Clinical Scenario:

22 y/o F, with a history of hypothyroidism, presents to an Urgent Care c/o fatigue, myalgia, fever of 103, sore throat and cough for 2.5 days. Patient had a positive flu swab at the clinic and was sent home with Tamiflu.

Clinical Question:

Is the administration of Oseltamivir (Tamiflu) after 48 hours of symptom onset effective in reducing an average-risk patient’s symptoms?

PICO:

P: Influenza patient, flu patient, over 48 hours of symptoms, outpatient

I: Tamiflu, Oseltamivir, Antiviral, flu medication, late treatment

C: no treatment, placebo

O: effective, duration, symptom relief, severity

Search Strategy:

PubMed:

Tamiflu effectiveness for symptoms after 48 hours (Any time) – 617

Tamiflu effectiveness for symptoms after 48 hours (5 years publication date) – 260

Tamiflu impact after 48 hours (Any time) – 462

Tamiflu impact after 48 hours (5 years publication date) – 204

Google Scholar:

Tamiflu effectiveness for symptoms after 48 hours (Any time, sort by relevance) – 5,510

Tamiflu effectiveness for symptoms after 48 hours (2015-2020, sort by relevance) – 1,650

Tamiflu effectiveness for flu symptoms after 48 hours (Any time, sort by relevance) – 5,180

Tamiflu effectiveness for flu symptoms after 48 hours (Any time, sort by relevance) – 1,520

Science Direct:

Tamiflu effectiveness after 48 hours (Any time) – 129

Tamiflu effectiveness after 48 hours (5 years publication date) – 41

I selected my final articles from those within 5 years of publication for the most recent data and research available. Upon reviewing multiple articles, I also tried to use articles most relevant to the clinical question as a whole and to the patient population.

Articles Chosen for Inclusion:

Article 1:

• McLean HQ, Belongia EA, Kieke BA, Meece JK, Fry AM. Impact of Late Oseltamivir Treatment on Influenza Symptoms in the Outpatient Setting: Results of a Randomized Trial. Open Forum Infect Dis. 2015;2(3):ofv100. Published 2015 Jul 8. doi:10.1093/ofid/ofv100
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525010/
• Abstract
  • We conducted a double-blind, randomized trial of 134 outpatients with polymerase chain reaction-confirmed influenza to assess the effects of oseltamivir initiated 48–119 hours after illness onset. Oseltamivir treatment did not reduce illness duration, severity, or duration of virus detection. However, the power of this study was limited due to lower than expected enrollment.We conducted a double-blind, randomized trial of 134 outpatients with polymerase chain reaction-confirmed influenza to assess the effects of oseltamivir initiated 48–119 hours after illness onset. Oseltamivir treatment did not reduce illness duration, severity, or duration of virus detection. However, the power of this study was limited due to lower than expected enrollment.Keywords:influenza, oseltamivir Neuraminidase inhibitors (e.g., oseltamivir) will be an important countermeasure prior to vaccine availability during a pandemic. Most studies suggest that oseltamivir is most effective if initiated <48 hours after illness onset; early treatment mitigates severity and reduces illness duration by 1–3 days [1–5]. Drug delivery logistics will be challenging during a pandemic; initiating treatment <48 hours may not be possible. We conducted a double-blind, randomized, placebo-controlled trial during 4 influenza seasons: 2007–2008 through 2010–2011 to assess duration of influenza symptoms and viral shedding in outpatients who initiated late oseltamivir therapy (48–119 hours after illness onset). Currently, antiviral treatment is recommended as early as possible for any patient with confirmed or suspected influenza who is hospitalized or at higher risk for influenza complications [6].

Article 2:

• Lehnert R, Pletz M, Reuss A, Schaberg T. Antiviral Medications in Seasonal and Pandemic Influenza. Dtsch Arztebl Int. 2016;113(47):799–807. doi:10.3238/arztebl.2016.0799
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240024/
• Abstract
  • Background: Amantadine, oseltamivir, and zanamivir are currently available in Germany for the prevention and treatment of influenza. We review their efficacy and side-effect profiles.
  • Methods: This review is based on pertinent randomized and controlled trials (RCTs) and systematic reviews retrieved by a systematic literature search, and on other relevant literature.
  • Results: The efficacy of antiviral drugs for the prevention of symptomatic influenza ranges from 60% to 90% (number needed to treat [NNT], 8–89) depending on the population and type of drug in question. Antiviral drugs shorten the duration of illness by 0.5–1.5 days when given within 48 hours of the onset of symptoms. Neuraminidase inhibitors do not significantly lower the incidence of bronchitis in adults, or of otitis media in children; they do have a positive effect against reported, but not necessarily diagnostically confirmed pneumonia in adults (NNT, 89 [50–232]). The RCTs yielded no information about possible effects on severe cases of influenza, or on mortality, as they included only mildly or moderately ill patients, but observational studies have yielded some evidence of benefit. The most common side effects of oseltamivir (>10%) are headache, nausea, and vomiting; of zanamivir (>1%), a skin rash; and of amantadine (>1%), loss of appetite, nausea, and central nervous effects.
  • Conclusion: The benefits of antiviral drugs, particularly neuraminidase inhibitors, outweigh their risks. In deciding whether to use them, physicians should consider the properties of the currently circulating viruses and the patient’s individual risk constellation, as directed in clinical treatment recommendations.

Article 3:

• Fry, Alicia M., et al. “Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomized placebo-controlled trial.” The Lancet infectious diseases 14.2 (2014): 109-118.
• https://www.sciencedirect.com/science/article/pii/S1473309913702676
• Abstract:
  • Background: Influenza causes substantial morbidity and mortality worldwide. Few data exist for the efficacy of neuraminidase inhibitors, which are the only readily available influenza treatment options, especially in low-income settings. We assessed the efficacy of treatment with the neuraminidase inhibitor oseltamivir to reduce patient illness and viral shedding in people with influenza, in whom treatment was started within 5 days of symptom onset, in an urban setting in Bangladesh.
  • Methods: We undertook a double-blind, randomized, controlled trial between May, 2008, and December, 2010. Patients with a positive rapid influenza test identified by surveillance of households in Kamalapur, Bangladesh were randomly allocated on a 1:1 basis to receive oseltamivir or placebo twice daily for 5 days. Randomization lists for individuals enrolled less than 48 h and 48 h or longer since illness onset were generated with permuted blocks of variable length between two and eight. Participants and study staff were masked to treatment group. Participants provided nasal wash specimens at enrolment and 2, 4, and 7 days later, and were visited daily to record symptoms. All specimens were tested for influenza with reverse-transcriptase PCR, and if the result was positive, we isolated the virus. The primary endpoints were duration of clinical illness and viral shedding in patients treated less than and more than 48 h since illness onset and the frequency of oseltamivir resistance during treatment. Analyses were intention to treat unless otherwise specified. This trial is registered with ClinicalTrials.gov, number NCT00707941.
  • Interpretation: Oseltamivir treatment resulted in a modest reduction in the duration of symptoms and virus shedding in people with uncomplicated influenza infections, even when treatment was started 48 h or longer after illness onset.

Article 4:

• Dobson, Joanna, et al. “Oseltamivir treatment for influenza in adults: a meta-analysis of randomized controlled trials.” The Lancet 385.9979 (2015): 1729-1737.
• https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62449-1/fulltext
• Abstract:
  • Background: Despite widespread use, questions remain about the efficacy of oseltamivir in the treatment of influenza. We aimed to do an individual patient data meta-analysis for all clinical trials comparing oseltamivir with placebo for treatment of seasonal influenza in adults regarding symptom alleviation, complications, and safety.
  • Methods: We included all published and unpublished Roche-sponsored randomized placebo-controlled, double-blind trials of 75 mg twice a day oseltamivir in adults. Trials of oseltamivir for treatment of naturally occurring influenza-like illness in adults reporting at least one of the study outcomes were eligible. We also searched Medline, PubMed, Embase, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov trials register for other relevant trials published before Jan 1, 2014 (search last updated on Nov 27, 2014). We analyzed intention-to-treat infected, intention-to-treat, and safety populations. The primary outcome was time to alleviation of all symptoms analyzed with accelerated failure time methods. We used risk ratios and Mantel-Haenszel methods to work out complications, admittances to hospital, and safety outcomes.
  • Findings: We included data from nine trials including 4328 patients. In the intention-to-treat infected population, we noted a 21% shorter time to alleviation of all symptoms for oseltamivir versus placebo recipients (time ratio 0·79, 95% CI 0·74–0·85; p <0·0001). The median times to alleviation were 97·5 h for oseltamivir and 122·7 h for placebo groups (difference −25·2 h, 95% CI −36·2 to −16·0). For the intention-to-treat population, the estimated treatment effect was attenuated (time ratio 0·85) but remained highly significant (median difference −17·8 h). In the intention-to-treat infected population, we noted fewer lower respiratory tract complications requiring antibiotics more than 48 h after randomization (risk ratio [RR] 0·56, 95% CI 0·42–0·75; p=0·0001; 4·9% oseltamivir vs 8·7% placebo, risk difference −3·8%, 95% CI −5·0 to −2·2) and also fewer admittances to hospital for any cause (RR 0·37, 95% CI 0·17–0·81; p=0·013; 0·6% oseltamivir, 1·7% placebo, risk difference −1·1%, 95% CI −1·4 to −0·3). Regarding safety, oseltamivir increased the risk of nausea (RR 1·60, 95% CI 1·29–1·99; p<0·0001; 9·9% oseltamivir vs 6·2% placebo, risk difference 3·7%, 95% CI 1·8–6·1) and vomiting (RR 2·43, 95% CI 1·83–3·23; p<0·0001; 8·0% oseltamivir vs 3·3% placebo, risk difference 4·7%, 95% CI 2·7–7·3). We recorded no effect on neurological or psychiatric disorders or serious adverse events.
  • Interpretation: Our findings show that oseltamivir in adults with influenza accelerates time to clinical symptom alleviation, reduces risk of lower respiratory tract complications, and admittance to hospital, but increases the occurrence of nausea and vomiting.

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc.)	Outcome(s) studied	Key Findings	Limitations and Biases
McLean et al., 2015   Impact of Late Oseltamivir Treatment on Influenza Symptoms in the Outpatient Setting: Results of a Randomized Trial	Double-blind Randomized Controlled Trial	95 patients received Oseltamivir 48-119 hours after illness onset (late treatment). 39 received a placebo after 48-119 hours. 19 received treatment before 48 hours of illness onset (early treatment) and 12 received a placebo within 48 hours of onset. This study was randomized. Patient age ranged from 1 to 79 years old.	Reduction of symptoms with treatment. This was done through a symptom survey twice a day online or by telephone. Also looked at RT-PCR to determine viral detection after day three or four of starting treatment.	This study did not find a reduction of duration or severity of symptoms with treatment with Oseltamivir over 48 hours. Additionally, the study did not find that late treatment reduced RT-PCR positive results on day three or four after initiation of treatment.	Only evaluated uncomplicated influenza patients who presented to a clinic with flu-like symptoms, however this is relevant to the clinical question. The sample size was much smaller than originally anticipated due to multiple unforeseen events such as oseltamivir-resistant influenza viruses and funding cessation, which diminishes the potential effects of outliers and the overall results. Another factor to consider is that symptom severity rating is subjective.
Lehnert et al., 2016   Antiviral Medications in Seasonal and Pandemic Influenza	Systematic Review	13 systematic reviews/meta-analyses of randomized controlled trials, 6 randomized controlled trials and one review of systematic reviews through databases such as Cochrane Library and PubMed.	Reviewed multiple questions such as: Does timing of administration play a role in efficacy, effectiveness of antivirals prophylactically, antivirals role in disease severity, duration and ability to affect viral shedding.	Three studies found shorter or milder influenza symptoms even when Oseltamivir therapy was started after 48 hours of onset. One randomized controlled trial exhibited a 43 hour decrease in symptom duration if taken within 24 hours of influenza symptoms onset. Other key findings included one meta-analysis that found a significant reduction in pneumonia cases in adult patients with no comorbidities taking Oseltamivir.	The studies reviewed in this article have a publication date no later than 2015. However, this means that much of that data is likely to be several years older. Additionally, this study notes that many of the studies or analyses included were funded by pharmaceutical companies, which introduces bias. Only mild to moderate severity patients were included.
Fry et al., 2014   Efficacy of Oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomized placebo-controlled trial	Double Blind Randomized Placebo-Controlled Study	1,190 patients with 794 less than 48-hour symptom onset and 396 with 48 to 120 hours since symptom onset. 396 from the former group received a placebo and 398 Oseltamivir. Of the latter group, 196 received a placebo and 200 Oseltamivir. While a majority of the participants were 1-4 years old, there were participants 18+ years of age.	Symptom reduction with treatment less than and more than 48 hours after symptom onset. Virus detection via PCR on multiple days (2, 4 and 7) after treatment initiation.	Treatment with Oseltamivir on day 3 after illness onset reduced illness by one day in comparison to the placebo group.  Similarly, treatment for patients with symptom onset less than 48 hours also had a symptom reduction of one day in comparison to its placebo. Oseltamivir reduced viral shedding, even when administered after 48 hours of illness onset.	This study was published in 2014, outside of the typical 5-year parameter, however it was included because of its relevance to the clinical question. Additionally, this study was more focused on children than adults and in a low-income community in Bangladesh. The study also notes a limitation in only recording fever once a day.
Dobson et al., 2015   Oseltamivir treatment for influenza in adults: a meta-analysis of randomized controlled trials	Meta-analysis of randomized controlled trials	Nine trials of double-blind randomized placebo-controlled studies in which adult patients received Oseltamivir 75mg twice a day. A total of 4,328 patients across the nine trials.	Length of time to alleviation of symptoms when treated with Oseltamivir. Meta-analysis allowed for the study of side effects and prevention of influenza complications as well.	Oseltamivir decreased symptom duration by about one day in adults with influenza as well as decreased respiratory complications and hospital admission. There was an increase in incidence of nausea and vomiting in adults who took Oseltamivir.	Only looked at published and unpublished Roche-sponsored trials. Did not directly analyze the use of Oseltamivir after 48 hours of symptom onset.

Conclusion:

Alleviation of symptoms as well as influenza complications was found to decrease with adults treated with Oseltamivir, however this does not directly identify treatment onset date (Dobson et al., 2015). Reduction of influenza symptoms were not found in patients treated with Oseltamivir after 48 hours and did not decrease viral shedding or RT-PCR after late treatment (McLean et al., 2015). A systematic review from Lehnert et al. (2016) did find multiple studies exhibiting severity and duration decrease with Tamiflu treatment initiation after 48 hours and Fry et al. (2014) found a mild reduction in illness duration in those treated after three days of influenza onset. Therefore, Oseltamivir effectiveness upon administration after 48 hours of symptom onset remains inconclusive, however studies have shown mild reduction in symptom duration and severity when treated after 48 hours of illness onset.

Clinical Bottom Line:

According to the CDC, antiviral treatment for influenza should be started within 48 hours of illness onset. However, it does mention that treatment after 48 hours may provide benefit for certain individuals but does not specify the population. The clinical bottom line derived from the above articles is that while there is still variation in Oseltamivir effectiveness after 48 hours, data supports that such treatment is efficacious in mildly reducing symptoms and potentially infectiousness even after being administered greater than 48 hours from onset, especially in uncomplicated patients.  Without the use of this treatment, patient suffering can be extended as antivirals have the potential to reduce symptoms, and if such prolonged symptoms create additional outpatient or emergency department visits, additional benefits of treatment should be considered. In addition, side effects of Tamiflu such as nausea and vomiting must be considered, evaluated on a risk-benefit foundation and discussed with the patient prior to prescribing.

References:

Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases. Influenza Antiviral Medications: Summary for Clinicians. 2020. https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm

Dobson, Joanna, et al. “Oseltamivir treatment for influenza in adults: a meta-analysis of randomized controlled trials.” The Lancet 385.9979 (2015): 1729-1737.

Fry, Alicia M., et al. “Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomized placebo-controlled trial.” The Lancet infectious diseases 14.2 (2014): 109-118.

Lehnert R, Pletz M, Reuss A, Schaberg T. Antiviral Medications in Seasonal and Pandemic Influenza. Dtsch Arztebl Int. 2016;113(47):799–807. doi:10.3238/arztebl.2016.0799

McLean HQ, Belongia EA, Kieke BA, Meece JK, Fry AM. Impact of Late Oseltamivir Treatment on Influenza Symptoms in the Outpatient Setting: Results of a Randomized Trial. Open Forum Infect Dis. 2015;2(3):ofv100. Published 2015 Jul 8. doi:10.1093/ofid/ofv100