PICO Search Assignment Worksheet Name: Lucas Cavalier
Brief description of patient problem/setting (summarize the case very briefly)
13 y/o female presenting to urgent care with flu like symptoms for 6 days was previously treated for positive influenza A with Tamiflu. At the request of the patient’s mother another rapid influenza test was obtained and influenza A was positive. The mother of the child is requesting Baloxavir marboxil (Xofluza).
Search Question: Clearly state the question (including outcomes or criteria to be tracked)
What is the effectiveness of Baloxavir marboxil (Xofluza) in a pediatric patient with Tamiflu- resistant influenza A?
Question Type: What kind of question is this? (boxes now checkable in Word)
☐Prevalence ☐Screening ☐Diagnosis
☒Prognosis ☒Treatment ☐Harms
Assuming that the highest level of evidence to answer your question will be meta-analysis or systematic review, what other types of study might you include if these are not available (or if there is a much more current study of another type)?
Please explain your choices.
I found meta-analysis, randomized control trials and reviews on the use of Baloxavir marboxil. There is a limit to the number of systematic reviews, meta-analysis and RTCs for this medication because it is relatively new to the market. Another study that would be appropriate for this PICO would be a cohort study comparing Baloxavir marboxil to antiviral neuroamidase inhibitor. However because of Baloxavir marboxil being so new to market there are no current cohort studies.
PICO search terms:
| P | I | C | O |
| Influenza A | Oseltamivir | Baloxavir marboxil | Treatment |
| Influenza A Resistance | Tamiflu | Xofluza | Therapy |
| Influenza | Managment | ||
| Influenza adolescents | Adolescent outcome |
Search tools and strategy used:
PubMed
- Baloxavir marboxil 94
- Free Full Text 34
Cochrane
- Baloxavir marboxil 23 (trials only)
These articles were chosen because they directly answered my PICO question and had the best reflection of my clinical scenario. The articles that I chose included meta-analysis, randomized control trails comparing Baloxavir marboxil to placebo and a review of use of Baloxavir marboxil. All of these reports used mentioned resistant influenza cases.
Results found:
| Citation:
1) Hayden F.G et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. The New England Journal of Medicine. Vol 379 no. 10. September, 2018. Doi: 10.1056/NEJMoa1716197 https://www.nejm.org/doi/pdf/10.1056/NEJMoa1716197?articleTools=true |
| Article Type:
Randomized Control Trial |
| Abstract
BACKGROUND Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents. We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016–2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population. RESULTS In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively. CONCLUSIONS Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1 ClinicalTrials.gov number, NCT02954354.)
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| Citation:
2) Taieb, V., Ikeoka, H., Ma, F., Borkowska, S.A., Tone, K., & Hirotsu, N. A network meta-analysis of the efficacy and safety of baloxavir marboxil versus neuratransmindase inhibitors for the treatment of influenza in otherwise healthy patients. Apr 2019. Current Medical Research and Opinion. Doi: 10.1080/03007995.2019.1584505. https://www.tandfonline.com/doi/full/10.1080/03007995.2019.1584505
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| Article Type:
Meta Analysis |
| Abstract
OBJECTIVE: Baloxavir marboxil (baloxavir) is the first cap-dependent endonuclease inhibitor being studied for the treatment of influenza in single oral dosing regimen. This network meta-analysis (NMA) evaluated the efficacy and safety of baloxavir compared to other antivirals for influenza in otherwise healthy patients. METHODS: A systematic literature review was performed on 14 November 2016 in Medline, Embase, CENTRAL, and ICHUSHI to identify randomized controlled trials assessing antivirals for influenza. A NMA including 22 trials was performed to compare the efficacy and safety of baloxavir with other antivirals. RESULTS: The time to alleviation of all symptoms was significantly shorter for baloxavir compared to zanamivir (difference in median time 19.96 h; 95% CrI [3.23, 39.07]). The time to cessation of viral shedding was significantly shorter for baloxavir than zanamivir and oseltamivir (47.00 h; 95% CrI [28.18, 73.86] and 56.03 h [33.74, 87.86], respectively). The mean decline in virus titer from baseline to 24 h was significantly greater for baloxavir than for the other drugs. Other differences in efficacy outcomes were not significant. No significant differences were found between baloxavir and the other antivirals for safety, except total drug-related adverse events where baloxavir demonstrated a decrease compared to oseltamivir and laninamivir. CONCLUSIONS: The NMA suggests that baloxavir demonstrated better or similar efficacy results compared to other antivirals with a comparable safety profile. Baloxavir led to a significant decrease in viral titer versus zanamivir, oseltamivir and peramivir and decreased viral shedding versus zanamivir and oseltamivir. |
| Citation:
3) T. Yang. Baloxavir Marboxil. The First Cap-Dependent Endonuclease Inhibitor for the Treatment of Influenza. 2019. Annals of Pharmacotherapy. Doi: 10.1177/1060028019826565. https://journals.sagepub.com/doi/abs/10.1177/1060028019826565?rfr_dat=cr_pub%3Dpubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&journalCode=aopd
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| Article Type:
Review |
| Abstract:
OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trials, and clinical implications of baloxavir marboxil. DATA SOURCES: A MEDLINE search was conducted using the terms baloxavir, baloxavir marboxil, cap-dependent endonuclease inhibitor, and polymerase acidic endonuclease inhibitor. Additional data were obtained from the prescribing information and relevant guidelines. Study Selection and Data Extraction: All clinical trials were included. DATA SYNTHESIS: Baloxavir marboxil exploits a new mechanism of action of inhibiting cap-dependent endonuclease. Baloxavir was shown to be superior compared with placebo and noninferior compared with oseltamivir with regard to the primary end point. Baloxavir was well tolerated in the trials. A second phase III study investigating high-risk patients was completed with positive results. However, the full article is not yet published. Relevance to Patient Care and Clinical Practice: The small amount of literature limits baloxavir’s use in certain patient populations. Baloxavir offers advantages such as single-dose regimen, eliminating adherence concerns and lack of cross-resistance, making it an alternative for resistant viruses. Several uncertainties remain. Baloxavir has not been studied in hospitalized patients, patients with symptoms for >48 hours, or in combination with other antiviral agents. Furthermore, resistance to baloxavir can develop after 1 dose. Clinical studies are ongoing to evaluate baloxavir in young pediatric patients, hospitalized patients, and in combination therapy with neuraminidase inhibitors to further elucidate baloxavir’s place in therapy. CONCLUSION: Baloxavir is a new antiviral medication for the treatment of influenza. Given the new mechanism of action, baloxavir may be useful in treating patients with resistant viruses. |
| Citation:
4) Mifsud, E., Hayden, F., & Hurt, A. Antivirals targeting the polymerase complex of influenza viruses. 2019. Antivrial Research. 169. Doi: 10.1016/j.antiviral.2019.104545.
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| Article Type:
Review |
| Abstract:
Current influenza antivirals have limitations with regard to their effectiveness and the potential emergence of resistance. Encouragingly, several new compounds which inhibit the polymerase of influenza viruses have recently been shown to have enhanced pre-clinical and clinical effectiveness compared to the neuraminidase inhibitors, the mainstay of influenza antiviral therapy over the last two decades. In this review we focus on four compounds which inhibit polymerase function, baloxavir marboxil, favipiravir, pimodivir and AL-794 and discuss their clinical and virological effectiveness, their propensity to select for resistance and their potential for future combination therapy with the most commonly used neuraminidase inhibitor, oseltamivir. |
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 |
| Frederick G. Hayden, Norio Sugaya, Nobuo Hirotsu, Nelson Lee, Menno D. de Jong, Aeron C. Hurt, Tadashi Ishida, Hisakuni Sekino, Kota Yamada,., Simon Portsmouth, Keiko Kawaguchi, Takao Shishido, , Masatsugu Arai, Kenji Tsuchiya, M.., Takeki Uehara, Akira Watanabe.
(2018) |
Randomized Control Trial | sample of 1494 alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group | Alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir | Baloxavir marboxil is used for Influenza A &B as a single dose tablet
Baloxavir marboxil has shown promise in treating resistant influenza Phase 3 trial showed that Baloxamir marboxil shortened symptoms of influenza A patients by more than 26 hours. Baloxavir showed a greater reduction in viral load after 1 day versus placebo and oseltamivir. Report concluded that Baloxavir was less susceptible to influenza than others. No clinically significant side effects of Baloxavir marboxil. |
No limitations or biases noted or mentioned. |
| Taieb, V., Ikeoka, H., Ma, F., Borkowska, S.A., Tone, K., & Hirotsu, N
(2019) |
Meta Analysis | 22 trials was performed to compare the efficacy and safety of baloxavir with other antivirals.
|
Alleviation of all symptoms was significantly shorter for baloxavir compared to zanamivir (difference in median time 19.96 h; 95% CrI [3.23, 39.07]) | Compared baloxavir marboxil to other neruotransamidase inhibitors including laninamivir, zanamivir and oseltamivir.
Meta-anaylsis showed that baloxavir marboxil was superior in regards to virus titer levels. Baloxavir was found to be as efficacious or more compared to oseltamivir, peramivir, laninamivir and zanamivir, in terms of time to alleviation of all symptoms and viral shedding baloxavir in the reduction of individual influenza symptoms – cough, sore throat, headache, nasal symptoms, feverishness, muscle pain, fatigue and incidence of respiratory complications |
-One limitation of this analysis was that our analysis focused on otherwise healthy patients with confirmed influenza infection
Heterogeneity in the definition of outcomes between trials was another limitation.
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| T. Yang (2019) |
Review | phase I trial consisted of 2 studies; phase II and phase III
trials have been done to study the pharmacokinetics as well as the clinical efficacy and safety of baloxavir. |
recommend neuraminidase inhibitors or baloxavir
for the treatment of influenza Baloxavir marboxil is a newly approved antiviral drug for the treatment of uncomplicated influenza. Currently, baloxavir is the only medication in the new class of cap-dependent endonuclease inhibitors. Because of the lack of cross-resistance with other antiviral medications, baloxavir may be used as an alternative for the treatment of virus resistant to other medications |
Mechanism of action is different than neurotransamidase inhibitors by inhibiting cap-dependent endonuclease.
Advantage of Baloxavir is single dose regimen and lack of cross-resistance.
Baloxavir can be used as treatment for antiviral resistant influenza.
Further testing is needed for hospitalized patients, you pediatric patients and combination therapy. |
No limitations or biases noted or mentioned. this study. |
| Mifsud, E., Hayden, F., Hurt, A. | Review | 77 patients were used and the minimum age was 12. | Use of baloxavir significantly reduced viral load in patients with confirmed influenza
The use of the medication had a significantly less side effect profile with compared to neuramindase inhibitors. The mechanism of action is completely different than conventional anti-influenza medications. |
Prodrug that inhibits cap-dependent endonuclease activity of the PA protein of influenza A & B.
Baloxavir is indicated in patients older than the age of 12. Medications is well tolerated acroos multiple fields including adolescents, adults and complicated patients There is evidence that supports a lack of viral resistance to baloxavir and may be indicated in patients with neuramidase resistant influenza. |
No limitations or biases noted or mentioned. this study. |
Conclusions:
Hayden et al concluded that baloxavir marboxil was without evident safety concerns and was superior than the placebo for the treatment of influenza. Baloxavir marboxil was superior to other antiviral medications tested including oseltamivir and decreased viral load 1 day after initial dose in patients with uncomplicated influenza. Evidence also showed a decrease susceptibility to baloxavir after treatment.
Taieb et al. concluded that baloxavir provided better or similar efficacy results compared to other antivirals with a comparable safety profile. In addition, baloxavir showed significant decrease in viral titer versus zanamivir, oseltamivir and peramivire and demonstrated a better viral shedding outcome than oseltamivir and peramivire.
Yang concluded that the major change to the treatment of influenza would provide better patient outcomes. This is because baloxavir marboxil is a new cap-dependent endonuclease inhibitor and provides a new mechanism of action for the treatment of influenza. The use of this mediation attacks a different step in the replication of the influenza virus and focuses on viral replication.
Mifsud, Frederick and Hurt concluded that baloxavir effects the viral DNA of the influenza virus. Furthermore, Mifsud et al noted a major reduction in drug resistance for influenza. This fact makes since because it is a new drug that has a completely different mechanism of action compared to neuramidase inhibitors. The study continued to compare baloxavir to other anti-influenza mediations and noted that the viral shedding was significantly quicker than other medications or placebo.
My overall conclusion with the use of baloxavir marboxil is favorable for an alternative treatment of influenza. It is important to note that these studies performed testing in uncomplicated influenza patients and provided quality evidence when compared to placebo or other antiviral medications (neuraminidase inhibitors). Furthermore, the studies suggested the use of baloxavir marboxil for the use of oseltamivir resistant influenza, which is indicated in patients with recurrent influenza or contraindication use of neuraminidase inhibitors.
Clinical bottom line:
I will weigh my studies in the following order: Taieb et al, Hayden et al, Yang, and Mifsud.
Taieb et al article was weighed highest because it was the only article that was meta-analysis based on my research concerning baloxavir marboxil. The authors thorough described the research method used for the study and provided thorough exclusion and inclusion criteria that provide a more accurate analysis of baloxavir marboxil. Taieb et al compared baloxavir to other antiviral medications and used data points to give a better representation of how effective the medication was against influenza.
Hayden et al was weighed second because it was a randomized control trial involving baloxavir marboxil against placebo in a double blinded study. The patients involved were diagnosed with uncomplicated influenza. The RCT showed an alleviation of influenza like symptoms by 24 hours sooner than placebo group. The sample size was substantial for the trial (over 1000) and there was evidence of greater reductions in viral load 1 day after initial dose.
Yang’s article was a review that focused on the pharmacotherapy, clinical trials and clinical impplications of baloxavir marboxil. The article focused on the fact that baloxavir mechanism of action is different than standard neuraminidase inhibitors. The article further states that the use of baloxavir reduces symptoms of the flu by nearly 24 hours in 75% of cases.
Mifsud’s article focused on the mechanism of action and the proteins involved in the study. The author compared these specifics to other anti-influenza medications and showed a significant decrease in side effect profiles and a better results with viral shedding and length of symptoms.
Magnitude of any effects
I believe that with the research conducted and the fact that the medication is FDA approved baloxavir marboxil is an effective medication in reducing the symptoms of influenza. Furthermore, evidence points to the use of baloxavir marboxil being used in patient with neuraminidase inhibitor resistant influenza. The evidence supports that the viral shedding is significant when compared to other influenza treatment regimens. This is indicated because the mechanism of action is different with baloxavir than other anti-influenza medications.
Clinical Significance
Based on the findings in these articles it is evident that the use of baloxavir marboxil is indicated for influenza. However, more evidence is needed for the use of Tamiflu resistant influenza. The data in these articles do not directly point to the fact that baloxavir is effective against Tamiflu resistant influenza. I think that further testing needs to be completed to better understand the side effects and adverse effects of the medication especially in patients with complicated influenza. Research needs to focus on the use of baloxavir with the inpatient setting because of the prevalence of influenza. By using this medication in hospital settings and other institutions it may decrease the mortality and morbidity because it obviously shows a reduction in symptom days. In addition, baloxavir has a better viral shedding outcome in patients with uncomplicated influenza and that may be beneficial to inpatient units who are combating influenza. The price of the medication needs to be on the minds of the American people. This drug is new to the market and most insurance companies have not caught up with the new antiviral options on the market. It is important to weigh the options of using baloxavir for the treatment of influenza especially if that helps with the cost of hospitalization stays or other expensive medical procedures incurred from the ramifications of the influenza virus.
Any other considerations important in weighing this evidence to guide practice:
It is important to note that this medication is new and still in its infancy. Needless to say more patients need to take the medication and more rigorous studies need to be conducted to better understand the side effect profile and the clinical outcome of the medication.
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