Negative test results may indicate something else is causing symptoms, while a positive result may require an in-person exam and a prescription for antivirals, depending on severity of symptoms.
“My preference is to see patients in person so I can listen to their lungs and look at their sinuses to check for infection,” said Dr. Rao. “However, it depends on personal preference; some patients prefer to ride it out at home.”
Currently, oseltamivir is the only antiviral approved for early treatment of flu that is available in a generic version. Other options recommended by the CDC include zanamivir (Relenza), peramivir (Rapivab), and baloxavir marboxil (Xofluza).
The drugs have various modes of administration, and some are not recommended for use in certain patient groups. For example, zanamivir is given with an inhaler device and should not be used by people with chronic breathing issues, such as asthma. Like oseltamivir, it is taken twice daily for five days.
Peramivir is an intravenous medication typically reserved for critically ill hospitalized patients. Baloxavir, a newer option that comes in a single-dose pill, is approved for relatively healthy adults but is still being tested in certain populations, including pregnant people and those with complicated illnesses.
Oseltamivir, taken as a pill or liquid suspension twice a day for five days, is considered most effective if given within 48 hours of flu onset and can potentially shorten the duration of symptoms by up to 24 hours, according to the CDC. However, findings from the recent JAMA study raise doubts about whether oseltamivir should be promoted as a way to prevent hospitalization in low-risk patients.
Many people may have a general impression that taking oseltamivir within the treatment window could be helpful while not causing any harm, said Dr. McDonald. However, the JAMA analysis suggests that the risk of side effects may be greater than the potential for avoiding complications from the virus.
“If my 45-year-old brother who's generally healthy had the flu, I would tell him that it's unlikely oseltamivir will make a difference in the course of his illness,” said Dr. McDonald. “If he rests and drinks lots of fluids, he will likely get better on his own, but if he takes the medication, he may experience nausea and vomiting and may not feel better any sooner.”
In the absence of an antiviral option, patients may request antibiotics, said Dr. Liu. Physicians should be prepared to explain why antibiotics aren't effective against viruses and that they should only be prescribed if a patient has a concurrent bacterial infection.
“It's important to educate patients about why antibiotics are not being prescribed—not only do they not treat viral infections but they can also cause harm,” he said. “Inappropriate prescribing has been associated with bacterial resistance and side effects.”
Nationally, there is an increase in macrolide-resistant pneumococcus, which makes bacterial pneumonias difficult to treat, he added. Although bacterial infections following influenza or viral infections can happen, pre-emptive prescribing is not recommended.
Instead of sending low-risk patients away with nothing, Dr. McDonald suggests writing a “prescription” for managing symptoms at home. For example, the nonprofit organization Choosing Wisely has a free downloadable Antiviral Prescription Pad that allows physicians to check off an appropriate diagnosis and recommended home treatment for flu and other viral infections.
Patients managing their illness at home should be counseled about warning signs that might indicate development of secondary bacterial pneumonia, experts said. Symptoms such as shortness of breath, coughing up discolored sputum, dizziness, or low urine production warrant either consulting a physician or visiting the ED, depending on severity.
“If someone feels better after a couple of days, then gets worse, with fever and cough returning, they should see their doctor to diagnose a possible secondary bacterial infection,” said Dr. McDonald. “If it's been three to five days and they still feel very unwell and have shortness of breath and feel very dehydrated, they should visit the ED for immediate medical attention.”
Treating high-risk patients
The JAMA study highlights an important gap in the available data on oseltamivir, said Dr. Poland. Older patients and those at higher risk of complications are poorly represented in studies conducted by industry sponsors, which have an obvious conflict of interest and may seek to exclude participants for whom they believe efficacy may not be very high.
In the meta-analysis, the overall patient pool was relatively young, with a mean age of 45.3 years, and the rate of hospitalization was very low across all studies, 0.6%, regardless of whether patients took oseltamivir. In addition, the subgroup analysis of higher-risk patients showed a significantly lower relative risk of hospitalization in industry- vs. non-industry-sponsored studies (0.50 vs. 1.32, respectively).
Conclusive data on older, high-risk populations may be difficult to acquire, however, the JAMA authors noted. To be sufficiently powered, such a trial would require more than 15,000 participants, which would only be possible during an epidemic or pandemic year.
Future studies should also look at other end points in high-risk populations, such as mortality, length-of-stay, and ICU admissions, said Dr. Adalja. The JAMA study looked only at hospitalization rates, leaving it unclear whether oseltamivir reduces deaths or the need for mechanical ventilation.
In the meantime, oseltamivir remains a reasonable option for older patients or those with other risk factors, said Dr. Rao.
“I work in a long-term care facility with an extremely vulnerable patient population, mostly older than age 60,” she said. “I treat every case of flu with antivirals because I'm really worried about people progressing quickly and getting other infections. For high-risk patients, I don't anticipate making any practice changes.”
Currently, oseltamivir is the only viable option for treating flu in most patients with serious chronic conditions, agreed Dr. Poland.
“I've depended on this drug to decrease risk of hospitalization,” he said. “I will still give it to this group of patients pending a comprehensive expert review suggesting otherwise.”